HiChIP-based Epigenomic Footprinting Identifies a Promoter Variant of UXS1 that Confers Genetic Susceptibility to Gastroesophageal Cancer.

Genome-wide association studies (GWAS) have identified more than a hundred single nucleotide variants (SNVs) associated with the risk of gastroesophageal cancer (GEC). The majority of the identified SNVs map to noncoding regions of the genome. Uncovering the causal SNVs and the genes they modulate could help improve GEC prevention and treatment. Here, we used HiChIP against histone 3 lysine 27 acetylation (H3K27ac) to simultaneously annotate active promoters and enhancers, identify the interactions between them, and detect nucleosome free regions (NFRs) harboring potential causal SNVs in a single assay. Application of H3K27Ac HiChIP in GEC relevant models identified 61 potential functional SNVs that reside in NFRs and interact with 49 genes at 17 loci. The approach led to a 67% reduction in the number of SNVs in linkage disequilibrium at these 17 loci, and at seven loci a single putative causal SNV was identified. One SNV, rs147518036, located within the promoter of the UDP-glucuronate decarboxylase 1 (UXS1) gene appeared to underlie the GEC risk association captured by the rs75460256 index SNV. The rs147518036 SNV creates a GABPA DNA recognition motif, resulting in increased promoter activity, and CRISPR-mediated inhibition of the UXS1 promoter reduced viability of GEC cells. These findings provide a framework that simplifies the identification of potentially functional regulatory SNVs and target genes underlying risk-associated loci. In addition, the study implicates increased expression of the enzyme UXS1 and activation of its metabolic pathway as a predisposition to gastric cancer, which highlights potential therapeutic avenues to treat this disease.

ERAS following Gastrectomy for Octo- and Nonagenarians: A Single-Center Retrospective Analysis.

Background: The safety and efficacy of enhanced recovery after surgery (ERAS) following elective gastrectomy for gastric cancer in patients >80 years of age are not well described. The aim of this study was to explore whether an ERAS protocol following gastrectomy in this age group can be safely implemented and reduce postoperative length of stay. Methods: A retrospective, single-center analysis was performed. All patients >80 years of age with gastric cancer undergoing elective subtotal and total gastrectomy between January 2010 and December 2021 were identified. With the implementation of an ERAS protocol in January 2016, patients treated beforehand were allocated to Group A (pre-ERAS) and Group B (ERAS). The length of stay, incidence of postoperative complications and representation/readmission to the hospital were compared between the groups. Results: Of the 221 patients identified, 56 met the inclusion criteria with 22 patients (39.3%) allocated to Group A and 34 patients (60.7%) to Group B. There were no differences with regard to the type of resection and surgical approach. Length of stay was shorter in Group B (5 days, range 2-27 versus 10 days, 3-109, P = .040). A trend toward more discharges by postoperative day 3 was noted among patients in Group B (7/34, 20.6% versus 2/22, 9.1%, P = .253). There were no differences in the incidence of postoperative complications or readmission hospital between the groups. Conclusion: Among patients >80 years of age, ERAS following gastrectomy for cancer is associated with a reduced length of stay and can be safely implemented.

Enhanced recovery after surgery after radical gastrectomy: Improved compliance over time is associated with a shorter postoperative hospital stay.

BACKGROUND: Changing adherence over time to enhanced recovery after surgery (ERAS) protocols following radical gastrectomy and the impact this has on length of stay (LoS) is not well described. This study aimed to explore the changes in adherence to core ERAS elements over time and the relationship between compliance and LoS. METHODS: A retrospective, single center cohort study was performed between 01/2016-12/2021. An ad hoc analysis revealed the point at which a significant difference in the number of patients being discharge on postoperative day (PoD) 3 was noted allowing allocation of patients to Group A (01/2016-12/2019) or B (01/2020-12/2021). Compliance with core ERAS elements was compared and the relationship between compliance and discharge by (PoD) 3 assessed. Variables significant on univariate analysis were assessed using binary multivariate regression. RESULTS: Of the 268 patients identified, 187 met the inclusion criteria (Group A 112 and Group B 75). More patients in Group B mobilized on PoD 1 (60.0 vs. 31.3%, p = <0.001), tolerated postgastrectomy diet by PoD 3 (84.6 vs. 62.5%, p = 0.049), and were discharged by PoD 3 (34.7 vs. 20.5%, p = 0.002). Protocol compliance of >75% was associated with discharge on PoD 3 (area under the curve, 0.726). Active mobilization on PoD 1 (OR 3.5, p = 0.009), compliance ≥75% (OR 3.3, p = 0.036), and preoperative nutritional consult (OR 0.2, p = 0.002) were independently associated with discharge on PoD 3. Discharge on PoD 3 did not increase readmission or representation to hospital. CONCLUSION: Early mobilization, protocol compliance >75%, and preoperative nutritional consult were associated with discharge on PoD 3 after radical gastrectomy.

