European Journal Of Cancer Research Articles

Abstract B32: LY2940680, a hedgehog (Hh) pathway inhibitor, demonstrates anti-tumor activity in patients with advanced basal cell carcinoma (BCC)

Abstract We previously reported interim dose escalation results from this multi-center, open-label Phase 1 clinical trial (NCT01226485) (Bendell et al, EJC 2012). Here, we report the final aggregate safety results and the anti-tumor activity demonstrated by LY2940680, a novel Hh pathway inhibitor, in locally advanced (la) and metastatic (m) BCC. Methods: The primary objective of this study was to determine a recommended Phase 2 dose and regimen of LY2940680 that could be safely administered to patients with advanced cancer, including BCC. Patients deemed eligible for experimental therapy were enrolled in the study and dosed once daily (QD) for 28 day cycles until discontinuation. The maximum tolerated dose (MTD) was determined using a 3+3 dose escalation design. Based on initial anti-tumor activity, a cohort of la/m BCC patients was enrolled. Safety, PK/PD, and tumor response data were collected and analyzed. Results: A total of 84 advanced cancer patients were dosed, including 47 patients with la/m BCC. Median age was 62.5 years (range: 29-89). Advanced cancer patients received escalating doses ranging from 50 mg to 600 mg QD resulting in a MTD of 400 mg QD. The most commonly reported treatment-emergent adverse events (TEAE) possibly related to study drug (>20%) were dysgeusia (Gr 1-2: 46.4%, Gr 3: 2.4%), fatigue (Gr 1-2: 44.0%, Gr 3: 3.6%), nausea (Gr 1-2: 42.9%, Gr 3: 2.4%), muscle spasms (Gr 1-2: 35.7%, Gr 3: 4.8%), decreased appetite (Gr 1-2: 35.7%, Gr 3: 0%), vomiting (Gr 1-2: 29.7%, Gr 3: 2.4%), alopecia (Gr 1-2: 33.3%, Gr 3: 0%), and weight decrease (Gr 1-2: 26.2%, Gr 3: 1.2%). PK analysis showed no clear relationship between exposure (PK) and toxicity. PD marker analysis of Gli-1 mRNA from unaffected skin biopsies suggested all doses were biologically active (inhibition median of 91.7% with interquartile range (80.9-95.7%) in all patients with available pre- and post-treatment biopsies). The most common reasons for treatment discontinuation were progression of disease (n = 43), adverse event (n = 10) and withdrawal by subject (n = 10). All reported clinical responses (per RECIST 1.1) were in patients with la/m BCC. Overall response rate (ORR) for patients with la/m BCC (n = 47) was 46.8% (95% CI: 32.1-61.9%) and clinical benefit rate (CR+PR+SD) was 93.6% (95% CI: 82.5-98.7%). The median duration of response was estimated at 10.2 months (95% CI: 5.6- not estimable). Responses were observed in patients who were Hh treatment naïve (11/16) but also in patients who previously failed Hh therapy (11/31). Conclusion: LY2940680 treatment resulted in an acceptable safety profile in patients with advanced cancer including la/m BCC. Clinical responses were observed in la/m BCC patients naïve to Hh inhibitor treatment and also in those who had failed treatment with other Hh inhibitor agents. This phase 1 study supports further clinical development of LY2940680 in advanced BCC and potentially in other malignancies Citation Information: Bendell J. et al. European Journal of Cancer (EJC) 2012 48(6 Suppl) Abstract 594. Citation Format: Johanna Bendell, Valerie Andre, Alan Ho, Ragini Kudchadkar, Michael Migden, Jeffrey Infante, Ramon Tiu, Celine Pitou, Trevor Tucker, Les Brail, Daniel Von Hoff. LY2940680, a hedgehog (Hh) pathway inhibitor, demonstrates anti-tumor activity in patients with advanced basal cell carcinoma (BCC). [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B32.

