Marinos Pericleous

Prostate cancer and the influence of dietary factors and supplements: a systematic review

BackgroundProstate cancer is the second most common cause of cancer worldwide after lung cancer. There is increasing evidence that diet and lifestyle plays a crucial role in prostate cancer biology and tumourigenesis. Prostate cancer itself represents a good model of cancer in which to look for chemopreventive agents due to the high disease prevalence, slowly progressive nature, and long latency period. Dietary agents have gained considerable attention, often receiving much publicity in the media.AimTo review the key evidence available for potential chemopreventive nutrients.MethodsThe methodology for this review involved a PubMed search from 1990 to 2013 using the key-words “diet and prostate cancer”, “nutrition and prostate cancer”, “dietary factors and prostate cancer”, “prostate cancer epidemiology”, “prostate cancer prevention”, “prostate cancer progression”.ResultsRed meat, dietary fat and milk intake should be minimised as they appear to increase the risk of prostate cancer. Fruit and vegetables and polyphenols may be preventive in prostate cancer, but further studies are needed to draw more solid conclusions and to clarify their role in patients with an established diagnosis of prostate cancer. Selenium and vitamin supplements cannot be advocated for the prevention of prostate cancer and indeed higher doses may be associated with a worse prognosis. There is no specific evidence regarding benefits of probiotics or prebiotics in prostate cancer.ConclusionsFrom the wealth of evidence available, many recommendations can be made although more randomised control trials are required. These need to be carefully designed due to the many confounding factors and heterogeneity of the population.

Prognostic Impact of Novel Molecular Subtypes of Small Intestinal Neuroendocrine Tumor

Purpose: Small intestinal neuroendocrine tumors (SINET) are the commonest malignancy of the small intestine; however, underlying pathogenic mechanisms remain poorly characterized. Whole-genome and -exome sequencing has demonstrated that SINETs are mutationally quiet, with the most frequent known mutation in the cyclin-dependent kinase inhibitor 1B gene (CDKN1B) occurring in only ∼8% of tumors, suggesting that alternative mechanisms may drive tumorigenesis. The aim of this study is to perform genome-wide molecular profiling of SINETs in order to identify pathogenic drivers based on molecular profiling. This study represents the largest unbiased integrated genomic, epigenomic, and transcriptomic analysis undertaken in this tumor type. Experimental Design: Here, we present data from integrated molecular analysis of SINETs (n = 97), including whole-exome or targeted CDKN1B sequencing (n = 29), HumanMethylation450 BeadChip (Illumina) array profiling (n = 69), methylated DNA immunoprecipitation sequencing (n = 16), copy-number variance analysis (n = 47), and Whole-Genome DASL (Illumina) expression array profiling (n = 43). Results: Based on molecular profiling, SINETs can be classified into three groups, which demonstrate significantly different progression-free survival after resection of primary tumor (not reached at 10 years vs. 56 months vs. 21 months, P = 0.04). Epimutations were found at a recurrence rate of up to 85%, and 21 epigenetically dysregulated genes were identified, including CDX1 (86%), CELSR3 (84%), FBP1 (84%), and GIPR (74%). Conclusions: This is the first comprehensive integrated molecular analysis of SINETs. We have demonstrated that these tumors are highly epigenetically dysregulated. Furthermore, we have identified novel molecular subtypes with significant impact on progression-free survival. Clin Cancer Res; 22(1); 250–8. ©2015 AACR.

The impact of diet and nutrition in the prevention and progression of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer mortality worldwide. There is growing evidence for a chemopreventive role of nutrition in the development of HCC in at risk populations. Bibliographical searches were performed in PubMed for the terms ‘nutrition and hepatocellular carcinoma’, ‘nutrition and liver cancer’, ‘nutrition and hepatic cancer’, ‘diet and hepatocellular carcinoma’, ‘diet and liver cancer’. High dietary sugar intake should be discouraged in at risk populations. Coffee, polyphenols, vanadium, dietary fibre, fruits and vegetables show encouraging results in terms of chemoprevention. Red meat intake may be associated with increased risk of HCC. The evidence for fatty acids is inconclusive, but they might exert anti-cancer effects. Inconclusive results are available on vitamins, selenium probiotics and prebiotics. There is increasing evidence that diet may play an important role in the development of HCC, and may also have a chemopreventive role in at risk populations.

