Is self-management feasible and acceptable for addressing nutrition and physical activity needs of cancer survivors?

This is the accepted version of the following article: [Lawn S, Zrim S, Leggett S, Miller M, Woodman R, Jones L, Kichenadasse G, Sukumaran S, Karapetis C and Koczwara B (2014) Is self-management feasible and acceptable for addressing nutrition and physical activity needs of cancer survivors? . Original Research Paper. Health Expectations], which has been published in final form at [DOI:10.1111/hex.12327]. Background: Self-management is recommended for patients with chronic conditions but its use with cancer survivors is underexplored. Optimal strategies for achieving lifestyle changes in cancer survivors are not known. Objective: We aimed to determine feasibility, acceptability and preliminary efficacy of self-management based nutrition and physical activity interventions for cancer survivors. Design, Setting and Participants: Adult survivors (n=25) during (Group1, n=11) or post (Group2, n=14) curative chemotherapy for solid tumours, most (n=20, 80%) with breast cancer, were recruited prospectively from a single clinical centre. Intervention: The Flinders Living Well Self-Management Program™, a generic self-management care planning program, was utilised to establish patient-led nutrition and exercise goals within a tailored 12-week intervention. Fortnightly progress reviews occurred with assessments at baseline, 6 and 12 weeks. Results: Most participants (84%) found the intervention acceptable/very acceptable. Both groups showed a trend towards significant improvement in the self-management capability ‘knowledge about changing risk factors’ (p=0.047); and Group2 showed a trend towards significantly improved ‘psychological impacts’ (p=0.007). Goal ratings improved for both groups (p=0.001). Quality of life improved for both groups for emotional functioning (p=0.03). Physical functioning improved for Group2 (p=0.05); however, most symptom domains worsened for Group1, as expected given their treatment stage. Discussion and Conclusions: Self-management interventions are feasible for this population. In particular, building self-management capacity during the active phase of patients’ cancer treatment provides health and psychosocial benefits. Larger randomised controlled trials are required to further determine efficacy. Further translational research is also needed to determine acceptability, feasibility, enablers and barriers for clinicians embedding this approach into routine cancer survivorship care

Body mass index and postoperative complications in kidney transplant recipients

Background: There is a growing number of overweight and obese patients receiving kidney transplants, despite elevated body mass index (BMI) being associated with postoperative complications. Understanding associations between BMI and complications would allow more objectivity when recommending patients for transplantation or otherwise. Methods: We analysed a retrospective cohort of 508 adult patients who received primary kidney grafts at a single centre in South Australia, 2002–2009, using hospital records and Australia and New Zealand Dialysis and Transplant Registry (ANZDATA) data. Complications within 1 year of transplantation were classified into: surgical, wound, urological, delayed graft function, early nephrectomy and admission to intensive care unit (ICU). Results: Overall, 62% of transplant recipients had a BMI above 25 kg/m2 at transplant. Higher BMI was associated with an increased risk of wound complications (P < 0.001), early nephrectomy (P = 0.002) and delayed graft function (P = 0.03), but not associated with surgical or urological complications, or ICU admission. These associations were stronger for Indigenous Australians than other patients, especially for surgical complications. There was no BMI value above which risks of complications increase substantially. Conclusion: Delayed graft function is an important determinant of patient outcomes. Wound complications can be serious, and are more common in patients with higher BMI. This may justify the use of elevated BMI as a contraindication for transplantation, although no obvious cut-off value exists. Investigations into other measures of body fat composition and distribution are warranted.Stephanie Zrim, Tim Furlong, Blair S Grace and Anthony Mead

Dasatinib cellular uptake and efflux in chronic myeloid leukemia cells: therapeutic implications

