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Low skeletal muscle index/density (SMI/SMD) is prevalent in cancer, adversely prognostic and associated with tumour stage and the systemic inflammatory response (SIR). Age and SMI/SMD has not been widely studied. The present study analyses the association between age and SMI/SMD after adjustment for other clinicopathological factors. Patients undergoing resectional surgery for TNM Stage I-III disease within the West of Scotland between 2011 and 2014 were identified. A single CT slice was obtained from each patients staging CT scan. SMI and SMD were stratified normal/abnormal. The SIR was stratified using Systemic Inflammatory Grade (SIG). When stratified by age (< 50/50s/60s/70s/80+), 39%/38%/48%/62%/74% and 27%/48%/64%/82%/92% of patients had a low SMI and SMD respectively (both p < 0.001). Older age (OR 1.47, p < 0.001), female sex (OR 1.32, p = 0.032), lower socioeconomic deprivation (OR 1.15, p = 0.004), higher ASA (OR 1.30, p = 0.019), emergency presentation (OR 1.82, p = 0.003), lower BMI (OR 0.67, p < 0.002) and higher SIG (OR 1.23, p < 0.001) were independently associated with low SMI. Older age (OR 2.28, p < 0.001), female sex (OR 1.38, p = 0.038), higher ASA (OR 1.92, p < 0.001), emergency presentation (OR 1.71, p = 0.023), and higher SIG (OR 1.37, p < 0.001) were independently associated with lower SMD. Tumour factors were not independently associated with either SMI/SMD. Age was a major factor associated with low SMI/SMD in patients with colon cancer. Therefore, in these patients it is likely that this represents largely constitutional body composition as opposed to being a disease mediated effect. Adjustment for age is required when considering the cancer mediated effect on SMI/SMD in patients with colon cancer.
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Composición Corporal , Neoplasias del Colon , Inflamación , Estadificación de Neoplasias , Tomografía Computarizada por Rayos X , Humanos , Masculino , Femenino , Neoplasias del Colon/patología , Neoplasias del Colon/diagnóstico por imagen , Persona de Mediana Edad , Anciano , Anciano de 80 o más Años , Factores de Edad , Inflamación/patología , Músculo Esquelético/patología , Músculo Esquelético/diagnóstico por imagen , AdultoRESUMEN
BACKGROUND: Transforming growth factor ß-activated protein kinase-1 (TAK1) plays an important role in MAPK and NFκB pathways and has been associated with colorectal cancer. The aim of this study was to determine how cytoplasmic and juxtanuclear punctate staining of TAK1 relates to immune checkpoint expression and cancer specific survival in colorectal cancer. METHODS: Protein expression was assessed by immunohistochemistry on tissue microarrays from primary curative colorectal cancer resected specimens. Expression levels of cytoplasmic TAK1 by QuPath digital quantification and punctate TAK1 staining was scored using a manual point scoring technique and correlated with clinicopathological features, immune checkpoint expression and cancer-specific survival. Bulk RNA sequencing was performed in specimens to determine mutational profiles and differentially expressed genes. RESULTS: A cohort of 875 patients who had undergone colorectal cancer resection were assessed for TAK1 expression. Higher levels of cytoplasmic TAK1 expression correlated with elevated PD1 and PD-L1 expression (p < 0.010). High punctate TAK1 expression was more commonly identified in poorly differentiated colorectal cancers (p = 0.036), had dysregulated mutational and transcriptional profiles with decreased insulin-like growth factor 2(IGF2) expression (p < 0.010), and independently predicted poor cancer-specific survival (HR 2.690, 95% CI 1.419-5.100, p = 0.002). The association of punctate TAK1 expression and recurrence remained after subgroup analysis for microsatellite-stable colorectal cancer (p = 0.028). DISCUSSION: Punctate TAK1 expression is associated with worse cancer specific survival. TAK1 signalling may be an important pathway to investigate underlying mechanisms for recurrence in microsatellite-stable colorectal cancer.
