Economic evaluation of skin cancer prevention in Australia

Objectives
Australia has the highest incidence of skin cancer in the world, despite prevention campaigns being implemented since the early 1980s. This study assesses the cost-effectiveness of a skin cancer prevention program (named SunSmart) since it was introduced, together with its potential cost-effectiveness as an upgraded and ongoing national program.

Methods
The reduction in melanoma incidence attributable to SunSmart was modelled as the primary end-point. Historical expenditures on SunSmart were obtained from representative Australian states in three latitude zones. Melanoma incidence rates from these states were used to model key health outcomes. Non-melanoma skin cancer was modelled separately based on national survey results.

Results
We estimate that SunSmart has averted 28,000 disability-adjusted life-years (DALYs), equivalent to 22,000 life-years saved, in the state of Victoria since its introduction in 1988, as well as saving money from cost offset in skin cancer management (dominant). An upgraded national program for the next 20 years is estimated to avert 120,000 DALYs, with associated reductions in the use of health care resources. It remains a dominant intervention in which every dollar invested in SunSmart will return an estimated AU$2.30.

Conclusions
This study demonstrates that a sustained modest investment in skin cancer control is likely to be an excellent value for money.

Economic evaluation of a skin cancer prevention program in Australia : past achievements and future prospects

Objectives
Australia has the highest incidence of skin cancer in the world. Skin cancer prevention campaigns have been implemented in Australia for over two decades. The most notable is under the brand name, SunSmart. The aim of the current study is to assess the cost-effectiveness of SunSmart in the past and the potential cost-effectiveness of an ongoing national SunSmart program with optimal investment in the future.

Methods
An economic evaluation from a health sector perspective was conducted using the reduction in skin cancer incidence attributable to the SunSmart program modelled as the primary end-point. Historical SunSmart program expenditures were obtained from three representative states in three latitude zones, covering different levels of UVR exposure. Melanoma incidence rates from the three representative state cancer registers were used to model the health outcomes. Program effectiveness was assessed by the comparison between the well-resourced SunSmart state (Victoria) and the under-invested states (New South Wales and Queensland). Non-Melanoma Skin Cancer (NMSC) was modelled based on national survey results. 2003 was chosen as the reference year and future costs/outcomes over a 20 year time horizon were discounted at 3%.
The future level of investment in a national SunSmart was chosen to strengthen current practice by increasing current investment to a realistic and achievable level. This conservative increase in investment (expressed as ‘$ per capita’) reflected the investment level that has been achieved in Victoria over sustained periods. To model the potential cost-effectiveness of an upgraded national SunSmart program, a conservative approach was taken, whereby the same magnitude of effectiveness from 1988 to 2003 was applied to future skin cancer incidence.

Results
SunSmart in Victoria has saved 22,300 life-years, averted 27,900 disability-adjusted life-years(DALYs)(discounted) since its introduction in 1988 and achieved an incremental cost-effectiveness ratio (ICER) of $AUD 680 per life-year saved (LYS) and $AUD 540 per DALY averted. When the cost-offset from the estimated reduction in skin cancer treatment costs were taken into account, SunSmart achieved ‘dominance’. The net cost of SunSmart in the past was an estimated saving of $AUD 93 million. An upgraded national SunSmart for the next 20 years would save 91,000 life-years and avert 122,000 DALYs (discounted), involving an increased investment level from the current $AUD 0.07 per capita to the historical average of $AUD 0.28 per capita. The ICER for the upgraded SunSmart program was estimated at $AUD 940 per LYS and $AUD 700 per DALY averted. When the cost-offset is included, the program achieves dominance with a cost saving of $AUD 115 million – an estimated $AUD 2.32 return for every dollar invested between 2003 and 2022.

Conclusions
This study demonstrates that a sustained modest investment in skin cancer control is likely to be excellent value-for-money. While the available data base is certainly not prefect, key parameters would have to change dramatically for this conclusion to be challenged.