Hepatic artery embolization in advanced neuroendocrine tumors: Efficacy and long-term outcomes.

Transarterial embolization (TAE) and transarterial chemoembolization (TACE) are established treatments for symptom control in patients with advanced neuroendocrine tumors (NETs) with significant hepatic tumor burden.

Gastric mixed adenoneuroendocrine carcinoma with a trilineage cell differentiation: case report and review of the literature.

Most gastric neuroendocrine tumours are well differentiated and considered as neuroendocrine neoplasms, whilst poorly differentiated lesions are considered as neuroendocrine carcinomas and account for only 6–16% of gastric neuroendocrine tumours. Gastric mixed adenoneuroendocrine carcinomas are rare malignancies usually composed of a neuroendocrine carcinoma and an adenocarcinoma with a variable grade of differentiation. Here, we report an unusual and rare gastric mixed adenoneuroendocrine carcinoma with a trilineage cell differentiation including a neuroendocrine carcinoma, an adenocarcinoma and a squamous cell carcinoma. A brief discussion of the histopathological features, biological behaviour and treatment of this rare tumour type is presented.

Progressive epigenetic dysregulation in neuroendocrine tumour liver metastases

The incidence of small intestinal neuroendocrine tumours (SINETs) is increasing and distant metastases are present at diagnosis in 70% of cases, the liver being the commonest site of metastasis (Yao et al. 2008). Despite this, our understanding of the mechanisms underlying metastatic progression of SINETs is currently limited, and prior studies of the molecular biology of SINET liver metastases (LM) have been performed predominantly in small cohorts utilising candidate-based techniques. SINETs have a low rate of mutations compared to most cancers. The most frequently mutated gene is CDKN1B (encoding p27, a cell cycle regulator); however, mutations in this gene occur in only 8% of tumours, and there is no characteristic mutational hotspot (Francis et al. 2013). Furthermore, mutation of CDKN1B does not correlate with the expression of p27 (Crona et al. 2015). We previously identified that SINETs are epigenetically dysregulated, and a panel of candidate driver epimutation genes has been identified (Karpathakis et al. 2016). Therefore, we postulated that metastatic progression in SINETs may also be epigenetically regulated. Here, we present the findings from the largest molecular profiling study of SINET LM performed to date, integrating copy number variance (CNV), DNA methylation, and RNA expression profiling to characterise the mechanisms underlying metastatic progression. Experimental details of DNA methylation, CNV and RNA expression profiling are as previously published (Karpathakis et al. 2016). Patients provided informed consent for their tissue to be analysed in this study, which was Research Ethics Committee approved (Ref: 09/H0722/27). All cases were reviewed by two expert NET histopathologists (TVL/MN). Nucleic acids were extracted using standard methods (Qiagen, QIAamp DNA Mini kit; Roche, High Pure RNA Paraffin kit). H&E-stained sections were evaluated to ensure >80% purity of tumour specimens. Methylation profiling was performed on the HumanMethylation450 BeadChip (HM450) (Illumina). Methylation data were analysed using ChAMP pipeline (https://www.bioconductor.org/packages/release/bioc/ html/ChAMP.html). Whole-genome methylation profiling using methylated DNA immunoprecipitation sequencing (MeDIP) was performed as previously described. MeDIP data were analysed using the custom pipeline MeDUSA, v2.0 (https://www.ucl.ac.uk/cancer/research/departmentcancer-biology/medical-genomics-group/past-projects/ medusa-project). Gene expression levels were quantified using the whole genome cDNA-mediated annealing, selection and ligation (DASL) (Illumina) assay. Expression data were analysed using the ‘LIMMA’ package in R (https://bioconductor.org/packages/release/bioc/html/ limma.html). Raw data from this study has previously been deposited in GEO (Accession number: GSE73832) (Karpathakis et al. 2016). In summary, n = 90 samples underwent array-based DNA methylation analysis, n = 26 samples underwent methylation-specific immunoprecipitation followed by DNA sequencing and n = 49 underwent array-based RNA expression analysis. Of cases with relevant clinical data, 93% had received no systemic treatment prior to specimen collection (27/29 cases). The CNV profile of SINET LM (n = 20) mirrors that of primary tumours with the most frequent alteration of chr18 LOH seen in 79% of cases. A greater proportion of LM demonstrates amplification of chr20 (42%) and deletion of chr19 (35%), whereas gain of 17q is found only in LM (21%). A trend of increased incidence of CNVs was seen in LM compared to that of SINET primary tumours (SINET primary: median 78 mbp; LM: median 114 mbp, P = 0.08). Comparison of methylation profiles of SINET LM to those of primary SINETs identified 29,263 methylation

