James H. Park

The relationship between tumour stroma percentage, the tumour microenvironment and survival in patients with primary operable colorectal cancer

BACKGROUND Tumour stroma percentage (TSP) has previously been reported to predict survival in patients with colorectal cancer (CRC); however, whether this is independent of other aspects of the tumour microenvironment is unknown. In the present study, the relationship between TSP, the tumour microenvironment and survival was examined in patients undergoing elective, curative CRC resection. PATIENTS AND METHODS Patients undergoing resection at a single centre (1997-2008) were identified from a prospective database. TSP was measured at the invasive margin and its association with cancer-specific survival (CSS) and clinicopathological characteristics examined. RESULTS Three hundred and thirty-one patients were included in the analysis. TSP was associated with CSS in patients with stage I-III disease [hazard ratio (HR) 1.84, 95% confidence interval (CI) 1.17-2.92, P = 0.009], independent of age, systemic inflammation, N stage, venous invasion and Klintrup-Mäkinen score. Furthermore, TSP was associated with reduced CSS in patients with node-negative disease (HR 2.14, 95% CI 1.01-4.54, P = 0.048) and those who received adjuvant chemotherapy (HR 2.83, 95% CI 1.23-6.53, P = 0.015), independent of venous invasion and host inflammatory responses. TSP was associated with several adverse pathological characteristics, including advanced T and N stage. Furthermore, TSP was associated with an infiltrative invasive margin and inversely associated with necrosis. CONCLUSIONS The TSP was a significant predictor of survival in patients undergoing elective, curative CRC resection, independent of adverse pathological characteristics and host inflammatory responses. In addition, TSP was strongly associated with local tumour growth and invasion.BACKGROUND Tumour stroma percentage (TSP) has previously been reported to predict survival in patients with colorectal cancer (CRC); however, whether this is independent of other aspects of the tumour microenvironment is unknown. In the present study, the relationship between TSP, the tumour microenvironment and survival was examined in patients undergoing elective, curative CRC resection. PATIENTS AND METHODS Patients undergoing resection at a single centre (1997-2008) were identified from a prospective database. TSP was measured at the invasive margin and its association with cancer-specific survival (CSS) and clinicopathological characteristics examined. RESULTS Three hundred and thirty-one patients were included in the analysis. TSP was associated with CSS in patients with stage I-III disease [hazard ratio (HR) 1.84, 95% confidence interval (CI) 1.17-2.92, P = 0.009], independent of age, systemic inflammation, N stage, venous invasion and Klintrup-Mäkinen score. Furthermore, TSP was associated with reduced CSS in patients with node-negative disease (HR 2.14, 95% CI 1.01-4.54, P = 0.048) and those who received adjuvant chemotherapy (HR 2.83, 95% CI 1.23-6.53, P = 0.015), independent of venous invasion and host inflammatory responses. TSP was associated with several adverse pathological characteristics, including advanced T and N stage. Furthermore, TSP was associated with an infiltrative invasive margin and inversely associated with necrosis. CONCLUSIONS The TSP was a significant predictor of survival in patients undergoing elective, curative CRC resection, independent of adverse pathological characteristics and host inflammatory responses. In addition, TSP was strongly associated with local tumour growth and invasion.

Colorectal Cancer, Systemic Inflammation, and Outcome: Staging the Tumor and Staging the Host.

Objective:This study aims to examine the clinical utility of the combination of TNM stage and modified Glasgow Prognostic Score (mGPS) in patients undergoing potentially curative resection of colorectal cancer (CRC). Background:Of measures of the systemic inflammatory response, the mGPS has been most extensively validated in patients with cancer. Methods:Data from 1000 consecutive patients undergoing potentially curative CRC resection from a single institution (January 1997–May 2013) were included. The relationship between mGPS [0–C-reactive protein (CRP) ⩽ 10 mg/L, 1—CRP > 10 mg/L and albumin ≥35 g/L, 2—CRP > 10 mg/L and albumin < 35 g/L], TNM stage, and cancer-specific survival (CSS) and overall survival (OS) was examined using Kaplan-Meier log-rank survival analysis and multivariate Cox regression analysis. Results:An mGPS of 0, 1, and 2 was observed in 63%, 21%, and 16% of patients, respectively. Median follow-up was 56 months (interquartile range: 28–107 months). TNM and mGPS were independently associated with CSS and OS (all P < 0.001). In all patients, TNM and mGPS stratified 5-year CSS and OS from 97% and 87% (stage I, mGPS = 0) to 32% and 26% (stage III, mGPS = 2), respectively. In patients undergoing elective resection of colon cancer (n = 575), 5-year CSS and OS ranged from 100% and 87% (stage I, mGPS = 0) to 37% and 30% (stage III, mGPS = 2), respectively. Conclusions:This study shows how the combination of TNM and mGPS effectively stratifies outcome in patients undergoing potentially curative resection of CRC. These data support routine staging of both the tumor and the host in patients with CRC.