Survival in esophageal cancer with nonregional lymphadenopathy: a propensity score-matched analysis.

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.

Influence of Neoadjuvant Immunotherapy-Chemotherapy on Perioperative Outcomes in Locally Advanced Esophageal Adenocarcinoma.

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.

Transitioning to Neoadjuvant Therapy for Resectable Non-Small Cell Lung Cancer: Trends and Surgical Outcomes in a Regionalized Pulmonary Oncology Network.

BACKGROUND: Several regulatory agencies have approved the use of the neoadjuvant chemo-immunotherapy for resectable stage II and III of non-small cell lung cancer (NSCLC) and numerous trials investigating novel agents are underway. However, significant concerns exist around the feasibility and safety of offering curative surgery to patients treated within such pathways. The goal in this study was to evaluate the impact of a transition towards a large-scale neoadjuvant therapy program for NSCLC. METHODS: Medical charts of patients with clinical stage II and III NSCLC who underwent resection from January 2015 to December 2020 were reviewed. The primary outcome was perioperative complication rate between neoadjuvant-treated versus upfront surgery patients. Multivariable logistic regression estimated occurrence of postoperative complications and overall survival was assessed as an exploratory secondary outcome by Kaplan-Meier and Cox-regression analyses. RESULTS: Of the 428 patients included, 106 (24.8%) received neoadjuvant therapy and 322 (75.2%) upfront surgery. Frequency of minor and major postoperative complications was similar between groups (P = .22). Occurrence in postoperative complication was similar in both cohort (aOR = 1.31, 95% CI 0.73-2.34). Neoadjuvant therapy administration increased from 10% to 45% with a rise in targeted and immuno-therapies over time, accompanied by a reduced rate of preoperative radiation therapy use. 1-, 2-, and 5-year overall survival was higher in neoadjuvant therapy compared to upfront surgery patients (Log-Rank P = .017). CONCLUSIONS: No significant differences in perioperative outcomes and survival were observed in resectable NSCLC patients treated by neoadjuvant therapy versus upfront surgery. Transition to neoadjuvant therapy among resectable NSCLC patients is safe and feasible from a surgical perspective.

Esophagectomy versus observation following endoscopic submucosal dissection of pT1b esophageal adenocarcinoma.

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.

Transabdominal Management of Epiphrenic Diverticula in the Setting of Achalasia: A Single-center Review.

BACKGROUND: The perioperative and functional outcomes of patients with epiphrenic diverticula (ED) on a background of achalasia managed via a minimally invasive transabdominal approach are under-reported. We describe our center's experience over 10 years of treating such patients. METHODS: A single-center, retrospective chart of a prospectively maintained hospital database was performed. All patients with a diagnosis of ED and manometrically proven achalasia were identified. Demographic, clinical, and surgical data were extracted from the institution's medical records. Patients were stratified by whether they underwent myotomy only or myotomy plus diverticulectomy and compared in a univariate manner. RESULTS: There were 18 patients who met the inclusion criteria. The median age of the cohort was 67.1 years (range 53.1 to 77.8), the maximal size of the diverticula was 3.5 cm (range 2.0 to 7.0), and the distance of the proximal lip of the diverticulum to the incisors was 33.5 cm (range 28.0 to 38.0). In terms of surgical intervention, 14 patients (77.8%) underwent myotomy plus diverticulectomy, and 4 (22.2%) underwent myotomy alone. The duration of surgery was significantly longer in the former (177.5 vs. 75.0 min, P =0.031). In total, 9/18 (50.0%) of patients were discharged on the day of surgery. There was a trend to more major postoperative complications following diverticulectomy plus myotomy, with 2/13 (15.4%) patients suffering staple line leaks. Excellent long-term functional outcomes were achieved, with 81.3% of patients having sustained resolution of their symptoms. CONCLUSIONS: Laparoscopic transabdominal approach for the treatment of ED offers an acceptable risk profile and favorable functional outcomes in patients with underlying achalasia.

