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Abstract Lower than normal levels of oxygen (hypoxia) is a hallmark of all solid tumours rendering them frequently resistant to both radiotherapy and chemotherapy regimes. Furthermore, tumour hypoxia and activation of the hypoxia inducible factor (HIF) transcriptional pathway is associated with poorer prognosis. Driven by both genetic and epigenetic changes, cancer cells do not only survive but thrive in hypoxic conditions. Detailed knowledge of these changes and their functional consequences is of great clinical utility and is already helping to determine phenotypic plasticity, histological tumour grading and overall prognosis and survival stratification in several cancer types. As epigenetic changes - contrary to genetic changes - are potentially reversible, they may prove to be potent therapeutic targets to add to the cancer physicians' armorarium in the future. Here, we review the therapeutic potential of epigenetic modifications (including DNA methylation, histone modifications and miRNAs) occurring in hypoxia with particular reference to cancer and tumourigenesis.

Polyposis associated with mutations in the gene MUTYH is an autosomal recessive syndrome characterised by the development of multiple colorectal adenomas and cancer. It is the first cancer-predisposition disorder to be associated with defects in the pathway of base-excision repair. We review our knowledge to date of the disease, discuss base-excision repair in relation to cellular defence against oxidative damage, and give an overview of the molecular genetics and clinicopathological features of tumours associated with MUTYH mutations. No longer a research finding, genetic testing for MUTYH is now a necessary part of molecular diagnosis in familial cancer clinics throughout Australia and the UK. Current recommendations for the screening and management of the disease are also discussed. [ABSTRACT FROM AUTHOR]

Introduction: Several guidelines have given recommendations for optimal use of biomarkers and molecular imaging. However, those guidelines' implementation may not be always possible due to local policies or lack of access to several diagnostic studies. Aim(s): To identify which biomarkers and molecular imaging are used in daily practice. Materials and methods: Seventy-two NET centers (68%: European) completed a web-based survey, based on 14 questions, regarding: a) local availability of biomarkers and molecular imaging studies; b) choice of the appropriate diagnostic modalities for different types of NET; and c) follow-up intervals. Results: Common biomarkers, as well as OctreoScan and 16F-FGD-PET scan, are available to the majority. Only 18% have access to DOPA or 68Ga PETs. Ten percent and 9% would never perform or perform OctreoScan only in selected patients, respectively, at diagnosis. Nine percent would perform routinely FGD-PET at diagnosis. Almost all are using Chromogranin-A for all NET and 45% are using NSE for midgut and hindgut NET. Thirty-eight percent and 55% are using urine 5-HIAA levels, in pancreatic and hindgut NET, respectively. The majority would perform functional imaging routinely during follow-up. Follow-up intervals depend on tumor histology, according to the majority. Conclusion: The availability of new molecular imaging studies is still limited. Some biomarkers and molecular imaging studies are used sub-optimally. Most centers are following ENETS Guidelines with regards to follow-up intervals. [ABSTRACT FROM AUTHOR]

Abstract BMC Research Notes recently published a research article regarding the use of ligated DNA extracted from formalin-fixed paraffin embedded (FFPE) tissue on the Illumina Infinium methylation platform - “Interpretation of genome-wide infinium methylation data from ligated DNA in formalin-fixed, paraffin-embedded paired tumor and normal tissue” Jasmine et al. BMC Research Notes 2012, 5:117. This article repeatedly refers to our previous work and concludes that methylation data obtained from ligated FFPE extracted DNA should be used with great caution. In this Discussion we review the data analysis performed in Jasmine et al’s paper and suggest limitations which subsequently lead the authors to draw what we believe are incorrect conclusions. Moreover, we continue to analyse genome-wide methylation data from DNA extracted from FFPE tissue successfully on both the HumMeth27 and 450 K arrays.

Introduction: Recently, the first cancer methylomes have been created which identified differential methylation at CpG islandshores (2kb upstream of CpG islands) to be of particular importance in the tumourigenic process. Aim(s): To produce the first methylome in NETs using second generation sequencing -- enabling coverage of >20 million CpGs located throughout the genome in coding and non-coding regions. Materials and methods: Nine fresh frozen sporadic pancreatic NET liver metastases (three low, intermediate and high grade) and two normal pancreatic paraffin-embedded tissue samples underwent whole-genome CpG methylation-specific immunoprecipitation followed by sequencing on the Illumina GAIIx sequencer (MeDIP-seq). MeDIP-seq data were processed using our novel analysis pipeline MEDUSA (Methylated DNA Utility for Sequence Analysis). Results: Between 21 and 50 million QC approved unique reads were mapped per sample. Using a FDR of 0.01 (1%), DMRs were identified between normal pancreatic tissue and low (3546), intermediate (17542) and high (11219) grade pancreatic NETs and also between low and intermediate (5021), low and high (5292) and intermediate and high (6815) grade pancreatic NETs. Conclusion: This is the first MeDIP-seq analysis to be performed in NETs. Increasing global hypomethylation was observed between low to high grades of tumor. Gene ontology analysis identified pathways occurring in malignant glioma and nervous system cancer to be implicated in the development of intermediate and high grade tumors. [ABSTRACT FROM AUTHOR]

