Improved outcome in penile cancer with radiologically enhanced stratification protocol for lymph node staging procedures: a study in 316 inguinal basins with a mean follow-up of 5 years.

BACKGROUND: Lymph node metastasis is the main determinant of survival in penile cancer patients. Conventionally clinical palpability is used to stratify patients to Inguinal Lymph node dissection (ILND) if clinically node positive (cN +) or Dynamic sentinel node biopsy (DSNB) if clinically node negative (cN0). Studies suggest a false negative rate (FNR) of around 10% (5-13%) for DSNB. To our knowledge there are no studies reporting harder end point of survival and outcomes of all clinically node positive (cN +) patients. We present our outcome data of all patients with penile cancer including false negative rates and survival in both DSNB and ILND groups. METHODS: One hundred fifty-eight consecutive patients (316 inguinal basins), who had lymph node surgery for penile cancer in a tertiary referral centre from Jan 2008 to 2018, were included in the study. All patients underwent ultrasound (US) ± fine needle aspiration cytology (FNAC) and then MRI/ CT, if needed, to stage their disease. We used combined clinical and radiological criteria (node size, architecture loss, irregular margins) to stratify patients to DSNB vs ILND as opposed to clinical palpability alone. RESULTS: 11.2% i.e., 27/241 inguinal basins had lymph node positive disease by DSNB. 54.9% i.e., 39/71 inguinal basins (IBs) had lymph node-positive disease by ILND. 4 inguinal basins with no tracer uptake in sentinel node scans are being monitored at patient's request and have not had any recurrences to date. With a mean follow-up of 65 months (range 24-150), the false-negative rate (FNR) for DSNB is 0%. Judicious uses of cross-sectional imaging necessitated ILND in 2 inguinal basins with non-palpable nodes and negative US with false positive rate of 6.3% (2/32) for ILND. The same cohort of DSNB patients might have had 11.1% (3/27) FNR if only palpability criteria was used. 43 (28%) patients who did require cross sectional imaging as per our criteria had a low node positive rate of 4.7% (p = 0.03). Mean cancer specific survival of all node-positive patients was 105 months. CONCLUSION: The performance of DSNB improved with enhanced radiological stratification of patients to either DSNB or ILND. We for the first time report the comprehensive outcome of all lymph node staging procedures in penile cancer.

Accumulation of Sulforaphane and Alliin in Human Prostate Tissue.

Diets rich in cruciferous vegetables have been associated with a lower risk of incidence and progression of prostate cancer. Sulforaphane, an isothiocyanate derived from 4-methylsulphinylbutyl glucosinolate (glucoraphanin) that accumulates in certain of these vegetables, notably broccoli, has been implicated in their protective effects. Likewise, the consumption of garlic and its sulphur-containing compounds such as alliin have been associated with a reduction in risk of prostate cancer. In this study, we tested whether consuming glucoraphanin derived from broccoli seeds and alliin derived from garlic resulted in the occurrence of these potential bioactive compounds in the prostate, which may contribute to our understanding of the putative protective effects of these dietary components. We recruited 42 men scheduled for a trans-perineal prostate biopsy into a randomised, double-blinded, 2 × 2-factorial dietary supplement four-week intervention study, and 39 completed the study. The two active interventions were supplements providing glucoraphanin from broccoli (BroccoMax®) and alliin from garlic (Kwai Heartcare®). Following the intervention, prostate biopsy tissue was analysed for the presence of sulforaphane and its thiol conjugates and for alliin and associated metabolites. Sulforaphane occurred in significantly higher levels in the prostate tissue (both within the transition and peripheral zone) of men consuming the glucoraphanin containing supplements (p < 0.0001) compared to men not consuming these supplements. However, while alliin and alliin-derived metabolites were detected within the prostate, there was no significant difference in the concentrations of these compounds in the prostate of men consuming supplements derived from garlic compared to men not consuming these supplements.

Melanosis of the Bladder: Possible Pathogenetic Mechanisms.

Melanin accumulation within the bladder urothelium and/or macrophages in the lamina propria (melanosis of the bladder) is a very rare phenomenon of unknown pathogenesis. Its rarity argues for a complex, likely multifactorial, causation. We describe bladder melanosis developing after Botox therapy in an elderly woman with a history of overactive bladder, treated grade 2 uterovaginal prolapse, and episodes of urinary tract infection and speculate that one factor (probably of many) in its pathogenesis may be a derangement of local neurourothelial interactions.

