Search

Research on the association between dietary adherence and cancer risk is limited, particularly concerning overall cancer risk and its underlying mechanisms. Using the UK Biobank data, we prospectively investigate the associations between adherence to a Mediterranean diet (MedDiet) or a Mediterranean-Dietary Approaches to Stop Hypertension Diet Intervention for Neurodegenerative Delay diet (MINDDiet) and the risk of overall and 22 specific cancers, as well as the mediating effects of metabolites. Here we show significant negative associations of MedDiet and MINDDiet adherence with overall cancer risk. These associations remain robust across 14 and 13 specific cancers, respectively. Then, a sequential analysis, incorporating Cox regression, elastic net and gradient boost models, identify 10 metabolites associated with overall cancer risk. Mediation results indicate that these metabolites play a crucial role in the association between adherence to a MedDiet or a MINDDiet and cancer risk, independently and cumulatively. These findings deepen our understanding of the intricate connections between diet, metabolites, and cancer development. Research on the link between adherence to specific type of diets and cancer risk is scant, especially regarding overall cancer risk and the mediating mechanisms. Here, the authors use the UK Biobank data to show negative association of adherence to Mediterranean and Mediterranean-DASH Diet Intervention for Neurodegenerative Delay (MIND) diets with cancer risk and the metabolites mediating this association. [ABSTRACT FROM AUTHOR]

Gastrointestinal (GI) cancers account for a significant incidence and mortality rates of cancers globally. Utilization of a phenomic data approach allows researchers to reveal the mechanisms and molecular pathogenesis of these conditions. We aimed to investigate the association between the phenomic features and GI cancers in a large cohort study. We included 502,369 subjects aged 37–73 years in the UK Biobank recruited since 2006, followed until the date of the first cancer diagnosis, date of death, or the end of follow-up on December 31st, 2016, whichever occurred first. Socio-demographic factors, blood chemistry, anthropometric measurements and lifestyle factors of participants collected at baseline assessment were analysed. Unvariable and multivariable logistic regression were conducted to determine the significant risk factors for the outcomes of interest, based on the odds ratio (OR) and 95% confidence intervals (CI). The analysis included a total of 441,141 participants, of which 7952 (1.8%) were incident GI cancer cases and 433,189 were healthy controls. A marker, cystatin C was associated with total and each gastrointestinal cancer (adjusted OR 2.43; 95% CI 2.23–2.64). In this cohort, compared to Asians, the Whites appeared to have a higher risk of developing gastrointestinal cancers. Several other factors were associated with distinct GI cancers. Cystatin C and race appear to be important features in GI cancers, suggesting some overlap in the molecular pathogenesis of GI cancers. Given the small proportion of Asians within the UK Biobank, the association between race and GI cancers requires further confirmation. [ABSTRACT FROM AUTHOR]

Lung cancer is the second most common cancer in incidence and the leading cause of cancer deaths worldwide. Meanwhile, lung cancer screening with low-dose CT can reduce mortality. The UK National Screening Committee recommended targeted lung cancer screening on Sept 29, 2022, and asked for more modelling work to be done to help refine the recommendation. This study aims to develop and validate a risk prediction model—the CanPredict (lung) model—for lung cancer screening in the UK and compare the model performance against seven other risk prediction models. For this retrospective, population-based, cohort study, we used linked electronic health records from two English primary care databases: QResearch (Jan 1, 2005–March 31, 2020) and Clinical Practice Research Datalink (CPRD) Gold (Jan 1, 2004–Jan 1, 2015). The primary study outcome was an incident diagnosis of lung cancer. We used a Cox proportional-hazards model in the derivation cohort (12·99 million individuals aged 25–84 years from the QResearch database) to develop the CanPredict (lung) model in men and women. We used discrimination measures (Harrell's C statistic, D statistic, and the explained variation in time to diagnosis of lung cancer [R2 D ]) and calibration plots to evaluate model performance by sex and ethnicity, using data from QResearch (4·14 million people for internal validation) and CPRD (2·54 million for external validation). Seven models for predicting lung cancer risk (Liverpool Lung Project [LLP] v2 , LLP v3 , Lung Cancer Risk Assessment Tool [LCRAT], Prostate, Lung, Colorectal, and Ovarian [PLCO] M2012 , PLCO M2014 , Pittsburgh, and Bach) were selected to compare their model performance with the CanPredict (lung) model using two approaches: (1) in ever-smokers aged 55–74 years (the population recommended for lung cancer screening in the UK), and (2) in the populations for each model determined by that model's eligibility criteria. There were 73 380 incident lung cancer cases in the QResearch derivation cohort, 22 838 cases in the QResearch internal validation cohort, and 16 145 cases in the CPRD external validation cohort during follow-up. The predictors in the final model included sociodemographic characteristics (age, sex, ethnicity, Townsend score), lifestyle factors (BMI, smoking and alcohol status), comorbidities, family history of lung cancer, and personal history of other cancers. Some predictors were different between the models for women and men, but model performance was similar between sexes. The CanPredict (lung) model showed excellent discrimination and calibration in both internal and external validation of the full model, by sex and ethnicity. The model explained 65% of the variation in time to diagnosis of lung cancer R2 D in both sexes in the QResearch validation cohort and 59% of the R2 D in both sexes in the CPRD validation cohort. Harrell's C statistics were 0·90 in the QResearch (validation) cohort and 0·87 in the CPRD cohort, and the D statistics were 2·8 in the QResearch (validation) cohort and 2·4 in the CPRD cohort. Compared with seven other lung cancer prediction models, the CanPredict (lung) model had the best performance in discrimination, calibration, and net benefit across three prediction horizons (5, 6, and 10 years) in the two approaches. The CanPredict (lung) model also had higher sensitivity than the current UK recommended models (LLP v2 and PLCO M2012), as it identified more lung cancer cases than those models by screening the same amount of individuals at high risk. The CanPredict (lung) model was developed, and internally and externally validated, using data from 19·67 million people from two English primary care databases. Our model has potential utility for risk stratification of the UK primary care population and selection of individuals at high risk of lung cancer for targeted screening. If our model is recommended to be implemented in primary care, each individual's risk can be calculated using information in the primary care electronic health records, and people at high risk can be identified for the lung cancer screening programme. Innovate UK (UK Research and Innovation). For the Chinese translation of the abstract see Supplementary Materials section. [ABSTRACT FROM AUTHOR]

