Early life stress, low-grade systemic inflammation and weaker suppression of the default mode network (DMN) during face processing in Schizophrenia.

Childhood trauma (CT) is associated with lower cognitive and social cognitive function in schizophrenia. Recent evidence suggests that the relationship between CT and cognition is mediated by both low-grade systemic inflammation and reduced connectivity of the default mode network (DMN) during resting state. This study sought to test whether the same pattern of associations was observed for DMN connectivity during task based activity. Fifty-three individuals with schizophrenia (SZ) or schizoaffective disorder (SZA) and one hundred and seventy six healthy participants were recruited from the Immune Response and Social Cognition (iRELATE) project. A panel of pro-inflammatory markers that included IL-6, IL-8, IL-10, tumour necrosis factor-alpha (TNFa), and C-reactive protein (CRP), were measured in plasma using ELISA. DMN connectivity was measured during an fMRI social cognitive face processing task. Patients showed evidence of low grade systemic inflammation and significantly increased connectivity between the left lateral parietal (LLP) cortex-cerebellum and LLP-left angular gyrus compared to healthy participants. Across the entire sample, IL-6 predicted increased connectivity between LLP-cerebellum, LLP-precuneus, and mPFC-bilateral-precentral-gyri and left postcentral gyrus. In turn, and again in the entire sample, IL-6 (but no other inflammatory marker) mediated the relationship between childhood physical neglect and LLP-cerebellum. Physical neglect scores also significantly predicted the positive association between IL-6 and LLP-precuneus connectivity. This is to our knowledge the first study that provides evidence that higher plasma IL-6 mediates the association between higher childhood neglect and increased DMN connectivity during task based activity. Consistent with our hypothesis, exposure to trauma is associated with weaker suppression of the DMN during a face processing task, and this association was mediated via increased inflammatory response. The findings may represent part of the biological mechanism by which CT and cognitive performance are related.

Incidence and Impact of Non-alcoholic Fatty Liver Disease (NAFLD) in Patients with Adenocarcinoma of the Esophagus Treated with Curative Intent.

BACKGROUND AND AIMS: Esophageal adenocarcinoma (EAC) is associated with visceral obesity (VO). Non-alcoholic fatty liver disease (NAFLD) is common within this phenotype; however, its incidence and clinical significance in EAC have not been studied. STUDY DESIGN: A total of 559 patients with hepatic stetatosis (HS) defined by unenhanced CT were enrolled. In a sub-study, in 140 consecutive patients a liver biopsy was taken intraoperatively to study HS and non-alcoholic steatohepatitis (NASH). Postoperative complications were defined as per the Esophageal Complications Consensus Group (ECCG). Liver biochemistry was measured peri-operatively, with an ALT > 5 defined as acute liver injury (ALI). Mann-Whitney U test or Fisher's exact test was utilized and the Kaplan-Meier method for survival. RESULTS: 42% (n = 234/559) of patients had CT-defined HS. HS was associated with VO in 56% of cases, metabolic syndrome (Met S) in 37% and type 2 diabetes in 25%, compared with 44, 21, and 15% in non-HS patients (p < 0.01). Pathologic HS was present in 32% (45/140) and graded as mild, moderate, and severe in 73, 24, and 3%, respectively, with NASH reported in 16% and indefinite/borderline NASH in 42% of HS cases. Postoperative ALI was similar (p = 0.88) in both HS (10%) and non-HS cohorts (11%). Operative complication severity was similar in both cohorts. 5-yr survival was 53% (HS) vs 50% (p = 0.890). CONCLUSION: This study establishes for the first time the incidence and clinical impact of NAFLD in EAC patients undergoing surgery and highlights no major impact on oncologic outcomes, nor in the severity of complications.

CROSS Versus FLOT Regimens in Esophageal and Esophagogastric Junction Adenocarcinoma: A Propensity-Matched Comparison.

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.

Visceral obesity with and without metabolic syndrome: incidence and clinical impact in esophageal adenocarcinoma treated with curative intent.

