Adaptive radiotherapy for virally mediated head and neck cancer : predicting which patients may benefit most

Background: Recent clinical studies have demonstrated an emerging subgroup of head and neck cancers that are virally mediated. This disease appears to be a distinct clinical entity with patients presenting younger and with more advanced nodal disease, having lower tobacco and alcohol exposure and highly radiosensitive tumours. This means they are living longer, often with the debilitating functional side effects of treatment. The primary objective of this study was to determine how virally mediated nasopharyngeal and oropharyngeal cancers respond to radiation therapy treatment. The aim was to determine risk categories and corresponding adaptive treatment management strategies to proactively manage these patients. Method/Results: 121 patients with virally mediated, node positive nasopharyngeal or oropharyngeal cancer who received radiotherapy treatment with curative intent between 2005 and 2010 were studied. Relevant patient demographics including age, gender, diagnosis, TNM stage, pre-treatment nodal size and dose delivered was recorded. Each patient’s treatment plan was reviewed to determine if another computed tomography (re-CT) scan was performed and at what time point (dose/fraction) this occurred. The justification for this re-CT was determined using four categories: tumour and/or nodal regression, weight loss, both or other. Patients who underwent a re-CT were further investigated to determine whether a new plan was calculated. If a re-plan was performed, the dosimetric effect was quantified by comparing dose volume histograms of planning target volumes and critical structures from the actual treatment delivered and the original treatment plan. Preliminary results demonstrated that 25/121 (20.7%) patients required a re-CT and that these re-CTs were performed between fractions 20 to 25 of treatment. The justification for these re-CTs consisted of a combination of tumour and/or nodal regression and weight loss. 16/25 (13.2%) patients had a replan calculated. 9 (7.4%) of these replans were implemented clinically due to the resultant dosimetric effect calculated. The data collected from this assessment was statistically analysed to identify the major determining factors for patients to undergo a re-CT and/or replan. Specific factors identified included nodal size and timing of the required intervention (i.e. how when a plan is to be adapted). This data was used to generate specific risk profiles that will form the basis of a biologically guided adaptive treatment management strategy for virally mediated head and neck cancer. Conclusion: Preliminary data indicates that virally mediated head and neck cancers respond significantly during radiation treatment (tumour and/or nodal regression and weight loss). Implications of this response are the potential underdosing or overdosing of tumour and/or surrounding critical structures. This could lead to sub-optimal patient outcomes and compromised quality of life. Consequently, the development of adaptive treatment strategies that improve organ sparing for this patient group is important to ensure delivery of the prescribed dose to the tumour volume whilst minimizing the dose received to surrounding critical structures. This could reduce side effects and improve overall patient quality of life. The risk profiles and associated adaptive treatment approaches developed in this study will be tested prospectively in the clinical setting in Phase 2 of this investigation.

Why we need a population-based approach to clinical indicators for cancer: a case study using microscopic confirmation of lung cancer in Queensland

An important function of clinical cancer registries is to provide feedback to clinicians on various performance measures. To date, most clinical cancer registries in Australia are located in tertiary academic hospitals, where adherence to guidelines is probably already high. Microscopic confirmation is an important process measure for lung cancer care. We found that the proportion of patients with lung cancer without microscopic confirmation was much higher in regional public hospitals (27.1%) than in tertiary hospitals (7.5%), and this disparity remained after adjusting for age, sex and comorbidities. The percentage was also higher in the private than in the public sector. This case study shows that we need a population-based approach to measuring clinical indicators that includes regional public hospitals as a matter of priority and should ideally include the private sector.

