Search

Background: This study evaluated the perioperative outcomes for patients who had locally advanced esophageal adenocarcinoma (EAC) treated with neoadjuvant immunotherapy (IO) and chemotherapy versus a matched cohort of patients who received neoadjuvant chemotherapy (NAC) alone., Methods: A single-center non-randomized phase 2 trial was undertaken with locally advanced (cT3-4 and/or N+) EAC, and 49 patients completed neoadjuvant avelumab + docetaxel, cisplatin, 5FU (DCF) and esophagectomy between February 2018 and February 2020. These patients were matched with contemporary patients (January 2018 to June 2020) who met the inclusion criteria but received neoadjuvant chemotherapy alone (NAC) with a comparable docetaxel-based therapy. The postoperative outcomes then were compared between the two groups., Results: For this study, 99 patients with locally advanced EAC underwent esophagectomy and met the enrolment criteria. Of these patients, 50 received NAC alone and 49 received IO + NAC. Baseline characteristics such as age, gender, and clinical stage were comparable between the two groups. Operative approach and rate of minimally invasive esophagectomy (~ 60%) were similar in the two groups. For the NAC-alone and IO + NAC groups, the respective overall and major complication rates were similar between the two groups (50% vs. 51% [p = 0.91] and 20% vs. 26% [p = 0.44], respectively), with concordant rates for anastomotic leak (6 [12%] vs. 6 [12%]; p = 0.86) and respiratory complications (13 [26%] vs. 11 [22%]; p = 0.68). The two groups did not differ significantly in terms of hospital length of stay or 30- and 90-day mortality rates., Conclusion: The addition of immunotherapy to neoadjuvant chemotherapy for locally advanced esophageal adenocarcinoma does not appear to alter perioperative short-term outcomes significantly after esophagectomy., (© 2024. Society of Surgical Oncology.)

Background: Survival among patients with esophageal cancer with stage IV nonregional lymphadenopathy treated with neoadjuvant therapy and surgical resection is not well described. This study aimed to compare the survival outcomes of patients with nonregional lymphadenopathy with a propensity-matched cohort of patients with locoregional disease., Methods: This was a retrospective cohort analysis of a prospectively maintained database from a regional upper gastrointestinal cancer network in Quebec, Canada. From January 2010 to December 2022, patients with radiologically suspicious nonregional retroperitoneal or supraclavicular lymphadenopathy were identified. Using 1:1 propensity score matching, a control group without nonregional disease was created., Results: Of the 1235 patients identified, 39 met the inclusion criteria and were allocated to the study group of whom 35 of 39 (89%) had adenocarcinoma. Retroperitoneal and supraclavicular lymphadenopathy occurred in 26 of 39 patients (67%) and 13 of 39 patients (33%). Of the 39 patients, 34 (87%) received neoadjuvant chemotherapy, and 5 (13%) received chemoradiotherapy. After resection, ypN0 of nonregional lymph node stations occurred in 21 of 39 patients (54%). When comparing the study group with a matched non-stage IV control group, the median overall survival was similar in patients with retroperitoneal lymphadenopathy (21.0 months [95% CI, 8.0-21.0] vs 27.0 months [95% CI, 13.0-41.0]; P = .262) but not with supraclavicular disease (13.0 months; 95% CI, 8.0-18.0; P = .039). The median follow-up intervals were 40.1 months (95% CI, 1.0-83.0) for the study group and 70.0 (95% CI, 33.0-106.0) for the control groups., Conclusion: Compared with a matched cohort of patients with similar disease burden but not stage IV disease, retroperitoneal lymphadenopathy did not negatively affect survival outcomes. Multimodal curative intent therapy may be appropriate in select cases., (Copyright © 2024. Published by Elsevier Inc.)

Backround: Real-world, long-term survival outcomes of neoadjuvant, docetaxel-based therapy for esophageal and junctional adenocarcinoma are lacking. This study describes the long-term survival outcomes of patients with esophageal and junctional adenocarcinoma treated with neoadjuvant docetaxel-based chemotherapy and en bloc transthoracic esophagectomy., Methods: A retrospective cohort analysis of a prospectively maintained database from a regional upper gastrointestinal cancer network in Quebec, Canada, was performed. From January 2007 to December 2021, all patients with locally advanced (cT3 and/or N1) esophageal/Siewert I/II adenocarcinoma treated with neoadjuvant DCFx3 (Docetaxel/Cisplatin/5FU) or FLOTx4 (5FU/Leucovorin/Oxaliplatin/Docetaxel) and transthoracic en bloc esophagectomy were identified. Postoperative, pathological, and survival outcomes were compared., Results: Overall, 236 of 420 patients met the inclusion criteria. Tumor location was esophageal/Siewert I/Siewert II (118/33/85), most were cT3-4 (93.6%) and cN+ (61.0%). DCF and FLOT were used in 127 of 236 (53.8%) and 109 of 236 (46.2%). All neoadjuvant cycles were completed in 87.3% with no difference between the regimens. Operative procedures included Ivor Lewis (81.8%), left thoraco-abdominal esophagectomy (10.6%) and McKeown (7.6%) with an R0 resection in 95.3% and pathological complete response in 9.7% (DCF 12.6%/FLOT 6.4%, p = 0.111). The median lymph node yield was 32 (range 4-79), and 60.6% were ypN+. Median follow-up was longer for the DCF group (74.8 months 95% confidence interval [CI] 4-173 vs. 37.8 months 95% CI 2-119, p <0.001. Overall survival was similar between the groups (FLOT 97.3 months, 78.6-115.8 vs. DCF 92.9, 9.2-106.5, p = 0.420)., Conclusions: Neoadjuvant DCF and FLOT followed by transthoracic en bloc resection are both highly effective regimens for locally advanced esophageal adenocarcinoma with equivalent survival outcomes despite high disease load., (© 2023. Society of Surgical Oncology.)

