Publications by authors named "Paul G Horgan"

133 Publications

The role of faecal calprotectin in the identification of colorectal neoplasia in patients attending for screening colonoscopy.

Colorectal Dis 2021 Oct 6. Epub 2021 Oct 6.

Academic Unit of Surgery, School of Medicine, University of Glasgow, Glasgow Royal Infirmary, Glasgow, UK.

Introduction: Although the relationship between colorectal neoplasia and inflammation is well described, the role of faecal calprotectin (FC) in clinical practice to diagnose or screen patients for colorectal neoplasia is less defined. This prospective study characterises the relationship between faecal calprotectin (FC) and colorectal neoplasia in patients within the FOBT positive patients in the Scottish Bowel Screening Programme (SoBSP).

Methods: All FOBT positive patients attending for colonoscopy between February 2016 and July 2017 were invited to participate. Patients provided a stool sample for faecal calprotectin pre commencing bowel preparation. All demographics and endoscopic findings were collected prospectively.

Results: 352 patients were included. 210 patients had a FC >50µg. Colorectal cancer (CRC) patients had a higher median FC (138.5ug/g, p <0.05), in comparison to those without CRC, and 13/14 had a FC >50µg/g (93%). FC had a high sensitivity (92.8%) and negative predictive value (NPV) (99.3%) for CRC, but with a low specificity (41.7%) and positive predictive value (PPV) (6.2%). FC sensitivity increased sequentially as neoplasm progressed from non-advanced to malignant neoplasia (48.6% non-advanced adenoma vs. 92.9% CRC). However, there was no significant relationship observed between FC and non-cancer neoplasia.

Conclusion: In a FOBT positive screening population, FC was strongly associated with CRC (sensitivity 92.8%, specificity 41.7% for CRC, at 50µg/g). However, although sensitive for the detection of CRC, FC failed to show sufficient sensitivity nor specificity for the detection of non-cancer neoplasia. Based on these results we cannot recommend routine use of FC in a bowel screening population to detect cancer per se, but it is apparent that with further optimisation, faecal assessments including quantification of haemoglobin and inflammation could form part of a risk assessment tool aimed at refining selection of patients for colonoscopy in both symptomatic and screening populations.
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http://dx.doi.org/10.1111/codi.15942DOI Listing
October 2021

Longitudinal Changes in CT Body Composition in Patients Undergoing Surgery for Colorectal Cancer and Associations With Peri-Operative Clinicopathological Characteristics.

Front Nutr 2021 16;8:678410. Epub 2021 Aug 16.

Academic Unit of Surgery, School of Medicine, University of Glasgow, Glasgow Royal Infirmary, Glasgow, United Kingdom.

There is evidence for the direct association between body composition, the magnitude of the systemic inflammatory response, and outcomes in patients with colorectal cancer. Patients with a primary operable disease with and without follow-up CT scans were examined in this study. CT scans were used to define the presence and changes in subcutaneous fat, visceral fat, skeletal muscle mass, and skeletal muscle density (SMD). In total, 804 patients had follow-up scans and 83 patients did not. Furthermore, 783 (97%) patients with follow-up scans and 60 (72%) patients without follow-up scans were alive at 1 year. Patients with follow-up scans were younger ( < 0.001), had a lower American Society of Anaesthesiology Grade ( < 0.01), underwent a laparoscopic surgery ( < 0.05), had a higher BMI ( < 0.05), a higher skeletal muscle index (SMI) ( < 0.01), a higher SMD ( < 0.01), and a better 1-year survival ( < 0.001). Overall only 20% of the patients showed changes in their SMI ( = 161) and an even lower percentage of patients showed relative changes of 10% ( = 82) or more. In conclusion, over the period of ~12 months, a low-skeletal muscle mass was associated with a systemic inflammatory response and was largely maintained following surgical resection.
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http://dx.doi.org/10.3389/fnut.2021.678410DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8415565PMC
August 2021

MIR21-induced loss of junctional adhesion molecule A promotes activation of oncogenic pathways, progression and metastasis in colorectal cancer.

Cell Death Differ 2021 Oct 5;28(10):2970-2982. Epub 2021 Jul 5.

Division of Molecular Pathology, Centre for Evolution and Cancer, The Institute of Cancer Research, London, UK.

Junctional adhesion molecules (JAMs) play a critical role in cell permeability, polarity and migration. JAM-A, a key protein of the JAM family, is altered in a number of conditions including cancer; however, consequences of JAM-A dysregulation on carcinogenesis appear to be tissue dependent and organ dependent with significant implications for the use of JAM-A as a biomarker or therapeutic target. Here, we test the expression and prognostic role of JAM-A downregulation in primary and metastatic colorectal cancer (CRC) (n = 947). We show that JAM-A downregulation is observed in ~60% of CRC and correlates with poor outcome in four cohorts of stages II and III CRC (n = 1098). Using JAM-A knockdown, re-expression and rescue experiments in cell line monolayers, 3D spheroids, patient-derived organoids and xenotransplants, we demonstrate that JAM-A silencing promotes proliferation and migration in 2D and 3D cell models and increases tumour volume and metastases in vivo. Using gene-expression and proteomic analyses, we show that JAM-A downregulation results in the activation of ERK, AKT and ROCK pathways and leads to decreased bone morphogenetic protein 7 expression. We identify MIR21 upregulation as the cause of JAM-A downregulation and show that JAM-A rescue mitigates the effects of MIR21 overexpression on cancer phenotype. Our results identify a novel molecular loop involving MIR21 dysregulation, JAM-A silencing and activation of multiple oncogenic pathways in promoting invasiveness and metastasis in CRC.
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http://dx.doi.org/10.1038/s41418-021-00820-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8481293PMC
October 2021

The inflammatory microenvironment in screen-detected premaligant adenomatous polyps: early results from the integrated technologies for improved polyp surveillance (INCISE) project.

Eur J Gastroenterol Hepatol 2021 07;33(7):983-989

Academic Unit of Surgery, University of Glasgow, Glasgow Royal Infirmary.

Introduction: Around 40% of patients who attend colonoscopy following a positive stool screening test have adenomatous polyps. Identifying which patients have a higher propensity for malignant transformation is currently poorly understood. The aim of the present study was to assess whether the type and intensity of inflammatory infiltrate differ between screen-detected adenomas with high-grade dysplasia (HGD) and low-grade dysplasia (LGD).

Methods: A representative sample of 207 polyps from 134 individuals were included from a database of all patients with adenomas detected through the first round of the Scottish Bowel Screening Programme in NHS Greater Glasgow and Clyde (April 2009-April 2011). Inflammatory cell phenotype infiltrate was assessed by immunohistochemistry for CD3+, CD8+, CD45+ and CD68+ in a semi-quantitative manner at 20× resolution. Immune-cell infiltrate was graded as absent, weak, moderate or strong. Patient and polyp characteristics and inflammatory infiltrate were then compared between HGD and LGD polyps.