Adaptive radiotherapy for virally mediated head and neck cancer

Introduction: Clinical investigation has revealed a subgroup of head and neck cancers that are virally mediated. The relationship between nasopharyngeal cancer and Epstein Barr Virus (EBV) has long been established and more recently, the association between oropharyngeal cancer and Human Papillomavirus (HPV) has been revealed1,2 These cancers often present with nodal involvement and generally respond well to radiation treatment, evidenced by tumour regression1. This results in the need for treatment plan adaptation or re-planning in a subset of patients. Adaptive techniques allow the target region of the radiotherapy treatment plan to be altered in accordance with treatment-induced changes to ensure that under or over dosing does not occur3. It also assists in limiting potential overdosing of surrounding critical normal tissues4. We sought to identify a high-risk group based on nodal size to be evaluated in a future prospective adaptive radiotherapy trial. Method: Between 2005-2010, 121 patients with virally mediated, node positive nasopharyngeal (EBV positive) or oropharyngeal (HPV positive) cancers, receiving curative intent radiotherapy treatment were reviewed. Patients were analysed based on maximum size of the dominant node at diagnosis with a view to grouping them in varying risk categories to determine the need of re-planning. The frequency and timing of the re-planning scans were also evaluated. Results: Sixteen nasopharyngeal and 105 oropharyngeal tumours were reviewed. Twenty-five (21%) patients underwent a re-planning CT at a median of 22 (range, 0-29) fractions with 1 patient requiring re-planning prior to the commencement of treatment. Based on the analysis, patients were subsequently placed into risk categories; ≤35mm (Group 1), 36-45mm (Group 2), ≥46mm (Group 3). Re-planning CT’s were performed in Group 1- 8/68 (11.8%), Group 2- 4/28 (14.3%), Group 3- 13/25 (52%). Conclusion: In this series, patients with virally mediated head and neck cancer and nodal size > 46mm appear to be a high-risk group for the need of re-planning during a course of curative radiotherapy. This finding will now be tested in a prospective adaptive radiotherapy study. ‘Real World’ Implications: This research identifies predictive factors for those patients with virally mediated head and neck cancer that will benefit most from treatment adaptation. This will assist in minimising the side effects experienced by these patients thereby improving their quality of life after treatment.

Adaptive radiotherapy for virally mediated head and neck cancer

Purpose: Virally mediated head and neck cancers (VMHNC) often present with nodal involvement, and are generally considered radioresponsive, resulting in the need for a re-planning CT during radiotherapy (RT) in a subset of patients. We sought to identify a high-risk group based on nodal size to be evaluated in a future prospective adaptive RT trial. Methodology: Between 2005-2010, 121 patients with virally-mediated, node positive nasopharyngeal (EBV positive) or oropharyngeal (HPV positive) cancers, receiving curative intent RT were reviewed. Patients were analysed based on maximum size of the dominant node with a view to grouping them in varying risk categories for the need of re-planning. The frequency and timing of the re-planning scans were also evaluated. Results: Sixteen nasopharyngeal and 105 oropharyngeal tumours were reviewed. Twenty-five (21%) patients underwent a re-planning CT at a median of 22 (range, 0-29) fractions with 1 patient requiring re-planning prior to the commencement of treatment. Based on the analysis, patients were subsequently placed into 3 groups; ≤35mm (Group 1), 36-45mm (Group 2), ≥46mm (Group 3). Re-planning CT’s were performed in Group 1- 8/68 (11.8%), Group 2- 4/28 (14.3%), Group 3- 13/25 (52%). Sample size did not allow statistical analysis to detect a significant difference or exclusion of a lack of difference between the 3 groups. Conclusion: In this series, patients with VMHNC and nodal size > 46mm appear to be a high-risk group for the need of re-planning during a course of definitive radiotherapy. This finding will now be tested in a prospective adaptive RT study.

Can we deliver both population-based and personalized approaches to cancer care?

Responding to the individual needs of the person affected by cancer is a fundamental tenet of nursing care. The evidence base to enable highly personalized approaches to the way we provide care has grown enormously in recent years. Today, we have a much better understanding of the mechanisms underpinning health needs of people with cancer, as well as the wide range of environmental, sociocultural, psychological, and biological influences on these needs. This growing evidence base enables us to better target and tailor interventions in increasingly sophisticated ways.

