The relationship between tumor and host factors and survival in patients undergoing adjuvant chemotherapy for colorectal cancer.

2014 ◽  
Vol 32 (3_suppl) ◽  
pp. 525-525
Author(s):  
James Hugh Park ◽  
Colin H. Richards ◽  
Donald C. Mcmillan ◽  
Paul G. Horgan ◽  
Campbell S. D. Roxburgh
Keyword(s):  
Colorectal Cancer ◽  
Adjuvant Chemotherapy ◽  
Tumor Microenvironment ◽  
Inflammatory Responses ◽  
Prognostic Score ◽  
Glasgow Prognostic Score ◽  
Cancer Specific Survival ◽  
Local Inflammatory Response ◽  
Invasive Margin ◽  
The Relationship

525 Background: The tumor microenvironment and host inflammatory responses are important determinants of outcome in colorectal cancer (CRC), however their impact on survival in patients receiving adjuvant chemotherapy remains unclear. The aim of the present study was to examine the relationship between these factors, clinicopathological characteristics and survival in patients receiving adjuvant chemotherapy for CRC. Methods: 365 patients who had undergone CRC resection at a single institution between 1997-2008 were included; 88 patients subsequently received chemotherapy. Tumor stroma percentage (TSP) and necrosis were assessed on H and E sections and graded as low or high. Local inflammatory response was assessed using the Klintrup-Mäkinen (K-M), Galon and revised Immunoscore (CD45RO+ /CD8+, and CD3+/CD8+at the invasive margin and tumor center, respectively). Systemic inflammation was assessed using modified Glasgow Prognostic Score (mGPS). Results: Patients receiving adjuvant chemotherapy were younger with a lower ASA (both P<0.05), had advanced T- and N-stage (P<0.05 and P<0.001, respectively), poor tumor differentiation (P<0.05), venous invasion (VI) (P<0.01), margin involvement, infiltrative invasive margin (both P<0.05) and high TSP (P<0.01). In those patients who received adjuvant chemotherapy, on multivariate analysis of clinicopathological factors, VI (HR 3.00, 95%CI 1.22-7.37, P=0.017), TSP (HR 3.00, 95%CI 1.26-7.12, P=0.013), K-M score (HR 5.24, 95%CI 1.21-22.68, P=0.027) and mGPS (HR 3.10 95%CI 1.47-6.55, P=0.003) were independently associated with cancer-specific survival. When the interrelationships between factors independently associated with cancer survival were examined, VI, mGPS, K-M score and TSP were independent of each other (all P>0.05). Conclusions: Compared to standard CRC pathological staging, the present results suggest that assessment of both tumor microenvironment and host inflammatory responses may have superior prognostic value compared with TNM in patients receiving adjuvant chemotherapy.

The relationship between the non-canonical NF-κB pathway, tumour microenvironment, systemic inflammation and survival in patients undergoing surgery for colorectal caner.

2017 ◽  
Vol 35 (4_suppl) ◽  
pp. 631-631
Author(s):  
Meera Patel ◽  
Lindsay Bennett ◽  
Jean A Quinn ◽  
Hester Catharina van Wyk ◽  
Paul G. Horgan ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Inflammatory Responses ◽  
Venous Invasion ◽  
Tumour Microenvironment ◽  
Braf V600e ◽  
High Expression ◽  
Inflammatory Cell Infiltrate ◽  
Cancer Specific Survival ◽  
Local Inflammatory Response ◽  
The Relationship

