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.

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.

Neutrophil Extracellular Trap-Associated CEACAM1 as a Putative Therapeutic Target to Prevent Metastatic Progression of Colon Carcinoma.

Neutrophils promote tumor growth and metastasis at multiple stages of cancer progression. One mechanism through which this occurs is via release of neutrophil extracellular traps (NETs). We have previously shown that NETs trap tumor cells in both the liver and the lung, increasing their adhesion and metastasis following postoperative complications. Multiple studies have since shown that NETs play a role in tumor progression and metastasis. NETs are composed of nuclear DNA-derived web-like structures decorated with neutrophil-derived proteins. However, it is unknown which, if any, of these NET-affiliated proteins is responsible for inducing the metastatic phenotype. In this study, we identify the NET-associated carcinoembryonic Ag cell adhesion molecule 1 (CEACAM1) as an essential element for this interaction. Indeed, blocking CEACAM1 on NETs, or knocking it out in a murine model, leads to a significant decrease in colon carcinoma cell adhesion, migration and metastasis. Thus, this work identifies NET-associated CEACAM1 as a putative therapeutic target to prevent the metastatic progression of colon carcinoma.

Overall Volume Trends in Esophageal Cancer Surgery Results From the Dutch Upper Gastrointestinal Cancer Audit.

OBJECTIVE: In the pursuit of quality improvement, this study aimed to investigate volume-outcome trends in oncologic esophagectomy in the Netherlands. SUMMARY OF BACKGROUND DATA: Concentration of Dutch esophageal cancer care was dictated by introducing an institutional minimum of 20 resections/yr. METHODS: This nationwide cohort study included all esophagectomy patients registered in the Dutch Upper Gastrointestinal Cancer Audit in 2016-2019 from hospitals currently still performing esophagectomies. Annual esophagectomy hospital volume was assigned to each patient and categorized into quartiles. Multivariable logistic regression investigated short-term surgical outcomes. Restricted cubic splines investigated if volume-outcome relationships eventually plateaued. RESULTS: In 16 hospitals, 3135 esophagectomies were performed. First volume quartile hospitals performed 24-39 resections/yr; second, third, and fourth quartile hospitals performed 40-53, 54-69, and 70-101, respectively. Compared to quartile 1, in quartiles 2 to 4, overall/severe/technical complication, anastomotic leakage, and prolonged hospital/intensive care unit stay rates were significantly lower and textbook outcome and lymph node yield were higher. When raising the cut-off from the first to second quartile, higher-volume centers had less technical complications [Adjusted odds ratio (aOR): 0.82, 95% confidence interval (CI): 0.70-0.96], less anastomotic leakage (aOR: 0.80, 95% CI: 0.66-0.97), more textbook outcome (aOR: 1.25, 95% CI: 1.07-1.46), shorter intensive care unit stay (aOR: 0.80, 95% CI: 0.69-0.93), and higher lymph node yield (aOR: 3.56, 95% CI: 2.68-4.77). For most outcomes the volume-outcome trend plateaued at 50-60 annual resections, but lymph node yield and anastomotic leakage continued to improve. CONCLUSION: Although this study does not reflect on individual hospital quality, there appears to be a volume trend towards better outcomes in high-volume centers. Projects have been initiated to improve national quality of care by reducing hospital variation (irrespective of volume) in outcomes in The Netherlands.

FLOT-regimen Chemotherapy and Transthoracic en bloc Resection for Esophageal and Junctional Adenocarcinoma.

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.

The Effect of Preoperative Anemia and Perioperative Transfusion on Surgical Outcomes After Gastrectomy for Gastric Cancer.

