Understanding the treatment experiences of adults diagnosed with early-onset colorectal cancer: A qualitative study.

OBJECTIVE: Early-onset colorectal cancer (CRC) incidence in adults aged under 50 is increasing. There is a critical lack of knowledge regarding the challenges faced by early-onset CRC patients and their experiences of treatment. The aim of this study was to explore the lived experiences of individuals receiving treatment for early-onset CRC, and the resulting impact on their lives. METHODS: Semi-structured interviews of patients with early-onset CRC in the UK (n = 21) were conducted from August 2021 to March 2022. Interviews were recorded and transcribed verbatim. Data were analysed using thematic analysis. RESULTS: Results identified four key themes: (1) early-onset CRC treatment results in sudden physical, psychological and social impacts in all aspects of life; (2) early-onset CRC patients have unique supportive care needs which are not recognised in current practice; (3) there is a need for tailored information; (4) a lack of support was identified in the areas of mental health, sexual health and fertility. CONCLUSIONS: Our study highlights numerous unique issues experienced by the early-onset CRC patient group during treatment. There is a need for change in clinical practice, along with the development of international guidelines and tailored resources for both patients and healthcare professionals, in order to improve care.

The Global Landscape of Esophageal Squamous Cell Carcinoma and Esophageal Adenocarcinoma Incidence and Mortality in 2020 and Projections to 2040: New Estimates From GLOBOCAN 2020.

BACKGROUND & AIMS: The aim of this study was to provide an overview of the burden of esophageal cancer in 185 countries in 2020 and projections for the year 2040. METHODS: Estimates of esophageal cancer cases and deaths were extracted from the GLOBOCAN database for 2020. Age-standardized incidence and mortality rates were calculated overall, by sex, histologic subtype (adenocarcinoma [AC] and squamous cell carcinoma [SCC]), country, and level of human development for 185 countries. The predicted burden of incidence and mortality in 2040 was calculated based on global demographic projections. RESULTS: Globally, there were an estimated 604,100 new cases of, and 544,100 deaths from, esophageal cancer in 2020, corresponding to age-standardized incidence and mortality rates of 6.3 and 5.6 per 100,000, respectively. Most cases were SCCs (85% [512,500 cases]) and 14% (85,700 cases) were ACs. Incidence and mortality rates were 2- to 3-fold higher in male (9.3 and 8.2, respectively) compared with female (3.6 and 3.2, respectively) individuals. Global variations in incidence and mortality were observed across countries and world regions; the highest rates occurred in Eastern Asia and Southern and Eastern Africa and the lowest occurred in Western Africa and Central America regions. If rates remain stable, 957,000 new cases (141,300 AC cases and 806,000 SCC cases) and 880,000 deaths from esophageal cancer are expected in 2040. CONCLUSIONS: These updated estimates of the global burden of esophageal cancer represent an important baseline for setting priorities in policy making and developing and accelerating cancer control initiatives to reduce the current and projected burden. Although primary prevention remains key, screening and early detection represent important components of esophageal cancer control in high-risk populations.

Clinical Prediction Models for Pancreatic Cancer in General and At-Risk Populations: A Systematic Review.

INTRODUCTION: Identifying high-risk individuals using a risk prediction model could be a crucial first stage of screening pathways to improve the early detection of pancreatic cancer. A systematic review was conducted to critically evaluate the published primary literature on the development or validation of clinical risk prediction models for pancreatic cancer risk. METHODS: MEDLINE, Embase, and Web of Science were searched for relevant articles from the inception of each database up to November 2021. Study selection and data extraction were conducted by 2 independent reviewers. The Prediction model Risk Of Bias Assessment Tool (PROBAST) was applied to assess risk of bias. RESULTS: In total, 33 studies were included, describing 38 risk prediction models. Excluding studies with an overlapping population, this study consist of 15,848,100 participants, of which 58,313 were diagnosed with pancreatic cancer. Eight studies externally validated their model, and 13 performed internal validation. The studies described risk prediction models for pancreatic cancer in the general population (n = 14), patients with diabetes (n = 8), and individuals with gastrointestinal (and other) symptoms (symptoms included abdominal pain, unexplained weight loss, jaundice, and change in bowel habits and indigestion; n = 11). The commonly used clinical risk factors in the model were cigarette smoking (n = 27), age (n = 25), diabetes history (n = 22), chronic pancreatitis (n = 18), and body mass index (n = 14). In the 25 studies that assessed model performance, C-statistics ranged from 0.61 to 0.98. Of the 33 studies included, 6 were rated as being at a low risk of bias based on PROBAST. DISCUSSION: Many clinical risk prediction models for pancreatic cancer had been developed for different target populations. Although low risk-of-bias studies were identified, these require external validation and implementation studies to ensure that these will benefit clinical decision making.