Integrating genomic data of multiple cancers allows de novo cancer grouping and elucidating the shared genetic basis across cancers. Here, we conduct the pan-cancer and cross-population genome-wide association study (GWAS) meta-analysis and replication studies on 13 cancers including 250,015 East Asians (Biobank Japan) and 377,441 Europeans (UK Biobank). We identify ten cancer risk variants including five pleiotropic associations (e.g., rs2076295 at DSP on 6p24 associated with lung cancer and rs2525548 at TRIM4 on 7q22 nominally associated with six cancers). Quantifying shared heritability among the cancers detects positive genetic correlations between breast and prostate cancer across populations. Common genetic components increase the statistical power, and the large-scale meta-analysis of 277,896 breast/prostate cancer cases and 901,858 controls identifies 91 newly genome-wide significant loci. Enrichment analysis of pathways and cell types reveals shared genetic backgrounds across said cancers. Focusing on genetically correlated cancers can contribute to enhancing our insights into carcinogenesis. Investigating genetically correlated cancers can enhance our understanding of carcinogenesis. Here, the authors perform Pan-cancer and cross-population GWAS meta-analysis to identify novel cancer risk loci and highlight shared heritability between breast and prostate cancer. [ABSTRACT FROM AUTHOR]

Background: It is well known that the occurrence and development of ovarian cancer are closely related to the patient's weight and various endocrine factors in the body. Aim: Mendelian randomization (MR) was used to analyze the bidirectional relationship between insulin related characteristics and ovarian cancer. Methods: The data on insulin related characteristics are from up to 5567 diabetes free patients from 10 studies, mainly including fasting insulin level, insulin secretion rate, peak insulin response, etc. For ovarian cancer, UK Biobank data just updated in 2021 was selected, of which the relevant gene data was from 199741 Europeans. Mendelian randomization method was selected, with inverse variance weighting (IVW) as the main estimation, while MR Pleiotropy, MR Egger, weighted median and other methods were used to detect the heterogeneity of data and whether there was multi validity affecting conclusions. Results: Among all insulin related indicators (fasting insulin level, insulin secretion rate, peak insulin response), the insulin secretion rate was selected to have a causal relationship with the occurrence of ovarian cancer (IVW, P < 0.05), that is, the risk of ovarian cancer increased with the decrease of insulin secretion rate. At the same time, we tested the heterogeneity and polymorphism of this indicator, and the results were non-existent, which ensured the accuracy of the analysis results. Reverse causal analysis showed that there was no causal effect between the two (P>0.05). Conclusion: The impairment of the insulin secretion rate has a causal effect on the risk of ovarian cancer, which was confirmed by Mendel randomization. This suggests that the human glucose metabolism cycle represented by insulin secretion plays an important role in the pathogenesis of ovarian cancer, which provides a new idea for preventing the release of ovarian cancer. [ABSTRACT FROM AUTHOR]

