Publications by authors named "Donald C McMillan"

257 Publications

Computed tomography-defined low skeletal muscle index and density in cancer patients: observations from a systematic review.

J Cachexia Sarcopenia Muscle 2021 Oct 18. Epub 2021 Oct 18.

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

Background: Computed tomography (CT) analysis of body composition has garnered interest as a potential prognostic tool in those with cancer. A range of pre-defined thresholds currently exist within the literature to define low skeletal muscle mass and density. The aim of the present systematic review was to assess the prevalence of low skeletal muscle index (SMI) and density (SMD) within the literature, across a range of common solid tumours.

Methods: A systematic search of PubMed was carried out to identify studies reporting CT analysis of SMI and SMD in patients with colorectal, oesophageal, gastric, hepatobiliary, pancreatic, breast, and lung cancer. The type of cancer, whether curative or non-curative disease, the anthropomorphic parameter studied, threshold used to define low SMI and SMD, and the prevalence of these anthropomorphic measurements within the population were recorded.

Results: Of the 160 studies included, 156 reported an assessment of SMI and 35 reported assessment of SMD. The median prevalence of low SMI was 43% (30.1-57.1) and low SMD 49.4% (31.7-58.5) across the entire cohort. There was little variation in the prevalence of low SMI and SMD when studies were divided into curative and non-curative cohorts-40.7% (27.5-51.3) vs. 48.4% (30.9-60.1) and 37.8% (32.2-52.2) vs. 55.3% (38.5-64.7) respectively. When divided into colorectal, oesophageal, gastric, hepatobiliary, pancreatic, breast and lung cancers, similar prevalence of low SMI (46.0% %, 49.8%, 35.7%, 41.1%, 32.3%, 34%, and 49.5%) and low SMD were also observed (52.1%, 54.3%, 71.2%, 56.8%, 55.3%, and 52.6%). This was maintained when studies were stratified into cohorts by threshold used-low SMI (Martin 48.9%, Prado 49.9%, and Others 36.0%) and low SMD (Martin 52.4% and Others 48.6%).

Conclusions: Low SMI and SMD are endemic across a range of cancer types and disease stage, challenging pre-existing dogma of the determinants of prevalence.
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http://dx.doi.org/10.1002/jcsm.12831DOI Listing
October 2021

Systematic review of tumour budding and association with common mutations in patients with colorectal cancer.

Crit Rev Oncol Hematol 2021 Oct 4;167:103490. Epub 2021 Oct 4.

Institute of Cancer Sciences, University of Glasgow, Wolfson Wohl Cancer Research Centre, Garscube Estate, Glasgow, G61 1QH, United Kingdom. Electronic address:

Introduction: Despite a well-known prognostic role in colorectal cancer, the genomic profiling of tumour budding remains to be elucidated. We aim to review the association of common mutations with tumour budding.

Methods: A systematic review of studies relating to tumour budding and genetic mutation in CRC was performed. The relationship between mutational status and tumour budding was evaluated using meta-analysis.

Results: A total of 6153 patients from 17 articles were included. According to the meta-analysis, high-grade tumour budding was significantly associated with KRAS mutation (OR = 1.52, 95 %CI: 1.13-2.02, P = 0.005) and MSS/pMMR (OR = 2.06, 95 %CI: 1.42-2.97, P = 0.0001).

Conclusion: The significant association between high-grade tumour budding and mutated KRAS or MSS/pMMR may suggest a role of these mutations in the development of the tumour budding phenotype and be useful for stratifying patient outcome in CRC.
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http://dx.doi.org/10.1016/j.critrevonc.2021.103490DOI Listing
October 2021

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

Effect of Hepatocellular Carcinoma Surveillance Programmes on Overall Survival in a Mixed Cirrhotic UK Population: A Prospective, Longitudinal Cohort Study.

J Clin Med 2021 Jun 24;10(13). Epub 2021 Jun 24.

Department of Gastroenterology, Glasgow Royal Infirmary, Glasgow G4 0SF, UK.