Adaptive radiotherapy for virally mediated head and neck cancer

Purpose: Virally mediated head and neck cancers (VMHNC) often present with nodal involvement, and are generally considered radioresponsive, resulting in the need for a re-planning CT during radiotherapy (RT) in a subset of patients. We sought to identify a high-risk group based on nodal size to be evaluated in a future prospective adaptive RT trial. Methodology: Between 2005-2010, 121 patients with virally-mediated, node positive nasopharyngeal (EBV positive) or oropharyngeal (HPV positive) cancers, receiving curative intent RT were reviewed. Patients were analysed based on maximum size of the dominant node with a view to grouping them in varying risk categories for the need of re-planning. The frequency and timing of the re-planning scans were also evaluated. Results: Sixteen nasopharyngeal and 105 oropharyngeal tumours were reviewed. Twenty-five (21%) patients underwent a re-planning CT at a median of 22 (range, 0-29) fractions with 1 patient requiring re-planning prior to the commencement of treatment. Based on the analysis, patients were subsequently placed into 3 groups; ≤35mm (Group 1), 36-45mm (Group 2), ≥46mm (Group 3). Re-planning CT’s were performed in Group 1- 8/68 (11.8%), Group 2- 4/28 (14.3%), Group 3- 13/25 (52%). Sample size did not allow statistical analysis to detect a significant difference or exclusion of a lack of difference between the 3 groups. Conclusion: In this series, patients with VMHNC and nodal size > 46mm appear to be a high-risk group for the need of re-planning during a course of definitive radiotherapy. This finding will now be tested in a prospective adaptive RT study.

Adaptive radiotherapy for virally mediated head and neck cancer

Purpose: Virally mediated head and neck cancers (VMHNC) often present with nodal involvement, and are generally considered radioresponsive, resulting in the need for plan adaptation during radiotherapy in a subset of patients. We sought to identify a high-risk group based on pre-treatment nodal size to be evaluated in a future prospective adaptive radiotherapy trial. Methodology: Between 2005-2010, 121 patients with virally-mediated, node positive nasopharyngeal or oropharyngeal cancers, receiving definitive radiotherapy were reviewed. Patients were analysed based on maximum size of the dominant node at diagnosis with a view to grouping them in varying risk categories for the need of re-planning. The frequency and timing of the re-planning scans were also evaluated. Results: Sixteen nasopharyngeal and 105 oropharyngeal tumours were reviewed. Twenty-five (21%) patients underwent a re-planning CT at a median of 22 (range, 0-29) fractions with 1 patient requiring re-planning prior to the commencement of treatment. Based on the analysis, patients were subsequently placed into 3 groups defined by pre-treatment nodal size; ≤ 35mm (Group 1), 36-45mm (Group 2), ≥ 46mm (Group 3). Applying these groups to the patient cohort, re-planning CT’s were performed in Group 1- 8/68 (11.8%), Group 2- 4/28 (14.3%), Group 3- 13/25 (52%). Conclusion: In this series, patients with VMHNC and nodal size > 46mm appear to be a high-risk group for the need of plan adaptation during a course of definitive radiotherapy. This finding will now be tested in a prospective adaptive radiotherapy study.

Embedding information and communication technologies in the early childhood classroom

New technologies and the pace of change in modern society mean changes for classroom teaching and learning. Information and communication technologies (ICTs) feature in everyday life and provide ample opportunities for enhancing classroom programs. This article outlines how ICTs complement curriculum implementation in one year two classroom. It suggests practical strategies demonstrating how teachers can make ICTs work for them and progressively teach children how to make ICTs work for them.

Growth of confined cancer spheroids : a combined experimental marker, critical modelling approach

A critical step in the dissemination of ovarian cancer is the formation of multicellular spheroids from cells shed from the primary tumour. The objectives of this study were to apply bioengineered three-dimensional (3D) microenvironments for culturing ovarian cancer spheroids in vitro and simultaneously to build on a mathematical model describing the growth of multicellular spheroids in these biomimetic matrices. Cancer cells derived from human epithelial ovarian carcinoma were embedded within biomimetic hydrogels of varying stiffness and grown for up to 4 weeks. Immunohistochemistry, imaging and growth analyses were used to quantify the dependence of cell proliferation and apoptosis on matrix stiffness, long-term culture and treatment with the anti-cancer drug paclitaxel. The mathematical model was formulated as a free boundary problem in which each spheroid was treated as an incompressible porous medium. The functional forms used to describe the rates of cell proliferation and apoptosis were motivated by the experimental work and predictions of the mathematical model compared with the experimental output. This work aimed to establish whether it is possible to simulate solid tumour growth on the basis of data on spheroid size, cell proliferation and cell death within these spheroids. The mathematical model predictions were in agreement with the experimental data set and simulated how the growth of cancer spheroids was influenced by mechanical and biochemical stimuli including matrix stiffness, culture duration and administration of a chemotherapeutic drug. Our computational model provides new perspectives on experimental results and has informed the design of new 3D studies of chemoresistance of multicellular cancer spheroids.