Editorial introductions

Editorial introductions

Clinical practice guidelines and consensus statements in oncology--an assessment of their methodological quality.

BackgroundConsensus statements and clinical practice guidelines are widely available for enhancing the care of cancer patients. Despite subtle differences in their definition and purpose, these terms are often used interchangeably. We systematically assessed the methodological quality of consensus statements and clinical practice guidelines published in three commonly read, geographically diverse, cancer-specific journals. Methods Consensus statements and clinical practice guidelines published between January 2005 and September 2013 in Current Oncology, European Journal of Cancer and Journal of Clinical Oncology were evaluated. Each publication was assessed using the Appraisal of Guidelines for Research and Evaluation II (AGREE II) rigour of development and editorial independence domains. For assessment of transparency of document development, 7 additional items were taken from the Institute of Medicine’s standards for practice guidelines and the Journal of Clinical Oncology guidelines for authors of guidance documents.MethodsConsensus statements and clinical practice guidelines published between January 2005 and September 2013 in Current Oncology, European Journal of Cancer and Journal of Clinical Oncology were evaluated. Each publication was assessed using the Appraisal of Guidelines for Research and Evaluation II (AGREE II) rigour of development and editorial independence domains. For assessment of transparency of document development, 7 additional items were taken from the Institute of Medicine's standards for practice guidelines and the Journal of Clinical Oncology guidelines for authors of guidance documents.FindingsThirty-four consensus statements and 67 clinical practice guidelines were evaluated. The rigour of development score for consensus statements over the three journals was 32% lower than that of clinical practice guidelines. The editorial independence score was 15% lower for consensus statements than clinical practice guidelines. One journal scored consistently lower than the others over both domains. No journals adhered to all the items related to the transparency of document development. One journal’s consensus statements endorsed a product made by the sponsoring pharmaceutical company in 64% of cases.ConclusionGuidance documents are an essential part of oncology care and should be subjected to a rigorous and validated development process. Consensus statements had lower methodological quality than clinical practice guidelines using AGREE II. At a minimum, journals should ensure that that all consensus statements and clinical practice guidelines adhere to AGREE II criteria. Journals should consider explicitly requiring guidelines to declare pharmaceutical company sponsorship and to identify the sponsor’s product to enhance transparency.

Circulating microRNAs: Understanding the Limits for Quantitative Measurement by Real‐Time PCR

Ever since the discovery of small, non-coding RNAs in circulation, microRNAs have gained significant attention as biomarkers or, in some instances, regulators of disease and/or associated complications. Until now, most articles published use real-time quantitative PCR (qPCR) for assessment of

Reporting characteristics of cancer pain: A systematic review and quantitative analysis of articles published in cancer journals

Objective: Common symptom requiring palliation in oncologic care is cancer pain. Cancer pain is recognized as global health burden. This paper sought to systematically examine the extent to which there is an adequate scientific research base on cancer pain and henceforth its reporting characteristics in the cancer journal literature. Materials and Methods: Search was conducted in PubMed sought to locate all studies published in 19 cancer journals from 2009 to 2010. The journals included were: Anti-cancer drugs; breast cancer research and treatment; British Journal of Cancer; Bulletin in Cancer; cancer; Cancer and Chemotherapy; Cancer Chemotherapy and Pharmacology; Clinical Cancer Research; Cancer Epidemiology Biomarkers and Prevention; Cancer Genetics and Cytogenetics; Cancer Immunology and Immunotherapy; Cancer Letters; cancer research; European Journal of Cancer; Indian Journal of Cancer; International Journal of Gynecological Cancer; Journal of Cancer Research and Clinical Oncology; Journal of National Cancer Institute; Lung Cancer. Journal contents were searched to identify studies that included pain in title/abstract. Results: During the years 2009 and 2010, of the selected 14,537 articles published in the journals reviewed, only 1.19% (173 articles) was on cancer pain. Conclusion: While researchers in the field of cancer care have studied pain, the total percentage for studies is still a low 1.19%. It is critical that more research be reported upon which to base cancer pain therapy in an evidence-based oncologic care model.

