Critical research gaps and translational priorities for the successful prevention and treatment of breast cancer

INTRODUCTION Breast cancer remains a significant scientific, clinical and societal challenge. This gap analysis has reviewed and critically assessed enduring issues and new challenges emerging from recent research, and proposes strategies for translating solutions into practice. METHODS More than 100 internationally recognised specialist breast cancer scientists, clinicians and healthcare professionals collaborated to address nine thematic areas: genetics, epigenetics and epidemiology; molecular pathology and cell biology; hormonal influences and endocrine therapy; imaging, detection and screening; current/novel therapies and biomarkers; drug resistance; metastasis, angiogenesis, circulating tumour cells, cancer 'stem' cells; risk and prevention; living with and managing breast cancer and its treatment. The groups developed summary papers through an iterative process which, following further appraisal from experts and patients, were melded into this summary account. RESULTS The 10 major gaps identified were: (1) understanding the functions and contextual interactions of genetic and epigenetic changes in normal breast development and during malignant transformation; (2) how to implement sustainable lifestyle changes (diet, exercise and weight) and chemopreventive strategies; (3) the need for tailored screening approaches including clinically actionable tests; (4) enhancing knowledge of molecular drivers behind breast cancer subtypes, progression and metastasis; (5) understanding the molecular mechanisms of tumour heterogeneity, dormancy, de novo or acquired resistance and how to target key nodes in these dynamic processes; (6) developing validated markers for chemosensitivity and radiosensitivity; (7) understanding the optimal duration, sequencing and rational combinations of treatment for improved personalised therapy; (8) validating multimodality imaging biomarkers for minimally invasive diagnosis and monitoring of responses in primary and metastatic disease; (9) developing interventions and support to improve the survivorship experience; (10) a continuing need for clinical material for translational research derived from normal breast, blood, primary, relapsed, metastatic and drug-resistant cancers with expert bioinformatics support to maximise its utility. The proposed infrastructural enablers include enhanced resources to support clinically relevant in vitro and in vivo tumour models; improved access to appropriate, fully annotated clinical samples; extended biomarker discovery, validation and standardisation; and facilitated cross-discipline working. CONCLUSIONS With resources to conduct further high-quality targeted research focusing on the gaps identified, increased knowledge translating into improved clinical care should be achievable within five years

cDNA sequencing improves the detection of P53 missense mutations in colorectal cancer

<p>Abstract</p> <p>Background</p> <p>Recently published data showed discrepancies beteween <it>P53 </it>cDNA and DNA sequencing in glioblastomas. We hypothesised that similar discrepancies may be observed in other human cancers.</p> <p>Methods</p> <p>To this end, we analyzed 23 colorectal cancers for <it>P53 </it>mutations and gene expression using both DNA and cDNA sequencing, real-time PCR and immunohistochemistry.</p> <p>Results</p> <p>We found <it>P53 </it>gene mutations in 16 cases (15 missense and 1 nonsense). Two of the 15 cases with missense mutations showed alterations based only on cDNA, and not DNA sequencing. Moreover, in 6 of the 15 cases with a cDNA mutation those mutations were difficult to detect in the DNA sequencing, so the results of DNA analysis alone could be misinterpreted if the cDNA sequencing results had not also been available. In all those 15 cases, we observed a higher ratio of the mutated to the wild type template by cDNA analysis, but not by the DNA analysis. Interestingly, a similar overexpression of <it>P53 </it>mRNA was present in samples with and without <it>P53 </it>mutations.</p> <p>Conclusion</p> <p>In terms of colorectal cancer, those discrepancies might be explained under three conditions: 1, overexpression of mutated <it>P53 </it>mRNA in cancer cells as compared with normal cells; 2, a higher content of cells without <it>P53 </it>mutation (normal cells and cells showing <it>K-RAS </it>and/or <it>APC </it>but not <it>P53 </it>mutation) in samples presenting <it>P53 </it>mutation; 3, heterozygous or hemizygous mutations of <it>P53 </it>gene. Additionally, for heterozygous mutations unknown mechanism(s) causing selective overproduction of mutated allele should also be considered. Our data offer new clues for studying discrepancy in <it>P53 </it>cDNA and DNA sequencing analysis.</p

Little evidence for an epidemic of myopia in Australian primary school children over the last 30 years