Visceral obesity (VO) and metabolic syndrome (MetS) are risk factors for esophageal adenocarcinoma (EAC); however, their impact on operative and oncological outcomes is unclear. The aim of this study was to determine the incidence of VO and MetS among patients with EAC, and to assess their independent impact on operative and oncological outcomes. A total of 454 consecutive patients undergoing treatment with curative intent were studied. Total, subcutaneous, visceral fat area (VFA), and lean body mass (LBM) were measured by computed tomography pretreatment, with VO defined as VFA >163.8cm2 for men and 80.1cm2 for women. MetS was defined per the ATPIII definition. Multivariable logistic and Cox proportional hazards regression were utilized to determine independent predictors of oncologic and operative outcomes. A total of 227 patients (50.0%) had VO. A total of 134 (30%) overall had MetS, 44% in the VO cohort. VO was associated with Barrett's esophagus (P = 0.002) and lower cT (P = 0.006) and cN stage (P = 0.011), and improved disease-specific (P = 0.021) and overall survival (P = 0.012). No survival benefit existed for patients with VO who also had MetS. For operative complications, neither VO nor MetS increased the severity of complications, or mortality. However, VO was significantly (P = 0.035) associated with anastomotic leak and pneumonia (P = 0.037). MetS alone did not increase complication risk. VO increases specific major operative complications with no increase in mortality. VO improved survival, mainly relating to earlier stage disease; however, co-existent MetS abrogated this benefit. These seemingly paradoxical outcomes highlight manageable and potentially targetable perioperative challenges in the context of an overall favorable oncologic vista.

The Complexity of Defining Postoperative Pneumonia After Esophageal Cancer Surgery: A Spectrum of Lung Injury Rather Than a Simple Infective Complication?

OBJECTIVE: To analyze the spectrum of Centers for Disease Control and Prevention (CDC)-defined pneumonia after esophageal cancer surgery. SUMMARY BACKGROUND DATA: Pneumonia is commonly documented after esophageal cancer surgery, and reducing its incidence is central to both ERAS development and to the evidence-base for minimally invasive approaches. The existing definitions of pneumonia based on hospital acquired pneumonia classifications may be suboptimal in this context and merits strict academic scrutiny. METHODS: Patients (2013-2018) treated with curative intent by open surgery were studied. Pneumonia was defined per the CDC definition. Risk factors and associations were analyzed, as was the implications of positive cultures. Multivariable logistic regression examined independently predictive factors of pneumonia and oncologic outcomes. RESULTS: Of 343 patients, 56 (16%) had defined pneumonia, 22 (39%) with positive cultures. Preoperative respiratory disease predicted pneumonia ( P = 0.043). Neoadjuvant therapy was significantly ( P = 0.004) associated with culture negative pneumonia, and age ( P = 0.001) with culture positive pneumonia. In multivariable analysis, pneumonia was associated ( P < 0.05) with respiratory comorbidity, tumor site, and neoadjuvant chemoradiation. Pneumonia did not impact on overall survival (P = 0.807). DISCUSSION: CDC-defined pneumonia occurred in 16% of cases. Culture-negative pneumonia accounted for 61% of cases and was significantly associated with neoadjuvant chemoradiation. Pneumonia as currently defined seems to represent a spectrum of etiology and severity in the post-esoph-agectomy patient, with infection per se rarely proven, suggesting a need to reevaluate its definition, severity classification, and preventive and treatment strategies.

Acute Kidney Injury After Esophageal Cancer Surgery: Incidence, Risk Factors, and Impact on Oncologic Outcomes.

