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1.  The randomised clinical trial and the hazard ratio – medical research’s Emperor’s New Clothes? 
BMC Cancer  2014;14:260.
As the enthusiasm for individualized treatment and targeted therapies continues to gain momentum, it seems timely to re-assess whether our current research tools are fit for purpose. Randomized Clinical Trials compare groups of patients, the Hazard Ratio is a ‘group summary statistic’, and modeling shows that the same Hazard Ratio score could result from a number of scenarios. Thus the current tools do not provide definitive information as to how to treat an individual patient. We therefore need to concentrate on the use of predictive factor analyses to identify the characteristics of subgroups of patients who respond to specific treatments.
PMCID: PMC4003285  PMID: 24731512
Randomised clinical trials; Hazard ratio; Individualized treatment; Targeted therapy; Predictive analyses
2.  Effect of dabrafenib on melanoma cell lines harbouring the BRAFV600D/R mutations 
BMC Cancer  2013;13:17.
Conventional therapeutic agents are largely unsatisfactory into the treatment of malignant melanoma. Recently, an innovative approach based on inhibitors of the mutated BRAF gene (which represents the most prevalent alteration in melanoma patients) appears very promising from the clinical point of view. On this regard, a new compound, dabrafenib (GSK2118436), has been demonstrated to be effective in patients carrying the BRAFV600E/K mutations. We here tested dabrafenib for its capability to inhibit cell growth on primary melanoma cell lines, established from patients' tumour tissues and carrying the BRAFV600D/R mutations.
Three melanoma cell lines were tested: M257 wild-type BRAF, LCP BRAFV600R and WM266 BRAFV600D. The MTT assays were performed using standardized approaches. To evaluate the inhibition of MAPK pathway and the consequent inhibition of cellular proliferation, the phosphorylation of ERK was examined by Western Blot analysis performed on total protein extracts from cell lines after treatment with dabrafenib.
Our experiments demonstrated an effective action of Dabrafenib (GSK2118436) and the inhibition of MAPK pathway in melanoma cell lines carrying BRAFV600D/R mutations.
These results could be helpful to enlarge the number of melanoma patients who may benefit of a more effective targeted treatment.
PMCID: PMC3586362  PMID: 23317446
BRAF inhibitor; Dabrafenib; Growth inhibition; Melanoma therapy
3.  HPV infection, anal intra-epithelial neoplasia (AIN) and anal cancer: current issues 
BMC Cancer  2012;12:398.
Human papillomavirus (HPV) is well known as the major etiological agent for ano-genital cancer. In contrast to cervical cancer, anal cancer is uncommon, but is increasing steadily in the community over the last few decades. However, it has undergone an exponential rise in the men who have sex with men (MSM) and HIV + groups. HIV + MSM in particular, have anal cancer incidences about three times that of the highest worldwide reported cervical cancer incidences.
There has therefore traditionally been a lack of data from studies focused on heterosexual men and non-HIV + women. There is also less evidence reporting on the putative precursor lesion to anal cancer (AIN – anal intraepithelial neoplasia), when compared to cervical cancer and CIN (cervical intraepithelial neoplasia). This review summarises the available biological and epidemiological evidence for HPV in the anal site and the pathogenesis of AIN and anal cancer amongst traditionally non-high risk groups.
There is strong evidence to conclude that high-grade AIN is a precursor to anal cancer, and some data on the progression of AIN to invasive cancer.
PMCID: PMC3488563  PMID: 22958276
Anal cancer; Anal intraepithelial neoplasia; AIN; Progression; Human papillomavirus
4.  Improving quality of breast cancer surgery through development of a national breast cancer surgical outcomes (BRCASO) research database 
BMC Cancer  2012;12:136.
Common measures of surgical quality are 30-day morbidity and mortality, which poorly describe breast cancer surgical quality with extremely low morbidity and mortality rates. Several national quality programs have collected additional surgical quality measures; however, program participation is voluntary and results may not be generalizable to all surgeons. We developed the Breast Cancer Surgical Outcomes (BRCASO) database to capture meaningful breast cancer surgical quality measures among a non-voluntary sample, and study variation in these measures across providers, facilities, and health plans. This paper describes our study protocol, data collection methods, and summarizes the strengths and limitations of these data.
We included 4524 women ≥18 years diagnosed with breast cancer between 2003-2008. All women with initial breast cancer surgery performed by a surgeon employed at the University of Vermont or three Cancer Research Network (CRN) health plans were eligible for inclusion. From the CRN institutions, we collected electronic administrative data including tumor registry information, Current Procedure Terminology codes for breast cancer surgeries, surgeons, surgical facilities, and patient demographics. We supplemented electronic data with medical record abstraction to collect additional pathology and surgery detail. All data were manually abstracted at the University of Vermont.
