Insulin increases De Novo Steroidogenesis in prostate cancer cells

Androgen-dependent pathways regulate maintenance and growth of normal and malignant prostate tissues. Androgen deprivation therapy (ADT) exploits this dependence and is used to treat metastatic prostate cancer; however, regression initially seen with ADT gives way to development of incurable castration-resistant prostate cancer (CRPC). Although ADT generates a therapeutic response, it is also associated with a pattern of metabolic alterations consistent with metabolic syndrome including elevated circulating insulin. Because CRPC cells are capable of synthesizing androgens de novo, we hypothesized that insulin may also influence steroidogenesis in CRPC. In this study, we examined this hypothesis by evaluating the effect of insulin on steroid synthesis in prostate cancer cell lines. Treatment with 10 nmol/L insulin increased mRNA and protein expression of steroidogenesis enzymes and upregulated the insulin receptor substrate insulin receptor substrate 2 (IRS-2). Similarly, insulin treatment upregulated intracellular testosterone levels and secreted androgens, with the concentrations of steroids observed similar to the levels reported in prostate cancer patients. With similar potency to dihydrotestosterone, insulin treatment resulted in increased mRNA expression of prostate-specific antigen. CRPC progression also correlated with increased expression of IRS-2 and insulin receptor in vivo. Taken together, our findings support the hypothesis that the elevated insulin levels associated with therapeutic castration may exacerbate progression of prostate cancer to incurable CRPC in part by enhancing steroidogenesis.

A randomised trial of a psychosocial intervention for cancer patients integrated into routine care: The PROMPT study (promoting optimal outcomes in mood through tailored psychosocial therapies)

Background Despite evidence that up to 35% of patients with cancer experience significant distress, access to effective psychosocial care is limited by lack of systematic approaches to assessment, a paucity of psychosocial services, and patient reluctance to accept treatment either because of perceived stigma or difficulties with access to specialist psycho-oncology services due to isolation or disease burden. This paper presents an overview of a randomised study to evaluate the effectiveness of a brief tailored psychosocial Intervention delivered by health professionals in cancer care who undergo focused training and participate in clinical supervision. Methods/design Health professionals from the disciplines of nursing, occupational therapy, speech pathology, dietetics, physiotherapy or radiation therapy will participate in training to deliver the psychosocial Intervention focusing on core concepts of supportive-expressive, cognitive and dignity-conserving care. Health professional training will consist of completion of a self-directed manual and participation in a skills development session. Participating health professionals will be supported through structured clinical supervision whilst delivering the Intervention. In the stepped wedge design each of the 5 participating clinical sites will be allocated in random order from Control condition to Training then delivery of the Intervention. A total of 600 patients will be recruited across all sites. Based on level of distress or risk factors eligible patients will receive up to 4 sessions, each of up to 30 minutes in length, delivered face-to-face or by telephone. Participants will be assessed at baseline and 10-week follow-up. Patient outcome measures include anxiety and depression, quality of life, unmet psychological and supportive care needs. Health professional measures include psychological morbidity, stress and burnout. Process evaluation will be conducted to assess perceptions of participation in the study and the factors that may promote translation of learning into practice. Discussion This study will provide important information about the effectiveness of a brief tailored psychological Intervention for patients with cancer and the potential to prevent development of significant distress in patients considered at risk. It will yield data about the feasibility of this model of care in routine clinical practice and identify enablers and barriers to its systematic implementation in cancer settings.

Does the effect of weight lifting on lymphedema following breast cancer differ by diagnostic method: results from a randomized controlled trial

The lymphedema diagnostic method used in descriptive or intervention studies may influence results found. The purposes of this work were to compare baseline lymphedema prevalence in the physical activity and lymphedema (PAL) trial cohort and to subsequently compare the effect of the weight-lifting intervention on lymphedema, according to four standard diagnostic methods. The PAL trial was a randomized controlled intervention study, involving 295 women who had previously been treated for breast cancer, and evaluated the effect of 12 months of weight lifting on lymphedema status. Four diagnostic methods were used to evaluate lymphedema outcomes: (i) interlimb volume difference through water displacement, (ii) interlimb size difference through sum of arm circumferences, (iii) interlimb impedance ratio using bioimpedance spectroscopy, and (iv) a validated self-report survey. Of the 295 women who participated in the PAL trial, between 22 and 52% were considered to have lymphedema at baseline according to the four diagnostic criteria used. No between-group differences were noted in the proportion of women who had a change in interlimb volume, interlimb size, interlimb ratio, or survey score of ≥5, ≥5, ≥10%, and 1 unit, respectively (cumulative incidence ratio at study end for each measure ranged between 0.6 and 0.8, with confidence intervals spanning 1.0). The variation in proportions of women within the PAL trial considered to have lymphoedema at baseline highlights the potential impact of the diagnostic criteria on population surveillance regarding prevalence of this common morbidity of treatment. Importantly though, progressive weight lifting was shown to be safe for women following breast cancer, even for those at risk or with lymphedema, irrespective of the diagnostic criteria used.