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INTRODUCTION: The prognostic value of CT-derived liver volume in terms of cancer outcomes is not clear. The aim of the present study was to examine the relationship between liver area on a single axial CT-slice and the total liver volume in patients with colonic cancer. Furthermore, we examine the relationship between liver volume, determined using this novel method, clinicopathological variables and survival. METHODS: Consecutive patients who underwent potentially curative surgery for colonic cancer were identified from a prospectively maintained database. Maximal liver area on axial CT-slice (cm2) and total volume (cm3), were obtained by the manual segmentation of pre-operative CT-images in a PACS viewer. The maximal liver area was normalized for body height2 to create the liver index (LI) and values, categorized into tertiles. The primary outcome of interest was overall survival (OS). Relationships between LI and clinico-pathological variables were examined using chi-square analysis and binary logistic regression. The relationship between LI and OS was examined using cox proportional hazard regression. RESULTS: A total of 359 patients were included. A total of 51% (n = 182) of patients were male and 73% (n = 261) were aged 65 years or older. 81% (n = 305) of patients were alive 3-years post-operatively. The median maximal liver area on the axial CT slice was 178.7 (163.7-198.4) cm2. The median total liver volume was 1509.13 (857.8-3337.1) cm3. Maximal liver area strongly correlated with total liver volume (R2 = 0.749). The median LI was 66.8 (62.0-71.6) cm2/m2. On multivariate analysis, age (p < 0.001), sex (p < 0.05), BMI (p < 0.001) and T2DM (p < 0.05) remained significantly associated with LI. On univariate analysis, neither LI (continuous) or LI (tertiles) were significantly associated with OS (p = 0.582 and p = 0.290, respectively). CONCLUSIONS: The simple, reliable method proposed in this study for quantifying liver volume using CT-imaging was found to have an excellent correlation between observers and provided results consistent with the contemporary literature. This method may facilitate the further examination of liver volume in future cancer studies.
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Neoplasias del Colon , Hígado , Humanos , Masculino , Femenino , Bases de Datos Factuales , Tomografía Computarizada por Rayos XRESUMEN
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.
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Neoplasias Colorrectales , Humanos , Animales , Ratones , Estudios Retrospectivos , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/metabolismo , Transducción de Señal , Hipoxia , Queratinas/metabolismo , Factor de Transcripción STAT3/genética , Factor de Transcripción STAT3/metabolismo , Línea Celular TumoralRESUMEN
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.
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Neoplasias Colorrectales , Linfocitos , Humanos , Pronóstico , Estudios Retrospectivos , Neutrófilos , Neoplasias Colorrectales/cirugía , Síndrome de Respuesta Inflamatoria Sistémica/diagnóstico , Síndrome de Respuesta Inflamatoria Sistémica/etiologíaRESUMEN
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.
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Hernia Abdominal , Colgajo Miocutáneo , Neoplasias Pélvicas , Neoplasias del Recto , Humanos , Estudios Retrospectivos , Perineo/cirugía , Neoplasias Pélvicas/cirugía , Colgajo Miocutáneo/trasplante , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/etiología , Estudios de Cohortes , Neoplasias del Recto/cirugía , Recto del Abdomen/trasplanteRESUMEN
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.
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Neoplasias Primarias Secundarias , Neoplasias del Recto , Humanos , Terapia Neoadyuvante , Estudios Retrospectivos , Reproducibilidad de los Resultados , Pronóstico , Neoplasias del Recto/diagnóstico por imagen , Neoplasias del Recto/terapia , Quimioradioterapia , Quimioradioterapia Adyuvante , Biomarcadores , Imagen por Resonancia Magnética , Resultado del Tratamiento , Estadificación de NeoplasiasRESUMEN
High vagal nerve activity, reliability measured by HRV, is considered protective in cancer, reducing oxidative stress, inflammation and opposing sympathetic nerve activity. The present monocentric study examines the relationship between HRV, TNM stage, co-morbidity, systemic inflammation and survival in patients who underwent potentially curative resections for colorectal cancer (CRC). Time-domain HRV measures, Standard Deviation of NN-intervals (SDNN) and Root Mean Square of Successive Differences (RMSSD), were examined as categorical (median) and continuous variables. Systemic inflammation was determined using systemic inflammatory grade (SIG) and co-morbidity using ASA. The primary end point was overall survival (OS) and was analysed using Cox regression. There were 439 patients included in the study and the median follow-up was 78 months. Forty-nine percent (n = 217) and 48% (n = 213) of patients were categorised as having low SDNN (< 24 ms) and RMSSD (< 29.8 ms), respectively. On univariate analysis, SDNN was not significantly associated with TNM stage (p = 0.830), ASA (p = 0.598) or SIG (p = 0.898). RMSSD was not significantly associated with TNM stage (p = 0.267), ASA (p = 0.294) or SIG (p = 0.951). Neither SDNN or RMSSD, categorical or continuous, were significantly associated with OS. In conclusion, neither SDNN or RMSSD were associated with TNM stage, ASA, SIG or survival in patients undergoing potentially curative surgery for CRC.
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Neoplasias Colorrectales , Inflamación , Humanos , Frecuencia Cardíaca/fisiología , Reproducibilidad de los Resultados , Neoplasias Colorrectales/epidemiología , Neoplasias Colorrectales/cirugía , MorbilidadRESUMEN
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.
