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Laparoscopic gastrectomy has evolved differently in Eastern and Western countries. Feasibility, safety and oncological outcomes of laparoscopic gastrectomy were addressed step-by-step by several randomized controlled trials from the East. Few phase III studies were published from the West that largely did not show a difference between the laparoscopic and open approach. Despite this, laparoscopic gastrectomy is seen as the standard for the surgical treatment of early and advanced gastric cancer in many European countries. Here, we review and comment on some important studies on laparoscopic gastrectomy for gastric cancer from Eastern and Western countries and also comment on current and future challenges.

Background Large studies comparing totally minimally invasive oesophagectomy (TMIE) with laparoscopically assisted (hybrid) oesophagectomy are lacking. Although randomized trials have compared TMIE invasive with open oesophagectomy, daily clinical practice does not always resemble the results reported in such trials. The aim of the present study was to compare complications after totally minimally invasive, hybrid and open Ivor Lewis oesophagectomy in patients with oesophageal cancer. Methods The study was performed using data from the International Esodata Study Group registered between February 2015 and December 2019. The primary outcome was pneumonia, and secondary outcomes included the incidence and severity of anastomotic leakage, (major) complications, duration of hospital stay, escalation of care, and 90-day mortality. Data were analysed using multivariable multilevel models. Results Some 8640 patients were included between 2015 and 2019. Patients undergoing TMIE had a lower incidence of pneumonia than those having hybrid (10.9 versus 16.3 per cent; odds ratio (OR) 0.56, 95 per cent c.i. 0.40 to 0.80) or open (10.9 versus 17.4 per cent; OR 0.60, 0.42 to 0.84) oesophagectomy, and had a shorter hospital stay (median 10 (i.q.r. 8–16) days versus 14 (11–19) days (P = 0.041) and 11 (9–16) days (P = 0.027) respectively). The rate of anastomotic leakage was higher after TMIE than hybrid (15.1 versus 10.7 per cent; OR 1.47, 1.01 to 2.13) or open (15.1 versus 7.3 per cent; OR 1.73, 1.26 to 2.38) procedures. Conclusion Compared with hybrid and open Ivor Lewis oesophagectomy, TMIE resulted in a lower pneumonia rate, a shorter duration of hospital stay, but higher anastomotic leakage rates. Therefore, no clear advantage was seen for either TMIE, hybrid or open Ivor Lewis oesophagectomy when performed in daily clinical practice.

Background: Transthoracic minimally invasive esophagectomy (MIE) is increasingly performed as part of curative multimodality treatment. There appears to be no robust evidence on the preferred location of the anastomosis after transthoracic MIE. Objective: To compare an intrathoracic with a cervical anastomosis in a randomized clinical trial. Design, Setting, and Participants: This open, multicenter randomized clinical superiority trial was performed at 9 Dutch high-volume hospitals. Patients with midesophageal to distal esophageal or gastroesophageal junction cancer planned for curative resection were included. Data collection occurred from April 2016 through February 2020. Intervention: Patients were randomly assigned (1:1) to transthoracic MIE with intrathoracic or cervical anastomosis. Main Outcomes and Measures: The primary end point was anastomotic leakage requiring endoscopic, radiologic, or surgical intervention. Secondary outcomes were overall anastomotic leak rate, other postoperative complications, length of stay, mortality, and quality of life. Results: Two hundred sixty-two patients were randomized, and 245 were eligible for analysis. Anastomotic leakage necessitating reintervention occurred in 15 of 122 patients with intrathoracic anastomosis (12.3%) and in 39 of 123 patients with cervical anastomosis (31.7%; risk difference, -19.4% [95% CI, -29.5% to -9.3%]). Overall anastomotic leak rate was 12.3% in the intrathoracic anastomosis group and 34.1% in the cervical anastomosis group (risk difference, -21.9% [95% CI, -32.1% to -11.6%]). Intensive care unit length of stay, mortality rates, and overall quality of life were comparable between groups, but intrathoracic anastomosis was associated with fewer severe complications (risk difference, -11.3% [-20.4% to -2.2%]), lower incidence of recurrent laryngeal nerve palsy (risk difference, -7.3% [95% CI, -12.1% to -2.5%]), and better quality of life in 3 subdomains (mean differences: dysphagia, -12.2 [95% CI, -19.6 to -4.7]; problems of choking when swallowing, -10.3 [95% CI, -16.4 to 4.2]; trouble with talking, -15.3 [95% CI, -22.9 to -7.7]). Conclusions and Relevance: In this randomized clinical trial, intrathoracic anastomosis resulted in better outcome for patients treated with transthoracic MIE for midesophageal to distal esophageal or gastroesophageal junction cancer. Trial Registration: Trialregister.nl Identifier: NL4183 (NTR4333).