Living with advanced breast cancer: Challenges and opportunities

Living with advanced breast cancer: Challenges and opportunities

‘Chemobrain’: concentration and memory effects in people receiving chemotherapy - a descriptive phenomenological study

There is an international literature which claims that there is a link between chemotherapeutic agents and cognitive impairment. Deficits in concentration and memory can have a major impact on decision making about education and careers, and on general quality of life. The literature to date is generally anecdotal, or reports on quantitative research that does not address patients' interpretations of impaired cognition. It was the intention of this study to capture experiences and perceptions of cognitive impairment as told by people receiving chemotherapy. A descriptive phenomenological approach was employed and four participants were interviewed twice. Analysis was conducted using Nvivo software alongside Hycner's analysis framework so that researchers could produce narratives to represent experiences for each case. The description for each case illuminates uniqueness and commonality. 'Chemobrain' is a significant and important issue for many patients but they are often unaware, prior to chemotherapy, that cognition may be affected. There is no shared understanding between patients and healthcare professionals and there is a lack of information about the phenomena which disempower patients. Healthcare professionals should develop knowledge and skills to recognise and address chemotherapy-induced cognitive impairment.

Foreword to Reflections on Drug Research by Sir James Black

In August 2002 Jim Black was diagnosed with inoperable metastatic prostate cancer. His urologist told me that life expectancy was around 2 years. Together we assessed our way of life and what mattered. At this time Jim was 78, and still enthusiastically going to work every weekday, mainly concentrating on his gastrin antagonist project. There was no question of this being slowed down but rather an appreciation that time was finite, and that he had less time than previously assumed to move this project forward, and also to initiate new projects or encourage longstanding trusted friends and colleagues to do so. So plans for the future, lobbying for financial support and preparing papers for publication continued. John Smythe of Edinburgh and the European Journal of Cancer was a champion who facilitated publication, and Malcolm Boyce of Hammersmith Medicines Research was and continues to be a much valued collaborator in the drive to bring the gastrin antagonist to market. On a wider level, Jim continued to be keen to talk to and enthuse young researchers to follow their dreams, not to settle for a safe confirmatory project along a well trodden path, but to push their able brains to the limits and work in novel exciting areas. Sadly not always the areas that Research Councils find attractive. As Jim became frailer over the last 6 months of his life, he was forced to spend more time at home at the computer than in his office at King's. The essay which follows this introduction on his reflections on drug research, covering both his personal experience and his thoughts for the future was written at this time. He wrote slowly and thoughtfully with many drafts of his manuscripts. His last alterations to this draft were made on February 10 2010. He died on March 22 having spent most of the previous 5 months in hospitals or hospices. His first request when he reached St Christopher's Hospice in south London was that the IT manager would set up his computer at the bedside. St Christopher's did not let him down. It has been a huge privilege to share life with such a deep and powerful intellect, and also unforgettably enjoyable to share the fun and friendships of our wider life together.

‘It's hard to take because I am a man's man’: an ethnographic exploration of cancer and masculinity

This paper reports on a study into male participation in cancer support groups, which elicited data on the impact of cancer on masculinities. This small qualitative pilot study, which took place in Belfast in Northern Ireland, involved semi-structured interviews with eight men with a history of cancer who were no longer being actively treated (i.e. they were not receiving chemotherapy or radiotherapy), and who were proficient in spoken and written English. Whereas most studies into men with cancer that have looked at issues of masculinity have been on prostate and/or testicular cancer and have tended to focus upon sexual ability and activity, this study identified more sociological issues of concern that also present challenges to masculinity and to male identity. Economic concerns were identified as being major issues for men, as were their changing role vis-à-vis their family, friends and colleagues, and changes to their body and to their body image. The findings from this study indicate that cancer support services need to be gender sensitive in order to ensure that interventions do not undermine masculine values but address men's concerns and foster their positive coping strategies.