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Anemia , Neoplasias del Colon , Humanos , Neoplasias del Colon/patología , Pronóstico , Estadificación de Neoplasias , BiologíaRESUMEN
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.
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Neoplasias Colorrectales , Neoplasias Hepáticas , Humanos , Pronóstico , Transcriptoma , Hepatectomía , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/cirugía , Neoplasias Hepáticas/secundario , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/cirugía , Neoplasias Colorrectales/patología , Microambiente Tumoral/genéticaRESUMEN
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.
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Neoplasias Colorrectales , Fragilidad , Desnutrición , Humanos , Masculino , Fragilidad/complicaciones , Fragilidad/diagnóstico , Fragilidad/epidemiología , Factores de Riesgo , Inflamación/diagnóstico , Inflamación/epidemiología , Complicaciones Posoperatorias/diagnóstico , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/etiología , Neoplasias Colorrectales/epidemiología , Neoplasias Colorrectales/cirugía , Composición Corporal , Desnutrición/complicaciones , Desnutrición/diagnóstico , Desnutrición/epidemiología , Estudios Retrospectivos , Medición de RiesgoRESUMEN
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.
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Composición Corporal , Neoplasias del Colon , Humanos , Masculino , Composición Corporal/fisiología , Músculo Esquelético/patología , Neoplasias del Colon/patología , Grasa Intraabdominal/diagnóstico por imagen , Tomografía Computarizada por Rayos X/métodosRESUMEN
Objectives: Establish the prevalence of low skeletal muscle index and density in our population, by comparing age and sex matched cohorts of patients with and without cancer, using standardized methodology for CT-Body composition (CT-BC). Methods: A retrospective analysis of prospectively collected data. Patients admitted to our institution between 17th March 2020 - 1st May 2020, with confirmed coronavirus disease and imaging suitable for CT-BC (n=52), were age and sex matched with patients undergoing resection for colorectal cancer (n=52). Results: 104 patients were included in the final analysis. 43% (n=45) were male, 77% (n=80) were aged 65 years or older, 50% (n=50) were overweight (BMI ≥25) and 53% (n=55) were systemically inflamed (mGPS ≥1). The prevalence of a low SMI (56% vs. 65%) and low SMD (83% vs. 67%) was similar between cohorts. A low SMI and SMD were both associated with age (p<0.05 and p<0.01, respectively) on univariate analysis. On multivariate analysis, a low SMD was independently associated with age (OR 2.38 (1.34-4.22), p=0.003) and mGPS (OR 2.10 (1.20-3.68), p=0.01). Conclusions: In conclusion, the prevalence of a low SMI and low SMD was similar in non-cancer and cancer cohorts in our institution.
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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.
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CXCL8 is an inflammatory chemokine elevated in the colorectal cancer (CRC) tumour microenvironment. CXCR2, the major receptor for CXCL8, is predominantly expressed by neutrophils. In the cancer setting, CXCL8 plays important roles in neutrophil chemotaxis, facilitating angiogenesis, invasion, and metastasis. This study aimed to assess the spatial distribution of CXCL8 mRNA expression in CRC specimens, explore associations with clinical characteristics, and investigate the underlying biology of aberrant CXCL8 levels. CXCR2 expression was also assessed in a second cohort of unique CRC primary tumours and synchronously resected matched liver metastases. A previously constructed tissue microarray consisting of a cohort of stage I-IV CRC patients undergoing surgical resection with curative intent (n = 438) was probed for CXCL8 via RNAscope®. Analysis was performed using HALO® digital pathology software to quantify expression in the tumour and stromal compartments. Scores were assessed for association with clinical characteristics. Mutational analyses were performed on a subset of these patients to determine genomic differences in patients with high CXCL8 expression. A second cohort of stage IV CRC patients with primary and matched metastatic liver tumours was stained via immunohistochemistry for CXCR2, and scores were assessed for clinical significance. CXCL8 expression within the stromal compartment was associated with reduced cancer-specific survival in the first cohort (p = 0.035), and this relationship was potentiated in right-sided colon cancer cases (p = 0.009). High CXCL8 within the stroma was associated with driving a more stromal-rich phenotype and the presence of metastases. When stromal CXCL8 scores were combined with tumour-infiltrating macrophage counts or systemic neutrophil counts, patients classified as high for both markers had significantly poorer prognosis. CXCR2+ immune cell infiltration was associated with increased stromal invasion in liver metastases (p = 0.037). These data indicate a role for CXCL8 in driving unfavourable tumour histological features and promoting metastases. This study suggests that inhibiting CXCL8/CXCR2 should be investigated in patients with right-sided colonic disease and stroma-rich tumours.
