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

Background: 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. Material and methods: 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. Results: 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. Conclusions: 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.

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.

CT-derived body composition: Differential association with disease, age and inflammation in a retrospective cohort study.

BACKGROUND: Low skeletal muscle mass and density, as assessed by CT-body composition (CT-BC), are recognised to have prognostic value in non-cancer and cancer patients. The aim of the present study was to compare CT-BC parameters between non-cancer (abdominal aortic aneurysm, AAA) and cancer (colorectal cancer, CRC) patients. METHODS: Two retrospective multicentre cohorts were compared. Thresholds of visceral fat area (VFA, Doyle), skeletal fat index (SFI, Ebadi), skeletal muscle index (SMI, Martin), and skeletal muscle density (SMD, Martin) were applied to these cohorts and compared. The systemic inflammatory response (SIR) was measured by the systemic inflammatory grade (SIG). RESULTS: 1695 patients were included; 759 patients with AAA and 936 patients with CRC. Low SMD (33% vs. 66%, p <0.001) was more prevalent in the CRC cohort. Low SMI prevalence was similar in both cohorts (51% vs. 51%, p = 0.80). Compared with the AAA cohort, the CRC cohort had a higher prevalence of raised SIG (p <0.001). Increasing age (OR 1.54, 95% CI 1.38-1.72, p < 0.001) and elevated SIG (OR 1.23, 95% CI 1.09-1.40, p = 0.001) were independently associated with increased odds of low SMI. Increasing age (OR 1.90, 95% CI 1.66-2.17, p < 0.001) CRC diagnosis (OR 5.89, 95% CI 4.55-7.62, p < 0.001), ASA > 2 (OR 1.37, 95% CI 1.08-1.73, p = 0.01), and elevated SIG (OR 1.19, 95% CI 1.03-1.37, p = 0.02) were independently associated with increased odds of low SMD. CONCLUSIONS: Increasing age and systemic inflammation appear to be important determinants of loss of skeletal muscle mass and quality irrespective of disease.

JAK/STAT3 represents a therapeutic target for colorectal cancer patients with stromal-rich tumors.

Colorectal cancer (CRC) is a heterogenous malignancy underpinned by dysregulation of cellular signaling pathways. Previous literature has implicated aberrant JAK/STAT3 signal transduction in the development and progression of solid tumors. In this study we investigate the effectiveness of inhibiting JAK/STAT3 in diverse CRC models, establish in which contexts high pathway expression is prognostic and perform in depth analysis underlying phenotypes. In this study we investigated the use of JAK inhibitors for anti-cancer activity in CRC cell lines, mouse model organoids and patient-derived organoids. Immunohistochemical staining of the TransSCOT clinical trial cohort, and 2 independent large retrospective CRC patient cohorts was performed to assess the prognostic value of JAK/STAT3 expression. We performed mutational profiling, bulk RNASeq and NanoString GeoMx® spatial transcriptomics to unravel the underlying biology of aberrant signaling. Inhibition of signal transduction with JAK1/2 but not JAK2/3 inhibitors reduced cell viability in CRC cell lines, mouse, and patient derived organoids (PDOs). In PDOs, reduced Ki67 expression was observed post-treatment. A highly significant association between high JAK/STAT3 expression within tumor cells and reduced cancer-specific survival in patients with high stromal invasion (TSPhigh) was identified across 3 independent CRC patient cohorts, including the TrasnSCOT clinical trial cohort. Patients with high phosphorylated STAT3 (pSTAT3) within the TSPhigh group had higher influx of CD66b + cells and higher tumoral expression of PDL1. Bulk RNAseq of full section tumors showed enrichment of NFκB signaling and hypoxia in these cases. Spatial deconvolution through GeoMx® demonstrated higher expression of checkpoint and hypoxia-associated genes in the tumor (pan-cytokeratin positive) regions, and reduced lymphocyte receptor signaling in the TME (pan-cytokeratin- and αSMA-) and αSMA (pan-cytokeratin- and αSMA +) areas. Non-classical fibroblast signatures were detected across αSMA + regions in cases with high pSTAT3. Therefore, in this study we have shown that inhibition of JAK/STAT3 represents a promising therapeutic strategy for patients with stromal-rich CRC tumors. High expression of JAK/STAT3 proteins within both tumor and stromal cells predicts poor outcomes in CRC, and aberrant signaling is associated with distinct spatially-dependant differential gene expression.

