The relationship between patient physiology, the systemic inflammatory response and survival in patients undergoing curative resection of colorectal cancer

<p>Background: It is increasingly recognised that host-related factors may be important in determining cancer outcome. The aim was to examine the relationship between patient physiology, the systemic inflammatory response and survival after colorectal cancer resection.</p> <p>Methods: Patients undergoing potentially curative resection of colorectal cancer were identified from a prospectively maintained database. Patient physiology was assessed using the physiological and operative severity score for the enumeration of mortality and morbidity (POSSUM) criteria. The systemic inflammatory response was assessed using the modified Glasgow Prognostic Score (mGPS). Multivariate 5-year survival analysis was carried out with calculation of hazard ratios (HR).</p> <p>Results: A total of 320 patients were included. During follow-up (median 74 months), there were 136 deaths: 83 colorectal cancer related and 53 non-cancer related. Independent predictors of cancer-specific survival were age (HR: 1.46, P<0.01), Dukes stage (HR: 2.39, P<0.001), mGPS (HR: 1.78, P<0.001) and POSSUM physiology score (HR: 1.38, P=0.02). Predictors of overall survival were age (HR: 1.64, P<0.001), smoking (HR: 1.52, P=0.02), Dukes stage (HR: 1.64, P<0.001), mGPS (HR: 1.60, P<0.001) and POSSUM physiology score (HR: 1.27, P=0.03). A relationship between mGPS and POSSUM physiology score was also established (P<0.006).</p> <p>Conclusion: The POSSUM physiology score and the systemic inflammatory response are strongly associated and both are independent predictors of cancer specific and overall survival in patients undergoing potentially curative resection of colorectal cancer.</p&gt

Neutrophil/lymphocyte ratio predicts chemotherapy outcomes in patients with advanced colorectal cancer

BACKGROUND: Advances in the treatment of metastatic colorectal cancer (mCRC) in the last decade have significantly improved survival; however, simple biomarkers to predict response or toxicity have not been identified, which are applicable to all community oncology settings worldwide. The use of inflammatory markers based on differential white-cell counts, such as the neutrophil/ lymphocyte ratio (NLR), may be simple and readily available biomarkers. METHODS: Clinical information and baseline laboratory parameters were available for 349 patients, from two independent cohorts, with unresectable mCRC receiving first-line palliative chemotherapy. Associations between baseline prognostic variables, including inflammatory markers such as the NLR and tumour response, progression and survival were investigated. RESULTS: In the training cohort, combination-agent chemotherapy (P ¼ 0.001) and NLRp5 (P ¼ 0.003) were associated with improved clinical benefit. The ECOG performance status X1 (P ¼ 0.002), NLR45 (P ¼ 0.01), hypoalbuminaemia (P ¼ 0.03) and single-agent chemotherapy (Po0.0001) were associated with increased risk of progression. The ECOG performance status X1 (P ¼ 0.004) and NLR45 (P ¼ 0.002) predicted worse overall survival (OS). The NLR was confirmed to independently predict OS in the validation cohort (Po0.0001). Normalisation of the NLR after one cycle of chemotherapy in a subset of patients resulted in improved progression-free survival (P ¼ 0.012). CONCLUSION: These results have highlighted NLR as a potentially useful clinical biomarker of systemic inflammatory response in predicting clinically meaningful outcomes in two independent cohorts. Results of this study have also confirmed the importance of a chronic systemic inflammatory response influencing clinical outcomes in patients with mCRC

Scoring of senescence signalling in multiple human tumour gene expression datasets, identification of a correlation between senescence score and drug toxicity in the NCI60 panel and a pro-inflammatory signature correlating with survival advantage in peritoneal mesothelioma

Background: Cellular senescence is a major barrier to tumour progression, though its role in pathogenesis of cancer and other diseases is poorly understood in vivo. Improved understanding of the degree to which latent senescence signalling persists in tumours might identify intervention strategies to provoke "accelerated senescence" responses as a therapeutic outcome. Senescence involves convergence of multiple pathways and requires ongoing dynamic signalling throughout its establishment and maintenance. Recent discovery of several new markers allows for an expression profiling approach to study specific senescence phenotypes in relevant tissue samples. We adopted a "senescence scoring" methodology based on expression profiles of multiple senescence markers to examine the degree to which signals of damage-associated or secretory senescence persist in various human tumours. Results: We first show that scoring captures differential induction of damage or inflammatory pathways in a series of public datasets involving radiotherapy of colon adenocarcinoma, chemotherapy of breast cancer cells, replicative senescence of mesenchymal stem cells, and progression of melanoma. We extended these results to investigate correlations between senescence score and growth inhibition in response to similar to 1500 compounds in the NCI60 panel. Scoring of our own mesenchymal tumour dataset highlighted differential expression of secretory signalling pathways between distinct subgroups of MPNST, liposarcomas and peritoneal mesothelioma. Furthermore, a proinflammatory signature yielded by hierarchical clustering of secretory markers showed prognostic significance in mesothelioma. Conclusions: We find that "senescence scoring" accurately reports senescence signalling in a variety of situations where senescence would be expected to occur and highlights differential expression of damage associated and secretory senescence pathways in a context-dependent manner