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Neoplasias Colorrectales , Neoplasias Hepáticas , Neoplasias Colorrectales/patología , Humanos , Inmunohistoquímica , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/secundario , ARN Mensajero , Microambiente TumoralRESUMEN
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.
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Neoplasias Colorrectales , Transición Epitelial-Mesenquimal , Biomarcadores , Biomarcadores de Tumor , Cadherinas , Neoplasias Colorrectales/patología , Humanos , Microambiente Tumoral , beta CateninaRESUMEN
INTRODUCTION: Obesity is associated with an increased risk of colorectal cancer (CRC). Unlike the indirect measures such as BMI, CT-Body composition (CT-BC) allows for the assessment of both volume and distribution of adipose tissue. Therefore, the aim of this study was to examine the relationship between host characteristics, BMI, CT-BC measurements and the incidence of colorectal neoplasia. METHODS: Patients undergoing CT Colonography (CTC) as part of the Scottish Bowel Screening Programme, between July 2009 and February 2016, were eligible for inclusion. Data were collected including demographic data, clinicopathological variables and CT-BC measurements including skeletal muscle index (SMI), subcutaneous fat index (SFI) and visceral fat area (VFA). CTC, colonoscopy, and pathology reports were used to identify CRC incidence. Associations between demographic data, clinicopathological variables, CT-BC measurements, colorectal neoplasia and advanced colorectal neoplasia were analysed using univariate and multivariate binary logistics regression. RESULTS: 286 patients met the inclusion criteria. Neoplasia was detected in 105 (37%) of the patients with advanced neoplasia being detected in 72 (69%) of patients. On multivariate analysis sex (p < 0.05) and high VFA (p < 0.001) remained independently associated with colorectal neoplasia. On multivariate analysis a high SFI (p < 0.01) remained independently associated with advanced colorectal neoplasia. BMI was not associated with either colorectal neoplasia or advanced colorectal neoplasia. CONCLUSION: When directly compared to BMI, CT derived fat measurements were more closely associated with the degree of neoplasia in patients undergoing colorectal cancer screening. In patients investigated with CT colonography, CT adipose measures may stratify the risk and grade of neoplasia.
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Colonoscopía , Neoplasias Colorrectales , Composición Corporal , Índice de Masa Corporal , Neoplasias Colorrectales/diagnóstico por imagen , Neoplasias Colorrectales/epidemiología , Humanos , Tamizaje Masivo , Valor Predictivo de las Pruebas , Tomografía Computarizada por Rayos XRESUMEN
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.
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Neoplasias Colorrectales , Complejo de Antígeno L1 de Leucocito , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/patología , Heces/química , Humanos , Inflamación , Complejo de Antígeno L1 de Leucocito/análisis , Sensibilidad y EspecificidadRESUMEN
INTRODUCTION: Frailty is a complex multifactorial syndrome characterised by a significant increase in vulnerability and worsened health outcomes. Despite a range of proposed frailty screening measures, the prevalence and prognostic value of frailty in patients undergoing surgery for colorectal cancer is not clear. AIM: The aim of this present review was to examine the use of commonly employed frailty screening measures in patients undergoing surgery for colorectal cancer. METHODS: A systematic search of PubMed and Medline was carried out to identify studies reporting the use of frailty screening tools or measures in patients undergoing surgery for colorectal cancer. The screening measure used and prevalence of frailty within the population were recorded. Outcomes of interest were the incidence of post-operative complications, 30-day mortality and overall survival. RESULTS: Of the 15 studies included (n = 97, 898 patients), 9 studies were retrospective and included patients aged 70 years or older (n = 96, 120 patients). 5 of 12 studies reported that frailty was independently associated with the incidence of post-operative complications. There was also evidence that frailty was independently associated with 30-day mortality (1 of 4 studies, n = 9, 252 patients) and long-term survival (2 of 3 studies, n = 1, 420 patients). CONCLUSIONS: Frailty was common in patients with colorectal cancer and the assessment of frailty may have prognostic value in patients undergoing surgery. However, the basis of the relationship between frailty and post-operative outcomes is not clear and merits further study.
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Neoplasias Colorrectales , Fragilidad , Anciano , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/epidemiología , Neoplasias Colorrectales/cirugía , Detección Precoz del Cáncer , Anciano Frágil , Fragilidad/complicaciones , Fragilidad/diagnóstico , Fragilidad/epidemiología , Humanos , Prevalencia , Pronóstico , Estudios RetrospectivosRESUMEN
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.