BACKGROUND: The aim of this study is to examine the interaction between preoperative anemia and perioperative transfusions with postoperative morbidity and mortality among patients undergoing gastrectomy for cancer. MATERIALS AND METHODS: The American College of Surgeons National Surgical Quality Improvement Program database was queried from 2005 to 2016. Restricted cubic splines modeled the nonlinear relationship between preoperative hematocrit (Hct) and 30-day overall morbidity, sepsis, and mortality. Preoperative Hct was categorized based on cut points for the three models. Multiple regression modeling examined the interactive effect of preoperative anemia and postoperative transfusion on surgical outcomes. RESULTS: Among 9936 included patients, complication incidence was 38.9% (sepsis 12.7%; mortality 6.0%). Preoperative Hct cut points were identified at 29 and 42. Hct <29 was associated with higher risk of morbidity (OR 2.47, 95%CI 2.10-2.93). Postoperative transfusion was associated with lower risk of morbidity for Hct <29 (OR 0.56, 95%CI 0.43-0.73) but increased risk between 29 and 42 (OR 1.59, 95%CI 1.21-2.08). Similar relationships were found for sepsis and mortality. CONCLUSIONS: Preoperative Hct <29 is associated with an increased risk of surgical complications after gastrectomy for cancer and perioperative transfusions appear to be beneficial for Hct <29 only. There may be a role for better optimization of red cell mass among high-risk patients before gastrectomy for cancer.

Transition from open to minimally invasive en bloc esophagectomy can be achieved without compromising surgical quality.

BACKGROUND: En bloc esophagectomy results in higher lymph node (LN) retrieval than standard esophagectomy. Minimally invasive esophagectomy (MIE) has gained traction due to improved short-term outcomes, but many large series report LN yields well below the international benchmark of 23. We sought to determine if an established approach to open en bloc resection can be safely transferred to MIE using LN yield as a quality benchmark. METHODS: An open approach to en bloc esophagectomy (OE) was established over 5 years (~ 300 cases) before en bloc MIE was introduced in 2010. Patients undergoing curative-intent en bloc Ivor-Lewis and McKeown esophagectomy for cancer from 2010 to 2019 by a single surgeon with formal minimally invasive surgery training were identified from a prospectively collected database. Mann-Whitney U and χ2 tests and cumulative sum analysis were used for statistical analysis. "Failure" was defined as LN yield less than AJCC's 8th edition guidelines: 10 LNs for pT1 cancers, 20 for pT2 and 30 for pT3-4. RESULTS: A total of 269 esophageal resections met inclusion criteria [193(72%) OE; 76(28%) MIE]. Age, sex, BMI and comorbidities were comparable between groups. Tumors were larger and more often locally advanced in OE. Median LN retrieval was sufficient by international standards in both groups [OE:34(27-46); MIE:28(22-39); p = 0.01]. "Failures" occurred in 33(17%) of OE and 12(16%) MIE cases (p = 0.63). No learning effect was observed for LN yield. R0 resection rate was comparable [OE:191(99%); MIE:73(96%); p = 0.90]. Operative time was longer for MIE [275(246-300)] than OE [240(210-270) minutes], p < 0.0001, while estimated blood loss (OE:350(250-500)mL; MIE:300(200-400)mL; p = 0.02] and length of stay [OE:8(6-13); MIE7(6-9) days; p = 0.02] were higher for OE. Morbidity and mortality were comparable between groups and LN yield did not impact survival. CONCLUSIONS: Under appropriate conditions, an established approach to open en bloc esophagectomy can be safely transferred to MIE without compromising surgical quality.

Early diagnosis is associated with improved clinical outcomes in benign esophageal perforation: an individual patient data meta-analysis.