Trends in pathology diagnoses during 10 years of a colorectal cancer screening programme.

AIMS: We report pathology findings from the first 10 years of the faecal-occult blood-based Northern Ireland Bowel Cancer Screening Programme, presenting summary data and trends in pathology diagnoses and clinicopathological features of screen-detected cancers. METHODS AND RESULTS: Data were analysed from a comprehensive polyp-level pathology database representing all endoscopy specimens from programme inception in 2010 until 2021. A total of 9800 individuals underwent 13 472 endoscopy procedures, yielding 25 967 pathology specimens and 32 119 diagnoses. Index specimen diagnoses (4.1%) and index colonoscopies (10.4%) yielded a diagnosis of colorectal cancer, representing 1045 cancers from 1020 individuals (25 with synchronous cancers). A further 13 index cancers were identified via computed tomography colonography; 65.3% of cancer diagnoses were in males; 41.7% were stage I, 23.1% stage II, 25.8% stage III and 1.8% stage IV (7.6% unstaged). Of 233 pT1 cancers diagnosed within local excision specimens, 79 (33.9%) had completion surgery. Ten-year trends showed a steady decline in the proportion of index colonoscopies that yielded a diagnosis of cancer (14.7% in year 1; 4.8% in year 11) or advanced colorectal polyp. There was a strong upward trend in diagnoses of sessile serrated lesions, which overtook hyperplastic polyps in proportions of total index diagnoses by the end of the study time-frame (8.7% compared to 8.5%). CONCLUSIONS: Over the first 10 years of a population colorectal cancer screening programme, 'real world' pathology data demonstrate success in the form of reduced diagnoses of cancer and advanced colorectal polyp with passage of successive screening rounds. Interesting trends with respect to serrated polyp diagnoses are also evident, probably related to pathologist and endoscopist behaviour.

Dietary Inflammatory Potential and the Risk of Serrated and Adenomatous Colorectal Polyps.

Studies of dietary inflammation potential and risks of colorectal cancer precursors are limited, particularly for sessile serrated lesions (SSLs). This study examines the association using the energy-adjusted dietary inflammatory index (E-DIITM), a measure of anti- and/or pro-inflammatory diet, in a large US colonoscopy-based case-control study of 3246 controls, 1530 adenoma cases, 472 hyperplastic polyp cases, and 180 SSL cases. Odds ratios (ORs) and 95% confidence intervals (CIs) were derived from logistic regression models. Analyses were stratified by participant characteristics, and urinary prostaglandin E2 metabolite (PGE-M) and high-sensitivity plasma C-reactive protein (hs-CRP) levels, inflammation biomarkers. Highest E-DII™ intake was associated with significantly increased risks of colorectal adenomas (OR 1.36, 95% CI 1.11, 1.67), and hyperplastic polyps (OR 1.43, 95% CI 1.06, 1.98), compared with participants consuming the lowest E-DII™ quartile. A similar, but non-significant, increased risk was also observed for SSLs (OR 1.41, 95% CI 0.82, 2.41). The positive association was stronger in females (pinteraction <0.001), normal weight individuals (ptrend 0.01), and in individuals with lower inflammatory biomarkers (ptrend 0.02 and 0.01 for PGE-M and hs-CRP, respectively). A high E-DII™ is associated with colorectal polyp risk, therefore promoting an anti-inflammatory diet may aid in preventing colorectal polyps.

Activation of innate-adaptive immune machinery by poly(I:C) exposes a therapeutic vulnerability to prevent relapse in stroma-rich colon cancer.