Non-invasive collection and examination of human corneal epithelial cells

Purpose. To report the development of a new apparatus for non-invasive collection of human corneal epithelial cells.

Methods. Previous methods of non-invasive, irrigative corneal cell collection resulted in low cell yields limiting potential analysis. A new ocular surface cell collection apparatus (OSCCA) was designed to collect more epithelial cells from direct irrigation of the corneal surface to allow for clinical comparisons. Forty-five samples were obtained (unilateral or bilateral over seven visits) from five human participants. Cell yield, size, phenotype, and corneal staining (prior and post eye wash) were examined.

Results. On average 364 ± 230 epithelial cells were collected from the cornea per eye. Epithelial cell sizes ranged from 8.21 to 51.69 μm in diameter, and 67.30 to 2098.85 μm2 area. The proportion of corneal specific cells collected per sample was 75 ± 14% as determined by positive K3 expression with AE5. On average, 77 ± 0.2% of epithelial cells harvested were nucleated, the remainder were non-nucleated ghost cells. Corneal staining was reduced in the OSCCA-washed vs. contralateral non-washed eyes (p = 0.02).

Conclusions. The OSCCA allows collection of human corneal epithelial cells with significantly higher yields, and greater specificity than previously reported. Reduced corneal staining observed post eye-wash demonstrated the safety of the technique, and its ability to remove cells directly from the corneal surface. The OSCCA could provide an objective non-invasive method of investigating pathological changes, effects of topical therapeutics, and impact of contact lenses and care-solutions of the cells of the ocular surface.

Nucleic acid aptamer-guided cancer therapeutics and diagnostics: the next generation of cancer medicine

Conventional anticancer therapies, such as chemo- and/or radio-therapy are often unable to completely eradicate cancers due to abnormal tumor microenvironment, as well as increased drug/radiation resistance. More effective therapeutic strategies for overcoming these obstacles are urgently in demand. Aptamers, as chemical antibodies that bind to targets with high affinity and specificity, are a promising new and novel agent for both cancer diagnostic and therapeutic applications. Aptamer-based cancer cell targeting facilitates the development of active targeting in which aptamer-mediated drug delivery could provide promising anticancer outcomes. This review is to update the current progress of aptamer-based cancer diagnosis and aptamer-mediated active targeting for cancer therapy in vivo, exploring the potential of this novel form of targeted cancer therapy.

Host manipulation by cancer cells: Expectations, facts, and therapeutic implications.

Similar to parasites, cancer cells depend on their hosts for sustenance, proliferation and reproduction, exploiting the hosts for energy and resources, and thereby impairing their health and fitness. Because of this lifestyle similarity, it is predicted that cancer cells could, like numerous parasitic organisms, evolve the capacity to manipulate the phenotype of their hosts to increase their own fitness. We claim that the extent of this phenomenon and its therapeutic implications are, however, underappreciated. Here, we review and discuss what can be regarded as cases of host manipulation in the context of cancer development and progression. We elaborate on how acknowledging the applicability of these principles can offer novel therapeutic and preventive strategies. The manipulation of host phenotype by cancer cells is one more reason to adopt a Darwinian approach in cancer research.

Descending pathways from the paraventricular nucleus contribute to the recruitment of brainstem nuclei following a systemic immune challenge

