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

Background: Tumour budding has been reported to reflect invasiveness, metastasis and unfavourable prognosis in colorectal cancer. The aim of the study was to examine the relationship between tumour budding and clinicopathological characteristics, tumour microenvironment and survival in patients with primary operable colorectal cancer. Methods: A total of 303 patients from a prospective data set of patients with primary operable colorectal cancer were included in the study. The presence of budding was determined through assessment of all tumour-containing H&E slides and the number of tumour buds was counted using a 10 high-powered field method. Routine pathologic sections were used to assess: tumour necrosis, the tumour inflammatory cell infiltrate using Klintrup–Makinen (KM) grade and tumour stroma percentage (TSP) combined as the Glasgow Microenvironment Score (GMS). Results: High-grade tumour budding was present in 39% of all tumours and in 28% of node-negative tumours respectively. High-grade budding was significantly associated with T stage (P<0.001), N stage (P<0.001), TNM stage (P<0.001), serosal involvement (P<0.001), venous invasion (P<0.005), KM grade (P=0.022), high tumour stroma (P<0.001) and GMS (P<0.001). Tumour budding was associated with reduced cancer-specific survival (CSS) (HR=4.03; 95% confidence interval (CI), 2.50–6.52; P<0.001), independent of age (HR=1.47; 95% CI, 1.13–1.90; P=0.004), TNM stage (HR=1.52; 95% CI, 1.02–2.25; P=0.040), venous invasion (HR=1.73; 95% CI, 1.13–2.64; P=0.012) and GMS (HR=1.54; 95% CI, 1.15–2.07; P=0.004). Conclusions: The presence of tumour budding was associated with elements of the tumour microenvironment and was an independent adverse prognostic factor in patients with primary operable colorectal cancer. Specifically high tumour budding stratifies effectively the prognostic value of tumour stage, venous invasion and GMS. Taken together, tumour budding should be assessed routinely in patients with primary operable colorectal cancer

Signal transduction and activator of transcription-3 (STAT3) in patients with colorectal cancer: associations with the phenotypic features of the tumour and host

Purpose: In patients with colorectal cancer (CRC), a high-density local inflammatory infiltrate response is associated with improved survival, whereas elevated systemic inflammatory responses are associated with poor survival. One potential unifying mechanism is the IL-6/JAK/STAT3 pathway. The present study examines the relationship between tumour total STAT3 and phosphorylated STAT3Tyr705 (pSTAT3) expression, host inflammatory responses and survival in patients undergoing resection of stage I-III CRC. Experimental Design: Immunohistochemical assessment of STAT3/pSTAT3 expression was performed using a tissue microarray and tumour cell expression divided into tertiles using the weighted histoscore. The relationship between STAT3/pSTAT3 expression and local inflammatory (CD3+, CD8+, CD45R0+, FOXP3+ T-cell density and Klintrup-Mäkinen grade) and systemic inflammatory responses and cancer-specific survival were examined. Results: 196 patients were included in the analysis. Cytoplasmic and nuclear STAT3 expression strongly correlated (r=0.363, P<0.001); nuclear STAT3 and pSTAT3 expression weakly correlated (r=0.130, P=0.068). Cytoplasmic STAT3 was inversely associated with the density of CD3+ (P=0.012), CD8+ (P=0.003) and FOXP3+ T-lymphocytes (P=0.002) within the cancer cell nests and was associated with an elevated systemic inflammatory response as measured by modified Glasgow Prognostic Score (mGPS2: 19% vs. 4%, P=0.004). The combination of nuclear STAT3/pSTAT3 stratified five-year survival from 81% to 62% (P=0.012), however was not associated with survival independent of venous invasion, tumour perforation or tumour budding. Conclusion In patients undergoing CRC resection, STAT3 expression was associated with adverse host inflammatory responses and reduced survival. Up-regulation of tumour STAT3 may be an important mechanism whereby the tumour deregulates local and systemic inflammatory responses

Relationship between tumour PTEN/Akt/COX-2 expression, inflammatory response and survival in patients with colorectal cancer