Paclitaxel resistance and multicellular spheroid formation are induced by kallikrein-related peptidase 4 in serous ovarian cancer cells in an ascites mimicking microenvironment

High tumor kallikrein-related-peptidase 4 (KLK4) levels are associated with a poor outcome for women with serous epithelial ovarian cancer (EOC), for which peritoneal dissemination and chemoresistance are key events. To determine the role of KLK4 in these events, we examined KLK4-transfected SKOV-3 and endogenous KLK4 expressing OVCA432 cells in 3-dimensional (3D) suspension culture to mimic the ascites microenvironment. KLK4-SKOV-3 cells formed multicellular aggregates (MCAs) as seen in ascites, as did SKOV-3 cells treated with active KLK4. MCA formation was reduced by treatment with a KLK4 blocking antibody or the selective active site KLK4 sunflower trypsin inhibitor (SFTI-FCQR). KLK4-MCAs formed larger cancer cell foci in mesothelial cell monolayers than those formed by vector and native SKOV-3 cells, suggesting KLK4-MCAs are highly invasive in the peritoneal microenvironment. A high level of KLK4 is expressed by ascitic EOC cells compared to matched primary tumor cells, further supporting its role in the ascitic microenvironment. Interestingly, KLK4 transfected SKOV-3 cells expressed high levels of the KLK4 substrate, urokinase plasminogen activator (uPA), particularly in 3D-suspension, and high levels of both KLK4 and uPA were observed in patient cells taken from ascites. Importantly, the KLK4-MCAs were paclitaxel resistant which was reversed by SFTI-FCQR and to a lesser degree by the general serine protease inhibitor, Aprotinin, suggesting that in addition to uPA, other as yet unidentified substrates of KLK4 must be involved. Nonetheless, these data suggest that KLK4 inhibition, in conjunction with paclitaxel, may improve the outcome for women with serous epithelial ovarian cancer and high KLK4 levels in their tumors.

Diurnal temperature range and childhood asthma : a time-series study

BACKGROUND: Hot and cold temperatures have been associated with childhood asthma. However, the relationship between daily temperature variation and childhood asthma is not well understood. This study aimed to examine the relationship between diurnal temperature range (DTR) and childhood asthma. METHODS: A Poisson generalized linear model combined with a distributed lag non-linear model was used to examine the relationship between DTR and emergency department admissions for childhood asthma in Brisbane, from January 1st 2003 to December 31st 2009. RESULTS: There was a statistically significant relationship between DTR and childhood asthma. The DTR effect on childhood asthma increased above a DTR of 10[degree sign]C. The effect of DTR on childhood asthma was the greatest for lag 0--9 days, with a 31% (95% confidence interval: 11% -- 58%) increase of emergency department admissions per 5[degree sign]C increment of DTR. Male children and children aged 5--9 years appeared to be more vulnerable to the DTR effect than others. CONCLUSIONS: Large DTR may trigger childhood asthma. Future measures to control and prevent childhood asthma should include taking temperature variability into account. More protective measures should be taken after a day of DTR above10[degree sign]C.

Genetic association of the KLK4 locus with risk of prostate cancer

The Kallikrein-related peptidase, KLK4, has been shown to be significantly overexpressed in prostate tumours in numerous studies and is suggested to be a potential biomarker for prostate cancer. KLK4 may also play a role in prostate cancer progression through its involvement in epithelial-mesenchymal transition, a more aggressive phenotype, and metastases to bone. It is well known that genetic variation has the potential to affect gene expression and/or various protein characteristics and hence we sought to investigate the possible role of single nucleotide polymorphisms (SNPs) in the KLK4 gene in prostate cancer. Assessment of 61 SNPs in the KLK4 locus (±10 kb) in approximately 1300 prostate cancer cases and 1300 male controls for associations with prostate cancer risk and/or prostate tumour aggressiveness (Gleason score <7 versus ≥7) revealed 7 SNPs to be associated with a decreased risk of prostate cancer at the Ptrend<0.05 significance level. Three of these SNPs, rs268923, rs56112930 and the HapMap tagSNP rs7248321, are located several kb upstream of KLK4; rs1654551 encodes a non-synonymous serine to alanine substitution at position 22 of the long isoform of the KLK4 protein, and the remaining 3 risk-associated SNPs, rs1701927, rs1090649 and rs806019, are located downstream of KLK4 and are in high linkage disequilibrium with each other (r2≥0.98). Our findings provide suggestive evidence of a role for genetic variation in the KLK4 locus in prostate cancer predisposition.