Results: CD3+ infiltrate was significantly higher in HGD polyps compared to LGD polyps (74 vs. 69%; P < 0.05). CD8+ infiltrate was significantly higher in HGD polyps compared to LGD polyps (36 vs. 13%; P < 0.001) whereas CD45+ infiltrate was not significantly different (69 vs. 64%; P = 0.401). There was no significant difference in CD68+ infiltrate (P = 0.540) or total inflammatory cell infiltrate (calculated from CD3+ and CD68+) (P = 0.226).

Conclusions: This study reports an increase in CD3+ and CD8+ infiltrate in HGD colonic adenomas when compared to LGD adenomas. It may therefore have a use in the prognostic stratification and treatment of dysplastic polyps.
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http://dx.doi.org/10.1097/MEG.0000000000002202DOI Listing
July 2021

The Relationship Between Co-morbidity, Screen-Detection and Outcome in Patients Undergoing Resection for Colorectal Cancer.

World J Surg 2021 07 27;45(7):2251-2260. Epub 2021 Mar 27.

Academic Unit of Surgery, University of Glasgow, New Lister Building, Glasgow Royal Infirmary, 8-16 Alexandra Parade, Glasgow, G31 2ER, UK.

Background: Bowel cancer screening increases early stage disease detection and reduces cancer-specific mortality. We assessed the relationship between co-morbidity, screen-detection and survival in colorectal cancer.

Methods: A retrospective, observational cohort study compared screen-detected (SD) and non-screen-detected (NSD) patients undergoing potentially curative resection (April 2009-March 2011). Co-morbidity was quantified using ASA, Lee and Charlson Indices. Systemic inflammatory response was measured using the neutrophil lymphocyte ratio (NLR). Covariables were compared using crosstabulation and the χ2 test for linear trend. Survival was analysed using Cox Regression.

Results: Of 770 patients, 331 had SD- and 439 NSD-disease. A lower proportion of SD patients had a high ASA (≥3) compared to NSD (27.2% vs 37.3%; p = 0.007). There was no significant difference in the proportion of patients with a high (≥2) Lee Index (16.3% SD vs 21.9% NSD; p = 0.054) or high (≥3) Charlson Index (22.7% SD vs 26.9% NSD; p = 0.181). On univariate analysis, NSD (HR 2.182 (1.594-2.989;p < 0.001)), emergency presentation (HR 3.390 (2.401-4.788; p < 0.001)), advanced UICC-TNM (III or IV) (p < 0.001), high ASA (≥3) (HR 1.857 (1.362-2.532; p < 0.001)), high Charlson Index (≥3) (HR 1.800 (1.333-2.432; p < 0.001)) and high (≥3) NLR (HR 1.825 (1.363-2.442; p < 0.001)) were associated with poorer overall survival (OS). NSD predicted poorer cancer-specific survival (CSS) (HR 2.763 (1.776-4.298; p < 0.001)). On multivariate analysis, NSD retained significance as an independent predictor of poorer OS (HR 1.796 (1.224-2.635; p = 0.003)) and CSS (HR 1.924 (1.193-3.102; p = 0.007)).

Conclusions: Patients with SD cancers have significantly lower ASA scores. After adjusting for ASA, co-morbidity and a broad range of covariables, SD patients retain significantly better OS and CSS.
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http://dx.doi.org/10.1007/s00268-021-06079-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8154830PMC
July 2021

The prognostic value of combined measures of the systemic inflammatory response in patients with colon cancer: an analysis of 1700 patients.

Br J Cancer 2021 May 24;124(11):1828-1835. Epub 2021 Mar 24.

Academic Unit of Surgery-Glasgow Royal Infirmary, Glasgow, UK.

Background: The pre-operative systemic inflammatory response (SIR) measured using an acute-phase-protein-based score (modified Glasgow Prognostic Score (mGPS)) or the differential white cell count (neutrophil-lymphocyte ratio (NLR)) demonstrates prognostic significance following curative resection of colon cancer. We investigate the complementary use of both measures to better stratify outcomes.

Methods: The effect on survival of mGPS and NLR was examined using uni/multivariate analysis (UVA/MVA) in patients undergoing curative surgery for colon cancer. The synergistic effect of these scores in predicting OS/CSS was examined using a Systemic Inflammatory Grade (SIG).

Results: One thousand seven hundred and eight patients with TNM-I-III colon cancer were included. On MVA both mGPS and NLR were significant for OS (HR 1.16/1.21, respectively). Three-year survival stratified by mGPS was 83-58%(TNM-I-III), 87-65%(TNM-II) and 75-49%(TNM-III), and by NLR was 84-62%(TNM-I-III), 88-69%(TNM-II) and 77-49%(TNM-III). When mGPS and NLR were combined to form an overall SIG 0/1/2/3/4, this stratified 3-year OS 88%/84%/76%/65%/60% and CSS 93%/90%/82%/73%/70%, respectively (both p < 0.001). SIG stratified OS 93-68%/82-48% and CSS 97-80%/86-58% in TNM Stage II/III disease, respectively (all p < 0.001).

Conclusions: The present study shows that the pre-operative SIR in patients undergoing curative surgery for colon cancer is best measured using a SIG utilising mGPS and NLR.
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http://dx.doi.org/10.1038/s41416-021-01308-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8144393PMC
May 2021

Vascular calcification and response to neoadjuvant therapy in locally advanced rectal cancer: an exploratory study.

J Cancer Res Clin Oncol 2021 Nov 12;147(11):3409-3420. Epub 2021 Mar 12.

Academic Unit of Colorectal Surgery, University of Glasgow, Glasgow Royal Infirmary, Level 2, New Lister Building 10, 16 Alexandra Parade, Glasgow, G31 2ER, UK.

Purpose: Patients with locally advanced rectal cancer (LARC) may experience a clinical complete response (cCR) to neoadjuvant chemoradiotherapy (NACRT) and opt for non-operative management. Pathological factors that relate to NACRT response have been well described. Host factors associated with response, however, are poorly defined. Calcification of the aortoiliac (AC) vessels supplying the rectum may influence treatment response.

Methods: Patients with LARC having NACRT prior to curative surgery at Glasgow Royal Infirmary (GRI) and St Mark's hospital (SMH) between 2008 and 2016 were identified. AC was scored on pre-treatment CT imaging. NACRT response was assessed using pathologic complete response (pCR) rates, tumour regression grades (TRGs), the NeoAdjuvant Rectal score and T-/N-downstaging. Associations were assessed using Chi-squared, Mantel-Haenszel and Fisher's exact tests.

Results: Of 231 patients from GRI, 79 (34%) underwent NACRT for LARC. Most were male (58%), aged over 65 (51%) with mid- to upper rectal tumours (56%) and clinical T3/4 (95%), node-positive (77%) disease. pCR occurred in 10 patients (13%). Trends were noted between higher clinical T stage and poor response by Royal College of Pathologist's TRG (p = 0.021) and tumour height > 5 cm and poor response by Mandard TRG (0.068). In the SMH cohort, 49 of 333 (15%) patients underwent NACRT; 8 (16%) developed a pCR. AC was not associated with NACRT response in either cohort.