The optimal management of stage III non-small cell lung cancer (NSCLC) is widely debated and is a rapidly evolving area. However, less than one in five stage III patients in England receive optimal multimodality treatment. The aim of this study was to map commonalities and differences in clinician judgement as well as infrastructure and resources for managing stage III NSCLC. We carried out a national survey of practice in stage III NSCLC management in the UK using a 30-min web-based survey. Invitations were sent via e-mail to the British Thoracic Oncology Group and the Society of Cardiothoracic Surgery membership and a healthcare professional market research panel. In total, 160 respondents completed the survey. Although opinion was variable, there was a preference for surgery and adjuvant chemotherapy in stage III N2 (single station) NSCLC that could be treated with lobectomy, but this preference switched to chemoradiotherapy in single-station N2 requiring a pneumonectomy or multi-station N2. The PD-L1 status influenced the treatment decision in 'potentially resectable' N2 for a number of clinicians who opted for concurrent chemoradiotherapy with adjuvant durvalumab when PD-L1 ≥ 1%. A joint clinic with surgeons and oncologists was considered the most important factor for shared decision making with patients. There are barriers to recommending trimodality treatment, e.g. concerns over the negative impact on quality of life. A proportion of clinicians favoured palliative treatment in certain clinical scenarios, including supraclavicular fossa lymph node metastases, patients with borderline fitness or high PD-L1 expressors >50%. This survey has highlighted the need for infrastructure development, such as reflex PD-L1 testing and joint surgical and oncology clinics. Further research into the impact of multimodality treatment on quality of life and education to improve confidence in multimodality treatment could all drive improvements in stage III NSCLC management. • There is variability in both opinion and practice in potentially resectable stage III NSCLC but factors such as pattern of lymph node involvement, extent of potential resection, PD-L1 status and patient fitness influence decision making. • A consensus four-point definition of potentially resectable stage III N2 NSCLC has been validated with widespread agreement. • UK clinicians feel a critical factor for best outcomes in potentially resectable stage III N2 is joint thoracic surgery and oncology clinics, which should be a priority for implementation across the UK. • There are barriers to recommending trimodality treatment in potentially resectable stage III N2, e.g. concerns over the negative impact on quality of life. • A proportion of clinicians favour palliative treatment in certain clinical scenarios in unresectable stage III NSCLC. An education programme to expand the confidence in recommending curative-intent treatment in such scenarios may help to improve outcomes. [ABSTRACT FROM AUTHOR]

With its identification as a proto-oncogene in chronic lymphocytic leukaemia and central role in regulating NF-κB signalling, it is perhaps not surprising that there have been an increasing number of studies in recent years investigating the role of BCL-3 (B-Cell Chronic Lymphocytic Leukaemia/Lymphoma-3) in a wide range of human cancers. Importantly, this work has begun to shed light on our mechanistic understanding of the function of BCL-3 in tumour promotion and progression. Here, we summarize the current understanding of BCL-3 function in relation to the characteristics or traits associated with tumourigenesis, termed 'Hallmarks of Cancer'. With the focus on colorectal cancer, a major cause of cancer related mortality in the UK, we describe the evidence that potentially explains why increased BCL-3 expression is associated with poor prognosis in colorectal cancer. As well as promoting tumour cell proliferation, survival, invasion and metastasis, a key emerging function of this proto-oncogene is the regulation of the tumour response to inflammation. We suggest that BCL-3 represents an exciting new route for targeting the Hallmarks of Cancer; in particular by limiting the impact of the enabling hallmarks of tumour promoting inflammation and cell plasticity. As BCL-3 has been reported to promote the stem-like potential of cancer cells, we suggest that targeting BCL-3 could increase the tumour response to conventional treatment, reduce the chance of relapse and hence improve the prognosis for cancer patients. [ABSTRACT FROM AUTHOR]

Background: Minimal residual disease (MRD) is defined as the presence of sub-microscopic levels of leukaemia. Measurement of MRD from bone marrow at the end of induction chemotherapy (day 28) for childhood acute lymphoblastic leukaemia (ALL) can highlight a large group of patients (>40%) with an excellent (>90%) short-term event-free survival (EFS). However, follow-up in recent published trials is relatively short, raising concerns about using this result to infer the safety of further therapy reduction in the future.Methods: We examined MRD data on 225 patients treated on one of three UKALL trials between 1997 and 2003 to assess the long-term (>10 years follow-up) outcome of those patients who had low-risk MRD (<0.01%) at day 28.Results: Our pilot data define a cohort of 53% of children with MRD <0.01% at day 28 who have an EFS of 91% and long-term overall survival of 97%. Of 120 patients with day-28 MRD <0.01% and extended follow-up, there was one death due to treatment-related toxicity, one infectious death while in complete remission, and four relapse deaths.Conclusions: The excellent outcome for childhood ALL in patients with MRD <0.01% after induction chemotherapy is sustained for more than 10 years from diagnosis. This supports the potential exploration of further reduction of therapy in this group, in an attempt to reduce treatment-related mortality and late effects. [ABSTRACT FROM AUTHOR]

Abstract: Colorectal cancer (CRC) is the third most common cancer in the UK, with over 37,500 people being diagnosed every year. Survival rates for CRC have doubled in the last 30 years and it is now curable if diagnosed early, but still over half of all sufferers do not survive for longer than 5 years after diagnosis. The major complication to treating this disease is that of metastasis, specifically to the liver, which is associated with a 5 year survival of less than 5%. These statistics highlight the importance of the development of earlier detection techniques and more targeted therapeutics. The future of treating this disease therefore lies in increasing understanding of the mutations which cause tumourigenesis, and insight into the development and progression of this complex disease. This can only be achieved through the use of functional models which recapitulate all aspects of the human disease. There is a wide range of models of CRC available to researchers, but all have their own strengths and weaknesses. Here we review how CRC can be modelled and discuss the future of modelling this complex disease, with a particular focus on how genetically engineered mouse models have revolutionised this area of research. [Copyright &y& Elsevier]