OBJECTIVE: Stroma-rich tumours represent a poor prognostic subtype in stage II/III colon cancer (CC), with high relapse rates and limited response to standard adjuvant chemotherapy. DESIGN: To address the lack of efficacious therapeutic options for patients with stroma-rich CC, we stratified our human tumour cohorts according to stromal content, enabling identification of the biology underpinning relapse and potential therapeutic vulnerabilities specifically within stroma-rich tumours that could be exploited clinically. Following human tumour-based discovery and independent clinical validation, we use a series of in vitro and stroma-rich in vivo models to test and validate the therapeutic potential of elevating the biology associated with reduced relapse in human tumours. RESULTS: By performing our analyses specifically within the stroma-rich/high-fibroblast (HiFi) subtype of CC, we identify and validate the clinical value of a HiFi-specific prognostic signature (HPS), which stratifies tumours based on STAT1-related signalling (High-HPS v Low-HPS=HR 0.093, CI 0.019 to 0.466). Using in silico, in vitro and in vivo models, we demonstrate that the HPS is associated with antigen processing and presentation within discrete immune lineages in stroma-rich CC, downstream of double-stranded RNA and viral response signalling. Treatment with the TLR3 agonist poly(I:C) elevated the HPS signalling and antigen processing phenotype across in vitro and in vivo models. In an in vivo model of stroma-rich CC, poly(I:C) treatment significantly increased systemic cytotoxic T cell activity (p<0.05) and reduced liver metastases (p<0.0002). CONCLUSION: This study reveals new biological insight that offers a novel therapeutic option to reduce relapse rates in patients with the worst prognosis CC.

Development of a semi-automated method for tumour budding assessment in colorectal cancer and comparison with manual methods.

AIMS: Tumour budding (TB) is an established prognostic feature in multiple cancers but is not routinely assessed in pathology practice. Efforts to standardise and automate assessment have shifted from haematoxylin and eosin (H&E)-stained images towards cytokeratin immunohistochemistry. The aim of this study was to compare manual H&E and cytokeratin assessment methods with a semi-automated approach built within QuPath open-source software. METHODS AND RESULTS: TB was assessed in cores from the advancing tumour edge in a cohort of stage II/III colon cancers (n = 186). The total numbers of buds detected with each method were as follows: manual H&E, n = 503; manual cytokeratin, n = 2290; and semi-automated, n = 5138. More than four times the number of buds were identified manually with cytokeratin assessment than with H&E assessment. One thousand seven hundred and thirty-four individual buds were identified with both manual and semi-automated assessments applied to cytokeratin images, representing 75.7% of the buds identified manually (n = 2290) and 33.7% of the buds detected with the semi-automated method (n = 5138). Higher semi-automated TB scores were due to any discrete area of cytokeratin immunopositivity within an accepted area range being identified as a bud, regardless of shape or crispness of definition, and to the inclusion of tumour cell clusters within glandular lumina ('luminal pseudobuds'). Although absolute numbers differed, semi-automated and manual bud counts were strongly correlated across cores (ρ = 0.81, P < 0.0001). All methods of TB assessment demonstrated poorer survival associated with higher TB scores. CONCLUSIONS: We present a new QuPath-based approach to TB assessment, which compares favourably with established methods and offers a freely available, rapid and transparent tool that is also applicable to whole slide images.

Microscopic colitis in Northern Ireland: an updated clinicopathological audit and assessment of compliance with European guidelines.

