Long-term follow-up of patients undergoing resection of tnm stage i colorectal cancer: an analysis of tumour and host determinants of outcome

Background Screening for colorectal cancer improves cancer-specific survival (CSS) through the detection of early-stage disease; however, its impact on overall survival (OS) is unclear. The present study examined tumour and host determinants of outcome in TNM Stage I disease. Methods All patients with pathologically confirmed TNM Stage I disease across 4 hospitals in the North of Glasgow between 2000 and 2008 were included. The preoperative modified Glasgow Prognostic Score (mGPS) was used as a marker of the host systemic inflammatory response (SIR). Results There were 191 patients identified, 105 (55 %) were males, 91 (48 %) were over the age of 75 years and 7 (4 %) patients underwent an emergency operation. In those with a preoperative CRP result (n = 150), 35 (24 %) patients had evidence of an elevated mGPS. Median follow-up of survivors was 116 months (minimum 72 months) during which 88 (46 %) patients died; 7 (8 %) had postoperative deaths, 15 (17 %) had cancer-related deaths and 66 (75 %) had non-cancer-related deaths. 5-year CSS was 95 % and OS was 76 %. On univariate analysis, advancing age (p < 0.001), emergency presentation (p = 0.008), and an elevated mGPS (p = 0.012) were associated with reduced OS. On multivariate analysis, only age (HR = 3.611, 95 % CI 2.049–6.365, p < 0.001) and the presence of an elevated mGPS (HR = 2.173, 95 % CI 1.204–3.921, p = 0.010) retained significance. Conclusions In patients undergoing resection for TNM Stage I colorectal cancer, an elevated mGPS was an objective independent marker of poorer OS. These patients may benefit from a targeted intervention

The 100 most influential manuscripts in gastric cancer: a bibliometric analysis

Background Bibliometric analysis highlights the key topics and publications which have shaped the understanding and management of Gastric cancer. Here the 100 most cited manuscripts in the field of gastric cancer (GC) are analysed. Methods The Thomson Reuters Web of Science database with the search terms 'gastric cancer’ or ‘gastric carcinoma’ or ‘stomach cancer’ or ‘stomach carcinoma’ or ‘gastroscopy’ was used to identify all English language full manuscripts for the study. The 100 most cited papers were further analysed by topic, journal, author, year and institution. Results 122,616 eligible papers were returned and the median (range) citation number was 417 (2893–299). The most cited paper (by Parsonnet) focused on H.Pylori risk and gastric cancer (2893 citations). Cancer Research published the highest number of papers (n = 13, 6901 citations) and The New England Journal of Medicine (NEJM) had the most citations (n = 8, 9358 citations). The country and year with the greatest number of publications were the USA (n = 29), and 1998 (n = 10). The most ubiquitous topic was the pathology of gastric cancer (n = 57) followed by aetiology of gastric cancer (n = 47), and basic science of gastric cancer (n = 44). Conclusion The most cited manuscripts highlighted in this study describe the science related to the pathogenesis of GC including surgery and regimens that have resulted in the contemporary understanding and treatment of GC. This work provides the most influential references related to GC and serves as a guide as to what makes a citable paper

The role of cancer related inflammation, Src family kinases and matrix metalloproteinase 9 in colorectal cancer