631 Background: In patients with colorectal cancer (CRC) the local and systemic inflammatory responses (LIR and SIR) are important determinants of disease progression. The present study examines the association of transcription factor RelB, a key member of the non-canonical NF-κB pathway and its association with LIR and SIR in patients undergoing resection of CRC. Methods: Patients with stage I-III CRC who underwent curative resection in a single institution and were in a previously constructed tissue microarray were studied. IHC was utilised to examine cytoplasmic and nuclear RelB expression. The relationship between RelB, clinicopathological characteristics, LIR (Klintrup-Mäkinen (KM) grade, CD3+ and CD8+T-cell density), SIR and cancer-specific survival (CSS) was examined. Results: 208 patients were included in the analysis. Cytoplasmic RelB (cyto-RelB) was associated with nuclear RelB ( p=0.006). High expression of cyto-RelB was associated with MMR competence ( p=0.010) but not with TNM stage ( p=0.468), venous invasion ( p=0.973), tumour budding ( p=0.068), tumour necrosis ( p=0.786), tumour cell proliferation ( p=0.907), BRAF V600E mutation ( p=0.585) or administration of adjuvant chemotherapy ( p=0.853). High cyto-RelB was inversely associated with mGPS (mGPS >1: low cyto-RelB – 19% vs. high cyto-RelB – 8%, p=0.017). Also, cyto-RelB was inversely associated with tumour inflammatory cell infiltrate at the margin, Klintrup-Mäkinen grade ( p=0.059), (CD3+ p=0.010, CD8+ p=0.007) and in the tumour (CD3+ p=0.002) and a trend with tumour stroma percentage ( p=0.079). High expression of cyto-RelB was not significantly associated with CSS ( p=0.052). Conclusions: In patients undergoing CRC resection, high expression of cyto-RelB was associated with an adverse host local inflammatory response. Up-regulation of the non-canonical NF- κB pathway may be an important mechanism whereby the tumour deregulates local inflammatory responses and evades host immunosurveillance. Further investigation of inflammation based signal transduction pathways in patients with colorectal cancer is warranted.

Signal transduction and activator of transcription 3 (STAT3), host inflammatory responses and survival of patients with colorectal cancer.

2016 ◽  
Vol 34 (4_suppl) ◽  
pp. 606-606
Author(s):  
James Hugh Park ◽  
Donald C. Mcmillan ◽  
Jennifer Clark ◽  
Paul G. Horgan ◽  
Campbell S.D. Roxburgh ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Inflammatory Responses ◽  
Prognostic Score ◽  
Glasgow Prognostic Score ◽  
Lymph Node Involvement ◽  
Clinicopathological Characteristics ◽  
Cancer Specific Survival ◽  
Stat3 Pathway ◽  
Modified Glasgow Prognostic Score ◽  
Inflammatory Status

606 Background: In patients with colorectal cancer (CRC), the local and systemic inflammatory responses (LIR and SIR) are important determinants of disease progression, and may be linked by activation of the IL-6/JAK/STAT3 pathway. The present study examines the associations between STAT3 expression and activation with LIR and SIR of patients undergoing resection of CRC. Methods: Patients with stage I-III CRC who underwent curative resection in a single institution and who were included in a previously constructed tissue microarray were studied. IHC was utilised to examine cytoplasmic total STAT3 and nuclear phosphorylated STAT3Tyr705 (pSTAT3) expression. The relationship between STAT3/pSTAT3 expression and clinicopathological characteristics, LIR (Klintrup-Makinen (KM) grade, CD3+ and CD8+T-cell density) and SIR (modified Glasgow Prognostic Score (mGPS)) and cancer-specific survival (CSS) was examined. Results: 201 patients were included. Cytoplasmic STAT3 expression was associated with nuclear pSTAT3 expression (P= 0.019). Increased cytoplasmic STAT3 expression was associated with high density of T-cells within the intraepithelial compartment (CD3+: low STAT3 – 49% vs. high STAT3 – 29%, P= 0.008; CD8+: low STAT3 – 43% vs. high STAT3 – 20%, P = 0.002) and with an elevated mGPS (mGPS > 1: low STAT3 – 31% vs. high STAT3 – 49%, P= 0.003) but not with any other clinicopathological features. Increased nuclear pSTAT3 expression was associated with younger age and lymph node involvement (P< 0.05) but was not associated with the LIR or SIR. Combined assessment of cytoplasmic STAT3 and nuclear pSTAT3 expression stratified 5-year CSS from 78% (both low) to 50% (both high) (P= 0.006). Conclusions: Activation of the IL-6/JAK/STAT3 pathway may be an important determinant of the LIR and SIR in patients with colorectal cancer. Furthermore, assessment of host inflammatory responses may identify patients likely to benefit from therapies targeting this pathway. Taken together with the results of recent clinical trials, the results of the present study suggest that recruitment of patients into future trials of such agents should be stratified by the inflammatory status of the patient.