Introduction: Surveillance for hepatocellular carcinoma (HCC) is recommended by national and international guidelines. However, there are no trial data on whether surveillance improves clinical outcomes in a UK cirrhosis population of mixed aetiology. Our aim was to determine the impact of, and adherence to, surveillance on overall survival.

Methods: We prospectively collected data on consecutive patients diagnosed with HCC between January 2009 and December 2015 at two large UK centres. We assessed outcomes depending on whether they had been entered into an HCC surveillance programme, and if they had adhered to that.

Results: Out of 985 patients diagnosed with HCC in this study, 40.0% had been enrolled in a surveillance programme. Of these, 76.6% were adherent with surveillance and 24.4% were not. Adherence to surveillance was significantly associated with improved overall survival, even when accounting for lead-time bias using different approaches (HR for 270 days lead-time adjustment 0.64, 0.53 to 0.76, < 0.001).

Conclusions: When adjusted for lead-time bias, HCC surveillance is associated with improved overall survival; however, the beneficial effect of surveillance on survival was lower than reported in studies that did not account fully for lead-time bias.
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http://dx.doi.org/10.3390/jcm10132770DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8269358PMC
June 2021

Relation Between Body Composition, Systemic Inflammatory Response, and Clinical Outcomes in Patients Admitted to an Urban Teaching Hospital with COVID-19.

J Nutr 2021 08;151(8):2236-2244

Emergency Department, Glasgow Royal Infirmary, Glasgow, United Kingdom.

Background: COVID-19 has been associated with cases of severe respiratory illness, admissions to intensive therapy units (ITUs), and high mortality rates.

Objectives: The aim of the present study was to examine the relation between computed tomography- body composition (CT-BC) measurements, systemic inflammation, and clinical outcomes in those with COVID-19.

Methods: Patients who presented to our institution between March 17 and May 1, 2020, with a positive PCR test for COVID-19 or characteristic radiological changes, were assessed for inclusion. Data collected included general demographic details, clinicopathological variables, poGPS, NLR , CT-BC measurements, and clinical outcomes including ITU admission and 30-d mortality, of those admitted.

Results: Sixty-three patients met the study inclusion criteria. Forty-two patients (67%) were aged ≥70 y, 30 (47.6%) were male and 34.9% ( n = 22) had a poGPS ≥1. ITU admission was significantly associated with a high VFA ( P < 0.05). Thirty-day mortality was associated with high VFA (P < 0.05) and low SMI (P < 0.05).

Conclusions: Sarcopenia in the presence of obesity was associated with clinical outcomes including greater 30-d mortality.
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http://dx.doi.org/10.1093/jn/nxab142DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8195217PMC
August 2021

The relation between acute changes in the systemic inflammatory response and circulating thiamine and magnesium concentrations after elective knee arthroplasty.

Sci Rep 2021 05 28;11(1):11271. Epub 2021 May 28.

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

Thiamine diphosphate (TDP) and magnesium are co-factors for key enzymes in human intermediary metabolism. However, their role in the systemic inflammatory response (SIR) is not clear. Therefore, the aim of the present study was to examine the relation between acute changes in the SIR and thiamine and magnesium dependent enzyme activity in patients undergoing elective knee arthroplasty (a standard reproducible surgical injury in apparently healthy individuals). Patients (n = 35) who underwent elective total knee arthroplasty had venous blood samples collected pre- and post-operatively for 3 days, for measurement of whole blood TDP, serum and erythrocyte magnesium, erythrocyte transketolase activity (ETKA), lactate dehydrogenase (LDH), glucose and lactate concentrations. Pre-operatively, TDP concentrations, erythrocyte magnesium concentrations, ETKA and plasma glucose were within normal limits for all patients. In contrast, 5 patients (14%) had low serum magnesium concentrations (< 0.75 mmol/L). On post-operative day1, both TDP concentrations (p < 0.001) and basal ETKA (p < 0.05) increased and serum magnesium concentrations decreased (p < 0.001). Erythrocyte magnesium concentrations correlated with serum magnesium concentrations (r = 0.338, p < 0.05) and remained constant during SIR. Post-operatively 14 patients (40%) had low serum magnesium concentrations. On day1 serum magnesium concentrations were directly associated with LDH (p < 0.05), WCC (p < 0.05) and neutrophils (p < 0.01). Whole blood TDP and basal ETKA increased while serum magnesium concentrations decreased, indicating increased requirement for thiamine and magnesium dependent enzyme activity during SIR. Therefore, thiamine and magnesium represent potentially modifiable therapeutic targets that may modulate the host inflammatory response. Erythrocyte magnesium concentrations are likely to be reliable measures of status, whereas serum magnesium concentrations and whole blood TDP may not.ClinicalTrials.gov: NCT03554668.
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http://dx.doi.org/10.1038/s41598-021-90591-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8163855PMC
May 2021

