Cachexia index for prognostication in surgical patients with locally advanced oesophageal or gastric cancer: multicentre cohort study.

BACKGROUND: Features of cancer cachexia adversely influence patient outcomes, yet few currently inform clinical decision-making. This study assessed the value of the cachexia index (CXI), a novel prognostic marker, in patients for whom neoadjuvant chemotherapy and surgery for oesophagogastric cancer is planned. METHODS: Consecutive patients newly diagnosed with locally advanced (T3-4 or at least N1) oesophagogastric cancer between 1 January 2010 and 31 December 2015 were identified through the West of Scotland and South-East Scotland Cancer Networks. CXI was calculated as (L3 skeletal muscle index) × (serum albumin)/(neutrophil lymphocyte ratio). Sex-stratified cut-off values were determined based on the area under the curve (AUC), and patients were divided into groups with low or normal CXI. Primary outcomes were disease progression during neoadjuvant chemotherapy and overall survival (at least 5 years of follow-up). RESULTS: Overall, 385 patients (72% men, median age 66 years) were treated with neoadjuvant chemotherapy for oesophageal (274) or gastric (111) cancer across the study interval. Although patients with a low CXI (men: CXI below 52 (AUC 0.707); women: CXI below 41 (AUC 0.759)) were older with more co-morbidity, disease characteristics were comparable to those in patients with a normal CXI. Rates of disease progression during neoadjuvant chemotherapy, leading to inoperability, were higher in patients with a low CXI (28 versus 12%; adjusted OR 3.07, 95% c.i. 1.67 to 5.64; P < 0.001). Low CXI was associated with worsened postoperative mortality (P = 0.019) and decreased overall survival (median 14.9 versus 56.9 months; adjusted HR 1.85, 1.42 to 2.42; P < 0.001). CONCLUSION: CXI is associated with disease progression, worse postoperative mortality, and overall survival, and could improve prognostication and decision-making in patients with locally advanced oesophagogastric cancer.

Global Leadership Initiative on Malnutrition cachexia: an inflammation-first approach for the diagnosis of disease-related malnutrition.

PURPOSE OF REVIEW: The following article examines the rationale for an inflammation-first approach for diagnosing cachexia and how the current Global Leadership Initiative on Malnutrition (GLIM) framework may be adapted to facilitate this. RECENT FINDINGS: Recently, the GLIM have published guidance on the measurement of inflammation in the context of cachexia, advocating that C-reactive protein (CRP) should be utilized for quantification. The inclusion of a systemic inflammatory biomarker for the diagnosis of cachexia questions whether it may be more aptly considered a systemic inflammatory syndrome. SUMMARY: The current consensus of the GLIM is that cachexia is 'disease-related malnutrition with inflammation'. In line with this definition, the GLIM proposed a two-step diagnostic framework: screening for malnutrition using validated screening tools and then confirming the presence of disease-related malnutrition with phenotypic (nonvolitional weight loss, low BMI, and reduced muscle mass) and aetiologic criterion reduced food intake/assimilation, and inflammation or disease burden). The GLIM are to be commended for guidance on the measurement of systemic inflammation in their current proposal, given the relative importance to clinical outcomes in patients with cancer. However, the use of CRP is somewhat rudimentary and contrasts other cancer cachexia guidelines and contemporary clinical cancer research.

The relationship between systemic inflammatory response, screen detection and outcome in colorectal cancer.

