The single cell transcriptional landscape of esophageal adenocarcinoma and its modulation by neoadjuvant chemotherapy.

Immune checkpoint blockade has recently proven effective in subsets of patients with esophageal adenocarcinoma (EAC) but little is known regarding the EAC immune microenvironment. We determined the single cell transcriptional profile of EAC in 8 patients who were treatment-naive (n = 4) or had received neoadjuvant chemotherapy (n = 4). Analysis of 52,387 cells revealed 10 major cell subsets of tumor, immune and stromal cells. Prior to chemotherapy tumors were heavy infiltrated by T regulatory cells and exhausted effector T cells whilst plasmacytoid dendritic cells were markedly expanded. Two dominant cancer-associated fibroblast populations were also observed whilst endothelial populations were suppressed. Pathological remission following chemotherapy associated with broad reversal of immune abnormalities together with fibroblast transition and an increase in endothelial cells whilst a chemoresistant epithelial stem cell population correlated with poor response. These findings reveal features that underlie and limit the response to current immunotherapy and identify a range of novel opportunities for targeted therapy.

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.

Perioperative outcomes after laparoscopic cholecystectomy in elderly patients: a systematic review and meta-analysis.

BACKGROUND: Laparoscopic cholecystectomy is increasingly performed in an ever ageing population; however, the risks are poorly quantified. The study aims to review the current evidence to quantify further the postoperative risk of cholecystectomy in the elderly population compared to younger patients. METHOD: A systematic literature search of PubMed, EMBASE and the Cochrane Library databases were conducted including studies reporting laparoscopic cholecystectomy in the elderly population. A meta-analysis was reported in accordance with the recommendations of the Cochrane Library and PRISMA guidelines. Primary outcome was overall complications and secondary outcomes were conversion to open surgery, bile leaks, postoperative mortality and length of stay. RESULTS: This review identified 99 studies incorporating 326,517 patients. Increasing age was significantly associated with increased rates of overall complications (OR 2.37, CI95% 2.00-2.78), major complication (OR 1.79, CI95% 1.45-2.20), risk of conversion to open cholecystectomy (OR 2.17, CI95% 1.84-2.55), risk of bile leaks (OR 1.50, CI95% 1.07-2.10), risk of postoperative mortality (OR 7.20, CI95% 4.41-11.73) and was significantly associated with increased length of stay (MD 2.21 days, CI95% 1.24-3.18). CONCLUSION: Postoperative outcomes such as overall and major complications appear to be significantly higher in all age cut-offs in this meta-analysis. This study demonstrated there is a sevenfold increase in perioperative mortality which increases by tenfold in patients > 80 years old. This study appears to confirm preconceived suspicions of higher risks in elderly patients undergoing cholecystectomy and may aid treatment planning and informed consent.

Meta-analysis of prognostic factors of overall survival in patients undergoing oesophagectomy for oesophageal cancer.

INTRODUCTION: Currently, the American Joint Commission on Cancer (AJCC) staging system is used for prognostication for oesophageal cancer. However, several prognostically important factors have been reported but not incorporated. This meta-analysis aimed to characterize the impact of preoperative, operative, and oncological factors on the prognosis of patients undergoing curative resection for oesophageal cancer. METHODS: This systematic review was performed according to PRISMA guidelines and eligible studies were identified through a search of PubMed, Scopus, and Cochrane CENTRAL databases up to 31 December 2018. A meta-analysis was conducted with the use of random-effects modeling to determine pooled univariable hazard ratios (HRs). The study was prospectively registered with the PROSPERO database (Registration: CRD42018157966). RESULTS: One-hundred and seventy-one articles including 73,629 patients were assessed quantitatively. Of the 122 factors associated with survival, 39 were significant on pooled analysis. Of these. the strongly associated prognostic factors were 'pathological' T stage (HR: 2.07, CI95%: 1.77-2.43, P < 0.001), 'pathological' N stage (HR: 2.24, CI95%: 1.95-2.59, P < 0.001), perineural invasion (HR: 1.54, CI95%: 1.36-1.74, P < 0.001), circumferential resection margin (HR: 2.17, CI95%: 1.82-2.59, P < 0.001), poor tumor grade (HR: 1.53, CI95%: 1.34-1.74, P < 0.001), and high neutrophil:lymphocyte ratio (HR: 1.47, CI95%: 1.30-1.66, P < 0.001). CONCLUSION: Several tumor biological variables not included in the AJCC 8th edition classification can impact on overall survival. Incorporation and validation of these factors into prognostic models and next edition of the AJCC system will enable personalized approach to prognostication and treatment.

