An Update to the Malthus Model for Radiotherapy Utilisation in England.

AIMS: The Malthus Programme predicts national and local radiotherapy demand by combining cancer incidence data with decision trees detailing the indications, and appropriate dose fractionation, for radiotherapy. Since the last model update in 2017, technological advancements and the COVID-19 pandemic have led to increasing hypofractionation of radiotherapy schedules. Indications for radiotherapy have also evolved, particularly in the context of oligometastatic disease. Here we present a brief update on the model for 2021. We have updated the decision trees for breast, prostate, lung and head and neck cancers, and incorporated recent cancer incidence data into our model, generating a current estimate of fraction demand for these four cancer sites across England. MATERIALS AND METHODS: The decision tree update was based on evidence from practice-changing randomised controlled trials, published guidelines, audit data and expert opinion. Site- and stage-specific incidence data were taken from the National Disease Registration Service. We used the updated model to estimate the proportion of patients who would receive radiotherapy (appropriate rate of radiotherapy) and the fraction demand per million population at a national and Clinical Commissioning Group level in 2021. RESULTS: The total predicted fraction demand has decreased by 11.4% across all four cancer sites in our new model, compared with the 2017 version. This reduction can be explained primarily by greater use of hypofractionated treatments (including stereotactic ablative radiotherapy) and a shift towards earlier stage presentation. The only large change in appropriate rate of radiotherapy was an absolute decrease of 3% for lung cancer. CONCLUSIONS: Compared with our previous model, the current version predicts a reduction in fraction demand across England. This is driven principally by hypofractionation of radiotherapy regimens, using technology that requires increasingly complex planning. Treatment complexity and local service factors need to be taken into account when translating fraction burden into linear accelerator demand or throughput.

Variations in Demand across England for the Magnetic Resonance-Linac Technology, Simulated Utilising Local-level Demographic and Cancer Data in the Malthus Project.

AIMS: Cancer incidence varies across England, which affects the local-level demand for treatments. The magnetic resonance-linac (MR-linac) is a new radiotherapy technology that combines imaging and treatment. Here we model the demand and demand variations for the MR-linac across England. MATERIALS AND METHODS: Initial clinical indications were provided by the MR-linac consortium and introduced into the Malthus radiotherapy clinical decision trees. The Malthus model contains Clinical Commissioning Group (CCG) population, cancer incidence and stage presentation data (for lung and prostate) and simulated the demand for the MR-linac for all CCGs and Radiotherapy Operational Delivery Networks (RODN) across England. RESULTS: Based on the initial target clinical indications, the MR-linac could service 16% of England's fraction burden. The simulated fractions/million population demand/annum varies between 3000 and 10 600 fractions/million at the CCG level. Focussing only on the cancer population, the simulated fractions/1000 cancer cases demand/annum ranges from 1028 to 1195 fractions/1000 cases. If a national average for fractions/million demand was then used, at the RODN level, the variation from actual annual demand ranges from an overestimation of 8400 fractions to an underestimation of 5800 fractions. When using the national average fractions/1000 cases, the RODN demand varies from an overestimation of 3200 fractions to an underestimation of 3000 fractions. CONCLUSIONS: Planning cancer services is complex due to regional variations in cancer burden. The variations in simulated demand of the MR-linac highlight the requirement to use local-level data when planning to introduce a new technology.

Palliative Lung Radiotherapy: Higher Dose Leads to Improved Survival?