AIM: A raised systemic inflammatory response correlates with poorer colorectal cancer (CRC) outcomes. Faecal immunochemical test bowel screening aims to detect early-stage disease. We assessed the relationship between systemic inflammatory response, screen detection and CRC survival. METHOD: A retrospective, observational cohort study compared screen-detected and non-screen-detected CRC patients undergoing resection. Systemic inflammatory response was measured using lymphocyte/monocyte, neutrophil/lymphocyte and platelet/lymphocyte ratios (LMR, NLR, PLR). Covariables were compared using χ2 testing and survival with Cox regression. RESULTS: A total of 761 patients were included (326 screen-detected, 435 non-screen-detected). Screen-detected patients had lower systemic inflammatory response: low (<2.4) LMR (28.8% vs. 44.6%; P < 0.001), moderate (3-5) or high (>5) NLR (26.1% vs. 30.6%, P < 0.001; and 7.7% vs. 19.5%, P < 0.001) and high (>150) PLR (47.2% vs. 64.6%; P < 0.001). Median follow-up was 63 months. On univariate analysis, non-screen detection (hazard ratio [HR] 2.346, 95% CI 1.687-3.261; P < 0.001), advanced TNM (P < 0.001), low LMR (HR 2.038, 95% CI 1.514-2.742; P < 0.001), moderate NLR (HR 1.588, 95% CI 1.128-2.235; P = 0.008), high NLR (HR 2.382, 95% CI 1.626-3.491; P < 0.001) and high PLR (HR 1.827, 95% CI 1.326-2.519; P < 0.001) predicted poorer overall survival (OS). Non-screen detection (HR 2.713, 95% CI 1.742-4.226; P < 0.001), TNM (P < 0.001), low LMR (HR 1.969, 95% CI 1.340-2.893; P < 0.001), high NLR (HR 2.368, 95% CI 1.448-3.875; P < 0.001) and high PLR (HR 2.110, 95% CI 1.374-3.240; P < 0.001) predicted poorer cancer-specific survival (CSS). On multivariate analysis, non-screen detection (HR 1.698, 95% CI 1.152-2.503; P = 0.008) and low LMR (HR 1.610, 95% CI 1.158-2.238; P = 0.005) independently predicted poorer OS. Non-screen detection (HR 1.847, 95% CI 1.144-2.983; P = 0.012) and high PLR (HR 1.578, 95% CI 1.018-2.444; P = 0.041) predicted poorer CSS. CONCLUSION: Screen-detected CRC patients have a lower systemic inflammatory response. Non-screen detection and systemic inflammatory response (measured by LMR and PLR respectively) were independent predictors of poorer OS and CSS.

Robotic-assisted surgery for left-sided colon and rectal resections is associated with reduction in the postoperative surgical stress response and improved short-term outcomes: a cohort study.

INTRODUCTION: There is growing evidence that the use of robotic-assisted surgery (RAS) in colorectal cancer resections is associated with improved short-term outcomes when compared to laparoscopic surgery (LS) or open surgery (OS), possibly through a reduced systemic inflammatory response (SIR). Serum C-reactive protein (CRP) is a sensitive SIR biomarker and its utility in the early identification of post-operative complications has been validated in a variety of surgical procedures. There remains a paucity of studies characterising post-operative SIR in RAS. METHODS: Retrospective study of a prospectively collected database of consecutive patients undergoing OS, LS and RAS for left-sided and rectal cancer in a single high-volume unit. Patient and disease characteristics, post-operative CRP levels, and clinical outcomes were reviewed, and their relationships explored within binary logistic regression and propensity scores matched models. RESULTS: A total of 1031 patients were included (483 OS, 376 LS, and 172 RAS). RAS and LS were associated with lower CRP levels across the first 4 post-operative days (p < 0.001) as well as reduced complications and length of stay compared to OS in unadjusted analyses. In binary logistic regression models, RAS was independently associated with lower CRP levels at Day 3 post-operatively (OR 0.35, 95% CI 0.21-0.59, p < 0.001) and a reduction in the rate of all complications (OR 0.39, 95% CI 0.26-0.56, p < 0.001) and major complications (OR 0.5, 95% CI 0.26-0.95, p = 0.036). Within a propensity scores matched model comparing LS versus RAS specifically, RAS was associated with lower post-operative CRP levels in the first two post-operative days, a lower proportion of patients with a CRP ≥ 150 mg/L at Day 3 (20.9% versus 30.5%, p = 0.036) and a lower rate of all complications (34.7% versus 46.7%, p = 0.033). CONCLUSIONS: The present observational study shows that an RAS approach was associated with lower postoperative SIR, and a better postoperative complications profile.

Cardiopulmonary exercise testing, computed tomography-derived body composition, systemic inflammation and survival after elective abdominal aortic aneurysm repair: A retrospective cohort study.

