The DietCompLyf study: A prospective cohort study of breast cancer survival and phytoestrogen consumption

DietCompLyf is a multi-centre prospective study designed to investigate associations between phytoestrogens - naturally occurring plant compounds with oestrogenic properties - and other diet and lifestyle factors with breast cancer recurrence and survival. 3159 women with grades I-III breast cancer were recruited 9-15 months post-diagnosis from 56 UK hospitals. Detailed information on clinico-pathological, diet, lifestyle and quality of life is collected annually up to 5 years. Biological samples have also been collected as a resource for subsequent evaluation. The characteristics of the patients and associations between pre-diagnosis intake of phytoestrogens (isoflavones and lignans; assessed using the EPIC-Norfolk UK 130 question food frequency questionnaire) and breast cancer (i) risk factors and (ii) prognostic factors are described for 1797 women who had complete data for all covariates and phytoestrogens of interest. Isoflavone intakes were higher in the patients who were younger at diagnosis, in the non-smokers, those who had breast-fed and those who took supplements. Lignan intakes were higher in patients with a higher age at diagnosis, in ex-smokers, those who had breast-fed, who took supplements, had a lower BMI at diagnosis, lower age at menarche and were nulliparous. No significant associations between pre-diagnosis phytoestrogen intake and factors associated with improved breast cancer prognosis were observed. The potential for further exploration of the relationship between phytoestrogens and breast cancer recurrence and survival, and for the establishment of evidence to improve dietary and lifestyle advice offered to patients following breast cancer diagnosis using DietCompLyf data is discussed.

Biomarkers in nutrition: new frontiers in research and application

Nutritional biomarkers-biochemical, functional, or clinical indices of nutrient intake, status, or functional effects--are needed to support evidence-based clinical guidance and effective health programs and policies related to food, nutrition, and health. Such indices can reveal information about biological or physiological responses to dietary behavior or pathogenic processes, and can be used to monitor responses to therapeutic interventions and to provide information on interindividual differences in response to diet and nutrition. Many nutritional biomarkers are available; yet there has been no formal mechanism to establish consensus regarding the optimal biomarkers for particular nutrients and applications.

Human papilloma viruses (HPVs) no co-existence in breast cancer and cervical cells in the same patient

High-risk HPVs were detected in both breast cancer tissues and cervical cells from 56 breast cancer patients. The results suggested that HPV infection did not coexist in breast and cervical tissues. HPV infection of the breast cancer tissue is more likely to happen in patients without cervical infection.

Epidemiology of MPN: What Do We Know?

The myeloproliferative neoplasms, are characterised by overproduction of myeloid cells. Chronic myeloid leukaemia, polycythaemia vera, essential thrombocythaemia, myelofibrosis and the very rare disorders chronic neutrophilic leukaemia, chronic eosinophilic leukaemia not otherwise specified and mastocytosis are all included in the group. Incidence and prevalence rates reported in the worldwide literature are presented in this review. Survival data on each condition is described. Information on the aetiology of the disorders is discussed including body mass index, diet, smoking and alcohol, allergies, associated medical conditions, occupation and environmental exposures with focus on recent new studies. The aetiology of the myeloproliferative neoplasms remains unknown, and this review of the current state of knowledge highlights the need for further comprehensive research.

Cancer survivors with self-reported late effects: their health status, care needs and service utilisation

OBJECTIVE: Cancer survivors (CSs) are at risk of developing late effects (LEs) associated with the disease and its treatment. This paper compares the health status, care needs and use of health services by CSs with LEs and CSs without LEs.

METHODS: Cancer survivors (n = 613) were identified via the Northern Ireland Cancer Registry and invited to participate in a postal survey that was administered by their general practitioner. The survey assessed self-reported LEs, health status, health service use and unmet care needs. A total of 289 (47%) CSs responded to the survey, and 93% of respondents completed a LEs scale.

RESULTS: Forty-one per cent (111/269) of CSs reported LEs. Survivors without LEs and survivors with LEs were comparable in terms of age and gender. The LEs group reported a significantly greater number of co-morbidities, lower physical health and mental health scores, greater overall health service use and more unmet needs. Unadjusted logistic regression analysis found that cancer site, time since diagnosis and treatment were significantly associated with reporting of LEs. CSs who received combination therapies compared with CSs who received single treatments were over two and a half times more likely to report LEs (OR = 2.63, 95% CI = 1.32-5.25) after controlling for all other variables.

