Mechanisms underlying obesity-related insulin resistance

This thesis investigates the effect of body composition on insulin resistance and the impact of supplementation with nutritional support or carbohydrate treatment. Insulin resistance occurs as a response to a number of stressors, including surgery. However, the mechanism underlying the development of insulin resistance is as yet unclear. Adipose tissue distribution appears to play a role in the development of insulin resistance and obesity-related complications. In obese and non-obese patients undergoing open abdominal surgery who received preoperative carbohydrate or placebo, there was a significant fall in perioperative insulin sensitivity and changes in the expression of genes relating to carbohydrate and fat oxidation. There was no influence of perioperative carbohydrate or obesity on change in insulin sensitivity. Patients undergoing neoadjuvant chemotherapy for oesophageal cancer underwent pre and post chemotherapy assessment of insulin sensitivity and body composition. There was a significant reduction in insulin sensitivity despite minimal change in body composition and adequate nutritional intake. These studies have provided further information about the optimal methods for assessment of insulin sensitivity and body composition as well as an insight into mechanisms underlying the association between body composition and insulin sensitivity

Postoperative inflammation and insulin resistance in relation to body composition, adiposity and carbohydrate treatment: a randomised controlled study

Background and Aims: The aims of this study were to identify whether differences in distribution of adipose tissue and skeletal muscle in obese and non-obese individuals contribute to the magnitude of the postoperative inflammatory response and insulin resistance, with and without preoperative treatment with carbohydrate drinks. Methods: Thirty-two adults (16 obese/16 non-obese) undergoing elective major open abdominal surgery participated in this 22 factorial, randomised, double-blind, placebo-controlled study. Participants received Nutricia preOp® or placebo (800 ml on the night before surgery/400 ml 2-3 h preoperatively) after stratifying for obesity. Insulin sensitivity was measured using the hyperinsulinaemic-euglycaemic clamp pre- and postoperatively. Vastus lateralis, omental and subcutaneous fat biopsies were taken pre- and postoperatively and analysed after RNA extraction. The primary endpoint was within subject differences in insulin sensitivity. Results: Major abdominal surgery was associated with a 42% reduction in insulin sensitivity from mean(SD) M value of 37.3(11.8) μmol kg-1 fat free mass (FFM) to 21.7(7.4) μmol kg-1 67 FFM, but this was not influenced by obesity or preoperative carbohydrate treatment. Activation of the triggering receptor expressed on myeloid cells (TREM1) pathway was seen in response to surgery in omental fat samples. In postoperative muscle samples, gene expression differences indicated activation of the peroxisome proliferator-activated receptor (PPAR-α)/retinoid X-receptor (RXR-α) pathway in obese but not in non-obese participants. There were no significant changes in gene expression pathways associated with carbohydrate treatment. Conclusion: The reduction in insulin sensitivity associated with major abdominal surgery was confirmed but there were no differences associated with preoperative carbohydrates or obesity

The presence of tumour-associated lymphocytes confers a good prognosis in pancreatic ductal adenocarcinoma: an immunohistochemical study of tissue microarrays

Background Tumour-associated lymphocytes (TALs) have been linked with good prognosis in several solid tumours. This study aimed to evaluate the prognostic significance of CD3, CD8 and CD20 positive lymphocytes in pancreatic ductal adenocarcinoma. Methods After histological re-evaluation of the tumours of 81 patients who underwent surgical resection for exclusively pancreatic ductal adenocarcinoma, tissue micro-arrays (TMA) were constructed and immunohistochemistry was performed for CD3, CD8 and CD20. The number of lymphocytes within specific tumour compartments (i.e. stromal and intratumoural) was quantified. X-tile software (Yale School of Medicine, CT, USA) was used to stratify patients into 'high’ and 'low’ for each of the lymphocytes stained and their association with survival. Receiver operating curves (ROC) were constructed to evaluate the association between the TALs, alone and in combination, with clinicopathological features. Results CD3 and CD8 positive lymphocytes were associated with grade of tumour differentiation. The presence of intratumoural CD3 positive cells was associated with improved survival (p = 0.028), and intratumoural and stromal CD3 in combination also correlated with improved survival (p = 0.043). When CD20 positive lymphocyte levels were high, survival improved (p = 0.029) and similar results were seen for CD20 in combination with intratumoural CD3 (p = 0.001) and stromal CD8 (p = 0.013). Conclusions This study has shown a correlation between the presence of TALs and survival in pancreatic ductal adenocarcinoma

Mortality and pulmonary complications in patients undergoing surgery with perioperative SARS-CoV-2 infection: an international cohort study