Tumour extracellular vesicles induce neutrophil extracellular traps to promote lymph node metastasis.

Lymph nodes (LNs) are frequently the first sites of metastasis. Currently, the only prognostic LN assessment is determining metastatic status. However, there is evidence suggesting that LN metastasis is facilitated by the formation of a pre-metastatic niche induced by tumour derived extracellular vehicles (EVs). Therefore, it is important to detect and modify the LN environmental changes. Earlier work has demonstrated that neutrophil extracellular traps (NETs) can sequester and promote distant metastasis. Here, we first confirmed that LN NETs are associated with reduced patient survival. Next, we demonstrated that NETs deposition precedes LN metastasis and NETs inhibition diminishes LN metastases in animal models. Furthermore, we discovered that EVs are essential to the formation of LN NETs. Finally, we showed that lymphatic endothelial cells secrete CXCL8/2 in response to EVs inducing NETs formation and the promotion of LN metastasis. Our findings reveal the role of EV-induced NETs in LN metastasis and provide potential immunotherapeutic vulnerabilities that may occur early in the metastatic cascade.

Postoperative Outcomes and Quality of Life After Left Thoracoabdominal Esophagogastrectomy: Contrasting Esophagogastrostomy with Esophagojejunostomy.

BACKGROUND: Following left thoracoabdominal (LTA) esophagogastrectomy, gastrointestinal continuity can be re-established via esophagogastrostomy or esophagojejunostomy. We explored how the method of reconstruction impacted postoperative outcomes and quality of life (QoL). METHODS: From January 2007 to January 2022, patients undergoing LTA were identified from a single center's prospectively maintained database. Following esophagogastrectomy or extended total gastrectomy, an esophagogastrostomy (GAS) or Roux-en-Y esophagojejunostomy (R-Y) was fashioned. Postoperative outcomes were compared according to the method of reconstruction. The Functional Assessment of Cancer Therapy-Esophagus (FACT-E) questionnaire compared QoL. RESULTS: Of the 147 LTA patients identified, 135 (92%) were included-97 GAS (72%) and 38 R-Y patients (28%). R-Y patients had more ypT3/4 lesions (97% vs. 61%, p ≤ 0.001) and a similar incidence of ypN+/M+ disease. Anastomotic leaks were more common among GAS patients (17% vs. 3%, p = 0.023), however grade 3/4 complications (26.6% vs. 19.4%, p = 0.498), reoperation, intensive care admission, hospital representation and readmission were similar. FACT-E data were available for 68/97 (70%) GAS patients and 22/38 (58%) R-Y patients, with scores for 80/21/24/18/23/24 patients at baseline/preoperatively/1 month/3-6 months/1-3 years/3+ years postoperatively, respectively. Comparing between the groups, the scores were similar at each timepoint. FACT-E improved between baseline and preoperatively (79, 34-124 vs. 102, 81-123, p = 0.027). Only at 3+ years were postoperative scores equivalent to preoperative values. GAS patients had more reflux and esophagitis >6 months postoperatively (54% vs. 13%, p = 0.048; 62% vs. 0%, p ≤ 0.001). CONCLUSION: While the type of reconstruction did not affect QoL, it did affect the postoperative course.

Survival and perioperative outcomes of octo- and nonagenarians with resectable esophageal carcinoma.

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.

Remoteness from urban centre does not affect gastric cancer outcomes with established care pathway to specialist centre.

BACKGROUND: Patients living in rural communities experience difficulty accessing specialized medical care. Rural patients with cancer present with more advanced disease, have reduced access to treatment and have poorer overall survival than urban patients. This study's aim was to evaluate outcomes of patients with gastric cancer living in rural and remote areas versus urban and suburban communities in the context of an established care corridor to a tertiary care centre. METHODS: All patients treated for gastric cancer at the McGill University Health Centre during 2010-2018 were included. Travel, lodging and cancer care coordination were provided for patients from remote and rural areas and coordinated centrally by dedicated nurse navigators servicing these regions. Statistics Canada's remoteness index was used to categorize patients into a rural and remote group and an urban and suburban group. RESULTS: A total of 274 patients were included. Compared with patients from urban and suburban areas, patients from rural and remote areas were younger and their clinical tumour stage was higher at presentation. The number of curative resections and palliative surgeries and rate of nonresection were comparable (p = 0.96). Overall, disease-free and progression-free survival were comparable between the groups, and having locally advanced cancer correlated with poorer survival (p < 0.001). CONCLUSION: Although patients with gastric cancer from rural and remote areas had more advanced disease at presentation, their treatment patterns and survival were comparable to those of patients from urbanized areas in the context of a publicly funded care corridor to a multidisciplinary specialist cancer centre. Equitable access to health care is necessary to diminish any preexisting disparities among patients with gastric cancer.

