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Vardy J.,University of Sydney | Vardy J.,Concord Cancer Center | Agar M.,Braeside Hospital | Agar M.,University of New South Wales
Journal of Clinical Oncology

The WHO analgesic ladder for the treatment of cancer pain provides a three-step sequential approach for analgesic administration based on pain severity that has global applicability. Nonopioids were recommended for mild pain, with the addition of mild opioids for moderate pain and strong opioids for severe pain. Here, we review the evidence for the use of nonopioid analgesic agents in patients with cancer and describe the mode of action of the main drug classes. Evidence supports the use of anti-inflammatory drugs such as acetaminophen/paracetamol and nonsteroidal anti-inflammatory drugs (NSAIDs) for mild cancer pain. Adding an NSAID to an opioid for stronger cancer pain is efficacious, but the risk of long-term adverse effects has not been quantified. There is limited evidence to support using acetaminophen with stronger opioids. Corticosteroids have a specific role in spinal cord compression and brain metastases, where improved analgesia is a secondary benefit. There is limited evidence for adding corticosteroids to stronger opioids when pain control is the primary objective. Systematic reviews suggest a role for antidepressant and anticonvulsant medications for neuropathic pain, but there are methodologic issues with the available studies. Bisphosphonates improve pain in patients with bony metastases in some tumor types. Denosumab may delay worsening of pain compared with bisphosphonates. Larger studies of longer duration are required to address outstanding questions concerning the use of nonopioid analgesia for stronger cancer pain. © 2014 by American Society of Clinical Oncology. Source

Selamat M.H.,University of Malaya | Loh S.Y.,University of Malaya | Loh S.Y.,University of Sydney | Mackenzie L.,University of Sydney | And 2 more authors.

Background: Cognitive impairment, colloquially termed "chemobrain", occurs in 10-40% of all cancer patients, and is an emerging target of cancer survivorship research. Aim: This study reviews published qualitative studies to explore cognitive impairments or chemobrain among breast cancer survivors, with particular attention given to the impact on quality of life. Method: Using keywords, we searched ten electronic databases (CINAHL, EMBASE, Proquest, OVID SP, MEDLINE, Oxford Journal, Science Direct, PubMED). Findings: Of 457 papers, seven relevant papers were included. Data was extracted and concepts were analysed using a meta ethnography approach. Four second order intepretations were identified, on the basis of which, four third order intrepretations were constructed. Linked together in a line of argument, was a consistent account on their struggles to selfmanage the chemobrain impairments that impact their daily lives. Five concepts emerged from the analysis of the primary findings: i) real experiences of cognitive changes, ii) calls for help, iii) impact of cognitive impairments, iv) coping and v) survivorship and meaning. Further synthesis resulted in four new order intepretations: i) The chemobrain struggle, ii) The substantial impact of chemobrain on life domains, iii) The struggle to readjust and to self manage, and iv) 'thankful yet fearful' representation. Discussion: Awareness of cognitive changes were context-dependent on healthcare settings and cultural contexts as strong determinants. Subjects verified the existence of chemobrain but healthcare providers mis-recognised, under-recognised, and sometimes negated it perhaps due to its unknown aetiology. Asian breast cancer survivors appear less vocal than their western counterparts. Conclusion: The current literature on the lived experiences of how women experienced chemobrain provides a consistent report that chemobrain is real, persistent and with detrimental impacts on quality of life - manifested as a constant struggles. A greater awareness of the effects of chemobrain with improved functional assessment and interventions is warranted. © 2014 Selamat et al. Source

Linton A.,University of Sydney | Linton A.,Concord Cancer Center | Pavlakis N.,University of Sydney | O'Connell R.,1 Clinical Trials Center | And 8 more authors.
British Journal of Cancer