AIM: We previously reported the first population-based study of the epidemiology of microscopic colitis in Northern Ireland. The aim of the current study is to provide updated data on incidence, diagnostic methods and clinicopathological associations, following dissemination of the previous report. A further aim was to compare the findings against relevant recommendations from the 2020 European guidelines. METHOD: Study cases were identified via the Belfast Health and Social Care Trust pathology laboratory system for new cases of collagenous colitis or lymphocytic colitis diagnosed from 2017 to 2020 inclusive. Demographic and clinical information was collated from electronic healthcare records. RESULTS: Two hundred and seventeen new diagnoses of microscopic colitis were made between 2017 and 2020, comprising 89 (41%) collagenous colitis and 128 (59%) lymphocytic colitis. The overall incidence of microscopic colitis, expressed per 100,000 adult population, ranged from 7.6 to 11.5 (5.9 to 9.0 per 100,000 total population). The 2019 peak of 11.5 cases per 100,000 adult population represents a 71.6% increase in incidence compared with the mean incidence of 6.7 per 100,000 adult population from previous data for 2008-2016. There has also been a significant increase in number of cases diagnosed on separate sampling from the right and left colon (85% in 2019-2020 compared with 30% in 2008-2016; p < 0.001). Overall compliance with coeliac serology testing has improved, with 89% tested in 2017-2018 compared with 75% in 2008-2016. CONCLUSION: Clinicopathological communication has contributed to an increased incidence of microscopic colitis in Northern Ireland through better endoscopic diagnostic sampling and pathology coding practices. Coeliac serology testing has also improved, although continued clinical awareness is required of the need for coeliac serology testing in all patients diagnosed with microscopic colitis.

Inequalities in the decline and recovery of pathological cancer diagnoses during the first six months of the COVID-19 pandemic: a population-based study.

BACKGROUND: The restructuring of healthcare systems to cope with the demands of the COVID-19 pandemic has led to a reduction in clinical services such as cancer screening and diagnostics. METHODS: Data from the four Northern Ireland pathology laboratories were used to assess trends in pathological cancer diagnoses from 1st March to 12th September 2020 overall and by cancer site, sex and age. These trends were compared to the same timeframe from 2017 to 2019. RESULTS: Between 1st March and 12th September 2020, there was a 23% reduction in cancer diagnoses compared to the same time period in the preceding 3 years. Although some recovery occurred in August and September 2020, this revealed inequalities across certain patient groups. Pathological diagnoses of lung, prostate and gynaecological malignancies remained well below pre-pandemic levels. Males and younger/middle-aged adults, particularly the 50-59-year-old patient group, also lagged behind other population demographic groups in terms of returning to expected numbers of pathological cancer diagnoses. CONCLUSIONS: There is a critical need to protect cancer diagnostic services in the ongoing pandemic to facilitate timely investigation of potential cancer cases. Targeted public health campaigns may be needed to reduce emerging inequalities in cancer diagnoses as the COVID-19 pandemic continues.

Circulating Sex Hormones Are Associated With Gastric and Colorectal Cancers but Not Esophageal Adenocarcinoma in the UK Biobank.

INTRODUCTION: Gastrointestinal cancers show an unexplained male predominance, but few prospective studies have investigated sex hormones and gastrointestinal cancer risk. This study aimed to determine the impact of circulating sex hormones on risk of esophageal, gastric, and colorectal cancers in men and women. METHODS: We included 219,425 men and 147,180 women from the UK Biobank. Sex hormones were quantified using chemiluminescent immunoassay. Gastrointestinal cancers were identified from cancer registry linkages. Sex hormone concentrations and risk of gastrointestinal cancers were investigated using Cox proportional hazards regression. RESULTS: During the 10 years of follow-up, 376 esophageal adenocarcinoma, 108 esophageal squamous cell carcinoma, and 333 gastric and 2,868 colorectal cancer cases were identified. Increased hazard ratios (HRs) were found for sex hormone-binding globulin (SHBG) and risk of gastric cancer in men (Q4 vs Q1 HR 1.43, 95% confidence interval [CI] 0.95-2.17, Ptrend = 0.01). Free testosterone was inversely associated with esophageal squamous cell carcinoma in women (Q4 vs Q1 HR 0.32, 95% CI 0.11-0.98, Ptrend = 0.05). For colorectal cancer, SHBG was associated with a reduced risk among men (Q4 vs Q1 HR 0.89, 95% CI 0.77-1.03, Ptrend = 0.04) and free testosterone concentrations was associated with a reduction in risk among women (Q4 vs Q1 HR 0.80, 95% CI 0.66-0.97, Ptrend = 0.01). No associations were found for esophageal adenocarcinoma. DISCUSSION: In this large prospective investigation of prediagnostic sex hormones and risk of gastrointestinal cancers, men with higher SHBG concentrations had higher gastric, yet lower colorectal, cancer risks, whereas women with higher free testosterone levels had a lower risk of esophageal squamous cell carcinoma and colorectal cancer.