Risk factors and outcomes associated with anastomotic leaks following esophagectomy: a systematic review and meta-analysis.

Anastomotic leaks (AL) are a major complication after esophagectomy. This meta-analysis aimed to determine identify risks factors for AL (preoperative, intra-operative, and post-operative factors) and assess the consequences to outcome on patients who developed an AL. This systematic review was performed according to PRISMA guidelines, and eligible studies were identified through a search of PubMed, Scopus, and Cochrane CENTRAL databases up to 31 December 2018. A meta-analysis was conducted with the use of random-effects modeling and prospectively registered with the PROSPERO database (Registration CRD42018130732). This review identified 174 studies reporting outcomes of 74,226 patients undergoing esophagectomy. The overall pooled AL rates were 11%, ranging from 0 to 49% in individual studies. Majority of studies were from Asia (n = 79). In pooled analyses, 23 factors were associated with AL (17 preoperative and six intraoperative). AL were associated with adverse outcomes including pulmonary (OR: 4.54, CI95%: 2.99-6.89, P < 0.001) and cardiac complications (OR: 2.44, CI95%: 1.77-3.37, P < 0.001), prolonged hospital stay (mean difference: 15 days, CI95%: 10-21 days, P < 0.001), and in-hospital mortality (OR: 5.91, CI95%: 1.41-24.79, P = 0.015). AL are a major complication following esophagectomy accounting for major morbidity and mortality. This meta-analysis identified modifiable risk factors for AL, which can be a target for interventions to reduce AL rates. Furthermore, identification of both modifiable and non-modifiable risk factors will facilitate risk stratification and prediction of AL enabling better perioperative planning, patient counseling, and informed consent.

Colonic Perforation: A Medical Complication.

Hypothyroidism is a common comorbidity that on acute presentation is often overlooked. It can be an easily managed condition; however non-compliance can have severe consequences. In the presented case it was requirement for emergency surgery that resulted in stoma formation. This case is a first example of the need to include patient's decision making process with regards to medication adherence in the setting of chronic disease.

Pathologic Lymph Node Regression After Neoadjuvant Chemotherapy Predicts Recurrence and Survival in Esophageal Adenocarcinoma: A Multicenter Study in the United Kingdom.

PURPOSE: There is limited evidence regarding the prognostic effects of pathologic lymph node (LN) regression after neoadjuvant chemotherapy for esophageal adenocarcinoma, and a definition of LN response is lacking. This study aimed to evaluate how LN regression influences survival after surgery for esophageal adenocarcinoma. METHODS: Multicenter cohort study of patients with esophageal adenocarcinoma treated with neoadjuvant chemotherapy followed by surgical resection at five high-volume centers in the United Kingdom. LNs retrieved at esophagectomy were examined for chemotherapy response and given a LN regression score (LNRS)-LNRS 1, complete response; 2, <10% residual tumor; 3, 10%-50% residual tumor; 4, >50% residual tumor; and 5, no response. Survival analysis was performed using Cox regression adjusting for confounders including primary tumor regression. The discriminatory ability of different LN response classifications to predict survival was evaluated using Akaike information criterion and Harrell C-index. RESULTS: In total, 17,930 LNs from 763 patients were examined. LN response classified as complete LN response (LNRS 1 ≥1 LN, no residual tumor in any LN; n = 62, 8.1%), partial LN response (LNRS 1-3 ≥1 LN, residual tumor ≥1 LN; n = 155, 20.3%), poor/no LN response (LNRS 4-5; n = 303, 39.7%), or LN negative (no tumor/regression; n = 243, 31.8%) demonstrated superior discriminatory ability. Mortality was reduced in patients with complete LN response (hazard ratio [HR], 0.35; 95% CI, 0.22 to 0.56), partial LN response (HR, 0.72; 95% CI, 0.57 to 0.93) or negative LNs (HR, 0.32; 95% CI, 0.25 to 0.42) compared with those with poor/no LN response. Primary tumor regression and LN regression were discordant in 165 patients (21.9%). CONCLUSION: Pathologic LN regression after neoadjuvant chemotherapy was a strong prognostic factor and provides important information beyond pathologic TNM staging and primary tumor regression grading. LN regression should be included as standard in the pathologic reporting of esophagectomy specimens.

Current and Future Immunotherapy-Based Treatments for Oesophageal Cancers.