Background:Although the prognosis of most patients presenting with malignant pleural mesothelioma (MPM) is poor, a small proportion survives long term. We investigated factors associated with survival in a large patient series. Methods:All patients registered with the NSW Dust Diseases Board (2002-2009) were included in an analysis of prognostic factors using Kaplan-Meier and Cox regression analysis. On the basis of these analyses, we developed a risk score (Prognostic Index (PI)). Results:We identified 910 patients: 90% male; histology (epithelioid 60%; biphasic 13%; sarcomatoid 17%); stage (Tx-I-II 48%; III-IV 52%); and calretinin expression (91%). Treatment: chemotherapy(CT) 44%, and extrapleural-pneumonectomy (EPP) 6%. Median overall survival (OS) was 10.0 months. Longer OS was associated with: age <70 (13.5 vs 8.5 months; P<0.001); female gender (12.0 vs 9.9 months; P<0.001); epithelioid subtype (13.3 vs 6.2 months; P<0.001); ECOG status 0 (27.4 vs 9.7 months; P=0.015), calretinin expression (10.9 vs 5.5 months; P<0.001); neutrophil-lymphocyte ratio (NLR) <5 (11.9 vs 7.5 months; P<0.001); platelet count <400 (11.5 vs 7.2 months; P<0.001); and normal haemoglobin (16.4 vs 8.8 months; P<0.001). On time-dependent analysis, patients receiving pemetrexed-based chemotherapy (HR=0.83; P=0.048) or EPP (HR=0.41; P<0.001) had improved survival. Age, gender, histology, calretinin and haematological factors remained significant on multivariate analysis. In all, 24% of patients survived >20 months: 16% of these receiving EPP, and 66% CT. The PI offered improved prognostic discrimination over one of the existing prognostic models (EORTC). Conclusions:We identified calretinin expression, age, gender, histological subtype, platelet count and haemoglobin level as independent prognostic factors. Patients undergoing EPP or pemetrexed-based chemotherapy demonstrated better survival, but 84% and 34% of long survivors, respectively, did not receive radical surgery or chemotherapy.British Journal of Cancer advance online publication, 4 September 2014; doi:10.1038/bjc.2014.478 www.bjcancer.com. Source

Rennie G.,University of Sydney | Chen A.C.,University of Sydney | Dhillon H.,University of Sydney | Vardy J.,University of Sydney | And 3 more authors.
Nutritional Neuroscience

Nicotinamide, or vitamin B3, is a precursor of nicotinamide adenine dinucleotide (NAD+) and is involved in a multitude of intra- and inter-cellular processes, which regulate some of the cell’s metabolic, stress, and immune responses to physiological or pathological signals. As a precursor of NAD+, which is a key coenzyme in the production of adenosine triphosphate or cellular energy, nicotinamide has been investigated for potential neuroprotective effects in cellular, animal, and human studies. Objectives: We aimed to summarize the current evidence on the effect of dietary and supplemental nicotinamide on cognitive function. Methods: A literature review was conducted on the effects of nicotinamide and its derivatives as a preventive and therapeutic agent for disorders of neurocognitive function. Specific conditions examined include agerelated cognitive decline, Alzheimer’s disease, Parkinson’s disease, and ischaemic and traumatic brain injury. Results: Data from animal and human interventional studies and epidemiological research suggests that nicotinamide may be beneficial in preserving and enhancing neurocognitive function. Discussion: Nicotinamide is non-toxic, inexpensive and widely available, and interventional studies in humans, using supplemental doses of nicotinamide, are now warranted. © W. S. Maney & Son Ltd 2015. Source

Gasiorowski R.E.,University of Sydney | Gasiorowski R.E.,Concord Cancer Center | Clark G.J.,University of Sydney | Bradstock K.,University of Sydney | Hart D.N.J.,University of Sydney
British Journal of Haematology

Novel therapies with increased efficacy and decreased toxicity are desperately needed for the treatment of acute myeloid leukaemia (AML). The anti CD33 immunoconjugate, gemtuzumab ozogamicin (GO), was withdrawn with concerns over induction mortality and lack of efficacy. However a number of recent trials suggest that, particularly in AML with favourable cytogenetics, GO may improve overall survival. This data and the development of alternative novel monoclonal antibodies (mAb) have renewed interest in the area. Leukaemic stem cells (LSC) are identified as the subset of AML blasts that reproduces the leukaemic phenotype upon transplantation into immunosuppressed mice. AML relapse may be caused by chemoresistant LSC and this has refocused interest on identifying and targeting antigens specific for LSC. Several mAb have been developed that target LSC effectively in xenogeneic models but only a few have begun clinical evaluation. Antibody engineering may improve the activity of potential new therapeutics for AML. The encouraging results seen with bispecific T cell-engaging mAb-based molecules against CD19 in the treatment of B-cell acute lymphobalstic leukaemia, highlight the potential efficacy of engineered antibodies in the treatment of acute leukaemia. Potent engineered mAb, possibly targeting novel LSC antigens, offer hope for improving the current poor prognosis for AML. © 2013 John Wiley & Sons Ltd. Source

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