Environmental Cancer Risk Factors: A review

The risk of cancer in humans is increased by a wide spectrum of factors, which ranges from exposure to an identified agent, such as environmental chemicals or a virus, to a culturally determined behaviour, such as smoking, or to socio-economic conditions. We are today able to intervene on some of these factors, while others affect risk by as yet undetermined pathways. Only progress in the understanding of the mechanisms by which these factors act can lead to specific means of cancer prevention. There is no compelling reason to believe that the number of carcinogenic agents, to which humans can be exposed, is infinite, nor is it unreasonable to assume that it will eventually be possible to identify most of them. The variety of cancer risk factors of which we are presently aware implies, however, that it would be impossible to have just one simple approach to cancer control and cancer prevention. It is rather encouraging that the applicability of new laboratory methods to epidemiological surveys seems to open the way to a laboratory-integrated epidemiology.     

Cross-Resistance Studies of Isogenic Drug-Resistant Breast Tumor Cell Lines Support Recent Clinical Evidence Suggesting that Sensitivity to Paclitaxel may be Strongly Compromised by Prior Doxorubicin Exposure

Less than half of breast cancer patients respond to second-line chemotherapy with paclitaxel after failing treatment with anthracyclines such as doxorubicin. A recent clinical trial by Paridaens et al. [J. Clin. Oncol. 18 : 724-733, 2000] examined whether patients may derive a better clinical benefit if paclitaxel was administered before doxorubicin. While overall survival was similar regardless of the order of drug administration, a >4-fold reduction in the response rate to paclitaxel was observed after late crossover from doxorubicin, compared to the response rate to doxorubicin after late crossover from paclitaxel. This may be related to differences in the ability of the drugs to induce cross-resistance to each other. To test this hypothesis, we examined whether isogenic breast tumor cells selected for resistance to doxorubicin exhibit greater cross-resistance to paclitaxel and other drugs than identical cells selected for resistance to paclitaxel. We found that cells selected for resistance to paclitaxel showed strong resistance (>/=40-fold) to paclitaxel and docetaxel, with little cross-resistance (4-fold) to doxorubicin. In contrast, cells selected for resistance to doxorubicin exhibited 50-fold resistance to doxorubicin and a dramatic 4700-fold and 14,600-fold cross-resistance to paclitaxel and docetaxel, respectively. Doxorubicin-resistant cells exhibited higher P-glycoprotein and breast cancer resistance protein (BCRP) levels than paclitaxel-resistant cells. In addition, procaspase-9 was strongly downregulated in doxorubicin-resistant cells but not in paclitaxel-resistant cells. These differences may account for the contrasting cross-resistance profiles observed for the two cell lines and may help to explain why treatment of breast cancer patients with paclitaxel appears to be compromized by prior doxorubicin exposure.     

MicroRNA in rectal cancer

In rectal cancer, one of the most common cancers worldwide, the proper staging of the disease determines the subsequent therapy. For those with locally advanced rectal cancer, a neoadjuvant chemoradiotherapy (CRT) is recommended before any surgery. However, response to CRT ranges from complete response (responders) to complete resistance (non-responders). To date we are not able to separate in advance the first group from the second, due to the absence of a valid biomarker. Therefore all patients receive the same therapy regardless of whether they reap benefits. On the other hand almost all patients receive a surgical resection after the CRT, although a watch-and-wait procedure or an endoscopic resection might be sufficient for those who responded well to the CRT. Being highly conserved regulators of gene expression, microRNAs (miRNAs) seem to be promising candidates for biomarkers. Many studies have been analyzing the miRNAs expressed in rectal cancer tissue to determine a specific miRNA profile for the ailment. Unfortunately, there is only a small overlap of identified miRNAs between different studies, posing the question as to whether different methods or differences in tissue storage may contribute to that fact or if the results simply are not reproducible, due to unknown factors with undetected influences on miRNA expression. Other studies sought to find miRNAs which correlate to clinical parameters (tumor grade, nodal stage, metastasis, survival) and therapy response. Although several miRNAs seem to have an impact on the response to CRT or might predict nodal stage, there is still only little overlap between different studies. We here aimed to summarize the current literature on rectal cancer and miRNA expression with respect to the different relevant clinical parameters.     

Additive Effect of the Combination of Griseofulvin and Ketoconazole Against Microsporum canis in Vitro: Additiver Effekt der Kombination von Griseofulvin und Ketoconazol gegen Microsporum canis in vitro

The susceptibility of 28 strains of Microsporum canis to griseofulvin, to ketoconazole and to a combination of both antifungal drugs was determined. Griseofulvin proved to be more active than ketoconazole. The combination of both antifungal agents was found to exert an additive effect.     

