Recurrence and Survival after Minimally Invasive and Open Esophagectomy for Esophageal Cancer - A Post Hoc Analysis of the Ensure Study.

OBJECTIVE: The aim of this study was to determine the impact of operative approach (open [OE], hybrid [HMIE] and total minimally invasive esophagectomy [TMIE]) on operative and oncologic outcomes for patients treated with curative intent for esophageal and junctional cancer. SUMMARY BACKGROUND DATA: The optimum oncologic surgical approach to esophageal and junctional cancer is unclear. METHODS: This secondary analysis of the European multicenter ENSURE study includes patients undergoing curative-intent esophagectomy for cancer between 2009-2015 across 20 high-volume centers. Primary endpoints were disease-free survival (DFS) and the incidence and location of disease recurrence. Secondary endpoints included among others R0 resection rate, lymph node yield and overall survival (OS). RESULTS: In total, 3,199 patients were included. Of these, 55% underwent OE, 17% HMIE and 29% TMIE. DFS was independently increased post TMIE (HR 0.86 [95% CI 0.76-0.98], P=0.022) compared with OE. Multivariable regression demonstrated no difference in absolute locoregional recurrence risk according to operative approach (HMIE vs. OE OR 0.79, P=0.257, TMIE vs. OE OR 0.84, P=0.243). The probability of systemic recurrence was independently increased post HMIE (OR 2.07, P=0.031), but not TMIE (OR 0.86, P=0.508). R0 resection rates (P=0.005) and nodal yield (P<0.001) were independently increased after TMIE, but not HMIE (P=0.424; P=0.512) compared with OE. OS was independently improved following both HMIE (HR 0.79, P=0.009) and TMIE (HR 0.82, P=0.003) as compared with OE. CONCLUSION: In this European multicenter study, TMIE was associated with improved surgical quality and DFS, while both TMIE and HMIE were associated with improved OS as compared with OE for esophageal cancer.

Impact of 18FFDG-PET/CT and Laparoscopy in Staging of Locally Advanced Gastric Cancer: A Cost Analysis in the Prospective Multicenter PLASTIC-Study.

BACKGROUND: Unnecessary D2-gastrectomy and associated costs can be prevented after detecting non-curable gastric cancer, but impact of staging on treatment costs is unclear. This study determined the cost impact of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18FFDG-PET/CT) and staging laparoscopy (SL) in gastric cancer staging. MATERIALS AND METHODS: In this cost analysis, four staging strategies were modeled in a decision tree: (1) 18FFDG-PET/CT first, then SL, (2) SL only, (3) 18FFDG-PET/CT only, and (4) neither SL nor 18FFDG-PET/CT. Costs were assessed on the basis of the prospective PLASTIC-study, which evaluated adding 18FFDG-PET/CT and SL to staging advanced gastric cancer (cT3-4 and/or cN+) in 18 Dutch hospitals. The Dutch Healthcare Authority provided 18FFDG-PET/CT unit costs. SL unit costs were calculated bottom-up. Gastrectomy-associated costs were collected with hospital claim data until 30 days postoperatively. Uncertainty was assessed in a probabilistic sensitivity analysis (1000 iterations). RESULTS: 18FFDG-PET/CT costs were €1104 including biopsy/cytology. Bottom-up calculations totaled €1537 per SL. D2-gastrectomy costs were €19,308. Total costs per patient were €18,137 for strategy 1, €17,079 for strategy 2, and €19,805 for strategy 3. If all patients undergo gastrectomy, total costs were €18,959 per patient (strategy 4). Performing SL only reduced costs by €1880 per patient. Adding 18FFDG-PET/CT to SL increased costs by €1058 per patient; IQR €870-1253 in the sensitivity analysis. CONCLUSIONS: For advanced gastric cancer, performing SL resulted in substantial cost savings by reducing unnecessary gastrectomies. In contrast, routine 18FFDG-PET/CT increased costs without substantially reducing unnecessary gastrectomies, and is not recommended due to limited impact with major costs. TRIAL REGISTRATION: NCT03208621. This trial was registered prospectively on 30-06-2017.

Prognostic value of Mandard score and nodal status for recurrence patterns and survival after multimodal treatment of oesophageal adenocarcinoma.