BACKGROUND: Cardio-pulmonary exercise testing (CPEX) is selectively used before intervention for abdominal aortic aneurysm (AAA). Sarcopenia, a chronic condition defined by reduced skeletal muscle function and volume, can be assessed radiologically by computed tomography (CT)-derived body composition analysis (CT-BC), and is associated with systemic inflammation. OBJECTIVE: The aim was to describe the association between CT-BC, CPEX, inflammation and survival in patients undergoing elective intervention for AAA. SETTING: Patients were recruited retrospectively from a single, secondary-care centre-operative database. Cases undergoing elective endovascular aneurysm repair (EVAR) and open surgical repair (OSR) between 31 March 2015 and 25 June 2020 were included. PATIENTS: There were 176 patients (130 EVAR, 46 OSR) available for analysis in the final study; median (interquartile range [IQR]) follow-up was 60.5 [27] months, and all completed a minimum of 2 years follow-up. MAIN OUTCOME MEASURES: Preoperative CPEX tests were recorded. CT sarcopenia score [CT-SS, range 0 to 2, calculated based on normal/low SMI (0/1) and normal/low SMD (0/1)] assessed radiological sarcopenia. Preoperative modified Glasgow Prognostic score (mGPS) was used to assess systemic inflammation. RESULTS: Mean [95% confidence interval (CI) survival in the CT-SS 0 vs. CT-SS 1 vs. CT-SS 2 subgroups was 80.1 (73.6 to 86.6) months vs. 70.3 (63.5 to 77.1) months vs. 63.8 (53.4 to 74.2) months] ( P  = 0.01). CT-SS was not associated with CPEX results ( P  > 0.05). Elevated CT-SS [hazard ratio (HR) 1.83, 95% CI, 1.16 to 2.89, P  < 0.01] was independently associated with increased hazard of long-term mortality; however, CPEX results were not ( P  > 0.05). CONCLUSION: CPEX test results were not consistently associated with body composition and did not have significant prognostic value in patients undergoing elective treatment for AAA.

A systematic review of the neutrophil to lymphocyte and platelet to lymphocyte ratios in patients with lower extremity arterial disease.

Lower extremity arterial disease (LEAD) is caused by atherosclerotic plaque in the arterial supply to the lower limbs. The neutrophil to lymphocyte and platelet to lymphocyte ratios (NLR, PLR) are established markers of systemic inflammation which are related to inferior outcomes in multiple clinical conditions, though remain poorly described in patients with LEAD. This review was carried out in accordance with PRISMA guidelines. The MEDLINE database was interrogated for relevant studies. Primary outcome was the prognostic effect of NLR and PLR on clinical outcomes following treatment, and secondary outcomes were the prognostic effect of NLR and PLR on disease severity and technical success following revascularisation. There were 34 studies included in the final review reporting outcomes on a total of 19870 patients. NLR was investigated in 21 studies, PLR was investigated in two studies, and both NLR & PLR were investigated in 11 studies. Relating to increased levels of systemic inflammation, 20 studies (100%) reported inferior clinical outcomes, 13 (92.9%) studies reported increased disease severity, and seven (87.5%) studies reported inferior technical results from revascularisation. The studies included in this review support the role of elevated NLR and PLR as key components influencing the clinical outcomes, severity, and success of treatment in patients with LEAD. The use of these easily accessible, cost effective and routinely available markers is supported by the present review.

Lactate dehydrogenase: relationship with the diagnostic GLIM criterion for cachexia in patients with advanced cancer.

BACKGROUND: Although suggestive of dysregulated metabolism, the relationship between serum LDH level, phenotypic/aetiologic diagnostic Global Leadership Initiative on Malnutrition (GLIM) criteria and survival in patients with advanced cancer has yet to examined. METHODS: Prospectively collected data from patients with advanced cancer, undergoing anti-cancer therapy with palliative intent, across nine sites in the UK and Ireland between 2011-2016, was retrospectively analysed. LDH values were grouped as <250/250-500/>500 Units/L. Relationships were examined using χ2 test for linear-by-linear association and binary logistics regression analysis. RESULTS: A total of 436 patients met the inclusion criteria. 46% (n = 200) were male and 59% (n = 259) were ≥65 years of age. The median serum LDH was 394 Units/L and 33.5% (n = 146) had an LDH > 500 Units/L. LDH was significantly associated with ECOG-PS (p < 0.001), NLR (p < 0.05), mGPS (p < 0.05) and 3-month survival (p < 0.001). LDH was significantly associated with 3-month survival independent of weight loss (p < 0.01), BMI (p < 0.05), skeletal muscle mass (p < 0.01), metastatic disease (p < 0.05), NLR (p < 0.05) and mGPS (p < 0.01). DISCUSSION: LDH was associated with performance status, systemic inflammation and survival in patients with advanced cancer. LDH measurement may be considered as an aetiologic criteria and become a potential therapeutic target in the treatment of cancer cachexia.

Adverse Tumour and Host Biology May Explain the Poorer Outcomes Seen in Emergency Presentations of Colon Cancer.