The article presents an abstract of the article "A Prognostic Index for Systemic AIDS-Related Non-Hodgkin Lymphoma Treated in the Era of Highly Active Antiretroviral Therapy," published in the August 16, 2005 issue of the journal "Annals of Internal Medicine," vol. 143. In response to the question related to the problem, the author replied that Human immunodeficiency virus (HIV) is the cause of AIDS, an illness that interferes with the ability to fight off infection and certain types of cancer. The International Prognostic Index is an index that helps doctors to predict survival of people with lymphoma. 111 patients with HIV infection and lymphoma diagnosed since 1996.

Colorectal cancer (CRC) is a leading cause of cancer mortality worldwide. Accurate cancer risk assessment approaches could increase rates of early CRC diagnosis, improve health outcomes for patients and reduce pressure on diagnostic services. The faecal immunochemical test (FIT) for blood in stool is widely used in primary care to identify symptomatic patients with likely CRC. However, there is a 6-16% noncompliance rate with FIT in clinic and ~90% of patients over the symptomatic 10 µg/g test threshold do not have CRC. A polygenic risk score (PRS) quantifies an individual's genetic risk of a condition based on many common variants. Existing PRS for CRC have so far been used to stratify asymptomatic populations. We conducted a retrospective cohort study of 50,387 UK Biobank participants with a CRC symptom in their primary care record at age 40+. A PRS based on 201 variants, 5 genetic principal components and 22 other risk factors and markers for CRC were assessed for association with CRC diagnosis within 2 years of first symptom presentation using logistic regression. Associated variables were included in an integrated risk model and trained in 80% of the cohort to predict CRC diagnosis within 2 years. An integrated risk model combining PRS, age, sex, and patient-reported symptoms was predictive of CRC development in a testing cohort (receiver operating characteristic area under the curve, ROCAUC: 0.76, 95% confidence interval: 0.71-0.81). This model has the potential to improve early diagnosis of CRC, particularly in cases of patient noncompliance with FIT., Competing Interests: Competing interests The authors declare no competing interests. Ethical approval Data from the UK Biobank Resource were accessed under Application Number 74981. UK Biobank was approved as tissue bank resource by North West Multi-centre Research Ethics Committee. All UK Biobank participants gave written informed consent for use of their data for health research. Participants who withdrew consent during this study were excluded from analysis., (© 2024. The Author(s).)

Both the incidence and prevalence of well-differentiated neuroendocrine tumours from the small intestine (Si-NET) are gradually increasing. Most patients have non-functioning tumours with subtle GI symptoms and tumours are often discovered incidentally by endoscopy or at advanced disease stages by imaging depicting mesenteric lymph node and /or liver metastases while around 30% of the patients present with symptoms of the carcinoid syndrome. Adequate biochemical assessment and staging including functional imaging is crucial for treatment-related decision-making that should take place in an expert multidisciplinary team setting. Preferably, patients should be referred to specialised ENETS Centres of Excellence or centres of high expertise in the field. This guidance paper provides the current evidence and best knowledge for the management of Si-NET grade (G) 1-3 following 10 key questions of practical relevance for the diagnostic and therapeutic decision making., (© 2024 British Society for Neuroendocrinology.)