The systemic inflammatory response and clinicopathological characteristics in patients admitted to hospital with COVID-19 infection: Comparison of 2 consecutive cohorts.

PLoS One 2021 27;16(5):e0251924. Epub 2021 May 27.

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

Background: In order to manage the COVID-19 systemic inflammatory response, it is important to identify clinicopathological characteristics across multiple cohorts.

Methods: The aim of the present study was to compare the 4C mortality score, other measures of the systemic inflammatory response and clinicopathological characteristics in two consecutive cohorts of patients on admission with COVID-19. Electronic patient records for 2 consecutive cohorts of patients admitted to two urban teaching hospitals with COVID-19 during two 7-week periods of the COVID-19 pandemic in Glasgow, U.K. (cohort 1: 17/3/2020-1/5/2020) and (cohort 2: 18/5/2020-6/7/2020) were examined for routine clinical, laboratory and clinical outcome data.

Results: Compared with cohort 1, cohort 2 were older (p<0.001), more likely to be female (p<0.05) and have less independent living circumstances (p<0.001). More patients in cohort 2 were PCR positive, CXR negative (both p<0.001) and had low serum albumin concentrations (p<0.001). 30-day mortality was similar between both cohorts (23% and 22%). In cohort 2, age >70 (p<0.05), male gender (p<0.05), COPD (p<0.05), cognitive impairment (p<0.05), frailty (p<0.001), delirium (p = 0.001), CRP>150mg/L (p<0.05), albumin <30 g/L (p<0.01), elevated perioperative Glasgow Prognostic Score (p<0.05), elevated neutrophil-lymphocyte ratio (p<0.001), low haematocrit (p<0.01), elevated PT (p<0.05), sodium <133 mmol/L (p<0.01) elevated urea (p<0.001), creatinine (p<0.001), glucose (p<0.05) and lactate (p<0.001) and the 4C score (p<0.001) were associated with 30-day mortality. In multivariate analysis, greater frailty (CFS>3) (OR 11.3, 95% C.I. 2.3-96.7, p<0.05), low albumin (<30g/L) (OR 2.5, 95% C.I. 1.0-6.2, p<0.05), high NLR (≥3) (OR 2.2, 95% C.I. 1.5-4.5, p<0.05) and the 4C score (OR 2.4, 95% C.I. 1.0-5.6, p<0.05) remained independently associated with 30-day mortality.

Conclusion: In addition to the 4C mortality score, frailty score and a low albumin were strongly independently associated with 30-day mortality in two consecutive cohorts of patients admitted to hospital with COVID-19.

Trial Registration: clinicaltrials.gov: NCT04484545.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0251924PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8159002PMC
June 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 β-catenin and patient survival in colorectal cancer systematic review and meta-analysis.

Crit Rev Oncol Hematol 2021 Jul 13;163:103337. Epub 2021 May 13.