Acceptability of the distress thermometer and problem list to community-based telephone cancer helpline operators, and to cancer patients and carers

Background Cancer can be a distressing experience for cancer patients and carers, impacting on psychological, social, physical and spiritual functioning. However, health professionals often fail to detect distress in their patients due to time constraints and a lack of experience. Also, with the focus on the patient, carer needs are often overlooked. This study investigated the acceptability of brief distress screening with the Distress Thermometer (DT) and Problem List (PL) to operators of a community-based telephone helpline, as well as to cancer patients and carers calling the service. Methods Operators (n = 18) monitored usage of the DT and PL with callers (cancer patients/carers, >18 years, and English-speaking) from September-December 2006 (n = 666). The DT is a single item, 11-point scale to rate level of distress. The associated PL identifies the cause of distress. Results The DT and PL were used on 90% of eligible callers, most providing valid responses. Benefits included having an objective, structured and consistent means for distress screening and triage to supportive care services. Reported challenges included apparent inappropriateness of the tools due to the nature of the call or level of caller distress, the DT numeric scale, and the level of operator training. Conclusions We observed positive outcomes to using the DT and PL, although operators reported some challenges. Overcoming these challenges may improve distress screening particularly by less experienced clinicians, and further development of the PL items and DT scale may assist with administration. The DT and PL allow clinicians to direct/prioritise interventions or referrals, although ongoing training and support is critical in distress screening.

The obesity-associated polymorphisms FTO rs9939609 and MC4R rs17782313 and endometrial cancer risk in non-Hispanic white women

Overweight and obesity are strongly associated with endometrial cancer. Several independent genome-wide association studies recently identified two common polymorphisms, FTO rs9939609 and MC4R rs17782313, that are linked to increased body weight and obesity. We examined the association of FTO rs9939609 and MC4R rs17782313 with endometrial cancer risk in a pooled analysis of nine case-control studies within the Epidemiology of Endometrial Cancer Consortium (E2C2). This analysis included 3601 non-Hispanic white women with histologically-confirmed endometrial carcinoma and 5275 frequency-matched controls. Unconditional logistic regression models were used to assess the relation of FTO rs9939609 and MC4R rs17782313 genotypes to the risk of endometrial cancer. Among control women, both the FTO rs9939609 A and MC4R rs17782313 C alleles were associated with a 16% increased risk of being overweight (p = 0.001 and p = 0.004, respectively). In case-control analyses, carriers of the FTO rs9939609 AA genotype were at increased risk of endometrial carcinoma compared to women with the TT genotype [odds ratio (OR) = 1.17; 95% confidence interval (CI): 1.03–1.32, p = 0.01]. However, this association was no longer apparent after adjusting for body mass index (BMI), suggesting mediation of the gene-disease effect through body weight. The MC4R rs17782313 polymorphism was not related to endometrial cancer risk (per allele OR = 0.98; 95% CI: 0.91–1.06; p = 0.68). FTO rs9939609 is a susceptibility marker for white non-Hispanic women at higher risk of endometrial cancer. Although FTO rs9939609 alone might have limited clinical or public health significance for identifying women at high risk for endometrial cancer beyond that of excess body weight, further investigation of obesity-related genetic markers might help to identify the pathways that influence endometrial carcinogenesis.

A randomised controlled trial of a theory-based intervention to improve sun protective behaviour in adolescents ('you can still be HOT in the shade') : study protocol

Background: Most skin cancers are preventable by encouraging consistent use of sun protective behaviour. In Australia, adolescents have high levels of knowledge and awareness of the risks of skin cancer but exhibit significantly lower sun protection behaviours than adults. There is limited research aimed at understanding why people do or do not engage in sun protective behaviour, and an associated absence of theory-based interventions to improve sun safe behaviour. This paper presents the study protocol for a school-based intervention which aims to improve the sun safe behaviour of adolescents. Methods/design: Approximately 400 adolescents (aged 12-17 years) will be recruited through Queensland, Australia public and private schools and randomized to the intervention (n = 200) or 'wait-list' control group (n = 200). The intervention focuses on encouraging supportive sun protective attitudes and beliefs, fostering perceptions of normative support for sun protection behaviour, and increasing perceptions of control/self-efficacy over using sun protection. It will be delivered during three × one hour sessions over a three week period from a trained facilitator during class time. Data will be collected one week pre-intervention (Time 1), and at one week (Time 2) and four weeks (Time 3) post-intervention. Primary outcomes are intentions to sun protect and sun protection behaviour. Secondary outcomes include attitudes toward performing sun protective behaviours (i.e., attitudes), perceptions of normative support to sun protect (i.e., subjective norms, group norms, and image norms), and perceived control over performing sun protective behaviours (i.e., perceived behavioural control). Discussion: The study will provide valuable information about the effectiveness of the intervention in improving the sun protective behaviour of adolescents.