BACKGROUND: This study evaluated the association of pathological tumour response (tumour regression grade, TRG) and a novel scoring system, combining both TRG and nodal status (TRG-ypN score; TRG1-ypN0, TRG>1-ypN0, TRG1-ypN+ and TRG>1-ypN+), with recurrence patterns and survival after multimodal treatment of oesophageal adenocarcinoma. METHODS: This Dutch nationwide cohort study included patients treated with neoadjuvant chemoradiotherapy followed by oesophagectomy for distal oesophageal or gastro-oesophageal junctional adenocarcinoma between 2007 and 2016. The primary endpoint was the association of Mandard score and TRG-ypN score with recurrence patterns (rate, location, and time to recurrence). The secondary endpoint was overall survival. RESULTS: Among 2746 inclusions, recurrence rates increased with higher Mandard scores (TRG1 30.6%, TRG2 44.9%, TRG3 52.9%, TRG4 61.4%, TRG5 58.2%; P < 0.001). Among patients with recurrent disease, the distribution (locoregional versus distant) was the same for the different TRG groups. Patients with TRG1 developed more brain recurrences (17.7 versus 9.8%; P = 0.001) and had a longer mean overall survival (44 versus 35 months; P < 0.001) than those with TRG>1. The TRG>1-ypN+ group had the highest recurrence rate (64.9%) and worst overall survival (mean 27 months). Compared with the TRG>1-ypN0 group, patients with TRG1-ypN+ had a higher risk of recurrence (51.9 versus 39.6%; P < 0.001) and worse mean overall survival (33 versus 41 months; P < 0.001). CONCLUSION: Improved tumour response to neoadjuvant therapy was associated with lower recurrence rates and higher overall survival rates. Among patients with recurrent disease, TRG1 was associated with a higher incidence of brain recurrence than TRG>1. Residual nodal disease influenced prognosis more negatively than residual disease at the primary tumour site.

Outcomes after gastrectomy according to the Gastrectomy Complications Consensus Group (GCCG) in the Dutch Upper GI Cancer Audit (DUCA).

BACKGROUND: In 2019, the Gastrectomy Complications Consensus Group (GCCG) published a standardized set of complications aiming toward uniform reporting of post-gastrectomy complications. This study aimed to report outcomes after gastrectomy in the Netherlands according to GCCG definitions and compare them to previously reported national results and the European database reported by the GCCG. METHODS: This nationwide, population-based cohort study included all patients undergoing gastrectomy for gastric cancer registered in the DUCA in 2020-2021. Postoperative morbidity and 30-day/in-hospital mortality were analyzed according to the GCCG definitions. For all patients, baseline characteristics and outcomes were compared with the GCCG cohort consisting of 27 European expert centers (GASTRODATA; 2017-2018). RESULTS: In 2020-2021, 782 patients underwent gastrectomy in the Netherlands. Variation was seen in baseline characteristics between the Dutch and the GCCG cohort (N = 1349), most notably in minimally invasive surgery (80.6% vs 19.6%, p < 0.001). In the Netherlands, 223 (28.5%) patients developed a total of 407 complications, the most frequent being non-surgical infections (28.5%) and anastomotic leakage (13.4%). The overall complication and 30-day mortality rates were similar between the Dutch and GCCG cohort (28.5% vs 29.8%, p = 0.563; 3.7% vs 3.6%, p = 0.953). Higher surgical and endoscopic/radiologic reintervention rates were observed in the Netherlands compared to the GCCG cohort (10.7% vs 7.8%, p = 0.025; 10.9% vs 2.9%, p < 0.001). CONCLUSION: Reporting outcomes according to the standardized GCCG definitions allows for international benchmarking. Postoperative outcomes were comparable between Dutch and GCCG cohorts, but both exceed the international benchmark for expert gastrectomy care, highlighting targets for national and international quality improvement.

International consensus on the management of metastatic gastric cancer: step by step in the foggy landscape : Bertinoro Workshop, November 2022.

BACKGROUND: Many gastric cancer patients in Western countries are diagnosed as metastatic with a median overall survival of less than twelve months using standard chemotherapy. Innovative treatments, like targeted therapy or immunotherapy, have recently proved to ameliorate prognosis, but a general agreement on managing oligometastatic disease has yet to be achieved. An international multi-disciplinary workshop was held in Bertinoro, Italy, in November 2022 to verify whether achieving a consensus on at least some topics was possible. METHODS: A two-round Delphi process was carried out, where participants were asked to answer 32 multiple-choice questions about CT, laparoscopic staging and biomarkers, systemic treatment for different localization, role and indication of palliative care. Consensus was established with at least a 67% agreement. RESULTS: The assembly agreed to define oligometastases as a "dynamic" disease which either regresses or remains stable in response to systemic treatment. In addition, the definition of oligometastases was restricted to the following sites: para-aortic nodal stations, liver, lung, and peritoneum, excluding bones. In detail, the following conditions should be considered as oligometastases: involvement of para-aortic stations, in particular 16a2 or 16b1; up to three technically resectable liver metastases; three unilateral or two bilateral lung metastases; peritoneal carcinomatosis with PCI ≤ 6. No consensus was achieved on how to classify positive cytology, which was considered as oligometastatic by 55% of participants only if converted to negative after chemotherapy. CONCLUSION: As assessed at the time of diagnosis, surgical treatment of oligometastases should aim at R0 curativity on the entire disease volume, including both the primary tumor and its metastases. Conversion surgery was defined as surgery on the residual volume of disease, which was initially not resectable for technical and/or oncological reasons but nevertheless responded to first-line treatment.