A Review of Scheduling Strategies for Radiotherapy and Immune Checkpoint Inhibition in Locally Advanced Rectal Cancer.

Colorectal cancer (CRC) is the third most common malignancy across the globe and, despite advances in treatment strategies, survival rates remain low. Rectal cancer (RC) accounts for most of these cases, and traditional management strategies for advanced disease include total neoadjuvant therapy (TNT) with chemoradiotherapy followed by curative surgery. Unfortunately, approximately 10-15% of patients have no response to treatment or have recurrence at a short interval following radiotherapy. The introduction of immunotherapy in the form of immune checkpoint blockade (ICB) in metastatic colorectal cancer has improved clinical outcomes, yet most patients with RC present with microsatellite stable disease, which lacks the immune-rich microenvironment where ICB is most effective. There is evidence that combining radiotherapy with ICB can unlock the mechanisms that drive resistance in patients; however, the sequencing of these therapies is still debated. This review offers a comprehensive overview of clinical trials and preclinical models that use radiotherapy-immunotherapy combinations in RC in an attempt to extrapolate the ideal sequencing of the two treatment modalities. The results highlight the dearth of evidence to answer the question of whether ICB should be given before, during, or after radiotherapy, yet it is suggested that improving the relevance of our preclinical models will provide a platform with higher translational value and will lead to appropriate clinical trial designs.

Improving radiotherapy in immunosuppressive microenvironments by targeting complement receptor C5aR1.

An immunosuppressive microenvironment causes poor tumor T cell infiltration and is associated with reduced patient overall survival in colorectal cancer. How to improve treatment responses in these tumors is still a challenge. Using an integrated screening approach to identify cancer-specific vulnerabilities, we identified complement receptor C5aR1 as a druggable target, which when inhibited improved radiotherapy, even in tumors displaying immunosuppressive features and poor CD8+ T cell infiltration. While C5aR1 is well-known for its role in the immune compartment, we found that C5aR1 is also robustly expressed on malignant epithelial cells, highlighting potential tumor cell-specific functions. C5aR1 targeting resulted in increased NF-κB-dependent apoptosis specifically in tumors and not normal tissues, indicating that, in malignant cells, C5aR1 primarily regulated cell fate. Collectively, these data revealed that increased complement gene expression is part of the stress response mounted by irradiated tumors and that targeting C5aR1 could improve radiotherapy, even in tumors displaying immunosuppressive features.

Effect of differing flap reconstruction strategies in perineal closure following advanced pelvic oncological resection: a retrospective cohort study.

INTRODUCTION: Advancing approaches to locally invasive pelvic malignancy creates a large tissue defect resulting in perineal wound complications, dehiscence, and perineal hernia. Use of reconstructive flaps such as vertical rectus abdominus myocutaneous (VRAM) flap, gracilis, anterolateral thigh and gluteal flaps have been utilised in our institution to address perineal closure. The authors compared outcomes using different flap techniques along with primary perineal closure in advanced pelvic oncological resection. METHODS: A prospectively maintained database of patients undergoing advanced pelvic oncological resection in a single tertiary hospital was retrospectively analysed. This study included consecutive patients between 2014 and 2021 according to the Strengthening The Reporting of Cohort Studies in Surgery (STROCSS) criteria. Primary outcome measures were the frequency of postoperative perineal complications between primary closure, VRAM, gluteal and thigh (anterolateral thigh and gracilis) reconstruction. RESULTS: One hundred twenty-two patients underwent advanced pelvic resection with perineal closure. Of these, 40 patients underwent extra-levator abdominoperineal resection, and 70 patients underwent pelvic exenteration. Sixty-four patients received reconstructive flap closure, which included VRAM (22), gluteal (21) and thigh flaps (19). Perineal infection and dehiscence rates were low. Infection rates were lower in the flap group despite a higher rate of radiotherapy ( P <0.050). Reoperation rates were infrequent (<10%) but specific for each flap, such as donor-site hernia following VRAM and flap dehiscence after thigh flap reconstruction. CONCLUSIONS: In patients who are at high risk of postoperative perineal infections, reconstructive flap closure offers acceptable outcomes. VRAM, gluteal and thigh flaps offer comparable outcomes and can be tailored to the individual patient.