BACKGROUND: Time of diagnosis (TOD) of benign esophageal perforation is regarded as an important risk factor for clinical outcome, although convincing evidence is lacking. The aim of this study is to assess whether time between onset of perforation and diagnosis is associated with clinical outcome in patients with iatrogenic esophageal perforation (IEP) and Boerhaave's syndrome (BS). METHODS: We searched MEDLINE, Embase and Cochrane library through June 2018 to identify studies. Authors were invited to share individual patient data and a meta-analysis was performed (PROSPERO: CRD42018093473). Patients were subdivided in early (≤ 24 h) and late (> 24 h) TOD and compared with mixed effects multivariable analysis while adjusting age, gender, location of perforation, initial treatment and center. Primary outcome was overall mortality. Secondary outcomes were length of hospital stay, re-interventions and ICU admission. RESULTS: Our meta-analysis included IPD of 25 studies including 576 patients with IEP and 384 with BS. In IEP, early TOD was not associated with overall mortality (8% vs. 13%, OR 2.1, 95% CI 0.8-5.1), but was associated with a 23% decrease in ICU admissions (46% vs. 69%, OR 3.0, 95% CI 1.2-7.2), a 22% decrease in re-interventions (23% vs. 45%, OR 2.8, 95% CI 1.2-6.7) and a 36% decrease in length of hospital stay (14 vs. 22 days, p < 0.001), compared with late TOD. In BS, no associations between TOD and outcomes were found. When combining IEP and BS, early TOD was associated with a 6% decrease in overall mortality (10% vs. 16%, OR 2.1, 95% CI 1.1-3.9), a 19% decrease in re-interventions (26% vs. 45%, OR 1.9, 95% CI 1.1-3.2) and a 35% decrease in mean length of hospital stay (16 vs. 22 days, p = 0.001), compared with late TOD. CONCLUSIONS: This individual patient data meta-analysis confirms the general opinion that an early (≤ 24 h) compared to a late diagnosis (> 24 h) in benign esophageal perforations, particularly in IEP, is associated with improved clinical outcome.

Modern era surgical outcomes of elective and emergency giant paraesophageal hernia repair at a high-volume referral center.

INTRODUCTION: Repair of giant paraesophageal hernia (PEH) has historically been associated with significant morbidity and mortality such that elective repair is only offered to symptomatic patients. Recent reports suggest modern era outcomes have improved such that elective repair may now be safer than historically thought. Furthermore, the morbidity of emergency surgery may still be significant. These changes may have important implications for patient selection for elective repair. The objectives of this study were to determine and compare modern era surgical outcomes after elective and emergency repair of giant PEHs at a high-volume tertiary care center. METHODS: A retrospective review was conducted for all Type II-IV giant PEH repairs performed between 1 January 2012 and 31 December 2017. Type 1 hiatal hernias, fundoplication for reflux, and any co-surgery other than cholecystectomy were excluded from the final analysis. Baseline patient demographics, operative details, postoperative complications within 30 days and in-hospital or 30-day mortality were tabulated from the electronic medical record. Data were reported as median (interquartile range) unless otherwise specified. RESULTS: A total of 352 cases were reviewed, of which 204 met inclusion criteria (18 emergency, 186 elective). Eight had Type II PEH, 146 had Type III, and 50 had Type IV. Median length of stay was shorter in the elective group [1 (1) day elective vs. 5 (7) days emergency, p < 0.0001], and emergency patients were less likely to return directly to their original residence at discharge (13, 72% emergency vs 185, 99.4% elective, p < 0.0001). There were significantly more major complications (Clavien-Dindo score ≥ 3) in the emergency group (5, 28% emergency vs. 10, 5% elective, p = 0.005). There were no perioperative deaths in either group. Morbidity and mortality in both groups were less than historically reported. CONCLUSIONS: Informed consent discussions and patient selection for repair of giant PEHs should reflect modern era and institution-specific outcomes.

Same day discharge for benign laparoscopic hiatal surgery: a feasibility analysis.