Genome-wide and panel-based cell-free DNA characterization of patients with resectable esophageal adenocarcinoma.

Circulating tumor DNA (ctDNA) holds promise in resectable esophageal adenocarcinoma (EAC) to predict patient outcome but is not yet sensitive enough to be clinically applicable. Our aim was to combine ctDNA mutation data with shallow whole-genome sequencing (sWGS)-derived copy number tumor fraction estimates (ichorCNA) to improve pathological response and survival prediction in EAC. In total, 111 stage II/III EAC patients with baseline (n = 111), post-neoadjuvant chemoradiotherapy (nCRT) (n = 68), and pre-surgery (n = 92) plasma samples were used for ctDNA characterization. sWGS (<5× coverage) was performed on all time-point samples, and copy number aberrations were estimated using ichorCNA. Baseline and pre-surgery samples were sequenced using a custom amplicon panel for mutation detection. Detection of baseline ctDNA was successful in 44.3% of patients by amplicon sequencing and 10.5% by ichorCNA. Combining both, ctDNA could be detected in 50.5% of patients. Baseline ctDNA positivity was related to higher T stage (cT3, 4) (p = 0.017). There was no relationship between pathological response and baseline ctDNA positivity. However, baseline ctDNA metrics (variant allele frequency > 1% or ichorCNA > 3%) were associated with a high risk of disease progression [HR = 2.23 (95% CI 1.22-4.07), p = 0.007]. The non-clearance of a baseline variant or ichorCNA > 3% in pre-surgery samples was related to early progression [HR = 4.58 (95% CI 2.22-9.46), p < 0.001]. Multi-signal analysis improves detection of ctDNA and can be used for prognostication of resectable EAC patients. Future studies should explore the potential of multi-modality sequencing for risk stratification and treatment adaptation based on ctDNA results. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

History and evidence for state of the art of lymphadenectomy in esophageal cancer surgery.

The current curative multimodal treatment of advanced esophageal cancers consists of neoadjuvant or perioperative chemo(radio)therapy followed by a radical surgical resection of the primary tumor and a 2- or 3-field lymphadenectomy. One of the most important predictors of long-term survival of esophageal cancer patients is lymph node involvement. The distribution pattern of lymph node metastases in esophageal cancer is unpredictable and depends on the primary tumor location, histology, T-stage and application of neoadjuvant or perioperative treatment. The optimal extent of the lymphadenectomy remains controversial; there is no global consensus on this topic yet. Some surgeons advocate an aggressive and extended lymph node dissection to remove occult metastatic disease, to optimize oncological outcomes. Others promote a more restricted lymphadenectomy, since the benefit of an extended lymphadenectomy, especially after neoadjuvant chemoradiotherapy, has not been clearly demonstrated, and morbidity may be reduced. In this review, we describe the development of lymphadenectomy, followed by a summary of current evidence for lymphadenectomy in esophageal cancer treatment.

Western European Variation in the Organization of Esophageal Cancer Surgical Care.

Reasons for structural and outcome differences in esophageal cancer surgery in Western Europe remain unclear. This questionnaire study aimed to identify differences in the organization of esophageal cancer surgical care in Western Europe. A cross-sectional international questionnaire study was conducted among upper gastrointestinal (GI) surgeons from Western Europe. One surgeon per country was selected based on scientific output and active membership in the European Society for Diseases of the Esophagus or (inter)national upper GI committee. The questionnaire consisted of 51 structured questions on the structural organization of esophageal cancer surgery, surgical training, and clinical audit processes. Between October 2021 and October 2022, 16 surgeons from 16 European countries participated in this study. In 5 countries (31%), a volume threshold was present ranging from 10 to 26 annual esophagectomies, in 7 (44%) care was centralized in designated centers, and in 4 (25%) no centralizing regulations were present. The number of centers performing esophageal cancer surgery per country differed from 4 to 400, representing 0.5-4.9 centers per million inhabitants. In 4 countries (25%), esophageal cancer surgery was part of general surgical training and 8 (50%) reported the availability of upper GI surgery fellowships. A national audit for upper GI surgery was present in 8 (50%) countries. If available, all countries use the audit to monitor the quality of care. Substantial differences exist in the organization and centralization of esophageal cancer surgical care in Western Europe. The exchange of experience in the organizational aspects of care could further improve the results of esophageal cancer surgical care in Europe.