Pentoxifylline and Vitamin E Treatment for Prevention of Radiation Induced Side Effects in Women with Breast Cancer: A Phase Two, Double Blind, Placebo Controlled Randomised Clinical Trial (Ptx-5).

Abstract Background: A previous study has shown that pentoxifylline in combination with vitamin E can reverse radiation induced fibrosis. Our aim in the present study was to investigate if the same drugs could prevent radiation induced side effects in women with breast cancer.Patients and Methods: A randomised, placebo-controlled, double blind, parallel group trial was performed. Women with breast cancer were treated for 12 months with pentoxifylline 400 mg t.i.d. or placebo, in combination with vitamin E 100 mg t.i.d. starting 1-3 months after the completion of radiotherapy. The primary endpoint was passive abduction of the shoulder, and the secondary endpoint was difference in arm volumes. The trial is registered on the ISRCTN.org website, number ISRCTN39143623.Results: 83 patients were included in the study; 42 in the pentoxifylline + vitamine E group and 41 in the placebo + vitamine E group. Both treatments were generally well tolerated. Seven patients were withdrawn from treatment due to disease progression; four in the pentoxifylline group and three in the placebo group. At inclusion patients had impaired passive abduction of the shoulder. During treatment both groups improved significantly. With one year of follow-up median improvement from baseline was 3.7° (p=0.0035) in the pentoxifylline group and 9.4° (p= 0.0041) in the placebo group, but no difference between the groups was detected (p=0.20). Arm volumes increased over time in the placebo group (1.04%), but not in the pentoxifylline group (0.50%). This difference between the groups was statistically significantl(p=0.0172).Conclusions: The combination of pentoxifylline and vitamin E was safe and may be used for prevention of some radiation induced side effects. We found that pentoxifylline in combination with vitamin E diminished development of lymphoedema.(Accepted for publication in European Journal of Cancer)Updated results with longer follow-up will be presented. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 4100.

East of England Breast Cancer Survival Close to Best in Europe.

Abstract Background: The Eurocare-4 (2000-2002) period analysis documents a mean European age-adjusted 5-year relative breast cancer survival of 79% with higher individual figures for Finland (85.7%), Norway (84.1% and Sweden (86.3%) (Lancet Oncol 2007; 8: 784-96). The corresponding figure for England was 77.8%. We now compare these predicted survival estimates with actual age-adjusted relative 5-year breast cancer overall survival (Corazziari et al, European Journal of Cancer 2004; 40:15: 2307-2316) for women diagnosed with invasive breast cancer in the East of England from 2000-2002Method: The East of England covers a population of 5.5 million people. 5-year age-adjusted relative breast cancer survival was calculated overall, and in specific age groups, for all women with invasive breast cancer diagnosed from 2000-2002 in the East of England for comparison with the results from the Eurocare-4 study.Results:Age-adjusted 5-year relative breast cancer survival in East of England for period 2000-2002.AGE GROUPRELATIVE SURVIVAL95% CI45-5487.5%86.1-88.9%55-6489.5%88.1-90.9%65-7483.9%81.1-86.1%75+73.3%70.1-76.4%ALL WOMEN82.5%81.4-83.6% Conclusion: These data confirm breast cancer survival rates for East of England that are close to European best figures for women aged 45-64. The age-adjusted survival of 82.5% for all women however is being reduced by worse survival in women aged 65+ and a strategy that ensures optimal breast cancer treatment for women in this age group should allow overall survival to improve even further. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2069.