AIMS: Choosing the optimal palliative lung radiotherapy regimen is challenging. Guidance from The Royal College of Radiologists recommends treatment stratification based on performance status, but evidence suggests that higher radiotherapy doses may be associated with survival benefits. The aim of this study was to investigate the effects of fractionation regimen and additional factors on the survival of palliative lung cancer radiotherapy patients. MATERIALS AND METHODS: A retrospective univariable (n = 925) and multivariable (n = 422) survival analysis of the prognostic significance of baseline patient characteristics and treatment prescription was carried out on patients with non-small cell and small cell lung cancer treated with palliative lung radiotherapy. The covariates investigated included: gender, age, performance status, histology, comorbidities, stage, tumour location, tumour side, smoking status, pack year history, primary radiotherapy technique and fractionation scheme. The overall mortality rate at 30 and 90 days of treatment was calculated. RESULTS: Univariable analysis revealed that performance status (P < 0.001), fractionation scheme (P < 0.001), comorbidities (P = 0.02), small cell histology (P = 0.02), 'lifelong never' smoking status (P = 0.01) and gender (P = 0.06) were associated with survival. Upon multivariable analysis, only better performance status (P = 0.01) and increased dose/fractionation regimens of up to 30 Gy/10 fractions (P < 0.001) were associated with increased survival. Eighty-five (9.2%) and 316 patients (34%) died within 30 and 90 days of treatment, respectively. CONCLUSION: In this retrospective single-centre analysis of palliative lung radiotherapy, increased total dose (up to and including 30 Gy/10 fractions) was associated with better survival regardless of performance status.

Occupational exposure of UK adults to extremely low frequency magnetic fields.

BACKGROUND: Occupational exposure to extremely low frequency (ELF) magnetic fields (MF) in the UK general population is poorly documented. AIMS: To assess levels of occupational exposure to ELF MF in the UK and evaluate the use of a rigid job-exposure matrix (JEM) to assign exposures to subjects in the UK Adult Brain Tumour Study (UKABTS). METHODS: Personal ELF MF measurements were carried out. Exposure traces were divided into occupational, travel and elsewhere periods, under differing exposure metrics. Exposure was classified by Standard Occupational Classification (2000), Standard Industrial Classification (1997), and a combined occupation-industry classification. Statistical analyses (mixed effects model) determined the contribution of occupational exposure to the 24 h cumulative exposure and the contribution of occupation and industry to total variance. RESULTS: Data were obtained from 317 individuals, comprising UKABTS subjects (n = 192), occupational proxies for UKABTS subjects (n = 101) and "interest" readings (n = 24). 236 individuals provided occupational data covering 117 different occupations. Average exposure was significantly higher at work than at home. Elevated average occupational exposure was found for welding trades, printers, telephonists and filing and other records assistants. The discrimination of a rigid JEM based on occupation can be improved by linking the classification with industry and by the use of contextual information. CONCLUSIONS: This report substantially expands information on adult exposure to ELF MF in the UK. The accuracy of exposure assessments based solely on job codes is improved by linking with either industry code or contextual knowledge of equipment and of power lines or substations in the work environment.

Mathematical Modelling for Patient Selection in Proton Therapy.

Proton beam therapy (PBT) is still relatively new in cancer treatment and the clinical evidence base is relatively sparse. Mathematical modelling offers assistance when selecting patients for PBT and predicting the demand for service. Discrete event simulation, normal tissue complication probability, quality-adjusted life-years and Markov Chain models are all mathematical and statistical modelling techniques currently used but none is dominant. As new evidence and outcome data become available from PBT, comprehensive models will emerge that are less dependent on the specific technologies of radiotherapy planning and delivery.

Mechanisms Underlying the Anti-Inflammatory Effects of Clinacanthus nutans Lindau Extracts: Inhibition of Cytokine Production and Toll-Like Receptor-4 Activation.