The neoadjuvant rectal score and a novel magnetic resonance imaging based neoadjuvant rectal score are stage independent predictors of long-term outcome in locally advanced rectal cancer.

AIM: Neoadjuvant rectal (NAR) score is an early surrogate for longer-term outcomes in rectal cancer undergoing radiotherapy and resection. In an era of increasing organ preservation, resection specimens are not always available to calculate the NAR score. Post-treatment magnetic resonance imaging (MRI) re-staging of regression is subjective, limiting reproducibility. We explored the potential for a novel MRI-based NAR score (mrNAR) adapted from the NAR formula. METHODS: Locally advanced rectal cancer patients undergoing neoadjuvant therapy (nCRT) and surgery were retrospectively identified between 2008 and 2020 in a single cancer network. mrNAR was calculated by adapting the NAR formula, replacing pathological (p) stages with post-nCRT MR stages (ymr). Cox regression assessed relationships between clinicopathological characteristics, NAR and mrNAR with overall survival (OS) and recurrence-free survival (RFS). RESULTS: In total, 381 NAR and 177 mrNAR scores were calculated. On univariate analysis NAR related to OS (hazard ratio [HR] 2.05, 95% confidence interval [CI] 1.33-3.14, p = 0.001) and RFS (HR 2.52, 95% CI 1.77-3.59, p = 0.001). NAR 3-year OS <8 was 95.3%, 8-16 was 88.6% and >16 was 80%. mrNAR related to OS (HR 2.96, 95% CI 1.38-6.34, p = 0.005) and RFS (HR 2.99, 95% CI 1.49-6.00, p = 0.002). 3-year OS for mrNAR <8 was 96.2%, 8-16 was 92.4% and >16 was 78%. On multivariate analysis, mrNAR was a stage-independent predictor of OS and RFS. mrNAR corresponded to NAR score category in only 15% (positive predictive value 0.23) and 47.5% (positive predictive value 0.48) of cases for categories <8 and >16, respectively. CONCLUSIONS: Neoadjuvant rectal score is validated as a surrogate end-point for long-term outcomes. mrNAR categories do not correlate with NAR but have stage-independent prognostic value. mrNAR may represent a novel surrogate end-point for future neoadjuvant treatments that focus on organ preservation.

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 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.

Evaluation of the prognostic value of computed tomography-derived body composition in patients undergoing endovascular aneurysm repair.

BACKGROUND: Endovascular aneurysm repair (EVAR) is the most common mode of repair of abdominal aortic aneurysms (AAA) in the UK. EVAR ranges from standard infrarenal repair to complex fenestrated and branched EVAR (F/B-EVAR). Sarcopenia is defined by lower muscle mass and function, which is associated with inferior perioperative outcomes. Computed tomography-derived body composition analysis offers prognostic value in patients with cancer. Several authors have evaluated the role of body composition analysis in predicting outcomes in patients undergoing EVAR; however, the evidence base is limited by heterogeneous methodology. METHODS: Six hundred seventy-four consecutive patients (58 (8.6%) female, mean (SD) age 74.4 (6.8) years) undergoing EVAR and F/B-EVAR at three large tertiary centres were retrospectively recruited. Subcutaneous and visceral fat indices (SFI and VFI), psoas and skeletal muscle indices, and skeletal muscle density were measured at the L3 vertebral level from pre-operative computed tomographies. The maximally selected rank statistic technique was used to define optimal thresholds to predict mortality. RESULTS: There were 191 deaths during the median follow-up period of 60.0 months. Mean (95% CI) survival in the low SMI versus high SMI subgroups was 62.6 (58.5-66.7) versus 82.0 (78.7-85.3) months (P < 0.001). Mean (95% CI) survival in the low SFI versus high SFI subgroups was 56.4 (48.2-64.7) versus 77.1 (74.2-80.1) months (P < 0.001). One-year mortality in the low SMI versus high SMI subgroups was 10% versus 3% (P < 0.001). Low SMI was associated with increased odds of one-year mortality (OR 3.19, 95% CI 1.60-6.34, P < 0.001). Five-year mortality in the low SMI versus high SMI subgroups was 55% versus 28% (P < 0.001). Low SMI was associated with increased odds of five-year mortality (OR 1.54, 95% CI 1.11-2.14, P < 0.01). On multivariate analysis of all patients, low SFI (HR 1.90, 95% CI 1.30-2.76, P < 0.001) and low SMI (HR 1.88, 95% CI 1.34-2.63, P < 0.001) were associated with poorer survival. On multivariate analysis of asymptomatic AAA patients, low SFI (HR 1.54, 95% CI 1.01-2.35, P < 0.05) and low SMI (HR 1.71, 95% CI 1.20-2.42, P < 0.01) were associated with poorer survival. CONCLUSIONS: Low SMI and SFI are associated with poorer long-term survival following EVAR and F/B-EVAR. The relationship between body composition and prognosis requires further evaluation, and external validation of the thresholds proposed in patients with AAA is required.