Oesophageal cancer is a disease that causes significant morbidity and mortality worldwide, and the prognosis of this condition has hardly improved in the past few years. Standard treatment includes a combination of chemotherapy, radiotherapy and surgery; however, only a proportion of patients go on to treatment intended to cure the disease due to the late presentation of this disease. New treatment options are of utmost importance, and immunotherapy is a new option that has the potential to transform the landscape of this disease. This treatment is developed to act on the changes within the immune system caused by cancer, including checkpoint inhibitors, which have recently shown great promise in the treatment of this disease and have recently been included in the adjuvant treatment of oesophageal cancer in many countries worldwide. This review will outline the mechanisms by which cancer evades the immune system in those diagnosed with oesophageal cancer and will summarize current and ongoing trials that focus on the use of our own immune system to combat disease.

Definitive chemoradiotherapy versus neoadjuvant chemoradiotherapy followed by radical surgery for locally advanced oesophageal squamous cell carcinoma: meta-analysis.

BACKGROUND: The literature lacks robust evidence comparing definitive chemoradiotherapy (dCRT) with neoadjuvant chemoradiotherapy and surgery (nCRS) for oesophageal squamous cell carcinoma (ESCC). This study aimed to compare long-term survival of these approaches in patients with ESCC. METHODS: A systematic review performed according to PRISMA guidelines included studies identified from PubMed, Scopus, and Cochrane CENTRAL databases up to July 2021 comparing outcomes between dCRT and nCRS for ESCC. The main outcome measure was overall survival (OS), secondary outcome was disease-free survival (DFS). A meta-analysis was conducted using random-effects modelling to determine pooled adjusted multivariable hazard ratios (HRs). RESULTS: Ten studies including 14 092 patients were included, of which 30 per cent received nCRS. Three studies were randomized clinical trials (RCTs) and the remainder were retrospective cohort studies. dCRT and nCRS regimens were reported in six studies and surgical quality control was reported in two studies. Outcomes for OS and DFS were reported in eight and three studies respectively. Following meta-analysis, nCRS demonstrated significantly longer OS (HR 0.68, 95 per cent c.i. 0.54 to 0.87, P < 0.001) and DFS (HR 0.50, 95 per cent c.i. 0.36 to 0.70, P < 0.001) compared with dCRT. CONCLUSION: Neoadjuvant chemoradiotherapy followed by oesophagectomy correlated with improved survival compared with definitive chemoradiation in the treatment of ESCC; however, there is a lack of literature on RCTs.

Risk Factors, Diagnosis and Management of Chyle Leak Following Esophagectomy for Cancers: An International Consensus Statement.

This Delphi exercise aimed to gather consensus surrounding risk factors, diagnosis, and management of chyle leaks after esophagectomy and to develop recommendations for clinical practice. Background: Chyle leaks following esophagectomy for malignancy are uncommon. Although they are associated with increased morbidity and mortality, diagnosis and management of these patients remain controversial and a challenge globally. Methods: This was a modified Delphi exercise was delivered to clinicians across the oesophagogastric anastomosis collaborative. A 5-staged iterative process was used to gather consensus on clinical practice, including a scoping systematic review (stage 1), 2 rounds of anonymous electronic voting (stages 2 and 3), data-based analysis (stage 4), and guideline and consensus development (stage 5). Stratified analyses were performed by surgeon specialty and surgeon volume. Results: In stage 1, the steering committee proposed areas of uncertainty across 5 domains: risk factors, intraoperative techniques, and postoperative management (ie, diagnosis, severity, and treatment). In stages 2 and 3, 275 and 250 respondents respectively participated in online voting. Consensus was achieved on intraoperative thoracic duct ligation, postoperative diagnosis by milky chest drain output and biochemical testing with triglycerides and chylomicrons, assessing severity with volume of chest drain over 24 hours and a step-up approach in the management of chyle leaks. Stratified analyses demonstrated consistent results. In stage 4, data from the Oesophagogastric Anastomosis Audit demonstrated that chyle leaks occurred in 5.4% (122/2247). Increasing chyle leak grades were associated with higher rates of pulmonary complications, return to theater, prolonged length of stay, and 90-day mortality. In stage 5, 41 surgeons developed a set of recommendations in the intraoperative techniques, diagnosis, and management of chyle leaks. Conclusions: Several areas of consensus were reached surrounding diagnosis and management of chyle leaks following esophagectomy for malignancy. Guidance in clinical practice through adaptation of recommendations from this consensus may help in the prevention of, timely diagnosis, and management of chyle leaks.

Peri-operative Outcomes and Survival Following Palliative Gastrectomy for Gastric Cancer: a Systematic Review and Meta-analysis.