In patients with colorectal cancer (CRC), local and systemic inflammatory responses have been extensively reported to associate with cancer survival. However, the specific signalling pathways responsible for inflammatory responses are not clear. The PTEN/Akt pathway is a plausible candidate as it may play a role in mediating inflammation via COX-2, and has been associated with cancer progression. This study therefore examined the relationship between tumour PTEN/Akt/COX-2 expression, inflammatory responses and survival in CRC patients using a tissue microarray. In 201 CRC patients, activation of tumour-specific PTEN/Akt significantly associated with poorer CSS (12.0yrs v 7.3yrs, P=0.032), poorer differentiation (P=0.032), venous invasion (P=0.008) and peritoneal involvement (P=0.004). Patients were stratified for peri-nuclear expression of COX-2 to examine associations with inflammatory responses. In patients with absent peri-nuclear COX-2 expression, activation of tumour-specific PTEN/Akt significantly associated with poorer CSS (11.9yrs v 5.4yrs, P=0.001), poorer differentiation (P=0.018), venous invasion (P=0.003) and peritoneal involvement (P=0.001). However, no associations were seen with either the local or systemic inflammatory responses. In CRC patients, tumour-specific PTEN/Akt pathway activation was significantly associated with poorer CSS, particularly when peri-nuclear COX-2 expression was absent. However, activation of the PTEN/Akt pathway appears not to be responsible for the regulation of inflammatory responses

Level of impaired control predicts outcome of moderation-oriented treatment for alcohol problems

Aims To examine the ability of the Impaired Control Scale (ICS) to predict outcome of moderation-oriented treatment for alcohol problems and to compare this predictive ability directly with that of a widely used measure of alcohol dependence, the Severity of Alcohol Dependence Questionnaire (SADQ). Design Prospective follow-up study. Setting Out-patient treatment centres. Participants A combined sample 154 problem drinkers taking part in two clinical trials of Moderation-oriented Cue Exposure in the UK and Australia. Clients were followed-up 6 (UK) and 8 (Australia) months after the end of reatment. Measurements Outcome was categorized by combining drinking behaviour at follow-up with changes on the Alcohol Problems Questionnaire from before treatment to follow-up. Controlling for research site, baseline scores on Part 2 of the ICS (substitution method) and the SADQ-C were entered in logistic regression analyses with three outcome dichotomies as dependent variables. Findings Five per cent of clients were abstinent at follow-up, 13% non-problem drinkers, 25% much improved, 24% somewhat improved and 34% unimproved. Location of treatment and ICS2 scores were significant predictors of whether or not clients achieved a successful outcome (abstinence or non-problem drinking). Using a cut-point of 25 on the ICS, two-thirds of outcomes were classified correctly as either treatment successes or failures. SADQ-C score was not a significant predictor of treatment outcome. Conclusions The ICS predicts outcome of moderation-oriented treatment among moderately dependent problem drinkers recruited mainly via newspaper advertisements. The ICS should replace the SADQ as the basis for advice to clients in this population of problem drinkers regarding whether or not a moderation goal of treatment should be pursued

The relationship between tumour budding, tumour microenvironment and survival in patients with primary operable colorectal cancer