Background: Management following endoscopic submucosal dissection (ESD) of pT1b esophageal adenocarcinoma (EAC) remains controversial. This study compared pathological and survival outcomes of patients after endoscopic resection (ER) of pT1b EAC followed by either en bloc esophagectomy or observation., Methods: From 1/12 to 12/22, all patients with pT1b EAC treated with ER were identified from a prospectively maintained departmental database. ESD was curative (all of: Submucosal invasion < 500 μm; G1/2, LVI/PNI-; deep margin-) or non-curative (one or more of Submucosal invasion ≥ 500 μm; G3; LVI/PNI+; deep margin+). Patients were allocated to observation (OBS) or esophagectomy (SURG) based on patient factors/preference and pathological variables., Results: 56/171 ERs met the inclusion criteria. ER was curative in 8/56 (14%) and non-curative in 48/56 (86%). OBS was undertaken after 8/27 (30%) curative and 19/27 (70%) non-curative resections. All 29 SURG patients had non-curative ERs and were younger, had lower Charlson comorbidity scores and had more deep margin + lesions than OBS patients. Post-esophagectomy, 15/29 (52%) had no residual disease within the surgical specimen while pT+N-/pT-N+/pT+N+ occurred in 5/3/6 (17%/10%/21%) patients. Of those with residual disease in the surgical specimen, 12/14 (86%) had deep margin + ERs; however, only ESD instead of EMR was independently associated with a lower risk of residual disease (OR 0.431, 95% CI - 0.016 to 1.234, p = 0.045). OBS and SURG patients had equivalent overall survival outcomes and recurrence was low in both groups even following non-curative ER. Follow-up was 28 months (0-102) and 30 months (0-97), respectively., Conclusion: In select patients, including some of those with a non-curative ESD resection of pT1B EAC, surveillance alone may be appropriate. Alternatives beyond traditional pathological features is needed to direct patient care more accurately., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The outcomes of different treatment modalities for patients aged 80 and above with locally advanced and resectable esophageal carcinoma are not well described. The aim of this study was to explore survival and perioperative outcomes among this specific group of patients. A retrospective, cohort analysis was performed on a prospectively maintained esophageal cancer database from the McGill regional upper gastroinestinal cancer network. Between 2010 and 2020, all patients ≥80 years with cT2-4a, Nany, M0 esophageal carcinoma were identified and stratified according to the treatment modality: Neoadjuvant chemotherapy (nCT) or chemoradiotherapy (nCRT); definitive CRT (dCRT); upfront surgery; palliative CT/RT; or best supportive care (BSC). Of the 162 patients identified, 79 were included in this study. The median age was 83 years (80-97), most were cT3 (73%), cN- (56%), and had adenocarcinoma (62%). Treatment included: nCT/nCRT (16/79, 20%); surgery alone (19/79, 24%); dCRT (12/29, 15%); palliative RT/CT (27/79, 34%); and BSC (5/79, 6%). Neoadjuvant treatment was completed in 10/16 (63%). Of the 35/79 who underwent surgery, major complications occurred in 13/35 (37%) and 90-day mortality in 3/35 (9%). Overall survival (OS) for the cohort at 1- and 3-years was 58% and 19%. Among patients treated with nCT/nCRT, this was 94% and 46% respectively. Curative intent treatment (nCT/nCRT/upfront surgery/dCRT) had significantly increased 1- and 3- year OS compared with non-curative treatment (76%/31% vs. 34%/3.3%). Multimodal standard of care treatment is feasible and safe in select octo/nonagenarians, and may be associated with improved OS. Age alone should not bias against treatment with curative intent., (© The Author(s) 2023. Published by Oxford University Press on behalf of International Society for Diseases of the Esophagus. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: It has recently been reported that mismatch repair (MMR) status and microsatellite instability (MSI) status in gastroesophageal carcinomas predict surgical, chemotherapeutic and immunotherapeutic outcomes; however, there is extensive variability in the reported incidence and clinical implications of MMR/MSI status in gastroesophaegal adenocarcinomas. We characterized a Canadian surgical patient cohort with respect to MMR status, clinicopathologic correlates and anatomic tumour location., Methods: We investigated MMR and BRAF V600E status of gastroesophaegal adenocarcinomas in patients who underwent gastrectomy or esophagectomy with extended (D2) lymphadenectomy at a single centre between 2011 and 2019. We correlated patterns of MMR expression in the overall cohort and in anatomic location-defined subgroups with treatment response and overall survival using multivariate analysis., Results: In all, 226 cases of gastroesophaegal adenocarcinoma (63 esophageal, 98 gastroesophageal junctional and 65 gastric) were included. The MMR-deficient (dMMR) immunophenotype was found in 28 tumours (12.3%) (15 junctional [15.3%], 13 gastric [20.0%] and none of the esophageal). The majority (25 [89%]) of dMMR cases showed MLH1/PMS2 loss without concurrent BRAF V600E mutation. Two MSH2/ MSH6-deficient gastric tumours and 1 MSH6-deficient junctional tumour were detected. The pathologic response to preoperative chemotherapy was comparable in the dMMR and MMR-proficient (pMMR) cohorts. However, dMMR status was associated with significantly longer median overall survival than pMMR status (5.8 yr v. 2.4 yr, hazard ratio [HR] 1.91, 95% confidence interval [CI] 1.06-3.46), particularly in junctional tumours (4.6 yr v. 1.9 yr, HR 2.97, 95% CI 1.27-6.94)., Conclusion: Our study shows that MMR status has at least prognostic value, which supports the need for biomarker testing in gastroesophageal adenocarcinomas, including junctional adenocarcinomas. This highlights the clinical significance of determining the MMR status in all adenocarcinomas of the upper gastrointestinal tract. Response to induction chemotherapy, however, was not influenced by MMR status., Competing Interests: Competing interests: Lorenzo Ferri reports grants or contracts from the Cancer Research Society (grant # 25320). Lorenzo Ferri and Veena Sangwan report grants or contracts from the Montreal General Hospital Foundation. Amit Katz reports grants or contracts from the Israel Cancer Research Fund. Pierre Fiset reports grants or contracts from Bristol Myers Squibb, and payments and honoraria for expert consultation and presentations on biomarker testing and pathology at advisory boards from Amgen, Bristol Myers Squibb, F. Hoffmann-La Roche, Incyte Corp., Merck, Novartis, Pfizer and Precision Rx-Dx. No other competing interests were declared., (© 2023 CMA Impact Inc. or its licensors.)

Background: Adenocarcinoma of the proximal stomach is the fastest rising malignancy in North America. It is commonly associated with peritoneal accumulation of malignant ascites (MA), a fluid containing cancer and inflammatory cells and soluble proteins. Peritoneal metastasis (PM) is the most common site of gastric cancer (GC) progression after curative-intent surgery and is the leading cause of death among GC patients., Methods/results: Using a panel of gastric adenocarcinoma cell lines (human: MKN 45, SNU-5; murine: NCC-S1M), we demonstrate that prior incubation of GC cells with MA results in a significant (> 1.7-fold) increase in the number of cells capable of adhering to human peritoneal mesothelial cells (HPMC) (p < 0.05). We then corroborate these findings using an ex vivo PM model and show that MA also significantly enhances the ability of GC cells to adhere to strips of human peritoneum (p < 0.05). Using a multiplex ELISA, we identify MIF and VEGF as consistently elevated across MA samples from GC patients (p < 0.05). We demonstrate that agents that block the effects of MIF or VEGF abrogate the ability of MA to stimulate the adhesion of GC cells to adhere to human peritoneum and promote both ex vivo and in vivo metastases., Conclusion: Agents targeting MIF or VEGF may be relevant to the treatment or prevention of PM in GC patients., (© 2022. The Author(s) under exclusive licence to The International Gastric Cancer Association and The Japanese Gastric Cancer Association.)