Patient perspectives on involvement in cancer research in the UK

The patient's perspective is offered to identify the benefits of patient involvement in the research process so that it will lead to research that is reliable and relevant to cancer patients' needs. A brief outline of recent consumer involvement in research and initiatives being undertaken in the UK will provide a guide for those seeking to consider what has already been achieved. Practical suggestions are offered to those seeking to facilitate this mode of working. A wider conceptual approach suggests the interrelationships that should be built, through networks of communication, so that efficient, effective, economic and equitable health care may be provided to all those suffering from cancer. This should lead to an appreciation of work that still needs to be undertaken to achieve progress.     

BTLA expression declines on B cells of the aged and is associated with low responsiveness to the trivalent influenza vaccine

Virus-neutralizing antibody and B cell responses to influenza A viruses were measured in 35 aged and 28 middle-aged individuals following vaccination with the 2012 and 2013 trivalent inactivated influenza vaccines. Antibody responses to the vaccine strains were lower in the aged. An analysis of B cell subsets by flow cytometry with stains for immunoregulators showed that B cells of multiple subsets from the aged as compared to younger human subjects showed differences in the expression of the co-inhibitor B and T lymphocyte attenuator (BTLA). Expression of BTLA inversely correlated with age and appears to be linked to shifting the nature of the response from IgM to IgG. High BTLA expression on mature B cells was linked to higher IgG responses to the H1N1 virus. Finally, high BTLA expression on isotype switched memory B cells was linked to better preservation of virus neutralizing antibody titers and improved recall responses to vaccination given the following year.     

Exploiting the potential of autophagy in cisplatin therapy: A new strategy to overcome resistance

Resistance to cisplatin is a major challenge in the current cancer therapy. In order to explore new therapeutic strategies to cisplatin resistance, we evaluated, in a model of lung cancer (H1299 and H460 cell lines), the nature of the pathways leading to cell death. We observed that H1299 displayed a natural resistance to cisplatin due to an inability to trigger an apoptotic response that correlates with the induction of autophagy. However, pharmacological and genetic approaches showed how autophagy was a mechanism associated to cell death rather than to resistance. Indeed, pro-autophagic stimuli such as mTOR or Akt inhibition mediate cell death in both cell lines to a similar extent. We next evaluated the response to a novel platinum compound, monoplatin, able to promote cell death in an exclusive autophagy-dependent manner. In this case, no differences were observed between both cell lines. Furthermore, in response to monoplatin, two molecular hallmarks of cisplatin response (p53 and MAPKs) were not implicated, indicating the ability of this pro-autophagic compound to overcome cisplatin resistance. In summary, our data highlight how induction of autophagy could be used in cisplatin resistant tumours and an alternative treatment for p53 mutated patient in a synthetic lethally approach.     

Radiothérapie des sarcomes : hadronthérapie,pour qui,pour quoi ?

The radiobiological properties of the hadrons (neutrons, protons, carbon ions) led to their therapeutic use in sarcomas, as a referent therapy or as an alternative to photon therapy. An extensive review of the literature has been conducted to assess the present indications and the perspectives for hadrontherapy. Compared to photons, neutrons are characterized by a higher biological efficiency that is on particular importance for these tumours usually considered as radio-resistant. Neutrons have been considered as a standard therapy for sarcoma’ patients, contra-indicated for surgery or with a definitive R2 resection, but their indications and use have been restricted due to the occurrence of late severe toxicities related to their poor ballistic’ properties. Thanks to their physical properties (Bragg Peak), protons are characterized by a higher conformity index compared to photons (and neutrons) with optimal organs at risk preservation that permits a dose escalation. Protontherapy is to date the standard of care for base of skull, spinal and paraspinal sarcomas. Carbon ions combined both advantages from protons and neutrons. Literature data permits to consider this radiation modality as a referent therapy for unresectable sarcomas. The ongoing diffusions of protons and carbon ions radiotherapy facilities will permit to offer these therapies to more patients and to conduct studies that are warranted to determine their indications and their results.     

Therapeutic patient education in oncology: pedagogical notions for women's health and prevention

Therapeutic patient education has been defined by the World Health Organization as a comprehensive approach to support patients and their families to better understanding of their diseases. In oncology, the contribution of therapeutic education may enable the patients to have adequate information of the illness, to actively participate in the management of the disease, to understand how to live with the illness, to learn how to face the critical moments of the clinical course, and to live in harmony with all health professionals. In addition, there may be several advantages for health professionals: a reduction in emotional labour, increased professional satisfaction, and a reduction in the potential tensions and conflicts with patients and their relatives. We suggest that therapeutic patient education in oncology may be useful for both patients and health professionals and probably lead to a reduction in the costs of healthcare delivery.     