OBJECTIVE: To determine the incidence, risk factors, and consequences of AKI in patients undergoing surgery for esophageal cancer. SUMMARY OF BACKGROUND DATA: Esophageal cancer surgery is an exemplar of major operative trauma, with well-defined risks of respiratory, cardiac, anastomotic, and septic complications. However, there is a paucity of literature regarding AKI. METHODS: consecutive patients undergoing curative-intent surgery for esophageal cancer from 2011 to 2017 in 3 high-volume centers were studied. AKI was defined according to the AKI Network criteria. AKI occurred if, within 48 hours postoperatively, serum creatinine rose by 50% or by 0.3 mg/dL (26.5 µmol/L) from preoperative baseline. Complications were recorded prospectively. Multivariable logistic regression determined factors independently predictive of AKI. RESULTS: A total of 1135 patients (24.7%:75.3% female:male, with a mean age of 64, a baseline BMI of 27 kg m-2, and dyslipidemia in 10.2%), underwent esophageal cancer surgery, 85% having an open thoracotomy. Overall in-hospital mortality was 2.1%. Postoperative AKI was observed in 208 (18.3%) patients, with AKI Network 1, 2, and 3 in 173 (15.2%), 28 (2.5%), and 7 (0.6%), respectively. Of these, 70.3% experienced improved renal function within 48 hours. Preoperative factors independently predictive of AKI were age [P = 0.027, odds ratio (OR) 1.02 (1.00-1.04)], male sex [P = 0.015, OR 1.77 (1.10-2.81)], BMI at diagnosis [P < 0.001, OR 1.10 (1.07-1.14)], and dyslipidemia [P = 0.002, OR 2.14 (1.34-3.44)]. Postoperatively, AKI was associated with atrial fibrillation (P = 0.013) and pneumonia (P = 0.005). Postoperative AKI did not impact survival outcomes. CONCLUSION: AKI is common but mostly self-limiting after esophageal cancer surgery. It is associated with age, male sex, increased BMI, dyslipidemia, and postoperative morbidity.

Successful maintenance of process and outcomes for oesophageal cancer surgery in Ireland during the first wave of the COVID-19 pandemic.

INTRODUCTION: The emergence of the novel coronavirus Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and the coronavirus disease COVID-19 has impacted enormously on non-COVID-19-related hospital care. Curtailment of intensive care unit (ICU) access threatens complex surgery, particularly impacting on outcomes for time-sensitive cancer surgery. Oesophageal cancer surgery is a good example. This study explored the impact of the pandemic on process and short-term surgical outcomes, comparing the first wave of the pandemic from April to June in 2020 with the same period in 2019. METHODS: Data from all four Irish oesophageal cancer centres were reviewed. All patients undergoing resection for oesophageal malignancy from 1 April to 30 June inclusive in 2020 and 2019 were included. Patient, disease, and peri-operative outcomes (including COVID-19 infection) were compared. RESULTS: In 2020, 45 patients underwent oesophagectomy, and 53 in the equivalent period in 2019. There were no differences in patient demographics, co-morbidities, or use of neoadjuvant therapy. The median time to surgery from neoadjuvant therapy was 8 weeks in both 2020 and 2019. There were no significant differences in operative interventions between the two time periods. There was no difference in operative morbidity in 2020 and 2019 (28% vs 40%, p = 0.28). There was no in-hospital mortality in either period. No patient contracted COVID-19 in the perioperative period. CONCLUSIONS: Continuing surgical resection for oesophageal cancer was feasible and safe during the COVID-19 pandemic in Ireland. The national response to this threat was therefore successful by these criteria in the curative management of oesophageal cancer.

Interleukin 6 predicts increased neural response during face processing in a sample of individuals with schizophrenia and healthy participants: A functional magnetic resonance imaging study.

BACKGROUND: Deficits in facial emotion recognition are a core feature of schizophrenia and predictive of functional outcome. Higher plasma levels of the cytokine interleukin 6 (IL-6) have recently been associated with poorer facial emotion recognition in individuals with schizophrenia and healthy participants, but the neural mechanisms affected remain poorly understood. METHODS: Forty-nine individuals with schizophrenia or schizoaffective disorder and 158 healthy participants were imaged using functional magnetic resonance imaging during a dynamic facial emotion recognition task. Plasma IL-6 was measured from blood samples taken outside the scanner. Multiple regression was used in statistical parametric mapping software to test whether higher plasma IL-6 predicted increased neural response during task performance. RESULTS: Higher plasma IL-6 predicted increased bilateral medial prefrontal response during neutral face processing compared to angry face processing in the total sample (N = 207, tmax = 5.67) and increased left insula response during angry face processing compared to neutral face processing (N = 207, tmax = 4.40) (p < 0.05, family-wise error corrected across the whole brain at the cluster level). CONCLUSIONS: These findings suggest that higher peripheral IL-6 levels predict altered neural response within brain regions involved in social cognition and emotion during facial emotion recognition. This is consistent with recent neuroimaging research on IL-6 and suggesting a possible neural mechanism by which this cytokine might affect facial emotion recognition accuracy.