The Portuguese version of the Body Image Scale (BIS) – psychometric properties in a sample of breast cancer patients

Purpose The aim of this study was to analyse the psychometric properties of the Portuguese version of the body image scale (BIS; Hopwood, P., Fletcher, I., Lee, A., Al Ghazal, S., 2001. A body image scale for use with cancer patients. European Journal of Cancer, 37, 189–197). This is a brief and psychometric robust measure of body image for use with cancer patients, independently of age, cancer type, treatment or stage of the disease and it was developed in collaboration with the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Study Group. Method The sample is comprised of 173 Portuguese postoperative breast cancer patients that completed a battery of measures that included the BIS and other scales of body image and quality of life, in order to explore its construct validity. Results The Portuguese version of BIS confirmed the original unidimensional structure and demonstrated adequate internal consistency, both in the global sample ( α = .93) as in surgical subgroups (mastectomy = .92 and breast-conserving surgery = .93). Evidence for the construct validity was provided through moderate to largely sized correlations between the BIS and other related measures. In further support of its discriminant validity, significant differences in BIS scores were found between women who underwent mastectomy and those who underwent breast-conserving surgery, with the former presenting higher scores. Age and time since diagnosis were not associated with BIS scores. Conclusions The Portuguese BIS proved to be a reliable and valid measure of body image concerns in a sample of breast cancer patients, allowing a brief and comprehensive assessment, both on clinical and research settings.

Impact of revised lymph node measurement rules in the new RECIST version 1.1 on the tumor response evaluation in patients with advanced lung cancer

7567 Background: The new RECIST ver. 1.1 was published in a special edition of the European Journal of Cancer in the first quarter of 2009 (EJC 2009;45:228). The major change involves the rules for lymph node measurement, which is to measure SHORT axis in stead of the longest diameter of lymph node. To be considered pathologically enlarged and measurable, a size of lymph node must be at least 15mm in short axis when assessed by CT scan. Lymph nodes that are at least 10mm but less than 15mm in short axis may be pathologic and can be considered as non-measurable/non-target lesions (not measured). The purpose of our study was to evaluate the response assessment using RECIST ver. 1.1. in comparison with that using ver. 1.0 in patients with advanced lung cancer. Methods: Two radiologists independently reviewed the objective tumour response of 305 patients (pts) with advanced lung cancer who had primary lesion and lymph node metastases as target lesions measured more than 10 mm in the longest diameter. According to ver. 1.1, only the short axis will be measured both at baseline and at follow-up. The response rates were calculated according to both the versions of RECIST. The tumor responses were divided into four categories (CR, PR, SD, PD), following proportion of agreement and estimation of kappa statistics between two the criteria as agreement measure. Results: The best overall responses as assessed by RECIST ver. 1.0 and ver. 1.1 are shown in the table. Out of the 108 pts with PR by ver.1.0, 8.3 % were downgraded to SD and 1.0 % was categorized as PD by ver.1.1. On the other hand, out of the 190 pts with SD by ver.1.0, 6.3 % were upgraded to PR and 8.9 % were downgraded to PD by ver.1.1. The proportion of agreement was 86.2 % (263/305, 95% CI: 75.8 - 96.6) and the kappa coefficient was 0.734 (95% CI: 0.662 - 0.806). Conclusions: No significant impact was observed for the revised lymph node measurement rules in the new RECIST ver. 1.1 on the response evaluation in pts with advanced lung cancer registered in this analysis. [Table: see text] [Table: see text]

Is there consensus in the definition of endpoints in metastatic breast cancer?.