Potentially detrimental cardiovascular effects of oxygen in patients with chronic left ventricular systolic dysfunction

Background Although the haemodynamic effects of oxygen in healthy subjects are well documented, there have been no well-controlled studies of the effects of oxygen in patients with heart failure (HF). Aims To non-invasively evaluate haemodynamic and neurohumoral effects of oxygen in patients with HF at rest. Methods and results 13 men with heart failure and left ventricular systolic dysfunction (LVSD) were randomised in a double-blind, placebo-controlled, crossover trial to receive medical air or oxygen (40% and high concentration via Hudson non-rebreathing mask). Haemodynamic measurements were made with applanation tonometry, impedance cardiography and venous occlusion plethysmography. Plasma C-terminal B-type natriuretic peptide and A-type natriuretic peptide were measured. Data were analysed with paired t tests. Cardiac output fell by −0.58 (0.62) l/min on high-flow oxygen compared with −0.02 (0.58) l/min on air, p=0.031. Oxygen caused a reduction in heart rate (−4.02 (4.21) vs 0.41 (5.35) beats/min, respectively, p=0.021) and a trend towards increased systemic vascular resistance (875 (1174) vs 235 (321) dyne/s/m5, p=0.050). Oxygen led to a paradoxical increase in forearm blood flow (0.513 (0.391) vs 0.024 (0.246) ml/min/100 ml forearm volume on air, p=0.01). Natriuretic peptides were unchanged with oxygen. Conclusions High-concentration inhaled oxygen has significant haemodynamic effects in patients with LVSD and mild HF. Such effects may be detrimental in patients with decompensated HF.

The impact of anti-inflammatory agents on the outcome of patients with colorectal cancer.

Although there is increasing appreciation of the role of the host inflammatory response in determining outcome in patients in colorectal cancer, there has been little concerted effort to favourably manipulate cancer-associated inflammation, either alone or in combination with current oncological treatment. Epidemiological and cardiovascular disease studies have identified aspirin, other nonsteroidal anti-inflammatory drugs and statins as potential chemotherapeutic agents which may manipulate the host inflammatory response to the benefit of the patient with cancer. Similarly, evidence of a chemotherapeutic effect of histamine-2 receptor antagonists, again mediated by an immunomodulatory effect, has previously led to increased interest in their use in gastrointestinal cancer. Extensive pre-clinical data and a limited number of clinical investigations have proposed a direct effect of these agents on tumour biology, with an anti-tumour effect on several of the hallmarks of cancer, including proliferative capacity, evasion from apoptosis and cell cycle regulation, and invasive capability of tumour cells. Furthermore, clinical evidence has suggested a pertinent role in down-regulating the systemic inflammatory response whilst favourably influencing the local inflammatory response within the tumour microenvironment. Despite such compelling results, the clinical applicability of nonsteroidal anti-inflammatory drugs, statins and histamine-2 receptor antagonists has not been fully realised, particularly in patients identified at high risk on the basis of inflammatory parameters. In the present review, we examine the potential role that these agents may play in improving survival and reducing recurrence in patients with potentially curative colorectal cancer, and in particular focus on their effects on the local and systemic inflammatory response.