Early life Adversity, functional connectivity and cognitive performance in Schizophrenia: The mediating role of IL-6.

OBJECTIVE: Exposure to childhood trauma (CT) is associated with cognitive impairment in schizophrenia, and deficits in social cognition in particular. Here, we sought to test whether IL-6 mediated the association between CT and social cognition both directly, and sequentially via altered default mode network (DMN) connectivity. METHODS: Three-hundred-and-eleven participants (104 patients and 207 healthy participants) were included, with MRI data acquired in a subset of n = 147. CT was measured using the childhood trauma questionnaire (CTQ). IL-6 was measured in both plasma and in toll like receptor (TLR) stimulated whole blood. The CANTAB emotion recognition task (ERT) was administered to assess social cognition, and cortical connectivity was assessed based on resting DMN connectivity. RESULTS: Higher IL-6 levels, measured both in plasma and in toll-like receptor (TLR-2) stimulated blood, were significantly correlated with higher CTQ scores and lower cognitive and social cognitive function. Plasma IL-6 was further observed to partly mediate the association between higher CT scores and lower emotion recognition performance (CTQ total: ßindirect -0.0234, 95% CI: -0.0573 to -0.0074; CTQ physical neglect: ßindirect = -0.0316, 95% CI: -0.0741 to -0.0049). Finally, sequential mediation was observed between plasma IL-6 levels and DMN connectivity in mediating the effects of higher CTQ on lower social cognitive function (ßindirect = -0.0618, 95% CI: -0.1523 to -0.285). CONCLUSION: This work suggests that previous associations between CT and social cognition may be partly mediated via an increased inflammatory response. IL-6's association with changes in DMN activity further suggest at least one cortical network via which CT related effects on cognition may be transmitted.

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.

Prospective study of surgical site infections post-open esophageal cancer surgery, and the impact of care bundles.

SSIs represent common infection-related morbidity following major surgery. Modern care bundles have been established as prophylactic measures aimed at preventing SSI occurring postoperatively. SSI incidence and data on common culprit pathogens post-esophagectomy for cancer have not been previously reported. Patients (2013-2018) treated with curative intent were studied. SSI was defined as per the Center for Disease Control (CDC) definition. A care bundle pathway following the National Institute for Clinical Excellence (NICE) guidelines for prevention of SSIs was introduced in 2013 and was audited quarterly. Risk factors and associations of SSIs were analyzed, as was the prevalence of isolated pathogens. Multivariable logistic regression examined independently predictive factors of SSIs and oncologic outcomes. Of 343 patients, 34 (9.9%) developed a postoperative SSI, with a median (range) of 8 (6-17). Quarterly audit carried out over 6 years showed no significant annual variance or trend. The most prevalent pathogen cultured was Methicillin-sensitive Staphylococcus aureus (MSSA) in nine patients (32%) followed by Candida albicans (29%), Escherichia coli (14%), and Enterococcus faecium (11%). SSI was significantly associated with pneumonia (P = 0.001), respiratory failure (P = 0.014), atrial fibrillation (P = 0.004), anastomotic leak (P < 0.001), and in-hospital blood transfusions (P = 0.031). SSI did not impact the overall survival (P = 0.951). SSI rates can be maintained at less than 10% using strict care bundles and regular audit. The most common culprit pathogen is gram-positive MSSA representing 32% of cases. These data are novel and may represent a modern benchmark for SSI post-open esophagectomy for cancer. This study highlights the incidence and associations of SSI post-esophageal cancer surgery.

Modern oncological and operative outcomes in oesophageal cancer: the St. James's hospital experience.