Unit of Experimental Therapeutics, Institute of Cancer Sciences, University of Glasgow, Wolfson Wohl Cancer Research Centre, Garscube Estate, Glasgow, G61 1QH, United Kingdom. Electronic address:

β-catenin is a key component of Wnt signalling, which plays a crucial role in CRC progression. Therefore, a meta-analysis was performed to assess the prognostic value of β-catenin expression in CRC patients. PubMed and Web of Science were searched for relevant publications referring to the association between β-catenin expression and outcome of CRC patients. Review Manager version 5.4 was employed to analysis data from 28 eligible studies (containing 5475 patients). Of these, 6 provided data on DFS, 6 provided data on CSS and 18 reports provided data on OS. High nuclear β-catenin expression was significantly associated with poorer DFS, CSS and OS in patients with CRC whereas, low membranous β-catenin expression was associated to poor OS. In conclusion, β-catenin has prognostic value and potential as a biomarker to stratify patients with CRC. However, further work with high quantity tissue cohorts and patient data is required to confirm this conclusion.
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http://dx.doi.org/10.1016/j.critrevonc.2021.103337DOI Listing
July 2021

Modified intramuscular adipose tissue content as a feasible surrogate marker for malnutrition in gastrointestinal cancer.

Clin Nutr 2021 05 17;40(5):2640-2653. Epub 2021 Apr 17.

Department of Gastrointestinal and Pediatric Surgery, Division of Reparative Medicine, Institute of Life Sciences, Mie University Graduate School of Medicine, Japan.

Background & Aims: Myosteatosis is gathering attention as a feasible indicator for sarcopenia and increased risk of morbidity. However, the prognostic value of intramuscular adipose tissue content (IMAC) as an assessment method for myosteatosis remains controversial. The objectives of this study are to compare the prognostic value of intramuscular adipose tissue content (IMAC) with our newly-developed modified IMAC (mIMAC), and to assess the clinical significance of mIMAC in colorectal cancer (CRC) and gastric cancer (GC).

Methods: We evaluated 892 patients with CRC or GC, and assessed preoperative IMAC and mIMAC to compare their prognostic and predictive values for postoperative infectious complications in both cohorts.

Results: Both preoperative IMAC and mIMAC were sex- and disease-dependent, and positively or negatively correlated with age in CRC and GC patients (IMAC: CRC: r = 0.33, P < 0.0001; GC: r = 0.304, P < 0.0001; mIMAC: CRC: r = -0.364, P < 0.0001; GC: r = -0.263, P < 0.0001). In contrast to IMAC, lower preoperative mIMAC was significantly associated with disease-development factors, and was an independent prognostic factor for both overall survival (OS) and disease-free survival (DFS) in both CRC (OS: hazard ratio (HR): 1.95, 95% confidence interval (CI): 1.25-3.03, p = 0.003; DFS: HR: 1.93, 95% CI: 1.22-3.04, p = 0.005) and GC patients (OS: HR: 2.11, 95% CI: 1.22-3.68, P = 0.008; DFS: HR: 2.03, 95% CI: 1.18-3.5, P = 0.011). Patients with postoperative remote infections had a poorer prognosis compared with those without in both cohorts (CRC: HR: 2.67, 95% CI: 1.46-4.89, P = 0.002; GC: HR: 3.01, 95% CI: 1.47-6.19, P = 0.003), and low mIMAC was an independent risk factor for postoperative remote infection in both cancers (CRC: odds ratio (OR): 2.56, 95% CI: 1.06-6.23, P = 0.038; GC: OR: 2.8, 95% CI: 1.03-7.58, P = 0.043). Finally, we assessed the correlation between IMAC or mIMAC and the representative frailty markers body mass index (BMI), serum albumin, and prognostic nutritional index (PNI). We found a positive correlation between preoperative mIMAC and all of these markers in both cohorts (CRC: BMI: r = 0.193, P < 0.0001; serum albumin: r = 0.42, P < 0.0001; PNI: r = 0.39, P < 0.0001; GC: BMI: r = 0.22, P < 0.0001; serum albumin: r = 0.212, P < 0.0001; PNI: r = 0.287, P < 0.0001).

