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Aims: The incidence of anal squamous cell cancer (SCCA) is rising. Although chemoradiotherapy (CRT) provides a chance of cure, a proportion of patients have an incomplete response or develop recurrence. This study assessed the value of inflammation-based prognostic indicators, including the modified Glasgow Prognostic Score (mGPS) and neutrophil:lymphocyte ratio (NLR), in patients with SCCA treated by CRT with curative intent., Material and Methods: Patients with histologically confirmed SCCA were identified from pathology records. Medical records were retrospectively reviewed and clinical, pathological and treatment characteristics were abstracted. The mGPS (0 = normal C-reactive protein [CRP] and albumin, 1 = CRP >10 mg/l and 2 = CRP >10 mg/l and albumin <35 mg/l) and NLR were calculated from routine blood tests obtained prior to CRT., Results: In total, 118 patients underwent CRT for SCCA between December 2007 and February 2018. Of these, 99 patients had appropriate pretreatment blood results available. Systemic inflammation as indicated by NLR >3 and mGPS >0 was present in 41% and 39% of patients, respectively. Most patients had T2 or larger tumours (n = 85, 86%) without nodal involvement (n = 64, 65%). An elevated mGPS was associated with more advanced T-stage (56% versus 35%, P = 0.036). NLR >5 was associated with nodal positivity (56% versus 31%, P = 0.047). On multivariate analysis, more advanced T-stage (odds ratio 7.49, 95% confidence interval 1.51-37.20, P = 0.014) and a raised mGPS (odds ratio 5.13, 95% confidence interval 1.25-21.14, P = 0.024) were independently related to incomplete CRT response. An elevated mGPS was prognostic of inferior survival (hazard ratio 3.09, 95% confidence interval 1.47-6.50, P = 0.003) and cancer-specific survival (hazard ratio 4.32, 95% confidence interval 1.54-12.15, P = 0.006), independent of TNM stage., Conclusion: Systemic inflammation, as measured by the mGPS, is associated with an incomplete CRT response and is independently prognostic of inferior survival in patients with SCCA. The mGPS may offer a simple marker of inferior outcome that could be used to identify high-risk patients., (Copyright © 2020 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

Current focus in colorectal cancer (CRC) management is on reducing overall mortality by increasing the number of early-stage cancers diagnosed and treated with curative intent. Despite the success of screening programs in down-staging CRC, interval cancer rates are substantial and other strategies are desirable. Sporadic CRC is largely associated with lifestyle factors including diet. Polyphenols are phytochemicals ingested as part of a normal diet, which are abundant in plant foods including fruits/berries and vegetables. These may exert their anti-carcinogenic effects via the modulation of inflammatory pathways. Key signal transduction pathways are fundamental to the association of inflammation and disease progression including those mediated by NF-κB and STAT, PI3K and COX. Our aim was to examine the evidence for the effect of dietary polyphenols intake on tumor and host inflammatory responses to determine if polyphenols may be effective as part of a dietary intervention. There is good epidemiological evidence of a reduction in CRC risk from case-control and cohort studies assessing polyphenol intake. It would be premature to suggest a major public health intervention to promote their consumption; however, dietary change is safe and feasible, emphasizing the need for further investigation of polyphenols and CRC risk.

Asthma is a pulmonary disorder, with an estimated 300 million people affected worldwide. While it is thought that endogenous reactive oxygen species (ROS) and reactive nitrogen species (RNS) such as hydrogen peroxide and nitric oxide, are important mediators of natural physiological processes, inflammatory cells recruited to the asthmatic airways have an exceptional capacity for producing a variety of highly reactive ROS and RNS believed to contribute to tissue damage and chronic airways inflammation. Antioxidant defense systems form a tightly regulated network that maintains the redox environment of the intra- as well as extracellular environment. Evidence for an oxidant-antioxidant imbalance in asthmatic airways is demonstrated in a number of studies, revealing decreased total antioxidant capacity as well as lower levels of individual antioxidants. Thiols in the form of GSH and sulfhydryl groups of proteins are among the most susceptible oxidant-sensitive targets, and hence, studies investigating protein thiol redox modifications in biology and disease have emerged. This perspective offers an overview of the combined efforts aimed at the elucidation of mechanisms whereby cysteine oxidations contribute to chronic inflammation and asthma, as well as insights into potential cysteine thiol-based therapeutic strategies., (© 2015 Wiley Periodicals, Inc.)

Determinants of cancer progression and survival are multifactorial and host responses are increasingly appreciated to have a major role. Indeed, the development and maintenance of a systemic inflammatory response has been consistently observed to confer poorer outcome, in both early and advanced stage disease. For patients, cancer-associated symptoms are of particular importance resulting in a marked impact on day-to-day quality of life and are also associated with poorer outcome. These symptoms are now recognised to cluster with one another with anorexia, weight loss and physical function forming a recognised cluster whereas fatigue, pain and depression forming another. Importantly, it has become apparent that these symptom clusters are associated with presence of a systemic inflammatory response in the patient with cancer. Given the understanding of the above, there is now a need to intervene to moderate systemic inflammatory responses, where present. In this context the rationale for therapeutic intervention using nonselective anti-inflammatory agents is clear and compelling and likely to become a part of routine clinical practice in the near future. The published literature on therapeutic intervention using anti-inflammatory agents for cancer-associated symptoms was reviewed. There are important parallels with the development of useful treatments for the systemic inflammatory response in patients with rheumatological disease and cardiovascular disease.