Microbiomes of Urine and the Prostate Are Linked to Human Prostate Cancer Risk Groups.

BACKGROUND: Bacteria play a suspected role in the development of several cancer types, and associations between the presence of particular bacteria and prostate cancer have been reported. OBJECTIVE: To provide improved characterisation of the prostate and urine microbiome and to investigate the prognostic potential of the bacteria present. DESIGN, SETTING, AND PARTICIPANTS: Microbiome profiles were interrogated in sample collections of patient urine (sediment microscopy: n = 318, 16S ribosomal amplicon sequencing: n = 46; and extracellular vesicle RNA-seq: n = 40) and cancer tissue (n = 204). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Microbiomes were assessed using anaerobic culture, population-level 16S analysis, RNA-seq, and whole genome DNA sequencing. RESULTS AND LIMITATIONS: We demonstrate an association between the presence of bacteria in urine sediments and higher D'Amico risk prostate cancer (discovery, n = 215 patients, p < 0.001; validation, n = 103, p < 0.001, χ2 test for trend). Characterisation of the bacterial community led to the (1) identification of four novel bacteria (Porphyromonas sp. nov., Varibaculum sp. nov., Peptoniphilus sp. nov., and Fenollaria sp. nov.) that were frequently found in patient urine, and (2) definition of a patient subgroup associated with metastasis development (p = 0.015, log-rank test). The presence of five specific anaerobic genera, which includes three of the novel isolates, was associated with cancer risk group, in urine sediment (p = 0.045, log-rank test), urine extracellular vesicles (p = 0.039), and cancer tissue (p = 0.035), with a meta-analysis hazard ratio for disease progression of 2.60 (95% confidence interval: 1.39-4.85; p = 0.003; Cox regression). A limitation is that functional links to cancer development are not yet established. CONCLUSIONS: This study characterises prostate and urine microbiomes, and indicates that specific anaerobic bacteria genera have prognostic potential. PATIENT SUMMARY: In this study, we investigated the presence of bacteria in patient urine and the prostate. We identified four novel bacteria and suggest a potential prognostic utility for the microbiome in prostate cancer.

The Urine Biomarker PUR-4 Is Positively Associated with the Amount of Gleason 4 in Human Prostate Cancers.

The Prostate Urine Risk (PUR) biomarker is a four-group classifier for predicting outcome in patients prior to biopsy and for men on active surveillance. The four categories correspond to the probabilities of the presence of normal tissue (PUR-1), D'Amico low-risk (PUR-2), intermediate-risk (PUR-3), and high-risk (PUR-4) prostate cancer. In the current study we investigate how the PUR-4 status is linked to Gleason grade, prostate volume, and tumor volume as assessed from biopsy (n = 215) and prostatectomy (n = 9) samples. For biopsy data PUR-4 status alone was linked to Gleason Grade group (GG) (Spearman's, ρ = 0.58, p < 0.001 trend). To assess the impact of tumor volume each GG was dichotomized into Small and Large volume cancers relative to median volume. For GG1 (Gleason Pattern 3 + 3) cancers volume had no impact on PUR-4 status. In contrast for GG2 (3 + 4) and GG3 (4 + 3) cancers PUR-4 levels increased in large volume cancers with statistical significance observed for GG2 (p = 0.005; Games-Howell). These data indicated that PUR-4 status is linked to the presence of Gleason Pattern 4. To test this observation tumor burden and Gleason Pattern were assessed in nine surgically removed and sectioned prostates allowing reconstruction of 3D maps. PUR-4 was not correlated with Gleason Pattern 3 amount, total tumor volume or prostate size. A strong correlation was observed between amount of Gleason Pattern 4 tumor and PUR-4 signature (r = 0.71, p = 0.034, Pearson's). These observations shed light on the biological significance of the PUR biomarker and support its use as a non-invasive means of assessing the presence of clinically significant prostate cancer.

Testicular vasculitis: a diagnostic conundrum.