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

2019 ◽  
Vol 26 (13) ◽  
pp. 4397-4404 ◽  
Author(s):  
Hester C. van Wyk ◽  
Antonia Roseweir ◽  
Peter Alexander ◽  
James H. Park ◽  
Paul G. Horgan ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Tumor Microenvironment ◽  
Evaluation Method ◽  
Venous Invasion ◽  
Staging System ◽  
Consensus Conference ◽  
Tumor Budding ◽  
Inflammatory Cell Infiltrate ◽  
Cancer Specific Survival ◽  
The Relationship

Abstract Background Tumor budding is an independent prognostic factor in colorectal cancer (CRC) and has recently been well-defined by the International Tumour Budding Consensus Conference (ITBCC). Objective The aim of the present study was to use the ITBCC budding evaluation method to examine the relationship between tumor budding, tumor factors, tumor microenvironment, and survival in patients with primary operable CRC. Methods Hematoxylin and eosin-stained slides of 952 CRC patients diagnosed between 1997 and 2007 were evaluated for tumor budding according to the ITBCC criteria. The tumor microenvironment was evaluated using tumor stroma percentage (TSP) and Klintrup–Makinen (KM) grade to assess the tumor inflammatory cell infiltrate. Results High budding (n = 268, 28%) was significantly associated with TNM stage (p < 0.001), competent mismatch repair (MMR; p < 0.05), venous invasion (p < 0.001), weak KM grade (p < 0.001), high TSP (p < 0.001), and reduced cancer-specific survival (CSS) (hazard ratio 8.68, 95% confidence interval 6.30–11.97; p < 0.001). Tumor budding effectively stratifies CSS stage T1 through to T4 (all p < 0.05) independent of associated factors. Conclusions Tumor budding effectively stratifies patients’ survival in primary operable CRC independent of other phenotypic features. In particular, the combination of T stage and budding should form the basis of a new staging system for primary operable CRC.

Comorbidity and systemic inflammation are independent prognostic factors in patients with colorectal cancer: A ScotScan collaborative study.

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. 707-707
Author(s):  
James Hugh Park ◽  
Anniken Fuglestad ◽  
Anne Helene Kostner ◽  
Antonia K. Roseweir ◽  
Joanne Edwards ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Systemic Inflammation ◽  
Inflammatory Responses ◽  
Prognostic Score ◽  
Collaborative Study ◽  
Glasgow Prognostic Score ◽  
Clinicopathological Characteristics ◽  
Stage Ii ◽  
Royal Infirmary ◽  
Modified Glasgow Prognostic Score