OBJECTIVE: To examine the association between tumor/host factors (including the systemic inflammatory response), mode of presentation, and short/long-term outcomes in patients undergoing curative resectional surgery for TNM I to III colon cancer. BACKGROUND: Emergency presentations of colon cancer are associated with worse long-term outcomes than elective presentations despite adjustment for TNM stage. A number of differences in tumor and host factors have been identified between elective and emergency presentations and it may be these factors that are associated with adverse outcomes. METHODS: Patients undergoing curative surgery for TNM I to III colon cancer in the West of Scotland from 2011 to 2014 were identified. Tumor/host factors independently associated with the emergency presentation were identified and entered into a subsequent survival model to determine those that were independently associated with overall survival/cancer-specific survival (OS/CSS). RESULTS: A total of 2705 patients were identified. The emergency presentation was associated with a worse 3-year OS and CSS compared with elective presentations (70% vs 86% and 91% vs 75%). T stage, age, systemic inflammatory grade, anemia (all P < 0.001), N stage ( P = 0.077), extramural venous invasion ( P = 0.003), body mass index ( P = 0.001), and American Society of Anesthesiologists Classification classification ( P = 0.021) were independently associated with emergency presentation. Of these, body mass index [hazard ratio (HR), 0.82], American Society of Anesthesiologists Classification (HR, 1.45), anemia (HR, 1.29), systemic inflammatory grade (HR. 1.11), T stage (HR, 1.57), N stage (HR, 1.80), and adjuvant chemotherapy (HR, 0.47) were independently associated with OS. Similar results were observed for CSS. CONCLUSIONS: Within patients undergoing curative surgery for colon cancer, the emergency presentation was not independently associated with worse OS/CSS. Rather, a combination of tumor and host factors account for the worse outcomes observed.

The relationship between micronutrient status, frailty, systemic inflammation, and clinical outcomes in patients admitted to hospital with COVID-19.

BACKGROUND: Micronutrients have been associated with disease severity and poorer clinical outcomes in patients with COVID-19. However, there is a paucity of studies examining if the relationship with micronutrient status and clinical outcomes is independent of recognised prognostic factors, specifically frailty and the systemic inflammatory response (SIR). The aim of the present study was to examine the relationship between micronutrient status, frailty, systemic inflammation, and clinical outcomes in patients admitted with COVID-19. METHODS: Retrospective analysis of prospectively collected data was performed on patients with confirmed COVID-19, admitted to hospital between the 1st April 2020-6th July 2020. Clinicopathological characteristics, frailty assessment, biochemical and micronutrient laboratory results were recorded. Frailty status was determined using the Clinical Frailty scale. SIR was determined using serum CRP. Clinical outcomes of interest were oxygen requirement, ITU admission and 30-day mortality. Categorical variables were analysed using chi-square test and binary logistics regression analysis. Continuous variables were analysed using the Mann-Whitney U or Kruskal Wallis tests. RESULTS: 281 patients were included. 55% (n = 155) were aged ≥ 70 years and 39% (n = 109) were male. 49% (n = 138) of patients were frail (CFS > 3). 86% (n = 242) of patients had a serum CRP > 10 mg/L. On univariate analysis, frailty was significantly associated with thirty-day mortality (p < 0.001). On univariate analysis, serum CRP was found to be significantly associated with an oxygen requirement on admission in non-frail patients (p = 0.004). Over a third (36%) of non-frail patients had a low vitamin B1, despite having normal reference range values of red cell B2, B6 and selenium. Furthermore, serum CRP was found to be significantly associated with a lower median red cell vitamin B1 (p = 0.029). CONCLUSION: Vitamin B1 stores may be depleted in COVID-19 patients experiencing a significant SIR and providing rationale for thiamine supplementation. Further longitudinal studies are warranted to delineate the trend in thiamine status following COVID-19.

The relationship between computed tomography-derived body composition, systemic inflammation, and survival in patients with abdominal aortic aneurysm.