Background: Changes in the size and density of esophageal malignancy during neoadjuvant chemotherapy (NCT) may be useful in predicting overall survival (OS). The aim of this study was to explore this relationship in patients with adenocarcinoma., Methods: A retrospective single-centre cohort study was performed. Consecutive patients with esophageal adenocarcinoma who received NCT followed by en bloc resection with curative intent were identified. Pre- and post-NCT computed tomography scans were reviewed. The percentage difference between the greatest tumor diameter, esophageal wall thickness and tumor density was calculated. Multivariate Cox regression analysis identified variables independently associated with OS. A ROC analysis was performed on radiological markers to identify optimal cut-off points with Kaplan-Meier plots subsequently created., Results: Of the 167 identified, 88 (51.5%) had disease of the gastro-esophageal junction and 149 (89.2%) were clinical T3. In total, 122 (73.1%) had node-positive disease. Increased tumor density (HR 1.01 per % change, 95% CI 1.00-1.02, p = 0.007), lymphovascular invasion (HR 3.23, 95% CI 1.34-7.52, p = 0.006) and perineural invasion (HR 2.51, 95% CI 1.03-6.08, p = 0.048) were independently associated with a decrease in OS. Patients who had a decrease in their tumor density during the time they received NCT of ≥ 20% in Hounsfield units had significantly longer OS than those who did not (75.5 months versus 34.4 months, 95% CI 38.83-105.13/18.63-35.07, p = 0.025)., Conclusions: Interval changes in the density, not size, of esophageal adenocarcinoma during the time that NCT are independently associated with OS., (© 2022. The Society for Surgery of the Alimentary Tract.)

Objective: To compare overall (OS) and recurrence-free survival (RFS) in esophageal adenocarcinoma patients with a pathologically complete response (pCR) following neoadjuvant chemotherapy (nCT) or neoadjuvant chemoradiotherapy (nCRT)., Background: In the absence of survival differences in several prior studies comparing nCT with nCRT, the higher rate of pCR after nCRT has been suggested as reason to prefer this modality over nCT., Methods: An international cohort study included data from 8 high-volume centers. Inclusion criteria was patients with esophageal adenocarcinoma, between 2008 and 2018, who had a pCR after nCT or nCRT. Univariate analysis was used to compare demographic factors, and Kaplan-Meier survival analysis used to compare 5-year OS and RFS between groups., Results: In all, 465 patients with pCR following neoadjuvant treatment were included; 132 received nCT and 333 received nCRT. There was no statistically significant difference in 5-year OS between groups (78.8% (nCT) vs 65.5% (nCRT), P =0.099), with a similar result demonstrated in multivariate analysis (HR=1.19, 95% CI 0.77-1.84). 5-year RFS was significantly reduced in patients with a pCR following neoadjuvant chemoradiotherapy (75.3% (nCRT) vs 87.1% (nCT), P =0.026). Multivariate analysis confirmed nCRT was associated with a poorer 5-year RFS (HR=1.70, 95% CI 1.22-2.99). nCRT associated with a significantly greater prevalence of 5-year distant recurrence (odds ratio=2.50, 95% CI 1.25-4.99)., Conclusions: The results of this international cohort study show that the prognosis of pCR following different neoadjuvant regimes differs, bringing into question the validity of this measure as an oncological surrogate when comparing neoadjuvant treatment schemes for esophageal adenocarcinoma., Competing Interests: The authors report no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: The FLOT protocol and the CROSS trimodality regimen represent current standards in the management of locally advanced esophageal adenocarcinoma. In the absence of published Randomised Controlled Trial data, this propensity-matched comparison evaluated tolerance, toxicity, impact on sarcopenia and pulmonary physiology, operative complications, and oncologic metrics., Methods: Two hundred and twenty-two patients, 111 in each arm, were included from 2 high-volume centers. Computed tomography-measured sarcopenia, and pulmonary function (forced expiratory volume in first second/forced vital capacity/diffusion capacity for carbon monoxide) were compared pretherapy and posttherapy. Operative complications were defined as per the Esophageal Complications Consensus Group (ECCG) criteria, and severity per Clavien-Dindo. Tumor regression grade and R status were measured, and survival estimated per Kaplan-Meier., Results: A total of 83% were male, cT3/cN+ was 92%/68% for FLOT, and 86%/60% for CROSS. The full prescribed regimen was tolerated in 40% of FLOT patients versus 92% for CROSS. Sarcopenia increased from 16% to 33% for FLOT, and 14% to 30% in CROSS ( P <0.01 between arms). Median decrease in diffusion capacity for carbon monoxide was -8.25% (-34 to 25) for FLOT, compared with -13.8%(-38 to 29), for CROSS ( P =0.01 between arms). Major pathologic response was 27% versus 44% for FLOT and CROSS, respectively ( P =0.03). In-hospital mortality, respectively, was 1% versus 2% ( P =0.9), and Clavien Dindo >III 22% versus 27% ( P =0.59), however, respiratory failure was increased by CROSS, at 13% versus 3% ( P <0.001). Three-year survival was similar at 63% (FLOT) and 60% (CROSS) ( P =0.42)., Conclusions: Both CROSS and FLOT resulted in equivalent survival. Operative outcomes were similar, however, the CROSS regimen increased postoperative respiratory failure and atrial fibrillation. Less than half of patients received the prescribed FLOT regimen, although toxicity rates were acceptable. These data support clinical equipoise, caution, however, may be advised with CROSS in patients with greatest respiratory risk., Competing Interests: The authors report no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Surgical resection, the cornerstone of curative intent treatment for gastric adenocarcinoma, is associated with a high rate of infection-related post-operative complications, leading to an increased incidence of metastasis to the peritoneum. However, the mechanisms underlying this process are poorly understood. Lipopolysaccharide (LPS), an antigen from Gram-negative bacteria, represents a potential mechanism via induction of local and systemic inflammation through activation of Toll-like receptor (TLR). Here, we use both a novel ex vivo model of peritoneal metastasis and in vivo animal models to assess gastric cancer cell adhesion to peritoneum both before and after inhibition of the TLR4 pathway. We demonstrate that activation of TLR4 by either LPS or Gram-negative bacteria (E. coli) significantly increases the adherence of gastric cancer cells to human peritoneal mesothelial cells, and that this increased adherence is abrogated by inhibition of the TLR4 signal cascade and downstream TAK1 and MEK1/2 pathways. We also demonstrate that the influence of LPS on adherence extends to peritoneal tissue and metastatic spread. Furthermore, we show that loss of TLR4 at the site of metastasis reduces tumor cell adhesion, implicating the TLR4 signaling cascade in potentiating metastatic adhesion and peritoneal spread. These results identify potential therapeutic targets for the clinical management of patients undergoing resection for gastric cancer., (© 2021. The Author(s), under exclusive licence to Springer Nature B.V.)