707 Background: Although inextricably linked, both comorbidity and systemic inflammatory responses have been shown to determine survival in patients undergoing surgery for colorectal cancer (CRC). The present study examines the interrelationships between comorbidity (ASA grade) and systemic inflammation (modified Glasgow Prognostic Score (mGPS)) in patients from the ScotScan dataset. Methods: Clinicopathological characteristics and outcome of consecutive patients undergoing potentially curative resection of TNM I-III CRC in Glasgow Royal Infirmary (Scotland) and Sørlandet Hospital (Norway) were prospectively collected. ASA grade and mGPS (0-CRP ≤ 10mg/L, 1-CRP > 10mg/L, 2-CRP > 10mg/L and albumin < 35g/L) prior to surgery was recorded and relationship with overall survival (OS) examined. Results: 2,295 patients (Scotland: n = 1,234 , Norway: n = 1,061) were included. Patients from Norway were more likely to be older, female and have higher ASA grade (all P < 0.001), and more likely to have colon cancer (76% vs. 67%, P < 0.001). Patients from Norway were less likely to be systemically inflamed (mGPS = 0: 72% vs. 65%, P < 0.001), even after propensity score matching ( n = 736, OR 0.36 95%CI0.25-0.51, P < 0.001). ASA grade and mGPS were significantly associated; 21% of ASA 1 patients had mGPS ≥ 1 compared to 41% of ASA four patients ( P < 0.001). In the propensity-matched cohort, both increasing ASA (HR 1.98 95% CI1.57-2.49, P < 0.001) and mGPS (HR 1.20 95% CI1.02-1.41, P = 0.027) were associated with OS independent of age, N stage and adjuvant therapy use; results in the whole cohort were similar. The combination of ASA grade and mGPS was examined with respect to OS in patients with stage II-III CRC (Table 1). In patients with stage II disease, 3-year OS was stratified from 96% (ASA 1, mGPS0) to 67% (ASA 3, mGPS2) ( P < 0.001); in patients with stage II disease, 3-year OS was stratified from 84% to 44% ( P < 0.001). Conclusions: Using a large, prospectively collected dataset of patients undergoing resection of CRC in two countries, the results of the present study confirm the independent prognostic value of measures of comorbidity and systemic inflammation prior to surgery.

Chemotherapy dose reductions in obese patients undergoing adjuvant chemotherapy for colorectal cancer: secondary analyses of trial data and the Greater Manchester and Cheshire Cancer Network Audit.

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 763-763
Author(s):  
Prakhar Srivastava ◽  
Lee Malcolmson ◽  
Mark P. Saunders ◽  
Andrew Renehan
Keyword(s):  
Colorectal Cancer ◽  
Overall Survival ◽  
Adjuvant Chemotherapy ◽  
Stage Iv ◽  
Obese Patients ◽  
Cancer Specific Survival ◽  
Stage Iv Cancer ◽  
Cancer Network ◽  
The Relationship ◽  
Dose Reductions

763 Background: In patients with stage II/III colorectal cancer receiving adjuvant chemotherapy, doses are calculated using body surface area (BSA) but often capped at BSA > 2.0. Dose capping might be a mechanism of reported poorer survival in obese patients. We aimed to investigate the different dosing schedules across BMI categories, using trial and ‘real world’ audit datasets, and determine its impact upon overall survival. Methods: Data was accessed for 1122 patients from the control arm of the MOSAIC trial (accessed via the Data Project Sphere) and 327 patients from the Greater Manchester and Cheshire Cancer Network (GMCCN) audit. Pearson’s χ2 and correlation coefficient were used to assess the relationship between BMI (expressed as normal, overweight and obese: and as continuous, respectively) and dose reductions. A multiple logistic regression model was constructed to compare the odds of receiving dose reductions in each BMI category. 4-year overall survival was calculated for each BMI category and dose status. Results: In MOSAIC, there were increasing dose reductions by BMI category: normal, 3%; overweight, 5%; and obese, 11%, with similar patterns in the GMCCN OxMdG group. Obese patients in MOSAIC and the GMCCN OxMdG group had 3- and 12-fold higher odds (OR = 3.4 and 12.5, CI = 1.6-7.0 and 2.0-78.1), respectively, of receiving dose reductions. However, these differences did not translate to differences in overall survival by BMI category or dose status. Conclusions: In our investigated datasets, there appears to be a relationship between increasing BMI and dose reductions, though it is modest and does not manifest as a detrimental influence on overall survival. Our findings agreed with other studies performed using stage IV cancer patients, although the relationship between increasing BMI and dose reductions is more prominent in patients with metastatic disease. Investigating other outcome measures such as cancer-specific survival and chemotherapy related toxicity is required for clarity.

The relationship between the local inflammatory response and postoperative infective complications following resection for colorectal cancer.