Conclusions: AC was not associated with NACRT response in this cohort. Larger contemporary cohorts are required to better assess host determinants of NACRT response and develop predictive models to improve patient selection.
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http://dx.doi.org/10.1007/s00432-021-03570-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8484095PMC
November 2021

The effect of anesthesia on the magnitude of the postoperative systemic inflammatory response in patients undergoing elective surgery for colorectal cancer in the context of an enhanced recovery pathway: A prospective cohort study.

Medicine (Baltimore) 2021 Jan;100(2):e23997

School of Medicine, Academic Unit of Surgery, Institute of Cancer Sciences, University of Glasgow, Glasgow, UK.

Abstract: There are reports that the use of regional anesthesia (RA) may be associated with better perioperative surgical stress response in cancer patients compared with general anesthetics (GA). However, the role of anesthesia on the magnitude of the postoperative systemic inflammatory response (SIR) in colorectal cancer patients, within an enhanced recovery pathway (ERP), is not clear.The aim of the present study was to examine the effect of anesthesia, within an enhanced recovery pathway, on the magnitude of the postoperative SIR in patients undergoing elective surgery for colorectal cancer.Database of 507 patients who underwent elective open or laparoscopic colorectal cancer surgery between 2015 and 2019 at a single center was studied. The anesthetic technique used was categorized into either GA or GA + RA using a prospective proforma. The relationship between each anesthetic technique and perioperative clinicopathological characteristics was examined using binary logistic regression analysis.The majority of patients were male (54%), younger than 65 years (41%), either normal or overweight (64%), and were nonsmokers (47%). Also, the majority of patients underwent open surgery (60%) and received mainly general + regional anesthetic technique (80%). On univariate analysis, GA + RA was associated with a lower day 4 CRP (≤150/>150 mg/L) concentration. On day 4, postoperative CRP was associated with anesthetic technique [odds ratio (OR) 0.58; confidence interval (CI) 0.31-1.07; P = .086], age (OR 0.70; CI 0.50-0.98; P = .043), sex (OR 1.15; CI 0.95-2.52; P = .074), smoking (OR 1.57; CI 1.13-2.19; P = .006), preoperative mGPS (OR 1.55; CI 1.15-2.10; P = .004), and preoperative dexamethasone (OR 0.70; CI 0.47-1.03; P = .072). On multivariate analysis, day 4 postoperative CRP was independently associated with anesthetic technique (OR 0.56; CI 0.32-0.97; P = .039), age (OR 0.74; CI 0.55-0.99; P = .045), smoking (OR 1.58; CI 1.18-2.12; P = .002), preoperative mGPS (OR 1.41; CI 1.08-1.84; P = .012), and preoperative dexamethasone (OR 0.68; CI 0.50-0.92; P = .014).There was a modest but an independent association between RA and a lower magnitude of the postoperative SIR. Future work is warranted with multicenter RCT to precisely clarify the relationship between anesthesia and the magnitude of the postoperative SIR.
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http://dx.doi.org/10.1097/MD.0000000000023997DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7808526PMC
January 2021

Relationship between immune checkpoint proteins, tumour microenvironment characteristics, and prognosis in primary operable colorectal cancer.

J Pathol Clin Res 2021 03 18;7(2):121-134. Epub 2020 Dec 18.

Unit of Experimental Therapeutics, Institute of Cancer Sciences, Wolfson-Wohl Cancer Research Centre, Glasgow, UK.

The tumour microenvironment is an important factor for colorectal cancer prognosis, affecting the patient's immune response. Immune checkpoints, which regulate the immune functions of lymphocytes, may provide prognostic power. This study aimed to investigate the prognostic value of the immune checkpoints TIM-3, LAG-3 and PD-1 in patients with stage I-III colorectal cancer. Immunohistochemistry was employed to detect TIM-3, LAG-3, PD-1 and PD-L1 in 773 patients with stage I-III colorectal cancer. Immune checkpoint protein expression was assessed in tumour cells using the weighted histoscore, and in immune cells within the stroma using point counting. Scores were analysed for associations with survival and clinical factors. High tumoural LAG-3 (hazard ratio [HR] 1.45 95% confidence interval [CI] 1.00-2.09, p = 0.049) and PD-1 (HR 1.34 95% CI 1.00-1.78, p = 0.047) associated with poor survival, whereas high TIM-3 (HR 0.60 95% CI 0.42-0.84, p = 0.003), LAG-3 (HR 0.58 95% CI 0.40-0.87, p = 0.006) and PD-1 (HR 0.65 95% CI 0.49-0.86, p = 0.002) on immune cells within the stroma associated with improved survival, while PD-L1 in the tumour (p = 0.487) or the immune cells within the stroma (p = 0.298) was not associated with survival. Furthermore, immune cell LAG-3 was independently associated with survival (p = 0.017). Checkpoint expression scores on stromal immune cells were combined into a Combined Immune Checkpoint Stromal Score (CICSS), where CICSS 3 denoted all high, CICSS 2 denoted any two high, and CICSS 1 denoted other combinations. CICSS 3 was associated with improved patient survival (HR 0.57 95% CI 0.42-0.78, p = 0.001). The results suggest that individual and combined high expression of TIM-3, LAG-3, and PD-1 on stromal immune cells are associated with better colorectal cancer prognosis, suggesting there is added value to investigating multiple immune checkpoints simultaneously.
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http://dx.doi.org/10.1002/cjp2.193DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7869939PMC
March 2021

The relationship between F-FDG-PETCT-derived tumour metabolic activity, nutritional risk, body composition, systemic inflammation and survival in patients with lung cancer.

Sci Rep 2020 11 30;10(1):20819. Epub 2020 Nov 30.

Academic Unit of Surgery, School of Medicine, University of Glasgow, Glasgow Royal Infirmary, New Lister Building, Glasgow, G4 0SF, UK.