Colorectal cancer (CRC) is the third most common cancer in the UK with 41,000 new cases diagnosed in 2011. Despite undergoing potentially curative resection, a significant amount of patients develop recurrence. Biomarkers that aid prognostication or identify patients who are suitable for adjuvant treatments are needed. The TNM staging system does a reasonably good job at offering prognostic information to the treating clinician, but it could be better and identifying methods of improving its accuracy are needed. Tumour progression is based on a complex relationship between tumour behaviour and the hosts’ inflammatory responses. Sustained tumour cell proliferation, evading growth suppressors, resisting apoptosis, replicative immortality, sustained angiogenesis, invasion & metastasis, avoiding immune destruction, deregulated cellular energetics, tumour promoting inflammation and genomic instability & mutation have been identified as hallmarks. These hallmarks are malignant behaviors are what makes the cell cancerous and the more extreme the behaviour the more aggressive the cancer the more likely the risk of a poor outcome. There are two primary genomic instability pathways: Microsatellite Instability (MSI) and Chromosomal Instability (CI) also referred to as Microsatellite Stability (MSS). Tumours arising by these pathways have a predilection for specific anatomical, histological and molecular biological features. It is possible that aberrant molecular expression of genes/proteins that promote malignant behaviors may also act as prognostic and predictive biomarkers, which may offer superior prognostic information to classical prognostic features. Cancer related inflammation has been described as a 7th hallmark of cancer. Despite the systemic inflammatory response (SIR) being associated with more aggressive malignant disease, infiltration by immune cells, particularly CD8+ lymphocytes, at the advancing edge of the tumour have been associated with improved outcome and tumour MSI. It remains unknown if the SIR is associated with tumour MSI and this requires further study. The mechanisms by which colorectal cancer cells locally invade through the bowel remain uncertain, but connective tissue degradation by matrix metalloproteinases (MMPs) such as MMP-9 have been implicated. MMP-9 has been found in the cancer cells, stromal cells and patient circulation. Although tumoural MMP-9 has been associated with poor survival, reports are conflicting and contain relatively small sample sizes. Furthermore, the influence of high serum MMP-9 on survival remains unknown. Src family kinases (SFKs) have been implicated in many adverse cancer cell behaviors. SFKs comprise 9 family members BLK, C-SRC, FGR, FYN, HCK, LCK, LYN, YES, YRK. C-SRC has been the most investigated of all SFKs, but the role of other SFKs in cellular behaviors and their prognostic value remains largely unknown. The development of Src inhibitors, such as Dasatinib, has identified SFKs as a potential therapeutic target for patients at higher risk of poor survival. Unfortunately, clinical trials so far have not been promising but this may reflect inadequate patient selection and SFKs may act as useful prognostic and predictive biomarkers. In chapter 3, the association between cancer related inflammation, tumour MSI, clinicopathological factors and survival was tested in two independent cohorts. A training cohort consisting of n=182 patients and a validation cohort of n=677 patients. MSI tumours were associated with a raised CRP (p=0.003). Hypoalbuminaemia was independently associated with poor overall survival in TNM stage II cancer (HR 3.04 (95% CI 1.44 – 6.43);p=0.004), poor recurrence free survival in TNM stage III cancer (HR 1.86 (95% 1.03 – 3.36);p=0.040) and poor overall survival in CI colorectal cancer (HR 1.49 (95% CI 1.06 – 2.10);p=0.022). Interestingly, MSI tumours were associated with poor overall survival in TNM stage III cancer (HR 2.20 (95% CI 1.10 – 4.37);p=0.025). In chapter 4, the role of MMP-9 in colorectal cancer progression and survival was examined. MMP-9 in the tissue was assessed using IHC and serum expression quantified using ELISA. Serum MMP-9 was associated with cancer cell expression (Spearman’s Correlation Coefficient (SCC) 0.393, p<0.001)) and stromal expression (SCC 0.319, p=0.002). Serum MMP-9 was associated with poor recurrence-free (HR 3.37 (95% CI 1.20 – 9.48);p=0.021) and overall survival (HR 3.16 (95% CI 1.22 – 8.15);p=0.018), but tumour MMP-9 was not survival or MSI status. In chapter 5, the role of SFK expression and activation in colorectal cancer progression and survival was studied. On PCR analysis, although LYN, C-SRC and YES were the most highly expressed, FGR and HCK had higher expression profiles as tumours progressed. Using IHC, raised cytoplasmic FAK (tyr 861) was independently associated with poor recurrence free survival in all cancers (HR 1.48 (95% CI 1.02 – 2.16);p=0.040) and CI cancers (HR 1.50 (95% CI 1.02 – 2.21);p=0.040). However, raised cytoplasmic HCK (HR 2.04 (95% CI 1.11 – 3.76);p=0.022) was independently associated with poor recurrence-free survival in TNM stage II cancers. T84 and HT29 cell lines were used to examine the cellular effects of Dasatinib. Cell viability was assessed using WST-1 assay and apoptosis assessed using an ELISA cell death detection assay. Dasatinib increased T84 tumour cell apoptosis in a dose dependent manner and resulted in reduced expression of nuclear (p=0.008) and cytoplasmic (p=0.016) FAK (tyr 861) expression and increased nuclear FGR expression (p=0.004). The results of this thesis confirm that colorectal cancer is a complex disease that represents several subtypes of cancer based on molecular biological behaviors. This thesis concentrated on features of the disease related to inflammation in terms of genetic and molecular characterisation. MSI cancers are closely associated with systemic inflammation but despite this observation, they retain their relatively improved survival. MMP-9 is a feature of tissue remodeling during inflammation and is also associated with degradation of connective tissue, advanced T-stage and poor outcome when measured in the serum. The lack of stromal quantification due to TMA use rather than full sections makes the value of tumoural MMP-9 immunoreactivity in the prognostication and its association with MSI unknown and requires further study. Finally, SFK activation was also associated with SIR, however, only cytoplasmic HCK was independently associated with poor survival in patients with TNM stage II disease, the group of patients where identifying a novel biomarker is most needed. There is still some way to go before these biomarkers are translated into clinical practice and future work needs to focus on obtaining a reliable and robust scientific technique with validation in an adequately powered independent cohort