An International Multicenter Study Exploring Whether Surveillance After Esophageal Cancer Surgery Impacts Oncological and Quality of Life Outcomes (ENSURE).

OBJECTIVE: To determine the impact of surveillance on recurrence pattern, treatment, survival and health-related quality-of-life (HRQL) following curative-intent resection for esophageal cancer. SUMMARY BACKGROUND DATA: Although therapies for recurrent esophageal cancer may impact survival and HRQL, surveillance protocols after primary curative treatment are varied and inconsistent, reflecting a lack of evidence. METHODS: European iNvestigation of SUrveillance after Resection for Esophageal cancer was an international multicenter study of consecutive patients undergoing surgery for esophageal and esophagogastric junction cancers (2009-2015) across 20 centers (NCT03461341). Intensive surveillance (IS) was defined as annual computed tomography for 3 years postoperatively. The primary outcome measure was overall survival (OS), secondary outcomes included treatment, disease-specific survival, recurrence pattern, and HRQL. Multivariable linear, logistic, and Cox proportional hazards regression analyses were performed. RESULTS: Four thousand six hundred eighty-two patients were studied (72.6% adenocarcinoma, 69.1% neoadjuvant therapy, 45.5% IS). At median followup 60 months, 47.5% developed recurrence, oligometastatic in 39%. IS was associated with reduced symptomatic recurrence (OR 0.17 [0.12-0.25]) and increased tumor-directed therapy (OR 2.09 [1.58-2.77]). After adjusting for confounders, no OS benefit was observed among all patients (HR 1.01 [0.89-1.13]), but OS was improved following IS for those who underwent surgery alone (HR 0.60 [0.47-0.78]) and those with lower pathological (y)pT stages (Tis-2, HR 0.72 [0.58-0.89]). IS was associated with greater anxiety ( P =0.016), but similar overall HRQL. CONCLUSIONS: IS was associated with improved oncologic outcome in select cohorts, specifically patients with early-stage disease at presentation or favorable pathological stage post neoadjuvant therapy. This may inform guideline development, and enhance shared decision-making, at a time when therapeutic options for recurrence are expanding.

Neoadjuvant Chemoradiotherapy Versus Chemotherapy for the Treatment of Locally Advanced Esophageal Adenocarcinoma in the European Multicenter ENSURE Study.

OBJECTIVE: This study aimed to compare clinicopathologic, oncologic, and health-related quality of life (HRQL) outcomes following neoadjuvant chemoradiation (nCRT) and chemotherapy (nCT) in the ENSURE international multicenter study. BACKGROUND: nCT and nCRT are the standards of care for locally advanced esophageal cancer (LAEC) treated with curative intent. However, no published randomized controlled trial to date has demonstrated the superiority of either approach. METHODS: ENSURE is an international multicenter study of consecutive patients undergoing surgery for LAEC (2009-2015) across 20 high-volume centers (NCT03461341). The primary outcome measure was overall survival (OS), secondary outcomes included histopathologic response, recurrence pattern, oncologic outcome, and HRQL in survivorship. RESULTS: A total of 2211 patients were studied (48% nCT, 52% nCRT). pCR was observed in 4.9% and 14.7% ( P <0.001), with R0 in 78.2% and 94.2% ( P <0.001) post nCT and nCRT, respectively. Postoperative morbidity was equivalent, but in-hospital mortality was independently increased [hazard ratio (HR)=2.73, 95% CI: 1.43-5.21, P= 0.002] following nCRT versus nCT. Probability of local recurrence was reduced (odds ratio=0.71, 95% CI: 0.54-0.93, P =0.012), and distant recurrence-free survival time reduced (HR=1.18, 95% CI: 1.02-1.37, P =0.023) after nCRT versus nCT, with no difference in OS among all patients (HR=1.10, 95% CI: 0.98-1.25, P =0.113). On subgroup analysis, patients who underwent R0 resection following nCT as compared with nCRT had improved OS (median: 60.7 months, 95% CI: 49.5-71.8 vs 40.8 months, 95% CI: 42.8-53.4, P <0.001). CONCLUSIONS: In this European multicenter study, nCRT compared with nCT was associated with reduced probability of local recurrence but reduced distant recurrence-free survival for patients with LAEC, without differences in OS. These data support tailored patient-specific decision-making in the overall approach to achieving optimum outcomes in LAEC.