Background: Tumor budding is an independent prognostic factor in colorectal cancer (CRC) and has recently been well-defined by the International Tumour Budding Consensus Conference (ITBCC). Objective: The aim of the present study was to use the ITBCC budding evaluation method to examine the relationship between tumor budding, tumor factors, tumor microenvironment, and survival in patients with primary operable CRC. Methods: Hematoxylin and eosin-stained slides of 952 CRC patients diagnosed between 1997 and 2007 were evaluated for tumor budding according to the ITBCC criteria. The tumor microenvironment was evaluated using tumor stroma percentage (TSP) and Klintrup–Makinen (KM) grade to assess the tumor inflammatory cell infiltrate. Results: High budding (n = 268, 28%) was significantly associated with TNM stage (p < 0.001), competent mismatch repair (MMR; p < 0.05), venous invasion (p < 0.001), weak KM grade (p < 0.001), high TSP (p < 0.001), and reduced cancer-specific survival (CSS) (hazard ratio 8.68, 95% confidence interval 6.30–11.97; p < 0.001). Tumor budding effectively stratifies CSS stage T1 through to T4 (all p < 0.05) independent of associated factors. Conclusions: Tumor budding effectively stratifies patients’ survival in primary operable CRC independent of other phenotypic features. In particular, the combination of T stage and budding should form the basis of a new staging system for primary operable CRC. Tumor budding has been defined as a single tumor cell or small cluster of four or fewer tumor cells at the invasive front12,18 and should be considered a promising and strong prognostic factor in colorectal cancer (CRC).19 Widespread reporting of tumor budding has not progressed to routine clinical practice due to a lack of consensus on scoring methods. However, routine reporting is now advocated by using the approach outlined by the International Tumour Budding Consensus Conference (ITBCC), with recommendations for the assessment and reporting of tumor budding in CRC.6 The ITBCC recommends that tumor budding should be included in future CRC guidelines and protocols and should be considered, along with other clinicopathological factors, in a multidisciplinary setting. The recent dataset for histopathological reporting of CRC by the royal pathologist stated that they would reconsider reporting tumor budding when new data become available.4 The tumor microenvironment also plays an important role in CRC outcomes. Marked peritumoral inflammation has been associated with favorable outcome,3,14 while the presence of a high tumor stroma percentage (TSP) has been validated as a stage-independent marker of reduced survival in patients with primary operable CRC.7,8. Both contribute to the development of a tumor microenvironment score that can potentially supplement the current TNM staging system.9 The aim of this study was to assess the proposed method by ITBCC in clinical practice and investigate the relationship between tumor budding and tumor factors, tumor microenvironment, and survival in primary operable CRC

Pre-operative, biopsy-based assessment of the tumour microenvironment in patients with primary operable colorectal cancer

The tumour microenvironment (TME) is recognised as an important prognostic characteristic and therapeutic target in patients with colorectal cancer (CRC). However, assessment generally utilises surgically resected specimens, precluding neoadjuvant targeting. The present study investigated the feasibility of intra‐epithelial CD3+ T‐lymphocyte density and tumour stroma percentage (TSP) assessment using preoperative colonoscopic biopsies from 115 patients who had undergone resection of stages I–III CRC, examining the relationship between biopsy and surgically resected specimen‐based assessment, and the relationship with cancer‐specific survival (CSS). High biopsy CD3+ density was associated with high CD3+ density in the invasive margin, cancer stroma and intra‐epithelial compartments of surgically resected specimens (area under the curve > 0.62, p < 0.05 for all) and with high Immunoscore. High biopsy TSP predicted high TSP in resected specimens (p = 0.001). Intra‐class correlation coefficient for both measures was >0.7 (p < 0.001), indicating excellent concordance between individuals. Biopsy CD3+ density (hazard ratio [HR] 0.23, p = 0.002) and TSP (HR 2.23, p = 0.029) were independently associated with CSS; this was comparable to the prognostic value of full section assessment (HR 0.21, p = 0.004, and HR 2.25, p = 0.033 respectively). These results suggest that assessment of the TME is comparable in biopsy and surgically resected specimens from patients with CRC, and biopsy‐based assessment could allow for stratification prior to surgery or commencement of therapy targeting the TME

Magazine and reader constructions of 'metrosexuality' and masculinity: a membership categorisation analysis