Background: Cancer-associated inflammation is increasingly recognised to be an important determinant of oncological outcome. In colorectal cancer, the presence of peri-tumoural inflammatory/lymphocytic infiltrates predicts improved survival. To date, these infiltrates, assessed visually on haematoxylin and eosin (H&E) stained sections, have failed to enter routine clinical practice, partly due to their subjective assessment and considerable inter-observer variation. The present study aims to develop an automated scoring method to enable consistent and reproducible assessment of tumour inflammatory infiltrates in colorectal cancer., Methods: 154 colorectal cancer patients who underwent curative resection were included in the study. The local inflammatory infiltrate was assessed using the method described by Klintrup-Makinen. H&E tumour sections were uploaded to an image analysis programme (Slidepath, Leica Biosystems). An image analysis algorithm was developed to count the inflammatory cells at the invasive margin. The manual and automated assessments of the tumour inflammatory infiltrates were then compared., Results: The automated inflammatory cell counts assessed using the freehand annotation method (p<0.001) and the rectangular box method (p<0.001) were significantly associated with both K-M score (p<0.001) and K-M grade (p<0.001). The inflammatory cell counts were divided using quartiles to group tumours with similar inflammatory cell densities. There was good agreement between the manual and automated scoring methods (intraclass correlation coefficient (ICC)=0.82). Similar to the visual K-M scoring system, the automated K-M classification of the inflammatory cell counts, using quartiles, was significantly associated with venous invasion (p<0.05) and modified Glasgow Prognostic Score (mGPS) (p⩽0.05). On univariate survival analysis, both automated K-M category (p<0.05) and automated K-M grade (p<0.005) were associated with cancer-specific survival., Conclusion: The results of the present study demonstrate that automated assessment effectively recapitulates the clinical value of visual assessment of the local inflammatory cell infiltrate at the invasive margin of colorectal tumours. In addition, it is possible to obtain an objective assessment of tumour inflammatory infiltrates using routinely stained H&E sections. An automated, computer-based scoring method is therefore a workable and cost-effective approach to clinical assessment of local immune cell infiltrates in colorectal cancer., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Background: The systemic inflammation-based prognostic scores, modified Glasgow Prognostic Score (mGPS) and the neutrophil-lymphocyte ratio (NLR) are now recognised to be useful in predicting survival in a variety of solid organ malignancies, including colorectal cancer (CRC) before treatment. However, there would appear to have been no direct comparison of these longitudinal measurements of systemic inflammation. Therefore, the aim of the present study was to compare the prognostic value of longitudinal measures of systemic inflammation, the mGPS and NLR in patients undergoing potentially curative resection for CRC., Methods: Three hundred and twenty-six patients underwent potentially curative resection for CRC between 2006 and 2010. Full biochemical and haematological data both pre- and post-operatively (3-6 months) were available for 206 patients., Results: In 206 patients, there was no significant overall change in either the mGPS or the NLR, from pre- to post-operatively. On univariate survival analysis, T-stage (P<0.001), tumour, node, metastasis stage (P<0.005), pre-operative mGPS (P<0.05), pre-operative NLR (<0.05), post-operative mGPS (P<0.001) and post-operative NLR (P<0.005) were associated with cancer-specific survival. On multivariate survival analysis, comparing pre-operative mGPS and NLR, both pre-operative mGPS and NLR were independently associated with reduced cancer-specific survival (mGPS hazard ratio (HR) 1.97, CI 1.16-3.34, P<0.05, and NLR HR 3.07, CI 1.23-7.63, P<0.05). When the same multivariate comparison was carried out on post-operative data, only the post-operative mGPS was independently associated with cancer-specific survival (HR 4.81, CI 2.13-10.83, P<0.001)., Conclusion: The results of the present study support the longitudinal assessment of the systemic inflammatory response, in particular the mGPS, in patients undergoing potentially curative resection for CRC.

Background: Cancer-associated inflammation, in the form of local and systemic inflammatory responses, appear to be linked to tumour necrosis and have prognostic value in patients with colorectal cancer. However, their relationship with circulating biochemical mediators is unclear. The aim of the present study was to examine the interrelationships between circulating mediators, in particular interleukin-6 (IL-6) and tumour necrosis, and local and systemic inflammatory responses in patients undergoing resection for colorectal cancer., Methods: Data were collected from preoperative blood tests for 118 patients who underwent resection for colorectal cancer. Analysis of circulating IL-6, IL-10, vascular endothelial growth factor (VEGF), differential white cell count, C-reactive protein, and albumin were carried out. Routine pathology specimens were examined for tumour characteristics including necrosis and the extent of the inflammatory cell infiltrate. Body composition was examined using body mass index (BMI), total body fat, subcutaneous body fat, visceral fat, and skeletal muscle mass., Results: Circulating IL-6 concentrations were significantly associated with increased T stage (P<0.05), tumour necrosis (P<0.001), IL-10 (P<0.001), VEGF (P<0.001), modified Glasgow Prognostic Score (mGPS; P<0.001), white cell (P<0.01) and platelet (P<0.01) counts, and low skeletal muscle index (P<0.01). When normalised for T stage, tumour necrosis was associated with IL-6 (P<0.001), IL-10 (P<0.01), VEGF (P<0.001), mGPS (P<0.001), neutrophil-lymphocyte ratio (NLR; P<0.05), white cell (P<0.001), neutrophil (P<0.05), and platelet counts (P<0.005), and skeletal muscle index (P<0.001)., Conclusion: The present study provides, for the first time, supportive evidence for the hypothesis that tumour necrosis, independent of T stage, is associated with elevated circulating IL-6 concentrations, thereby modulating both local and systemic inflammatory responses including angiogenesis that, in turn, may promote tumour progression and metastases.

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.

Context: Prognostication in advanced cancer is challenging. Biomarkers of systemic inflammation (C-reactive protein and albumin) combined in the modified Glasgow Prognostic Score (mGPS) have been used to assist prognostication in various cancer types., Objectives: The aim of this study was to examine whether an inflammation-based prognostic score (mGPS) is useful in prognostication in advanced cancer patients., Methods: Cancer patients who had biomarkers (C-reactive protein and albumin) recorded were allocated an mGPS ranging from 0-2. Groups were compared using Jonckheere-Terpstra and Chi-squared tests. Survival analyses were carried out using Kaplan-Meier and multivariate Cox regression models., Results: A total of 296 patients were included, and a representative subgroup of 102 had biomarkers recorded. The mGPS was predictive of death (P=0.014) adjusted for sex, cancer site, age, hemoglobin, and white cell count. Patients with an mGPS of 2 had 2.7 times the risk of death of those with an mGPS of 0 (P=0.011). Patients with an mGPS less than 2 had an 86.1% and 74.3% chance of being alive at two and four weeks, respectively., Conclusion: A role for the mGPS in prognostication near the end of life is suggested. Biomarkers (e.g., mGPS) may assist clinical decisions as to whether intensive treatments are appropriate and may facilitate end-of-life care planning., (Copyright © 2012 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved.)