Intratumour heterogeneity (ITH) and tumour evolution are well-documented phenomena in human cancers. While the advent of next-generation sequencing technologies has facilitated the large-scale capture of genomic data, the field of single-cell genomics is nascent but rapidly advancing and generating many new insights into the complex molecular mechanisms of tumour biology. In this review, we provide an overview of current single-cell DNA sequencing technologies, exploring how recent methodological advancements have enumerated new insights into ITH and tumour evolution. Areas highlighted include the potential power of single-cell genome sequencing studies to explore evolutionary dynamics contributing to tumourigenesis through to progression, metastasis, and therapy resistance. We also explore the use of in situ sequencing technologies to study ITH in a spatial context, as well as examining the use of single-cell genomics to perform lineage tracing in both normal and malignant tissues. Finally, we consider the use of multimodal single-cell sequencing technologies. Taken together, it is hoped that these many facets of single-cell genome sequencing will improve our understanding of tumourigenesis, progression, and lethality in cancer, leading to the development of novel therapies. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland., (© 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.)

Abstract: In the UK, four in ten people will develop some form of cancer during their lifetime, with an individual''s relative risk depending on many factors, including age, lifestyle and genetic make-up. Much research has gone into identifying the genes that are mutated in tumorigenesis with the over-whelming majority of genetically-modified (GM) mice in cancer research showing accelerated tumorigenesis or recapitulating key aspects of the tumorigenic process. Yet if six out of ten people will not develop some form of cancer during their lifetime, together with the fact that some cancer patients experience spontaneous regression/remission, it suggests there are ways of ‘resisting’ cancer. Indeed, there are wildtype, spontaneously-arising mutants and GM mice that show some form of ‘resistance’ to cancer. Identification of mice with increased resistance to cancer is a novel aspect of cancer research that is important in terms of providing both chemopreventative and therapeutic options. In this review we describe the different mouse lines that display a ‘cancer resistance’ phenotype and discuss the molecular basis of their resistance. [Copyright &y& Elsevier]

Objectives: The Trp620 allotype of PTPN22 confers susceptibility to rheumatoid arthritis (RA) and certain other classical autoimmune diseases. There has been a report of other variants within the PTPN22 locus that alter risk of RA; protective haplotype '5', haplotype group '6-10' and susceptibility haplotype '4', suggesting the possibility of other PTPN22 variants involved in the pathogenesis of RA independent of R620W (rs2476601). Our aim was to further investigate this possibility. Methods: A total of 4,460 RA cases and 4,481 controls, all European, were analysed. Single nucleotide polymorphisms rs3789607, rs12144309, rs3811021 and rs12566340 were genotyped over New Zealand (NZ) and UK samples. Publicallyavailable Wellcome Trust Case Control Consortium (WTCCC) genotype data were used. Results: The protective effect of haplotype 5 was confirmed (rs3789607; (OR = 0.91, P = 0.016), and a second protective effect (possibly of haplotype 6) was observed (rs12144309; OR = 0.90, P = 0.021). The previously reported susceptibility effect of haplotype 4 was not replicated; instead a protective effect was observed (rs3811021; OR = 0.85, P = 1.4×10-5). Haplotypes defined by rs3789607, rs12144309 and rs3811021 coalesced with the major allele of rs12566340 within the adjacent BFK (Bcell lymphoma 2 (BCL2) family kin) gene. We, therefore, tested rs12566340 for association with RA conditional on rs2476601; there was no evidence for an independent effect at rs12566340 (P = 0.76). Similarly, there was no evidence for an independent effect at rs12566340 in type 1 diabetes (P = 0.85). Conclusions: We have no evidence for a common variant additional to rs2476601 within the PTPN22 locus that influences the risk of RA. Arg620Trp is almost certainly the single common causal variant. [ABSTRACT FROM AUTHOR]

OBJECTIVES:Azathioprine is an accepted treatment of inflammatory bowel disease (IBD), but concerns exist regarding its carcinogenic potential. Studies in renal transplant and rheumatology patients have reported an increased cancer risk. In IBD, studies suggest a small increased risk of lymphoma and protection against colorectal cancer, but the overall risk of malignancy has not been established.METHODS:We conducted a nested case–control study using the General Practice Research Database. Records of IBD patients were examined for azathioprine prescriptions and cancers. Prescriptions per year of follow-up were grouped for analysis. Azathioprine use was compared between IBD cases (with a diagnosed cancer) and IBD controls (without).RESULTS:Overall, 15,471 patients with IBD and over 1 year of appropriate data were identified. Among these, 392 developed cancer, of whom 10.5% received at least one prescription for azathioprine, compared with 1,914 (12.7%) of the controls. Analyzing the occurrence of any cancer against azathioprine prescription showed a nonsignificant protective effect (odds ratio (OR)=0.92, 95% confidence interval (CI)=0.79–1.06). Correction for the effects of age and smoking removed this effect (OR=1.04, 95% CI=0.89–1.21). Diagnosis of lymphoma was associated with ever use of azathioprine with OR of 3.22, CI=1.01–10.18.CONCLUSIONS:We found evidence of an increased risk of lymphoma, which is consistent with previous studies. We found no overall increase in risk of cancer in individuals with IBD who had taken azathioprine. Our study does not show a need for azathioprine cessation in the medium term in IBD because of the risk of malignancy. [ABSTRACT FROM AUTHOR]