Learning Curve of Laparoscopic Gastrectomy: A Multicenter Study.

OBJECTIVE: To evaluate the learning curve of laparoscopic gastrectomy (LG) after an implementation program. BACKGROUND: Although LG is increasingly being performed worldwide, little is known about the learning curve. METHODS: Consecutive patients who underwent elective LG for gastric adenocarcinoma with curative intent in each of the 5 highest-volume centers in the Netherlands were enrolled. Generalized additive models and a 2-piece model with a break point were used to determine the learning curve length. Analyses were corrected for casemix and were performed for LG and for the subgroups distal gastrectomy (LDG) and total gastrectomy (LTG). The learning curve effect was assessed for (1) anastomotic leakage; and (2) the occurrence of postoperative complications, conversions to open surgery, and short-term oncological parameters. RESULTS: In total 540 patients were included for analysis, 108 patients from each center; 268 patients underwent LDG and 272 underwent LTG. First, for LG, no learning effect regarding anastomotic leakage could be identified: the rate of anastomotic leakage initially increased, then reached a plateau after 36 cases at 10% anastomotic leakage. Second, the level of overall complications reached a plateau after 20 cases, at 38% overall complications, and at 5% conversions. For both LDG and LTG, each considered separately, fluctuations in secondary outcomes and anastomotic leakage followed fluctuations in casemix. CONCLUSION: On the basis of our study of the first 108 procedures of LG in 5 high-volume centers with well-trained surgeons, no learning curve effect could be identified regarding anastomotic leakage. A learning curve effect was found with respect to overall complications and conversion rate.

Trends in Distal Esophageal and Gastroesophageal Junction Cancer Care: The Dutch Nationwide Ivory Study.

OBJECTIVE: This study evaluated the nationwide trends in care and accompanied postoperative outcomes for patients with distal esophageal and gastro-esophageal junction cancer. SUMMARY OF BACKGROUND DATA: The introduction of transthoracic esophagectomy, minimally invasive surgery, and neo-adjuvant chemo(radio)therapy changed care for patients with esophageal cancer. METHODS: Patients after elective transthoracic and transhiatal esophagectomy for distal esophageal or gastroesophageal junction carcinoma in the Netherlands between 2007-2016 were included. The primary aim was to evaluate trends in both care and postoperative outcomes for the included patients. Additionally, postoperative outcomes after transthoracic and tran-shiatal esophagectomy were compared, stratified by time periods. RESULTS: Among 4712 patients included, 74% had distal esophageal tumors and 87% had adenocarcinomas. Between 2007 and 2016, the proportion of transthoracic esophagectomy increased from 41% to 81%, and neo-adjuvant treatment and minimally invasive esophagectomy increased from 31% to 96%, and from 7% to 80%, respectively. Over this 10-year period, postoperative outcomes improved: postoperative morbidity decreased from 66.6% to 61.8% ( P = 0.001), R0 resection rate increased from 90.0% to 96.5% (P <0.001), median lymph node harvest increased from 15 to 19 ( P <0.001), and median survival increased from 35 to 41 months ( P = 0.027). CONCLUSION: In this nationwide cohort, a transition towards more neo-adju-vant treatment, transthoracic esophagectomy and minimally invasive surgery was observed over a 10-year period, accompanied by decreased postoperative morbidity, improved surgical radicality and lymph node harvest, and improved survival.

Contrast-Enhanced Radiologic Evaluation of Gastric Conduit Emptying After Esophagectomy.