Since the launch of men's lifestyle magazines in the 1980s, academic literature has predominantly focused on them as a cultural phenomenon arising from entrepreneurial and commercial initiatives and/or as cultural texts that proffer representations of masculinity such as 'new lad' and 'new dad'. This paper steps aside from the focus on culture and, instead, treats magazine content as a discursive space in which gender and sexuality are oriented to, negotiated, and accomplished within and beyond the magazine itself (i.e. through readers' responses). Specifically, membership categorisation analysis is deployed to explore how the relatively new (and perhaps alternative) category for men - 'metrosexual' - is presented and received. Our analysis suggests that masculinity concerns are central in debates about 'metrosexuality', with self-identified 'metrosexuals' invoking heterosexual prowess and self-respect on the one hand, and critics (e.g. selfidentified 'real men') lamenting 'metrosexuality' for its perceived effeminacy and lack of authenticity on the other. Implications for understanding contemporary masculinities are discussed

The association between markers of tumour cell metabolism, the tumour microenvironment and outcomes in patients with colorectal cancer

Tumour cell anaerobic metabolism has been reported to be a prognostic factor in colorectal cancer. The present study investigated the association between monocarboxylate transporter (MCT) 1, MCT 2, lactate dehydrogenase (LDH) 1 and LDH 5, the tumour microenvironment, and outcome in patients with colorectal cancer. A cohort of 150 patients with stage I‐III CRC were utilised to assess tumour cell expression of MCT‐1, MCT‐2, LDH‐1 and LDH‐5 by immunohistochemistry. Expression levels were dichotomised and associations with tumour factors, the tumour microenvironment and survival analysed. Nuclear LDH‐5 associates with poor prognosis (HR 1.68 95% CI 0.99–2.84, p = 0.050) and trends toward increased tumour stroma percentage (TSP, p = 0.125). Cytoplasmic MCT‐2 also trends toward increased TSP (p = 0.081). When combined into a single score; nuclear LDH‐5 + TSP significantly associated with decreased survival independent of stage (HR 2.61 95% CI 1.27–5.35, p = 0.009), increased tumour budding (p = 0.002) and decreased stromal T‐lymphocytes (p = 0.014). Similarly, cytoplasmic MCT‐2 + TSP significantly associated with decreased survival (HR 2.32 95% CI 1.31–4.11, p = 0.003), decreased necrosis (p = 0.039), and increased tumour budding (p = 0.004). The present study reports that the combination of TSP and nuclear LDH‐5 was significantly associated with survival, increased tumour budding, and decreased stromal T‐lymphocytes. This supports the hypothesis that increased stromal invasion promotes tumour progression via modulation of tumour metabolism. Moreover, MCT‐2 and LDH‐5 may provide promising therapeutic targets for patients with stromal‐rich CRC

Mothers behaving badly: chaotic hedonism and the crisis of neoliberal social reproduction

This article focuses on the significance of the plethora of representations of mothers ‘behaving badly’ in contemporary anglophone media texts, including the films Bad Moms, Fun Mom Dinner and Bad Mom’s Christmas, the book and online cartoons Hurrah for Gin and the recent TV comedy dramas Motherland, The Let Down and Catastrophe. All these media texts include representations of, first, mothers in the midst of highly chaotic everyday spaces where any smooth routine of domesticity is conspicuous by its absence; and second, mothers behaving hedonistically, usually through drinking and partying, behaviour that is more conventionally associated with men or women without children. After identifying the social type of the mother behaving badly (MBB), the article locates and analyses it in relation to several different social and cultural contexts. These contexts are: a neoliberal crisis in social reproduction marked by inequality and overwork; the continual if contested role of women as ‘foundation parents’; and the negotiation of longer-term discourses of female hedonism. The title gestures towards a popular British sitcom of the 1990s, Men Behaving Badly, which popularized the idea of the ‘new lad’; and this article suggests that the new lad’s counterpart, the ladette, is mutating into the mother behaving badly, or the ‘lad mom’. Asking what work this figure does now, in a later neoliberal context, it argues that the mother behaving badly is simultaneously indicative of a widening and liberating range of maternal subject positions and symptomatic of a profound contemporary crisis in social reproduction. By focusing on the classed and racialised dynamics of the MBB – by examining who exactly is permitted to be hedonistic, and how – and by considering the MBB’s limited and partial imagining of progressive social change, the article concludes by emphasizing the urgency of creating more connections between such discourses and ‘parents behaving politically’