Background: The host inflammatory response is an important determinant of cancer outcome. We examined different methods of assessing the local inflammatory response in colorectal tumours and explored relationships with both clinicopathological characteristics and survival., Methods: Cohort study of patients (n=130) with primary operable colorectal cancer and mature follow-up. Local inflammatory response at the invasive margin was assessed with: (1) a semi-quantitative assessment of peritumoural inflammation using Klintrup-Makinen (K-M) grading and (2) an assessment of individual immune cell infiltration (lymphocytes, plasma cells, neutrophils, macrophages and eosinophils)., Results: The peritumoural inflammatory response was K-M low grade in 48% and high grade in 52%. Inflammatory cells were primarily macrophages, lymphocytes and neutrophils with relatively few plasma cells or eosinophils. On univariate analysis, K-M grade, lymphocyte infiltration and plasma cell infiltration were associated with cancer-specific survival. On multivariate analysis, only systemic inflammatory response, TNM (tumour, node and metastases) stage, venous invasion, tumour necrosis and K-M grade were independently associated with cancer-specific survival. There was no relationship between local infiltration of inflammatory cells and a systemic inflammatory response. However, high K-M grade, lymphocyte infiltration and plasma cell infiltration were associated with a number of favourable pathological characteristics, including an absence of venous invasion., Conclusion: Infiltration of inflammatory cells in the invasive margin of colorectal tumours is beneficial to survival. The adaptive immune response appears to have a prominent role in the prevention of tumour progression in patients with colorectal cancer.

Background: There is some evidence that systemic inflammation may be associated with survival in patients with prostate cancer; however, it is unclear whether this is independent of grade. We therefore investigated the role of inflammation-based prognostic scores, the modified Glasgow Prognostic Score (mGPS) and neutrophil lymphocyte ratio (NLR), and their associations with Gleason grade in patients with prostate cancer., Methods: Patients from a cohort, the Glasgow Inflammation Outcome Study, who had diagnosis of prostate cancer, were included in this study. The mGPS was constructed by combining C-reactive protein and albumin whereas NLR by calculating the ratio of neutrophils to lymphocytes. We estimated 5-year relative survival and relative excess risk (RER) of death by mGPS and NLR categories after adjusting for age, socioeconomic circumstances and Gleason grade., Results: In all, 897 prostate cancer patients were identified; of those 422 (47%) died during a maximum follow-up of 6.2 years. Systemic inflammation appeared to have significant prognostic value. The mGPS predicted poorer 5-year overall and relative survival independent of age, socioeconomic circumstances, disease grade and NLR. Raised mGPS also had a significant association with excess risk of death (mGPS 2: RER =2.41, 95% confidence interval 1.37-4.23) among aggressive, clinically significant prostate cancer (Gleason grades 8-10)., Conclusions: The mGPS is a strong measure of systemic inflammation, when compared with NLR. Prostate cancer patients with a raised mGPS had significantly higher risk of death for overall as well high-grade disease. Inflammation-based prognostic scores predict outcome in patients with prostate cancer and should be added to their routine clinical assessment.

Background: 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., Methods: 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., Results: For cancer-specific survival, age (P = 0.047), tumor, node, metastasis system stage (P < 0.001), high-risk Petersen Index (P < 0.001), LCRI (P = 0.021), and mGPS (P < 0.001) were independent factors by multivariate analysis. For overall survival, age (P < 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 < 0.001) were independent factors. Older age related to increasing comorbidity (ACE-27, CCI, LCRI [P < 0.005]) and increased mGPS (P < 0.005). Smoking and deprivation related to increasing comorbidity (P < 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)., Conclusions: 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.

Introduction: A selective combination of C-reactive protein and albumin (termed the modified Glasgow Prognostic Score, mGPS) has been shown to have prognostic value, independent of tumour stage, in lung, gastrointestinal and renal cancers. It is also of interest that liver function tests such as bilirubin, alkaline phosphatase and γ-glutamyl transferase, as well as serum calcium, have also been reported to predict cancer survival. The aim of the present study was to examine the relationship between an inflammation-based prognostic score (mGPS), biochemical parameters, tumour site and survival in a large cohort of patients with cancer., Methods: Patients (n=21,669) who had an incidental blood sample taken between 2000 and 2006 for C-reactive protein, albumin and calcium (and liver function tests where available) and a diagnosis of cancer were identified. Of this group 9608 patients who had an ongoing malignant process were studied (sampled within 2 years before diagnosis). Also a subgroup of 5397 sampled at the time of diagnosis (sampled within 2 months prior to diagnosis) were examined. Cancers were grouped by tumour site in accordance with International Classification of Diseases 10 (ICD 10)., Results: On follow up, there were 6005 (63%) deaths of which 5122 (53%) were cancer deaths. The median time from blood sampling to diagnosis was 1.4 months. Increasing age, male gender and increasing deprivation was associated with a reduced 5-year overall and cancer-specific survival (all P<0.001). An elevated mGPS, adjusted calcium, bilirubin, alkaline phosphatase, aspartate transaminase, alanine transaminase and γ-glutamyl transferase were associated with a reduced 5-year overall and cancer-specific survival (independent of age, sex and deprivation in all patients sampled), as well as within the time of diagnosis subgroup (all P<0.001). An increasing mGPS was predictive of a reduced cancer-specific survival in all cancers (all P<0.001)., Conclusion: The results of the present study indicate that the mGPS is a powerful prognostic factor when compared with other biochemical parameters and independent of tumour site in patients with cancer.

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., 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)., 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)., 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.

The presence of systemic inflammation before surgery, as evidenced by the glasgow prognostic score (mGPS), predicts poor long-term survival in colorectal cancer. The aim was to examine the relationship between the preoperative mGPS and the development of postoperative complications in patients undergoing potentially curative resection for colorectal cancer. Patients (n=455) who underwent potentially curative resections between 2003 and 2007 were assessed consecutively, and details were recorded in a database. The majority of patients presented for elective surgery (85%) were over the age of 65 years (70%), were male (58%), were deprived (53%), and had TNM stage I/II disease (61%), had preoperative haemoglobin (56%), white cell count (87%) and mGPS 0 (58%) in the normal range. After surgery, 86 (19%) patients developed a postoperative complication; 70 (81%) of which were infectious complications. On multivariate analysis, peritoneal soiling (P<0.01), elevated preoperative white cell count (P<0.05) and mGPS (P<0.01) were independently associated with increased risk of developing a postoperative infection. In elective patients, only the mGPS (OR=1.75, 95% CI=1.17-2.63, P=0.007) was significantly associated with increased risk of developing a postoperative infection. Preoperative elevated mGPS predicts increased postoperative infectious complications in patients undergoing potentially curative resection for colorectal cancer.

