Tracking Salmonella-Specific CD4 T Cells In Vivo Reveals a Local Mucosal Response to a Disseminated Infection

AbstractA novel adoptive transfer system was used to track the fate of naive Salmonella-specific CD4 T cells in vivo. These cells showed signs of activation in the Peyer's patches as early as 3 hr after oral infection. The activated CD4 T cells then produced IL-2 and proliferated in the T cell areas of these tissues before migrating into the B cell-rich follicles. In contrast, Salmonella-specific CD4 T cells were not activated in the spleen and very few of these cells migrated to the liver, despite the presence of bacteria in both organs. These results show that the T cell response to pathogenic Salmonella infection is localized to the gut-associated lymphoid tissue and does not extend efficiently to the major sites of late infection

Management of malignant T1 colorectal cancer polyps: results from a 10-year prospective observational study

Aim: The recurrence risk associated with residual malignant cells (bowel wall/regional nodes) following T1 colorectal cancer (CRC) polypectomy must be weighed against operative morbidity. Our aim was to describe the management and outcomes of a large prospective cohort of T1 CRCs. Method: All T1 CRCs diagnosed between March 2007 and March 2017 at the Glasgow Royal Infirmary were included. Patients were grouped by polypectomy, rectal local excision and formal resection status. χ2 testing, multivariate binary logistic and Cox regression were performed. Results: Of 236 patients, 90 (38.1%) underwent polypectomy only, six (2.6%) polypectomy and then rectal excision, 57 (24.2%) polypectomy and then resection, 14 (5.9%) rectal excision only and 69 (29.2%) primary resection. Polypectomy only correlated with male sex (P = 0.028), older age (P < 0.001), distal CRCs (P < 0.001) and pedunculated polyps (P < 0.001); primary resection with larger polyps (P < 0.001); polypectomy then resection with piecemeal excision (P = 0.002) and involved polypectomy margin (P < 0.001). Poor differentiation (OR 7.860, 95% CI 1.117–55.328; P = 0.038) independently predicted lymph node involvement. Submucosal venous invasion (hazard ratio [HR] 10.154, 95% CI 2.087–49.396; P = 0.004) and mucinous subtype (HR 7.779, 95% CI 1.566–38.625; P = 0.012) independently predicted recurrence. Submucosal venous invasion (HR 5.792, 95% CI 1.056–31.754; P = 0.043) predicted CRC-specific survival. Although 64.4% of polypectomy-only patients had margin involvement/other risk factors, none developed recurrence. Of 94 with polypectomy margin involvement, five (5.3%) had confirmed residual tumour. Overall, lymph node metastases (7.1%), recurrence (4.2%) and cancer-specific mortality (3.0%) were rare. Cancer-specific 5-year survival was high: polypectomy only (100%), polypectomy and then resection (98.2%), primary resection (100%). Conclusion: Surveillance may be safe for more T1 CRC polyp patients. Multidisciplinary team discussion and informed patient choice are critical

The relationship between anaesthetic technique, clinicopathological characteristics and the magnitude of the postoperative systemic inflammatory response in patients undergoing elective surgery for colon cancer

Background/aim: The magnitude of the postoperative systemic inflammatory response (SIR) is now recognised to be associated with both short and long-term outcomes in patients undergoing surgery for colon cancer. During such surgery, it is unclear whether the anaesthetic regimens influence the magnitude of the postoperative SIR, independent of other factors. The aim of the present study was to examine the association between anaesthetic agents, clinicopathological characteristics and the magnitude of the postoperative SIR in patients undergoing elective surgery for colon cancer. Methods: Patients with colon cancer who underwent elective open or laparoscopic surgery between 2008 and 2016 (n = 409) were studied at a single center. The relationship between type of anaesthesia, surgical technique; open (n = 241) versus laparoscopic (n = 168) and clinicopathological characteristics was examined by using chi-square testing. The chi-square test was used to determine which anaesthetic group influences the POD 2 CRP for only patients undergoing elective open colon surgery. Results: The majority of patients were <75 years old, male, normal weight or obese, underwent open surgery and had regional anaesthesia, in particular an epidural approach. There was a significant association between type of anaesthesia and post-operative CRP on day 2 (p <0.001) in patients undergoing open surgery but not laparoscopic surgery. Other factors associated with type of anaesthesia included; year of operation (p <0.01), surgical technique (p <0.001), and preoperative dexamethasone (p <0.01). Conclusion: In patients undergoing surgery for elective colon cancer, the type of anaesthesia varied over time. The type of anaesthesia appears to influence the magnitude of the postoperative SIR on post-operative day 2 in open surgery but not laparoscopic surgery. Future work using prospective study design is required to better define this relationship