BACKGROUND: Nasogastric tube (NGT) insertion is the standard of care in many hospitals after esophagectomy for gastric conduit decompression. An upper gastrointestinal contrast passage evaluation (UGI-CE) is a diagnostic test to evaluate passage through the gastric conduit. The authors hypothesized that introducing routine UGI-CE after esophagectomy results in earlier removal of the NGT and resumption of oral intake. METHODS: This retrospective study evaluated two consecutive series of patients undergoing esophagectomy, one before (control group) and one after the introduction of a routine UGI-CE on postoperative day (POD) 3 or 4 (UGI-CE group). If contrast passage was found on the UGI-CE, the NGT was capped and removed. In the control group, the NGT was routinely capped and removed on day 5 after surgery. The primary outcome was the POD on which oral diet was initiated. The secondary outcomes were the day of NGT removal, NGT reinsertions, postoperative complications, and length of hospital stay. RESULTS: Each cohort included 74 patients. In the UGI-CE group, the contrast test was performed on median POD 3.5 (IQR, 3-4). The median day of NGT removal, initiation of clear liquids, and full liquid and solid intake was 1 to 2 days earlier in the UGI-CE group than in the control group (i.e. POD 4, 4, 5, and 6 vs. POD 5, 5, 6.5, and 8; all p < 0.001). The study found no significant differences in NGT reinsertions, pneumonias, anastomotic leakages, or hospital stay. CONCLUSION: The routine use of a UGI-CE after esophagectomy led to earlier removal of the NGT and earlier resumption of oral intake.

Preoperative Risk Stratification in Esophageal Cancer Surgery: Comparing Risk Models with the Clinical Judgment of the Surgeon.

BACKGROUND: Numerous prediction models estimating the risk of complications after esophagectomy exist but are rarely used in practice. The aim of this study was to compare the clinical judgment of surgeons using these prediction models. METHODS: Patients with resectable esophageal cancer who underwent an esophagectomy were included in this prospective study. Prediction models for postoperative complications after esophagectomy were selected by a systematic literature search. Clinical judgment was given by three surgeons, indicating their estimated risk for postoperative complications in percentage categories. The best performing prediction model was compared with the judgment of the surgeons, using the net reclassification improvement (NRI), category-free NRI (cfNRI), and integrated discrimination improvement (IDI) indexes. RESULTS: Overall, 159 patients were included between March 2019 and July 2021, of whom 88 patients (55%) developed a complication. The best performing prediction model showed an area under the receiver operating characteristic curve (AUC) of 0.56. The three surgeons had an AUC of 0.53, 0.55, and 0.59, respectively, and all surgeons showed negative percentages of cfNRIevents and IDIevents, and positive percentages of cfNRInonevents and IDIevents. This indicates that in the group of patients with postoperative complications, the prediction model performed better, whereas in the group of patients without postoperative complications, the surgeons performed better. NRIoverall was 18% for one surgeon, while the remainder of the NRIoverall, cfNRIoverall and IDIoverall scores showed small differences between surgeons and the prediction models. CONCLUSION: Prediction models tend to overestimate the risk of any complication, whereas surgeons tend to underestimate this risk. Overall, surgeons' estimations differ between surgeons and vary between similar to slightly better than the prediction models.

Feasibility and Safety of Tailored Lymphadenectomy Using Sentinel Node-Navigated Surgery in Patients with High-Risk T1 Esophageal Adenocarcinoma.

BACKGROUND: Selective lymphadenectomy using sentinel node-navigated surgery (SNNS) might offer a less invasive alternative to esophagectomy in patients with high-risk T1 esophageal adenocarcinoma (EAC). The aim of this study was to evaluate the feasibility and safety of a new treatment strategy, consisting of radical endoscopic resection of the tumor followed by SNNS. METHODS: In this multicenter pilot study, ten patients with a radically resected high-risk pT1cN0 EAC underwent SNNS. A hybrid tracer of technetium-99m nanocolloid and indocyanine green was injected endoscopically around the resection scar the day before surgery, followed by preoperative imaging. During surgery, sentinel nodes (SNs) were identified using a thoracolaparoscopic gammaprobe and fluorescence-based detection, and subsequently resected. Endpoints were surgical morbidity and number of detected and resected (tumor-positive) SNs. RESULTS: Localization and dissection of SNs was feasible in all ten patients (median 3 SNs per patient, range 1-6). The concordance between preoperative imaging and intraoperative detection was high. In one patient (10%), dissection was considered incomplete after two SNs were not identified intraoperatively. Additional peritumoral SNs were resected in four patients (40%) after fluorescence-based detection. In two patients (20%), a (micro)metastasis was found in one of the resected SNs. One patient experienced neuropathic thoracic pain related to surgery, while none of the patients developed functional gastroesophageal disorders. CONCLUSIONS: SNNS appears to be a feasible and safe instrument to tailor lymphadenectomy in patients with high-risk T1 EAC. Future research with long-term follow-up is warranted to determine whether this esophageal preserving strategy is justified for high-risk T1 EAC.