BACKGROUND: Many patients with gastric cancer present with late stage disease. Palliative gastrectomy remains a contentious intervention aiming to debulk tumour and prevent or treat complications such as gastric outlet obstruction, perforation and bleeding. METHODS: We conducted a systematic review of the literature for all papers describing palliative resections for gastric cancer and reporting peri-operative or survival outcomes. Data from peri-operative and survival outcomes were meta-analysed using random effects modelling. Survival data from patients undergoing palliative resections, non-resective surgery and palliative chemotherapy were also combined. This study was registered with the PROSPERO database (CRD42019159136). RESULTS: One hundred and twenty-eight papers which included 58,675 patients contributed data. At 1 year, there was a significantly improved survival in patients who underwent palliative gastrectomy when compared to non-resectional surgery and no treatment. At 2 years following treatment, palliative gastrectomy was associated with significantly improved survival compared to chemotherapy only; however, there was no significant improvement in survival compared to patients who underwent non-resectional surgery after 1 year. Palliative resections were associated with higher rates of overall complications versus non-resectional surgery (OR 2.14; 95% CI, 1.34, 3.46; p < 0.001). However, palliative resections were associated with similar peri-operative mortality rates to non-resectional surgery. CONCLUSION: Palliative gastrectomy is associated with a small improvement in survival at 1 year when compared to non-resectional surgery and chemotherapy. However, at 2 and 3 years following treatment, survival benefits are less clear. Any survival benefits come at the expense of increased major and overall complications.

Hepatic and Intra-abdominal Tuberculosis: 2016 Update.

Mycobacterium tuberculosis (TB) infection affects nearly 10 million people a year and causes 1.5 million deaths. TB is common in the immunosuppressed population with 12 % of all new diagnoses occurring in human immune deficiency virus (HIV)-positive patients. Extra-pulmonary TB occurs in 12 % of patients with active TB infection of which 3.5 % is hepatobiliary and 6-38 % is intra-abdominal. Hepatobiliary and intra-abdominal TB can present with a myriad of non-specific symptoms, and therefore, diagnosis requires a high level of suspicion. Accurate and rapid diagnosis requires a multidisciplinary team (MDT) approach using radiology, interventional radiology, surgery and pathology services. Treatment of TB is predominantly medical, yet surgery plays an important role in managing the complications of hepatobiliary and intra-abdominal TB.

Evolving management of metaplasia and dysplasia in Barrett's epithelium.

Oesophageal cancer affects more than 450000 people worldwide and despite continued medical advancements the incidence of oesophageal cancer is increasing. Oesophageal cancer has a 5 year survival of 15%-25% and now globally attempts are made to more aggressively diagnose and treat Barrett's oesophagus the known precursor to invasive disease. Currently diagnosis the of Barrett's oesophagus is predominantly made after endoscopic visualisation and histopathological confirmation. Minimally invasive techniques are being developed to improve the viability of screening programs. The management of Barrett's oesophagus can vary greatly dependent on the presence and severity of dysplasia. There is no consensus between the major international medical societies to determine and agreed surveillance and intervention pathway. In this review we analysed the current literature to demonstrate the evolving management of metaplasia and dysplasia in Barrett's epithelium.

Vascular access in the obese: superficialisation of native radio-cephalic and brachio-cephalic fistulae.

PURPOSE: The Department of Health estimates that currently in the UK, 61.3% of the population are overweight or obese (BMI >25 kg/m2). Fistulae in the obese often fail to mature or prove inadequate to needle due to excessive depth (>6 mm). This study is a summary of our experience with brachio and radio-cephalic vein superficialisation in the obese. METHODS: From May 2008 to October 2012, 22 patients underwent superficialisation of the cephalic vein following radio-cephalic or brachio-cephalic Arterio-venous fistula (AVF) creation. Data were obtained from a prospective database (Cyberen®) and retrospectively analysed. RESULTS: The study included 23 AVFs in 22 patients (seven males, 15 females), of which 13 were brachio-cephalic and 10 radio-cephalic. The mean age of the patients was 56 years (median 60, range 19-78 years). The mean BMI was 36.7 kg/m2 (median 32, 25-58 kg/m2). Six-week post procedure duplex ultrasonography recorded the mean fistula depth to be 7.7 mm (median 8 mm, 5-15 mm) and mean flow rates were 961 ml/min (median 800 ml/min, 320-1968 ml/min).Of the 23, 21 fistulae matured successfully. There were no procedure-related complications. During follow-up, two patients underwent transplantation prior to fistula use and three patients died of unrelated causes. The remaining 16 fistulae remain in use and under access surveillance. CONCLUSIONS: Superficialisation of brachio/radio-cephalic fistulae is an excellent option to optimise the cephalic vein for needling, assisting primary patency. Superficialisation of the cephalic vein helps maintain long-term functional access in overweight and obese patients.