Vasculitis is rare in the context of testicular lesions but, when found, can be classified as a single organ vasculitis or part of a multi-organ inflammatory process. In the context of a patient with a pre-existing autoimmune disorder, this finding might cause diagnostic confusion and preferentially bias a physician towards attributing the condition to the known diagnosis or its treatment. This diagnostic bias can interfere with patient care and lead to over caution, resulting in a worse outcome for the patient involved. We describe such a patient with rheumatoid arthritis on biologic therapy.

Accumulation of Dietary S-Methyl Cysteine Sulfoxide in Human Prostate Tissue.

SCOPE: Observational studies have associated consumption of cruciferous vegetables with reduced risk of prostate cancer. This effect has been associated with the degradation products of glucosinolates-thioglycosides that accumulate within crucifers. The possible role of S-methyl cysteine sulfoxide, a metabolite that also accumulates in cruciferous vegetables, and its derivatives, in cancer prevention is relatively unexplored compared to glucosinolate derivatives. The hypothesis that consuming a broccoli soup results in the accumulation of sulfate (a SMCSO derivative) and other broccoli-derived metabolites in prostate tissue is tested. METHODS AND RESULTS: Eighteen men scheduled for transperineal prostate biopsy were recruited into a 4-week parallel single blinded diet supplementation study (NCT02821728). Nine men supplemented their diet with three 300 mL portions of a broccoli soup each week for four weeks prior to surgery. Analyses of prostate biopsy tissues reveal no detectable levels of glucosinolates and derivatives. In contrast, SMCSO is detected in prostate tissues of the participants, with significantly higher levels in tissue of men in the supplementation arm. SMCSO was also found in blood and urine samples from a previous intervention study with the identical broccoli soup. CONCLUSION: The consequences of SMCSO accumulation in prostate tissues and its potential role in prevention of prostate cancer remains to be investigated.

A four-group urine risk classifier for predicting outcomes in patients with prostate cancer.

OBJECTIVES: To develop a risk classifier using urine-derived extracellular vesicle (EV)-RNA capable of providing diagnostic information on disease status prior to biopsy, and prognostic information for men on active surveillance (AS). PATIENTS AND METHODS: Post-digital rectal examination urine-derived EV-RNA expression profiles (n = 535, multiple centres) were interrogated with a curated NanoString panel. A LASSO-based continuation ratio model was built to generate four prostate urine risk (PUR) signatures for predicting the probability of normal tissue (PUR-1), D'Amico low-risk (PUR-2), intermediate-risk (PUR-3), and high-risk (PUR-4) prostate cancer. This model was applied to a test cohort (n = 177) for diagnostic evaluation, and to an AS sub-cohort (n = 87) for prognostic evaluation. RESULTS: Each PUR signature was significantly associated with its corresponding clinical category (P < 0.001). PUR-4 status predicted the presence of clinically significant intermediate- or high-risk disease (area under the curve = 0.77, 95% confidence interval [CI] 0.70-0.84). Application of PUR provided a net benefit over current clinical practice. In an AS sub-cohort (n = 87), groups defined by PUR status and proportion of PUR-4 had a significant association with time to progression (interquartile range hazard ratio [HR] 2.86, 95% CI 1.83-4.47; P < 0.001). PUR-4, when used continuously, dichotomized patient groups with differential progression rates of 10% and 60% 5 years after urine collection (HR 8.23, 95% CI 3.26-20.81; P < 0.001). CONCLUSION: Urine-derived EV-RNA can provide diagnostic information on aggressive prostate cancer prior to biopsy, and prognostic information for men on AS. PUR represents a new and versatile biomarker that could result in substantial alterations to current treatment of patients with prostate cancer.

Transcriptional changes in prostate of men on active surveillance after a 12-mo glucoraphanin-rich broccoli intervention-results from the Effect of Sulforaphane on prostate CAncer PrEvention (ESCAPE) randomized controlled trial.