BACKGROUND: Recently reported prevalences of myopia in primary school children vary greatly in different regions of the world. This study aimed to estimate the prevalence of refractive errors in an unselected urban population of young primary school children in eastern Sydney, Australia, between 1998 and 2004, for comparison with our previously published data gathered using the same protocols and other Australian studies over the last 30 years. METHODS: Right eye refractive data from non-cycloplegic retinoscopy was analysed for 1,936 children aged 4 to 12 years who underwent a full eye examination whilst on a vision science excursion to the Vision Education Centre Clinic at the University of New South Wales. Myopia was defined as spherical equivalents equal to or less than -0.50 D, and hyperopia as spherical equivalents greater than +0.50 D. RESULTS: The mean spherical equivalent decreased significantly (p < 0.0001) with age from +0.73 ± 0.1D (SE) at age 4 to +0.21 ± 0.11D at age 12 years. The proportion of children across all ages with myopia of -0.50D or more was 8.4%, ranging from 2.3% of 4 year olds to 14.7% of 12 year olds. Hyperopia greater than +0.50D was present in 38.4%. A 3-way ANOVA for cohort, age and gender of both the current and our previous data showed a significant main effect for age (p < 0.0001) but not for cohort (p = 0.134) or gender (p = 0.61). CONCLUSIONS: Comparison of our new data with our early 1990s data and that from studies of over 8,000 Australian non-clinical rural and urban children in the 1970's and 1980's provided no evidence for the rapidly increasing prevalence of myopia described elsewhere in the world. In fact, the prevalence of myopia in Australian children continues to be significantly lower than that reported in Asia and North America despite changing demographics. This raises the issue of whether these results are a reflection of Australia's stable educational system and lifestyle over the last 30 years

Reduction of missed appointments at an urban primary care clinic: a randomised controlled study

<p>Abstract</p> <p>Background</p> <p>Missed appointments are known to interfere with appropriate care and to misspend medical and administrative resources. The aim of this study was to test the effectiveness of a sequential intervention reminding patients of their upcoming appointment and to identify the profile of patients missing their appointments.</p> <p>Methods</p> <p>We conducted a randomised controlled study in an urban primary care clinic at the Geneva University Hospitals serving a majority of vulnerable patients. All patients booked in a primary care or HIV clinic at the Geneva University Hospitals were sent a reminder 48 hrs prior to their appointment according to the following sequential intervention: 1. Phone call (fixed or mobile) reminder; 2. If no phone response: a Short Message Service (SMS) reminder; 3. If no available mobile phone number: a postal reminder. The rate of missed appointment, the cost of the intervention, and the profile of patients missing their appointment were recorded.</p> <p>Results</p> <p>2123 patients were included: 1052 in the intervention group, 1071 in the control group. Only 61.7% patients had a mobile phone recorded at the clinic. The sequential intervention significantly reduced the rate of missed appointments: 11.4% (n = 122) in the control group and 7.8% (n = 82) in the intervention group (p < 0.005), and allowed to reallocate 28% of cancelled appointments. It also proved to be cost effective in providing a total net benefit of 1846. - EUR/3 months. A satisfaction survey conducted with 241 patients showed that 93% of them were not bothered by the reminders and 78% considered them to be useful. By multivariate analysis, the following characteristics were significant predictors of missed appointments: younger age (OR per additional decade 0.82; CI 0.71-0.94), male gender (OR 1.72; CI 1.18-2.50), follow-up appointment >1year (OR 2.2; CI: 1.15-4.2), substance abuse (2.09, CI 1.21-3.61), and being an asylum seeker (OR 2.73: CI 1.22-6.09).</p> <p>Conclusion</p> <p>A practical reminder system can significantly increase patient attendance at medical outpatient clinics. An intervention focused on specific patient characteristics could further increase the effectiveness of appointment reminders.</p

Noncutaneous malignant melanoma: a prognostic model from a retrospective multicenter study

Abstract Background We performed multicenter study to define clinical characteristics of noncutaneous melanomas and to establish prognostic factors patients who received curative resection. Methods Of the 141 patients who were diagnosed of non-cutaneous melanoma at 4 institutions in Korea between June 1992 and May 2005, 129 (91.5%) satisfied the selection criteria. Results Of the 129 noncutaneous melanoma patients, 14 patients had ocular melanoma and 115 patients had mucosal melanoma. For mucosal melanoma, anorectum was the most common anatomic site (n = 39, 30.2%) which was followed by nasal cavity (n = 30, 23.3%), genitourinary (n = 21, 16.3%), oral cavity (n = 14, 10.9%), upper gastrointestinal tract (n = 6, 4.7%) and maxillary sinus (n = 5, 3.9%) in the order of frequency. With the median 64.5 (range 4.3-213.0) months follow-up, the median overall survival were 24.4 months (95% CI 13.2-35.5) for all patients, and 34.6 (95% CI 24.5-44.7) months for curatively resected mucosal melanoma patients. Adverse prognostic factors of survival for 87 curatively resected mucosal melanoma patients were complete resection (R1 resection margin), and age > 50 years. For 14 ocular melanoma, Survival outcome was much better than mucosal melanoma with 73.3% of 2 year OS and 51.2 months of median OS (P = .04). Conclusion Prognosis differed according to primary sites of noncutaneous melanoma. Based on our study, noncutaneous melanoma patients should be treated differently to improve survival outcome.Peer Reviewe