Clinacanthus nutans has had a long history of use in folk medicine in Malaysia and Southeast Asia; mostly in the relief of inflammatory conditions. In this study, we investigated the effects of different extracts of C. nutans upon lipopolysaccharide (LPS) induced inflammation in order to identify its mechanism of action. Extracts of leaves and stem bark of C. nutans were prepared using polar and non-polar solvents to produce four extracts, namely polar leaf extract (LP), non-polar leaf extract (LN), polar stem extract (SP), and non-polar stem extracts (SN). The extracts were standardized by determining its total phenolic and total flavonoid contents. Its anti-inflammatory effects were assessed on LPS induced nitrite release in RAW264.7 macrophages and Toll-like receptor (TLR-4) activation in TLR-4 transfected human embryonic kidney cells (HEK-Blue(TM)-hTLR4 cells). The levels of inflammatory cytokines (TNF-α, IFN-γ, IL-1ß, IL-6, IL-12p40, and IL-17) in treated RAW264.7 macrophages were quantified to verify its anti-inflammatory effects. Western blotting was used to investigate the effect of the most potent extract (LP) on TLR-4 related inflammatory proteins (p65, p38, ERK, JNK, IRF3) in RAW264.7 macrophages. All four extracts produced a significant, concentration-dependent reduction in LPS-stimulated nitric oxide, LPS-induced TLR-4 activation in HEK-Blue(TM)-hTLR4 cells and LPS-stimulated cytokines production in RAW264.7 macrophages. The most potent extract, LP, also inhibited all LPS-induced TLR-4 inflammatory proteins. These results provide a basis for understanding the mechanisms underlying the previously demonstrated anti-inflammatory activity of C. nutans extracts.

p53 binds the nuclear matrix in normal cells: binding involves the proline-rich domain of p53 and increases following genotoxic stress.

The tumour suppressor p53 is a multifunctional protein important for the maintenance of genomic integrity. It is able to form molecular complexes with different DNA targets and also with cellular proteins involved in DNA transcription and DNA repair. In mammalian cells the biochemical processing of DNA occurs on a nuclear sub-structure termed the nuclear matrix. Previously Deppert and co-workers have identified p53 in association with the nuclear matrix in viral- and non-viral transformed cell lines. In the present study we demonstrate, for the first time, that p53 is bound to the nuclear matrix in primary cultures of normal mammalian cells and that this binding increases following DNA damage. Analysis of cell lines expressing structural mutants of p53 revealed that association with the nuclear matrix is independent of the tertiary and quaternary structure of p53. However, the proline-rich domain towards the N-terminus of p53 (residues 67 to 98) appeared important for binding to the nuclear matrix. This was demonstrated by TET-ON regulated expression of p53-derived constructs in p53(-/-) murine embryonic fibroblasts (MEF p53(-/-)). The proline-rich domain of p53 has potential for SH3 protein-protein interaction, and has a role in p53-mediated apoptosis and possibly base excision repair of DNA damage. We discuss our observations in relation to the ability of p53 to facilitate DNA repair and also review evidence indicating that matrix-bound p53 in SV40-transformed cells may facilitate the transforming potential of SV40 large T antigen.

Quantifying uncertainty in radiotherapy demand at the local and national level using the Malthus model.

The Malthus programme produces a model for the local and national level of radiotherapy demand for use by commissioners and radiotherapy service leads in England. The accuracy of simulation is dependent on the population cancer incidence, stage distribution and clinical decision data used by the model. In order to quantify uncertainty in the model, a global sensitivity analysis of the Malthus model was undertaken. As predicted, key decision points in the model relating to stage distribution and indications for surgical or non-surgical initial management of disease were observed to yield the strongest effect on simulated radiotherapy demand. The proportion of non-small cell lung cancer patients presenting with stage IIIB/IV disease had the largest effect on fraction burden in the four most common cancer types treated with radiotherapy, where a 1% change in stage IIIb/IV disease yielded a 1.3% change in fraction burden for lung cancer patients. A 1% change in mastectomy rate yielded a 0.37% change in fraction burden for breast cancer patients. The model is also highly sensitive to changes in the radiotherapy indications in colon and gastric cancer. Broadly, the findings of the sensitivity analysis mirror those previously published by other groups. Sensitivity analysis of the local-level population and cancer incidence data revealed that the cancer registration rate in the 50-64 year female population had the highest effect on simulation results. The analysis reveals where additional effort should be undertaken to provide accurate estimates of important parameters used in radiotherapy demand models.