Background: Palliative chemotherapy is the mainstay of treatment for metastatic gastric adenocarcinoma but in some patients, surgically correctable factors such as obstruction lead to intolerance of further systemic treatment. The aim of this study was to evaluate the role of selective palliative surgery in incurable gastric cancer. Methods: All patients with stage IV and locally advanced unresectable gastric adenocarcinoma treated at a single centre from March 2006 to January 2019 were included. Data were retrieved from a prospectively maintained database. Patients were categorized into palliative surgery (PS) and no surgery (NS). Results: Of 666 patients with gastric cancer treated over the study period, 146 patients had stage IV gastric adenocarcinoma and 121 patients met inclusion criteria. Sites of metastases were peritoneum (55; 46%), non-regional lymph nodes (10; 8%), solid organ (17, 14%), adjacent organ invasion (4, 3.3%) and a combination of factors (32, 26%). Forty-six (38%) patients underwent palliative surgery which included anatomical gastrectomy (total, subtotal, distal or proximal, 78%) gastro-jejunal bypass and feeding jejunostomy (12%). Thirty-day post-operative complications occurred in 24 patients (52%) with one mortality (2.1%). Following surgery, 52% received systemic chemotherapy. For the PS and NS groups respectively, median overall survival was 9.1 versus 9.4 months ( p  = 0.6) and median progression-free survival was 7.1 versus 6.7 months ( p  = 0.2) after a follow up period of 7.3 (4.7-13.1) versus 7.8 (2.6-13.4) months ( p  = 0.46). Conclusion: Targeted surgical intervention for incurable gastric cancer can be used to palliate symptoms and facilitate continuation of systemic therapy with acceptable risks and post-operative outcomes.

Backgrounds: Due to a lack of randomized and large studies, the optimal surgical approach for Siewert 2 gastroesophageal junctional (GEJ) adenocarcinoma remains unknown. This population-based cohort study aimed to compare survival between esophagectomy and total gastrectomy for the treatment of Siewert 2 GEJ adenocarcinoma., Methods: Data from the National Cancer Database (NCDB) from 2010 to 2016 was used to identify patients with non-metastatic Siewert 2 GEJ adenocarcinoma who received either esophagectomy (n = 999) or total gastrectomy (n = 8595). Propensity score-matching (PSM) and multivariable analyses were used to account for treatment selection bias., Results: Comparison of the unmatched cohort's baseline demographics showed that the patients who received esophagectomy were younger, had a lower burden of medical comorbidities, and had fewer clinical positive lymph nodes. The patients in the unmatched cohort who received gastrectomy had a significantly shorter overall survival than those who received esophagectomy (median, 47 vs. 68 months [p < 0.001]; 5-year survival, 45 % vs. 53 %). After matching, gastrectomy was associated with significantly reduced survival compared with esophagectomy (median, 51 vs. 68 months [p < 0.001]; 5-year survival, 47 % vs. 53 %), which remained in the adjusted analyses (hazard ratio [HR], 1.22; 95 % confidence interval [CI], 1.09-1.35; p < 0.001)., Conclusions: In this large-scale population study with propensity-matching to adjust for confounders, esophagectomy was prognostically superior to gastrectomy for the treatment of Siewert 2 GEJ adenocarcinoma despite comparable lymph node harvest, length of stay, and 90-day mortality. Adequately powered randomized controlled trials with robust surgical quality assurance are the next step in evaluating the prognostic outcomes of these surgical strategies for GEJ cancer., (© 2021. The Author(s).)

Background: This study investigated the role of the neutrophil-to-lymphocyte ratio (NLR) in predicting anastomotic leak (AL) after esophagectomy for esophageal adenocarcinoma., Methods: This is a retrospective analysis of a prospectively collected database from the McGill University Health Center. Included were all patients with esophageal adenocarcinoma who underwent esophagectomy between 2005 and 2016. Patients with chronic infections, concurrent active malignancies, and autoimmune conditions were excluded. NLR values were obtained on postoperative days (POD) 0, 1, 2, and 3. Receiver operating characteristic curve study and multivariable logistic analysis were conducted to evaluate the diagnostic value of NLR., Results: The study included 330 patients, and AL developed in 16%. Mean NLR values on POD1, 2, and 3 were higher in patients with leaks (20 vs 14 on POD1, P < .001; 20 vs 12 on POD2, P < .001; and 19 vs 10 on POD3, P < .001). The NLR value on POD3 was associated with an area under the curve of 70% and a negative predictive value of 92.4%. Multivariable analyses identified higher American Society of Anesthesiologists Physical Status Classification, increasing NLR trend (between POD1 and POD3), POD1 NLR, POD2 NLR, and POD3 NLR as independent factors associated with AL., Conclusions: Patients who developed AL demonstrate higher mean NLR values in the early postoperative period with rising trends. Conversely a low NLR is associated with a high negative predictive value for AL. This simple metric allows risk stratification that may guide treatment decisions in esophagectomy patients., (Copyright © 2021 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background and Aims: The FLOT4-AIO trial established the FLOT regimen as a compelling option for gastric, junctional and esophageal adenocarcinoma. Data on FLOT with en-bloc transthoracic esophagectomy (TTE) are limited. This study explored operative complications, tolerance, toxicity, physiological impact, and oncologic outcomes., Study Design: An observational cohort study on consecutive patients at 3 tertiary centers undergoing FLOT and TTE. Toxicity, operative complications (per ECCG definitions), tumor regression grade (TRG), recurrences and survival were documented, as well as pre and post FLOT assessment of sarcopenia and pulmonary physiology., Results: 175 patients (cT2-4a, Nany) commenced treatment, 84% male, median age 65, 94% cT3/T4a, 73% cN+. 89% completed 4 preoperative cycles, and 35% all cycles. Grade 3/4 toxicities included neutropenia (12%), diarrhoea (13%), and infection (15%). Sarcopenia increased from 18% to 37% (P = 0.020), and diffusion capacity (DLCO) decreased by 8% (-34% + 25%; P < 0.010). On pathology, ypT3/4 was 59%, and ypN+54%, with 10% TRG 1, 14% TRG 2, and 76% TRG3-5, and R0 95%. 161 underwent TTE, with an in-hospital mortality of 0.6%, 24%-pneumonia, 11%-anastomotic leak, and Clavien Dindo ≥III in 27%. At a median follow up of 12 months (1-85), 33 relapsed, 8 (5%) locally, and 3yr survival was 60%., Conclusion: FLOT and en bloc TTE was safe, with no discernible impact on operative complications, with 24% having a major pathologic response. Caveats include a limited pathologic response in the majority, and negative impact on muscle mass and lung physiology, and low use of adjuvant cycles. These data may provide a real-world benchmark for this complex care pathway., Competing Interests: The authors report no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