Abstract Abstract #3102 Objective: Progression-free survival (PFS) is defined as the time between treatment initiation and tumor progression or death from any cause, with censoring of patients who are lost to follow-up. Time to tumor progression (TTP) is theoretically different from PFS in that the event of interest is only disease progression. Both PFS and TTP have been considered as appropriate endpoints in drug development, but the extent to which investigators agree on their definition is unknown. We therefore assessed the recent literature regarding the consistence of the definition of PFS and TTP when used as primary endpoints in advanced breast cancer.
 Methods: We searched PubMed using the medical subject headings “breast neoplasms” and “drug therapy”, limiting the search to phase III trials on systemic antineoplastic therapies published between January 1, 2000, and December 31, 2007 in one of ten leading medical journals in the field (Annals of Oncology, Breast Cancer Research and Treatment, British Journal of Cancer, Cancer, European Journal of Cancer, Journal of Clinical Oncology, Journal of the National Cancer Institute, Lancet Oncology, The Lancet and The New England Journal of Medicine). We excluded randomized phase II trials, factorial trials, studies on high-dose chemotherapy, papers reporting combined analyses of two or more separate trials, and companion studies on correlative biology or prognostic factors.
 Results: The search yielded 59 trials enrolling a total of 23,371 evaluable patients in 122 treatment arms. PFS was the primary endpoint in 14 cases, and TTP in 21 when all treatment lines and modalities were considered (response rate was used in 20 cases, and overall survival in only one). For first-line chemotherapy trials (N=24), PFS and TTP were used as primary endpoints in 5 and 7 cases, respectively. In 5 of the 21 trials using TTP as the primary endpoint, no definition of this endpoint was reported in the article. Analysis of the other 16 cases showed that progressive disease was always considered an event in TTP analysis. However, in 13 of these cases, death (either from breast cancer or from any cause) was also counted as an event. The definition of PFS was reported in the article in 13 of the 14 trials using this primary endpoint. In all cases, the events of interest in Kaplan-Meier analyses included both progressive disease and death. In some cases, both terms (PFS and TTP) were even used to denote the same endpoint in the same paper.
 Conclusion: Our review suggests that investigators are frequently using PFS and TTP interchangeably in metastatic breast cancer. Such use of terms may lead to confusion when results of different trials are evaluated in perspective, and standardization of the definitions seems therefore in order. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3102.

Enough rehabilitation for our elderly cancer patients?

One of the authors has recently published an article in the European Journal of Cancer on the management of unfit older cancer patients, yet there was still no mention made concerning the problem of rehabilitation of the elderly. For these patients, rehabilitation includes taking care of their nutritional status, their mobility, and improvement of their quality of life. While for clinical oncologists the rehabilitation of the elderly with cancer has not yet been considered an important priority, it is quite evident to geriatricians that rehabilitation in older patients requires a special approach. In fact, very little has so far been published on this issue for older cancer patients in Europe and USA. It may beworth mentioning that, to geriatricians, rehabilitation is an intervention whose purpose is to restore functional ability and enhance residual functional capability, thereby improving qualityof life in elderly peoplewith disabling impairment, which in this instance is from the cancer itself or from the cancer treatment. Of course, to establish a rehabilitative programme (patient-focused goals for rehabilitation), it is necessary to know the functional status prior to the diagnosis. It is also very important to consider the many aspects that influence the collaboration and the delivery of treatment, such as visual and hearing impairment, cognitive status (cognitive impairment, dementia), education, psychological condition (anxiety, depression), and motivation. Other geriatric syndromes must also be ascertained such as delirium, incontinence, falls, and comorbidities or inter-

Vincristine pharmacokinetics is related to clinical outcome in children with standard risk acute lymphoblastic leukemia

Vincristine is a key drug in the treatment of childhood and adult acute lymphoblastic leukemia (ALL), and many other childhood malignancies. Despite decades of wide clinical use, no data on the correlation between vincristine pharmacokinetics and long-term clinical outcome have been published. We here report clinical data (median follow-up time 10.5 years, range 7.3-12 years) for 86 children with B-cell precursor ALL, in whom vincristine kinetics were studied on treatment day 1. The median total plasma clearance was 429 and 331 ml/min per m(2) and the area under the plasma concentration-time curve (AUC) was 4.49 and 5.40 mg/l x min in relapse and non-relapse patients, respectively (not significant). In standard risk patients, where treatment depends more heavily on vincristine than in other subgroups, the relative risk (RR) of relapse was significantly increased for patients with clearance values above median (RR 5.2; P = 0.036), or AUC values below median (RR 5.8; P = 0.025). Our data suggest a relationship between the antileukemic effect and the systemic exposure of the drug, which warrants further studies.