Evaluation of a Tumor Microenvironment–Based Prognostic Score in Primary Operable Colorectal Cancer

Purpose: The tumor microenvironment is recognized as an important determinant of progression and outcome in colorectal cancer. The aim of the present study was to evaluate a novel tumor microenvironment–based prognostic score, based on histopathologic assessment of the tumor inflammatory cell infiltrate and tumor stroma, in patients with primary operable colorectal cancer. Experimental Design: Using routine pathologic sections, the tumor inflammatory cell infiltrate and stroma were assessed using Klintrup–Mäkinen (KM) grade and tumor stroma percentage (TSP), respectively, in 307 patients who had undergone elective resection for stage I–III colorectal cancer. The clinical utility of a cumulative score based on these characteristics was examined. Results: On univariate analysis, both weak KM grade and high TSP were associated with reduced survival (HR, 2.42; P = 0.001 and HR, 2.05; P = 0.001, respectively). A cumulative score based on these characteristics, the Glasgow Microenvironment Score (GMS), was associated with survival (HR, 1.93; 95% confidence interval, 1.36–2.73; P < 0.001), independent of TNM stage and venous invasion (both P < 0.05). GMS stratified patients in to three prognostic groups: strong KM (GMS = 0), weak KM/low TSP (GMS = 1), and weak KM/high TSP (GMS = 2), with 5-year survival of 89%, 75%, and 51%, respectively (P < 0.001). Furthermore, GMS in combination with node involvement, venous invasion, and mismatch repair status further stratified 5-year survival (92% to 37%, 93% to 27%, and 100% to 37%, respectively). Conclusions: The present study further confirms the clinical utility of assessment of the tumor microenvironment in colorectal cancer and introduces a simple, routinely available prognostic score for the risk stratification of patients with primary operable colorectal cancer. Clin Cancer Res; 21(4); 882–8. ©2014 AACR.

The role of tumour budding in predicting survival in patients with primary operable colorectal cancer: A systematic review

Tumour budding reflects a detachment of tumour cells at the invasive front of carcinomas and is presumed to be an early step in the metastatic process. Tumour budding has received some attention in colorectal cancer as it has been proposed as an additional prognostic factor in colorectal cancer that may stratify patients into risk categories. The purpose of the review was to examine (1): The different methods of detection using either routine stains (H&E) or immunohistochemistry; (2): to compare studies that examined the different methods used to identify tumour budding; and (3) to examine the impact of tumour budding on survival in primary operable colorectal cancer. Results from the present review suggest that tumour budding can be considered a promising and strong prognostic factor in colorectal cancer. However, the implementation of the assessment of tumour budding in routine pathological work will depend on a selected, internationally accepted scoring system and validation against other established prognostic factors in patients with colorectal cancer.

Mismatch repair status in patients with primary operable colorectal cancer: associations with the local and systemic tumour environment.

Background:Mismatch repair-deficient (dMMR) colorectal cancer (CRC) is associated with a conspicuous local immune infiltrate; however, its relationship with systemic inflammatory responses remains to be determined. The present study aims to examine the relationships and prognostic value of assessment of the local and systemic environment in the context of MMR status in patients with CRC.Methods:The relationship between MMR status, determined using immunohistochemistry, and the local inflammatory cell infiltrate, differential white cell count, neutrophil : platelet score (NPS), neutrophil : lymphocyte ratio and modified Glasgow Prognostic Score (mGPS), and cancer-specific survival was examined in 228 patients undergoing resection of stage I–III CRC.Results:Thirty-five patients (15%) had dMMR CRC. Mismatch repair deficiency was associated with a higher density of CD3+, CD8+ and CD45R0+ T lymphocytes within the cancer cell nests and an elevated mGPS (mGPS2: 23% vs 9%, P=0.007) and NPS (NPS2: 19% vs 3%, P=0.001). CD3+ density (P<0.001), mGPS (P=0.01) and NPS (P=0.042) were associated with survival independent of MMR status (P=0.367) and stratified 5-year survival of patients with MMR-competent CRC from 94% to 67%, 83% to 46% and 78% to 60% respectively.Conclusions:Mismatch repair deficiency was associated with local and systemic environments, and in comparison with their assessment, dMMR had relatively poor prognostic value in patients with primary operable CRC. In addition to MMR status, local and systemic inflammatory responses should be assessed in these patients.

The Neutrophil-Platelet Score (NPS) Predicts Survival in Primary Operable Colorectal Cancer and a Variety of Common Cancers.