After resection, it is important to identify colon cancer patients, who are at a high risk of recurrence and who may benefit from adjuvant treatment. The Petersen Index (PI), a prognostic model based on pathological criteria is validated in Dukes' B and C disease. Similarly, the modified Glasgow Prognostic Score (mGPS) based on biochemical criteria has also been validated. This study compares both the scores in patients undergoing curative resection of colon cancer. A total of 244 patients underwent elective resection between 1997 and 2005. The PI was constructed from pathological reports; the mGPS was measured pre-operatively. The median follow-up was 67 months (minimum 36 months) during which 109 patients died; 68 of them from cancer. On multivariate analysis of age, Dukes' stage, PI and mGPS, age (hazard ratio, HR, 1.74, P=0.001), Dukes' stage (HR, 3.63, P<0.001), PI (HR, 2.05, P=0.010) and mGPS (HR, 2.34, P<0.001) were associated independently with cancer-specific survival. Three-year cancer-specific survival rates for Dukes' B patients with the low-risk PI were 98, 92 and 82% for the mGPS of 0, 1 and 2, respectively (P<0.05). The high-risk PI population is small, in particular for Dukes' B disease (9%). The mGPS further stratifies those patients classified as low risk by the PI. Combining both the scoring systems could identify patients who have undergone curative surgery but are at high-risk of cancer-related death, therefore guiding management and trial stratification.

The relationship between the systemic inflammatory response, tumour proliferative activity, T-lymphocytic infiltration, and COX-2 expression and survival was examined in patients with transitional cell carcinoma of the urinary bladder (n=103). Sixty-one patients had superficial disease and 42 patients had invasive disease. Cancer-specific survival was shorter in those patients with invasive compared with superficial bladder cancer (P<0.001). On univariate analysis, stratified by stage, increased Ki-67 labelling index (P<0.05), increased COX-2 expression (P<0.05), C-reactive protein (P<0.05) and adjuvant therapy (P<0.01) were associated with poorer cancer-specific survival. On multivariate analysis of these significant factors, stratified by stage, only C-reactive protein (HR 2.89, 95% CI 1.42-5.91, P=0.004) and adjuvant therapy (HR 0.29, 95% CI 0.14-0.62, P=0.001) were independently associated with poorer cancer-specific survival. These results would suggest that tumour-based factors such as grade, COX-2 expression or T-lymphocytic infiltration are subordinate to systemic factors such as C-reactive protein in determining survival in patients with transitional cell carcinoma of the urinary bladder.

There is increasing evidence that the presence of a systemic inflammatory response plays an important role in survival following curative resection for colorectal cancer. The present study evaluated the relationship between C-reactive protein concentrations and survival in a cohort of patients receiving adjuvant 5-fluorouracil (5-FU) chemotherapy following potentially curative resection for colorectal cancer. In all, 222 patients undergoing potentially curative resection for colorectal cancer were studied. Of these, 50 patients received adjuvant 5-FU-based chemotherapy. Circulating concentrations of C-reactive protein were measured prior to surgery. The minimum follow-up was 15 months; the median follow-up of the survivors was 38 months. During this period 61 patients died, 32 patients of their cancer and 29 of intercurrent disease. In those patients who did not receive adjuvant chemotherapy, age (P < 0.001), Dukes stage (P < 0.05) and an elevated C-reactive protein (P < 0.01) were significantly associated with survival. In those patients who did receive adjuvant chemotherapy, an elevated C-reactive protein concentration (P < 0.01) was significantly associated with survival. The presence of a systemic inflammatory response is an independent predictor of poor outcome in patients receiving adjuvant 5-FU-based chemotherapy following potentially curative resection for colorectal cancer.

There is increasing evidence that the presence of an ongoing systemic inflammatory response is associated with poor outcome in patients with advanced cancer. The aim of the present study was to examine whether an inflammation-based prognostic score (Glasgow Prognostic score, GPS) was associated with survival, in patients with inoperable gastro-oesophageal cancer. Patients diagnosed with inoperable gastro-oesophageal carcinoma and who had measurement of albumin and C-reactive protein concentrations, at the time of diagnosis, were studied (n=258). Clinical information was obtained from a gastro-oesophageal cancer database and analysis of the case notes. Patients with both an elevated C-reactive protein (>10 mg l(-1)) and hypoalbuminaemia (<35 g l(-1)) were allocated a GPS score of 2. Patients in whom only one of these biochemical abnormalities was present were allocated a GPS score of 1, and patients with a normal C-reactive protein and albumin were allocated a score of 0. On multivariate survival analysis, age (hazard ratio (HR) 1.22, 95% CI 1.02-1.46, P<0.05), stage (HR 1.55, 95% CI 1.30-1.83, P<0.001), the GPS (HR 1.51, 95% CI 1.22-1.86, P<0.001) and treatment (HR 2.53, 95% CI 1.80-3.56, P<0.001) were significant independent predictors of cancer survival. A 12-month cancer-specific survival in patients with stage I/II disease receiving active treatment was 67 and 60% for a GPS of 0 and 1, respectively. For stage III/IV disease, 12 months cancer-specific survival was 57, 25 and 12% for a GPS of 0, 1 and 2, respectively. In the present study, the GPS predicted cancer-specific survival, independent of stage and treatment received, in patients with inoperable gastro-oesophageal cancer. Moreover, the GPS may be used in combination with conventional staging techniques to improve the prediction of survival in patients with inoperable gastro-oesophageal cancer.

Prediction of outcome in patients with metastatic breast cancer remains problematical. The present study evaluated the value of an inflammation-based score (Glasgow Prognostic Score, GPS) in patients with metastatic breast cancer. The GPS was constructed as follows: patients with both an elevated C-reactive protein (>10 mg l(-1)) and hypoalbuminaemia (<35 g l(-1)) were allocated a score of 2. Patients in whom only one or none of these biochemical abnormalities was present were allocated a score of 1 or 0, respectively. In total, 96 patients were studied. During follow-up 51 patients died of their cancer. On multivariate analysis of the GPS and treatment received, only the GPS (HR 2.26, 95% CI 1.45-3.52, P<0.001) remained significantly associated with cancer-specific survival. The presence of a systemic inflammatory response (the GPS) appears to be a useful indicator of poor outcome independent of treatment in patients with metastatic breast cancer.

The value of an inflammation-based prognostic score (Glasgow Prognostic score, GPS) was compared with performance status (ECOG-ps) in a longitudinal study of patients (n=101) with inoperable non-small-cell lung cancer (NSCLC). At diagnosis, stratified for treatment, only the GPS (HR 2.32, 95% CI 1.52-3.54, P<0.001) was a significant predictor of survival. In contrast, neither the GPS nor ECOG-ps measured at 3-6 months follow-up were significant predictors of residual survival. This study confirms the prognostic value of the GPS, at diagnosis, in patients with inoperable NSCLC. However, the role of the GPS and ECOG-ps during follow-up has not been established.