BACKGROUND: Advances in minimally invasive surgery and the development of enhanced recovery pathways have favored the spread of day-surgery programs. Despite laparoscopic approaches being accepted as the standard of care for benign hiatal diseases, safety and feasibility of same day discharges for laparoscopic hiatal surgeries other than fundoplication has yet to be established. OBJECTIVE: This study aimed to assess the feasibility of same day discharge for primary and revisional laparoscopic hiatal surgeries including paraesophageal hernia repairs (PEHR), fundoplication for reflux, and Heller myotomy (±diverticulectomy). METHODS: A retrospective cohort study including all patients undergoing elective laparoscopic hiatal procedures in the division of Thoracic surgery between 2011 and 2016 at McGill University Health Centre was performed. Planned day-surgery (DAYCASE) was compared to planned inpatient (INPATIENT) cohorts with respect to operative and postoperative outcomes, length of stay, readmission, and emergency room visits. RESULTS: A total of 261 patients were identified, 161 female (62%); median age 62 (20). The case distribution was: PEHR (123; 47.1%), Heller myotomy (94;36%, 7 diverticulectomy), and fundoplication (44; 16.9%). Twenty patients had revisional procedures (7.7%). Same day discharge was planned in 98 cases (38%) and was successful in 80 (81.6%). Proportion of DAYCASE increased form 12% prior to 2013 to 67% in 2016. INPATIENTs were older (median 66 vs. 60 years), and had a higher proportion of PEHR (55 vs. 34%), p < 0.05. Both cohorts were comparable in gender proportion, ASA classification, and length of surgery. Complications, readmission, and emergency visits did not differ between the two cohorts. On multivariate analysis, female gender (OR 37, 95% CI 1.46-936, p = 0.028), surgery beginning after noon (OR 5.4, 95% CI 1.1-26.9, p = 0.038), intraoperative complications (OR 20.4 95% CI 1.5-286, p = 0.025), and postoperative complications (OR 52.1, 95% CI 4.5-602, p = 0.002) were independently associated with unplanned admission. CONCLUSIONS: Day-case surgery for complex laparoscopic hiatal procedures is feasible and can be achieved in a significant number of patients without compromising safety.

Neutrophil extracellular traps sequester circulating tumor cells via ß1-integrin mediated interactions.

Despite advances in cancer treatment, metastasis remains today the main cause of cancer death. Local control through complete surgical resection of the primary tumor continues to be a key principle in cancer treatment. However, surgical interventions themselves lead to adverse oncologic outcomes and are associated with significantly increased rates of metastasis. Neutrophils through release of neutrophil extracellular traps (NETs) in response to infections were shown to be able to capture circulating cancer cells, and in doing so, support the development of metastatic disease. To be able to intervene on this process, understanding the exact molecular nature of these mechanisms is crucial. We therefore hypothesize and demonstrate that ß1-integrin is an important factor mediating the interactions between circulating tumor cells and NETs. We show that ß1-integrin expression on both cancer cells and NETs is important for the adhesion of circulating tumor cells to NETs both in vitro and in vivo. Using a murine model of intra-abdominal sepsis to mimic the postoperative inflammatory environment, we show that ß1-integrin expression is upregulated in the context of inflammation in vivo. Ultimately, we show that this increased early cancer cell adhesion to NETs in vivo and this effect is abrogated when mice are administered DNAse 1. Our data therefore sheds light on the first molecular mechanism by which NETs can trap circulating tumor cells (CTCs), broadening our understanding of this process.

Gram-positive pneumonia augments non-small cell lung cancer metastasis via host toll-like receptor 2 activation.

Surgical resection of early stage nonsmall cell lung cancer (NSCLC) is necessary for cure. However, rates of postoperative bacterial pneumonias remain high and may confer an increased risk for metastasis. Toll-like receptors (TLRs) mediate the inflammatory cascade by recognizing microbial products at the surface of numerous cell types in the lung; however, little is known about how host TLRs influence NSCLC metastasis. TLR2 recognizes gram-positive bacterial cell wall components activating innate immunity. We demonstrate that lower respiratory tract infection with Streptococcus pneumonia augments the formation of murine H59 NSCLC liver metastases in C57BL/6 mice through host TLR2 activation. Infected mice demonstrate increased H59 and human A549 NSCLC adhesion to hepatic sinusoids in vivo compared with noninfected controls, a response that is significantly diminished in TLR2 knock-out mice. Intra-tracheal injection of purified TLR2 ligand lipoteichoic acid into mice similarly augments in vivo adhesion of H59 cells to hepatic sinusoids. Additionally, H59 and A549 NSCLC cells incubated with bronchoepithelial conditioned media show increased cell adhesion to extracellular matrix components in vitro and hepatic sinusoids in vivo in a manner that is dependent on bronchoepithelial TLR2 activation and interleukin-6 secretion. TLR2 is therefore a potential therapeutic target for gram-positive pneumonia-driven NSCLC metastasis.

Civilian Airway Trauma: A Single-Institution Experience.