Copyright © 2008 American Association for Cancer ResearchPurpose: The organic cation transporter OCT-1 mediates active transport of imatinib. We recently showed that low OCT-1 activity is a major contributor to suboptimal response in chronic myeloid leukemia (CML) patients treated with imatinib. The relevance of OCT-1 activity and efflux pumps in determining intracellular uptake and retention (IUR) of dasatinib was assessed. Experimental Design: The effect of OCT inhibitors on [14C]dasatinib and [14C]imatinib IUR was compared using peripheral blood mononuclear cells from newly diagnosed CML patients. The role of efflux transporters was studied using ABCB1- and ABCG2-overexpressing cell lines and relevant inhibitors. Results: Unlike imatinib, there was no significant difference in the dasatinib IUR at 37°C and 4°C (P = 0.8), and OCT-1 inhibitors including prazosin did not reduce dasatinib IUR significantly. In CML mononuclear cells, prazosin inhibitable IUR was significantly higher for imatinib than dasatinib (6.38 versus 1.48 ng/200,000 cells; P = 0.002; n = 11). Patients with high OCT-1 activity based on their imatinib uptake had IC50dasatinib values equivalent to patients with low OCT-1 activity. Dasatinib IUR was significantly lower in ABCB1-overexpressing cell lines compared with parental cell lines (P < 0.05). PSC833 (ABCB1 inhibitor) significantly increased the dasatinib IUR (P < 0.05) and reduced IC50dasatinib (from 100 to 8 nmol/L) in K562-DOX cell line. The ABCG2 inhibitor Ko143 significantly increased dasatinib IUR in ABCG2-overexpressing cell lines and reduced IC50dasatinib. Conclusion: Unlike imatinib, dasatinib cellular uptake is not significantly affected by OCT-1 activity, so that expression and function of OCT-1 is unlikely to affect response to dasatinib. Dasatinib is a substrate of both efflux proteins, ABCB1 and ABCG2.Devendra K. Hiwase, Verity Saunders, Duncan Hewett, Amity Frede, Stephanie Zrim, Phuong Dang, Laura Eadie, L. Bik To, Junia Melo, Sharad Kumar, Timothy P. Hughes and Deborah L. Whit

Blocking cytokine signaling along with intense Bcr-Abl kinase inhibition induces apoptosis in primary CML progenitors

In chronic myeloid leukemia (CML) cell lines, brief exposure to pharmacologically relevant dasatinib concentrations results in apoptosis. In this study, we assess the impact of intensity and duration of Bcr-Abl kinase inhibition on primary CD34(+) progenitors of chronic phase CML patients. As CML cells exposed to dasatinib in vivo are in a cytokine-rich environment, we also assessed the effect of cytokines (six growth factors cocktail or granulocyte-macrophage colony-stimulating factor (CSF) or granulocyte-CSF) in combination with dasatinib. In the presence of cytokines, short-term intense Bcr-Abl kinase inhibition (>or=90% p-Crkl inhibition) with 100 nM dasatinib did not reduce CD34(+) colony-forming cells (CFCs). In contrast, without cytokines, short-term exposure to dasatinib reduced CML-CD34(+) CFCs by 70-80%. When cytokines were added immediately after short-term exposure to dasatinib, CML-CD34(+) cells remained viable, suggesting that oncogene dependence of these cells can be overcome by concomitant or subsequent exposure to cytokines. Additional inhibition of Janus tyrosine kinase (Jak) activity re-established the sensitivity of CML progenitors to intense Bcr-Abl kinase inhibition despite the presence of cytokines. These findings support the contention that therapeutic strategies combining intense Bcr-Abl kinase inhibition and blockade of cytokine signaling pathways can be effective for eradication of CML progenitors.D. K. Hiwase, D. L. White, J. A. Powell, V. A. Saunders, S. A. Zrim, A. K. Frede, M. A. Guthridge, A. F. Lopez, R. J. D'Andrea, L. B. To, J. V. Melo, S. Kumar and T. P. Hughe

The genomic basis of circadian and circalunar timing adaptations in a midge

Organisms use endogenous clocks to anticipate regular environmental cycles, such as days and tides. Natural variants resulting in differently timed behaviour or physiology, known as chronotypes in humans, have not been well characterized at the molecular level. We sequenced the genome of Clunio marinus, a marine midge whose reproduction is timed by circadian and circalunar clocks. Midges from different locations show strain-specific genetic timing adaptations. We examined genetic variation in five C. marinus strains from different locations and mapped quantitative trait loci for circalunar and circadian chronotypes. The region most strongly associated with circadian chronotypes generates strain-specific differences in the abundance of calcium/calmodulin-dependent kinase II.1 (CaMKII.1) splice variants. As equivalent variants were shown to alter CaMKII activity in Drosophila melanogaster, and C. marinus (Cma)-CaMKII.1 increases the transcriptional activity of the dimer of the circadian proteins Cma-CLOCK and Cma-CYCLE, we suggest that modulation of alternative splicing is a mechanism for natural adaptation in circadian timing