BACKGROUND: Oesophageal cancer has a reputation for poor survival, and a relatively high risk of major postoperative morbidity and mortality. Encouragingly, a recent international cancer registry study reports a doubling of survival outcomes in Ireland over the last 20 years. This study focused on both oncologic and operative outcomes in patients treated with curative intent requiring surgery at a high-volume center. METHODS: All patients undergoing surgery or multimodal therapy with curative intent from 2009 to 2018 were studied. All data was recorded prospectively and maintained internally. The period 2009-2013 was compared with 2014-2018 to monitor any change in trends. RESULTS: Four hundred and seventy-five patients (adenocarcinoma 77%, mean age 65; 76% male; 64% neoadjuvant therapy) underwent open surgical resection, 54% via en bloc 2-stage, 19.8% en bloc 3-stage, and 26.5% by a transhiatal approach. New onset atrial fibrillation was the commonest index complication, in 108 (22.7%), 80 (18%) developed suspected pneumonia/respiratory tract infection, 20 (4.2%) an anastomotic leak, and 25 (5.2%) a chyle leak. The 90-day mortality rate was 1.2% and 0.8% at 30 days. The median survival was 77.17 months, with a 5-year survival of 56%. CONCLUSION: Consistent with registry data on population survival for oesophageal cancer, this study highlights markedly improved survival outcomes in patients treated curatively, reflecting international trends, as well as low mortality rates; however, cardiorespiratory complications remain significant.

Inflammatory Proteins and Clinical Response to Psychological Therapy in Patients with Depression: An Exploratory Study.

In people with depression, immune dysfunctions have been linked with treatment non-response, but examinations of psychological therapy outcomes, particularly longitudinal biomarker studies, are rare. This study investigated relationships between inflammation, depressive subtypes and clinical outcomes to psychological therapy. Adults with depression (n = 96) were assessed before and after a course of naturalistically-delivered psychological therapy. In total, 32 serum inflammatory proteins were examined alongside therapy outcomes and depressive subtypes (somatic/cognitive symptom subtype, and bipolar/unipolar depression). Overall, 49% of participants responded to treatment. High levels of tumour necrosis factor (TNFα), interleukin-6 (IL-6) and soluble intracellular adhesion molecule-1 (sICAM1), and low interferon-γ (IFNγ), preceded a poorer response to therapy. After therapy, non-responders had elevated c-reactive protein (CRP), thymus and activation-regulated chemokine (TARC) and macrophage chemoattractant protein-4 (MCP4), and attenuated IFNy. Non-somatic depressive symptoms were universally not associated with proteins, while somatic-depressive symptom severity was positively correlated with several pro-inflammatory markers. In the somatic subgroup only, IL-6 and serum amyloid alpha (SAA) decreased between pre- and post-therapy timepoints. Regardless of treatment response, IL-7, IL-8, IL-15 and IL-17 increased over time. These results suggest that inflammation is associated with somatic symptoms of depression and non-response to psychological therapy. Future work may enhance the prospective prediction of treatment-response by examining larger samples of individuals undertaking standardised treatment programmes.

Adverse Biology in Adenocarcinoma of the Esophagus and Esophagogastric Junction Impacts Survival and Response to Neoadjuvant Therapy Independent of Anatomic Subtype.

OBJECTIVE: The aim of this study was to propose and test a novel adverse pathology classification in AEG. BACKGROUND: Recent scientific advances show genomic and molecular concordance across all AEG types, suggesting a rationale for a biologic classification. We tested a 3-dimension adverse pathology classification across the entire junction and per Siewert anatomic subtype. METHODS: Of 1625 patients with AEG, 650 underwent radical surgery, 55% post-neoadjuvant therapy (NeoT). Adverse features defined a priori were poor differentiation (PD), lymphatic invasion (LI), vascular invasion (VI), and perineural invasion (PN), with 3 groupings: 0 (no adverse feature), 1 to 2, and 3 to 4. Multivariable logistic and Cox proportional hazards regression were applied. RESULTS: For adverse pathology, 31%, 46%, and 23% had 0, 1 to 2, and 3 to 4, respectively. Fifty percent of cases were AEG I, 25% AEG II, and 25% AEG III. Median survival was not reached, 49 and 17 months for 0, 1 to 2, and 3 to 4 adverse pathology, respectively (P < 0.001), and 76, 51, and 34 months for AEG I, II, and III, respectively (P < 0.001); AEG I was significantly (P< 0.001) associated with lower c (y)pT and c (y)pN stages, and LI, VI, PN, and PD (poor vs other). The pathology model was significant for survival along with (y)pT and (y)pN, and predicted response to chemotherapy and chemoradiation irrespective of anatomic subtype (P < 0.001). CONCLUSION: A novel classification using standard pathology as proxy for poor biology is associated with survival and response to therapy. This effect is observed across the entire AEG spectrum, highlighting how biology should be aligned with anatomy in the modern paradigm of AEG management and design of clinical trials.