Cross-Platform Array Screening Identifies COL1A2, THBS1, TNFRSF10D and UCHL1 as Genes Frequently Silenced by Methylation in Melanoma

Epigenetic regulation of tumor suppressor genes (TSGs) has been shown to play a central role in melanomagenesis. By integrating gene expression and methylation array analysis we identified novel candidate genes frequently methylated in melanoma. We validated the methylation status of the most promising genes using highly sensitive Sequenom Epityper assays in a large panel of melanoma cell lines and resected melanomas, and compared the findings with those from cultured melanocytes. We found transcript levels of UCHL1, COL1A2, THBS1 and TNFRSF10D were inversely correlated with promoter methylation. For THBS1 and UCHL1 the effect of this methylation on expression was confirmed at the protein level. Identification of these candidate TSGs and future research designed to understand how their silencing is related to melanoma development will increase our understanding of the etiology of this cancer and may provide tools for its early diagnosis

Integrative Genome Comparison of Primary and Metastatic Melanomas

A cardinal feature of malignant melanoma is its metastatic propensity. An incomplete view of the genetic events driving metastatic progression has been a major barrier to rational development of effective therapeutics and prognostic diagnostics for melanoma patients. In this study, we conducted global genomic characterization of primary and metastatic melanomas to examine the genomic landscape associated with metastatic progression. In addition to uncovering three genomic subclasses of metastastic melanomas, we delineated 39 focal and recurrent regions of amplification and deletions, many of which encompassed resident genes that have not been implicated in cancer or metastasis. To identify progression-associated metastasis gene candidates, we applied a statistical approach, Integrative Genome Comparison (IGC), to define 32 genomic regions of interest that were significantly altered in metastatic relative to primary melanomas, encompassing 30 resident genes with statistically significant expression deregulation. Functional assays on a subset of these candidates, including MET, ASPM, AKAP9, IMP3, PRKCA, RPA3, and SCAP2, validated their pro-invasion activities in human melanoma cells. Validity of the IGC approach was further reinforced by tissue microarray analysis of Survivin showing significant increased protein expression in thick versus thin primary cutaneous melanomas, and a progression correlation with lymph node metastases. Together, these functional validation results and correlative analysis of human tissues support the thesis that integrated genomic and pathological analyses of staged melanomas provide a productive entry point for discovery of melanoma metastases genes

The HELLP syndrome: Clinical issues and management. A Review

<p>Abstract</p> <p>Background</p> <p>The HELLP syndrome is a serious complication in pregnancy characterized by haemolysis, elevated liver enzymes and low platelet count occurring in 0.5 to 0.9% of all pregnancies and in 10–20% of cases with severe preeclampsia. The present review highlights occurrence, diagnosis, complications, surveillance, corticosteroid treatment, mode of delivery and risk of recurrence.</p> <p>Methods</p> <p>Clinical reports and reviews published between 2000 and 2008 were screened using Pub Med and Cochrane databases.</p> <p>Results and conclusion</p> <p>About 70% of the cases develop before delivery, the majority between the 27th and 37th gestational weeks; the remainder within 48 hours after delivery. The HELLP syndrome may be complete or incomplete. In the Tennessee Classification System diagnostic criteria for HELLP are haemolysis with increased LDH (> 600 U/L), AST (≥ 70 U/L), and platelets < 100·10⁹/L. The Mississippi Triple-class HELLP System further classifies the disorder by the nadir platelet counts. The syndrome is a progressive condition and serious complications are frequent. Conservative treatment (≥ 48 hours) is controversial but may be considered in selected cases < 34 weeks' gestation. Delivery is indicated if the HELLP syndrome occurs after the 34th gestational week or the foetal and/or maternal conditions deteriorate. Vaginal delivery is preferable. If the cervix is unfavourable, it is reasonable to induce cervical ripening and then labour. In gestational ages between 24 and 34 weeks most authors prefer a single course of corticosteroid therapy for foetal lung maturation, either 2 doses of 12 mg betamethasone 24 hours apart or 6 mg or dexamethasone 12 hours apart before delivery. Standard corticosteroid treatment is, however, of uncertain clinical value in the maternal HELLP syndrome. High-dose treatment and repeated doses should be avoided for fear of long-term adverse effects on the foetal brain. Before 34 weeks' gestation, delivery should be performed if the maternal condition worsens or signs of intrauterine foetal distress occur. Blood pressure should be kept below 155/105 mmHg. Close surveillance of the mother should be continued for at least 48 hours after delivery.</p