BACKGROUND: Epidemiological evidence suggests that consumption of cruciferous vegetables is associated with reduced risk of prostate cancer progression, largely attributed to the biological activity of glucosinolate degradation products, such as sulforaphane derived from glucoraphanin. Because there are few therapeutic interventions for men on active surveillance for prostate cancer to reduce the risk of cancer progression, dietary approaches are an appealing option for patients. OBJECTIVE: We evaluated whether consumption of a glucoraphanin-rich broccoli soup for 1 y leads to changes in gene expression in prostate tissue of men with localized prostate cancer. METHODS: Forty-nine men on active surveillance completed a 3-arm parallel randomized double-blinded intervention study for 12 mo and underwent transperineal template biopsy procedures and dietary assessment at the start and end of the study. Patients received a weekly 300 mL portion of soup made from a standard broccoli (control) or from 1 of 2 experimental broccoli genotypes with enhanced concentrations of glucoraphanin, delivering 3 and 7 times that of the control, respectively. Gene expression in tissues from each patient obtained before and after the dietary intervention was quantified by RNA sequencing followed by gene set enrichment analyses. RESULTS: In the control arm, there were several hundred changes in gene expression in nonneoplastic tissue during the 12 mo. These were associated with an increase in expression of potentially oncogenic pathways including inflammation processes and epithelial-mesenchymal transition. Changes in gene expression and associated oncogenic pathways were attenuated in men on the glucoraphanin-rich broccoli soup in a dose-dependent manner. Although the study was not powered to assess clinical progression, an inverse association between consumption of cruciferous vegetables and cancer progression was observed. CONCLUSION: Consuming glucoraphanin-rich broccoli soup affected gene expression in the prostate of men on active surveillance, consistent with a reduction in the risk of cancer progression. This trial was registered at clinicaltrials.gov as NCT01950143.

DESNT: A Poor Prognosis Category of Human Prostate Cancer.

BACKGROUND: A critical problem in the clinical management of prostate cancer is that it is highly heterogeneous. Accurate prediction of individual cancer behaviour is therefore not achievable at the time of diagnosis leading to substantial overtreatment. It remains an enigma that, in contrast to breast cancer, unsupervised analyses of global expression profiles have not currently defined robust categories of prostate cancer with distinct clinical outcomes. OBJECTIVE: To devise a novel classification framework for human prostate cancer based on unsupervised mathematical approaches. DESIGN, SETTING, AND PARTICIPANTS: Our analyses are based on the hypothesis that previous attempts to classify prostate cancer have been unsuccessful because individual samples of prostate cancer frequently have heterogeneous compositions. To address this issue, we applied an unsupervised Bayesian procedure called Latent Process Decomposition to four independent prostate cancer transcriptome datasets obtained using samples from prostatectomy patients and containing between 78 and 182 participants. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Biochemical failure was assessed using log-rank analysis and Cox regression analysis. RESULTS AND LIMITATIONS: Application of Latent Process Decomposition identified a common process in all four independent datasets examined. Cancers assigned to this process (designated DESNT cancers) are characterized by low expression of a core set of 45 genes, many encoding proteins involved in the cytoskeleton machinery, ion transport, and cell adhesion. For the three datasets with linked prostate-specific antigen failure data following prostatectomy, patients with DESNT cancer exhibited poor outcome relative to other patients (p=2.65×10-5, p=4.28×10-5, and p=2.98×10-8). When these three datasets were combined the independent predictive value of DESNT membership was p=1.61×10-7 compared with p=1.00×10-5 for Gleason sum. A limitation of the study is that only prediction of prostate-specific antigen failure was examined. CONCLUSIONS: Our results demonstrate the existence of a novel poor prognosis category of human prostate cancer and will assist in the targeting of therapy, helping avoid treatment-associated morbidity in men with indolent disease. PATIENT SUMMARY: Prostate cancer, unlike breast cancer, does not have a robust classification framework. We propose that this failure has occurred because prostate cancer samples selected for analysis frequently have heterozygous compositions (individual samples are made up of many different parts that each have different characteristics). Applying a mathematical approach that can overcome this problem we identify a novel poor prognosis category of human prostate cancer called DESNT.

Increased transcriptional and metabolic capacity for lipid metabolism in the peripheral zone of the prostate may underpin its increased susceptibility to cancer.