Background: The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on postoperative recovery needs to be understood to inform clinical decision making during and after the COVID-19 pandemic. This study reports 30-day mortality and pulmonary complication rates in patients with perioperative SARS-CoV-2 infection. Methods: This international, multicentre, cohort study at 235 hospitals in 24 countries included all patients undergoing surgery who had SARS-CoV-2 infection confirmed within 7 days before or 30 days after surgery. The primary outcome measure was 30-day postoperative mortality and was assessed in all enrolled patients. The main secondary outcome measure was pulmonary complications, defined as pneumonia, acute respiratory distress syndrome, or unexpected postoperative ventilation. Findings: This analysis includes 1128 patients who had surgery between Jan 1 and March 31, 2020, of whom 835 (74·0%) had emergency surgery and 280 (24·8%) had elective surgery. SARS-CoV-2 infection was confirmed preoperatively in 294 (26·1%) patients. 30-day mortality was 23·8% (268 of 1128). Pulmonary complications occurred in 577 (51·2%) of 1128 patients; 30-day mortality in these patients was 38·0% (219 of 577), accounting for 81·7% (219 of 268) of all deaths. In adjusted analyses, 30-day mortality was associated with male sex (odds ratio 1·75 [95% CI 1·28–2·40], p\textless0·0001), age 70 years or older versus younger than 70 years (2·30 [1·65–3·22], p\textless0·0001), American Society of Anesthesiologists grades 3–5 versus grades 1–2 (2·35 [1·57–3·53], p\textless0·0001), malignant versus benign or obstetric diagnosis (1·55 [1·01–2·39], p=0·046), emergency versus elective surgery (1·67 [1·06–2·63], p=0·026), and major versus minor surgery (1·52 [1·01–2·31], p=0·047). Interpretation: Postoperative pulmonary complications occur in half of patients with perioperative SARS-CoV-2 infection and are associated with high mortality. Thresholds for surgery during the COVID-19 pandemic should be higher than during normal practice, particularly in men aged 70 years and older. Consideration should be given for postponing non-urgent procedures and promoting non-operative treatment to delay or avoid the need for surgery. Funding: National Institute for Health Research (NIHR), Association of Coloproctology of Great Britain and Ireland, Bowel and Cancer Research, Bowel Disease Research Foundation, Association of Upper Gastrointestinal Surgeons, British Association of Surgical Oncology, British Gynaecological Cancer Society, European Society of Coloproctology, NIHR Academy, Sarcoma UK, Vascular Society for Great Britain and Ireland, and Yorkshire Cancer Research

Burnout Among Surgeons in the UK During the COVID-19 Pandemic: A Cohort Study

BackgroundSurgeon burnout has implications for patient safety and workforce sustainability. The aim of this study was to establish the prevalence of burnout among surgeons in the UK during the COVID-19 pandemic.MethodsThis cross-sectional online survey was set in the UK National Health Service and involved 601 surgeons across the UK of all specialities and grades. Participants completed the Maslach Burnout Inventory and a bespoke questionnaire. Outcome measures included emotional exhaustion, depersonalisation and low personal accomplishment, as measured by the Maslach Burnout Inventory-Human Services Survey (MBI-HSS).ResultsA total of 142 surgeons reported having contracted COVID-19. Burnout prevalence was particularly high in the emotional exhaustion (57%) and depersonalisation (50%) domains, while lower on the low personal accomplishment domain (15%). Burnout prevalence was unrelated to COVID-19 status; however, the greater the perceived impact of COVID-19 on work, the higher the prevalence of emotional exhaustion and depersonalisation. Degree of worry about contracting COVID-19 oneself and degree of worry about family and friends contacting COVID-19 was positively associated with prevalence on all three burnout domains. Across all three domains, burnout prevalence was exceptionally high in the Core Trainee 1–2 and Specialty Trainee 1–2 grades.ConclusionsThese findings highlight potential undesirable implications for patient safety arising from surgeon burnout. Moreover, there is a need for ongoing monitoring in addition to an enhanced focus on mental health self-care in surgeon training and the provision of accessible and confidential support for practising surgeons

Identification of Surgeon Burnout via a Single-Item Measure

BackgroundBurnout is endemic in surgeons in the UK and linked with poor patient safety and quality of care, mental health problems, and workforce sustainability. Mechanisms are required to facilitate the efficient identification of burnout in this population. Multi-item measures of burnout may be unsuitable for this purpose owing to assessment burden, expertise required for analysis, and cost.AimsTo determine whether surgeons in the UK reporting burnout on the 22-item Maslach Burnout Inventory (MBI) can be reliably identified by a single-item measure of burnout.MethodsConsultant (n = 333) and trainee (n = 217) surgeons completed the MBI and a single-item measure of burnout. We applied tests of discriminatory power to assess whether a report of high burnout on the single-item measure correctly classified MBI cases and non-cases.ResultsThe single-item measure demonstrated high discriminatory power on the emotional exhaustion burnout domain: the area under the curve was excellent for consultants and trainees (0.86 and 0.80), indicating high sensitivity and specificity. On the depersonalisation domain, discrimination was acceptable for consultants (0.76) and poor for trainees (0.69). In contrast, discrimination was acceptable for trainees (0.71) and poor for consultants (0.62) on the personal accomplishment domain.ConclusionsA single-item measure of burnout is suitable for the efficient assessment of emotional exhaustion in consultant and trainee surgeons in the UK. Administered regularly, such a measure would facilitate the early identification of at-risk surgeons and swift intervention, as well as the monitoring of group-level temporal trends to inform resource allocation to coincide with peak periods