The Malthus Programme: developing radiotherapy demand models for breast and prostate cancer at the local, regional and national level.

AIMS: The Malthus Programme has delivered a tool for modelling radiotherapy demand in England. The model is capable of simulating demand at the local level. This article investigates the local and regional level variation in predicted demand with respect to Breast and Prostate cancer, the two tumour types responsible for the majority of radiotherapy treatment workload in England. MATERIALS AND METHODS: Simulations were performed using the Malthus model, using base population incidence data for the period from 2007-2009. Simulations were carried out at the level of Primary Care Trusts, Cancer Networks, and nationwide, with annual projections for 2012, 2016 and 2020. Benchmarking was undertaken against previously published models from the UK, Canada and Australia. RESULTS: For breast cancer, the fraction burden for 2012 varied from 5537 fractions per million in Tower Hamlets PCT to 18 896 fractions per million in Devon PCT (national mean - 13 592 fractions per million). For prostate cancer, the fraction burden for 2012 varied from 4874 fractions per million in Tower Hamlets PCT to 23 181 fractions per million in Lincolnshire PCT (national mean - 15 087 fractions per million). Predictions of population growth by age cohort for 2016 and 2020 result in the regional differences in radiotherapy demand becoming greater over time. Similar effects were also observed at the level of the cancer network. CONCLUSIONS: Our model shows the importance of local population demographics and cancer incidence rates when commissioning radiotherapy services.

Radiotherapy demand and activity in England 2006-2020.

AIMS: This paper compares the predictions of radiotherapy demand for England from the Malthus model with those from the earlier National Radiotherapy Advisory Group (NRAG) model, from the international literature and also with observed radiotherapy usage in England as a whole as recorded in the English radiotherapy dataset (RTDS). MATERIALS AND METHODS: We reviewed the evidence base for radiotherapy for each type and stage of cancer using national and international guidelines, meta-analyses, systematic reviews and key clinical trials. Twenty-two decision trees were constructed and radiotherapy demand was calculated using English cancer incidence data for 2007, 2008 and 2009, accurate to the Primary Care Trust (PCT) level (population 91,500-1,282,384). The stage at presentation was obtained from English cancer registry data. In predictive mode, the model can take account of changes in cancer incidence as the population grows and ages. RESULTS: The Malthus model indicates reduced indications for radiotherapy, principally for lung cancer and rarer tumours. Our estimate of the proportion of patients who should receive radiotherapy at some stage of their illness is 40.6%. This is lower than previous estimates of about 50%. Nevertheless, the overall estimate of demand in terms of attendances is similar for the NRAG and Malthus models. The latter models that 48,827 attendances should have been delivered per million population in 2011. National data from RTDS show 32,071 attendances per million in 2011. A 50% increase in activity would be required to match estimated demand. This underprovision extends across all cancers and represents reduced access and the use of dose fractionation at odds with international norms of evidence-based practice. By 2016, demand is predicted to grow to about 55,206 attendances per million and by 2020 to 60,057. DISCUSSION: Services have increased their activity by 14% between 2006 and 2011, but estimated demand has increased by 11%. Access remains low and English radiotherapy dose fractionation still does not comply with international evidence-based practice.

Exposure to radio frequency electromagnetic fields from wireless computer networks: duty factors of Wi-Fi devices operating in schools.