Hypothalamic nuclei, particularly the paraventricular nuclei (PVN), are important brain sites responsible for central nervous system responses during an immune challenge. The brainstem catecholamine cells of the nucleus tractus solitarius (NTS) and ventrolateral medulla (VLM) have been shown to play critical roles in relaying systemic immune signals to the PVN. However, whilst it is well recognised that PVN divisions also innervate the NTS and VLM, it is not known whether descending PVN pathways can modulate the recruitment of brainstem cells during an immune challenge. Using systemic administration of the proinflammatory cytokine interleukin-1β, in combination with Fos immunolabelling, we firstly investigated the effect of PVN lesions on NTS and VLM catecholamine and non-catecholamine cell responses. We found that ibotenic acid lesions of the PVN significantly reduced numbers of Fos-positive non-catecholamine, noradrenergic and adrenergic cells observable in the VLM and NTS after interleukin-1β administration. We then investigated the origins of descending inputs to the VLM and NTS, activated by systemic interleukin-1β, by mapping the distribution of Fos-positive retrogradely-labelled cells in divisions of the PVN after iontophoretically depositing choleratoxin-b subunit into the NTS or VLM one week prior to interleukin-1β administration. We found that, after either NTS or VLM deposits, the majority of retrogradely-labelled Fos-positive cells activated by interleukin-1β were localised in the medial and lateral parvocellular PVN divisions. Retrogradely-labelled Fos-positive cells were also observed in the NTS after VLM deposits, and in the VLM after NTS tracer deposits, suggesting reciprocal communication between these two nuclei after systemic interleukin-1β. Thus the present study shows that the PVN has the capacity to modulate NTS and VLM responses after an immune challenge and that these may result from descending projections arising in the medial and lateral PVN divisions. These findings suggest that central nervous system responses to an immune challenge are likely to involve complex reciprocal connections between the PVN and the brainstem as well as between brainstem nuclei themselves.

Unwanted sexual advances at work: variations by employment arrangement in a sample of working Australians

Objective: We tested the hypothesis that the risk of experiencing unwanted sexual advances at work (UWSA) is greater for precariously-employed workers in comparison to those in permanent or continuing employment. Methods: A cross-sectional population-based telephone survey was conducted in Victoria (66% response rate, N=1,101). Employment arrangements were analysed using eight differentiated categories, as well as a four-category collapsed measure to address small cell sizes. Self-report of unwanted sexual advances at work was modelled using multiple logistic regression in relation to employment arrangement, controlling for gender, age, and occupational skill level. Results: Forty-seven respondents reported UWSA in our sample (4.3%), mainly among women (37 of 47). Risk of UWSA was higher for younger respondents, but did not vary significantly by occupational skill level or education. In comparison to Permanent Full-Time, three employment arrangements were strongly associated with UWSA after adjustment for age, gender, and occupational skill level: Casual Full-Time OR = 7.2 (95% Confidence Interval 1.7-30.2); Fixed-Term Contract OR = 11.4 (95% CI 3.4-38.8); and Own-Account Self-Employed OR = 3.8 (95% CI 1.2-11.7). In analyses of females only, the magnitude of these associations was further increased. Conclusions: Respondents employed in precarious arrangements were more likely to report being exposed to UWSA, even after adjustment for age and gender. Implications: Greater protections from UWSA are likely needed for precariously employed workers.

MicroRNAs: biogenesis, roles for carcinogenesis and as potential biomarkers for cancer diagnosis and prognosis

MicroRNAs (miRNAs) are short non-coding RNAs of 20-24 nucleotides that play important roles in carcinogenesis. Accordingly, miRNAs control numerous cancer-relevant biological events such as cell proliferation, cell cycle control, metabolism and apoptosis. In this review, we summarize the current knowledge and concepts concerning the biogenesis of miRNAs, miRNA roles in cancer and their potential as biomarkers for cancer diagnosis and prognosis including the regulation of key cancer-related pathways, such as cell cycle control and miRNA dysregulation. Moreover, microRNA molecules are already receiving the attention of world researchers as therapeutic targets and agents. Therefore, in-depth knowledge of microRNAs has the potential not only to identify their roles in cancer, but also to exploit them as potential biomarkers for cancer diagnosis and identify therapeutic targets for new drug discovery.