Outcomes for Esophageal Squamous Cell Carcinoma Treated with Curative Intent in a Western Cohort: Should Multimodal Therapy Be the Gold Standard?

INTRODUCTION: The standard of care for treatment of oesophageal squamous cell carcinoma (SCC) continues to evolve. Neoadjuvant chemoradiotherapy (neoCRT) provides a significant survival benefit compared to surgery alone but it is unclear whether definitive chemoradiation (dCRT) is superior. METHODS: Retrospective analysis of outcomes from patients treated in a national high-volume centre (2000-2014) where both neoCRT and dCRT are used with curative intent. Propensity score match analysis was used to match patients undergoing dCRT with those undergoing surgery ± neoCRT. RESULTS: A total of 668 patients were treated for SCC in this time period, 361 (54.0%) of whom were treated with curative intent. In patients treated with curative intent, 179 (49.6%) had dCRT, and of these 32 (18%) did not complete the treatment regimen. One hundred and seven patients (29.6%) underwent surgery only, and 75 patients (20.8%) had multimodal therapy. The proportion of patients treated with curative intent increased over this time period. The five-year disease-specific and overall survival rate of patients treated with multimodal therapy was 62 and 50%, respectively, compared with 25 and 20% for patients the dCRT group and 44 and 38%, respectively, for the surgery only cohort (p < 0.001). Patients with a complete pathological response had a 90% five-year disease-specific survival and 76% overall survival rate. Multimodal treatment rather than dCRT was a significant predictor of overall survival (OR 1.7 95% CI 1.3-2.4, p = 0.002). In 106 patients matched, those undergoing dCRT had a significantly poorer overall survival versus those receiving surgery as a component of their care (20.47 ± 3.74 months versus 30.65 ± 10.07 months, p = 0.002). CONCLUSION: This study provides evidence, consistent with CROSS data, that multimodal therapy for SCC can provide excellent outcomes with respect to overall survival, pathologic complete response rates, R0 resections and treatment-related mortality. A large RCT with specific arms for multimodal, dCRT and surgery alone is required.

Sarcopenia: Prevalence, and Impact on Operative and Oncologic Outcomes in the Multimodal Management of Locally Advanced Esophageal Cancer.

OBJECTIVE: The aim of this article was to study the prevalence and significance of sarcopenia in the multimodal management of locally advanced esophageal cancer (LAEC), and to assess its independent impact on operative and oncologic outcomes. SUMMARY OF BACKGROUND DATA: Sarcopenia in cancer may confer negative outcomes, but its prevalence and impact on modern multimodal regimens for LAEC have not been systematically studied. METHODS: Two hundred fifty-two consecutive patients were studied. Lean body mass (LBM), skeletal muscle index (SMI), and fat mass (FM) were determined pre-treatment, preoperatively, and 1 year postoperatively. Sarcopenia was defined by computed tomography (CT) at L3 as SMI < 52.4 cm/m for males and SMI < 38.5 cm/m for females. All complications were recorded prospectively, including comprehensive complications index (CCI), Clavien-Dindo complication (CDC), and pulmonary complications (PPCs). Multivariable linear, logistic, and Cox regression analysis was performed. RESULTS: In-hospital mortality was 1%, and CCI was 21 ±â€Š19. Sarcopenia increased (P = 0.02) from 16% at diagnosis to 31% post-neoadjuvant therapy, with loss of LBM (-3.0 ±â€Š5.4 kg, P < 0.0001), but not FM (-0.3 ±â€Š2.7 kg, P= 0.31) during treatment. On multivariable analysis, preoperative sarcopenia was associated with CCI (P = 0.043), and CDC ≥IIIb (P = 0.003). PPCs occurred in 36% nonsarcopenic versus 55% sarcopenic patients (P = 0.01). Sarcopenia did not impact disease-specific (P = 0.14) or overall survival (P = 0.11) after resection. At 1 year, 35% had sarcopenia, significantly associated with pre-treatment BMI (P = 0.013) but not complications (P = 0.20). CONCLUSIONS: Sarcopenia increases through multimodal therapy, is associated with an increased risk of major postoperative complications, and is prevalent in survivorship. These data highlight a potentially modifiable marker of risk that should be assessed and targeted in modern multimodal care pathways.