The aim of the present study was to examine the relationship between the clinicopathological status, the pre- and postoperative systemic inflammatory response and survival in patients undergoing potentially curative resection for ductal adenocarcinoma of the head of the pancreas. Patients (n = 65) who underwent resection of ductal adenocarcinoma of the head of pancreas between 1993 and 2001, and had pre- and postoperative measurements of C-reactive protein, were included in the study. The majority of patients had stage III disease (International Union Against Cancer Criteria, IUCC), positive circumferential margin involvement (R1), tumour size greater than 25 mm with perineural and lymph node invasion and died within the follow-up period. On multivariate analysis, tumour size (hazard ratio (HR) 2.10, 95% confidence interval (CI) 1.20-3.68, P = 0.009), vascular invasion (HR 2.58, 95% CI 1.48-4.50, P < 0.001) and postoperative C-reactive protein (HR 2.00, 95% CI 1.14-3.52, P = 0.015) retained independent significance. Those patients with a postoperative C-reactive protein < or = 10 mg l(-1) had a median survival of 21.5 months compared with 8.4 months in those patients with a C-reactive protein >10 mg l(-1) (P < 0.001). The results of the present study indicate that, in patients who have undergone potentially curative resection for ductal adenocarcinoma of the head of pancreas, the presence of a systemic inflammatory response predicts poor outcome.

The value of an inflammation-based prognostic score (GPS) was compared with performance status (ECOG) in patients (n=109) receiving platinum-based chemotherapy for inoperable non-small-cell lung cancer. On multivariate analysis with ECOG, white cell count and the GPS entered as covariates, only the GPS was a significant independent predictor of survival (HR 1.88, 95% CI 1.25-2.84, P=0.002).

The aim of this study was to examine the inter-relationship between the inflammatory response and resting energy expenditure in patients with non-small cell lung cancer (NSCLC) before and after the onset of weight loss. Healthy subjects (n=7) and patients with NSCLC without weight loss (n=12) were studied. Resting energy expenditure adjusted for metabolically active tissue, as measured by total body potassium, was approximately 15% higher in the NSCLC group (P<0.01). Moreover, the resting energy expenditure, correlated with the magnitude of the inflammatory response (r=0.753, P<0.01). Six cancer patients subsequently lost weight and the relationship between resting energy expenditure and the inflammatory response was maintained. These results highlight the impact of the inflammatory response on the increase in the resting energy expenditure which precedes the onset of weight loss in patients with NSCLC.

The assessment of prognosis in patients with advanced cancer remains problematical. The value of C-reactive protein concentration in this context has not been clearly defined. Patients with a diagnosis of colorectal (n = 182), gastric (n = 87), breast (n = 99), or bronchogenic (n = 404) cancer and who had measurements of C-reactive protein and albumin were identified. Median survival, from the time of sampling, ranged from 478 days in the colorectal cancer patients to 60 days in patients with bronchogenic cancer. On univariate analysis, there was, in each tumor type, a significant relationship between the duration of survival and both log10 C-reactive protein and albumin concentrations (P < or = 0.0002). On multivariate analysis, in each tumor type, log10 C-reactive protein remained a significant independent predictor of survival (P < or = 0.0002). When all four groups of cancer patients were analyzed (n = 772), the hazard ratio for a 10-fold increase in C-reactive protein concentration in cancer-specific survival was 2.21 (95% confidence interval = 1.92-2.56, P < 0.0001) and the corresponding hazard ratio for non-cancer survival was 5.48 (95% confidence interval = 3.55-8.46, P < 0.0001). The results of the present study indicate that in advanced cancer patients the presence of a systemic inflammatory response and the magnitude of that response predict the duration of cancer-specific and non-cancer survival.

The association between hypoalbuminemia and poor prognosis in patients with cancer is well recognized. However, the factors that contribute to the fall in albumin concentrations are not well understood. In the present study, we examined the relationship between circulating albumin concentrations, weight loss, the body cell mass (measured using total body potassium), and the presence of an inflammatory response (measured using C-reactive protein) in male patients (n = 40) with advanced lung or gastrointestinal cancer. Albumin concentrations were significantly correlated with the percent ideal body weight (r = 0.390, p < 0.05), extent of reported weight loss (r = -0.492, p < 0.01), percent predicted total body potassium (adjusted for age, height, and weight, r = 0.686, p < 0.001), and log10 C-reactive protein concentrations (r = -0.545, p < 0.001). On multiple regression analysis, the percent predicted total body potassium and log10 C-reactive protein concentrations accounted for 63% of the variation in albumin concentrations (r2 = 0.626, p < 0.001). The interrelationship between albumin, body cell mass, and the inflammatory response is consistent with the concept that the presence of an ongoing inflammatory response contributes to the progressive loss of these vital protein components of the body and the subsequent death of patients with advanced cancer.

HSF1 is the major heat shock transcriptional factor that binds heat shock element (HSE) in the promoter of heat shock proteins (Hsps) and controls rapid Hsp induction in cells subjected to various environmental stresses. Although at least four members of the vertebrate HSF family have been described, details of their individual physiological roles remain relatively obscure. To assess whether HSF1 exhibited redundant or unique in vivo functions, we created Hsf1(-/-) deficient mice. We demonstrate that homozygous Hsf1(-/-) mice can survive to adulthood but exhibit multiple phenotypes including: defects of the chorioallantoic placenta and prenatal lethality; growth retardation; female infertility; elimination of the 'classical' heat shock response; and exaggerated tumor necrosis factor alpha production resulting in increased mortality after endotoxin challenge. Because basal Hsp expression is not altered appreciably by the HSF1 null mutation, our findings suggest that this factor, like Drosophila Hsf protein, might be involved in regulating other important genes or signaling pathways. Our results establish direct causal effects for the HSF1 transactivator in regulating critical physiological events during extra-embryonic development and under pathological conditions such as sepsis to modulate pro-inflammatory responses, indicating that these pathways have clinical importance as therapeutic targets in humans.