The CRN institutions pre-filled 30% (22 out of 72) of elements using electronic data. The remaining elements, including detailed pathology margin status and breast and lymph node surgeries, required chart abstraction. The mean age was 61 years (range 20-98 years); 70% of women were diagnosed with invasive ductal carcinoma, 20% with ductal carcinoma in situ, and 10% with invasive lobular carcinoma.
The BRCASO database is one of the largest, multi-site research resources of meaningful breast cancer surgical quality data in the United States. Assembling data from electronic administrative databases and manual chart review balanced efficiency with high-quality, unbiased data collection. Using the BRCASO database, we will evaluate surgical quality measures including mastectomy rates, positive margin rates, and partial mastectomy re-excision rates among a diverse, non-voluntary population of patients, providers, and facilities.
PMCID: PMC3350402  PMID: 22472011
5.  Report on emerging technologies for translational bioinformatics: a symposium on gene expression profiling for archival tissues 
BMC Cancer  2012;12:124.
With over 20 million formalin-fixed, paraffin-embedded (FFPE) tissue samples archived each year in the United States alone, archival tissues remain a vast and under-utilized resource in the genomic study of cancer. Technologies have recently been introduced for whole-transcriptome amplification and microarray analysis of degraded mRNA fragments from FFPE samples, and studies of these platforms have only recently begun to enter the published literature.
The Emerging Technologies for Translational Bioinformatics symposium on gene expression profiling for archival tissues featured presentations of two large-scale FFPE expression profiling studies (each involving over 1,000 samples), overviews of several smaller studies, and representatives from three leading companies in the field (Illumina, Affymetrix, and NuGEN). The meeting highlighted challenges in the analysis of expression data from archival tissues and strategies being developed to overcome them. In particular, speakers reported higher rates of clinical sample failure (from 10% to 70%) than are typical for fresh-frozen tissues, as well as more frequent probe failure for individual samples. The symposium program is available at
Multiple solutions now exist for whole-genome expression profiling of FFPE tissues, including both microarray- and sequencing-based platforms. Several studies have reported their successful application, but substantial challenges and risks still exist. Symposium speakers presented novel methodology for analysis of FFPE expression data and suggestions for improving data recovery and quality assessment in pre-analytical stages. Research presentations emphasized the need for careful study design, including the use of pilot studies, replication, and randomization of samples among batches, as well as careful attention to data quality control. Regardless of any limitations in quantitave transcriptomics for FFPE tissues, they are often the only biospecimens available for large patient populations with long-term history and clinical follow-up. Current challenges can be expected to remain as RNA sequencing matures, and they will thus motivate ongoing research efforts into noise reduction and identification of robust, translationally relevant biological signals in expression data from FFPE tissues.
PMCID: PMC3342119  PMID: 22458912
6.  Eastern asian expert panel opinion: designing clinical trials of molecular targeted therapy for hepatocellular carcinoma 
BMC Cancer  2010;10:620.
The largest burden of hepatocellular carcinoma (HCC) lies in Asia, secondary to hepatitis B virus (HBV) infection. Improved survival with sorafenib has fostered new research but many challenges remain in designing clinical trials. The disease, its management, and populations affected by it are heterogeneous worldwide and within Asia. An expert conference of Eastern Asian oncologists and hepatologists was convened to foster consensus in clinical trial design. The panel identified key areas that need to be addressed to facilitate clinical trials in Asia. Stratification by viral etiology is desirable within Asia and by region in global trials. Antiviral therapy should also be considered as a stratification factor and incorporated into HCC management in trials. The panel agreed that histological diagnosis is not required for trial entry and that Barcelona-Clinic Liver Cancer (BCLC) staging is acceptable for trials as long as portal hypertension can be better defined with standardized methodology. Consensus in treatment must be sought to allow multi-national trials and it must be recognized that first-line sorafenib is not largely feasible in Asia. Finally, Asian nations must be urged to participate in clinical trials, many of which are ongoing, to advance new treatment options in this challenging disease.
PMCID: PMC2989333  PMID: 21062497
7.  A simple algebraic cancer equation: calculating how cancers may arise with normal mutation rates 
BMC Cancer  2010;10:3.