2014 ◽  
Vol 32 (3_suppl) ◽  
pp. 413-413
Author(s):  
Michelle Leana Ramanathan ◽  
Campbell S. D. Roxburgh ◽  
Paul G. Horgan ◽  
Donald C. Mcmillan
Keyword(s):  
Colorectal Cancer ◽  
Inflammatory Response ◽  
Curative Resection ◽  
Inflammatory Responses ◽  
Surgical Site Infections ◽  
Local Inflammation ◽  
Elective Resection ◽  
Local Inflammatory Response ◽  
The Relationship ◽  
Infective Complications

413 Background: In patients with colorectal cancer, the presence of both systemic and/ or local inflammatory responses are predictors of survival independent of tumour stage. The relationship between a raised perioperative systemic inflammatory response and the development of postoperative infective complications is also well established. The aim of the present study was to examine the relationship between the local inflammatory response and the development of postoperative infective complications, in patients undergoing resection for colorectal cancer. Methods: Patients with histologically proven colorectal cancer who, on the basis of laparotomy findings and preoperative abdominal computed tomography, were considered to have undergone potentially curative resection were included in the study (n = 310). Patient characteristics and postoperative complications within 30 days were recorded in a prospective surgical database. Local inflammation was analysed using Klintrup-Makinen criteria and Jass scoring on routine hematoxylin and eosin slides. Results: The majority of patients were 65 or older (66%), male (57%), had colonic tumours (68%) and node negative disease (60%). Most patients underwent elective resection (87%) and were from a deprived area (55%). During follow up 109 (35%) patients developed a postoperative complication; 88 (81%) of which had infective complications. There were no significant associations between local inflammation, as evidenced by Klintrup-Makinen criteria and Jass score, and all infective complications (p = 0.929, p = 0.317), surgical site infections (p = 0.956, p = 0.115), or anastomotic leak (p = 0.771, p = 0.157). Conclusions: The results of the present study show that there is no significant relationship between the degree of local inflammation, as evidenced by Klintrup-Makinen criteria and Jass score, and the development of postoperative infective complications following potentially curative resection for colorectal cancer.

The host inflammatory responses, tumor stroma percentage, and survival in colorectal cancer.

2014 ◽  
Vol 32 (3_suppl) ◽  
pp. 549-549
Author(s):  
James Hugh Park ◽  
Colin H. Richards ◽  
Donald C. Mcmillan ◽  
Paul G. Horgan ◽  
Campbell S. D. Roxburgh
Keyword(s):  
Colorectal Cancer ◽  
Inflammatory Response ◽  
Inflammatory Cell ◽  
Inflammatory Responses ◽  
Tumor Stroma ◽  
Inflammatory Cell Infiltrate ◽  
Cell Infiltrate ◽  
Local Inflammatory Response ◽  
Invasive Margin ◽  
N Stage

549 Background: The role of host inflammatory responses in determining colorectal cancer (CRC) outcome is increasingly recognised. In particular, a marked local inflammatory response is associated with improved survival. However, determinants of this response are not clear. A plausible factor in the density, location and type of the inflammatory cell infiltrate is the extent of tumor stroma. The aim of the present study was to examine the relationship between tumor stroma percentage (TSP), tumor inflammatory infiltrate and survival in patients undergoing elective CRC resection. Methods: 335 patients who had undergone elective resection for stage I-III CRC at a single institution between 1997-2008 were included. TSP at the invasive margin (IM) was assessed on H and E sections and grouped as low (≤50%) or high (>50%). Local inflammatory response was assessed at the IM using Klintrup-Mäkinen (K-M) score and at the IM, tumor stroma and cancer cell nests (CCNs) using the following T-cell markers: CD3, CD8, CD45R0, FOXP3. Systemic inflammatory response was assessed using modified Glasgow Prognostic Score (mGPS). Results: Eighty-three patients (25%) had high TSP. High TSP was associated with increased T stage, N stage (both p < 0.01), margin and serosal involvement (both p < 0.05), an infiltrative invasive margin (p < 0.001) and tumor necrosis (p = 0.001). TSP was associated with decreased infiltration by CD3+ and CD8+ cells at the CCNs (p < 0.01 and p < 0.05 respectively) but not at the IM or stroma. K-M score showed a trend towards an inverse association with TSP (p = 0.067). CD45R0+ and FOXP3+cell infiltration and mGPS were not associated with TSP. On multivariate analysis, TSP was associated with poorer cancer-specific survival (HR 1.93, 95% CI 1.15-3.23, p = 0.012), independent of N stage, VI (both p < 0.05), low CD8 at the IM and CCNs (both p < 0.01) and mGPS (p = 0.001). Conclusions: TSP was associated with the presence of high risk pathological characteristics and down-regulation of host intra-tumoral immune responses and was independently associated with poorer cancer survival. The extent of tumor stroma is an important factor in the nature of the tumor inflammatory cell infiltrate and outcome in patients undergoing elective surgery for CRC.