Introduction Recent in-vitro studies have suggested that a critical checkpoint early in the inflammatory process involves the interaction between neutrophils and platelets. This confirms the importance of the innate immune system in the elaboration of the systemic inflammatory response. The aim of the present study was to examine whether a combination of the neutrophil and platelet counts were predictive of survival in patients with cancer. Methods Patients with histologically proven colorectal cancer who underwent potentially curative resection at a single centre between March 1999 and May 2013 (n = 796) and patients with cancer from the Glasgow Inflammation Outcome Study, who had a blood sample taken between January 2000 and December 2007 (n = 9649) were included in the analysis. Results In the colorectal cancer cohort, there were 173 cancer and 135 non-cancer deaths. In patients undergoing elective surgery, cancer-specific survival (CSS) at 5 years ranged from 97% in patients with TNM I disease and NPS = 0 to 57% in patients with TNM III disease and NPS = 2 (p = 0.019) and in patients undergoing elective surgery for node-negative colon cancer from 98% (TNM I, NPS = 0) to 65% (TNM II, NPS = 2) (p = 0.004). In those with a variety of common cancers there were 5218 cancer and 929 non-cancer deaths. On multivariate analysis, adjusting for age and sex and stratified by tumour site, incremental increase in the NPS was significantly associated with poorer CSS (p<0.001). Conclusion The neutrophil-platelet score predicted survival in a variety of common cancers and highlights the importance of the innate immune system in patients with cancer.

Neutrophil count is the most important prognostic component of the differential white cell count in patients undergoing elective surgery for colorectal cancer

BACKGROUND Systemic inflammatory scoring systems such as the NLR have been reported to have prognostic value in many solid organ cancers. The aim of this study was to examine the relationships between the components of the white cell count (WCC) and survival in patients undergoing elective surgery for colorectal cancer. METHODS Patients undergoing elective resection at a single center (1997 to 2008) were identified from a prospective database (n = 508). Patient demographics and preoperative laboratory measurements including the differential WCC and their association with cancer-specific survival (CSS) and overall survival were examined. RESULTS There were 172 cancer deaths and 120 noncancer deaths. On Kaplan-Meier analysis of the whole cohort, age, Tumor, Nodal, and Metastasis stage, venous invasion, margin involvement, peritoneal involvement and tumor perforation, and white cell and neutrophil count (all P < .05) were associated with CSS. In those with node-negative colon cancer (n = 226), on multivariate analysis, age, venous invasion, modified Glasgow Prognostic Score, and neutrophil count (all P < .05) were independently associated with CSS. CONCLUSION Of the components of a differential WCC, only the neutrophil count was independently associated with survival, particularly in node-negative colon cancer.

Tumour invasiveness, the local and systemic environment and the basis of staging systems in colorectal cancer

Background:The present study aimed to examine the relationship between tumour invasiveness (T stage), the local and systemic environment and cancer-specific survival (CSS) of patients with primary operable colorectal cancer.Methods:The tumour microenvironment was examined using measures of the inflammatory infiltrate (Klintrup-Makinen (KM) grade and Immunoscore), tumour stroma percentage (TSP) and tumour budding. The systemic inflammatory environment was examined using modified Glasgow Prognostic Score (mGPS) and neutrophil:lymphocyte ratio (NLR). A 5-year CSS was examined.Results:A total of 331 patients were included. Increasing T stage was associated with colonic primary, N stage, poor differentiation, margin involvement and venous invasion (P<0.05). T stage was significantly associated with KM grade (P=0.001), Immunoscore (P=0.016), TSP (P=0.006), tumour budding (P<0.001), and elevated mGPS and NLR (both P<0.05). In patients with T3 cancer, N stage stratified survival from 88 to 64%, whereas Immunoscore and budding stratified survival from 100 to 70% and from 91 to 56%, respectively. The Glasgow Microenvironment Score, a score based on KM grade and TSP, stratified survival from 93 to 58%.Conclusions:Although associated with increasing T stage, local and systemic tumour environment characteristics, and in particular Immunoscore, budding, TSP and mGPS, are stage-independent determinants of survival and may be utilised in the staging of patients with primary operable colorectal cancer.