Risk Factors for Anastomotic Stricture Post-esophagectomy with a Standardized Sutured Anastomosis.

BACKGROUND: Benign anastomotic strictures occur frequently after esophagectomy, and impact on postoperative recovery, nutritional status, and quality of life. This large cohort study explored the incidence of stricture after transthoracic (2- and 3-stage) and transhiatal resections with uniform single-layer sutured anastomotic technique, and aimed to identify independent risk factors. METHODS: Patients undergoing esophagectomy with gastric conduit reconstruction between February 2001 and October 2014 were studied prospectively. Symptomatic anastomotic stricture was defined as dysphagia requiring endoscopic dilatation, and refractory strictures as those requiring >5 dilatations. Multivariable logistic regression was performed to determine factors independently associated with stricture development. RESULTS: Five-hundred and twenty-four patients, 77 % with adenocarcinoma, underwent esophagectomy [2-stage, n = 328 (62.6 %); 3-stage, n = 129 (23.3 %); transhiatal, n = 74 (14.1 %)], with an overall inhospital mortality rate of 2.7 %. 58.5 % of patients received neoadjuvant therapy [chemotherapy only, n = 119 (22.7 %); chemoradiation, n = 188 (35.9 %)]. Anastomotic stricture developed in 125 patients (24.5 %), was refractory in 20 (3.9 %) and required a median of 2 dilatations (range 1-18). On multivariable analysis, ASA grade (P < 0.05), cervical anastomosis (P < 0.001), and a significant postoperative cardiac event (P < 0.05) were independently associated with stricture risk. Refractory strictures were independently associated with anastomotic leak (P = 0.01) and transhiatal resections (P < 0.001). CONCLUSION: Benign anastomotic strictures are common, particularly with cervical reconstruction, and after transhiatal resection. Refractory strictures are rare. Where fitness and oncologic equivalence apply, a thoracic anastomosis provides significant advantages compared with a cervical anastomosis in terms of anastomotic stricture risk.

Gut Hormone Suppression Increases Food Intake After Esophagectomy With Gastric Conduit Reconstruction.

OBJECTIVES: To characterize the gut hormone profile and determine the effect of satiety gut hormone blockade on food intake in disease-free postesophagectomy patients. BACKGROUND: Improved oncologic outcomes for esophageal cancer have resulted in increased survivorship and a focus on health-related quality of life. Anorexia and early satiety are common, but putative causative factors, in particular the gut-brain hormonal axis, have not been systematically studied. METHODS: In a double-blind, placebo-controlled, randomized crossover study, disease-free patients at least 1 year postresection and gastric conduit reconstruction received either 1 mL 0.9% saline or 1 mL (100 µg) octreotide acetate subcutaneously followed by a standardized ad libitum meal on each of two assessments. Fasting and postprandial plasma glucagon-like peptide 1 (GLP-1), peptide YY (PYY), and ghrelin immunoreactivity were measured. Gut hormone responses and calorie intake postsaline versus octreotide were compared between experimental and control groups. RESULTS: Eighteen subjects [esophagectomy (ES), n = 10, 2.4 ±â€Š0.75 years postresection; and unoperated control subjects, n = 8] were studied. ES demonstrated significant weight loss at 3, 6, 12, and 24 months postoperatively (all P < 0.05). Ghrelin levels were similar (P = 0.58) for both groups, but postprandial GLP-1 and PYY responses were significantly (P < 0.001) greater among ES as compared with controls. After octreotide, ad libitum calorie intake increased among ES (1.5 ±â€Š0.2 fold-change, P = 0.02) but not controls (1.1 ±â€Š0.1 fold-change, P = 0.30). CONCLUSIONS: ES demonstrated an exaggerated postprandial satiety gut hormone response that was attenuated by octreotide, thus identifying a potential therapeutic target to modulate in the ES patient with early satiety.