CONCLUSIONS: The CS population with LEs comprises a particularly vulnerable group of survivors who have multiple health care problems and needs and who require tailored care plans that take account of LEs and their impact on health-related quality of life.

S100A2 is a BRCA1/p63 coregulated tumour suppressor gene with roles in the regulation of mutant p53 stability

Here, we show for the first time that the familial breast/ovarian cancer susceptibility gene, BRCA1, along with interacting ΔNp63 proteins, transcriptionally upregulate the putative tumour suppressor protein, S100A2. Both BRCA1 and ΔNp63 proteins are required for S100A2 expression. BRCA1 requires ΔNp63 proteins for recruitment to the S100A2 proximal promoter region, while exogenous expression of individual ΔNp63 proteins cannot activate S100A2 transcription in the absence of a functional BRCA1. Consequently, mutation of the ΔNp63/p53 response element within the S100A2 promoter completely abrogates the ability of BRCA1 to upregulate S100A2. S100A2 shows growth control features in a range of cell models. Transient or stable exogenous S100A2 expression inhibits the growth of BRCA1 mutant and basal-like breast cancer cell lines, while short interfering RNA (siRNA) knockdown of S100A2 in non-tumorigenic cells results in enhanced proliferation. S100A2 modulates binding of mutant p53 to HSP90, which is required for efficient folding of mutant p53 proteins, by competing for binding to HSP70/HSP90 organising protein (HOP). HOP is a cochaperone that is required for the efficient transfer of proteins from HSP70 to HSP90. Loss of S100A2 leads to an HSP90-dependent stabilisation of mutant p53 with a concomitant loss of p63. Accordingly, S100A2-deficient cells are more sensitive to the HSP-90 inhibitor, 17-N-allylamino-17-demethoxygeldanamycin, potentially representing a novel therapeutic strategy for S100A2- and BRCA1-deficient cancers. Taken together, these data demonstrate the importance of S100A2 downstream of the BRCA1/ΔNp63 signalling axis in modulating transcriptional responses and enforcing growth control mechanisms through destabilisation of mutant p53.

The prognostic significance of the aberrant extremes of p53 immunophenotypes in breast cancer

Aims: The utility of p53 as a prognostic assay has been elusive. The aims of this study were to describe a novel, reproducible scoring system and assess the relationship between differential p53 immunohistochemistry (IHC) expression patterns, TP53 mutation status and patient outcomes in breast cancer.

Methods and Results: Tissue microarrays were used to study p53 IHC expression patterns: expression was defined as extreme positive (EP), extreme negative (EN), and non-extreme (NE; intermediate patterns). Overall survival (OS) was used to define patient outcome. A representative subgroup (n = 30) showing the various p53 immunophenotypes was analysed for TP53 hotspot mutation status (exons 4-9). Extreme expression of any type occurred in 176 of 288 (61%) cases. As compared with NE expression, EP expression was significantly associated (P = 0.039) with poorer OS. In addition, as compared with NE expression, EN expression was associated (P = 0.059) with poorer OS. Combining cases showing either EP or EN expression better predicted OS than either pattern alone (P = 0.028). This combination immunophenotype was significant in univariate but not multivariate analysis. In subgroup analysis, six substitution exon mutations were detected, all corresponding to extreme IHC phenotypes. Five missense mutations corresponded to EP staining, and the nonsense mutation corresponded to EN staining. No mutations were detected in the NE group.

Conclusions: Patients with extreme p53 IHC expression have a worse OS than those with NE expression. Accounting for EN as well as EP expression improves the prognostic impact. Extreme expression positively correlates with nodal stage and histological grade, and negatively with hormone receptor status. Extreme expression may relate to specific mutational status.

Prosthodontic rehabilitation of a patient using a swing-lock lower denture after segmental mandibulectomy

A swing-lock denture is useful in partially dentate patients where the configuration of the remaining teeth means that either the retention or stability available for a conventional removable partial denture is compromised. Such removable prostheses can also prove to be extremely useful when providing prosthodontic rehabilitation following surgical resection of oral cancer. A 20 year-old patient was referred to the Restorative Department of Cork University Dental Hospital following segmental mandibulectomy to treat a calicifying epithelial odontogenic tumour (Pindborg Tumour). Initial treatment using a conventional lower partial denture failed. This paper outlines the successfully rehabilitation using a lower Cobalt-Chromium swing-lock partial denture.