The aim of this study was to examine the relationship between PET-CT derived tumour glucose uptake as measured by maximum standard glucose uptake (SUVmax) and total lesion glycolysis (TLG), nutritional risk as measured by the malnutrition universal screening tool (MUST), CT derived body composition as measured by skeletal muscle index (SMI) and skeletal muscle radiodensity (SMD), the systemic inflammatory response as measured by the modified Glasgow prognostic score (mGPS) and the neutrophil to lymphocyte ratio (NLR) and survival in patients with lung cancer, treated with radiotherapy. In a retrospective cohort study, 119 patients were included in final analyses. The majority of patients were over 65 (86%), female (52%), had a performance status (ECOG-PS) of 0 or 1 (57%), were at nutritional risk (57%), were overweight (53%), had visceral obesity (62%), had a normal SMI (51%), had a low SMD (62%) and were systemically inflammed (mGPS 1/2, 51%). An elevated TLG was associated with sex (p < 0.05), TNM stage (p < 0.001), MUST (p < 0.01) and mGPS (p < 0.01). An elevated mGPS was associated with age (p < 0.05), NLR (p < 0.01), MUST (p < 0.01), and TLG (p < 0.01). On univariate survival analysis, TNM stage (p < 0.01), mGPS (p < 0.05), NLR (p < 0.01), MUST (p ≤ 0.001), Low SMD (p < 0.05), SUVmax (p ≤ 0.001) and TLG (p < 0.001) were associated with overall survival. On multivariate survival analysis MUST (HR: 1.49 95%CI 1.12-01.98 p < 0.01) and TLG (HR: 2.02 95%CI 1.34-3.04 p = 0.001) remained independently associated with survival. In conclusion, elevated tumour metabolic activity was associated with more advanced stage, greater nutritional risk, the systemic inflammatory response and poorer survival but not body composition analysis in patients with lung cancer. These results suggest that detrimental body composition is not directly determined by tumour metabolic activity but rather an ongoing systemic inflammatory response.
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http://dx.doi.org/10.1038/s41598-020-77269-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7705735PMC
November 2020

The Glasgow Microenvironment Score associates with prognosis and adjuvant chemotherapy response in colorectal cancer.

Br J Cancer 2021 02 23;124(4):786-796. Epub 2020 Nov 23.

School of Medicine, University of Glasgow, Glasgow, UK.

Background: The Glasgow Microenvironment Score (GMS) combines peritumoural inflammation and tumour stroma percentage to assess interactions between tumour and microenvironment. This was previously demonstrated to associate with colorectal cancer (CRC) prognosis, and now requires validation and assessment of interactions with adjuvant therapy.

Methods: Two cohorts were utilised; 862 TNM I-III CRC validation cohort, and 2912 TNM II-III CRC adjuvant chemotherapy cohort (TransSCOT). Primary endpoints were disease-free survival (DFS) and relapse-free survival (RFS). Exploratory endpoint was adjuvant chemotherapy interaction.

Results: GMS independently associated with DFS (p = 0.001) and RFS (p < 0.001). GMS significantly stratified RFS for both low risk (GMS 0 v GMS 2: HR 3.24 95% CI 1.85-5.68, p < 0.001) and high-risk disease (GMS 0 v GMS 2: HR 2.18 95% CI 1.39-3.41, p = 0.001). In TransSCOT, chemotherapy type (p = 0.013), but not duration (p = 0.64) was dependent on GMS. Furthermore, GMS 0 significantly associated with improved DFS in patients receiving FOLFOX compared with CAPOX (HR 2.23 95% CI 1.19-4.16, p = 0.012).

Conclusions: This study validates the GMS as a prognostic tool for patients with stage I-III colorectal cancer, independent of TNM, with the ability to stratify both low- and high-risk disease. Furthermore, GMS 0 could be employed to identify a subset of patients that benefit from FOLFOX over CAPOX.
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http://dx.doi.org/10.1038/s41416-020-01168-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7884404PMC
February 2021

Aortic calcification is associated with non-infective rather than infective postoperative complications following colorectal cancer resection: an observational cohort study.

Eur Radiol 2021 Jun 17;31(6):4319-4329. Epub 2020 Nov 17.

Academic Unit of Colorectal Surgery, University of Glasgow, Level 2, New Lister Building, Glasgow Royal Infirmary, 10 - 16 Alexandra Parade, Glasgow, G31 2ER, UK.

Objectives: Complications following colorectal cancer resection are common. The degree of aortic calcification (AC) on CT has been proposed as a predictor of complications, particularly anastomotic leak. This study assessed the relationship between AC and complications in patients undergoing colorectal cancer resection.

Methods: Patients from 2008 to 2016 were retrospectively identified from a prospectively maintained database. Complications were classified using the Clavien-Dindo (CD) scale. Calcification was quantified on preoperative CT by visual assessment of the number of calcified quadrants in the proximal and distal aorta. Scores were grouped into categories: none, minor (< median AC score) and major (> median AC score). The relationship between clinicopathological characteristics and complications was assessed using logistic regression.

Results: Of 657 patients, 52% had proximal AC (> median score (1)) and 75% had distal AC (> median score (4)). AC was more common in older patients and smokers. Higher burden of AC was associated with non-infective complications (proximal AC 28% vs 16%, p = 0.004, distal AC 26% vs 14% p = 0.001) but not infective complications (proximal AC 28% vs 29%, p = 0.821, distal AC 29% vs 23%, p = 0.240) or anastomotic leak (proximal AC 6% vs 4%, p = 0.334, distal AC 7% vs 3%, p = 0.077). Independent predictors of complications included open surgery (OR 1.99, 95%CI 1.43-2.79, p = 0.001), rectal resection (OR 1.51, 95%CI 1.07-2.12, p = 0.018) and smoking (OR 2.56, 95%CI 1.42-4.64, p = 0.002).

Conclusions: These data suggest that high levels of AC are associated with non-infective complications after colorectal cancer surgery and not anastomotic leak.

Key Points: • Aortic calcification measured by visual quantification of the number of calcified quadrants at two aortic levels on preoperative CT is associated with clinical outcome following colorectal cancer surgery. • An increased burden of aortic calcification was associated with non-infective complications but not anastomotic leak. • Assessment of the degree of aortic calcification may help identify patients at risk of cardiorespiratory complications, improve preoperative risk stratification and assign preoperative strategies to improve fitness for surgery.
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http://dx.doi.org/10.1007/s00330-020-07189-7DOI Listing
June 2021

Comparison of the prognostic value of MUST, ECOG-PS, mGPS and CT derived body composition analysis in patients with advanced lung cancer.

Clin Nutr ESPEN 2020 12 6;40:349-356. Epub 2020 Sep 6.

Academic Unit of Surgery, School of Medicine, University of Glasgow, Glasgow Royal Infirmary, Glasgow, UK.

Background: Assessment of malnutrition, performance status and systemic inflammation are routine aspects of clinical assessment in patients with advanced cancer. There is increasing evidence that body composition measurements from routine staging CT also have prognostic value. To date the relative prognostic value of Malnutrition Universal Screening Tool (MUST), Eastern Cooperative Oncology Group Performance Status (ECOG-PS), modified Glasgow Prognostic score (mGPS) and CT derived body composition analysis in patients with advanced lung cancer has not been examined. The aim of the present study was to examine this relationship.

Methods: Clinicopathological characteristics including MUST, ECOG-PS, mGPS and body composition data were collected pre-radiotherapy from a prospectively maintained database of patients with advanced lung cancer (n = 643). Using the MUST score, patients were classified into low (MUST = 0, n = 189), medium (MUST = 1, n = 341) and high (MUST ≥ 2, n = 113) malnutrition risk and their relationship to systemic inflammatory response (SIR) and body composition with clinical outcomes were examined using univariate and multivariate analyses. Primary outcome of the study was overall survival.