BACKGROUND: Injuries to the airway in the neck and thorax are uncommon, but may be potentially life threatening. The objective of this study is to determine the clinical characteristics and outcomes for patients with airway injury. METHODS: From 1974 to 2014, a prospectively entered trauma database at a Level 1 trauma center was accessed to identify patients with injuries to the larynx, cervical trachea, or thoracic airway. Hospital charts were reviewed to obtain data on demographics, presentation, injury management, in-hospital and long-term morbidity and in-hospital mortality. Multivariate logistic regression was used to estimate predictors of mortality and long-term vocal cord morbidity. Data are expressed as N (%). RESULTS: One hundred and twenty patients were included (median injury severity score: 19 [interquartile range: 10-27]). There were 65 (54 %) blunt and 55 (46 %) penetrating injuries, with 90 (75 %) suffering multiple injuries. Sixteen (13 %) patients died from associated injuries (7: in ER; 9: after admission). Injuries were located in the cervical airway [101 (84 %)], thoracic airway [21 (18 %)], or both [2 (2 %)]. Eighty-six (72 %) patients were managed surgically. Predictors of in-hospital mortality included hemodynamic instability (OR 6.54, 95 % CI 1.11-37.14), GCS < 8 upon presentation (OR 4.35, 95 % CI 3.24-5.41), and head trauma (OR 4.10, 95 % CI 1.91-6.30). Fracture of cricoid or thyroid cartilages was a strong predictor of long-term vocal cord injury (OR 3.93, 95 % CI 1.25-12.59). CONCLUSIONS: Airway trauma remains a major challenge for early diagnosis, airway control, and management of both acute life-threatening injury and long-term morbidity.

Gram negative bacteria increase non-small cell lung cancer metastasis via Toll-like receptor 4 activation and mitogen-activated protein kinase phosphorylation.

Surgery is required for the curative treatment of lung cancer but is associated with high rates of postoperative pneumonias predominantly caused by gram negative bacteria. Recent evidence suggests that these severe infectious complications may decrease long term survival after hospital discharge via cancer recurrence, but the mechanism is unclear. Lung cancer cells have recently been demonstrated to express Toll-like receptors (TLR) that mediate pathogen recognition. We hypothesized that incubation of non-small cell lung cancer (NSCLC) cells with heat-inactivated Escherichia coli can augment cancer cell adhesion, migration and metastasis via TLR4 signaling. Incubation of murine and human NSCLC cells with E. coli increased in vitro cell adhesion to collagen I, collagen IV and fibronectin, and enhanced in vitro migration. Using hepatic intravital microscopy, we demonstrated that NSCLC cells have increased in vivo adhesion to hepatic sinusoids after coincubation with gram negative bacteria. These enhanced cell adhesion and migration phenotypes following incubation with E. coli were attenuated at three levels: inhibition of TLR4 (Eritoran), p38 MAPK (BIRB0796) and ERK1/2 phosphorylation (PD184352). Incubation of murine NSCLC cells in vitro with E. coli prior to intrasplenic injection significantly augmented formation of in vivo hepatic metastases 2 weeks later. This increase was abrogated by NSCLC TLR4 blockade using Eritoran. TLR4 represents a potential therapeutic target to help prevent severe postoperative infection driven cancer metastasis.

Functional outcomes and quality of life after proximal gastrectomy with esophagogastrostomy using a narrow gastric conduit.

BACKGROUND: The best surgical approach for tumors of the proximal stomach remains controversial. For proximal gastrectomy (PG), the evidence regarding quality of life (QoL) and functional outcomes is controversial. Moreover, there are limited data from non-Asian settings. METHODS: All patients who underwent PG from September 2005 to July 2013 were identified from an institutional database. Demographic, perioperative and pathologic characteristics were retrieved. Symptom scores (0 = best/4 = worst) for reflux symptoms, dysphagia and validated QoL metrics (FACT scale, where a higher score is better) were assessed during early and late follow-up. Eligible patients for analysis were those with no evidence of recurrence. RESULTS: Of 465 upper gastrointestinal cancer resections, 50 were PG for adenocarcinoma (42; 84%), neuroendocrine carcinoma (5; 10%) or other pathologies (3; 6%). R0 resection was achieved in 44 (89.8%) of 49 patients with malignant tumors. Median lymph node collection was 32 (range 7-57). QoL scores did not differ from preoperative to early follow-up but increased compared to both at late follow-up [preoperative, 125 (interquartile range 105-140); early follow-up, 122.5 (97-142); late follow-up, 147 (132-159); p < 0.05]. At early and late follow-up, 9 (21.4%) of 42 and 10 (33.3%) of 30 patients reported reflux symptoms, but most were mild. Endoscopic signs of esophagitis were found in 7 (29%) of 24 patients, but only two of these reported reflux symptoms. Conversely only three of eight patients with reflux symptoms had esophagitis on endoscopy. CONCLUSIONS: Global QoL is not reduced early after PG, and increases compared to baseline at late follow-up. Although reflux symptoms are reported by a quarter of patients, most are mild, and there is little correlation with esophagitis. PG should remain a viable option in the management of proximal gastric tumors.