Presentation of a plasmablastic lymphoma in a human immunodeficiency virus-positive patient after administration of an inferior alveolar dental block

Human immunodeficiency virus (HIV) is a serious worldwide healthcare problem with implications for all healthcare workers. The reported oral manifestations of the disease are numerous and have been categorised according to the strength of their association with HIV infection. Oral non-Hodgkin's lymphoma is strongly associated with HIV infection, and an increased incidence of such neoplasms is widely reported. This case report details the presentation of a rare subcategory of plasmablastic lymphoma in an HIV-positive patient after administration of an inferior alveolar dental block to facilitate extraction of mandibular teeth. This highly aggressive neoplasm is a large B-cell lymphoma with a predilection for the oral cavity. Unfortunately, the prognosis for such a tumour is poor as detailed in this case.

FOXP3+ regulatory T-cell counts correlate with histological response in Crohn's colitis treated with infliximab

Crohn's disease is a chronic inflammatory bowel disease of unknown aetiology. Mucosal inflammatory dysregulation is likely important, with increased production of pro-inflammatory cytokines, including tumour necrosis factor alpha (TNFα). The chimeric monoclonal antibody, infliximab, inhibits TNFα and promotes intestinal mucosal healing. Despite this, many patients still require surgical intervention. Patients who have undergone colonic resection post-infliximab therapy, show markedly variable morphological response to treatment. FOXP3+ CD4+ regulatory T-cells have been shown to have a protective role in autoimmune/inflammatory diseases and their sequestration to the bowel is found in those treated with infliximab. We examined the immunohistochemical profile of lymphoid aggregates in tissue sections from post-infliximab Crohn's colitis resection specimens, classified as morphological responders or non-responders, defined in relation to the absence/presence of mucosal ulceration and active inflammation, and a control group. Results indicated no significant diffences in CD68-positive cell counts but increased FOXP3-positive (P = 0.02) and CD4-positive (P = 0.05) cell counts in responders versus non-responders. Untreated control scores were similar to non-responders. Although based on small study numbers, our results suggest an association between upregulation of FOXP3+/CD4+ regulatory T-cells and morphological response to infliximab therapy. This represents a possible quantitative methodology for monitoring therapeutic response to infliximab therapy, based on immunohistochemical evaluation of endoscopic biopsy specimens.

DEAD-box helicase DP103 defines metastatic potential of human breast cancers

Despite advancement in breast cancer treatment, 30% of patients with early breast cancers experience relapse with distant metastasis. It is a challenge to identify patients at risk for relapse; therefore, the identification of markers and therapeutic targets for metastatic breast cancers is imperative. Here, we identified DP103 as a biomarker and metastasis-driving oncogene in human breast cancers and determined that DP103 elevates matrix metallopeptidase 9 (MMP9) levels, which are associated with metastasis and invasion through activation of NF-κB. In turn, NF-κB signaling positively activated DP103 expression. Furthermore, DP103 enhanced TGF-β-activated kinase-1 (TAK1) phosphorylation of NF-κB-activating IκB kinase 2 (IKK2), leading to increased NF-κB activity. Reduction of DP103 expression in invasive breast cancer cells reduced phosphorylation of IKK2, abrogated NF-κB-mediated MMP9 expression, and impeded metastasis in a murine xenograft model. In breast cancer patient tissues, elevated levels of DP103 correlated with enhanced MMP9, reduced overall survival, and reduced survival after relapse. Together, these data indicate that a positive DP103/NF-κB feedback loop promotes constitutive NF-κB activation in invasive breast cancers and activation of this pathway is linked to cancer progression and the acquisition of chemotherapy resistance. Furthermore, our results suggest that DP103 has potential as a therapeutic target for breast cancer treatment.

RAS testing of colorectal carcinoma—a guidance document from the Association of Clinical Pathologists Molecular Pathology and Diagnostics Group

Analysis of colorectal carcinoma (CRC) tissue for KRAS codon 12 or 13 mutations to guide use of anti-epidermal growth factor receptor (EGFR) therapy is now considered mandatory in the UK. The scope of this practice has been recently extended because of data indicating that NRAS mutations and additional KRAS mutations also predict for poor response to anti-EGFR therapy. The following document provides guidance on RAS (i.e., KRAS and NRAS) testing of CRC tissue in the setting of personalised medicine within the UK and particularly within the NHS. This guidance covers issues related to case selection, preanalytical aspects, analysis and interpretation of such RAS testing.