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.

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.

Spatially Resolved Transcriptomics Deconvolutes Prognostic Histological Subgroups in Patients with Colorectal Cancer and Synchronous Liver Metastases.

Strong immune responses in primary colorectal cancer correspond with better patient survival following surgery compared with tumors with predominantly stromal microenvironments. However, biomarkers to identify patients with colorectal cancer liver metastases (CRLM) with good prognosis following surgery for oligometastatic disease remain elusive. The aim of this study was to determine the practical application of a simple histological assessment of immune cell infiltration and stromal content in predicting outcome following synchronous resection of primary colorectal cancer and CRLM and to interrogate the underlying functional biology that drives disease progression. Samples from patients undergoing synchronous resection of primary colorectal cancer and CRLM were evaluated in detail through histological assessment, panel genomic and bulk transcriptomic assessment, IHC, and GeoMx spatial transcriptomics (ST) analysis. High immune infiltration of metastases was associated with improved cancer-specific survival. Bulk transcriptomic analysis was confounded by stromal content, but ST demonstrated that the invasive edge of the metastases of long-term survivors was characterized by adaptive immune cell populations enriched for type II IFN signaling and MHC-class II antigen presentation. In contrast, patients with poor prognosis demonstrated increased abundance of regulatory T cells and neutrophils with enrichment of Notch and TGFß signaling pathways at the metastatic tumor center. In summary, histological assessment can stratify outcomes in patients undergoing synchronous resection of CRLM, suggesting that it has potential as a prognostic biomarker. Furthermore, ST analysis has revealed significant intratumoral and interlesional heterogeneity and identified the underlying transcriptomic programs driving each phenotype. SIGNIFICANCE: Spatial transcriptomics uncovers heterogeneity between patients, between matched lesions in the same patient, and within individual lesions and identifies drivers of metastatic progression in colorectal cancer with reactive and suppressed immune microenvironments.

Volume-outcome relationship in intra-abdominal robotic-assisted surgery: a systematic review.

As robotic-assisted surgery (RAS) expands to smaller centres, platforms are shared between specialities. Healthcare providers must consider case volume and mix required to maintain quality and cost-effectiveness. This can be informed, in-part, by the volume-outcome relationship. We perform a systematic review to describe the volume-outcome relationship in intra-abdominal robotic-assisted surgery to report on suggested minimum volumes standards. A literature search of Medline, NICE Evidence Search, Health Technology Assessment Database and Cochrane Library using the terms: "robot*", "surgery", "volume" and "outcome" was performed. The included procedures were gynecological: hysterectomy, urological: partial and radical nephrectomy, cystectomy, prostatectomy, and general surgical: colectomy, esophagectomy. Hospital and surgeon volume measures and all reported outcomes were analysed. 41 studies, including 983,149 procedures, met the inclusion criteria. Study quality was assessed using the Newcastle-Ottawa Quality Assessment Scale and the retrieved data was synthesised in a narrative review. Significant volume-outcome relationships were described in relation to key outcome measures, including operative time, complications, positive margins, lymph node yield and cost. Annual surgeon and hospital volume thresholds were described. We concluded that in centres with an annual volume of fewer than 10 cases of a given procedure, having multiple surgeons performing these procedures led to worse outcomes and, therefore, opportunities should be sought to perform other complimentary robotic procedures or undertake joint cases.