Attitudes towards the use of perioperative steroids in resectional colorectal cancer surgery in the UK: a qualitative study

Introduction: Resectional surgery remains the mainstay of treatment for colorectal cancer. A heightened postoperative systemic inflammatory response has been shown to correlate negatively with short/long-term outcomes. Perioperative steroid administration may help to alleviate this systemic inflammatory response. This survey has been carried out to assess current attitudes towards perioperative steroid use and to gauge interest in a randomised control trial in this area. Method: An internet-based survey consisting of 9 questions was circulated via email. Those responses from outside the United Kingdom were excluded. Result: 74 doctors from the United Kingdom, predominantly Consultant Anaesthetists (54%) responded to this survey. 77% gave some or all of their patients steroids, in 75% of cases at the discretion of the anaesthetist. The main perceived benefit was to reduce postoperative nausea and vomiting. Diabetics and those deemed at high risk of wound infection were the group in whom most respondents would be reluctant to give steroids. 32% of respondents had no concerns. 87% of respondents felt that that a randomised trial in this field would be of clinical interest with most respondents (58%) preferring a three-armed trial – no steroids vs low dose steroids vs high dose steroids. Conclusion: – This survey indicated that perioperative steroid use is currently widespread. Sufficient equipoise exists for a trial in this area with regard to examining the impact of dexamethasone on postoperative complications and the postoperative systemic inflammatory response. Respondents favoured a 3-armed trial – no steroids vs low-dose steroids vs high-dose steroids

Possible dose dependent effect of perioperative dexamethasone and laparoscopic surgery on the postoperative systemic inflammatory response and complications following surgery for colon cancer

Background: Perioperative dexamethasone is associated with attenuation of the postoperative systemic inflammatory response and fewer postoperative complications following elective surgery for colorectal cancer. This study examined the impact of different doses of dexamethasone, given to reduce postoperative nausea and vomiting (PONV) after elective colonic resection for cancer, on the postoperative Glasgow Prognostic Score (poGPS) and morbidity. Methods: Patients from a single centre were included if they underwent potentially curative resection of colonic cancer from 2008 to 2017 (n = 480). Patients received no dexamethasone (209, 44%), or either 4 mg (166, 35%), or 8 mg (105, 21%), intravenously during anaesthesia, at the discretion of the anaesthetist. The postoperative Glasgow Prognostic Score (poGPS) on day 3 and 4, and complication rate at discharge were recorded. Results: When patients were grouped by surgical approach (open or laparoscopic) and dexamethasone dose (0 mg, 4 mg or 8 mg), there was a statistically significant linear trend toward a lower postoperative systemic inflammatory response (day 3 poGPS) with the use of minimally invasive surgery and higher doses of dexamethasone (p < 0.001). Furthermore, this combination of laparoscopic surgery and higher doses of dexamethasone was significantly associated with a lower proportion of postoperative complications (p < 0.001). At multivariate Cox regression, dexamethasone was not significantly associated with either improved or poorer cancer specific or overall survival. Conclusions: Higher doses of perioperative dexamethasone are associated with greater reduction in postoperative systemic inflammation and complications following surgery for colonic cancer without negative impact on survival

The pre treatment systemic inflammatory response is an important determinant of poor pathologic response for patients undergoing neoadjuvant therapy for rectal cancer