Lung carcinoid tumours are neuroendocrine neoplasms originating from the bronchopulmonary tract's neuroendocrine cells, accounting for only 1%-3% of all lung cancers but 30% of all neuroendocrine tumours. The incidence of lung carcinoids, both typical and atypical, has been increasing over the years due to improved diagnostic methods and increased awareness among clinicians and pathologists. The most recent WHO classification includes a subgroup of lung carcinoids with atypical morphology and higher mitotic count and/or Ki67 labelling index. Despite appropriate surgery, the 5-year survival rate for atypical carcinoids barely exceeds 50%-70%. The role of adjuvant therapy in lung carcinoids is not well-defined, and clinical decisions are generally based on the presence of high-risk features. Long-term follow-up is essential to monitor for recurrence, although the optimal follow-up protocol remains unclear. To address the lack of consensus in clinical management decisions, the European Neuroendocrine Tumor Society (ENETS) initiated a survey among 20 expert centres. The survey identified varied opinions on approaches to imaging, surgery, use of adjuvant therapy, and follow-up protocols. Notably, the absence of dedicated multidisciplinary lung neuroendocrine tumour boards in some centres was evident. Experts agreed on the need for a prospective adjuvant trial in high-risk patients, emphasizing the feasibility of such a study. In conclusion, the study highlights the need for a more uniform adoption of existing guidelines in the management of lung carcinoid tumours and emphasizes the importance of international collaboration to advance research and patient care. Close collaboration between healthcare providers and patients is vital for effective long-term surveillance and management of these rare tumours., (© 2024 British Society for Neuroendocrinology.)

Midgut neuroendocrine neoplasms (NENs) are one of the most common subtypes of NEN, and their incidence is rising globally. Despite being the most frequently diagnosed malignancy of the small intestine, little is known about their underlying molecular biology. Their unusually low mutational burden compared to other solid tumors and the unexplained occurrence of multifocal tumors makes the molecular biology of midgut NENs a particularly fascinating field of research. This review provides an overview of recent advances in the understanding of the interplay of the genetic, epigenetic, and transcriptomic landscape in the development of midgut NENs, a topic that is critical to understanding their biology and improving treatment options and outcomes for patients., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society.)

Background: People with cancer experience high rates of venous thromboembolism (VTE). Risk of subsequent cancer is also increased in people experiencing their first VTE. The causal mechanisms underlying this association are not completely understood, and it is unknown whether VTE is itself a risk factor for cancer., Methods: We used data from large genome-wide association study meta-analyses to perform bidirectional Mendelian randomization analyses to estimate causal associations between genetic liability to VTE and risk of 18 different cancers., Results: We found no conclusive evidence that genetic liability to VTE was causally associated with an increased incidence of cancer, or vice versa. We observed an association between liability to VTE and pancreatic cancer risk [odds ratio for pancreatic cancer: 1.23 (95% confidence interval: 1.08-1.40) per log-odds increase in VTE risk, P = 0.002]. However, sensitivity analyses revealed this association was predominantly driven by a variant proxying non-O blood group, with inadequate evidence to suggest a causal relationship., Conclusions: These findings do not support the hypothesis that genetic liability to VTE is a cause of cancer. Existing observational epidemiological associations between VTE and cancer are therefore more likely to be driven by pathophysiological changes which occur in the setting of active cancer and anti-cancer treatments. Further work is required to explore and synthesize evidence for these mechanisms., (© The Author(s) 2023. Published by Oxford University Press on behalf of the International Epidemiological Association.)

This article describes the public health response to an outbreak of meningococcal B disease, linked to a secondary school in Far North Queensland. Tropical Public Health Services in Cairns were notified of three cases of meningococcal disease in the same week in May 2022. The cases occurred in individuals who all attended, or worked in, the same secondary school. All cases were serogroup B and shared the same molecular genotype. The public health response included prompt provision of information, distribution of clearance antibiotics and two doses of MenB-4C vaccine to the entire staff and student population. Antibiotic coverage and vaccination coverage were achieved in 99% and 85% of the student population respectively. Following the intervention, no further cases were detected in the region during the subsequent nine months., (© Commonwealth of Australia CC BY-NC-ND)

This ENETS guidance paper aims to provide practical advice to clinicians for the diagnosis, treatment and follow-up of functioning syndromes in pancreatic neuroendocrine tumours (NET). A NET-associated functioning syndrome is defined by the presence of a clinical syndrome combined with biochemical evidence of inappropriately elevated hormonal levels. Different hormonal syndromes can be encountered in pancreatic NET patients, including insulinoma, gastrinoma as well as the rare glucagonoma, VIPoma, ACTHoma, PTHrPoma, carcinoid syndrome, calcitoninoma, GHRHoma and somatostatinoma. The recommendations provided in this paper focus on the biochemical, genetic and imaging work-up as well as therapeutic management of the individual hormonal syndromes in well-differentiated, grade 1-3, functioning NET with the primary tumour originating in the pancreas, and for specific subtypes also in the duodenum., (© 2023 The Authors. Journal of Neuroendocrinology published by John Wiley & Sons Ltd on behalf of British Society for Neuroendocrinology.)