Results: Compared with the patients at low nutrition risk (MUST = 0), patients at moderate to high risk (MUST 1-≥2) had poorer ECOG-PS > 1 (p < 0.01), elevated modified frailty index (mFI) (p < 0.001), elevated mGPS (p < 0.001), lower skeletal muscle index (SMI, p < 0.01) but not lower skeletal muscle density (SMD, p = 0.115). MUST was an important prognostic marker of 12 months overall survival (p = 0.001). On multivariate analysis, higher MUST (HR 1.16, 95% CI 1.03-1.31, p < 0.05), ECOG-PS > 1 (HR 1.23, 95% CI 1.10-1.39, p < 0.001), elevated mGPS (HR 1.20, 95% CI 1.09-1.33, p < 0.001) were independently associated with overall survival.

Conclusion: A large proportion of patients (71%) with advanced lung cancer were at moderate to high nutrition risk. Higher malnutrition risk and elevated inflammatory status were independently associated with poor overall survival. MUST, ECOG-PS and mGPS all had independent prognostic value and may form an important prognostic framework in treatment decision making and resource utilization.
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http://dx.doi.org/10.1016/j.clnesp.2020.08.003DOI Listing
December 2020

A comparison of the prognostic value of composite ratios and cumulative scores in patients with operable rectal cancer.

Sci Rep 2020 10 21;10(1):17965. Epub 2020 Oct 21.

Academic Unit of Surgery, School of Medicine, University of Glasgow, Glasgow Royal Infirmary, New Lister Building, Glasgow, G4 0SF, UK.

The aim of this study was to directly compare the prognostic value of cumulative scores and composite ratios in patients with operable rectal cancer. Within a single surgical unit preoperative differential blood cell results including neutrophil (N), lymphocyte (L), monocyte (M) and platelet (P) counts, as well as CRP (C) and albumin (A) levels were recorded. These results were used to construct a series of composite ratios (NLR, PLR, LMR, CAR) and cumulative scores (NLS, PLS, LMS, NPS, mGPS). The relationship between composite ratios and the cumulative scores and clinicopathological characteristics, cancer specific survival (CSS) and overall survival (OS) were examined. A total of 413 patients were included. When adjusted for TNM stage, surgical approach, time of surgery and margin involvement mGPS (p < 0.05) was associated with CSS. In addition, most composite ratios/scores showed correlations with neoadjuvant therapy (p < 0.001). When a direct comparison between NPS (myeloid) and mGPS (liver) was carried out they showed similar associations with both CSS and OS. Therefore, both composite ratios and cumulative scores have been shown to be prognostic in patients with operable rectal cancer.
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http://dx.doi.org/10.1038/s41598-020-73909-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7578034PMC
October 2020

The relationship between computed tomography derived skeletal muscle index, psoas muscle index and clinical outcomes in patients with operable colorectal cancer.

Clin Nutr ESPEN 2020 10 2;39:104-113. Epub 2020 Aug 2.

Academic Unit of Surgery, School of Medicine, University of Glasgow, Glasgow Royal Infirmary, Glasgow, UK.

Background: Computed tomography-based measures of body composition are emerging as important prognostic factors for patients with colorectal cancer (CRC). The aim of this study was to examine the relationship between total skeletal muscle index (SMI), psoas muscle index (PMI) and clinical outcomes in patients with operable CRC.

Methods: A retrospective cohort study of prospectively maintained database at Glasgow Royal Infirmary. CT image at L3 was carried out to assess total skeletal and psoas muscle areas and these were normalized for height squared to calculate SMI and PMI respectively. Patients were classified into high and low groups using calculated optimal thresholds and their relationship to clinical outcomes was studied using logistic regression analysis.

Results: Of the 1002 patients included, 55% were male, 50% had low SMI and 42% had low PMI. A moderate correlation was found between total skeletal muscle and psoas areas (r = 0.70, p < 0.001). On univariate analysis, low SMI was associated with length of hospital stay (OR, 1.47; 95% CI, 1.15-1.89, p = 0.002) and overall survival (HR, 2.29; 95% CI, 1.47-3.58, p < 0.001). On multivariate analysis, low SMI was independently associated with length of hospital stay (HR 1.32; 95% CI, 1.02-1.70, p < 0.05). On univariate analysis, low PMI was associated with length of hospital stay (OR, 1.34; 95% CI, 1.04-1.73, p < 0.05) and overall survival (OR, 1.43; 95% CI, 1.10-1.86 p < 0.01). On multivariate analysis, low PMI was not independently significant.

Conclusion: The present study shows that though both total skeletal muscle index and psoas muscle index were directly associated and had prognostic value, total skeletal muscle index had independent prognostic value in patients with operable CRC.
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http://dx.doi.org/10.1016/j.clnesp.2020.07.010DOI Listing
October 2020

The impact of preoperative systemic inflammation on the efficacy of intravenous iron infusion to correct anaemia prior to surgery for colorectal cancer.

Perioper Med (Lond) 2020 11;9:17. Epub 2020 Jun 11.

School of Medicine and Dentistry, University Department of Surgery, Academic Unit of Surgery, Glasgow Royal Infirmary, University of Glasgow, Level 2, New Lister Building, Alexandra Parade, Glasgow, G4 0SF UK.

Aim: Intravenous iron is increasingly used prior to surgery for colorectal cancer (CRC) to correct iron deficiency anaemia and reduce blood transfusion. Its utility in functional iron deficiency (FID) or anaemia of inflammation is less clear. This observational study examined post-iron infusion changes in haemoglobin (Hb) based on grouping by C-reactive protein (CRP) and ferritin.

Methods: Anaemic (M:Hb < 130 mg/L, F:Hb < 120 mg/L) patients with CRC receiving iron infusion, within a preoperative anaemia detection and correction protocol, at a single centre between 2016 and 2019 were included. Patients were grouped by iron deficiency (ferritin < 30 μg/L and CRP ≤ 5 mg/L, = 18), FID (ferritin < 30 μg/L and CRP > 5 mg/L, = 17), anaemia of inflammation (ferritin ≥ 30 μg/L and CRP > 5 mg/L, = 6), and anaemia of other causes (ferritin ≥ 30 μg/L and CRP ≤ 5 mg/L, = 6). Median change in Hb and postoperative day (POD) 1 Hb was compared by Kruskal-Wallis test.

Results: Iron-deficient patients had the greatest increase in Hb after infusion (24 mg/L), highest POD 1 Hb (108 mg/L), and required no blood transfusions. Patients with FID had the second greatest increase in Hb (15 mg/L) and second highest POD 1 Hb (103 mg/L). Those with anaemia of inflammation had little increase in Hb after infusion (3 mg/L) and lower POD 1 Hb (102 mg/L) than either iron-deficient group. Those without iron deficiency showed a decrease in haemoglobin after infusion (- 5 mg/L) and lowest POD 1 Hb (95 mg/L).

Conclusions: Preoperative intravenous iron is less efficacious in patients with anaemia of inflammation and FID undergoing surgery for CRC, compared with true iron deficiency. Further understanding of the role of perioperative iron infusions is required for maximum gain from therapy.
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http://dx.doi.org/10.1186/s13741-020-00146-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7288411PMC
June 2020

Histological phenotypic subtypes predict recurrence risk and response to adjuvant chemotherapy in patients with stage III colorectal cancer.