Conclusions: Preoperative mIMAC could be useful for perioperative and postoperative management in CRC and GC.
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http://dx.doi.org/10.1016/j.clnu.2021.03.036DOI Listing
May 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 relationship between hypoxia-inducible factor 1α (HIF-1α) and patient survival in breast cancer: Systematic review and meta-analysis.

Crit Rev Oncol Hematol 2021 Mar 19;159:103231. Epub 2021 Jan 19.

Unit of Experimental Therapeutics, Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences-University of Glasgow, Glasgow, UK.

Introduction: Hypoxia is a characteristic of many solid tumours and results in an increase in expression of HIF-1α. Many studies have investigated the prognostic value of HIF-1α expression in breast cancer (BC), however, the prognostic value remains unclear. Therefore, a systematic review and meta-analysis was undertaken to determine the prognostic value of HIF-1α in BC patients.

Methods: The electronic databases PubMed and Web of science were systematically searched to identify relevant papers. The clinical outcomes included disease-free survival (DFS), recurrence-free survival (RFS) and overall survival (OS) in BC patients. Review Manager version 5.4 was employed to analysis data from 30 eligible studies (containing 6201patients).

Results: High expression of HIF-1α was associated with poorer DFS and OS. There was an effect of survival analysis, study region, antibodies used, scoring and threshold methods on HIF-1α expression.

Conclusion: HIF-1α overexpression was significantly associated with poorer DFS and OS in breast cancer patients.
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http://dx.doi.org/10.1016/j.critrevonc.2021.103231DOI Listing
March 2021

Relationship between cytokines and symptoms in people with incurable cancer: A systematic review.

Crit Rev Oncol Hematol 2021 Mar 19;159:103222. Epub 2021 Jan 19.

St Columba's Hospice, Edinburgh, UK; Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.

Background: Development and spread of cancer is linked to the inflammatory response, in which cytokines serve a key role. The inflammatory response may also form the basis for symptoms of cancer. This systematic review examines the relationship between cytokines and symptoms in incurable cancer.

Methods: MEDLINE, EMBASE, Cochrane Library, CINAHL, Web of Science and PsycINFO databases were searched for studies from January 2004 to January 2020.

Results: Twenty studies were selected (n = 1806 patients, 119 controls). Symptoms studied included depression, fatigue, pain, and loss of appetite. Nine studies examined patients with a specified tumour type, the remainder included patients with a mix of tumour types. Thirty-one cytokines were examined; multiple associations between cytokines and symptoms were described, supporting the hypothesis that cytokines may have a key role in symptom generation.

Conclusion: Symptoms of incurable cancer are associated with circulating cytokines. Further study is required to characterise these relationships, and to explore their therapeutic potential.
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http://dx.doi.org/10.1016/j.critrevonc.2021.103222DOI Listing
March 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

A meta-analysis of CD274 (PD-L1) assessment and prognosis in colorectal cancer and its role in predicting response to anti-PD-1 therapy.

Crit Rev Oncol Hematol 2021 Jan 19;157:103147. Epub 2020 Nov 19.

School of Medicine, University of Glasgow, Glasgow, United Kingdom.

Background: PD-1 checkpoint inhibitors are novel therapeutic agents in colorectal cancer (CRC). Immunohistochemical staining for CD274 assessment is standardised in upper GI cancer, but not in CRC.

Methods: Methodologies of relevant studies were scrutinized and meta-analysis of survival and CD274/PDCD1 performed. Furthermore, anti-PD-1 therapy clinical trial results in CRC were assessed with particular emphasis on CD274 assessment.

Results: 24 studies were included. CD274 on immune cells was associated with good prognosis. CD274 on tumour cells has heterogenous outcomes and does not meet requirements of a prognostic marker. As a marker of response to anti-PD-1 therapy, CD274 assessment is not standardised in CRC.

Conclusion: CD274 does not appear useful as a prognostic marker. As a marker of response to anti-PD-1 therapy, assessment methodology requires standardisation. As the Combined Positive Score (CPS) is used in upper GI cancer, this seems a logical method to adopt. Thresholds for CRC remain to be determined.
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http://dx.doi.org/10.1016/j.critrevonc.2020.103147DOI Listing
January 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

Computed tomography-derived body composition analysis in patients with advanced cancer: clinical utility and future research.