Identifying mismatch repair-deficient colon cancer: near-perfect concordance between immunohistochemistry and microsatellite instability testing in a large, population-based series.

AIMS: Establishing the mismatch repair (MMR) status of colorectal cancers is important to enable the detection of underlying Lynch syndrome and inform prognosis and therapy. Current testing typically involves either polymerase chain reaction (PCR)-based microsatellite instability (MSI) testing or MMR protein immunohistochemistry (IHC). The aim of this study was to compare these two approaches in a large, population-based cohort of stage 2 and 3 colon cancer cases in Northern Ireland. METHODS AND RESULTS: The study used the Promega pentaplex assay to determine MSI status and a four-antibody MMR IHC panel. IHC was applied to tumour tissue microarrays with triplicate tumour sampling, and assessed manually. Of 593 cases with available MSI and MMR IHC results, 136 (22.9%) were MSI-high (MSI-H) and 135 (22.8%) showed abnormal MMR IHC. Concordance was extremely high, with 97.1% of MSI-H cases showing abnormal MMR IHC, and 97.8% of cases with abnormal IHC showing MSI-H status. Under-representation of tumour epithelial cells in samples from heavily inflamed tumours resulted in misclassification of several cases with abnormal MMR IHC as microsatellite-stable. MMR IHC revealed rare cases with unusual patterns of MMR protein expression, unusual combinations of expression loss, or secondary clonal loss of expression, as further illustrated by repeat immunostaining on whole tissue sections. CONCLUSIONS: MSI PCR testing and MMR IHC can be considered to be equally proficient tests for establishing MMR/MSI status, when there is awareness of the potential pitfalls of either method. The choice of methodology may depend on available services and expertise.

Esophageal Columnar Metaplasia in Childhood: A Population-Based Case Series Analysis.

BACKGROUND: Adults with Barrett's esophagus (BE) are often entered into surveillance for esophageal adenocarcinoma (EAC), although cancer risk is relatively low. BE can be detected in children (< 16 years). Little is known about the epidemiology of pediatric BE, and it is unclear what the optimal surveillance regimes are in children. AIM: To evaluate the demographic and clinical characteristics, and future neoplastic progression risk in all pediatric BE patients diagnosed in Northern Ireland between 1993 and 2010. METHODS: Data from the population-based Northern Ireland BE register were matched to the Northern Ireland Cancer Registry for EAC outcomes until end 2013. Age-adjusted incidence of pediatric BE was calculated, and characteristics between pediatric and adult BE patients compared using Chi-square tests. RESULTS: Over 18 years, 42 pediatric BE patients (< 16 years) were identified, equivalent to an age-adjusted incidence of < 2 per 100,000 children. There was a clear age differential, with BE incidence increasing with age within the pediatric population. The majority (85.7%) of patients were male, a significantly higher male/female ratio than adult BE patients (p < 0.001). No pediatric BE patients progressed to high-grade dysplasia (HGD) or EAC, although the eldest patient was aged 34 years by the end of follow-up. CONCLUSIONS: This is the largest series of pediatric BE ever reported. It demonstrates that pediatric BE is rare. The male preponderance of this condition is more apparent in childhood compared with adult cases. No children developed HGD/EAC during follow-up, suggesting that regular surveillance is not required, at least until adulthood.

Does Risk of Progression from Barrett's Esophagus to Esophageal Adenocarcinoma Change Based on the Number of Non-dysplastic Endoscopies?