Treatment of anastomotic leak after oesophagectomy for oesophageal cancer: large, collaborative, observational TENTACLE cohort study.

BACKGROUND: Anastomotic leak is a severe complication after oesophagectomy. Anastomotic leak has diverse clinical manifestations and the optimal treatment strategy is unknown. The aim of this study was to assess the efficacy of treatment strategies for different manifestations of anastomotic leak after oesophagectomy. METHODS: A retrospective cohort study was performed in 71 centres worldwide and included patients with anastomotic leak after oesophagectomy (2011-2019). Different primary treatment strategies were compared for three different anastomotic leak manifestations: interventional versus supportive-only treatment for local manifestations (that is no intrathoracic collections; well perfused conduit); drainage and defect closure versus drainage only for intrathoracic manifestations; and oesophageal diversion versus continuity-preserving treatment for conduit ischaemia/necrosis. The primary outcome was 90-day mortality. Propensity score matching was performed to adjust for confounders. RESULTS: Of 1508 patients with anastomotic leak, 28.2 per cent (425 patients) had local manifestations, 36.3 per cent (548 patients) had intrathoracic manifestations, 9.6 per cent (145 patients) had conduit ischaemia/necrosis, 17.5 per cent (264 patients) were allocated after multiple imputation, and 8.4 per cent (126 patients) were excluded. After propensity score matching, no statistically significant differences in 90-day mortality were found regarding interventional versus supportive-only treatment for local manifestations (risk difference 3.2 per cent, 95 per cent c.i. -1.8 to 8.2 per cent), drainage and defect closure versus drainage only for intrathoracic manifestations (risk difference 5.8 per cent, 95 per cent c.i. -1.2 to 12.8 per cent), and oesophageal diversion versus continuity-preserving treatment for conduit ischaemia/necrosis (risk difference 0.1 per cent, 95 per cent c.i. -21.4 to 1.6 per cent). In general, less morbidity was found after less extensive primary treatment strategies. CONCLUSION: Less extensive primary treatment of anastomotic leak was associated with less morbidity. A less extensive primary treatment approach may potentially be considered for anastomotic leak. Future studies are needed to confirm current findings and guide optimal treatment of anastomotic leak after oesophagectomy.

The effect of anastomotic leakage on the incidence of recurrence after tri-modality therapy for esophageal adenocarcinomas.

BACKGROUND: Neoadjuvant chemoradiotherapy (nCRTx) reduces the incidence of recurrence, while anastomotic leakage has shown increase the risk of recurrence. The primary objective of this retrospective study was to investigate the incidence and pattern of recurrence and secondary median recurrence-free interval and post-recurrence survival in patients with and without anastomotic leakage after multimodal therapy for esophageal adenocarcinoma. METHODS: Patients with recurrence after multimodal therapy between 2010 and 2018 were included. RESULTS: Six hundred and eighteen patients were included, 91 (14.7%) had leakage and 278 (45.0%) recurrence. Patients with leakage did not develop recurrence more often (48.4%) than those without (44.4%, [p = 0.484]). Recurrence-free interval for patients with (n = 44) and without leakage (n = 234) was 39 and 52 weeks, respectively (p = 0.049). Post-recurrence survival was 11 and 16 weeks, respectively (p = 0.702). Specified by recurrence site, post-recurrence survival for loco-regional recurrences was 27 versus 33 weeks (p = 0.387) for patients with and without leakage, for distant 9 versus 13 (p = 0.999), and for combined 11 versus 18 weeks (p = 0.492). CONCLUSION AND DISCUSSION: No higher incidence of recurrent disease was observed in patients with anastomotic leakage, however it is associated with a shorter recurrence-free interval. This could have implications for surveillance, as early detection of recurrent disease could influence therapeutic options.

Neoadjuvant chemotherapy in older patients with gastric cancer undergoing surgery: a population-based cohort study.