While emerging data suggest nucleotide oligomerization domain receptor 1 (NOD1), a cytoplasmic pattern recognition receptor, may play an important and complementary role in the immune response to bacterial infection, its role in cancer metastasis is entirely unknown. Hence, we sought to determine the effects of NOD1 on metastasis. NOD1 expression in paired human primary colon cancer, human and murine colon cancer cells were determined using immunohistochemistry and immunoblotting (WB). Clinical significance of NOD1 was assessed using TCGA survival data. A series of in vitro and in vivo functional assays, including adhesion, migration, and metastasis, was conducted to assess the effect of NOD1. C12-iE-DAP, a highly selective NOD1 ligand derived from gram-negative bacteria, was used to activate NOD1. ML130, a specific NOD1 inhibitor, was used to block C12-iE-DAP stimulation. Stable knockdown (KD) of NOD1 in human colon cancer cells (HT29) was constructed with shRNA lentiviral transduction and the functional assays were thus repeated. Lastly, the predominant signaling pathway of NOD1-activation was identified using WB and functional assays in the presence of specific kinase inhibitors. Our data demonstrate that NOD1 is highly expressed in human colorectal cancer (CRC) and human and murine CRC cell lines. Clinically, we demonstrate that this increased NOD1 expression negatively impacts survival in patients with CRC. Subsequently, we identify NOD1 activation by C12-iE-DAP augments CRC cell adhesion, migration and metastasis. These effects are predominantly mediated via the p38 mitogen activated protein kinase (MAPK) pathway. This is the first study implicating NOD1 in cancer metastasis, and thus identifying this receptor as a putative therapeutic target.

Background: Two reviews and an overview were produced for the Canadian Task Force on Preventive Health Care guideline on screening for esophageal adenocarcinoma in patients with chronic gastroesophageal reflux disease (GERD) without alarm symptoms. The goal was to systematically review three key questions (KQs): (1) The effectiveness of screening for these conditions; (2) How adults with chronic GERD weigh the benefits and harms of screening, and what factors contribute to their preferences and decision to undergo screening; and (3) Treatment options for Barrett's esophagus (BE), dysplasia or stage 1 EAC (overview of reviews)., Methods: Bibliographic databases (e.g. Ovid MEDLINE®) were searched for each review in October 2018. We also searched for unpublished literature (e.g. relevant websites). The liberal accelerated approach was used for title and abstract screening. Two reviewers independently screened full-text articles. Data extraction and risk of bias assessments were completed by one reviewer and verified by another reviewer (KQ1 and 2). Quality assessments were completed by two reviewers independently in duplicate (KQ3). Disagreements were resolved through discussion. We used various risk of bias tools suitable for study design. The GRADE framework was used for rating the certainty of the evidence., Results: Ten studies evaluated the effectiveness of screening. One retrospective study reported no difference in long-term survival (approximately 6 to 12 years) between those who had a prior esophagogastroduodenoscopy and those who had not (adjusted HR 0.93, 95% confidence interval (CI) 0.58-1.50). Though there may be higher odds of a stage 1 diagnosis than a more advanced diagnosis (stage 2-4) if an EGD had been performed in the previous 5 years (OR 2.27, 95% CI 1.00-7.67). Seven studies compared different screening modalities, and showed little difference between modalities. Three studies reported on patients' unwillingness to be screened (e.g. due to anxiety, fear of gagging). Eleven systematic reviews evaluated treatment modalities, providing some evidence of early treatment effect for some outcomes., Conclusions: Little evidence exists on the effectiveness of screening and values and preferences to screening. Many treatment modalities have been evaluated, but studies are small. Overall, there is uncertainty in understanding the effectiveness of screening and early treatments., Systematic Review Registrations: PROSPERO (CRD42017049993 [KQ1], CRD42017050014 [KQ2], CRD42018084825 [KQ3]).

Introduction: Although endoscopic resection for early gastric cancer is well established, anatomical resection with regional lymphadenectomy is recommended for lesions at high risk for occult lymph node metastasis (e.g., lymphovascular invasion, poor grade, and deep submucosal invasion). However, 75-95% high-risk early gastric cancer (HR-EGC) patients ultimately have node-negative disease and could potentially have undergone organ-sparing resection. Due to the inadequacy of standard modalities to reliably rule out nodal metastases in HR-EGC patients, sentinel lymph node (SLN) sampling was developed in Asia with promising results. However, the applicability of this technique in the West has been brought into question due to potential differences in tumor histology and body habitus. This prospective study aimed to test SLN sampling for North American EGC patients., Methods: All patients with biopsy-confirmed T0-2 N0-1 M0 gastric adenocarcinoma at the Montreal General Hospital-McGill University Health Centre were eligible for enrollment. Esophageal and GEJ cancers were excluded due to the high rate of intrathoracic lymph node involvement. Peritumoral submucosal injection with T 99 radiocolloid was performed endoscopically 24-30 h prior to surgery. Methylene blue dye injection was performed after induction of anesthesia. SLN basins were identified as those having > 10% of baseline tumor radiation signal or blue color, or both. After basins were individually removed, standard laparoscopic anatomical resection was then performed with D2 lymphadenectomy. ( ClinicalTrials.gov identifier: NCT03049345). Data are presented as median (interquartile range)., Results: From July 2016-April 2018, 253 patients with esophagogastric adenocarcinoma were evaluated. Of these, 10 met inclusion criteria (90% male, age 66(30) years). Subtotal gastrectomy was performed in nine patients (90%) and length of stay was 4 (2) days. At least one SLN basin was identified in nine cases (90%). The median #SLN basins identified was 2(2) with a median of 5(5) total SLNs retrieved per patient. In the one case for which no SLN basins were identified, only blue dye injection was used, whereas SLNs were identified in all cases using the dual tracer method. Final T-stage was pT1b/T2 in four (40%), pT1a in two (20%), and Tx in four (40%). Two patients (20%) had lymph node metastases on final pathological analysis, both of which were identified by SLN sampling (accuracy 100%; false negative rate 0%). No adverse events related to SLN retrieval were identified., Conclusions: This study represents the first prospective feasibility evaluation of sentinel lymph node sampling for early gastric cancer in North America with promising preliminary results. The dual tracer method was superior to single agent blue dye in identifying sentinel nodal basins. Considerable further study is necessary to verify the safety and utility of SLN mapping in North American patients with early gastric adenocarcinoma.

Background: Data are limited regarding the application of endoscopic submucosal dissection (ESD) in Western countries or for esophageal adenocarcinoma in any part of the world. We sought to review our experience employing ESD in patients with early esophageal cancer at a high volume North American esophageal cancer treatment center., Methods: A prospectively maintained database of all patients with esophageal cancer treated at the McGill University Health Center was used to identify ESDs performed for adenocarcinoma between 2012 and 2016. Patient demographics, pre-resection tumor characteristics, endoscopic resection technical variables, pathologic results, and short- and long-term outcomes were recorded., Results: Of 650 patients in the database, 26 underwent 27 procedures. The majority (67%) had pre-treatment EUS. There were no post-ESD bleeding events requiring re-intervention. Perforation occurred in 2/27 (7%), one of which required operative repair. Complete RO resection was achieved in 18/27(67%). Salvage laparoscopic esophagectomy was performed in six patients. At a median follow-up of 18.5 (7-35) months, cancer recurrence occurred in only one patient who subsequently underwent successful repeat ESD., Conclusions: Although technically challenging, ESD represents a safe and effective treatment of early esophageal adenocarcinoma and has the potential to become a more important tool in management of these early lesions in Western countries.