J Pathol Clin Res 2020 10 13;6(4):283-296. Epub 2020 May 13.

Institute of Cancer Sciences, University of Glasgow, Glasgow, UK.

Histological 'phenotypic subtypes' that classify patients into four groups (immune, canonical, latent and stromal) have previously been demonstrated to stratify survival in a stage I-III colorectal cancer (CRC) pilot cohort. However, clinical utility has not yet been validated. Therefore, this study assessed prognostic value of these subtypes in additional patient cohorts along with associations with risk of recurrence and response to chemotherapy. Two independent stage I-III CRC patient cohorts (internal and external cohort) were utilised to investigate phenotypic subtypes. The primary endpoint was disease-free survival (DFS) and the secondary endpoint was recurrence risk (RR). Stage II-III patients, from the SCOT adjuvant chemotherapy trial, were utilised to further validate prognostic value and for exploratory analysis assessing associations with adjuvant chemotherapy. In an 893-patient internal cohort, phenotypic subtype independently associated with DFS (p = 0.025) and this was attenuated in stage III patients (p = 0.020). Phenotypic subtype also independently associated with RR (p < 0.001) in these patients. In a 146-patient external cohort, phenotypic subtype independently stratified patients by DFS (p = 0.028), validating their prognostic value. In 1343 SCOT trial patients, the effect of treatment type significantly depended on phenotypic subtype (p = 0.011). Phenotypic subtype independently associated with DFS in stage III patients receiving FOLFOX (p = 0.028). Furthermore, the immune subtype significantly associated with better response to FOLFOX compared to CAPOX adjuvant chemotherapy in stage III patients (p = 0.013). In conclusion, histological phenotypic subtypes are an effective prognostic classification in patients with stage III CRC that associates with risk of recurrence and response to FOLFOX adjuvant chemotherapy.
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http://dx.doi.org/10.1002/cjp2.171DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7578335PMC
October 2020

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

PLoS One 2020 29;15(4):e0228580. Epub 2020 Apr 29.

Institute of Cancer Sciences, Department of Surgery, School of Medicine, Dentistry & Nursing-University of Glasgow, Glasgow, United Kingdom.

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.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0228580PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7190171PMC
July 2020

Systemic Inflammation and Outcome in 2295 Patients with Stage I-III Colorectal Cancer from Scotland and Norway: First Results from the ScotScan Colorectal Cancer Group.

Ann Surg Oncol 2020 Aug 4;27(8):2784-2794. Epub 2020 Apr 4.

Academic Unit of Surgery, School of Medicine Dentistry and Nursing, College of Medicine, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.

Background: Systemic inflammatory response (SIR) is an adverse prognostic marker in colorectal cancer (CRC) patients. The ScotScan Colorectal Cancer Group was established to examine how markers of the SIR differ between populations and may be utilised to guide prognosis.

Patients And Methods: Patients undergoing resection of stage I-III CRC from two prospective datasets in Scotland and Norway were included. The relationship between the modified Glasgow Prognostic Score (mGPS; combination of C-reactive protein and albumin) and overall survival (OS) was examined. The relationship between OS, adjuvant chemotherapy regime and mGPS was examined in patients with stage III colon cancer.

Results: A total of 2295 patients were included. Patients from Scotland were more inflamed despite controlling for associated characteristics using multivariate logistic regression or propensity score matching (OR 2.82, 95% CI 1.98-4.01, p < 0.001). mGPS had similar independent prognostic value in both cohorts (Scotland: HR 1.27, 95% CI 1.12-1.45; Norway: HR 1.23, 95% CI 1.01-1.49) and stratified survival independent of TNM group in the whole cohort. In patients with stage III colon cancer receiving adjuvant therapy, there appeared to be a survival benefit in systemically inflamed patients receiving oxaliplatin but not single-agent 5-fluorouracil or capecitabine.

Conclusions: The SIR differs between populations from different countries; however prognostic value remains similar. The present study strongly supports the routine reporting of the mGPS in patients with CRC.
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http://dx.doi.org/10.1245/s10434-020-08268-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7334267PMC
August 2020

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

Ann Med Surg (Lond) 2019 Dec 11;48:23-28. Epub 2019 Oct 11.

Academic Unit of Surgery, Glasgow Royal Infirmary, Glasgow, G31 2ER, United Kingdom.

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 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.
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http://dx.doi.org/10.1016/j.amsu.2019.10.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6820077PMC
December 2019

Perioperative Blood Transfusion is Associated with Postoperative Systemic Inflammatory Response and Poorer Outcomes Following Surgery for Colorectal Cancer.

Ann Surg Oncol 2020 Mar 29;27(3):833-843. Epub 2019 Oct 29.

Academic Unit of Surgery, University of Glasgow, Glasgow, UK.

Background: The present study investigated relationships between perioperative blood transfusion, postoperative systemic inflammatory response, and outcomes following surgery for colorectal cancer.

Methods: Data were recorded for patients (n = 544) undergoing potentially curative, elective surgery for colorectal cancer at a single center between 2012 and 2017. Transfusion history was obtained retrospectively from electronic records. Associations between blood transfusion, postoperative C-reactive protein (CRP), albumin, hemoglobin, complications, cancer-specific survival and overall survival (OS) were assessed using propensity score matching (n =116).

Results: Of 544 patients, the majority were male (n =294, 54%), over 65 years of age (n =350, 64%), and with colonic (n =347, 64%) node-negative disease (n =353, 65%). Eighty-six patients (16%) required perioperative blood transfusion. In the unmatched cohort, blood transfusion was associated with higher median postoperative day (POD) 3 CRP {143 [interquartile range (IQR) 96-221 mg/L] vs. 120 (IQR 72-188 mg/L); p = 0.004}, lower median POD 3 albumin [24 (IQR 20-26 g/L) vs. 27 (IQR 24-30 g/L); p < 0.001], more postoperative complications [odds ratio (OR) 3.28, 95% confidence interval (CI) 2.03-5.29] and poorer OS [hazard ratio (HR) 3.18, 95% CI 2.08-4.84]. In the propensity score matched cohort, blood transfusion was similarly associated with higher median POD 3 CRP [130 (IQR 93-196 mg/L) vs. 113 (IQR 66-173 mg/L); p = 0.046], lower median POD 3 albumin [24 (IQR 20-26 g/L) vs. 26 (IQR 24-30 g/L); p < 0.001], more postoperative complications (OR 2.91, 95% CI 1.36-6.20) and poorer OS (HR 2.38, 95% CI 0.99-5.73).

Conclusions: Perioperative blood transfusion was associated with postoperative inflammation, complications, and poorer survival in patients undergoing colorectal cancer surgery, with and without propensity score techniques.
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http://dx.doi.org/10.1245/s10434-019-07984-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7000540PMC
March 2020

The Relationship Between Tumor Budding, Tumor Microenvironment, and Survival in Patients with Primary Operable Colorectal Cancer.