Esophageal cancer's 100 most influential manuscripts: a bibliometric analysis

Bibliometric analysis highlights key topics and publications that have shaped the understanding and management of esophageal cancer (EC). Here, the 100 most cited manuscripts in the field of EC are analyzed. The Thomson Reuters Web of Science database with the search terms ‘esophageal cancer’ or ‘esophageal carcinoma’ or ‘oesophageal cancer’ or ‘oesophageal carcinoma’ or ‘gastroscopy’ was used to identify all English language full manuscripts for the study. The 100 most cited papers were further analyzed by topic, journal, author, year, and institution. A total of 121,556 eligible papers were returned and the median (range) citation number was 406.5 (1833 to 293). The most cited paper focused on the role of perioperative chemotherpy in EC (1833 citations). Gastroenterology published the highest number of papers (n = 15, 6362 citations) and The New England Journal of Medicine received the most citations (n = 12, 12125 citations). The country and year with the greatest number of publications were the USA (n = 50), and 1998, 1999, and 2000 (n = 7). The most ubiquitous topic was the pathology of EC (n = 66) followed by management of EC (n = 54), and studies related to EC prognosis (n = 44). The most cited manuscripts highlighted the pathology, management, and prognosis of EC and this bibliometirc review provides the most influential references serving as a guide to popular research themes

Systematic review and meta-analysis of the prognostic significance of Neutrophil-Lymphocyte Ratio (NLR) After R0 gastrectomy for cancer

Abstract Purpose A meta-analysis was performed to evaluate the prognostic value of neutrophil-lymphocyte ratio (NLR) in patients undergoing potentially curative gastrectomy for cancer (GC). Methods Thomson Reuters Web of Science, Ovid MEDLINE(R) and PUBMED databases were searched for relevant articles using search terms neutrophil-lymphocyte ratio (NLR), GC and survival. Articles reporting overall survival (OS), cancer-specific survival and disease-free survival (DFS), in patients undergoing R0 gastrectomy, were studied. Results Articles numbering 365 were identified during the preliminary search, and 10 containing 4164 patients were included in the final review. Most patients were &gt; 60 years of age, male (67%) and 2239 (53.8%) had pT3 disease. The number of NLR dichotomization thresholds reported numbered 7, with 2.00 and 3.00 (n = 2) the most common. NLR was associated with poor survival in eight studies with hazard ratios ranging from 1.54 (95% confidence interval (CI) 1.26–1.89) to 2.99 (1.99–4.49). Pooled odds ratio (OR) for OS was 2.31 (1.40–3.83, p = 0.001) and for DFS 2.72 (1.14–6.54, p = 0.020). Four studies presented T-stage data, OR 1.62 (1.33–1.96, p &lt; 0.001). Conclusion NLR is an important prognostic indicator associated with both OS and DFS after R0 resection of GC, but the critical level is equivocal. </jats:sec

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 &#60; 0.001), independent of TNM stage and venous invasion (both P &#60; 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 &#60; 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

Propensity score regression analysis of oesophageal cancer treatment with surgery alone or neoadjuvant chemotherapy

Background: Propensity score (PS) regression analysis can be used to minimize differences between cohorts in order to perform comparisons The aim of this study was to use PS analysis to examine the outcomes of oesophageal adenocarcinoma (OAC) treatment with surgery alone or neoadjuvant chemotherapy (NAC) followed by surgery (NACS), to see whether the benefits seen in a randomized trial (MRC OE02) were reproducible in a UK cancer network clinical practice. Methods: Consecutive patients undergoing potentially curative treatment for OAC in a regional cancer network were studied. Multiple regression models, including PS analysis, were developed to account for confounding factors. Primary outcome measures were disease‐free (DFS) and overall (OS) survival. Results: A cohort of 440 patients was included in a regression analysis controlling for confounders (176 surgery alone, 264 NACS). NACS was associated with a higher positive margin status rate compared with surgery alone (42·4 versus 26·7 per cent respectively; P < 0·001), an inferior 5‐year DFS rate (32·1 versus 56·9 per cent; P < 0·001) and a worse 5‐year OS rate (27·5 versus 47·3 per cent; P < 0·001). On regression adjustment based on propensity scores, NACS was not associated with DFS (P = 0·220) or OS (P = 0·431). The Mandard tumour regression grade (TRG) score was significantly associated with DFS (hazard ratio (HR) 0·21, 95 per cent c.i. 0·07 to 0·70) and OS (HR 0·27, 0·13 to 0·59). Five‐year DFS and OS rates related to TRG were 64 and 62 per cent respectively for 25 good responders versus 8·0 and 8·6 per cent for 127 poor responders (P < 0·001). Conclusion: The prescription of NAC to all patients with OAC risks delay in effective treatment of patients who are relatively chemoresistant, given the variability in pathological response. Identification of patients with OAC who may derive the most benefit from NAC should be the focus