Mechanisms underlying obesity-related insulin resistance

This thesis investigates the effect of body composition on insulin resistance and the impact of supplementation with nutritional support or carbohydrate treatment. Insulin resistance occurs as a response to a number of stressors, including surgery. However, the mechanism underlying the development of insulin resistance is as yet unclear. Adipose tissue distribution appears to play a role in the development of insulin resistance and obesity-related complications. In obese and non-obese patients undergoing open abdominal surgery who received preoperative carbohydrate or placebo, there was a significant fall in perioperative insulin sensitivity and changes in the expression of genes relating to carbohydrate and fat oxidation. There was no influence of perioperative carbohydrate or obesity on change in insulin sensitivity. Patients undergoing neoadjuvant chemotherapy for oesophageal cancer underwent pre and post chemotherapy assessment of insulin sensitivity and body composition. There was a significant reduction in insulin sensitivity despite minimal change in body composition and adequate nutritional intake. These studies have provided further information about the optimal methods for assessment of insulin sensitivity and body composition as well as an insight into mechanisms underlying the association between body composition and insulin sensitivity

Mixed Periampullary Adenocarcinoma and Somatostatinoma with Small Bowel Gastrointestinal Stromal Tumour in Neurofibromatosis Type 1

Context Gastrointestinal (GI) involvement is present in about one quarter of cases of neurofibromatosis type 1 (NF1). Adenocarcinomas have been reported in several organs. Gastrointestinal stromal tumors are the most common GI lesion seen in NFI. GISTs in combination with ampullary neuroendocrine tumors in NF-1 have been reported rarely. Case report We present the case of a 44-year-old man who presented with a history of obstructive jaundice and weight loss. Investigations revealed a pancreatic tumor associated with a common bile duct (CBD) stricture. At operation, an ampullary adenocarcinoma that infiltrated into the head of pancreas with an adjacent somatostatinoma was found. In addition, a small bowel GIST was present. Conclusions Mixed periampullary adenocarcinoma and somatostatinoma in a patient with NF1 has only been previously reported once. The current case highlights the spectrum of associated tumor types which can be seen in association with NF1. Patients with NF1 who present with jaundice and weight loss should be investigated in the usual manner with increased suspicion for duodenal and ampullary tumors.Image: MRCP demonstrating significant intra-hepatic biliary duct dilatation

Lymphoepithelial Cyst of the Pancreas and Elevated Cyst Fluid Carcinoembryonic Antigen: A Diagnostic Challenge

Context Pancreatic lymphoepithelial cysts are rare, benign cysts which can present diagnostic difficulties. Non-invasive imaging alone is unreliable in distinguishing between benign and malignant cysts. Endoscopic ultrasound (EUS) and fine needle aspiration (FNA) with analysis of cyst fluid is more reliable, but invasive. In addition, tumor markers such as carcinoembryonic antigen (CEA) can be grossly elevated in cyst fluid of benign cysts. Case report We present the case of a 67 year old man with an incidental finding of a pancreatic cyst. EUS and FNA-guided aspiration of cyst fluid was performed. Fluid CEA was grossly elevated and resectional surgery was performed. On histological examination the diagnosis was confirmed as lymphoepithelial cyst of the pancreas. Conclusion Tumor markers such as CEA can be elevated in the cyst fluid of benign pancreatic conditions such as lymphoepithelial cyst. Although the diagnosis is challenging preoperatively, if a systematic algorithm is followed, these conditions can be managed safely and efficiently.Image: Low power view of cyst lined by squamous epithelium with lymphoid tissue in wall and adjacent pancreatic lobule

Three Cases of Concomitant Intraductal Papillary Mucinous Neoplasm and Pancreatic Neuroendocrine Tumour

Context Intraductal papillary mucinous neoplasms (IPMNs) are uncommon tumours which can be associated with pancreatic and extrapancreatic malignancies. The association of IPMN and neuroendocrine tumours of the pancreas has been reported previously but is exceedingly rare. Case report We report three cases of IPMN treated with total pancreatectomy/extended distal pancreatectomy. Histopathological analysis of the resected specimens revealed concomitant IPMN and neuroendocrine tumour. Two patients had adenocarcinoma as well. Conclusions The presence of an IPMN may place the entire pancreas at risk of developing other tumour types and vigilance during all stages of management is necessary to ensure optimal treatment.Image: Total pancreatectomy and cholecystectomy