Background: Basic and clinical research support the hypothesis that activation of the coagulation and inflammation pathways may affect cancer onset, but there is limited epidemiological data to support this.Methods: We examined a large range of haemostatic and inflammation markers, including fibrinogen, in 19 303 male participants from three English cohorts followed for up to 30 years. After excluding the first 3 years of follow-up, 2908 incident cancers were accrued. Competing risk models were fitted to estimate rate ratios (RRs) for cancer incidence, adjusting for age and other confounders.Results: Baseline white blood cell (WBC) count and circulating levels of fibrinogen, C-reactive protein (CRP), factor VII antigen (VIIa) and prothrombin fragment F1.2 were positively associated with risk of smoking-related cancers, particularly lung cancer. The magnitude of these associations was highest for persistently raised fibrinogen levels. There was, however, substantial confounding by smoking with risk being fully (WBC, CRP and VIIa) or partially (fibrinogen) removed after adjustment. The pooled RRs (95% confidence interval) per one standard deviation increase in fibrinogen levels before and after adjustment for smoking habits were 1.23 (1.12, 1.36) and 1.12 (1.05, 1.20), respectively. The fibrinogen associations were present only among current smokers at entry. The effect of smoking on smoking-related cancers was partly mediated by fibrinogen levels.Conclusions: Our results are consistent with elevated circulating levels of fibrinogen and F1.2 being predictors of risk of smoking-related cancers. Further research is necessary to clarify whether elevated levels of fibrinogen and F1.2 are causally relevant or simply correlates of the smoking-cancer association. [ABSTRACT FROM AUTHOR]

Abstract: Aim: The aim of this paper was to compare demographics, treatment and outcomes from two large prospective audits of head and neck cancer patients in two disparate regions of the UK. Methods: In the Scottish Audit of Head and Neck Cancer (SAHNC) a total of 1910 patients with new head and neck cancers were registered in a two year period from September 1999 to August 2001. The South and West Audit of Head and Neck Cancer (SWAHN) was carried out in three phases between 1996 and 2002 with a total of 2050 cases. Results: There were more men in SAHNC than SWAHN (71% vs 67%, p <0.01) and patients in SAHNC presented at a younger age (76% aged 45–74 compared with 64%, p <0.001). Significantly more patients in Scotland had advanced (stage III/IV) laryngeal cancer (44% vs 30%, p <0.001). The overall disease specific five year survival was 54.5 for SAHNC and 54.2 for SWAHN. Conclusion: This comparison of large head and neck cancer cohorts provides important data to base UK head and neck cancer care and hypotheses regarding pathogenesis and the effects of treatment processes. Given the heterogeneity in disease, patient and healthcare characteristics between the two regions, the similarities in survival and process outcomes are striking. [Copyright &y& Elsevier]

Low-moderate risk alleles that are relatively common in the population may explain a significant proportion of the excess familial risk of ovarian cancer (OC) not attributed to highly penetrant genes. In this study, we evaluated the risks of OC associated with common germline variants in five oncogenes (BRAF, ERBB2, KRAS, NMI and PIK3CA) known to be involved in OC development. Thirty-four tagging SNPs in these genes were genotyped in approximately 1800 invasive OC cases and 3000 controls from population-based studies in Denmark, the United Kingdom and the United States. We found no evidence of disease association for SNPs in BRAF, KRAS, ERBB2 and PIK3CA when OC was considered as a single disease phenotype; but after stratification by histological subtype, we found borderline evidence of association for SNPs in KRAS and BRAF with mucinous OC and in ERBB2 and PIK3CA with endometrioid OC. For NMI, we identified a SNP (rs11683487) that was associated with a decreased risk of OC (unadjusted P(dominant)=0.004). We then genotyped rs11683487 in another 1097 cases and 1792 controls from an additional three case-control studies from the United States. The combined odds ratio was 0.89 (95% confidence interval (CI): 0.80-0.99) and remained statistically significant (P(dominant)=0.032). We also identified two haplotypes in ERBB2 associated with an increased OC risk (P(global)=0.034) and a haplotype in BRAF that had a protective effect (P(global)=0.005). In conclusion, these data provide borderline evidence of association for common allelic variation in the NMI with risk of epithelial OC. [ABSTRACT FROM AUTHOR]

The significance of heritable thrombophilia in pregnancy failure is controversial. We surveyed all UK Early Pregnancy Units and 70% responded. The majority test routinely for heritable thrombophilias; 80%, 76% and 88% undertook at least one screening test in late miscarriage, recurrent miscarriage and placental abruption, respectively. The range of thrombophilias sought is inconsistent: testing for proteins C and S deficiency and F5 R506Q (factor V Leiden) is most prevalent. Detection of heritable thrombophilia frequently leads to administration of antithrombotics in subsequent pregnancies. Thus, thrombophilia testing and use of antithrombotics are widespread in the UK despite controversies regarding the role of heritable thrombophilia in the pathogenesis of pregnancy complications, and the lack of robust evidence for the efficacy of antithrombotic therapy. [ABSTRACT FROM AUTHOR]