There is increasing evidence that, in most patients with advanced cancer, weight loss is associated with an inflammatory response. To examine the temporal relationship between weight loss, appetite, performance status, and the inflammatory response, 50 patients with advanced gastrointestinal cancer with weight loss were observed for six weeks. Patients were grouped according to whether they had lost weight (> 3%, n = 16), were weight stable (< 3% change, n = 25), or gained weight (> 3%, n = 9). At baseline, the group that subsequently lost weight had lower albumin and higher C-reactive protein concentrations (p < 0.05). On follow-up, there was an increase in C-reactive protein concentration and reductions in triceps skinfold thickness and Karnofsky performance status in the weight-losing group (p < 0.05). In contrast, Karnofsky performance status was improved in the group that gained weight (p < 0.05). Over the six to eight weeks, there was a difference in the changes of triceps skinfold thickness (p < 0.05) and Karnofsky performance status (p < 0.01) between the two groups. These results suggest that loss or gain of > 2.5 kg over a six- to eight-week period is required to produce a significant alteration in performance status in weight-losing patients with gastrointestinal cancer. Moreover, the results suggest that the presence of an inflammatory response is associated with further weight loss and the deterioration of performance status.

The relationship between weight loss, appetite, the inflammatory response, and quality of life in patients with advanced gastrointestinal cancer was examined. Height, weight, and skinfold anthropometry were measured in 119 patients. Blood was taken for analysis of C-reactive protein and albumin. Appetite, performance status, and quality of life were assessed using EuroQol EQ-5D and EORTC QLQ-C30 questionnaires. Weight loss was > 5% (median 17.1%) of their preillness weight in 97 patients; the remaining 22 patients were weight stable. Anthropometric measurements and circulating albumin concentrations were significantly lower (p < 0.01) and circulating concentrations of C-reactive protein were significantly higher in the weight-losing than in the weight-stable group (p < 0.001). Appetite scores, performance status, and EuroQol EQ-5D and EORTC QLQ-C30 scores were also lower in the weight-losing group (p < 0.01). When the weight-losing cancer patients were divided on the basis of whether they had a marked inflammatory response, albumin concentrations, appetite, and Karnofsky performance status were significantly lower (p < 0.05) in the group with a marked inflammatory response. The results of the present study are consistent with weight loss, reduction of appetite, and an elevated inflammatory response being important related factors in lowering the quality of life of gastrointestinal cancer patients.

This study examined the effect of an inflammatory response on measures of antioxidant status in patients with non-small cell lung cancer (NSCLC). In healthy, control subjects (n = 13) and NSCLC patients (n = 22) fasting concentrations of albumin, C-reactive protein, cholesterol, and the antioxidants alpha-tocopherol, retinol, lutein, lycopene, and alpha- and beta-carotene were measured. The two groups were similar in terms of age, sex, and body mass index. However, the cancer group had an inflammatory response as evidenced by significantly increased C-reactive protein concentrations. Concentrations of all the measured antioxidants of the NSCLC group were significantly lower than those of the control group (P < 0.01). The lowest concentrations were those of the carotenoids lycopene and alpha- and beta-carotene. In the cancer group there were significant negative correlations between concentrations of C-reactive protein and retinol (r = -0.682, P < 0.01), alpha-tocopherol (r = -0.464, P < 0.05), and lutein (r = -0.599, P < 0.01). The results of this study have implications for the interpretation of circulating antioxidant concentrations in patients with NSCLC.

It has been proposed that the increase in amino acid flux and derived protein synthesis rates observed in weight-losing cancer patients may contribute to an ongoing negative energy balance. The mediators and tissues responsible for such apparent increased protein synthesis have not been clearly identified. The aim of this study was to examine the relationship between protein synthetic rates in whole-body, skeletal muscle, and circulating cortisol concentrations in healthy subjects (n = 6) and cancer patients with evidence of an inflammatory response (n = 6). Protein synthetic rates were measured with a primed continuous 20-h infusion of [15N]glycine. Skeletal muscle was biopsied at laparotomy. Serum cortisol, resting energy expenditure, plasma proteins, nitrogen metabolites in urine, and skeletal muscle free amino acids were also measured. Derived whole-body and skeletal muscle protein synthetic rates in the cancer group were increased significantly (by 70 and 93%, respectively, p < 0.05). Circulating concentrations of cortisol, fibrinogen, and C-reactive protein were also significantly increased in the cancer group and indicated the presence of an inflammatory response. However, there was no significant increase in resting energy expenditure. Mechanisms by which apparent increases in whole-body and skeletal protein synthesis do not result in an increase in resting energy expenditure are discussed. We conclude that glycine utilization is increased in cancer patients but that rates of protein synthesis derived from [15N]glycine kinetics may not be valid in such patients.