Background: Neoadjuvant chemoradiotherapy according to the Chemo- Radiotherapy for Oesophageal cancer followed by Surgery Study (CROSS) has become a standard of care for patients with locally advanced resectable esophageal or junctional cancer. However, the long-term benefits and harms remain unclear.We aimed to assess the long-term outcomes of this regimen. Materials and Methods: From 2004 through 2008, 366 patients were randomly assigned to either five weekly cycles of intravenous carboplatin (area under the curve of 2 mg/mL/min) and paclitaxel (50 mg/m2 bodysurface area) on days 1, 8,15, 22, and 29 with concurrent radiotherapy (41.4 Gy in 23 fractions, 5 days per week) followed by surgery, or surgery alone. Follow-up data were collected through 2018. Overall survival was estimated with the Kaplan-Meier method and compared with Cox regression analyses. The effect beyond 5 years of follow-up was assessed by using landmark analyses. Also, cause-specific mortality was estimated with cumulative incidence functions and compared with Cox regression. Results: The median follow-up was 147 months (IQR 134-157). Patients who received neoadjuvant chemoradiotherapy had better overall survival (HR 0.70, 95%CI 0.55-0.89), with 10-year overall survival of 38% (95%CI 31- 45) in the neoadjuvant chemoradiotherapy plus surgery arm and 25% (95% CI 19-32) in the surgery alone arm. Landmark analyses showed that the overall survival benefit that was gained in the first 5 years, persisted beyond 5 years. The risk of death from esophageal cancer was lower for patients who received neoadjuvant chemoradiotherapy plus surgery (HR 0.60, 95% CI 0.46-0.80), while death from other causes was comparable between both study arms (HR 1.17, 95%CI 0.68-1.99). Conclusions: The overall survival benefit of patients with locally advanced resectable esophageal or esophagogastric junctional cancer who received neoadjuvant chemoradiotherapy plus surgery according to the CROSS regimen persists for at least 10 years, compared with surgery alone.

Esophageal cancer (EC) remains one of the most common and aggressive diseases worldwide. This review discusses some debates in the modern management of the disease. Endoscopic procedures for early cancer (T1a-b) are now embedded in routine care and the challenge will be to more accurately select patients for endoscopic resection with or without adjuvant therapy. Perioperative multimodal therapies are associated with improved survival compared to surgery alone for locally advanced esophageal cancer. However, there is no global consensus on the optimal regimen. Furthermore, histological subtype (adenocarcinoma vs. squamous cell cancer) plays a role in the choice for treatment. New studies are underway to resolve some issues. The extent of the lymphadenectomy during esophagectomy remains controversial especially after neoadjuvant chemoradiation. The ideal operation balances between limiting surgical trauma and optimizing survival. Minimally invasive esophagectomy and enhanced recovery pathways are associated with decreased morbidity and faster recovery albeit there is no consensus yet what approach should be used. Finally, immune checkpoint inhibitors present promising preliminary results in the novel treatment of advanced or metastatic EC but their widespread application in clinical practice is still awaited.

Background & aims: Barrett's esophagus (BE) increases risk for esophageal adenocarcinoma (EAC). Increased risk for BE has been associated with single nucleotide polymorphisms (SNPs) on chromosome 6p21 (within the HLA region) and on 16q23, where the closest protein-coding gene is FOXF1. The Barrett's and Esophageal Adenocarcinoma Consortium (BEACON) identified risk loci for BE and esophageal adenocarcinoma in CRTC1 and BARX1, and within 100 kb FOXP1. We aimed to identify SNPs that increased risk for BE in a genome-wide association study (GWAS) and to validate previously reported associations.Methods: we performed a GWAS to identify variants associated with BE and further analyzed promising variants identified by the BEACON. We performed genotype analysis of 10,158 patients with BE and 21,062 controls.Results: we identified 2 SNPs not previously associated with BE: rs3072 (2p24.1; odds ratio [OR] = 1.14; 95% CI: 1.09–1.18; P = 1.8 × 10?11) and rs2701108 (12q24.21; OR = 0.90; 95% CI: 0.86–0.93; P = 7.5 × 10?9). The closest protein-coding genes were GDF7 (rs3072), which encodes a ligand in the bone morphogenetic protein pathway, and TBX5 (rs2701108), which encodes a transcription factor that regulates esophageal and cardiac development. We also identified 3 SNPS already identified by the BEACON (rs2687201, rs11789015, and rs10423674). Meta-analysis of all data identified another SNP associated with BE and esophageal adenocarcinoma: rs3784262, near ALDH1A2 (OR = 0.90; 95% CI: 0.87–0.93; P = 3.72 × 10?9).Conclusions: we identified 2 loci associated with risk for BE and provide data to support a locus previously associated with risk in the BEACON. The genes we found to be associated with risk for BE encode transcription factors involved in thoracic, diaphragmatic, and esophageal development or proteins involved in the inflammatory response