Appendiceal goblet cell carcinoid tumour: a case of unexpected lung metastasis.

Goblet cell carcinoid tumours are often considered a subset of appendiceal neuroendocrine tumours which behave more aggressively. They usually metastasize through transcoelomic/peritoneal invasion and common sites include the ovaries, peritoneum, and liver. Metastases may have goblet cell carcinoid, signet ring cell carcinoma or classic carcinoid histology. We report the first case in the literature of a patient with a goblet cell carcinoid with lung metastasis, which was associated with unfavourable outcome.

Well-differentiated bronchial neuroendocrine tumors: Clinical management and outcomes in 105 patients.

Bronchial neuroendocrine tumors (NETs) are rare tumors representing approximately 20%‐30% of all neuroendocrine tumors and 2%‐3% of all adult lung cancers. Here, they present a large case series of well‐differentiated bronchial NETs with the aim of investigating the behavior of these tumors and long‐term outcomes.

Using an ‘action set’ for the management of acute upper gastrointestinal bleeding

Background: We studied the management of patients with acute upper gastrointestinal (GI) bleeding (AUGIB) at the Royal Free Hospital. The aim was to compare our performance with the national standard and determine ways of improving the delivery of care in accordance with the recently published ‘Scope for improvement’ report. Methods: We randomly selected patients who presented with haematemesis, melaena, or both, and had an oesophageogastroduodenoscopy (OGD) between April and October 2009. We developed local guidelines and presented our findings in various forums. We collaborated with the British Medical Journal’s Evidence Centre and Cerner Millennium electronic patient record system to create an electronic ‘Action Set’ for the management of patients presenting with AUGIB. We re-audited using the same standard and target. Results: With the action set, documentation of pre-OGD Rockall scores increased significantly (p ≤ 0.0001). The differences in the calculation and documentation of post-OGD full Rockall scores were also significant between the two audit loops (p = 0.007). Patients who inappropriately received proton-pump inhibitors (PPIs) before endoscopy were reduced from 73.8% to 33% (p = 0.02). Patients receiving PPIs after OGD were also reduced from 66% to 50% (p = 0.01). Discharges of patients whose full Rockall score was less than or equal to two increased from 40% to 100% (p = 0.43). Conclusion: The use of the Action Set improved calculation and documentation of risk scores and facilitated earlier hospital discharge for low-risk patients. Significant improvements were also seen in inappropriate use of PPIs. Actions sets can improve guideline adherence and can potentially promote cost-cutting and improve health economics.

Hepatobiliary disease associated with hypereosinophilia: a report of two patients and a review of the literature.

Gastrointestinal involvement in the idiopathic hypereosinophilic syndrome (HES) most commonly manifests as gastroenteritis. There are, however, case reports of cholangiopathy associated with hypereosinophilia [1–12], sometimes in conjunction with colitis—thus leading to difficulty distinguishing these cases from primary sclerosing cholangitis, which often occurs in conjunction with ulcerative colitis. There are also reports of chronic hepatitis associated with hypereosinophilia [13, 14]. We report two cases of the rare association of liver disease with HES: one with chronic eosinophilic cholangitis and the other with features of both severe chronic hepatitis and sclerosing cholangitis associated with hypereosinophilia. The latter is particularly rare, with a search finding no such report in the literature.