Background: It has been hypothesised that cerebral palsy (CP) and other congenital anomalies are attributable to feto-fetal transfusion problems in a monochorionic multiple gestation. Thus more than one organ could be compromised leading to the coexistence of two or more anomalies in a fetus. Such anomalies in a singleton birth may be attributable to early demise of the co-conceptus as a vanishing twin. Aim: To determine whether the coexistence of congenital anomalies and CP is greater than a chance finding by comparing the prevalence of congenital anomalies in children with CP with that in the general population of children. Methods: A population-based register of children with CP born in 1966-1991 in the counties of Merseyside and Cheshire, UK, comprised the index population. Coexisting congenital anomalies were recorded. For comparison the population prevalence of congenital anomalies was obtained from eight congenital malformation registers in the UK. Results: Children with CP were found to have highly significant increases in risk for microcephaly, isolated hydrocephaly, congenital anomalies of the eye, congenital cardiac anomalies, cleft lip and/or palate and congenital dislocation of the hips and talipes (p<0.001) and atresias of the oesophagus (p<0.001) and intestines (p<0.01). The relative risks ranged from 3.1 (95% Cl 1.9 to 4.8; p<0.001) for congenital malformations of the cardiac septa to 116.09 (95% Cl 84.0 to 162.3; p<0.001) for microcephaly. Conclusions: Congenital anomalies in children with CP are found much more frequently than expected by chance. A common pathogenic mechanism may account for the coexistence of disparate congenital anomalies. A hypothesis is proposed for such a common pathogenic mechanism. [ABSTRACT FROM AUTHOR]

Purpose . The purpose of this review is to inform both scientists and clinicians about the increase in cancer incidence throughout the Western World and to discuss environmental influences in cancer aetiology, in order to stimulate thoughts about plausible aetiological mechanisms and possible preventative measures. Design . Literature review. Materials and methods . This review was conducted by searching biomedical databases such as PubMed and Medline. Further research to obtain cancer incidence data involved accessing UK cancer registries, major cancer charities and government statistical records from the Office of National Statistics, the Department of Health, and the Department of Environment, Food and Rural Affairs. Results . Cancer incidence rates have increased in the Western World and this increased incidence affects the whole age spectrum. Epidemiological studies have provided some evidence of an association between exposure to environmental contaminants such as organochlorines and increased cancer risk. However, many epidemiological studies have been inconclusive. Similar reviews concerning environmental influences in cancer aetiology concluded that exposures to carcinogenic or endocrine‐disrupting chemicals exist at concentrations too low or have carcinogenic potential too weak to be considered a major factor in cancer aetiology. However, animal and in vitro studies together with epidemiological evidence discussed in this review would dispute that claim; even if healthy adults are not at risk, it would seem that the developing foetus, infant, child and young adults are at risk. In addition, studies discussed in this review show that low oestrogenic potency cannot be used as a marker of the capability of a chemical to cause oestrogenic responses and endocrine disruption. Genetic polymorphisms, which can predispose people to cancer, may interact with environmental contaminants such as organochlorines and endocrine disrupters, thus providing a modifying effect. Prevention measures have hitherto predominately centred on tobacco smoking cessation and diet education. Anecdotal evidence from practising physicians in pre‐industrial and traditional living societies, i.e. Canadian Inuits and Brazilian Indians suggests malignant disease was rare. A relatively new theory other than the somatic mutation theory has been proposed, the main premise being that carcinogenesis is a problem of tissue organization, comparable with organogenesis. Conclusions . It is feasible that chemical environmental contaminants, in particular synthetic pesticides and organochlorines with endocrine‐disrupting properties, could be major factors in cancer aetiology, particularly for hormone‐dependent malignancies, such as breast, testicular and prostate cancers. Animal and in vitro studies provide good evidence of a feasible mechanism whereby environmentally relevant levels of organochlorines and substances of low oestrogenic potency can cause endocrine disruption and consequently malignant disease. In addition, low oestrogenic potency should not be used as a marker of the capability of a chemical to cause oestrogenic responses and endocrine disruption. Preventative measures other than education about tobacco, diet and the promotion of physical activity should be considered. Moreover, it seems to be the most vulnerable members of society: the developing foetus, the developing child and adolescent and the genetically predisposed, who are at risk of developing cancer following involuntary exposure to environmental contaminants. This may be an appropriate time for governments to adopt the precautionary principle until substances to which members of society are involuntarily exposed are proved safe from long‐term, low‐level effects on human health. The World Health Organization estimates that between 1 and 5% of malignant disease in developed countries is attributable to environmental factors: it is possible that this figure may be underestimated. Anecdotal evidence suggests that cancer may be a disease of industrialization. Further research into the tissue organization field theory may be warranted, as some forms of pre‐malignant states are attributed to dysorganogenesis, for example an undescended testis. [ABSTRACT FROM AUTHOR]