The needs of carers of men with prostate cancer and barriers and enablers to meeting them: a qualitative study in England

The aim of this study was to explore the needs of carers of men with prostate cancer and to identify barriers and enablers to meeting these needs. Carers were recruited to focus groups or interviews. These were recorded, transcribed and analysed by two researchers using Nvivo QSR6 and the Framework approach to index, chart and analyse data to identify emergent themes of the needs of carers, and barriers and enablers to meeting these needs. Fifteen carers took part in focus groups and 19 were interviewed. Carers' needs varied and were often unmet because of barriers to existing services. Carers needed: information; emotional support; practical support; effective medical care for the patient. Barriers to carers meeting their needs included: lack of awareness of sources of help; lack of understanding of information; reluctance to ask for help; prioritising the patient's needs. Enablers included better signposting to information and sources of support, and assessment of their needs. Interventions to address these needs should be developed taking account of the barriers and enablers identified here, and the experience of reported interventions for carers of other cancer patients. Carers should be offered an assessment to establish their needs and directed to appropriate sources of help.     

Androgen receptor plasticity and its implications for prostate cancer therapy

Acquired resistance to a drug treatment is a common problem across many cancers including prostate cancer (PCa) - one of the major factors for male mortality. The androgen receptor (AR) continues to be the main therapeutic PCa target and despite the success of modern targeted therapies such as enzalutamide, resistance to these drugs eventually develops. The AR has found many ways to adapt to treatments including overexpression and production of functional, constitutively active splice variants. However, of particular importance are point mutations in the ligand binding domain of the protein that convert anti-androgens into potent AR agonists. This mechanism appears to be especially prevalent with the AR in spite of some distant similarities to other hormone nuclear receptors. Despite the AR being one of the most studied and attended targets in cancer, those gain-of-function mutations in the receptor remain a significant challenge for the development of PCa therapies. This drives the need to fully characterize such mutations and to consistently screen PCa patients for their occurrence to prevent adverse reactions to anti-androgen drugs. Novel treatments should also be developed to overcome this resistance mechanism and more attention should be given to the possibility of similar occurrences in other cancers.     

Apoptosis and non-apoptotic deaths in cancer development and treatment response

Resistance to apoptosis is closely linked to tumorigenesis, as it enables malignant cells to expand even in a stressful environment. Cells resistant to apoptosis are also assumed to be resistant to anti-cancer therapies. Apoptosis has therefore taken a central position in cell death research. However, its contribution to treatment success is highly debated for solid tumors. It becomes more and more clear that cells can also die by non-apoptotic mechanisms, such as autophagy, mitotic catastrophe and necrosis. In this review, we summarize the current knowledge regarding the molecular pathways that underlie these apoptotic and non-apoptotic death pathways, and discuss the clinical data that have now accumulated to evaluate their roles in tumor development and cancer treatment.     

Moving beyond symptom management towards cancer rehabilitation for older adults: Answering the 5W's

Older adults with cancer are quickly becoming the largest group of cancer survivors. Chronological age is a poor predictor of cancer treatment outcomes and of the need for rehabilitation services. While newer symptom management systems and assessments are slowly becoming used in the clinic to improve communication between providers and survivors, such assessments are rarely used to trigger a referral to rehabilitation. Cancer rehabilitation for older adults with cancer has the potential to improve the quality of life and decrease disability caused by cancer and its treatments. One barrier to referral to cancer rehabilitation remains an understanding of what cancer rehabilitation is, and who, when, where, and why to refer to rehabilitation services. This report utilizes examples of three popular geriatric, distress and symptom measures to help answer these questions.     

Obstacles to participation in randomised cancer clinical trials: a systematic review of the literature

Accrual to clinical trials continues to be a problem in many countries including Australia despite its fundamental importance to the progress of evidence-based medicine. This paper reviews the current literature addressing the obstacles to accrual excluding those related to protocol design. An electronic search of the literature identified publications in oncology specifically addressing the obstacles to participation in clinical trials. This search was supplemented by searches of key oncology journals. Obstacles fall into three main categories - clinician, patient and system; however, there are overlaps between categories. Clinician behaviour is the most important of these. Exclusion of patients for reasons other than defined eligibility criteria, concerns about increased time requirements, and suboptimal communication with patients all affect accrual. Risk management strategies for clinical trials need to be individualised to address the obstacles most likely to negatively impact on accrual. Communication between clinician and patient appears to be a greater issue than previously recognised. Time concerns need to be addressed as generational change affects the expectations of the medical workforce.     