The relationship between the mode of presentation, CT-derived body composition, systemic inflammatory grade and survival in colon cancer.

BACKGROUND: Within colorectal cancer, the systemic inflammatory response (SIR) and CT-derived body composition, particularly the loss of lean muscle mass, are independently associated with oncological outcomes; however, no study has included both non-metastatic and metastatic disease. The present study analyses the association between body composition, mode of presentation, SIR and survival in patients with TNM I-IV colon cancer. METHODS: Patients diagnosed with colon cancer from 2011 to 2014 were identified. The SIR was stratified using systemic inflammatory grade (SIG). Staging CT scans were used to define body composition: subcutaneous fat index (SFI), visceral fat area (VFA), skeletal muscle index (SMI) and skeletal muscle density (SMD). The effect of SIG and body composition on mode of presentation and 3-year overall survival (3-yr OS) was analysed. RESULTS: One thousand one hundred forty-six patients were identified; 14%/38%/40%/8% had TNM Stage I/II/III/IV colon cancer, respectively. Patients were predominantly aged 65 + (63%), male (52%) and BMI > 25 (62%). 79%74% had a high SFI/VFA, and 56%/62% had a low SMI/SMD, respectively. Abnormal body composition was prevalent across all disease stages and associated with TNM stage-high SFI in 87%/76%/81%/68% (P < 0.001), high VFA in 79%/73%/75%/67% (P = 0.189), low SMI in 43%/60%/55%/68% (P < 0.001) and low SMD in 55%/65%/61%/67% (P = 0.094) of TNM I/II/III/IV disease, respectively. Body composition was associated with SIG-high SFI in 83%/80%/77%/78%/66% (P = 0.004), high VFA in 78%/78%/70%/63%/61% (P = 0.002), low SMI in 48%/52%/62%/62%/79% (P < 0.001) and low SMD in 56%/60%/62%/70%/76% (P < 0.001) of patients with SIG 0/1/2/3/4, respectively. After adjustment for other factors, increased SIG (OR 1.95), visceral obesity (OR 0.65) and low SMI (OR 1.61) were associated with emergency presentation. In TNM Stage II colon cancer, low SMI and low SMD were associated with worse 3-yr OS (92% vs 87%, P < 0.001 and 96% vs 85%, P < 0.001, respectively). In TNM Stage III, a trend was seen between low SMI and SMD and 3-yr OS (77% vs 73%, P = 0.091 and 76% vs 75%, P = 0.034, respectively). In TNM Stage IV disease, low SMI was associated with 3-yr OS (43% vs 16%, P < 0.001). A trend, albeit not of significance, was seen between low SMD and 3-yr OS (32% vs 21%, P = 0.366). CONCLUSIONS: The present results show that abnormal body composition is prevalent across TNM I-IV colon cancer and associated with TNM stage and SIG. Body composition is independently associated with emergency presentation and long-term survival. Further research is required to analyse whether interventions including structured exercise programmes or attenuation of the SIR have an effect on CT-derived body composition and oncological outcomes.

Relationship between pre-operative glycated haemoglobin and surgical site infection in patients undergoing elective colon cancer surgery.