Ann Surg Oncol 2019 Dec 11;26(13):4397-4404. Epub 2019 Oct 11.

Unit of Gastrointestinal Cancer and Molecular Pathology, Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.

Background: Tumor budding is an independent prognostic factor in colorectal cancer (CRC) and has recently been well-defined by the International Tumour Budding Consensus Conference (ITBCC).

Objective: The aim of the present study was to use the ITBCC budding evaluation method to examine the relationship between tumor budding, tumor factors, tumor microenvironment, and survival in patients with primary operable CRC.

Methods: Hematoxylin and eosin-stained slides of 952 CRC patients diagnosed between 1997 and 2007 were evaluated for tumor budding according to the ITBCC criteria. The tumor microenvironment was evaluated using tumor stroma percentage (TSP) and Klintrup-Makinen (KM) grade to assess the tumor inflammatory cell infiltrate.

Results: High budding (n = 268, 28%) was significantly associated with TNM stage (p < 0.001), competent mismatch repair (MMR; p < 0.05), venous invasion (p < 0.001), weak KM grade (p < 0.001), high TSP (p < 0.001), and reduced cancer-specific survival (CSS) (hazard ratio 8.68, 95% confidence interval 6.30-11.97; p < 0.001). Tumor budding effectively stratifies CSS stage T1 through to T4 (all p < 0.05) independent of associated factors.

Conclusions: Tumor budding effectively stratifies patients' survival in primary operable CRC independent of other phenotypic features. In particular, the combination of T stage and budding should form the basis of a new staging system for primary operable CRC.
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http://dx.doi.org/10.1245/s10434-019-07931-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6863941PMC
December 2019

The relationship between members of the canonical NF-kB pathway, tumour microenvironment and cancer specific survival in colorectal cancer patients.

Histol Histopathol 2020 Jun 8;35(6):569-578. Epub 2019 Oct 8.

Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom.

Background: The aim of this study was to investigate the role of the upstream kinase TAK1 and the canonical NF-κB pathway colorectal in cancer (CRC). Immunohistochemistry was used to assess the expression of TAK1/pTAK1 and canonical NF-κB pathway members in a tissue microarray of 242 patients. The relationship between expression, the tumour microenvironment and cancer-specific survival were examined.

Results: All the investigated members of the pathway were expressed in CRC tissue. In addition, cytoplasmic pTAK1 was associated with the tumour microenvironment (P=0.045) and cancer-specific survival (CSS) (P=0.032). When cytoplasmic pTAK1 was stratified by BRAF status, cytoplasmic pTAK1 expression association with CSS was strengthened (P=0.014). Cytoplasmic IKKβ was significantly associated with the inflammatory cell infiltrate (P=0.015) as graded by Klintrup Makinen grade, systemic inflammation as assessed by neutrophil-lymphocyte ratio (P=0.03) and CSS (P=0.046). On multivariate analysis cytoplasmic IKKβ was independently associated with CSS (HR 1.75,95%CI 1.05-2.91, P=0.033).

Conclusion: Cytoplasmic pTAK1 was significantly associated with CSS and this was enhanced in patients with tumours that expressed wild type BRAF. High expression of cytoplasmic IKKβ was significantly associated with decreased CSS and with markers of the tumour microenvironment. These results support the hypothesis that NF-κB pathway members are poor prognostic markers in patients with CRC, but this requires to be validated in a large independent cohort.
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http://dx.doi.org/10.14670/HH-18-168DOI Listing
June 2020

Epithelial NOTCH Signaling Rewires the Tumor Microenvironment of Colorectal Cancer to Drive Poor-Prognosis Subtypes and Metastasis.

Cancer Cell 2019 09;36(3):319-336.e7

Cancer Research UK Beatson Institute, Glasgow, UK; Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Glasgow, UK. Electronic address:

The metastatic process of colorectal cancer (CRC) is not fully understood and effective therapies are lacking. We show that activation of NOTCH1 signaling in the murine intestinal epithelium leads to highly penetrant metastasis (100% metastasis; with >80% liver metastases) in Kras-driven serrated cancer. Transcriptional profiling reveals that epithelial NOTCH1 signaling creates a tumor microenvironment (TME) reminiscent of poorly prognostic human CRC subtypes (CMS4 and CRIS-B), and drives metastasis through transforming growth factor (TGF) β-dependent neutrophil recruitment. Importantly, inhibition of this recruitment with clinically relevant therapeutic agents blocks metastasis. We propose that NOTCH1 signaling is key to CRC progression and should be exploited clinically.
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http://dx.doi.org/10.1016/j.ccell.2019.08.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6853173PMC
September 2019

An exploratory study examining the relationship between performance status and systemic inflammation frameworks and cytokine profiles in patients with advanced cancer.

Medicine (Baltimore) 2019 Sep;98(37):e17019

Academic Unit of Surgery, School of Medicine, University of Glasgow, Glasgow Royal Infirmary, Glasgow.

The role of cytokines in the systemic inflammatory response (SIR) is now well established. This is in keeping with the role of the SIR in tumorigenesis, malignant spread, and the development of cachexia. However, the relationship between performance status/systemic inflammation frameworks and cytokine profiles is not clear. The aim of the present study was to examine the relationship between the Eastern cooperative oncology group performance status/modified Glasgow prognostic score (ECOG-PS/mGPS) and cooperative oncology group performance status/neutrophil platelet score (ECOG-PS/NPS) frameworks and their cytokine profile in patients with advanced cancer.This was a retrospective interrogation of data already collected as part of a recent clinical trial (NCT00676936). The relationship between the independent variables (ECOG-PS/mGPS and ECOG-PS/NPS frameworks), and dependent variables (cytokine levels) was examined using independent Mann-Whitney U and Kruskal Wallis tests where appropriate.Of the 40 patients included in final analysis the majority had evidence of an SIR assessed by mGPS (78%) or NPS (53%). All patients died on follow-up and the median survival was 91 days (4-933 days). With increasing ECOG-PS there was a higher median value of Interleukin 6 (IL-6, P = .016) and C-reactive protein (CRP, P < .01) and lower albumin (P < .01) and poorer survival (P < .001). With increasing mGPS there was a higher median value of IL-6 (P = .016), Macrophage migration inhibitory factor (MIF, P = .010), erythrocyte sedimentation rate (ESR, P < .01) and poorer survival (P < .01). With increasing NPS there was a higher median value of TGF-β (P < .001) and C-reactive protein (P = .020) and poor survival (P = .001). When those patients with an ECOG-PS 0/1 and mGPS0 were compared with those patients with an ECOG-PS 2 and mGPS2 there was a higher median value of IL-6 (P = .017) and poorer survival (P < .001). When those patients with an ECOG-PS 0/1 and NPS0 were compared with those patients with an ECOG-PS 2 and NPS1/2 there was a higher median value of IL-6 (P = .002), TGF-β (P < .001) and poorer survival (P < .01).In patients with advanced cancer IL-6 was associated with the ECOG-PS/mGPS and ECOG-PS/NPS frameworks and survival in patients with advanced cancer. Therefore, the present work provides supporting evidence that agents targeting IL-6 are worthy of further exploration.
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http://dx.doi.org/10.1097/MD.0000000000017019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6750290PMC
September 2019

Preoperative, biopsy-based assessment of the tumour microenvironment in patients with primary operable colorectal cancer.