Background: Human papillomavirus (HPV) is an evolving important risk factor for head and neck cancer (HNC), especially for individuals who do not smoke and drink alcohol. The aim of this study was to establish the prevalence of HPV infection and elucidate its association with head and neck squamous cell carcinoma (HNSCC) patients in UK population., Methods: The presence and association of HPV was investigated in HNSCC patients in this retrospective clinical study. Samples were obtained from archived biopsies and resections. HPV screening was performed by the use of polymerase chain reaction (PCR) using the GP5 + /GP6 + and the SPF1/2 consensus as primers and by immunohistochemistry (IHC). Samples of viral warts that were IHC positive for HPV and fibroepethelial polyps (FEP) were used, as positive and negative controls, respectively., Results: The cohort included 124 patients with HNSCC with an age range of 27-97 years (median, 60 years) and a male to female ratio of 2:1. Among the 124 HNSCC, 43/124 (34.7%) were from the tongue, 74/124 (60%) presented with advanced stage III or IV disease, 112/124 (90%) had a conventional phenotype, 84/124 (68%) were moderately differentiated, and 89/124 (72%) had bands or cords at the invasive front. Of the 124 patients with HNSCC, 84/124 (68%) demonstrated the presence of HPV, 0/124 (0%) was for oral squamous cell carcinomas (OSCC). HPV16 was the associated virus type in all positive samples. However, no significant association was observed between HPV positivity and other clinico-pathological variables including age and gender of the patients, stage, and malignancy differentiation., Conclusion: The results we provide suggest that HPV infection is low in HNSCC, in general, and absent in OSCC, specifically, in this UK population during this time period. This implies that HPV infection may not play an important role in HNSCC carcinogenesis compared to other risk factors in UK population. This information can aid in more effective treatment approaches for treating UK cases of HNSCC., Competing Interests: None

Discusses several diseases with reference to cutaneous lymphoma in Great Britain. Description of a form of mycosis fungoides presenting as tumors without any evidence of preceding skin disorder; Analysis of the fundamental nature of the various forms of cutaneous lymphoma; Concept of lymphomas as tumors of the immune system and the involvement of B and T lymphocytes in the pathogenesis of skin cancer.

Exposure to sex hormones is important in the pathogenesis of breast cancer and inability to tolerate such exposure may be reflected in increased asymmetrical growth of the breasts. This study aims to characterize, for the first time, asymmetry in breast volume (BV) and radiodense volume (DV) in a large ethnically diverse population. Automated measurements from digital raw mammographic images of 54,591 cancer-free participants (aged 47–73) in a UK breast screening programme were used to calculate absolute (cm3) and relative asymmetry in BV and DV. Logistic regression models were fitted to assess asymmetry associations with age and ethnicity. BV and DV absolute asymmetry were positively correlated with the corresponding volumetric dimension (BV or DV). BV absolute asymmetry increased, whilst DV absolute asymmetry decreased, with increasing age (P-for-linear-trend <0.001 for both). Relative to Whites, Blacks had statistically significantly higher, and Chinese lower, BV and DV absolute asymmetries. However, after adjustment for the corresponding underlying volumetric dimension the age and ethnic differences were greatly attenuated. Median relative (fluctuating) BV and DV asymmetry were 2.34 and 3.28% respectively. After adjusting for the relevant volumetric dimension (BV or DV), age and ethnic differences in absolute breast asymmetry were largely resolved. Previous small studies have reported breast asymmetry—breast cancer associations. Automated measurements of asymmetry allow the conduct of large-scale studies to further investigate these associations. [ABSTRACT FROM AUTHOR]

Comments on the oncogenesis and tumor progression of papillary carcinoma of the thyroid gland in Great Britain. Role of cyclooxygenase-2 (CO-2) in carcinogenesis for its elevated expression in various human tumor; Determination of the correlation between CO-2 and tumor type with consideration to age; Assessment of molecular expression in the malignant tumor's benign counterpart.

CBP and p300 are highly homologous lysine acetyltransferases involved in cell cycle regulation, DNA synthesis and DNA repair. Loss of function mutations of CBP and p300 are found in about one-third of cutaneous squamous cell carcinoma (cSCC) and often co-occur, yet their role in cSCC pathogenesis is unclear. Writing in The Journal of Pathology, Ichise and colleagues modeled combined heterozygous loss of Cbp/p300 in mouse keratinocytes expressing a transgenic Hras S35 allele that allows selective coupling of Hras to the Erk pathway. Epidermal thickening caused by expression of Hras S35 was exacerbated by reduced dosage of Cbp/p300 and eventually resulted in development of skin papillomas. This phenotype was associated with reduced expression of Mig6, an Egfr feedback inhibitor, and attendant enhancement of Egfr signaling to the Ras-Erk pathway. This model provides a mechanistic framework for understanding how Cbp/p300 loss of function mutations impact on skin tumorigenesis and suggests potential therapeutic options in CBP/p300 mutated human cSCC. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd., (© 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.)