Tamoxifen: Catalyst for the change to targeted therapy

In the early 1970s, a failed post-coital contraceptive, ICI 46,474, was reinvented as tamoxifen, the first targeted therapy for breast cancer. A cluster of papers published in the European Journal of Cancer described the idea of targeting tamoxifen to patients with oestrogen receptor positive tumours, and proposed the strategic value of using long-term tamoxifen therapy in an adjuvant setting with a consideration of the antitumour properties of the hydroxylated metabolites of tamoxifen. At the time, these laboratory results were slow to be embraced by the clinical community. Today, it is estimated that hundreds of thousands of breast cancer patients are alive today because of targeted long-term adjuvant tamoxifen therapy. Additionally, the first laboratory studies for the use of tamoxifen as a chemopreventive were published. Eventually, the worth of tamoxifen was tested as a chemopreventive and the drug is now known to have an excellent risk benefit ratio in high risk pre-menopausal women. Overall, the rigorous investigation of the pharmacology of tamoxifen facilitated tamoxifen’s ubiquitous use for the targeted treatment of breast cancer, chemoprevention and pioneered the exploration of selective oestrogen receptor modulators (SERMs). This new concept subsequently heralded the development of raloxifene, a failed breast cancer drug, for the prevention of osteoporosis and breast cancer without the troublesome side-effect of endometrial cancer noted in post-menopausal women who take tamoxifen. Currently, the pharmaceutical industry is exploiting the SERM concept for all members of the nuclear receptor superfamily so that medicines can now be developed for diseases once thought impossible.

Metabolic Syndrome

Metabolic Syndrome

A Novel Application for Murine Double Minute 2 Antagonists

Impairment of the p53 tumor suppressor network1 is thought to be involved in a large percentage of tumors either by mutations in the p53 gene2–4 or by increased expression of its major control system, the MDM25 (murine double minute 2; HDM2 for its human equivalent). It is important to realize that levels of p53 are subjected to an autoregulatory feedback loop by MDM26,7 as p53 upregulates MDM2 gene expression and MDM2 protein in turn binds to p53. MDM2 is an E3 ubiquitin ligase and transports p53 to the cytoplasm where it promotes p53 ubiquitination and degradation by the proteasome. In human cancer, increased levels of MDM26 are caused either by gene amplification, increased expression induced by activated p53, stabilization by an aberrantly spliced form of HMDX8, or augmented translation. In addition to these mechanisms, functional single-nucleotide polymorphisms (SNP) such as the 1 at nucleotide 309 (SNP309) in the MDM2 gene can modulate MDM2 expression and cause increased tumor progression.9 …

Sunbeds – do they increase risk of melanoma or not?

Epidemiologic studies conducted over the past 15 years have tended to show increased risk of melanoma in individuals using sunbeds [1] for tanning purposes. A recent meta-analysis has confirmed the impression that use increases risk, in those using these devices [2]. In this issue of the European Journal of Cancer, results of a new pan-European study by a group of experienced investigators show no risk associated with use of tanning beds [3]. Furthermore, in contrast to a host of studies conducted over the past 20 years and summarized in Elwood and Jopson [4] the new study found no association between melanoma risk and reported sunlight exposure. Why should this study show no association between artificial or solar UV and melanoma when previous investigations have indicated a significant increase in risk? A number of explanations can be examined. The first and simplest potential explanation is that participants sunlight exposure and tanning bed use was poorly remembered and hence inaccurately reported. If the degree of such misclassification is similar in cases and controls, the net effect is to bias results toward the null – exactly what is seen in the Bataille study. While this might be a potentially acceptable explanation for the lack of association with reported solar exposure, it is not compelling when applied to tanning beds. Tanning bed use is an activity that is carried out using scheduled sessions usually of fixed duration in commercial salons, and it costs money. It is difficult to accept that the degree of misclassification of tanning bed use would be of the same magnitude