Prevalence of breast cancer treatment sequelae over 6 years of follow-up

Background: There is a need to better describe and understand the prevalence of breast cancer treatment-related adverse effects amenable to physical therapy and rehabilitative exercise. Prior studies have been limited to single issues and lacked long term follow-up. The Pulling Through Study provides data on prevalence of adverse effects in breast cancer survivors followed over six years. Methods: A population-based sample of Australian women (n=287) diagnosed with invasive, unilateral breast cancer was followed for a median of 6.6 years and prospectively assessed for treatment-related complications at 6, 12, 18 months, and 6 years post-diagnosis. Assessments included post-surgical complications, skin or tissue reaction to radiation therapy, upper-body symptoms, lymphedema, 10% weight gain, fatigue, and upper-quadrant function. The proportion of women with positive indication for each complication and one or more complication was estimated using all available data at each time point. Women were only considered to have a specific complication if they reported the highest two levels of the Likert scale for self-reported issues. Results: At six years post-diagnosis over 60% of women experienced one or more side effects amenable to rehabilitative intervention. The proportion of women experiencing 3 or more side effects decreased throughout follow-up, while the proportion experiencing no side effects remained stable around 40% from 12 months to six years. Weight gain was the only complication to increase in prevalence over time. Conclusion: These data support the development of a multi-disciplinary prospective surveillance approach for the purposes of managing and treating adverse effects in breast cancer survivors.

Water-based exercise for patients with chronic arm lymphedema : a randomized controlled pilot trial

Objective: To evaluate the feasibility and effect of a water-based exercise (WBE) program on lymphedema status and shoulder range of motion (ROM) among women with breast cancer related lymphedema. Design: Single-blinded, randomized controlled pilot trial. Twenty-nine eligible breast cancer survivors (median 10 years after surgery) with arm lymphedema (median 21% inter limb difference) were included and randomized into intervention (n= 15) or control (n=14). Twenty-five participants completed the study. The intervention was at least twice weekly WBE for 8 weeks; supervised initially but performed independently during the study period. Outcomes of interest were feasibility as measured by retention and adherence, lymphedema status as measured by optoelectronic perometry, bioimpedance spectroscopy and tissue dielectric constant, and shoulder range of motion (ROM) as measured by goniometer. Results: Four participants were not measured at post-intervention and were not included in the analysis (retention). Four participants in the intervention group did not perform the minimum WBE criteria set (adherence). No effect was found on lymphedema status. Compared to the control group, median ROM change for flexion was 6 (1-10) degrees (p<0.001) and 6 (0-15.5) degrees (p=0,07) for external rotation. Clinically relevant increase in the intervention group was found for 36% in flexion (p≤0.05) and (57%) in external rotation (p≤0.05) compared to controls. Conclusions: This study shows WBE is feasible for breast cancer survivors with arm lymphedema and that shoulder ROM can be improved years after cancer treatment has been completed.

Exercise for health : a randomized, controlled trial evaluating impact of a pragmatic, translational exercise intervention on quality of life, function and treatment-related side effects following breast cancer

Purpose Exercise for Health was a randomized, controlled trial designed to evaluate two modes of delivering (face-to-face [FtF] and over-the-telephone [Tel]) an 8-month translational exercise intervention, commencing 6-weeks post-breast cancer surgery (PS). Methods Outcomes included quality of life (QoL), function (fitness and upper-body) and treatment-related side effects (fatigue, lymphoedema, body mass index, menopausal symptoms, anxiety, depression and pain). Generalised estimating equation modelling determined time (baseline [5-weeks PS], mid-intervention [6-months PS], post-intervention [12-months PS]), group (FtF, Tel, Usual Care [UC]) and time-by-group effects. 194 women representative of the breast cancer population were randomised to the FtF (n=67), Tel (n=67) and UC (n=60) groups. Results: There were significant (p<0.05) interaction effects on QoL, fitness and fatigue, with differences being observed between the treatment groups and the UC group. Trends observed for the treatment groups were similar. The treatment groups reported improved QoL, fitness and fatigue over time and changes observed between baseline and post-intervention were clinically relevant. In contrast, the UC group experienced no change, or worsening QoL, fitness and fatigue, mid-intervention. Although improvements in the UC group occurred by 12-months post-surgery, the change did not meet the clinically relevant threshold. There were no differences in other treatment-related side-effects between groups. Conclusion This translational intervention trial, delivered either face-to-face or over-the-telephone, supports exercise as a form of adjuvant breast cancer therapy that can prevent declines in fitness and function during treatment and optimise recovery post-treatment.