BACKGROUND: There is a large Barrett's esophagus patient population undergoing endoscopic surveillance. Methods to stratify patients into higher and lower risk groups may enable more varied surveillance intervals for patients with non-dysplastic Barrett's esophagus that could optimize use of endoscopy resources. OBJECTIVE: We aimed to assess whether risk of progression to esophageal adenocarcinoma differed in patients with multiple endoscopic biopsies negative for dysplasia. METHODS: We conducted a retrospective cohort study among individuals from the population-based Northern Ireland Barrett's register with a histologically confirmed diagnosis of non-dysplastic Barrett's esophagus (with intestinal metaplasia) between 1993 and 2010, who had at least one endoscopic biopsy conducted at least 12 months after diagnosis. We used Poisson regression to estimate incidence rate ratios (IRR) and 95% confidence intervals (CI) for the association between number of successive endoscopies showing non-dysplastic Barrett's esophagus and risk of esophageal adenocarcinoma alone, and combined with high-grade dysplasia, at the next endoscopy. RESULTS: We identified 1761 individuals who met our eligibility criteria. Subsequent risk of progression to esophageal adenocarcinoma was lower at the next endoscopy following two endoscopies showing non-dysplastic Barrett's esophagus (IRR 0.26, 95% CI 0.10-0.66) than following one endoscopy showing non-dysplastic Barrett's esophagus. Similar findings were apparent for risk of progression to esophageal adenocarcinoma or high-grade dysplasia (IRR 0.41, 95% CI 0.22-0.79). CONCLUSION: The lower risk of malignant progression in individuals with persistent non-dysplastic Barrett's esophagus over two consecutive endoscopic biopsies but not for longer term persistence does not support hypotheses of persistence being an indicator of less biologically aggressive lesions. Instead, the initial difference may be attributable to post-endoscopy cancers and support the necessity of adhering to robust quality standards for endoscopic procedures.

Histopathologist features predictive of diagnostic concordance at expert level among a large international sample of pathologists diagnosing Barrett's dysplasia using digital pathology.

OBJECTIVE: Guidelines mandate expert pathology review of Barrett's oesophagus (BO) biopsies that reveal dysplasia, but there are no evidence-based standards to corroborate expert reviewer status. We investigated BO concordance rates and pathologist features predictive of diagnostic discordance. DESIGN: Pathologists (n=51) from over 20 countries assessed 55 digitised BO biopsies from across the diagnostic spectrum, before and after viewing matched p53 labelling. Extensive demographic and clinical experience data were obtained via online questionnaire. Reference diagnoses were obtained from a review panel (n=4) of experienced Barrett's pathologists. RESULTS: We recorded over 6000 case diagnoses with matched demographic data. Of 2805 H&E diagnoses, we found excellent concordance (>70%) for non-dysplastic BO and high-grade dysplasia, and intermediate concordance for low-grade dysplasia (42%) and indefinite for dysplasia (23%). Major diagnostic errors were found in 248 diagnoses (8.8%), which reduced to 232 (8.3%) after viewing p53 labelled slides. Demographic variables correlating with diagnostic proficiency were analysed in multivariate analysis, which revealed that at least 5 years of professional experience was protective against major diagnostic error for H&E slide review (OR 0.48, 95% CI 0.31 to 0.74). Working in a non-teaching hospital was associated with increased odds of major diagnostic error (OR 1.76, 95% CI 1.15 to 2.69); however, this was neutralised when pathologists viewed p53 labelled slides. Notably, neither case volume nor self-identifying as an expert predicted diagnostic proficiency. Extrapolating our data to real-world case prevalence suggests that 92.3% of major diagnostic errors are due to overinterpreting non-dysplastic BO. CONCLUSION: Our data provide evidence-based criteria for diagnostic proficiency in Barrett's histopathology.

Statin use and risk of liver cancer: Evidence from two population-based studies.

Epidemiological studies of statin use and liver cancer risk have produced conflicting results. We examined the association between statin use and risk of primary liver cancer in two large independent study populations taking account of important covariates and main indications of statins such as high cholesterol and chronic liver disease. We performed a nested case-control study within the Scottish Primary Care Clinical Informatics Unit (PCCIU) database. Five controls were matched to cases with primary liver cancer and we used conditional logistic regression to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for associations with statin use. We also conducted a prospective cohort study within the UK Biobank using self-reported statin use and cancer-registry recorded primary liver cancer outcomes. Cox regression was used to calculate hazard ratios (HRs) and 95% CIs. In the PCCIU case-control analysis, 434 liver cancer cases were matched to 2,103 controls. In the UK Biobank cohort, 182 out of 475,768 participants developed incident liver cancer. Statin use was associated with 39% lower risk of liver cancer in the PCCIU (adjusted OR 0.61, 95% CI 0.43-0.87). When we examined specific subtypes of liver cancer in the UK Biobank, statin use was associated with lower risk of hepatocellular carcinoma (HCC; adjusted HR, 0.48; 95% CI, 0.24-0.94) but not intrahepatic bile duct carcinoma (IBDC; adjusted HR, 1.09; 95% CI, 0.45-2.64). In conclusion, we found a consistent inverse relationship between statin use and risk of primary liver cancer which was only seen for HCC but not IBDC.