The 8th Edition TNM Stage Reclassification of T4 Non-Small Cell Lung Cancer: A Granular Examination of Short and Long-Term Outcomes.

INTRODUCTION: Whilst the American Joint Committee on Cancer 7th edition (AJCC7) classified pT4 non-small-cell lung cancers (NSCLC) as those with extra-pulmonary invasion, the revised 8th edition (AJCC8) included tumors > 7cm regardless of extra-pleural spread. We examined perioperative and long-term outcomes of classical T4 definitions with patients whose tumors were greater than 7cm without extra-pulmonary invasion. MATERIALS AND METHODS: A retrospective single center cohort study was performed. All consecutive patients with pT4 lesions between 2011 and 2018 were identified based on either the AJCC7 or AJCC8 classification. Clinicopathological variables were extracted and compared in a univariate manner. A multivariate Cox regression analysis was performed to assess factors associated with overall survival. RESULTS: Forty patients were allocated to AJCC7 and 118 to AJCC8. Patients in the former were more likely to have positive lymph nodes, synchronous metastasis, multifocal disease and lymphovascular invasion. AJCC7 patients were more likely to undergo pneumonectomy despite significantly more being treated with neoadjuvant therapy. Ninety-day mortality was higher in the AJCC7 group. There was no difference in long-term overall survival. On multivariate analysis male gender, squamous cell histology and increasing tumor size were associated with an increased risk of death. CONCLUSION: Although long-term outcomes were similar, the heterogenicity within the AJCC8 classification emphasizes the need to contextualize the perioperative outcomes for patients with pT4 NSCLC. These data are important for future iterations of the TNM classification in view of emerging neoadjuvant options for patients with cT4 operable NSCLC.

Locoregional Recurrence of Esophageal Cancer Treated with Curative Intent Local Salvage Therapy: A Single Center Experience.

PURPOSE: Locoregional recurrence of esophageal carcinoma after neoadjuvant therapy and en bloc esophagectomy, although uncommon, is challenging to manage. Currently, there are no standard treatment approaches prompting many health care providers to adopt a palliative approach. We describe our experience and outcomes of treating this specific group of patients with a focus on salvage curative intent local therapy. METHODS: All patients undergoing en bloc esophagectomy following neoadjuvant therapy between 2007 and 2017 at the McGill University Health Centre, a tertiary referral center for esophageal cancer, were identified. Patient follow-up included a structured surveillance protocol with serial endoscopic and cross-sectional imaging studies. Local recurrence was defined as histologically confirmed recurrences at the anastomosis. Regional recurrence was defined as radiological evidence of celiac, mediastinal, or para-esophageal/conduit lymphadenopathy. Demographic, pathologic, therapeutic variables were extracted as well as disease free and overall survival. RESULTS: Of 755 patients identified, locoregional recurrences occurred in 27 patients (3.6%) of whom 18 were included in the analysis. The median disease-free survival post index operation was 15 months (IQR 10-23). The sites of recurrence were local (6/18, 33.3%); regional (8/18, 44.4%); and locoregional (4, 22.2%). Chemoradiation was the most common modality used to treat recurrence (10/18, 55.6%) whilst 4 (22.2%) underwent surgery. Following treatment for locoregional recurrence, 1-year overall survival was 61.1% and at 5 years was 22.2%. CONCLUSION: Consolidative salvage local therapy for locoregional recurrence after en bloc esophagectomy is feasible and can entail prolonged survival in a subset of patients.

Relation between mismatch repair status, chemoresponse, survival and anatomic location in gastroesophageal adenocarcinoma.

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.

Soluble factors in malignant ascites promote the metastatic adhesion of gastric adenocarcinoma cells.

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.