OBJECTIVE: Patient selection and risk stratification for elective repair of abdominal aortic aneurysm (AAA), either by open surgical repair or by endovascular aneurysm repair, remain challenging. Computed tomography (CT)-derived body composition analysis (CT-BC) and systemic inflammation-based scoring systems such as the systemic inflammatory grade (SIG) appear to offer prognostic value in patients with AAA undergoing endovascular aneurysm repair. The relationship between CT-BC, systemic inflammation, and prognosis has been explored in patients with cancer, but data in noncancer populations are lacking. The present study aimed to examine the relationship between CT-BC, SIG, and survival in patients undergoing elective intervention for AAA. METHODS: A total of 611 consecutive patients who underwent elective intervention for AAA at three large tertiary referral centers were retrospectively recruited for inclusion into the study. CT-BC was performed and analyzed using the CT-derived sarcopenia score (CT-SS). Subcutaneous and visceral fat indices were also recorded. SIG was calculated from preoperative blood tests. The outcomes of interest were overall and 5-year mortality. RESULTS: Median (interquartile range) follow-up was 67.0 (32) months, and there were 194 (32%) deaths during the follow-up period. There were 122 (20%) open surgical repair cases, 558 (91%) patients were male, and the median (interquartile range) age was 73.0 (11.0) years. Age (hazard ratio [HR]: 1.66, 95% confidence interval [CI]: 1.28-2.14, P < .001), elevated CT-SS (HR: 1.58, 95% CI: 1.28-1.94, P < .001), and elevated SIG (HR: 1.29, 95% CI: 1.07-1.55, P < .01) were independently associated with increased hazard of mortality. Mean (95% CI) survival in the CT-SS 0 and SIG 0 subgroup was 92.6 (84.8-100.4) months compared with 44.9 (30.6-59.2) months in the CT-SS 2 and SIG ≥2 subgroup (P < .001). Patients with CT-SS 0 and SIG 0 had 90% (standard error: 4%) 5-year survival compared with 34% (standard error: 9%) in patients with CT-SS 2 and SIG ≥2 (P < .001). CONCLUSIONS: Combining measures of radiological sarcopenia and the systemic inflammatory response offers prognostic value in patients undergoing elective intervention for AAA and may contribute to future clinical risk predication strategies.

The prognostic value of preoperative systemic inflammation-based scoring in patients undergoing endovascular repair of abdominal aortic aneurysm.

OBJECTIVE: Abdominal aortic aneurysm (AAA) is a common condition that is predominantly managed in the United Kingdom by endovascular aneurysm repair (EVAR). Activation of the systemic inflammatory response (SIR) appears to offer prognostic value in patients with vascular disease. The present study examines the relationship between the SIR and survival in patients undergoing standard and complex endovascular aneurysm repair (EVAR and fenestrated/branched [F/B]-EVAR). METHODS: Consecutive patients undergoing elective EVAR and F/B-EVAR were retrospectively identified from three tertiary vascular centers over a 5-year period. Neutrophil:lymphocyte ratio and modified Glasgow Prognostic Score were calculated from preoperative blood results and combined into the systemic inflammatory grade (SIG). The primary outcome was all-cause mortality during the follow-up period, which was compared between subgroups of SIGs. RESULTS: There were 506 patients included in the final study, with a median follow-up of 68.0 months (interquartile range, 27.3 months), and there were 163 deaths during the follow-up period. Mean survival in the SIG 0 vs SIG 1 vs SIG 2 vs SIG 3 vs SIG 4 subgroups was 80.7 months (95% confidence interval [CI], 76.5-85.0 months) vs 78.7 months (95% CI, 72.7-84.7 months) vs 61.0 months (95% CI, 51.1-70.8 months) vs 65.1 months (95% CI, 45.0-85.2 months) vs 54.9 months (95% CI, 34.4-75.3 months) (P < .05). In the entire cohort, age (P < .001), body mass index (P < .05), high creatinine (P < .05), and SIG (P < .05) were associated with survival on univariate analysis, with retained independent association for age (hazard ratio, 1.72; 95% CI, 1.29-2.31; P < .001) and SIG (hazard ratio, 1.20; 95% CI, 1.02-1.40; P < .05) on multivariate analysis. Increasing SIG (area under the curve, 0.68; 95% CI, 0.58-0.78; P < .01) predicted 1-year mortality. CONCLUSIONS: Markers of the SIR such the SIG may be used to identify patients at higher risk of adverse outcome in patients undergoing EVAR and F/B-EVAR for abdominal aortic aneurysms. These findings warrant further investigation in large prospective cohort studies.

The prognostic impact of pre-treatment cachexia in resectional surgery for oesophagogastric cancer: a meta-analysis and meta-regression.