Using the collaborative evidence based practice model : a systematic review and uptake of chlorhexidine-impregnated sponge dressings on central venous access devices in a tertiary cancer centre

Background: Greater research utilisation in cancer nursing practice is needed, in order to provide well-informed and effective nursing care to people affected by cancer. This paper aims to report on the implementation of evidence-based practice in a tertiary cancer centre. Methods: Using a case report design, this paper reports on the use of the Collaborative Model for Evidence Based Practice (CMEBP) in an Australian tertiary cancer centre. The clinical case is the uptake of routine application of chlorhexidine-impregnated sponge dressings for preventing centrally inserted catheter-related bloodstream infections. In this case report, a number of processes that resulted in a service-wide practice change are described. Results: This model was considered a feasible method for successful research utilisation. In this case report, chlorhexidine-impregnated sponge dressings were proposed and implemented in the tertiary cancer centre with an aim of reducing the incidence of centrally inserted catheter-related bloodstream infections and potentially improving patient health outcomes. Conclusion: The CMEBP is feasible and effective for implementing clinical evidence into cancer nursing practice. Cancer nurses and health administrators need to ensure a supportive infrastructure and environment for clinical inquiry and research utilisation exists, in order to enable successful implementation of evidence-based practice in their cancer centres.

Tocotrienol as potential anticancer agent

Vitamin E is composed of two structurally similar compounds: tocopherols (TPs) and tocotrienols (T3). Despite being overshadowed by TP over the past few decades, T3 is now considered to be a promising anticancer agent due to its potent effects against a wide range of cancers. A growing body of evidence suggests that in addition to its antioxidative and pro-apoptotic functions, T3 possesses a number of anticancer properties that make it superior to TP. These include the inhibition of epithelial-to-mesenchymal transitions, the suppression of vascular endothelial growth factor tumor angiogenic pathway and the induction of antitumor immunity. More recently, T3, but not TP, has been shown to have chemosensitization and anti-cancer stem cell effects, further demonstrating the potential of T3 as an effective anticancer therapeutic agent. With most of the previous clinical studies on TP producing disappointing results, research has now focused on testing T3 as the next generation vitamin E for chemoprevention and cancer treatment. This review will summarize recent developments in the understanding of the anticancer effects of T3. We will also discuss current progress in clinical trials involving T3 as an adjuvant to conventional cancer therapy.

Sensitivity to the MEK inhibitor E6201 in melanoma cells is associated with mutant BRAF and wildtype PTEN status

BACKGROUND: Melanoma is the most lethal form of skin cancer, but recent advances in molecularly targeted agents against the Ras/Raf/MAPK pathway demonstrate promise as effective therapies. Despite these advances, resistance remains an issue, as illustrated recently by the clinical experience with vemurafenib. Such acquired resistance appears to be the result of parallel pathway activation, such as PI3K, to overcome single-agent inhibition. In this report, we describe the cytotoxicity and anti-tumour activity of the novel MEK inhibitor, E6201, in a broad panel of melanoma cell lines (n = 31) of known mutational profile in vitro and in vivo. We further test the effectiveness of combining E6201 with an inhibitor of PI3K (LY294002) in overcoming resistance in these cell lines. RESULTS: The majority of melanoma cell lines were either sensitive (IC50 < 500 nM, 24/31) or hypersensitive (IC50 < 100 nM, 18/31) to E6201. This sensitivity correlated with wildtype PTEN and mutant BRAF status, whereas mutant RAS and PI3K pathway activation were associated with resistance. Although MEK inhibitors predominantly exert a cytostatic effect, E6201 elicited a potent cytocidal effect on most of the sensitive lines studied, as evidenced by Annexin positivity and cell death ELISA. Conversely, E6201 did not induce cell death in the two resistant melanoma cell lines tested. E6201 inhibited xenograft tumour growth in all four melanoma cell lines studied to varying degrees, but a more pronounced anti-tumour effect was observed for cell lines that previously demonstrated a cytocidal response in vitro. In vitro combination studies of E6201 and LY294002 showed synergism in all six melanoma cell lines tested, as defined by a mean combination index < 1. CONCLUSIONS: Our data demonstrate that E6201 elicits a predominantly cytocidal effect in vitro and in vivo in melanoma cells of diverse mutational background. Resistance to E6201 was associated with disruption of PTEN and activation of downstream PI3K signalling. In keeping with these data we demonstrate that co-inhibition of MAPK and PI3K is effective in overcoming resistance inherent in melanoma.