The relationship between components of tumour inflammatory cell infiltrate and clinicopathological factors and survival in patients with primary operable invasive ductal breast cancer

BACKGROUND: The importance of the components of host local inflammatory response in determining outcome in primary operable ductal invasive breast cancer is not clear. The aim of this study was to examine the relationship between components of the tumour inflammatory cell infiltrate and standard clinicopathological factors including hormone status (oestrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor (HER)-2), Ki-67 and survival in patients with primary operable invasive ductal breast cancer. METHODS: Tumour inflammatory cell infiltrate, hormone status (ER, PR and HER-2), Ki-67 and standard clinicopathological factors were determined using routine pathological and immuno-histochemical techniques in 468 patients. RESULTS: The large majority (94%) of ductal tumours had evidence of inflammatory cell infiltrate. The general inflammatory cell infiltrate was positively associated with high grade (P<0.001), the absence of ER (P<0.001), the absence of PR (P<0.01), the presence of vascular invasion (P<0.05) and high lymphocytic infiltrate, plasma cell infiltrate, other inflammatory cell infiltrate and macrophage infiltrate (all P<0.001). The median follow-up of the survivors was 165 months. During this period, 93 patients died of their cancer. On univariate analysis, stratified for ER status, tumour size (P<0.01), lymph node involvement (P<0.001), tumour plasma cell infiltrate (P<0.001), other inflammatory cell infiltrate (P<0.05) and treatment (P<0.05) were associated with poorer cancer-specific survival whereas lymphocyte infiltrate (P<0.001) was associated with improved cancer-specific survival. On multivariate analysis, stratified for ER status, lymph node involvement (P<0.05) was independently associated with poorer cancer-specific survival whereas increased tumour lymphocyte infiltrate (P<0.001) was independently associated with improved cancer-specific survival. CONCLUSION: The results of this study show that, using routine histology, the general inflammatory cell infiltrate was a common feature and was positively associated with high grade, the absence of ER, the absence of PR, the presence of vascular invasion and high-grade infiltration of lymphocytes, plasma cells, other inflammatory cells and macrophages. Also, that within a mature cohort of patients, a high lymphocytic infiltrate was associated with improved survival, independent of clinicopathological characteristics including ER status, in primary operable ductal invasive breast cancer. These results rationalise previous work and provide a sound basis for future studies in this important area of breast cancer research

Relationship between preoperative comorbidity, systemic inflammatory response, and survival in patients undergoing curative resection for colorectal cancer.

Besides tumor characteristics, colorectal cancer (CRC) outcomes are also determined by host factors, in particular the systemic inflammatory response. The basis of this relationship with survival is not known; however, systemic inflammation may reflect comorbidity. The present study examines relationships between host factors (including age, comorbidity, deprivation, and systemic inflammation) and survival in CRC. A total of 302 patients underwent curative elective CRC resection between 1997 and 2005. Data was collected on patient comorbidity (Charlson Comorbidity Index [CCI], Lee Cardiac Risk Index [LCRI], National Institute on Aging and National Cancer Institute Comorbidity Index [NIA/NCI], and Adult Comorbidity Evaluation-27 [ACE-27]), systemic inflammatory response (Glasgow Prognostic Score [mGPS]), deprivation [Carstairs Deprivation Index], body mass index, and smoking status. For cancer-specific survival, age (P = 0.047), tumor, node, metastasis system stage (P &lt; 0.001), high-risk Petersen Index (P &lt; 0.001), LCRI (P = 0.021), and mGPS (P &lt; 0.001) were independent factors by multivariate analysis. For overall survival, age (P &lt; 0.001), tumor, node, metastasis system stage (P = 0.001), high-risk Petersen Index (P = 0.002), postoperative infective complications (P = 0.002), ACE-27 (P = 0.008), and mGPS (P &lt; 0.001) were independent factors. Older age related to increasing comorbidity (ACE-27, CCI, LCRI [P &lt; 0.005]) and increased mGPS (P &lt; 0.005). Smoking and deprivation related to increasing comorbidity (P &lt; 0.05). The mGPS was associated with high comorbidity burden assessed with ACE-27 (P = 0.065), CCI (P = 0.016), LCRI (P = 0.095), and NIA/NCI (P = 0.084). Comorbidity does not fully explain the relationship between the mGPS and cancer-specific survival in CRC patients. Furthermore, comorbidity, in particular that measured by the LCRI, is an important independent indicator of cancer survival