The human prostate gland comprises three distinct anatomical glandular zones, namely the peripheral, central and transitional zones. Although prostate cancer can arise throughout the prostate, it is more frequent in the peripheral zone. In contrast, hyperplasia occurs most frequently in the transitional zone. In this paper, we test the hypothesis that peripheral and transitional zones have distinct metabolic adaptations that may underlie their different inherent predispositions to cancer and hyperplasia. In order to do this, we undertook RNA sequencing and high-throughput metabolic analyses of non-cancerous tissue from the peripheral and transitional zones of patients undergoing prostatectomy. Integrated analysis of RNAseq and metabolomic data revealed that transcription of genes involved in lipid biosynthesis is higher in the peripheral zone, which was mirrored by an increase in fatty acid metabolites, such as lysolipids. The peripheral zone also exhibited increased fatty acid catabolic activity and contained higher level of neurotransmitters. Such increased capacity for de novo lipogenesis and fatty acid oxidation, which is characteristic of prostate cancer, can potentially provide a permissive growth environment within the peripheral zone for cancer growth and also transmit a metabolic growth advantage to newly emerging clones themselves. This lipo-rich priming may explain the observed susceptibility of the peripheral zone to oncogenesis.

Dietary, lifestyle and clinicopathological factors associated with APC mutations and promoter methylation in colorectal cancers from the EPIC-Norfolk study.

The tumour suppressor APC is the most commonly altered gene in colorectal cancer (CRC). Genetic and epigenetic alterations of APC may therefore be associated with dietary and lifestyle risk factors for CRC. Analysis of APC mutations in the extended mutation cluster region (codons 1276-1556) and APC promoter 1A methylation was performed on 185 archival CRC samples collected from participants of the European Prospective Investigation into Cancer (EPIC)-Norfolk study, with the aim of relating these to high-quality seven-day dietary and lifestyle data collected prospectively. Truncating APC mutations (APC(+) ) and promoter 1A methylation (PM(+) ) were identified in 43% and 23% of CRCs analysed, respectively. Distal CRCs were more likely than proximal CRCs to be APC(+) or PM(+) (p = 0.04). APC(+) CRCs were more likely to be moderately/well differentiated and microsatellite stable than APC(-) CRCs (p = 0.05 and 0.03). APC(+) CRC cases consumed more alcohol than their counterparts (p = 0.01) and PM(+) CRC cases consumed lower levels of folate and fibre (p = 0.01 and 0.004). APC(+) or PM(+) CRC cases consumed higher levels of processed meat and iron from red meat and red meat products (p = 0.007 and 0.006). Specifically, CRC cases harbouring GC-to-AT transition mutations consumed higher levels of processed meat (35 versus 24 g/day, p = 0.04) and iron from red meat and red meat products (0.8 versus 0.6 mg/day, p = 0.05). In a logistic regression model adjusted for age, sex and cigarette-smoking status, each 19 g/day (1SD) increment increase in processed meat consumption was associated with cases with GC-to-AT mutations (OR 1.68, 95% CI 1.03-2.75). In conclusion, APC(+) and PM(+) CRCs may be influenced by diet and GC-to-AT mutations in APC are associated with processed meat consumption, suggesting a mechanistic link with dietary alkylating agents, such as N-nitroso compounds.

MLH1 promoter methylation, diet, and lifestyle factors in mismatch repair deficient colorectal cancer patients from EPIC-Norfolk.

There is conflicting evidence for the role diet and lifestyle play in the development of mismatch repair (MMR)-deficient colorectal cancers (CRC). In this study, associations between MMR deficiency, clinicopathological characteristics, and dietary and lifestyle factors in sporadic CRC were investigated. Tumor samples from 185 individuals in the EPIC-Norfolk study were analyzed for MLH1 gene promoter methylation and microsatellite instability (MSI). Dietary and lifestyle data were collected prospectively using 7-day food diaries (7dd) and questionnaires. MMR-deficient tumor cases (MLH1 promoter methylation positive, MSI-H) were more likely to be female, older at diagnosis, early Dukes' stage (A/B), and proximal in location (MSI-H P = 0.03, 0.03, 0.02, and 0.001, respectively). Tumors with positive MLH1 promoter methylation (>20%) were associated with poor differentiation (P = 0.03). Low physical activity was associated with cases without MSI (P = 0.05). MMR deficiency was not significantly associated with cigarette smoking or alcohol, folate, fruit, vegetable, or meat consumption. We conclude that MMR-deficient tumors represent a distinct subset of sporadic CRC that are proximal in location, early Dukes' stage, and poorly differentiated, in cases that are female and older at diagnosis. There is no overall role for diet and lifestyle in MMR status in CRC, consistent with age-related susceptibility to MLH1 promoter methylation.