Background: It is unknown why some cases of Barrett’s esophagus progress to invasive malignant disease rapidly while others do so more slowly or not at all. The aim of this study was to identify demographic and endoscopic factors that predict dysplastic and neoplastic progression in patients with Barrett’s esophagus., Methods: Patients with Barrett’s esophagus who were assessed in 2000–2010 were assessed for inclusion in this retrospective study. Demographic and endoscopic variables were collected from an endoscopy database and the medical chart. Dysplastic and neoplastic progression was examined by time-to-event analysis. We used Cox proportional hazard regression modelling and generalized estimating equation methods to identify variables that were most predictive of neoplastic progression., Results: A total of 518 patients had Barrett’s esophagus confirmed by endoscopy and pathology and at least 2 surveillance visits. Longer Barrett’s esophagus segment (≥ 3 cm) (odds ratio [OR] 1.2, 95% confidence interval [CI] 1.1–1.3) and increased age (≥ 60 yr) (OR 3.5, 95% CI 1.7–7.4) were independent predictors of progression from nondysplasia to dysplastic or neoplastic grades. Presence of mucosal irregularities (OR 8.6, 95% CI 2.4–30.4) and increased age (OR 5.1, 95% CI 1.6–16.6) were independent predictors of progression from nondysplasia to high-grade dysplasia or adenocarcinoma., Conclusion: Increased age, longer Barrett’s segment and presence of mucosal irregularities were associated with increased risk of dysplastic and neoplastic progression. In addition to dysplasia, these factors may help stratify patients according to risk of neoplastic progression and be used to individualize surveillance. More prospective studies with larger samples are required to validate these results., Competing Interests: None declared., (© 2019 Joule Inc. or its licensors)

Current treatment of locally advanced esophageal cancers (ECs) centres on a multimodal approach regardless of histology. While surgery remains the mainstay of curative intent therapy, its implementation alone results in suboptimal outcomes, which have improved significantly with the increased utilization of induction regimens comprising of concurrent chemoradiation (CRT) or chemotherapy alone followed by surgery. Due in large part to the positive results of the CROSS trial, neoadjuvant CRT has become the predominant standard applied in the West. However, the bulk of the data published to date suggests that a more nuanced approach to the management of locally advanced EC is required with respect to the application of radiation, which related to the differential sensitivity of esophageal adenocarcinoma (EAC) and esophageal squamous cell carcinoma (SCC) to radiation. While the latter demonstrates excellent radiosensitivity, which has translated into improved survival outcomes, the same cannot be said for patients with EAC who may be subject to greater toxicity without any benefit. Herein, the differential effectiveness of CRT in patients with EAC versus SCC is highlighted, with a focus on the randomized evidence to date.

Background: There is controversy about the safety and outcomes of completion total gastrectomy (CTG) for gastric adenocarcinoma. We compared a cohort of patients who underwent CTG for gastric remnant cancer (GRC) after partial gastrectomy for benign disease with patients who underwent primary total gastrectomy (PTG) for sporadic gastric cancer., Methods: We retrospectively reviewed a single-institution, prospectively maintained clinical database of patients who had undergone gastrectomy from 2005 to 2016 for demographic, surgical, clinical and tumour pathology data, as well as postoperative, pathologic and oncologic outcomes including complications, length of stay, disease-free survival and overall survival. We used the χ 2 and Wilcoxon rank-sum tests to compare groups and performed the Mantel-Cox log-rank test for Kaplan-Meier survival estimates. We compared the CTG group to all patients in the PTG group and to a 5:1 propensity-matched PTG cohort., Results: We analyzed data for 64 patients (9 CTG, 55 PTG). The groups were equivalent at baseline and had similar operative, perioperative treatment and pathologic characteristics. After propensity matching, the reoperation rate for complications was higher after CTG than PTG (22% v. 0%, p = 0.03), but there was no significant difference in the overall complication rate or length of stay. At 5 years, there was no difference in disease-free survival (28% v. 58%, p = 0.4) or overall survival (33% v. 44%, p = 0.7)., Conclusion: Our findings suggest that CTG for gastric adenocarcinoma can be undertaken safely a priori with no additional risk of recurrence or death compared to PTG for sporadic gastric cancer.

Purpose: Despite evidence of oncologic benefits from extended (D2) lymphadenectomy in gastric cancer from many East Asian studies, there is persistent debate over its use in the West, mainly due to perceived high rates of morbidity and mortality. This study evaluates the safety and efficacy of D2 dissection in a high-volume North American center., Methods: A prospectively entered database of all patients undergoing gastrectomy for cancer at a North American referral center from 2005 to 2016 was reviewed. Wedge resections, thoracoabdominal approach, emergency surgery, palliative operations, and non-adenocarcinoma cases were excluded., Results: Of 366 non-bariatric gastrectomies over this period, 175 met the inclusion criteria. Median age was 73 years and 69% were male. One hundred forty-one patients (80%) underwent D2 dissection, the rest having D1. There was no difference in postoperative complications (D1 = 44%: D2 = 42%), anastomotic leaks (D1 = 6%: D2 = 5%), and same-admission or 30-day mortality (D1 = 6%: D2 = 2%). D2 dissection was associated with higher pathological stage (72% > stage 1 vs 38% > stage 1; p < 0.05) and median lymph node yield (30 vs 14; p < 0.05), with no difference in complete resection (R0) rate (D1 = 98% vs D2 = 92%). Laparoscopic approach was employed in 34% (45/141) of D2 cases, resulting in shorter median length of stay (6 days vs 9; p < 0.05) and equivalent oncologic outcomes compared to open D2., Conclusion: This study supports the use of D2 lymphadenectomy, by either open or laparoscopic approach, in high-volume North American centers as a safe and effective oncologic procedure for gastric cancer, with equivalent complication rates and superior lymph node yield to traditional D1 dissection.

Endoscopic submucosal dissection as an organ sparing option for early gastric cancer is becoming increasingly accepted as an alternative to laparoscopic gastrectomy. Given the very limited North American data, we sought to compare outcomes between endoscopic and laparoscopic resection of gastric malignant and premalignant tumors. Patients undergoing laparoscopic gastrectomy or endoscopic submucosal dissection from 2007 to 2014 for adenocarcinoma or dysplasia at the McGill University Health Center were identified from a prospectively collected database and dichotomized according to the surgical approach. Patient demographics, tumor characteristics, stage, oncologic outcome, length of stay, and postoperative complications were recorded. Of 155 patients with gastric cancer identified, 67 were treated by laparoscopic gastrectomy (n = 37) or endoscopic submucosal dissection (ESD) (n = 30). There were significantly more invasive lesions in the laparoscopic group and patients subject to ESD harbored more T1 lesions. No significant difference in the rate of R0 resection or overall complications was observed between the groups. Accordingly, length of stay was significantly shorter in the ESD group. There were no significant differences in terms of overall and disease-free survival. In selected patients, ESD is associated with improved short-term outcomes and provides an appropriate oncologic resection option in a North American patient cohort.