Background Not all patients respond equally to neoadjuvant chemoradiotherapy (nCRT), with subsequent effects on survival. The systemic inflammatory response has been shown to predict long-term outcomes in colorectal cancer. The current study examined the association between systemic inflammation and nCRT in patients with rectal cancer. Methods Between 1999 and 2010, patients who underwent nCRT were identified. Serum measurements of hemoglobin, C-reactive protein, albumin, modified Glasgow prognostic score (mGPS), and differential white cell counts were obtained before and after nCRT. The Rödel scoring system measured pathologic tumor regression, and magnetic resonance imaging and computed tomography determined radiologic staging. Results The study included 79 patients. Of these patients, 37% were radiologically downstaged, and 44% were categorized as showing a good pathologic response (Rödel scores 3 and 4). As a validated measure of the systemic inflammatory response, mGPS (P = 0.022) was associated with a poor pathologic response to nCRT. A radiologic response was associated with a good pathologic response to treatment (P = 0.003). A binary logistic regression model identified mGPS (odds ratio [OR] 0.27; 95% confidence interval [CI] 0.07–0.96; P = 0.043) and radiologic response (OR 0.43; 95% CI 0.18–0.99; P = 0.048) as strong independent predictors of a pathologic response to treatment. Conclusion The current study showed that a systemic inflammatory response before nCRT is associated with a poor pathologic response. Further study in a prospective controlled trial setting is warranted. Stephan B. Dreyer and Arfon G. M. T. Powell—contributed equally. Colorectal cancer (CRC) is the third most common cancer and the second highest cause of cancer death in the United Kingdom.1 The 5-year survival rate for CRC still is less than 60% with surgery alone, offering the only chance of cure. Rectal cancers comprise about one third of surgical resections for colorectal cancer.2 The widely adapted surgical technique of total mesorectal excision (TME), increased centralization, specialization of rectal surgery, and earlier disease detection have led to improved survival in the last 30 years.3,4 Preoperative neoadjuvant radiotherapy with or without chemotherapy currently is accepted as a standard of care for patients with margin-threatening rectal cancer. This increases disease-free survival (DFS) and sphincter preservation rates and improves circumferential resection margins and local recurrence rates.5–8 Current management of CRC in the United Kingdom involves evaluating patients using magnetic resonance imaging (MRI) and computed tomography (CT) before treatment to identify those with margin-threatening disease (T3 or T4).9 These patients are offered neoadjuvant chemoradiotherapy (nCRT) before surgical resection.10 Not all patients respond to nCRT, and there is a need to identify biomarkers of response because treatment is associated with significant morbidity. Rödel et al.11 have shown that the presence of spontaneous apoptosis in the resected specimen is a good marker of tumor regression and improved prognosis. The prognostic value of the systemic inflammatory response (SIR) has been widely studied in gastrointestinal cancers, particularly in the operative setting, using measurements of circulating markers including C-reactive protein (CRP), albumin, the modified Glasgow prognostic score (mGPS), the neutrophil lympocyte ratio (NLR), the platelet-to-lymphocyte ratio (PLR), and more recently, the neutrophil-platelet score (NPS) and the derived neutrophil-to-lymphocyte ratio (dNLR).12–16 This study investigated the association between markers of the systemic inflammatory response and the pathologic response to nCRT in patients with rectal cancer

Temporal Expression of Bacterial Proteins Instructs Host CD4 T Cell Expansion and Th17 Development

Pathogens can substantially alter gene expression within an infected host depending on metabolic or virulence requirements in different tissues, however, the effect of these alterations on host immunity are unclear. Here we visualized multiple CD4 T cell responses to temporally expressed proteins in Salmonella-infected mice. Flagellin-specific CD4 T cells expanded and contracted early, differentiated into Th1 and Th17 lineages, and were enriched in mucosal tissues after oral infection. In contrast, CD4 T cells responding to Salmonella Type-III Secretion System (TTSS) effectors steadily accumulated until bacterial clearance was achieved, primarily differentiated into Th1 cells, and were predominantly detected in systemic tissues. Thus, pathogen regulation of antigen expression plays a major role in orchestrating the expansion, differentiation, and location of antigen-specific CD4 T cells in vivo

Postoperative C-reactive protein concentrations to predict infective complications following gastrectomy for cancer

Background and Objectives: Gastrectomy for gastric cancer is associated with significant infective postoperative complications. C-reactive protein (CRP) is a useful biomarker in the early detection of infective complications following major abdominal surgery. This single-centre retrospective study aimed to determine the relationship between postoperative CRP levels and development of postoperative infective complications after gastrectomy. Methods: Daily postoperative CRP levels were analyzed to determine a CRP threshold associated with infective complications. ROC curve analysis was used to determine which postoperative day (POD) gave the optimal cutoff. Multivariate analysis was performed to determine significant factors associated with complications. Results: One hundred and forty-four patients were included. A total of 61 patients (42%) had at least one infective complication. A CRP level of 220 mg/L was associated with the highest AUC (0.765) with a sensitivity of 70% and specificity of 76% (positive predictive value, 67%; negative predictive value, 78%). More patients with a CRP > 220 mg/L on POD 3 developed infective complications (67% vs. 21%, p < 0.001). Conclusions: A CRP of more than 220 mg/L on POD 3 may be useful to alert clinicians to the increased risk of a postoperative infective complication or enable earlier safe discharge from critical care for those with a lower value