Time Trends of Ovarian Cancer Incidence in China

The aim of this study was to examine the trend of ovary cancer incidence from 1999 to 2010 in China andpredict the burden up to 2020. Crude incidence, age specific incidence and age-adjusted incidence rates werecalculated. Joinpoint regression was performed to obtain estimated annual percentages and Bayesian age-periodcohortmodeling was used to predict the incidence rate until the year 2020. In China, the crude rate of ovarycancer was 7.91/100,000 and the age-adjusted rate was 5.35/100,000 overall during period 1999-2010. The ratesin urban regions were higher than in rural regions. A significant rising trend during 1999-2006 was followedby a drop during 2006-2010 in age-adjusted rates for urban females. In contrast, constant rise was observed inrural women. The decrease in ovary cancer of urban areas tended to be restricted to women aged 50 years andyounger. In contrast, increases of ovary cancer in rural areas appeared in virtually all age groups. Although theage-adjusted incidence rate for ovary cancer was predicted to be reduced after year 2011, the crude rate waslikely to be relative stable up to 2020. The burden of ovary cancer in China will continue to be relative stabledue to the aging population.     

Testing the Transtheoretical Model in Predicting Smoking Relapse among Malaysian Adult Smokers Receiving Assistance in Quitting

The role of The Transtheoretical Model (TTM) in predicting relapse is limited. We aimed to assess whether thismodel can be utilised to predict relapse during the action stage. The participants included 120 smokers who hadabstained from smoking for at least 24 hours following two Malaysian universities’ smoking cessation programme.The smokers who relapsed perceived significantly greater advantages related to smoking and increasing doubt intheir ability to quit. In contrast, former smokers with greater self-liberation and determination to abstain wereless likely to relapse. The findings suggest that TTM can be used to predict relapse among quitting smokers.     

Situations difficiles en radiothérapie : patients adultes agités

The causes of agitation in adult patients are numerous. Agitation may cause difficulty or impossibility to initiate the radiotherapy technique but also can lead to accidents harmful to patients. However, the decision to not irradiate agitated patients may lead to a loss of curability chance or chance to palliate symptoms. Before taking such a decision, thinking about the possibilities available to calm the patient should be undertaken with the patient and the referring practitioners to attempt to make this therapy if it is considered major in the management of cancer. In all cases, current adaptations of radiotherapy should be used to deliver an effective radiation of a suitable time and safely. It is notable that the medical literature is extremely rare on this subject.     

Improving the working lives of cancer clinicians

Cancer clinicians have to deal with particular difficulties in their work, including emotionally demanding interactions with patients and a high proportion of patients in whom curative treatment is ineffective. Perhaps, surprisingly, cancer clinicians are at no greater risk of poor mental health than other specialists, although levels among senior doctors are higher than among the employed general population. Being young, being single, feeling inadequately trained in communication and management skills and experiencing high levels of stress at work increase the risk of poor mental health for cancer clinicians and other senior doctors alike. Job satisfaction is important in that it appears to protect the mental health of cancer clinicians. Further work is required using a longitudinal approach to clarify risk factors. There is also a need to examine factors such as stress outside work that are likely to confer risk. We also need to understand how symptoms of poor mental health impair work performance. Having identified the risk factors, we need to begin to formulate interventions to improve the working lives of cancer clinicians through, for example, initiatives to improve communication and management skills, provide support to new consultants and facilitate teamwork.     

Targeting p53 as a therapeutic strategy in sensitizing TRAIL-induced apoptosis in cancer cells

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) has been intensively studied as a cancer therapeutic agent due to its unique ability to induce apoptosis in malignant cells but not in normal cells. However, as more human cancer cells are reported to be resistant to TRAIL treatment, it is important to develop new therapeutic strategies to overcome this resistance. p53 is an important tumor suppressor that is widely involved in cellular responses to various stresses. In this mini-review, we aim to provide an overview of the intricate relationship between p53 and the TRAIL-mediated apoptosis pathway, and to summarize the current approaches of targeting p53 as a therapeutic strategy to sensitize TRAIL-induced apoptosis in human cancer cells. Although in some cases TRAIL kills cancer cells in a p53-independent manner, it is believed that in cancers with wild-type and functional p53, targeting p53 may be an important strategy for overcoming TRAIL-resistance in cancer therapy.