Lung cancer is the leading cause of cancer mortality worldwide, with adenocarcinomas of the non-small cell lung carcinoma (NSCLC) subtype accounting for the majority of cases. Therefore, an urgent need exists for a more detailed dissection of the molecular events driving NSCLC development and the identification of clinically relevant biomarkers. Even though originally identified as a tumour suppressor, recent studies associate the cytoplasmically (mis)localised CDK inhibitor p27 Kip1 (p27) with unfavourable responses to chemotherapy and poor outcomes in NSCLC, supporting the hypothesis that the protein can execute oncogenic activities. In a recent issue of The Journal of Pathology, Calvayrac and coworkers uncover a novel molecular mechanism that can explain this oncogenic role of p27. They demonstrate that cytoplasmic p27 binds and inhibits the small GTPase RhoB and thereby relieves a selection pressure for RhoB loss that is frequently observed in NSCLC. This is supported not only by studies with genetically modified mice, but also through identification of a cohort of human lung cancer patients with cytoplasmic p27 and continued RhoB expression, where this signature correlates with decreased survival. This not only establishes a potentially useful biomarker, but also provides yet another facet of the complex roles p27 undertakes in tumourigenesis. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland., (© 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.)

Obesity and acute pancreatitis are both proinflammatory conditions. Importantly, obesity increases severity in acute pancreatitis by enhancing inflammation. In a recent issue of The Journal of Pathology, Pérez and Ruiz-Pérez et al connected obesity and pancreatitis for the first time, through the transcriptional regulator PPARγ coactivator 1α (PGC-1α). Obesity reduces pancreatic PGC-1α levels and potentiates not only oxidative but also IL-6-mediated inflammatory damage during acute pancreatitis by relieving the binding of PGC-1α to the NF-κB subunit p65. Blockade of the IL-6 receptor subunit gp130 ameliorated tissue injury, substantiating the importance of deregulated PGC-1α/p65/IL-6 signaling in obesity and acute pancreatitis. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd., (Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.)

In immunocompromised patients, reactivation of latent BK polyomavirus (BKPyV) can cause disease with lytic infections of the kidneys and the lower urinary tract. Emerging evidence also links BKPyV to oncogenesis and high-grade intrarenal and transitional cell carcinomas. These neoplasms strongly express polyomavirus large-T antigen as a defining feature; that is, they are 'large-T-positive carcinomas'. Such neoplasms arise in immunocompromised patients, typically in renal allograft recipients, and preferentially in tissues harbouring latent BKPyV. In recent articles in this journal, it was shown that tumour cells harbour replication-incompetent clonal BKPyV. The virus can be truncated and randomly integrated into the genome, and/or it can be mutated in an episomal state. Truncation and/or deletions in the BKPyV non-coding control region can hamper late viral gene expression, replication, and cell lysis, while facilitating overexpression of early genes, including that encoding large-T. Biologically active fusion proteins or alterations in human tumour suppressor or promoter function have not been described so far, making uncontrolled large-T gene expression in non-lytically infected cells a prime suspect for neoplastic transformation. Current concepts of BKPyV-induced disease, including recent reports from this journal, are discussed, and evolving paradigms of BKPyV-associated oncogenesis are highlighted. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland., (© 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.)

Recent next-generation sequencing studies demonstrate that multiple pathways are often deregulated in advanced and metastatic prostate cancer (PC). In a recent issue of The Journal of Pathology, an elegant study by Jefferies et al used in vivo modelling to demonstrate how activation of the PI3K, WNT, and MAPK pathway converges on mTORC1 signalling to drive aggressive disease. The study also highlights that approaches to target advanced PC require intelligent combination of agents to target single/multiple signalling pathways in combination with androgen receptor (AR) blockade. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd., (Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.)

The pathogenesis of oro-oesophaeal squamous cell carcinoma is causally linked to the consumption of alcohol. Beyond the carcinogenic effects of ethanol and its metabolites via DNA damage, the precise mechanisms by which alcohol drives tumourigenesis remain to be fully elucidated. A novel contributor now revealed is aberrant differentiation and proliferation mediated by suppression of PAX9, a key regulator of normal squamous maturation in oro-oesophageal tissues. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd., (Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.)

Identifies the effects of an deoxycholic acid and pouvoir hydrogene (pH) on NF-κB activation in oesophageal cells in a study in Great Britain. Physiological doses cultured to oesophageal cells; Findings revealed by polymerase chain reaction and cDNA membrane arrays; Role NF-κB in carcinogenesis.

Examines the aetiology of familial colorectal cancer in Great Britain. Correlation between familial adenomatous polyposis and colorectal cancer; Relationship between polymorphic DNA marker and tumor development; Characteristics of tumorigenesis.

This is the first full year of web based electronic submissions of the journal "Gut" and, as expected, one has seen a substantial rise in manuscript submissions. The journal's manuscripts come from all over the world. The most significant contributors being, in order of manuscript numbers, Great Britain, Japan, Germany, France, the U.S., Italy, the Netherlands, Canada, and China. Choosing highlights of the year is inevitably a difficult matter. The editor's choice has included articles on the mechanisms of oncogenesis in Barrett's oesophagus, adenovirus delivery of interleukin 10 as treatment for colitis, and evidence of prolonged immune activation in post-infective irritable bowel syndrome.