Background: Tumour necrosis is a marker of poor prognosis in some tumours but the mechanism is unclear. This study examined the prognostic value of tumour necrosis and host inflammatory responses in colorectal cancer. Methods: This was a retrospective study of patients undergoing potentially curative resection of colorectal cancer at a single surgical institution over a 10-year period. Patients who underwent preoperative radiotherapy were excluded. The systemic and local inflammatory responses were assessed using the modified Glasgow Prognostic Score and Klintrup-Makinen criteria respectively. Original tumour sections were retrieved and necrosis graded as absent, focal, moderate or extensive. Associations between necrosis and clinicopathological variables were examined, and multivariable survival analyses carried out. Results: A total of 343 patients were included between 1997 and 2007. Tumour necrosis was graded as absent in 32 (9·3 per cent), focal in 166 (48·4 per cent), moderate in 101 (29·4 per cent) and extensive in 44 (12·8 per cent). There were significant associations between tumour necrosis and anaemia ( P = 0·022), white cell count ( P = 0·006), systemic inflammatory response ( P < 0·001), local inflammatory cell infiltrate ( P = 0·004), tumour node metastasis (TNM) stage ( P = 0·015) and Petersen Index ( P = 0·003). On univariable survival analysis, tumour necrosis was associated with cancer-specific survival ( P < 0·001). On multivariable survival analysis, age (hazard ratio (HR) 1·29, 95 per cent confidence interval 1·00 to 1·66), systemic inflammatory response (HR 1·74, 1·27 to 2·39), low-grade local inflammatory cell infiltrate (HR 2·65, 1·52 to 4·63), TNM stage (HR 1·55, 1·02 to 2·35) and high-risk Petersen Index (HR 3·50, 2·21 to 5·55) were associated with reduced cancer-specific survival. Conclusion: The impact of tumour necrosis on colorectal cancer survival may be due to close associations with the host systemic and local inflammatory responses. Copyright © 2011 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Background: Cancer incidence is increasing in the United Kingdom, as well as on a global basis. Biochemical parameters, such as C-reactive protein and albumin (combined to form the modified Glasgow Prognostic Score, mGPS), alkaline phosphatase (Alk phos), gamma-glutamyl transferase (GGT) and serum calcium have been reported to be associated with cancer and non-cancer mortality. Therefore, to definitively examine the interrelationships between the above biochemical parameters, the mGPS and the presence of cancer, the Glasgow Inflammation Outcome Study was undertaken. The aim of this initial study was to examine the effect of cancer on markers of systemic inflammation induced by the liver (mGPS) and on levels of routine biochemical parameters.Methods: Patients (n=223 303) who had a single incidental sample taken for C-reactive protein, albumin, calcium and serum liver function tests where available, between 2000 and 2008 were studied. Those with a pathological diagnosis of cancer (n=22 715) were identified. The mGPS was constructed and liver function tests classified in accordance with the local reference ranges.Results: Patients with cancer had higher C-reactive protein and lower albumin levels (and thus a higher mGPS), higher adjusted calcium, Alk phos and GGT levels, but lower aspartate transaminase (AST) and alanine transaminase (ALT) levels (all P<0.001). The strongest associations (Spearman's correlation > or =0.3) in both the non-cancer and cancer groups were found between albumin, C-reactive protein and Alk phos, AST and ALT, AST and GGT and ALT and GGT (all P<0.001). On multivariate analysis, the associations with the presence of cancer remained with age, deprivation, C-reactive protein, albumin, adjusted calcium, Alk phos and GGT (all P<0.01). Patients following a diagnosis of cancer had lower albumin levels and thus higher mGPS (all P<0.001). Also, post-diagnosis patients were more likely to have lower adjusted calcium, bilirubin, Alk Phos, AST, ALT and GGT levels (all P<0.05). When the cancer diagnoses were ranked from those with the lowest proportion of mGPS 1 or 2 to those with the highest, the percentage of cases with a mGPS of 1 or 2 ranged from 21% in breast cancer to 46% in prostate cancer and to 68% in pulmonary cancer. Compared with breast cancer the mGPS was significantly higher in those diagnosed with dermatological, bladder, endocrinological, gynaecological, prostate, musculoskeletal, gastroesophageal, haematological, renal, colorectal, head and neck, pancreaticobiliary and pulmonary cancers (all P<0.001).Conclusion: The results of the present study indicate that the systemic inflammatory response is common in a large patient cohort, increased by the presence of cancer and associated with the perturbation of a number of biochemical parameters previously reported to be associated with mortality. There is a striking parallel between the proportions of cases with a mGPS of 1 or 2 and reported survival rates in these tumours. [ABSTRACT FROM AUTHOR]

The significance of the inter-relationship between tumour and host local/systemic inflammatory responses in primary operable invasive breast cancer is limited. The inter-relationship between the systemic inflammatory response (pre-operative white cell count, C-reactive protein and albumin concentrations), standard clinicopathological factors, tumour T-lymphocytic (CD4+ and CD8+) and macrophage (CD68+) infiltration, proliferative (Ki-67) index and microvessel density (CD34+) was examined using immunohistochemistry and slide-counting techniques, and their prognostic values were examined in 168 patients with potentially curative resection of early-stage invasive breast cancer. Increased tumour grade and proliferative activity were associated with greater tumour T-lymphocyte (P<0.05) and macrophage (P<0.05) infiltration and microvessel density (P<0.01). The median follow-up of survivors was 72 months. During this period, 31 patients died; 18 died of their cancer. On univariate analysis, increased lymph-node involvement (P<0.01), negative hormonal receptor (P<0.10), lower albumin concentrations (P<0.01), increased tumour proliferation (P<0.05), increased tumour microvessel density (P<0.05), the extent of locoregional control (P<0.0001) and limited systemic treatment (P0.01) were associated with cancer-specific survival. On multivariate analysis of these significant covariates, albumin (HR 4.77, 95% CI 1.35–16.85, P=0.015), locoregional treatment (HR 3.64, 95% CI 1.04–12.72, P=0.043) and systemic treatment (HR 2.29, 95% CI 1.23–4.27, P=0.009) were significant independent predictors of cancer-specific survival. Among tumour-based inflammatory factors, only tumour microvessel density (P<0.05) was independently associated with poorer cancer-specific survival. The host inflammatory responses are closely associated with poor tumour differentiation, proliferation and malignant disease progression in breast cancer.British Journal of Cancer (2008) 99, 1013–1019. doi:10.1038/sj.bjc.6604667 www.bjcancer.com Published online 16 September 2008 [ABSTRACT FROM AUTHOR]

Background: The aim of the present study was to evaluate the relationship between the preoperative and postoperative systemic inflammatory response and survival in patients undergoing potentially curative resection for colorectal cancer. Methods: One hundred and eighty patients with colorectal cancer were studied. Circulating concentrations of C-reactive protein (CRP) were measured before surgery and in the immediate postoperative period. Results: The peak in CRP concentration occurred on day 2 (P < 0.001). During the course of the study 59 patients died, 30 from cancer and 29 from intercurrent disease. Day 2 CRP concentrations were dichotomized. In univariable analysis, advanced tumour node metastasis stage (P = 0.002), a raised preoperative CRP level (P < 0.001) and the presence of hypoalbuminaemia (P = 0.043) were associated with poorer cancer-specific survival. Conclusion: Preoperative but not postoperative CRP concentrations are associated with poor tumour-specific survival in patients undergoing potentially curative resection for colorectal cancer. [ABSTRACT FROM AUTHOR]

The relationship between the systemic inflammatory response (as evidenced by elevated C-reactive protein and lowered albumin concentrations), clinico-pathologic status and relapse-free, cancer-specific and overall survival was examined in patients with invasive primary operable breast cancer (n=300). The median follow-up of the survivors was 46 months. During this period, 37 patients relapsed and 25 died of their cancer. On multivariate analysis, only tumour size (P<0.05), albumin (P<0.01) and systemic treatment (P<0.0001) were significant independent predictors of relapse-free, cancer-specific and overall survival. Lower serum albumin concentrations (