Alterations in PTEN and PIK3CA in colorectal cancers in the EPIC Norfolk study: associations with clinicopathological and dietary factors.

BACKGROUND: The PTEN tumour suppressor gene and PIK3CA proto-oncogene encode proteins which contribute to regulation and propagation of signal transduction through the PI3K/AKT signalling pathway. This study investigates the prevalence of loss of PTEN expression and mutations in both PTEN and PIK3CA in colorectal cancers (CRC) and their associations with tumour clinicopathological features, lifestyle factors and dietary consumptions. METHODS: 186 adenocarcinomas and 16 adenomas from the EPIC Norfolk study were tested for PTEN and PIK3CA mutations by DNA sequencing and PTEN expression changes by immunohistochemistry. Dietary and lifestyle data were collected prospectively using seven day food diaries and lifestyle questionnaires. RESULTS: Mutations in exons 7 and 8 of PTEN were observed in 2.2% of CRC and PTEN loss of expression was identified in 34.9% CRC. Negative PTEN expression was associated with lower blood low-density lipoprotein concentrations (p = 0.05). PIK3CA mutations were observed in 7% of cancers and were more frequent in CRCs in females (p = 0.04). Analysis of dietary intakes demonstrated no link between PTEN expression status and any specific dietary factor. PTEN expression negative, proximal CRC were of more advanced Dukes' stage (p = 0.02) and poor differentiation (p < 0.01). Testing of the prevalence of PIK3CA mutations and loss of PTEN expression demonstrated that these two events were independent (p = 0.55). CONCLUSION: These data demonstrated the frequent occurrence (34.9%) of PTEN loss of expression in colorectal cancers, for which gene mutations do not appear to be the main cause. Furthermore, dietary factors are not associated with loss of PTEN expression. PTEN expression negative CRC were not homogenous, as proximal cancers were associated with a more advanced Dukes' stage and poor differentiation, whereas distal cancers were associated with earlier Dukes' stage.

The dietary isothiocyanate sulforaphane modulates gene expression and alternative gene splicing in a PTEN null preclinical murine model of prostate cancer.

BACKGROUND: Dietary or therapeutic interventions to counteract the loss of PTEN expression could contribute to the prevention of prostate carcinogenesis or reduce the rate of cancer progression. In this study, we investigate the interaction between sulforaphane, a dietary isothiocyanate derived from broccoli, PTEN expression and gene expression in pre malignant prostate tissue. RESULTS: We initially describe heterogeneity in expression of PTEN in non-malignant prostate tissue of men deemed to be at risk of prostate cancer. We subsequently use the mouse prostate-specific PTEN deletion model, to show that sulforaphane suppresses transcriptional changes induced by PTEN deletion and induces additional changes in gene expression associated with cell cycle arrest and apoptosis in PTEN null tissue, but has no effect on transcription in wild type tissue. Comparative analyses of changes in gene expression in mouse and human prostate tissue indicate that similar changes can be induced in humans with a broccoli-rich diet. Global analyses of exon expression demonstrated that sulforaphane interacts with PTEN deletion to modulate alternative gene splicing, illustrated through a more detailed analysis of DMBT1 splicing. CONCLUSION: To our knowledge, this is the first report of how diet may perturb changes in transcription induced by PTEN deletion, and the effects of diet on global patterns of alternative gene splicing. The study exemplifies the complex interaction between diet, genotype and gene expression, and the multiple modes of action of small bioactive dietary components.

Systemic T-cell lymphoma presenting as an acute nonresolving eyelid mass.

A healthy 39-year-old man was referred with a 3-week history of nonresolving right upper eyelid cyst with no globe or orbital involvement. Histopathologic examination revealed a peripheral T-cell lymphoma of unspecified type, which was stage 3 on staging. He received combination cyclophosphamide, hydroxydoxorubicin, oncovin, and prednisolone therapy with an autologous bone marrow transplant and remains in complete remission 24 months posttreatment. A brief literature review of ocular adnexal T-cell lymphomas is presented.

Lifestyle factors and p53 mutation patterns in colorectal cancer patients in the EPIC-Norfolk study.