Staging the tumour and staging the host: Pre-treatment combined Neutrophil Lymphocyte Ratio and modified Glasgow Prognostic Score is associated with overall survival in patients with oesophagogastric cancers undergoing treatment with curative intent

Background: This study examined whether an innate systemic inflammatory response (SIR) measured by combination neutrophil to lymphocyte ratio (NLR) and modified Glasgow Prognostic Score (mGPS) was associated with overall survival (OS) in patients with esophagogastric cancer (EC) undergoing neoadjuvant chemotherapy (NAC) followed by surgery. Methods: Patients diagnosed with EC, managed with NAC prior to surgery at a regional referral center, between January 2010 and December 2015, were included. The mGPS and NLR were calculated within 12 weeks before NAC. Patients were grouped by combined NLR/mGPS score into three groups of increasing SIR: NLR ≤ 3 (n = 152), NLR > 3 + mGPS = 0 (n = 55), and NLR > 3 + mGPS > 0 (n = 32). Univariable and multivariable Cox regression was used to analyse OS. Results: Overall, 337 NAC patients were included, with 301 (89%) proceeding to surgery and 215 (64%) having R0 resection. There were 203 deaths, with a median follow-up of those alive at censor of 69 months (range 44–114). Higher combined NLR/mGPS score (n = 239) was associated with poorer OS independent of clinical stage and performance status (hazard ratio 1.28, 95% confidence interval 1.02–1.61; p = 0.032), higher rate of progression on NAC (7% vs. 7% vs. 19%; p = 0.003), and lower proportion of eventual resection (80% vs. 84% vs. 53%; p = 0.003). Conclusions: The combined NLR/mGPS score was associated with OS and initial treatment outcomes in patients undergoing NAC prior to surgery for EC, stratifying survival in addition to clinical staging and performance status. The host SIR may be a useful adjunct to multidisciplinary decision making

Yield of colorectal cancer at colonoscopy according to faecal haemoglobin concentration in symptomatic patients referred from primary care

Background: Lower gastrointestinal (GI) symptoms are poor predictors of colorectal cancer (CRC). This study examined the diagnostic yield of colonoscopy by faecal haemoglobin concentration (f‐Hb) in symptomatic patients assessed in primary care by faecal immunochemical testing (FIT). Methods: In three Scottish NHS Boards, FIT kits (HM‐JACKarc, Hitachi Chemical Diagnostics Systems Co., Ltd, Tokyo, Japan) were used by GPs to guide referrals for patients with lower GI symptoms (lab data studied for 12 months from December 2015 onward in Tayside, 18 months from June 2018 onward in Fife, and 5 months from September 2018 onward in Greater Glasgow and Clyde). CRC cases diagnosed at colonoscopy were ascertained from colonoscopy and pathology records. Results: 4841 symptomatic patients who underwent colonoscopy after FIT submission were included. Of 2166 patients (44.7%) with f‐Hb <10 µg Hb/g faeces (µg/g), 14 (0.6%) were diagnosed with CRC, with a number needed to scope (NNS) of 155. Of 2675 patients (55.3%) with f‐Hb ≥10 µg/g, 252 were diagnosed with CRC (9.4%) with a NNS of 11. Of 705 patients with f‐Hb ≥400 µg/g, 158 (22.4%) were diagnosed with CRC with a NNS of 5. Over half of those diagnosed with CRC with f‐Hb <10 µg/g had co‐existing anaemia. Conclusions: Symptomatic patients with f‐Hb ≥10 µg/g should undergo further investigation for CRC, while higher f‐Hb could be used to triage its urgency during the COVID‐19 recovery phase. Patients with f‐Hb <10 µg/g, without anaemia, are very unlikely to be diagnosed with CRC and the majority need no further investigation