There is increasing evidence that both local and systemic inflammatory responses play an important role in the progression of a variety of common solid tumours. The aim of the present study was to examine the relationship between tumour T-lymphocyte subset infiltration, the systemic inflammatory response and cancer-specific survival in patients with colorectal cancer. In all, 147 patients undergoing potentially curative resection for colorectal cancer were studied. Circulating concentrations of C-reactive protein were measured prior to surgery. CD4+and CD8+T-lymphocyte infiltration of the tumour was assessed using immunohistochemistry and a point counting technique. When patients were grouped according to the percentage tumour volume of CD4+T-lymphocytes, there was no difference in terms of age, sex, tumour site, stage and tumour characteristics. However, there was an inverse relationship between percentage tumour CD4+T-lymphocytes and C-reactive protein (P<0.01). On univariate analysis, both C-reactive protein concentrations (P<0.001) and percentage tumour volume of CD4+(P<0.05) T-lymphocytes were associated with cancer-specific survival. The results of the present study show that low tumour CD4+T-lymphocyte infiltration is associated with elevated C-reactive protein concentrations and both predict poor cancer-specific survival.British Journal of Cancer (2005) 92, 651-654. doi:10.1038/sj.bjc.6602419 www.bjcancer.com Published online 8 February 2005 [ABSTRACT FROM AUTHOR]

HSF1 is the major heat shock transcriptional factor that binds heat shock element (HSE) in the promoter of heat shock proteins (Hsps) and controls rapid Hsp induction in cells subjected to various environmental stresses. Although at least four members of the vertebrate HSF family have been described, details of their individual physiological roles remain relatively obscure. To assess whether HSF1 exhibited redundant or unique in vivo functions, we created Hsf1-/- deficient mice. We demonstrate that homozygous Hsf1-/- mice can survive to adulthood but exhibit multiple phenotypes including: defects of the chorioallantoic placenta and prenatal lethality; growth retardation; female infertility; elimination of the ‘classical’ heat shock response; and exaggerated tumor necrosis factor alpha production resulting in increased mortality after endotoxin challenge. Because basal Hsp expression is not altered appreciably by the HSF1 null mutation, our findings suggest that this factor, like Drosophila Hsf protein, might be involved in regulating other important genes or signaling pathways. Our results establish direct causal effects for the HSF1 transactivator in regulating critical physiological events during extraembryonic development and under pathological conditions such as sepsis to modulate pro-inflammatory responses, indicating that these pathways have clinical importance as therapeutic targets in humans. [ABSTRACT FROM AUTHOR]

The unusual amino acid composition of acute phase proteins may be relevant to our understanding of the mechanism of tissue wasting in chronic inflammatory disease. During periods in which demand for amino acids outstrips dietary supply, skeletal muscle protein may be mobilized to meet this demand. An imbalance in the amino acid composition of these proteins may thus be detrimental to the body's nitrogen economy. To address this problem, we have measured the synthetic rate of fibrinogen (perhaps the major acute phase protein) and plasma amino acid profiles in a group of patients with adenocarcinoma of the pancreas and an ongoing inflammatory response (serum C-reactive protein >10 mg/L in the absence of any other obvious infective or inflammatory cause). These were also measured in a control group with no evidence of inflammation. Fibrinogen synthesis was measured after an overnight fast, using a flooding dose of 2H5-phenylalanine. The fractional rate of fibrinogen synthesis was significantly elevated in the cancer group compared with healthy controls [39.3 (20.0-49.9) and 21.9 (13.2-37.7) %/d, respectively; median (range), P < 0.05]. The absolute rate of fibrinogen synthesis was also elevated [84 (33-143) and 26 (15-43) mg/(kg.d), respectively; median (range), P < 0.01]. We calculated that, in cancer patients with anorexia-cachexia (i.e., documented ongoing weight loss in the absence of an obvious cause such as obstruction or malabsorption), aromatic amino acid supply (predominantly tryptophan) most limits fibrinogen synthesis from skeletal muscle reserves. Demand for the nonessential amino acids serine and glycine was elevated. Assuming that tryptophan is limiting, up to 2.6 g muscle protein ( approximately 12 g skeletal muscle tissue) may be wasted to synthesize 1 g fibrinogen. Interpretation of the observation that circulating free tryptophan concentrations were significantly reduced in the cancer patients will have to await flux measurements. The metabolic changes accompanying the inflammatory response suggest that down-regulation of this process may be beneficial. [ABSTRACT FROM AUTHOR]

The value of combining Dukes' stage and C-reactive protein to form a cumulative prognostic score was assessed in 147 patients undergoing potentially curative resection for colorectal cancer. The cancer-specific survival rates at 3 years for patients with a cumulative prognostic score of 0, 1 and 2 were 100, 77 and 40%, respectively (HR 4.76, 2.78-8.15, P<0.001).British Journal of Cancer (2004) 90, 1707-1709. doi:10.1038/sj.bjc.6601757 www.bjcancer.com Published online 30 March 2004 [ABSTRACT FROM AUTHOR]

Survival prediction in patients presenting with malignancy of undefined primary origin (MUO) is challenging, with a lack of validated prognostic tools. Biomarkers of the systemic inflammatory response independently predict survival in other cancer types, but their role in MUO is unclear. The aim of this study was to assess biomarkers of the systemic inflammatory response in patients presenting with MUO. A biobank of 1049 patients presenting with MUO referred to a regional oncology service in Scotland was analysed. Key inflammatory biomarkers (white cell count, neutrophil count and C-reactive protein combined with albumin [to give the modified Glasgow Prognostic Score {mGPS}]) were examined. The relationship between these and survival was examined using Kaplan–Meier and Cox regression methods. Data were available for 1049 patients. Median survival was 4.3 months (interquartile range: 1.7–16.0 months). On multivariate analysis mGPS was independently associated with survival and stratified survival from 13.6 months (mGPS: 0) to 2.3 months (mGPS: 2) (p < 0.001). The mGPS was predictive of survival on multivariate analysis in patients found to have a non-cancer diagnosis (p = 0.034), an identified primary cancer (0.002), cancer of unknown primary (CUP) (p = 0.011), those for whom biopsy was not done (MUO) (p = 0.036), those found to have an identified primary cancer (0.002) and even those found to have a non-cancer diagnosis (p = 0.034) after further detailed investigations. In patients with CUP mGPS predicted survival regardless of the recognised clinicopathological prognostic subgroup (p < 0.001). The results of the present study demonstrate that biomarkers of the systemic inflammatory response are reliable prognostic factors in patients presenting with MUO. These simple, objective, routine clinical tests may inform clinical management. • Markers of systemic inflammation are strong prognostic factors in patients with malignancy of undefined primary origin (MUO). • The modified Glasgow Prognostic Score (mGPS) predicts survival in patients with MUO. • In patients with cancer of unknown primary (CUP), the mGPS predicts survival across recognised prognostic subgroups. • The mGPS is an objective bedside test that can guide clinical management of MUO/CUP. [ABSTRACT FROM AUTHOR]