Docetaxel is active in esophagogastric junction (EGJ) adenocarcinoma, and DCF (docetaxel/cisplatin/5-fluorouracil) has shown good results in the neoadjuvant setting. Its high rate of grade 3-4 mucosal toxicity (stomatitis and diarrhea) has limited its widespread adoption. A more recent docetaxel-based triplet, FLOT (5-fluorouracil, oxaliplatin and docetaxel) may be better tolerated. We conducted a pilot study of FLOT chemotherapy in EGJ adenocarcinoma patients and dysphagia to prospectively assess the rate of grade 3-4 mucosal toxicity and of pathological complete response (pCR) rate. Dysphagia and quality of life were measured with validated questionnaires. Ten patients were enrolled. Grade 3-4 mucosal toxicity rate was 0 %; pCR rate was 11 %; and near-complete pathological response rate 11 %. Dysphagia improvement or resolution was seen in 90 % of patients, and quality of life was stable before and after chemotherapy. FLOT is a safe and active neoadjuvant chemotherapy option for EGJ adenocarcinoma and should be compared to other standard regimens in randomized trials.

Background: Preoperative chemotherapy (ChT) or chemoradiation (ChRT) are associated with improved outcomes compared with up-front surgical resection in patients with locally advanced esophageal adenocarcinoma (EAC). Two randomized controlled trials comparing these therapies included nonradical resection and failed to reach significance. We hypothesized that additional regional radiotherapy does not benefit patients undergoing en bloc resection., Methods: We performed a multiinstitutional study using three prospectively entered databases from high-volume esophageal centers. Inclusion criteria were patients with EAC treated with preoperative ChT or ChRT, followed by modified en bloc esophagectomy. To minimize issues of stage migration and heterogeneity, we limited the study to patients with cT3 N1 M0 EAC. Survival was assessed by the Kaplan-Meier method, and step-wise multivariable analyses were used to explore variables independently associated with survival outcomes. Radical resections included two- and three-field lymphadenectomies, dependent solely on surgeon/institutional preference., Results: We identified 214 patients with cT3 N1 disease, of which 114 underwent preoperative ChT vs 100 who underwent ChRT. Median survival was 31.2 months (95% confidence interval, 20.7 to 41.7 months) for the ChT group vs 39.2 months (95% confidence interval, 27.3 to 51.0 months) for the ChRT group (p = 0.665). Mortality at 90 days was 5.3% for ChT vs 4% for ChRT (p = 0.754). No differences were noted between patterns of locoregional and distant recurrence between both groups. There were no significant differences in major postoperative morbidity between both groups., Conclusions: Given a modified en bloc esophagectomy, type of preoperative therapy was not a significant determinant of overall survival or disease-free survival. Although preoperative ChRT did not add perioperative risk, it also did not prolong survival. The role of preoperative radiotherapy in the setting of a planned radical resection should be further evaluated., (Copyright © 2016 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Introduction: We have previously identified Docetaxel, Cisplatin, and 5FU (DCF) as a safe, tolerable, and effective regimen in the neoadjuvant setting for locally advanced adenocarcinoma (ADC) of the esophagus and esophagogastric junction (EGJ). We hypothesized that DCF combined with enhanced surgical control would result in a low rate of local or regional recurrence, and thus reviewed our outcomes with this treatment regimen., Methods: A prospectively entered database of all esophageal and EGJ ADC patients resected at a high-volume referral center over 6 years (9/07-9/13) was reviewed for cases treated with curative intent neoadjuvant DCF followed by en bloc resection with extended lymphadenectomy (D2/D3). Recurrences was defined as locoregional (biopsy on endoscopy/regional lymph nodes (LNs)) and distant. Standard statistical techniques were used., Results: Of 279 patients with ADC, 86 (85% male, mean age 63 years (interquartile range 56-70)) underwent preoperative DCF and curative intent resection for locally advanced ADC (cT3 93%; cN+ 69%) of the EGJ (54%) or distal esophagus (46%). After median follow-up of 40 months, the overall 5-year survival was 54% and 43 (52%) had recurred at a median time of 14 months. Sites of recurrence included locoregional only in 2 of 45 (4%), distant only in 40 of 45 (89%), and locoregional and distant in 3 of 45 (7%)., Discussion: The present study demonstrates favourable oncologic outcomes with low local/regional recurrence and an excellent overall 5-year survival after neoadjuvant DCF for esophageal and EGJ ADCs. Because the majority of recurrences were distant, our data support the notion that efforts to improve outcomes in these patients should concentrate on enhancing systemic, rather than local, therapy.

Background: Positive resection margins are amongst the strongest predictors of cancer-related mortality for adenocarcinoma of the stomach and esophagus. Although intraoperative pathology consultation with frozen section of margins can predict final permanent section pathology, the accuracy of this approach is not known. We sought to determine the diagnostic accuracy of frozen section margin analysis in esophagogastric adenocarcinoma and the impact that it had on surgical therapy., Methods: Patients with resection of esophagogastric adenocarcinoma at a single centre from 1998 to 2008 were identified. Clinicopathologic data were collected. Frozen section results were compared to permanent section assessment, and sensitivity, specificity, positive, and negative predictive values were calculated. Patients with positive margins by frozen section were reviewed to assess the impact on surgical decision-making., Results: Of 220 patients who underwent surgery for adenocarcinoma of the esophagus and stomach (esophagus: 34/220, EGJ: 106/220, stomach 80/220), 56 % had an intraoperative consultation. Of these 122 patients, 66 % underwent frozen section. All errors on frozen section occurred on the interpretation of the proximal margin. The diagnostic accuracy of frozen section at the proximal margin was 93 % with sensitivity = 67 %, specificity = 100 %, positive predictive value = 100 %, and negative predictive value = 91 %. Signet ring cells were present in 83 % of false-negative readings. Surgical management was altered in 10 of the 13 of patients who had a true positive frozen section and 9 of these patients were converted to R0 resections., Conclusions: Although very specific, negative results on frozen section require greater caution when signet ring cells are present. For esophagogastric adenocarcinoma, frozen section alters management and may increase the rate of complete resection.