BACKGROUND: Cancer cachexia is not purely an end-stage phenomenon and can influence the outcomes of patients with potentially curable disease. This review examines the effect of pre-treatment cachexia on overall survival, in patients undergoing surgical resection of oesophagogastric cancer. METHODS: A systematic literature search of MEDLINE, EMBASE and Cochrane Library databases was conducted, from January 2000 to May 2022, to identify studies reporting the influence of cachexia on patients undergoing an oesophagogastric resection for cancer with curative intent. Meta-analyses of the primary (overall survival) and secondary (disease-free survival and postoperative mortality) outcomes were performed using random-effects modelling. Meta-regression was used to examine disease stage as a potential confounder. RESULTS: Ten non-randomized studies, comprising 7186 patients, were eligible for inclusion. The prevalence of pre-treatment cachexia was 35 per cent (95 per cent c.i.: 24-47 per cent). Pooled adjusted hazard ratios showed that cachexia was adversely associated with overall survival (HR 1.46, 95 per cent c.i.: 1.31-1.60, P < 0.001). Meta-analysis of proportions identified decreased overall survival at 1-, 3- and 5-years in cachectic cohorts. Pre-treatment cachexia was not a predictor of disease-free survival and further data are required to establish its influence on postoperative mortality. The proportion of patients with stage III/IV disease was a significant moderator of between-study heterogeneity. Cachexia may have a greater influence on overall survival in studies where more patients have a locally advanced malignancy. CONCLUSION: Pre-treatment cachexia adversely influences overall survival following resection of an oesophagogastric malignancy.

The Relationship between Clinical Frailty Score, CT-Derived Body Composition, Systemic Inflammation, and Survival in Patients with Chronic Limb-Threatening Ischemia.

BACKGROUND: Frailty is a chronic condition with complex etiology and impaired functional performance that has been associated with altered body composition and chronic inflammation. Chronic limb-threatening ischemia (CLTI) carries significant morbidity and mortality and is associated with poor quality of life. The present study aims to examine these relationships and their prognostic value in patients with CLTI. METHODS: Consecutive patients presenting as unscheduled admissions to a single tertiary center with CLTI were included over a 12-month period. Frailty was diagnosed using the Clinical Frailty Scale (CFS). Body composition was assessed using computerised tomography (CT) at the L3 vertebral level (CT-BC) to generate visceral and subcutaneous fat indices, skeletal muscle index, and skeletal muscle density. Skeletal muscle index and skeletal muscle density were combined to form the CT-sarcopenia score (CT-SS). Systemic inflammation was assessed by the modified Glasgow prognostic score (mGPS). The primary outcome was overall mortality. RESULTS: There were 190 patients included with a median (interquartile range) follow-up of 22 (6) months (range 15-32 months) and 79 deaths during the follow-up period. One hundred patients (53%) had a CFS >4. CFS >4 (hazard ratio [HR] 2.14, 95% confidence interval [CI] 1.25-3.66, P < 0.01), CT-SS (HR 1.47, 95% CI 1.03-2.09, P < 0.05), and mGPS (HR 1.54, 95% CI 1.11-2.13, P < 0.01) were independently associated with increased mortality. CT-SS (odds ratio 1.88, 95% CI 1.09-3.24, P < 0.01) was independently associated with CFS >4. Patients with CT-SS 0 and CFS ≤4 had 90% (standard error [SE] 5%) 1-year survival, compared with 35% (SE 9%) in patients with CT-SS 2 and CFS >4 (P < 0.001). Patients with mGPS 0 and CFS ≤4 had 94% (SE 4%) 1-year survival compared with 44% (SE 6%) in the mGPS 2 and CFS >4 subgroup (P < 0.001). CONCLUSIONS: Frailty assessed by CFS was associated with CT-BC. CFS, CT-SS, and mGPS were associated with poorer survival in patients presenting as unscheduled admissions with CLTI. CT-SS and mGPS may contribute to part of frailty and prognostic assessment in this patient cohort.

The relationship between the modified frailty index score (mFI-5), malnutrition, body composition, systemic inflammation and short-term clinical outcomes in patients undergoing surgery for colorectal cancer.