Curr Opin Support Palliat Care 2020 12;14(4):309-315

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

Purpose Of Review: With weight loss increasingly occurring against a background of obesity across a variety of advanced cancers, there has been increasing interest in computed tomography (CT)-derived body composition analysis. Various imaging software packages and thresholds are commonly in use in CT-derived body composition analysis. This review discusses the current research in field of body composition with emphasis on the information required for such measurements to be taken into routine clinical practice.

Recent Findings: CT is widely used for tumour staging in patients with cancer. Over the last decade, this imaging modality has been exploited to make measurements of body composition. Using a common landmark (L3) several different thresholds have been developed to stratify adipose and muscle tissue areas according to age, sex and BMI and their relationship with survival. A significant relationship between CT-derived body composition and clinical outcomes has been shown in different tumour types and geographical locations. However, there is considerable variation with methods, thresholds and muscle groups used for analysis. Therefore, there would appear to be a need to develop reliable methodology and population-specific reference ranges to guide clinical interpretation and enable routine clinical use.

Summary: There has been an explosion of clinical research interest in CT-derived body composition analysis. Such body composition analysis provides important host phenotype information which has prognostic value. For CT-derived body composition to be fit for use in routine clinical practice, there is need for universally accepted terminology, software, muscle group selection, prognostic thresholds to standardize such body composition analysis.
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http://dx.doi.org/10.1097/SPC.0000000000000529DOI 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

Prognostic factors in patients admitted to an urban teaching hospital with COVID-19 infection.

J Transl Med 2020 09 15;18(1):354. Epub 2020 Sep 15.

Academic Unit of Surgery, School of Medicine, University of Glasgow, New Lister Building, Royal Infirmary, Glasgow, G31 2ER, UK.

Background: Severe COVID-19 infection results in a systemic inflammatory response (SIRS). This SIRS response shares similarities to the changes observed during the peri-operative period that are recognised to be associated with the development of multiple organ failure.

Methods: Electronic patient records for patients who were admitted to an urban teaching hospital during the initial 7-week period of the COVID-19 pandemic in Glasgow, U.K. (17th March 2020-1st May 2020) were examined for routine clinical, laboratory and clinical outcome data. Age, sex, BMI and documented evidence of COVID-19 infection at time of discharge or death certification were considered minimal criteria for inclusion.

Results: Of the 224 patients who fulfilled the criteria for inclusion, 52 (23%) had died at 30-days following admission. COVID-19 related respiratory failure (75%) and multiorgan failure (12%) were the commonest causes of death recorded. Age ≥ 70 years (p < 0.001), past medical history of cognitive impairment (p ≤ 0.001), previous delirium (p < 0.001), clinical frailty score > 3 (p < 0.001), hypertension (p < 0.05), heart failure (p < 0.01), national early warning score (NEWS) > 4 (p < 0.01), positive CXR (p < 0.01), and subsequent positive COVID-19 swab (p ≤ 0.001) were associated with 30-day mortality. CRP > 80 mg/L (p < 0.05), albumin < 35 g/L (p < 0.05), peri-operative Glasgow Prognostic Score (poGPS) (p < 0.05), lymphocytes < 1.5 10/l (p < 0.05), neutrophil lymphocyte ratio (p ≤ 0.001), haematocrit (< 0.40 L/L (male)/ < 0.37 L/L (female)) (p ≤ 0.01), urea > 7.5 mmol/L (p < 0.001), creatinine > 130 mmol/L (p < 0.05) and elevated urea: albumin ratio (< 0.001) were also associated with 30-day mortality. On multivariate analysis, age ≥ 70 years (O.R. 3.9, 95% C.I. 1.4-8.2, p < 0.001), past medical history of heart failure (O.R. 3.3, 95% C.I. 1.2-19.3, p < 0.05), NEWS > 4 (O.R. 2.4, 95% C.I. 1.1-4.4, p < 0.05), positive initial CXR (O.R. 0.4, 95% C.I. 0.2-0.9, p < 0.05) and poGPS (O.R. 2.3, 95% C.I. 1.1-4.4, p < 0.05) remained independently associated with 30-day mortality. Among those patients who tested PCR COVID-19 positive (n = 122), age ≥ 70 years (O.R. 4.7, 95% C.I. 2.0-11.3, p < 0.001), past medical history of heart failure (O.R. 4.4, 95% C.I. 1.2-20.5, p < 0.05) and poGPS (O.R. 2.4, 95% C.I. 1.1-5.1, p < 0.05) remained independently associated with 30-days mortality.