J Pathol Clin Res 2020 01 14;6(1):30-39. Epub 2019 Oct 14.

Academic Unit of Surgery, School of Medicine Dentistry and Nursing, College of Medicine Veterinary and Life Sciences, University of Glasgow, Glasgow Royal Infirmary, Glasgow, UK.

The tumour microenvironment (TME) is recognised as an important prognostic characteristic and therapeutic target in patients with colorectal cancer (CRC). However, assessment generally utilises surgically resected specimens, precluding neoadjuvant targeting. The present study investigated the feasibility of intra-epithelial CD3 T-lymphocyte density and tumour stroma percentage (TSP) assessment using preoperative colonoscopic biopsies from 115 patients who had undergone resection of stages I-III CRC, examining the relationship between biopsy and surgically resected specimen-based assessment, and the relationship with cancer-specific survival (CSS). High biopsy CD3 density was associated with high CD3 density in the invasive margin, cancer stroma and intra-epithelial compartments of surgically resected specimens (area under the curve > 0.62, p < 0.05 for all) and with high Immunoscore. High biopsy TSP predicted high TSP in resected specimens (p = 0.001). Intra-class correlation coefficient for both measures was >0.7 (p < 0.001), indicating excellent concordance between individuals. Biopsy CD3 density (hazard ratio [HR] 0.23, p = 0.002) and TSP (HR 2.23, p = 0.029) were independently associated with CSS; this was comparable to the prognostic value of full section assessment (HR 0.21, p = 0.004, and HR 2.25, p = 0.033 respectively). These results suggest that assessment of the TME is comparable in biopsy and surgically resected specimens from patients with CRC, and biopsy-based assessment could allow for stratification prior to surgery or commencement of therapy targeting the TME.
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http://dx.doi.org/10.1002/cjp2.143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6966701PMC
January 2020

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

Eur J Surg Oncol 2019 Sep 20;45(9):1613-1618. Epub 2019 May 20.

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.
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http://dx.doi.org/10.1016/j.ejso.2019.05.020DOI Listing
September 2019

The relationship between body mass index, sex, and postoperative outcomes in patients undergoing potentially curative surgery for colorectal cancer.

Clin Nutr ESPEN 2019 04 11;30:185-189. Epub 2019 Jan 11.

Human Nutrition, School of Medicine, Dentistry and Nursing, College of Medical, Veterinary and Life of Sciences University of Glasgow, Glasgow Royal Infirmary, Glasgow, G31 2ER, UK.

Background: There is increasing evidence that an increased BMI is associated with increased complications after surgery for colorectal cancer (CRC). However, the basis of this relationship is not clear. Since men and women have different fat distribution, with men more likely to have excess visceral fat in BMI defined obesity, there may be a sex difference in the surgical site infection (SSIs) rate in the obese. Therefore, the aim of this study was to examine the relationship between sex, BMI, clinic-pathological characteristics and the development of postoperative infective complications after surgery for CRC and to establish whether there were gender differences in complication following surgery for CRC.

Design: Data were recorded prospectively for patients undergoing potentially curative surgery for CRC in a single centre between 1997 and 2016. Patient characteristics were recorded and complications were classified as either infective or non-infective. The relationship between sex, BMI, associated clinicopathological characteristics and presences of complications were examined by Chi-square test for linear association and multivariate binary logistic regression model.

Results: A total of 1039 patients were included. There were significant differences in the presence of complications between male and female (p ≤ 0.001), the rate of complication was higher in obese male (44%); in particular SSIs, wound infection and anastomotic leak (p ≤ 0.05). The rate of surgical site infection was 12% in male patients with normal BMI compared with 26% in those with a BMI ≥30 (p ≤ 0.001), while the rate of SSIs in female patients was 10% in those with normal BMI and those with a BMI ≥30. In males, BMI remained significantly associated with SSI on multivariate analysis [(OR = 1.42, 95% CI 1.13-1.78) P = 0,002].

Conclusions: Obesity prior to surgery for CRC increases the risk of infective complications in both male and female. Increased BMI in male patients was associated greater risk of SSIs and wound infection compared to female patients. Male obese patients should be considered at high risk of developing post-operative infective complications.
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http://dx.doi.org/10.1016/j.clnesp.2018.12.084DOI Listing
April 2019

Relationship between computed tomography-derived body composition, sex, and post-operative complications in patients with colorectal cancer.

Eur J Clin Nutr 2019 11 11;73(11):1450-1457. Epub 2019 Mar 11.

Academic Unit of Surgery, College of Medical, Veterinary and Life of Sciences, Royal Infirmary, University of Glasgow, Glasgow, G31 2ER, Scotland.

Introduction: In the UK, colorectal cancer is the fourth most common cancer and the second most common cause of cancer death. Surgery is the primary modality of treatment, but it is not without complications. Post-operative complications have been linked to preoperative of weight loss and loss of lean tissue, and also to obesity. Given sex differences in body composition, an examination of body composition and post-operative complications may provide valuable information. Therefore, the aim was to examine the relationship between male/female body composition and post-operative complications in patients with operable colorectal cancer.

Methods: Patients (n = 741) undergoing operation for colorectal cancer were examined. Preoperative CT scans were used to define the muscle mass and quality, visceral obesity, and subcutaneous adiposity. Post-operative complications, in particular, surgical site infection (SSI) and wound infection (WI) were considered as outcome measures.

Results: Male patients with greater subcutaneous adiposity had higher risk of SSI and WI (p < 0.01 and p ≤ 0.001, respectively). On multivariate analysis, Post-operative Glasgow Prognostic Score (poGPS) on Day 4 (OR 2.11, 95% CI 1.53-2.92, P = 0.001) laparoscopic surgery (OR 0.50, 95% CI 0.26-0.98, P = 0.044), and subcutaneous adiposity (OR 2.71, 95% CI 1.26-5.82, P = 0.011) remained significantly independently associated with overall SSI. Subcutaneous adiposity remained significantly independently associated with WI (OR 3.93, 95% CI 1.33-11.57, P = 0.013). In female patients, however, no significant association was found between any body composition measure and complications.

Conclusion: This study showed that increased subcutaneous and visceral adiposity were associated with infective complications in male, but not female patients, after colorectal cancer surgery. Therefore, it is important that sex be taken into account when evaluating the potential impact of body composition on post-operative outcomes in patients undergoing surgery for colorectal cancer.
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http://dx.doi.org/10.1038/s41430-019-0414-0DOI Listing
November 2019
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