Immune status is prognostic for poor survival in colorectal cancer patients and is associated with tumour hypoxia.

BACKGROUND: Immunohistochemical quantification of the immune response is prognostic for colorectal cancer (CRC). Here, we evaluate the suitability of alternative immune classifiers on prognosis and assess whether they relate to biological features amenable to targeted therapy. METHODS: Overall survival by immune (CD3, CD4, CD8, CD20 and FOXP3) and immune-checkpoint (ICOS, IDO-1 and PD-L1) biomarkers in independent CRC cohorts was evaluated. Matched mutational and transcriptomic data were interrogated to identify associated biology. RESULTS: Determination of immune-cold tumours by combined low-density cell counts of CD3, CD4 and CD8 immunohistochemistry constituted the best prognosticator across stage II-IV CRC, particularly in patients with stage IV disease (HR 1.98 [95% CI: 1.47-2.67]). These immune-cold CRCs were associated with tumour hypoxia, confirmed using CAIX immunohistochemistry (P = 0.0009), which may mediate disease progression through common biology (KRAS mutations, CRIS-B subtype and SPP1 mRNA overexpression). CONCLUSIONS: Given the significantly poorer survival of immune-cold CRC patients, these data illustrate that assessment of CD4-expressing cells complements low CD3 and CD8 immunohistochemical quantification in the tumour bulk, potentially facilitating immunophenotyping of patient biopsies to predict prognosis. In addition, we found immune-cold CRCs to associate with a difficult-to-treat, poor prognosis hypoxia signature, indicating that these patients may benefit from hypoxia-targeting clinical trials.

Information on Genetic Variants Does Not Increase Identification of Individuals at Risk of Esophageal Adenocarcinoma Compared to Clinical Risk Factors.

We previously developed a tool that identified individuals who later developed esophageal adenocarcinoma (based on age, sex, body mass index, smoking status, and prior esophageal conditions) with an area under the curve of 0.80. In this study, we collected data from 329,463 individuals in the UK Biobank cohort who were tested for genetic susceptibility to esophageal adenocarcinoma (a polygenic risk score based on 18 recognized genetic variants). We found that after inclusion of this genetic information, the area under the curve for identification of individuals who developed esophageal adenocarcinoma remained at 0.80. Testing for genetic variants associated with esophageal adenocarcinoma therefore seems unlikely to improve identification of individuals at risk of esophageal adenocarcinoma.

Alcohol intake, tobacco smoking, and esophageal adenocarcinoma survival: a molecular pathology epidemiology cohort study.

PURPOSE: To investigate the association between cigarette smoking, alcohol consumption, and esophageal adenocarcinoma survival, including stratified analysis by selected prognostic biomarkers. METHODS: A population-representative sample of 130 esophageal adenocarcinoma patients (n = 130) treated at the Northern Ireland Cancer Centre between 2004 and 2012. Cox proportional hazards models were applied to evaluate associations between smoking status, alcohol intake, and survival. Secondary analyses investigated these associations across categories of p53, HER2, CD8, and GLUT-1 biomarker expression. RESULTS: In esophageal adenocarcinoma patients, there was a significantly increased risk of cancer-specific mortality in ever, compared to never, alcohol drinkers in unadjusted (HR 1.96 95% CI 1.13-3.38) but not adjusted (HR 1.70 95% CI 0.95-3.04) analysis. This increased risk of death observed for alcohol consumers was more evident in patients with normal p53 expression, GLUT-1 positive or CD-8 positive tumors. There were no significant associations between survival and smoking status in esophageal adenocarcinoma patients. CONCLUSIONS: In esophageal adenocarcinoma patients, cigarette smoking or alcohol consumption was not associated with a significant difference in survival in comparison with never smokers and never drinkers in fully adjusted analysis. However, in some biomarker-selected subgroups, ever-alcohol consumption was associated with a worsened survival in comparison with never drinkers. Larger studies are needed to investigate these findings, as these lifestyle habits may not only be linked to cancer risk but also cancer survival.