Conclusion: Age ≥ 70 years and severe systemic inflammation as measured by the peri-operative Glasgow Prognostic Score are independently associated with 30-day mortality among patients admitted to hospital with COVID-19 infection.
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http://dx.doi.org/10.1186/s12967-020-02524-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7491021PMC
September 2020

Staging the Tumor and Staging the Host: Pretreatment Combined Neutrophil Lymphocyte Ratio and Modified Glasgow Prognostic Score Is Associated with Overall Survival in Patients with Esophagogastric Cancers Undergoing Treatment with Curative Intent.

Ann Surg Oncol 2021 Feb 5;28(2):722-731. Epub 2020 Sep 5.

Forth Valley Royal Hospital, Larbert, UK.

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.
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http://dx.doi.org/10.1245/s10434-020-09074-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7801291PMC
February 2021

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

Hypoalbuminemia Reflects Nutritional Risk, Body Composition and Systemic Inflammation and Is Independently Associated with Survival in Patients with Colorectal Cancer.

Cancers (Basel) 2020 Jul 21;12(7). Epub 2020 Jul 21.

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

It has long been recognized that albumin has prognostic value in patients with cancer. However, although the Global Leadership Initiative on Malnutrition GLIM criteria (based on five diagnostic criteria, three phenotypic criteria and two etiologic criteria) recognize inflammation as an important etiologic factor in malnutrition, there are limited data regarding the association between albumin, nutritional risk, body composition and systemic inflammation, and whether albumin is associated with mortality independent of these parameters. The aim of this study was to examine the relationship between albumin, nutritional risk, body composition, systemic inflammation, and outcomes in patients with colorectal cancer (CRC). A retrospective cohort study ( = 795) was carried out in which patients were divided into normal and hypoalbuminaemic groups (albumin  < 35 g/L) in the presence and absence of a systemic inflammatory response C-reactive protein (CRP > 10 and <10 mg/L, respectively). Post-operative complications, severity of complications and mortality were considered as outcome measures. Categorical variables were analyzed using Chi-square test χ or linear-by-linear association. Survival data were analyzed using univariate and multivariate Cox regression. In the presence of a systemic inflammatory response, hypoalbuminemia was directly associated with Malnutrition Universal Screening Tool MUST ( < 0.001) and inversely associated with Body Mass Index BMI ( < 0.001), subcutaneous adiposity ( < 0.01), visceral obesity ( < 0.01), skeletal muscle index ( < 0.001) and skeletal muscle density ( < 0.001). There was no significant association between hypoalbuminemia and either the presence of complications or their severity. In the absence of a systemic inflammatory response ( = 589), hypoalbuminemia was directly associated with MUST ( < 0.05) and inversely associated with BMI ( < 0.01), subcutaneous adiposity ( < 0.05), visceral adiposity ( < 0.05), skeletal muscle index ( < 0.01) and skeletal muscle density ( < 0.001). Hypoalbuminemia was, independently of inflammatory markers, associated with poorer cancer-specific and overall survival (both < 0.001). The results suggest that hypoalbuminemia in patients with CRC reflects both increased nutritional risk and greater systemic inflammatory response and was independently associated with poorer survival in patients with CRC.
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http://dx.doi.org/10.3390/cancers12071986DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7409314PMC
July 2020
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