Surgical site infections remain a significant cause of morbidity following colon cancer surgery. Although diabetes has been recognised as a risk factor, patients with asymptomatic diabetes are likely underdiagnosed. The aim of the present study was to determine the relationship between preoperative glycated haemoglobin (HbA1C), clinicopathological characteristics and the influence on surgical site infection in a cohort of patients undergoing potentially curative colon cancer surgery. Patients who underwent elective, potentially curative colon cancer surgery between January 2011 and December 2014 were assessed for HbA1C levels (mmol/mol) measured within 3 months preoperatively. Clinicopathological data were recorded in a maintained database. A multivariate binary logistic regression model was used to assess the relationship between HbA1C, clinicopathological characteristics and surgical site infections. A total of 362 patients had HbA1C levels preoperatively recorded. HbA1C was significantly associated with body mass index (BMI), diabetes, smoking status, visceral fat area and skeletal muscle index. As determined by multivariate analysis, preoperative HbA1C levels remained independently associated with an increased risk of surgical site infections (OR 1.69, 95% CI 1.05-2.7; P=0.031) together with BMI (OR 1.91, 95% CI 1.36-2.67; P<0.001). Notably, in the present study, tumour-based factors, such as tumour location and TNM status, were not associated with infective complications. By contrast, host factors, such as BMI and pre-operative HbA1C were associated with surgical site infections suggesting that these factors were of more importance in determining short-term outcomes. In conclusion, objective measurements of BMI and HbA1C effectively stratified the risk of developing surgical site infection from 8 to 59%; therefore, HbA1C levels should be determined to allow for preoperative optimisation.

The relationship between the Glasgow Microenvironment Score and markers of epithelial-mesenchymal transition in TNM II-III colorectal cancer.

Recently published work on the Glasgow Microenvironment Score (GMS) demonstrated its relevance as a biomarker in TNM II-III colorectal cancer (CRC). Epithelial-mesenchymal transition (EMT) markers in CRC have also shown promise as prognostic biomarkers. This study aimed to assess the relationship between GMS and markers of EMT in stage II-III CRC. A previously constructed tissue microarray of CRC tumors resected between 2000 and 2007 from the Western Infirmary, Stobhill, and Gartnavel General Hospitals in Glasgow was used. Immunohistochemistry was performed for 5 markers of EMT: E-cadherin, ß-catenin, Fascin, Snail, and Zeb1. Two-hundred and thirty-eight TNM II-III CRC with valid scores for all EMT markers and GMS were assessed. The prognostic significance of markers of EMT in this cohort and relationships between GMS and markers of EMT were determined. High cytoplasmic and nuclear ß-catenin and membrane Zeb-1 were significant for worse cancer-specific survival (hazard ratio [HR] 1.67, 95% confidence interval [CI] 1.01-2.76, P < .05; HR 2.22, 95% CI 1.24-3.97, P < .01; and HR 2.00, 95% CI 1.07-3.77, P = .03, respectively). GMS 0 was associated with low membrane Fascin (P = .03), whereas membrane and cytoplasmic Fascin were observed to be highest in GMS 1, but lower in GMS 2. Nuclear ß-catenin was lowest in GMS 0, but highest in GMS 2 (P = .03), in keeping with its role in facilitating EMT. Novel associations were demonstrated between GMS categories and markers of EMT, particularly ß-catenin and Fascin, which require further investigation in independent cohorts.

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.

Determinants of emergency presentation in patients with colorectal cancer: a systematic review and meta-analysis.

Colorectal cancer remains a significant cause of morbidity and mortality, even despite curative treatment. A significant proportion of patients present emergently and have poorer outcomes compared to elective presentations, independent of TNM stage. In this systematic review and meta-analysis, differences between elective/emergency presentations of colorectal cancer were examined to determine which factors were associated with emergency presentation. A literature search was carried out from 1990 to 2018 comparing elective and emergency presentations of colon and/or rectal cancer. All reported clinicopathological variables were extracted from identified studies. Variables were analysed through either systematic review or, if appropriate, meta-analysis. This study identified multiple differences between elective and emergency presentations of colorectal cancer. On meta-analysis, emergency presentations were associated with more advanced tumour stage, both overall (OR 2.05) and T/N/M/ subclassification (OR 2.56/1.59/1.75), more: lymphovascular invasion (OR 1.76), vascular invasion (OR 1.92), perineural invasion (OR 1.89), and ASA (OR 1.83). Emergencies were more likely to be of ethnic minority (OR 1.58). There are multiple tumour/host factors that differ between elective and emergency presentations of colorectal cancer. Further work is required to determine which of these factors are independently associated with emergency presentation and subsequently which factors have the most significant effect on outcomes.