The purpose of this article is to present a relatively easy to understand cancer model where transformation occurs when the first cell, among many at risk within a colon, accumulates a set of driver mutations. The analysis of this model yields a simple algebraic equation, which takes as inputs the number of stem cells, mutation and division rates, and the number of driver mutations, and makes predictions about cancer epidemiology.
The equation [p = 1 - (1 - (1 - (1 - u)d)k)Nm ] calculates the probability of cancer (p) and contains five parameters: the number of divisions (d), the number of stem cells (N × m), the number of critical rate-limiting pathway driver mutations (k), and the mutation rate (u). In this model progression to cancer "starts" at conception and mutations accumulate with cell division. Transformation occurs when a critical number of rate-limiting pathway mutations first accumulates within a single stem cell.
When applied to several colorectal cancer data sets, parameter values consistent with crypt stem cell biology and normal mutation rates were able to match the increase in cancer with aging, and the mutation frequencies found in cancer genomes. The equation can help explain how cancer risks may vary with age, height, germline mutations, and aspirin use. APC mutations may shorten pathways to cancer by effectively increasing the numbers of stem cells at risk.
The equation illustrates that age-related increases in cancer frequencies may result from relatively normal division and mutation rates. Although this equation does not encompass all of the known complexity of cancer, it may be useful, especially in a teaching setting, to help illustrate relationships between small and large cancer features.
PMCID: PMC2829925  PMID: 20051132
8.  The relation between smokeless tobacco and cancer in Northern Europe and North America. A commentary on differences between the conclusions reached by two recent reviews 
BMC Cancer  2009;9:256.
Smokeless tobacco is an alternative for smokers who want to quit but require nicotine. Reliable evidence on its effects is needed. Boffetta et al. and ourselves recently reviewed the evidence on cancer, based on Scandinavian and US studies. Boffetta et al. claimed a significant 60–80% increase for oropharyngeal, oesophageal and pancreatic cancer, and a non-significant 20% increase for lung cancer, data for other cancers being "too sparse". We found increases less than 15% for oesophageal, pancreatic and lung cancer, and a significant 36% increase for oropharyngeal cancer, which disappeared in recent studies. We found no association with stomach, bladder and all cancers combined, using data as extensive as that for oesophageal, pancreatic and lung cancer. We explain these differences.
For those cancers Boffetta et al. considered, we compared the methods, studies and risk estimates used in the two reviews.
One major reason for the difference is our more consistent approach in choosing between study-specific never smoker and combined smoker/non-smoker estimates. Another is our use of derived as well as published estimates. We included more studies, and avoided estimates for data subsets. Boffetta et al. also included some clearly biased or not smoking-adjusted estimates. For pancreatic cancer, their review included significantly increased never smoker estimates in one study and combined smoker/non-smoker estimates in another, omitting a combined estimate in the first study and a never smoker estimate in the second showing no increase. For oesophageal cancer, never smoker results from one study showing a marked increase for squamous cell carcinoma were included, but corresponding results for adenocarcinoma and combined smoker/non-smoker results for both cell types showing no increase were excluded. For oropharyngeal cancer, Boffetta et al. included a markedly elevated estimate that was not smoking-adjusted, and overlooked the lack of association in recent studies.
When conducting meta-analyses, all relevant data should be used, with clear rules governing the choice between alternative estimates. A systematic meta-analysis using pre-defined procedures and all relevant data gives a lower estimate of cancer risk from smokeless tobacco (probably 1–2% of that from smoking) than does the previous review by Boffetta et al.
PMCID: PMC3087330  PMID: 19638246
9.  Contamination and sample mix-up can best explain some patterns of mtDNA instabilities in buccal cells and oral squamous cell carcinoma 
BMC Cancer  2009;9:113.
The study of somatic DNA instabilities constitutes a debatable topic because different causes can lead to seeming DNA alteration patterns between different cells or tissues from the same individual. Carcinogenesis or the action of a particular toxic could generate such patterns, and this is in fact the leitmotif of a number of studies on mitochondrial DNA (mtDNA) instability. Patterns of seeming instabilities could also arise from technical errors at any stage of the analysis (DNA extraction, amplification, mutation screening/sequencing, and documentation). Specifically, inadvertent DNA contamination or sample mixing would yield mosaic variation that could be erroneously interpreted as real mutation differences (instabilities) between tissues from the same individual. From the very beginning, mtDNA studies comparing cancerous to non-cancerous tissues have suffered from such mosaic results. We demonstrate here that the phylogenetic linkage of whole arrays of mtDNA mutations provides strong evidence of artificial recombination in previous studies on buccal cells and oral squamous cell carcinoma.
PMCID: PMC2678148  PMID: 19371404

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