Contains fulltext : 288475.pdf (Publisher’s version ) (Open Access) Anastomotic leak (AL) is a severe complication after esophagectomy. Clinical presentation of AL is diverse and there is large practice variation regarding treatment of AL. This study aimed to explore different AL treatment strategies and their underlying rationale. This mixed-methods study consisted of an international survey among upper gastro-intestinal (GI) surgeons and focus groups with expert upper GI surgeons. The survey included 10 case vignettes and data sources were integrated after separate analysis. The survey was completed by 188 respondents (completion rate 69%) and 6 focus groups were conducted with 20 international experts. Prevention of mortality was the most important goal of primary treatment. Goals of secondary treatment were to promote tissue healing, return to oral feeding and safe hospital discharge. There was substantial variation in the preferred treatment principles (e.g. drainage or defect closure) and modalities (e.g. stent or endoVAC) within different presentations of AL. Patients with local symptoms were treated by supportive means only or by non-surgical drainage and/or defect closure. Drainage was routinely performed in patients with intrathoracic collections and often combined with defect closure. Patients with conduit necrosis were predominantly treated by resection and reconstruction of the anastomosis or by esophageal diversion. This mixed-methods study shows that overall treatment strategies for AL are determined by vitality of the conduit and presence of intrathoracic collections. There is large variation in preferred treatment principles and modalities. Future research may investigate optimal treatment for specific AL presentations and aim to develop consensus-based treatment guidelines for AL after esophagectomy.

I: Clinical factors: age and co-morbidityIn chapter 1-3 of this thesis the use of definitive chemoradiotherapy (dCRT) as a lessaggressive alternative treatment approach in elderly patients and in patients with severe comorbidities was studied. We showed that the use of nCRT plus surgery in operable patients with a potentially curative resectable esophageal adenocarcinoma (EAC) was associated with a better overall survival (OS) irrespective of age, number and type of co-morbidities. The administration of dCRT was preferably given in patients with esophageal squamous cell carcinoma (ESCC) with at least 2 co-morbidities or >75 years old. There was no difference in OS in patients who underwentdCRT compared to patients with nCRT plus surgery. These findings suggest a similar longtermsurvival after both treatment modalities in elderly patients with ESCC. In patients with EAC, nCRT plus surgery resulted in a better survival than dCRT, including patients with diabetes mellitus, hypertension or cardiovascular disease, as has been shown by others.II: Pathological factors: circumferential resection margin and extramural venous invasionThe prognostic value of the circumferential margin (CRM) after neoadjuvantchemoradiotherapy (nCRT) is not well defined yet. As described in chapter 4, nCRTaffected the CRM cutoff values. After nCRT, the CRM-R0 as defined according to theCollege of American Pathologists (CAP; >0 mm) was only prognostic for 2-year localrecurrence-free survival (LRFS). However, in the surgery-alone group, it was also prognosticfor the 2-year disease-free survival (DFS). CRM assessment depends on accurate histologicalexamination of residual tumor, which might be related to tumor heterogeneity. Current TNM classifications recognize lymphovascular invasion (LVI) as a prognostic factor in EC. It is important to report the type of vascular invasion (VI). Pathologists stress on the presence of extramural venous invasion (EMVI), i.e. tumor cells in the vasculature of vessels beyond the muscularis propria, as an independent predictor of poor prognosis in colorectal cancer (CRC). In chapter 5 and 6, we described the presence of EMVI in approximately 25% of patients with a at least pT3 tumor after surgery alone, and in 21.6% after nCRT. EMVI was common in tumors withadvanced T- and N-stage and also in tumors with perineural tumor growth and with LVI.III: Treatment-related factors: salvage surgeryIn chapter 7 we showed that even though the amplitude of breathing seemed relatively constant, offsets of the diaphragm positions, and consequently tumor positions, were large. This might result in geographical misses of tumor or dose deviations in terms of hot or cold spots in dose distribution. The magnitude of and variation in breathing amplitude and offset position can be determined more specific on 4DCT scan. The mean diaphragm expiration and inspiration delineations offset of the diaphragm that we observed were in the same order of magnitude as found in other studies with 4 D-CT scan.In chapter 8 we have evaluated the site of residual disease related to tumor target volumes at pathologic examination. In radical resected (R0) specimens, 19.8% had a pCR and 14% nearly no response (TRG 4-5). Residual tumor was limited to the esophagus (ypT+N0) in 57.8% and commonly in the adventitia (43.1%), while 7.3% was in the mucosa (ypT1a), 16.5% in the submucosa (ypT1b) and 6.4% only in lymph nodes (ypT0N+). In TRG 2-5 R0 specimens, macroscopic residue was in- and outside the gross tumor volume (GTV) in 33.3% and 8.9%, while microscopic residue in- and outside the clinical target volume (CTV) margin only in 58.9% and 1.1%, respectively. Residual nodal disease was observed proximally in two and distally to the CTV in 5 patients. Disease Free Survival (DFS) decreased if macroscopic tumor was outside the GTV (9 vs. 27 months; p=0.009) and in ypT2-4aN+.In chapter 9 we have shown that salvage surgery is a feasible and may be potentially curative in patients with locoregional regrowth EC after dCRT and nCRT.Besides a R0 resection, the presence of early and small tumor remnants (cT>2/N0) is the most favorable prognostic factor in patients after dCRT. This stresses the importance of better locoregional control through improved chemoradiation strategies in dCRT and adequate staging with accurate imaging methods to ensure a complete tumor resection.