The tumour suppressor p53 is one of the most commonly altered genes in colorectal cancer (CRC) development. Genetic alterations in p53 may therefore be associated with postulated lifestyle risk factors for CRC, such as red meat consumption. In the European Prospective Investigation into Cancer and Nutrition-Norfolk study, we examined whether detailed estimates of dietary and lifestyle factors measured at baseline related to later development of p53 mutations in CRCs. After 10-year follow-up, there were 185 incident CRCs of which 34% had somatic p53 mutations (p53+). We observed significantly higher mean intakes of alcohol, total meat and red meat, in the group with p53 mutations and advanced Dukes' stage disease (daily alcohol intake was 7 and 12 g for p53- and p53+ cases, respectively, P = 0.04; daily total meat intake was 69 and 100 g for p53- and p53+ cases, respectively, P = 0.03 and daily red meat intake was 39 and 75 g for p53- and p53+ cases, respectively, P = 0.01). Each 50 g/day increment in total meat intake was associated with having p53 mutations in cases with advanced Dukes' stages [odds ratio (OR): 3.43, 95% confidence interval (CI): 1.47-7.96]. Similarly, each 50 g/day increment in red meat intake was also significantly associated with having consistent p53 mutations in cases with advanced Dukes' stages (OR: 2.42, 95% CI: 1.18-4.96). These effects of total meat or red meat intake and advanced Dukes' stages were independent of age, sex, body mass index, smoking and alcohol intake. Furthermore, P values for interaction between daily total meat or red meat intake and Dukes' stages were statistically significant in multivariable models (Pinteraction < 0.001). Our results suggest that p53 mutations accelerate progression of CRC to advanced Dukes' stage in association with higher meat especially red meat intakes.

Dietary, lifestyle and clinicopathological factors associated with BRAF and K-ras mutations arising in distinct subsets of colorectal cancers in the EPIC Norfolk study.

BACKGROUND: BRAF and K-ras proto-oncogenes encode components of the ERK signalling pathway and are frequently mutated in colorectal cancer. This study investigates the associations between BRAF and K-ras mutations and clinicopathological, lifestyle and dietary factors in colorectal cancers. METHODS: 186 adenocarcinomas and 16 adenomas from the EPIC Norfolk study were tested for BRAF and K-ras mutations. Diet and lifestyle data were collected prospectively using seven day food diaries. RESULTS: BRAF V600E mutation was found in 15.6% of colorectal cancers but at higher frequencies in cancers with proximal location, poor differentiation and microsatellite instability (MSI) (all p < 0.001). K-ras mutation (mostly in codons 12 and 13) was found in 22.0% of colorectal cancers but at higher frequencies in cancers of more advanced Dukes' stage (p = 0.001), microsatellite stable (MSS) status (p = 0.002) and in individuals with lower blood high-density lipoprotein concentrations (p = 0.04). Analysis of dietary factors demonstrated no link between BRAF mutation and any specific dietary constituent, however, K-ras mutation was found at higher frequencies in individuals with higher white meat consumption (p < 0.001). Further analysis of specific mutation type demonstrated that G to A transitions in K-ras were observed at higher frequencies in individuals consuming lower amounts of fruit (p = 0.02). CONCLUSION: These data support the model of BRAF and K-ras mutations arising in distinct colorectal cancer subsets associated with different clinicopathological and dietary factors, acting as mutually exclusive mechanisms of activation of the same signalling pathway.

Phyllodes tumour of the prostate posing diagnostic and therapeutic dilemmas.

A rare case of phyllodes tumour of the prostate of which less than 100 cases have been reported in the literature. It has an unclear clinical course and uncertain management options. In an inoperable case such as this, the authors discuss the difficulties faced with its management and the limited, possibly palliative role, of hormonal treatment using luteinising hormone-releasing hormone analogue in managing it over a medium term.

Spontaneous mediastinal haemorrhage linked with thymic carcinoma and myelodysplasia: a case report.

We report an unusual sequence of clinico-pathological manifestations of myelodysplastic syndrome and thymic squamous cell carcinoma. A 77-year-old man with a two-month history of myelodysplastic syndrome was admitted with acute chest pain and shortness of breath. Radiological investigations revealed an anterior mediastinal mass, associated with mediastinal haemorrhage. The mass was excised via a standard median sternotomy and was found to be an infiltrating squamous cell carcinoma, which arose from a multilocular thymic cyst.