Cost-effectiveness analysis of screening for lung cancer with low dose spiral CT (computed tomography) in the Australian setting

Introduction:
Low dose spiral computed tomography (CT) is a sensitive screening tool for lung cancer that is currently being evaluated in both non-randomised studies and randomised controlled trials.
Methods:
We conducted a quantitative decision analysis using a Markov model to determine whether, in the Australian setting, offering spiral CT screening for lung cancer to high risk individuals would be cost-effective compared with current practice. This exploratory analysis was undertaken predominantly from the perspective of the government as third-party funder. In the base-case analysis, the costs and health outcomes (life-years saved and quality-adjusted life years) were calculated in a hypothetical cohort of 10,000 male current smokers for two alternatives: (1) screen for lung cancer with annual CT for 5 years starting at age 60 year and treat those diagnosed with cancer or (2) no screening and treat only those who present with symptomatic cancer.
Results:
For male smokers aged 60–64 years, with an annual incidence of lung cancer of 552 per 100,000, the incremental cost-effectiveness ratio was $57,325 per life-year saved and $105,090 per QALY saved. For females aged 60–64 years with the same annual incidence of lung cancer, the cost-effectiveness ratio was $51,001 per life-year saved and $88,583 per QALY saved. The model was used to examine the relationship between efficacy in terms of the expected reduction in lung cancer mortality at 7 years and cost-effectiveness. In the base-case analysis lung cancer mortality was reduced by 27% and all cause mortality by 2.1%. Changes in the estimated proportion of stage I cancers detected by screening had the greatest impact on the efficacy of the intervention and the cost-effectiveness. The results were also sensitive to assumptions about the test performance characteristics of CT scanning, the proportion of lung cancer cases overdiagnosed by screening, intervention rates for benign disease, the discount rate, the cost of CT, the quality of life in individuals with early stage screen-detected cancer and disutility associated with false positive diagnoses. Given current knowledge and practice, even under favourable assumptions, reductions in lung cancer mortality of less than 20% are unlikely to be cost-effective, using a value of $50,000 per life-year saved as the threshold to define a “cost-effective” intervention.
Conclusion:
The most feasible scenario under which CT screening for lung cancer could be cost-effective would be if very high-risk individuals are targeted and screening is either highly effective or CT screening costs fall substantially.

Targeting Hsp90 with small molecule inhibitors induces the over-expression of the anti-apoptotic molecule, survivin, in human A549, HONE-1 and HT-29 cancer cells

Survivin is a dual functioning protein. It inhibits the apoptosis of cancer cells by inhibiting caspases, and also promotes cancer cell growth by stabilizing microtubules during mitosis. Since the molecular chaperone Hsp90 binds and stabilizes survivin, it is widely believed that down-regulation of survivin is one of the important therapeutic functions of Hsp90 inhibitors such as the phase III clinically trialed compound 17-AAG. However, Hsp90 interferes with a number of molecules that up-regulate the intracellular level of survivin, raising the question that clinical use of Hsp90 inhibitors may indirectly induce survivin expression and subsequently enhance cancer anti-drug responses. The purpose of this study is to determine whether targeting Hsp90 can alter survivin expression differently in different cancer cell lines and to explore possible mechanisms that cause the alteration in survivin expression.

Anti-angiogenic therapy for lung cancer

This is the protocol for a review and there is no abstract. The objectives are as follows:

To determine the benefits and harms of angiogenesis inhibitors in the treatment of lung cancer when given alone, following or in combination with chemotherapy or chemo-radiotherapy (in the case of locally advanced non-metastatic NSCLC or limited stage SCLC).

The role of nanomedicine in cell based therapeutics in cancer and inflammation.

Cell based therapeutics is one of the most rapidly advancing medical fields, bringing together a range of fields including transplantation, tissue engineering and regeneration, biomaterials and stem cell biology. However, traditional cell-based therapeutics have many limitations, one of which is their harmful effects exhibited on healthy body cells due to their lack of specificity. Nanomedicine is providing an alternative treatment strategy that is more targeted and specific to a range of diseases. Varying from polymers conjugated with drugs or tissue targeting molecules, to proteins encapsulated within a polymer shell, nanomedicine will without a doubt play a major role in designing effective cell-based therapeutics that can overcome certain classical problems. These may include from addressing the problem of non-specificity of contemporary treatments to overcoming mechanical barriers, such as crossing cell membranes. This review summarises the recent work on nano-based cell therapy as a regenerative agent and as a therapeutic for cancer and neurological diseases.