Socioeconomic inequalities in cardiovascular mortality and the role of childhood socioeconomic conditions and adulthood risk factors : a prospective cohort study with 17-years of follow up

Background The mechanisms underlying socioeconomic inequalities in mortality from cardiovascular diseases (CVD) are largely unknown. We studied the contribution of childhood socioeconomic conditions and adulthood risk factors to inequalities in CVD mortality in adulthood. Methods The prospective GLOBE study was carried out in the Netherlands, with baseline data from 1991, and linked with the cause of death register in 2007. At baseline, participants reported on adulthood socioeconomic position (SEP) (own educational level), childhood socioeconomic conditions (occupational level of respondent’s father), and a broad range of adulthood risk factors (health behaviours, material circumstances, psychosocial factors). This present study is based on 5,395 men and 6,306 women, and the data were analysed using Cox regression models and hazard ratios (HR). Results A low adulthood SEP was associated with increased CVD mortality for men (HR 1.84; 95% CI: 1.41-2.39) and women (HR 1.80; 95%CI: 1.04-3.10). Those with poorer childhood socioeconomic conditions were more likely to die from CVD in adulthood, but this reached statistical significance only among men with the poorest childhood socioeconomic circumstances. About half of the investigated adulthood risk factors showed significant associations with CVD mortality among both men and women, namely renting a house, experiencing financial problems, smoking, physical activity and marital status. Alcohol consumption and BMI showed a U-shaped relationship with CVD mortality among women, with the risk being significantly greater for both abstainers and heavy drinkers, and among women who were underweight or obese. Among men, being single or divorced and using sleep/anxiety drugs increased the risk of CVD mortality. In explanatory models, the largest contributor to adulthood CVD inequalities were material conditions for men (42%; 95% CI: −73 to −20) and behavioural factors for women (55%; 95% CI: -191 to −28). Simultaneous adjustment for adulthood risk factors and childhood socioeconomic conditions attenuated the HR for the lowest adulthood SEP to 1.34 (95% CI: 0.99-1.82) for men and 1.19 (95% CI: 0.65-2.15) for women. Conclusions Adulthood material, behavioural and psychosocial factors played a major role in the explanation of adulthood SEP inequalities in CVD mortality. Childhood socioeconomic circumstances made a modest contribution, mainly via their association with adulthood risk factors. Policies and interventions to reduce health inequalities are likely to be most effective when considering the influence of socioeconomic circumstances across the entire life course and in particular, poor material conditions and unhealthy behaviours in adulthood.

Multilevel determinants of breast cancer survival : association with geographic remoteness and area-level socioeconomic disadvantage

A major priority for cancer control agencies is to reduce geographical inequalities in cancer outcomes. While the poorer breast cancer survival among socioeconomically disadvantaged women is well established, few studies have looked at the independent contribution that area- and individual-level factors make to breast cancer survival. Here we examine relationships between geographic remoteness, area-level socioeconomic disadvantage and breast cancer survival after adjustment for patients’ socio- demographic characteristics and stage at diagnosis. Multilevel logistic regression and Markov chain Monte Carlo simulation were used to analyze 18 568 breast cancer cases extracted from the Queensland Cancer Registry for women aged 30 to 70 years diagnosed between 1997 and 2006 from 478 Statistical Local Areas in Queensland, Australia. Independent of individual-level factors, area-level disadvantage was associated with breast-cancer survival (p=0.032). Compared to women in the least disadvantaged quintile (Quintile 5), women diagnosed while resident in one of the remaining four quintiles had significantly worse survival (OR 1.23, 1.27, 1.30, 1.37 for Quintiles 4, 3, 2 and 1 respectively).) Geographic remoteness was not related to lower survival after multivariable adjustment. There was no evidence that the impact of area-level disadvantage varied by geographic remoteness. At the individual level, Indigenous status, blue collar occupations and advanced disease were important predictors of poorer survival. A woman’s survival after a diagnosis of breast cancer depends on the socio-economic characteristics of the area where she lives, independently of her individual-level characteristics. It is crucial that the underlying reasons for these inequalities be identified to appropriately target policies, resources and effective intervention strategies.