Impact on colorectal cancer pathology reporting practice of migration from TNM 5 to TNM 8.

AIMS: The introduction of TNM 8 into UK pathology practice in January 2018 considers tumour deposits in colorectal cancer staging for the first time. The impact of this new classification on pathology reporting practices has yet to be evaluated. METHODS AND RESULTS: A clinical audit was conducted, comparing consecutive colorectal cancer resection specimens reported under TNM 5 classification guidelines in 2017 (n = 177) and TNM 8 guidelines in 2018 (n = 234). Tumour features (venous invasion, perineural invasion, lymph node metastatic disease, tumour deposits) and changes in reporting practices were evaluated among four specialist gastrointestinal pathologists working within a large pathology department. Adoption of TNM 8 practice led to an approximate doubling in the use of ancillary stains (41.0% of TNM 8 versus 22.0% of TNM 5 cases, P < 0.001) to help evaluate tumours. A narrowing of the range between pathologists was observed in reporting cases as having one or more form of regional, extramural, discontinuous tumour (TNM 5 range = 50.0-79.0%, TNM 8 range = 57.8-65.7%), with no change in the overall proportion of cases reported as such (62.7% versus 62.4%, P = 0.95). However, significant interobserver variation in reporting rates for individual parameters remained. CONCLUSION: TNM 8 colorectal cancer staging offers potentially greater reproducibility in pathology reporting of regional, extramural, discontinuous disease with similar proportions of patients reported as having one or more of these forms of tumour spread compared with TNM 5. Further guidance in defining individual features is required to reduce interobserver variation in pathology assessments and to help elucidate the clinical significance of each parameter.

The association between recreational screen time and cancer risk: findings from the UK Biobank, a large prospective cohort study.

BACKGROUND: Evidence is suggestive of sedentary behaviour being associated with an increased risk of endometrial cancer, but the evidence base is too limited to draw any conclusions for other cancers. The aim of the study was to investigate the association between recreational screen time and site-specific cancer risk. METHODS: We analysed data from the prospective UK Biobank cohort study. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for associations between daily recreational screen time (including television (TV) viewing time, computer use time and total screen time) and site-specific cancer risk. Partition models and isotemporal substitution models investigated the impact of substituting recreational screen time with physical activity. RESULTS: During a mean follow-up of 7.6 years, 28,992 incident cancers were identified among 470,578 adults. A 1-h increase in daily TV viewing time was associated with higher risks of oropharyngeal, oesophago-gastric and colon cancer in fully adjusted models. Participants who reported ≤1, compared with 1- ≤ 3, hours/day of TV viewing time had lower risks of lung, breast, and oesophago-gastric cancer. Findings were inconsistent for daily recreational computer use and daily total recreational screen time. The majority of observed associations were small, and were attenuated after excluding cancers diagnosed within the first two years of follow-up, except for oesophago-gastric and colon cancers (HR 1.05, 95% CI: 1.01, 1.10; and HR 1.04, 95% CI: 1.01, 1.07 per 1-h increase in daily TV viewing time, respectively). However, isotemporal substitution models showed reduced risk of some site-specific (oropharyngeal, lung, breast and colorectal) cancers when replacing 1-h/day of TV viewing with 1-h of moderate-intensity physical activity or walking. CONCLUSIONS: Our findings show that daily recreational screen time, particularly TV viewing, was associated with small increased risks of oesophago-gastric and colon cancer. Replacing 1-h/day of TV viewing with 1-h of moderate-intensity physical activity or walking was associated with lower risk of oropharyngeal, lung, breast and colorectal cancers. Further research from other large prospective cohort studies is required, while mechanistic research is warranted to enhance the biological plausibility of these findings.