Validity of the EuroQol-5 dimensions as a measure of recovery after pulmonary resection.

BACKGROUND: Surgical innovations advocated to improve patient recovery are often costly. Economic evaluation requires preference-based measures that reflect the construct of patient recovery. We investigated the responsiveness and construct validity of the EuroQol-5 dimensions (EQ-5D) as a measure of postoperative recovery after planned pulmonary resection for suspected malignant tumors. METHODS: Patients undergoing pulmonary resection completed the EQ-5D questionnaire and visual analog scales (VAS) for pain and fatigue at baseline (preoperatively) and at 1 and 3 mo postoperatively. Responsiveness and construct validity (discriminant and convergent) were investigated by testing a priori hypotheses. RESULTS: Fifty-five patients were analyzed (45% male, 62 ± 12 y, 29% video-assisted). There was no significant difference between median EQ-5D scores obtained at baseline (0.83 [interquartile range {IQR 0.80-1}]) compared to scores at 1 mo (0.83 [0.80-1], P = 0.86) and 3 mo after surgery (1 [0.83-1]; P = 0.09). At 1 mo after surgery, EQ-5D scores were significantly lower in patients undergoing thoracotomy versus video-assisted surgery (0.82 [IQR 0.77-0.89] versus 1 [0.83-1], P = 0.003), but there were no significant differences between patients ≥ 70-y old versus younger (0.95 [IQR 0.82-1] versus 0.83 [0.77-1], P = 0.09) or between patients with versus without complications (0.82 [IQR 0.79-0.95] versus 0.83 [0.80-1], P = 0.10). There was a low but significant correlation between EQ-5D and VAS scores of pain and fatigue (Rho -0.30 to -0.47, P ≤ 0.01). CONCLUSIONS: Despite evidence of convergent validity, the EQ-5D was not sensitive to the hypothesized trajectory of postoperative recovery and showed limited discriminant validity. This study suggests that the EQ-5D may not be appropriate to value recovery after lung resection.

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.

A Video-Based Procedure-Specific Competency Assessment Tool for Minimally Invasive Esophagectomy.