Selection of DNA aptamers against epithelial cell adhesion molecule for cancer cell imaging and circulating tumor cell capture

Epithelial cell adhesion molecule (EpCAM) is overexpressed in most solid cancers and is an ideal antigen for clinical applications in cancer diagnosis, prognosis, imaging, and therapy. Currently, most of the EpCAM-based diagnostic, prognostic, and therapeutic strategies rely on the anti-EpCAM antibody. However, the use of EpCAM antibody is restricted due to its large size and instability. In this study, we have successfully identified DNA aptamers that selectively bind human recombinant EpCAM protein. The aptamers can specifically recognize a number of live human cancer cells derived from breast, colorectal, and gastric cancers that express EpCAM but not bind to EpCAM-negative cells. Among the aptamer sequences identified, a hairpin-structured sequence SYL3 was optimized in length, resulting in aptamer sequence SYL3C. The Kd values of the SYL3C aptamer against breast cancer cell line MDA-MB-231 and gastric cancer cell line Kato III were found to be 38±9 and 67±8 nM, respectively, which are better than that of the full-length SYL3 aptamer. Flow cytometry analysis results indicated that the SYL3C aptamer was able to recognize target cancer cells from mixed cells in cell media. When used to capture cancer cells, up to 63% cancer cell capture efficiency was achieved with about 80% purity. With the advantages of small size, easy synthesis, good stability, high binding affinity, and selectivity, the DNA aptamers reported here against cancer biomarker EpCAM will facilitate the development of novel targeted cancer therapy, cancer cell imaging, and circulating tumor cell detection.

Efficacy of using cancer stem cell markers in isolating and characterizing liver cancer stem cells

Recent evidence suggests that a subset of hepatocellular carcinomas (HCCs) are derived from liver cancer stem cells (LCSCs). In order to isolate and characterize LCSCs, reliable markers that are specific to these cells are required. We evaluated the efficacy of a range of cancer stem cell (CSC) markers in isolating and characterizing LCSCs. We show that the most widely used CSC markers are not specific to LCSCs. By western analysis, protein expression of the common markers showed no significant difference between HCC tumor tissues and adjacent non-cancerous liver. Further, isolation of LCSCs from common HCC cell lines using FACScan and microbeads showed no consistent marker expression pattern. We also show that LCSCs have unique subtypes. Immunohistochemistry of HCC tissues showed that different HCCs express unique combinations of LCSC markers. Quantitative real-time polymerase chain reaction analysis showed that LCSCs isolated using different markers in the same HCC phenotype had different expression profiles. Likewise, LCSCs isolated from different HCC phenotypes with the same marker also had unique expression profiles and displayed varying resistance profiles to Sorafenib. Thus, using a range of commonly used CSC markers in HCCs and cell lines, we demonstrate that currently available markers are not specific for LCSCs. LCSCs have unique subtypes that express distinctive combinations of LCSC markers and altered drug resistance profiles, making their identification problematic.

Epidermal growth factor receptor-tyrosine kinase inhibitors in advanced squamous cell carcinoma of the lung: a meta-analysis.

Tyrosine kinase inhibitors (TKIs) targeting the epidermal growth factor receptor (EGFR) are well established in treating metastatic pulmonary adenocarcinoma, especially patients with activating EGFR mutations. EGFR mutations are rare in pulmonary squamous cell carcinomas (SCCs). There are conflicting data supporting the efficacy of EGFR-TKIs in advanced lung SCC. We analyzed the impact of EGFR-TKIs on progression-free survival (PFS) and overall survival (OS) in unselected patients with lung SCC.