Systemic inflammation, adjuvant chemotherapy, and survival in stage III colorectal cancer: Results from the ScotScan Colorectal Cancer Collaborative.

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. 228-228
Author(s):  
James Hugh Park ◽  
Anniken Jorlo Fuglestad ◽  
Anne Helene Kostner ◽  
Agata Oliwa ◽  
Campbell SD Roxburgh ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Adjuvant Chemotherapy ◽  
Adjuvant Therapy ◽  
Predictive Biomarker ◽  
Stage Iii ◽  
C Reactive Protein ◽  
Cancer Specific Survival ◽  
Reactive Protein ◽  
Chemotherapy Regime ◽  
The Relationship

228 Background: The systemic inflammatory response (SIR) is a poor prognostic marker in patients with colorectal cancer (CRC), and predicts poor outcome following adjuvant chemotherapy. Whether this may be influenced by chemotherapy regime is not known. The present study examined the relationship between the pre-operative SIR, adjuvant therapy regime, and survival of patients with stage III CRC in the ScotScan cohort. Methods: Patients with stage III CRC in Scotland (1997-2015, n= 317) and Norway (2000-17, n= 312) were included. The pre-operative SIR was measured using C-reactive protein (CRP≤10mg/L or > 10mg/L). Adjuvant status was categorised as none, 5-fluorouracil-only (5FU or capecitabine), or oxaliplatin-combination (Ox). Relationship with 3 year overall (OS) and cancer-specific survival (CSS) was examined. Results: Rates of Ox were comparable between cohorts (Scotland – 26% vs. Norway 28%), although more patients from Norway received single 5FU (4% vs. 19%, P= 0.005). 36% of each cohort were systemically inflamed. Ox was associated with superior OS (90%) and CSS (92%) when compared to 5FU (77% and 84%) and no therapy (61% and 72%, both P< 0.001). Stratified by SIR, patients with CRP≤10mg/L receiving Ox or 5FU had comparable 3yr OS greater than those receiving none (90% vs. 88% vs. 67%), whereas those with CRP > 10mg/L receiving Ox had superior survival than those receiving 5FU or no therapy (89% vs. 64% vs. 53%, P-for interaction = 0.101). Results were similar for CSS (CRP≤10mg/L: 91% vs. 94% vs. 79%; CRP > 10mg/L: 94% vs. 72% vs. 62%, P-for interaction= 0.01). Although patients receiving Ox were younger and less comorbid, both use of Ox and SIR remained independently associated with OS and CSS. Conclusions: Although selection bias in the choice of adjuvant therapy may confound analysis, this study suggests the SIR may aid in determining response to adjuvant therapy. Whereas non-inflamed patients with stage III CRC may benefit from single 5FU, those with an elevated SIR may benefit greater from more intensive, Ox-based regimes. These results remain to be validated, however support the use of the SIR as a prognostic and predictive biomarker in patients with stage III CRC.

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