BACKGROUND: While the current literature suggests an association with frailty and clinical outcomes in patients undergoing surgery for colorectal cancer (CRC), the basis of this relationship is unclear. AIM: Examine the relationship between frailty, malnutrition, body composition, systemic inflammation and short-term clinical outcomes in patients undergoing surgery for colorectal cancer. METHODS: Consecutive patients who underwent potentially curative resection for colorectal cancer, between April 2008 and April 2018, were identified from a prospectively maintained database. Frailty was defined using the modified five-item frailty index (mFI-5). Body composition measures included CT-derived skeletal muscle index (SMI) and density (SMD). Systemic inflammatory status was determined using Systemic Inflammatory Grade (SIG). Outcomes of interest were the incidence of post-operative complications and thirty-day mortality. Associations between categorical variables were examined using χ2 test and binary logistics regression analysis. RESULTS: 1002 patients met the inclusion criteria. 28% (n = 221) scored 2 or more on the mFI-5. 39% (n = 388) of patients had a post-operative complication (Clavien-Dindo I-IV) and 1% (n = 11) died within thirty days of surgery. On univariate analysis, mFI-5 frailty score, was significantly associated with advanced age (p < 0.001), colonic tumours (p < 0.001), reduced use of neo-adjuvant chemotherapy (p < 0.05), higher BMI (p < 0.05), low SMD (p < 0.001), elevated NLR (p < 0.05), elevated mGPS (p < 0.05), elevated SIG (p < 0.05), incidence of post-operative complications (p < 0.001) and thirty-day mortality (p < 0.05). On multivariate analysis, male sex (p < 0.05), elevated SIG (p < 0.05) and mFI-5 score (p < 0.01) remained significantly associated with the incidence of post-operative complications. mFI-5 frailty was found to remain significantly associated with the incidence post-operative complications in patients who were SIG 0 (p < 0.05). CONCLUSION: mFI-5 frailty score was found to be significantly associated with age, systemic inflammation and post-operative outcomes in patients undergoing potentially curative resections for CRC. Incorporation of an assessment of systemic inflammatory status in future frailty screening tools may improve their prognostic value.

Cancer cachexia: a nutritional or a systemic inflammatory syndrome?

Cancer cachexia has long been perceived as a nutritional syndrome. However, nutritional interventions have continued to be ineffective. With the recent recognition of the importance of systemic inflammation in the definition of this syndrome and treatment, has the time come to consider whether this syndrome is primarily a manifestation of systemic inflammation with the consequent implications for future treatment?

Spatial expression of IKK-alpha is associated with a differential mutational landscape and survival in primary colorectal cancer.

BACKGROUND: To understand the relationship between key non-canonical NF-κB kinase IKK-alpha(α), tumour mutational profile and survival in primary colorectal cancer. METHODS: Immunohistochemical expression of IKKα was assessed in a cohort of 1030 patients who had undergone surgery for colorectal cancer using immunohistochemistry. Mutational tumour profile was examined using a customised gene panel. Immunofluorescence was used to identify the cellular location of punctate IKKα expression. RESULTS: Two patterns of IKKα expression were observed; firstly, in the tumour cell cytoplasm and secondly as discrete 'punctate' areas in a juxtanuclear position. Although cytoplasmic expression of IKKα was not associated with survival, high 'punctate' IKKα expression was associated with significantly reduced cancer-specific survival on multivariate analysis. High punctate expression of IKKα was associated with mutations in KRAS and PDGFRA. Dual immunofluorescence suggested punctate IKKα expression was co-located with the Golgi apparatus. CONCLUSIONS: These results suggest the spatial expression of IKKα is a potential biomarker in colorectal cancer. This is associated with a differential mutational profile highlighting possible distinct signalling roles for IKKα in the context of colorectal cancer as well as potential implications for future treatment strategies using IKKα inhibitors.

The relationship between frailty, nutritional status, co-morbidity, CT-body composition and systemic inflammation in patients with COVID-19.

BACKGROUND: Frailty, determined by the Canadian Study of Health and Aging-Clinical Frailty Scale (CFS), is strongly associated with clinical outcomes including mortality in patients with COVID-19. However, the relationship between frailty and other recognised prognostic factors including age, nutritional status, obesity, sarcopenia and systemic inflammation is poorly understood. Therefore, the aim of this study was to examine the relationship between frailty and other prognostic domains, in patients admitted with COVID-19. METHODS: Patients who presented to our institutions between 1st April 2020-6th July 2020 with confirmed COVID-19 were assessed for inclusion. Data collected included general demographic details, clinicopathological variables, CFS admission assessment, Malnutrition Universal Screening Tool (MUST), CT-BC measurements and markers of systemic inflammation. RESULTS: 106 patients met the study inclusion criteria. The majority of patients were aged ≥ 70 years (67%), male (53%) and frail (scoring > 3 on the CFS, 72%). The majority of patients were not malnourished (MUST 0, 58%), had ≥ 1 co-morbidity (87%), were sarcopenic (low SMI, 80%) and had systemic inflammation (mGPS ≥ 1, 81%, NLR > 5, 55%). On multivariate binary logistics regression analysis, age (p < 0.01), COPD (p < 0.05) and NLR (p < 0.05) remained independently associated with frailty. On univariate binary logistics regression, NLR (p < 0.05) was significantly associated with 30-day mortality. CONCLUSION: Frailty was independently associated with age, co-morbidity, and systemic inflammation. The basis of the relationship between frailty and clinical outcomes in COVID-19 requires further study. Trial registration Registered with clinicaltrials.gov (NCT04484545).