BACKGROUND: In trials evaluating perioperative chemotherapy for gastric cancer, which serve as the basis for treatment guidelines, patients are selected. The generalizability of these trial findings to older patients is uncertain. METHODS: This population-based retrospective cohort study compared the survival outcomes of patients ≥ 75 years with gastric adenocarcinoma treated with or without neoadjuvant chemotherapy between 2015 and 2019. Additionally, the percentage of patients < 75 years and ≥ 75 years who did not proceeded to surgery after receiving neoadjuvant chemotherapy were examined. RESULTS: A total of 1995 patients, of whom 1249 aged < 75 years and 746 aged ≥ 75 years, were included. In the group of patients ≥ 75 years, 275 patients received neoadjuvant chemotherapy and 471 patients were directly scheduled for gastrectomy. Patients ≥ 75 years treated with or without neoadjuvant chemotherapy differed significantly from one and another in characteristics. Overall survival of patients ≥ 75 years treated with or without neoadjuvant chemotherapy was not significantly different (median 34.9 vs. 32.3 months; P = 0.506), also after adjusting for potential confounders (HR 0.87; P = 0.263). Of patients ≥ 75 years who received neoadjuvant chemotherapy, 43 (15.6%) did not proceed to surgery compared to 111 (8.9%) patients < 75 years (P < 0.001). CONCLUSION: Patients ≥ 75 years treated with or without chemotherapy were highly selected, and overall survival was not significantly different between both groups. Nonetheless, the proportion of patients who did not proceed to surgery following neoadjuvant chemotherapy was higher in patients ≥ 75 years compared to patients < 75 years. Therefore, neoadjuvant chemotherapy should be considered with more caution in patients ≥ 75 years, while identifying those who may benefit.

Tumor-immune landscape patterns before and after chemoradiation in resectable esophageal adenocarcinomas.

Immunotherapy is a new anti-cancer treatment option, showing promising results in clinical trials. To investigate potential immune biomarkers in esophageal adenocarcinoma (EAC), we explored immune landscape patterns in the tumor microenvironment before and after neoadjuvant chemoradiation (nCRT). Sections from matched pretreatment biopsies and post-nCRT resection specimens (n = 188) were stained for (1) programmed death-ligand 1 (PD-L1, CD274); (2) programmed cell death protein 1 (PD-1, CD279), forkhead box P3 (FOXP3), CD8, pan-cytokeratin multiplex; and (3) an MHC class I, II duplex. The densities of tumor-associated immune cells (TAICs) were calculated using digital image analyses and correlated to histopathological nCRT response [tumor regression grade (TRG)], survival, and post-nCRT immune patterns. PD-L1 positivity defined by a combined positive score of >1 was associated with a better response post-nCRT (TRG 1-3 versus 4, 5, p = 0.010). In addition, high combined mean densities of CD8+ , FOXP3+ , and PD-1+ TAICs in the tumor epithelium and stroma of biopsies were associated with a better response (TRG 1-3 versus 4, 5, p = 0.025 and p = 0.044, respectively). Heterogeneous TAIC density patterns were observed post-nCRT, with significantly higher CD8+ and PD-1+ TAIC mean densities compared with biopsies (both p = 0.000). Three immune landscape patterns were defined post-nCRT: 'inflamed', 'invasive margin', and 'desert', of which 'inflamed' was the most frequent (57%). Compared with matched biopsies, resection specimens with 'inflamed' tumors showed a significantly higher increase in CD8+ density compared with non-inflamed tumors post-nCRT (p = 0.000). In this cohort of EAC patients, higher TAIC densities in pretreatment biopsies were associated with response to nCRT. This warrants future research into the potential of the tumor-immune landscape for patient stratification and novel (immune) therapeutic strategies. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Intensive endoscopic therapy for untreated cervical anastomotic strictures after esophagectomy: a pilot study.

BACKGROUND: Cervical anastomotic strictures after esophagectomy cause significant disease burden. We aimed to study the technical feasibility and safety of intensive endoscopic therapy. METHODS: In this pilot study, we included 15 patients with an untreated benign cervical anastomotic stricture after esophagectomy. Intensive endoscopic therapy comprised three endoscopic modalities: in- and excision using a needle-knife, intralesional steroid injections and bougie dilation. In two endoscopic procedures, the stricture was dilated up to a luminal diameter of 18 mm. Patients were followed up to 6 months. RESULTS: A luminal diameter of 18 mm was achieved in 13 of 15 patients (87%) after two endoscopic procedures. No major adverse events related to the investigational treatment occurred. Median dysphagia scores significantly improved from 2 (IQR, interquartile range, 2-3) at baseline to 0 (IQR 0-1) after 14 days (p < 0.001). Eleven (73%) patients developed recurrent symptoms of dysphagia requiring a median of 1 (IQR 0-3) additional endoscopic dilation procedure. CONCLUSIONS: Achieving a luminal diameter of 18 mm in two procedures with intensive endoscopic therapy was technically feasible and effective in reducing dysphagia rapidly in patients with a cervical anastomotic stricture after esophagectomy. No major adverse events related to the investigational treatment were observed.