Importance: Minimally invasive esophagectomy (MIE) is a complex procedure with substantial learning curves. In other complex minimally invasive procedures, suboptimal surgical performance has convincingly been associated with less favorable patient outcomes as assessed by peer review of the surgical procedure. Objective: To develop and validate a procedure-specific competency assessment tool (CAT) for MIE. Design, Setting, and Participants: In this international quality improvement study, a procedure-specific MIE-CAT was developed and validated. The MIE-CAT contains 8 procedural phases, and 4 quality components per phase are scored with a Likert scale ranging from 1 to 4. For evaluation of the MIE-CAT, intraoperative MIE videos performed by a single surgical team in the Esophageal Center East Netherlands were peer reviewed by 18 independent international MIE experts (with more than 120 MIEs performed). Each video was assessed by 2 or 3 blinded experts to evaluate feasibility, content validity, reliability, and construct validity. MIE-CAT version 2 was composed with refined content aimed at improving interrater reliability. A total of 32 full-length MIE videos from patients who underwent MIE between 2011 and 2020 were analyzed. Data were analyzed from January 2021 to January 2023. Exposure: Performance assessment of transthoracic MIE with an intrathoracic anastomosis. Main Outcomes and Measures: Feasibility, content validity, interrater and intrarater reliability, and construct validity, including correlations with both experience of the surgical team and clinical parameters, of the developed MIE-CAT. Results: Experts found the MIE-CAT easy to understand and easy to use to grade surgical performance. The MIE-CAT demonstrated good intrarater reliability (range of intraclass correlation coefficients [ICCs], 0.807 [95% CI, 0.656 to 0.892] for quality component score to 0.898 [95% CI, 0.846 to 0.932] for phase score). Interrater reliability was moderate (range of ICCs, 0.536 [95% CI, -0.220 to 0.994] for total MIE-CAT score to 0.705 [95% CI, 0.473 to 0.846] for quality component score), and most discrepancies originated in the lymphadenectomy phases. Hypothesis testing for construct validity showed more than 75% of hypotheses correct: MIE-CAT performance scores correlated with experience of the surgical team (r = 0.288 to 0.622), blood loss (r = -0.034 to -0.545), operative time (r = -0.309 to -0.611), intraoperative complications (r = -0.052 to -0.319), and severe postoperative complications (r = -0.207 to -0.395). MIE-CAT version 2 increased usability. Interrater reliability improved but remained moderate (range of ICCs, 0.666 to 0.743), and most discrepancies between raters remained in the lymphadenectomy phases. Conclusions and Relevance: The MIE-CAT was developed and its feasibility, content validity, reliability, and construct validity were demonstrated. By providing insight into surgical performance of MIE, the MIE-CAT might be used for clinical, training, and research purposes.

Cost-effectiveness of minimally invasive versus open esophagectomy for esophageal cancer.

BACKGROUND: A recent randomized trial comparing minimally invasive (MIE) and open esophagectomy for esophageal cancer reported improved short-term outcomes. However, MIE has increased operative costs, and it is unclear whether the short-term benefits of MIE outweigh the increased operative costs. Therefore, the objective of this study was to determine the cost-effectiveness of MIE compared to open esophagectomy for esophageal cancer. METHODS: A decision-analysis model was developed to estimate the expected costs and outcomes after MIE and open esophagectomy from a health care system perspective with a time horizon of 1 year. Costs were represented in 2012 Canadian dollars, and effectiveness was measured in quality-adjusted life-years (QALYs). Probabilistic sensitivity analysis assessed parameter uncertainty. RESULTS: MIE was estimated to cost $1641 (95% confidence interval 1565, 1718) less than open esophagectomy, with an incremental gain of 0.022 QALYs (95% confidence interval 0.021, 0.023). MIE was therefore dominant over open esophagectomy. On deterministic sensitivity analyses, the results were most sensitive to variations in length of stay. Probabilistic sensitivity analysis demonstrated the robustness of the base case result, with 66, 77, and 82% probabilities of cost-effectiveness at willingness-to-pay thresholds of $0/QALY, $50,000/QALY, and $100,000/QALY, respectively. CONCLUSIONS: MIE is cost-effective compared to open esophagectomy in patients with resectable esophageal cancer.

Concerted epithelial and stromal changes during progression of Barrett's Esophagus to invasive adenocarcinoma exposed by multi-scale, multi-omics analysis.

Esophageal adenocarcinoma arises from Barrett's esophagus, a precancerous metaplastic replacement of squamous by columnar epithelium in response to chronic inflammation. Multi-omics profiling, integrating single-cell transcriptomics, extracellular matrix proteomics, tissue-mechanics and spatial proteomics of 64 samples from 12 patients' paths of progression from squamous epithelium through metaplasia, dysplasia to adenocarcinoma, revealed shared and patient-specific progression characteristics. The classic metaplastic replacement of epithelial cells was paralleled by metaplastic changes in stromal cells, ECM and tissue stiffness. Strikingly, this change in tissue state at metaplasia was already accompanied by appearance of fibroblasts with characteristics of carcinoma-associated fibroblasts and of an NK cell-associated immunosuppressive microenvironment. Thus, Barrett's esophagus progresses as a coordinated multi-component system, supporting treatment paradigms that go beyond targeting cancerous cells to incorporating stromal reprogramming.