Prognostic role of preoperative circulating systemic inflammatory response markers in primary breast cancer: meta-analysis.

BACKGROUND: Circulating markers of the systemic inflammatory response are prognostic in several cancers, but their role in operable breast cancer is unclear. A systematic review and meta-analysis of the literature was carried out. METHODS: A search of electronic databases up to August 2020 identified studies that examined the prognostic value of preoperative circulating markers of the systemic inflammatory response in primary operable breast cancer. A meta-analysis was carried out for each marker with more than three studies, reporting a HR and 95 per cent confidence interval for disease-free survival (DFS), breast cancer-specific survival (BCSS) or overall survival (OS). RESULTS: In total, 57 studies were reviewed and 42 were suitable for meta-analysis. Higher neutrophil-to-lymphocyte ratio (NLR) was associated with worse overall survival (OS) (pooled HR 1.75, 95 per cent c.i. 1.52 to 2.00; P < 0.001), disease-free survival (DFS) (HR 1.67, 1.50 to 1.87; P < 0.001), and breast cancer-specific survival (BCSS) (HR 1.89, 1.35 to 2.63; P < 0.001). This effect was also seen with an arithmetically-derived NLR (dNLR). Higher platelet-to-lymphocyte ratio (PLR) was associated with worse OS (HR 1.29, 1.10 to 1.50; P = 0.001) and DFS (HR 1.58, 1.33 to 1.88; P < 0.001). Higher lymphocyte-to-monocyte ratio (LMR) was associated with improved DFS (HR 0.65, 0.51 to 0.82; P < 0.001), and higher C-reactive protein (CRP) level was associated with worse BCSS (HR 1.22, 1.07 to 1.39; P = 0.002) and OS (HR 1.24, 1.14 to 1.35; P = 0.002). CONCLUSION: Current evidence suggests a role for preoperative NLR, dNLR, LMR, PLR, and CRP as prognostic markers in primary operable breast cancer. Further work should define their role in clinical practice, particularly reproducible thresholds and molecular subtypes for which these may be of most value.

Molecular mechanisms of tumour budding and its association with microenvironment in colorectal cancer.

Colorectal cancer (CRC) is the third most common cancer worldwide. Poor survival of CRC associated with the development of tumour metastasis led to the investigation of the potential biomarkers to predict outcomes in CRC patients. Tumour budding (TB) is a well-known independent prognostic marker for poor survival and disease metastasis. Therefore, it has been suggested that TB status is included in routine clinicopathological factors for risk assessment in CRC. In contrast with a vast majority of studies regarding the prognostic power of TB, there is no clear evidence pertaining to the underlying molecular mechanism driving this phenotype, or an understanding of TB relationship with the tumour microenvironment (TME). The aim of the present study is to present a comprehensive review of TB and tumour cell signalling pathways together with the cross-talk of immune cells that could drive TB formation in CRC.

The role of faecal calprotectin in diagnosis and staging of colorectal neoplasia: a systematic review and meta-analysis.

INTRODUCTION: The presence of inflammation is a key hallmark of cancer and, plays an important role in disease progression and survival in colorectal cancer (CRC). Calprotectin detected in the faeces is a sensitive measure of colonic inflammation. The role of FC as a diagnostic test that may categorise patients by risk of neoplasia is poorly defined. This systematic review and meta-analysis aims to characterise the relationship between elevations of FC and colorectal neoplasia. METHODS: A systematic review was performed using the keywords (MESH terms) and a statistical and meta-analysis was performed. RESULTS: A total of 35 studies are included in this review. CRC patients are more likely than controls to have an elevated FC OR 5.19, 95% CI 3.12-8.62, p < 0.001 with a heterogeneity (I2 = 27%). No tumour characteristics significantly correlated with FC, only stage of CRC shows signs that it may potentially correlate with FC. CONCLUSION: FC levels are significantly higher in CRC, with high sensitivity. Its low specificity prevents it from being used to diagnose or screen for CRC.