Introduction: Incidental pulmonary nodules are frequently identified during staging investigations for esophageal cancer patients. Their clinical significance is unclear and may bias treatment decisions towards palliative options., Methods: From 2005 to 2011, 423 esophageal cancer patients were treated at a tertiary hospital. Those with incidental pulmonary nodules were identified. Demographics, imaging, pathology and perioperative outcomes were analyzed., Results: Ninety-two patients (22 %) had lung nodules. Twenty-nine (32 %) were palliative due to poor performance status or extra-pulmonary distant metastasis on imaging. Sixty-three had no evidence of extra-pulmonary metastasis and underwent curative-intent treatment comprising of neoadjuvant therapy [35 (55 %)] followed by esophagectomy [with lung resection, 33 (52 %) or without lung resection, 30 (48 %)]. Of those 33 lung resections, there were 27 benign lesions, 4 stage I lung cancers, and 1 esophageal cancer metastasis. Of 30 patients with lung nodules that underwent curative esophagectomy without lung resection, none showed interval size increase on follow-up imaging [median 9 months (3-40)]. There was no difference in perioperative complications or mortality between patients with combined esophagectomy and lung resection and those with esophagectomy alone., Conclusion: Incidental pulmonary nodules in the absence of extra-pulmonary metastases in esophageal cancer patients are rarely metastases and should not bias caregivers towards palliative therapy.

Background: Endoscopic resection is an organ-sparing option for early esophageal adenocarcinoma, but should be used only in patients with a negligible risk of lymph node metastases (LNM). The objective was to develop a simple scoring system to predict LNM in T1 esophageal adenocarcinoma., Study Design: All primary esophagectomies performed for T1 esophageal adenocarcinoma without neoadjuvant therapy at 5 university institutions from 2000 to 2011 were analyzed. Patient and pathologic characteristics were compared between patients with LNM at the time of surgical resection and those without. Univariate and multivariate analyses were performed to establish a simple scoring system that estimated the risk of LNM, using variables from the final surgical pathology., Results: A total of 258 patients were included for analysis (mean age 65.2 years [SD 10.3 years], 88% male). The incidence of LNM was 7% (9 of 122) for T1a and 26% (35 of 136) for T1b. Tumor size (odds ratio [OR] 1.35 per cm, 95% CI 1.07 to 1.71) and lymphovascular invasion (OR 7.50, 95% CI 3.30 to 17.07) were the strongest independent predictors of LNM. A weighted scoring system was devised from the final multivariate model and included size (+1 point per cm), depth of invasion (+2 for T1b), differentiation (+3 for each step of dedifferentiation), and lymphovascular invasion (+6 if present). Total number of points estimated the probability of LNM (low risk [0 to 1 point], ≤ 2%; moderate risk [2 to 4 points], 3% to 6%; and high risk [5+ points], ≥ 7%)., Conclusions: We devised a simple scoring system that accurately estimates the risk of LNM to aid in decision-making in patients with T1 esophageal adenocarcinoma undergoing endoscopic resection., (Copyright © 2013 American College of Surgeons. Published by Elsevier Inc. All rights reserved.)

Background 80% of patients diagnosed with esophageal adenocarcinoma (EAC) die of disease. Current standard of care for EAC is systemic cytotoxic, platinum-based neoadjuvant chemotherapy followed by resection and additional rounds of chemotherapy. Locally advanced, resectable patients often fail to respond due to intrinsic and/or acquired chemoresistance. Traditional preclinical models fail to offer alternative salvage options. To our knowledge, this is the first high-fidelity dynamic 3D platform implemented to study esophageal function, pathophysiology, and drug effects. Methods Primary tissues obtained from EAC patients at diagnostic biopsy were propagated into patient-derived organoids (PDOs). The upper (mucosal) channel of the esophagus-chip was designated for PDO-derived epithelial cells, while the lower stromal channel was designated for matched fibroblasts. Autologous cell types were exposed to a physiologically relevant flow of nutrient media and microtissues were formed. Epithelial permeability was determined by cascade blue assay. Using this model, a clinically relevant chemotherapy protocol was administered to study patient-specific tumor response. To determine microtissue development and cellular fate in response to chemotherapy, level of several epithelial/mesenchymal biomarkers were evaluated. Results Study cohort consisted of both chemo-sensitive and -resistant EAC patients. Esophagus-chip models were developed with samples from patient-matched tumor and normal tissue. Chips recapitulated morphological and histological features of their parental tissues. Epithelial barrier integrity was established within 5 days on-chip. Scanning electron microscopy revealed the presence of pleomorphic cells and mature microvilli in EAC-chips. In vitro administration of docetaxel triplet chemotherapy demonstrated efficacy similar to that observed in the clinical setting when assessed directly or indirectly. Confocal imaging revealed treatment-associated differential expression of epithelial (CK7, CK19), and mesenchymal (vimentin) markers. Conclusion 3D-organoids conserve cellular heterogeneity of source patients, whereas esophagus-on-chip expand on this diversity by adding microphysiological relevance, stromal influence & flexible complexity. This high-fidelity biomimetic platform enables clinical mimicry and can predict patient-specific chemosensitivity within a clinically relevant timeframe. This esophagus-chip system is a promising potential replacement for both inefficient preclinical animal models and existing tumor-only avatars lacking stromal and microphysiological context. [ABSTRACT FROM AUTHOR]

Background Peri-operative docetaxel-based triplet chemotherapy is the standard-of-care treatment for advanced gastroesophageal adenocarcinoma (GEA). However, most patients recur due to innate or acquired resistance. Although distinct populations of cancer-associated fibroblasts (CAFs) within the tumor microenvironment play important roles in conferring chemoresistance in other cancer types, this paradigm has not been extensively studied in GEA. We aim to characterize CAF heterogeneity in a well-annotated cohort of GEA patients, identifying potential biomarkers and targets to overcome chemoresistance. Methods Immunofluorescence and flow cytometry assays were performed to validate previously reported CAF markers from the literature in primary patient fibroblasts. To identify specific CAF markers for GEA, an atlas was developed using single-cell RNA sequencing (scRNA-seq) data obtained from 46 GEA patient samples, including 28 patients with longitudinal samples over the docetaxel-based triplet chemotherapy treatment trajectory. Differential and gene ontology analyses were performed to characterize distinct CAF subpopulations and identify dynamic CAF markers across treatment timepoints, while correlating with in-patient treatment response to chemotherapy. In parallel, tumor organoid-CAF co-cultures were established for subsequent in vitro drug testing with standard-of-care chemotherapy. Results CAF markers (VIM, FAP, PDPN, and S100A4) were found to be differentially expressed in fibroblasts isolated from good and poor pathological-response tumours. Analysis of scRNA-seq data reveals two main subpopulations of CAFs: myofibroblast CAFs (myCAFs) and inflammatory CAFs (iCAFs). Two markers, CCL20 and CHRDL1, were identified as differentially expressed between good and poor pathological responders in iCAFs, while nine markers, including ISG20 and C20orf27, were differentially expressed between clinical partial responders and poor responders. Dynamic CAF markers, including STAG2 and HAT1, were differentially expressed across treatment timepoints and were associated with pathological or clinical response. Conclusions GEA CAFs demonstrate extensive heterogeneity and comprise two major subpopulations. Several CAF markers were found to be associated with patient chemotherapy pathological or clinical response to chemotherapy, either in the chemonaïve setting or in the context of changes over the course of therapy. These putative biomarkers will be further validated and investigated, both in additional samples and in co-culture settings, to gain a better understanding of their clinical relevance and targeting potential. [ABSTRACT FROM AUTHOR]