The growing use of wireless local area networks (WLAN) in schools has prompted a study to investigate exposure to the radio frequency (RF) electromagnetic fields from Wi-Fi devices. International guidelines on limiting the adverse health effects of RF, such as those of ICNIRP, allow for time-averaging of exposure. Thus, as Wi-Fi signals consist of intermittent bursts of RF energy, it is important to consider the duty factors of devices in assessing the extent of exposure and compliance with guidelines. Using radio packet capture methods, the duty factor of Wi-Fi devices has been assessed in a sample of 6 primary and secondary schools during classroom lessons. For the 146 individual laptops investigated, the range of duty factors was from 0.02 to 0.91%, with a mean of 0.08% (SD 0.10%). The duty factors of access points from 7 networks ranged from 1.0% to 11.7% with a mean of 4.79% (SD 3.76%). Data gathered with transmit time measuring devices attached to laptops also showed similar results. Within the present limited sample, the range of duty factors from laptops and access points were found to be broadly similar for primary and secondary schools. Applying these duty factors to previously published results from this project, the maximum time-averaged power density from a laptop would be 220 µW m(-2), at a distance of 0.5 m and the peak localised SAR predicted in the torso region of a 10 year old child model, at 34 cm from the antenna, would be 80 µW kg(-1).

Assessment of exposure to electromagnetic fields from wireless computer networks (wi-fi) in schools; results of laboratory measurements.

Laboratory measurements have been carried out with examples of Wi-Fi devices used in UK schools to evaluate the radiofrequency power densities around them and the total emitted powers. Unlike previous studies, a 20 MHz bandwidth signal analyzer was used, enabling the whole Wi-Fi signal to be captured and monitored. The radiation patterns of the laptops had certain similarities, including a minimum toward the torso of the user and two maxima symmetrically opposed across a vertical plane bisecting the screen and keyboard. The maxima would have resulted from separate antennas mounted behind the top left and right corners of the laptop screens. The patterns for access points were more symmetrical with generally higher power densities at a given distance. The spherically-integrated radiated power (IRP) ranged from 5 to 17 mW for 15 laptops in the 2.45 GHz band and from 1 to 16 mW for eight laptops in the 5 GHz band. For practical reasons and because access points are generally wall-mounted with beams directed into the rooms, their powers were integrated over a hemisphere. These ranged from 3 to 28 mW for 12 access points at 2.4 GHz and from 3 to 29 mW for six access points at 5 GHz. In addition to the spherical measurements of IRP, power densities were measured at distances of 0.5 m and greater from the devices, and consistent with the low radiated powers, these were all much lower than the ICNIRP reference level.

Investigation of the sources of residential power frequency magnetic field exposure in the UK Childhood Cancer Study.

There is an unexplained association between exposure to the magnetic fields arising from the supply and use of electricity, and increase in risk of childhood leukaemia. The UK Childhood Cancer Study (UKCCS) provides a large and unique source of information on residential magnetic field exposure in the UK. The purpose of this supplementary study was to investigate a sample of UKCCS homes in order to identify the particular sources that contribute to elevated time-averaged exposure. In all, 196 homes have been investigated, 102 with exposures estimated on the basis of the original study to be above 0.2 microT, and 21 higher than 0.4 microT, a threshold above which a raised risk has been observed. First, surveys were carried out outside the property boundaries of all 196 study homes, and then, where informed consent had been obtained, assessments were conducted inside the properties of 19 homes. The study found that low-voltage (LV) sources associated with the final electricity supply accounted together for 77% of exposures above 0.2 microT, and 57% of those above 0.4 microT. Most of these exposures were linked to net currents in circuits inside and/or around the home. High-voltage (HV) sources, including the HV overhead power lines that are the focus of public concern, accounted for 23% of the exposures above 0.2 microT, and 43% of those above 0.4 microT. Public health interest has focused on the consideration of precautionary measures that would reduce exposure to power frequency magnetic fields. Our study provides a basis for considering the options for exposure mitigation in the UK. For instance, in elevated-exposure homes where net currents are higher than usual, if it is possible to reduce the net currents, then the exposure could be reduced for a sizeable proportion of these homes. Further investigations would be necessary to determine whether this is feasible.

Proteolytic cleavage of p53 mutants in response to mismatched DNA.

Interaction of p53 with mismatched DNA induces proteolytic cleavage with release of a 35-kDa protein fragment from the p53-DNA complexes. The 35-kDa cleavage product is activated for specific biochemical function(s) and may play a role in the cellular response to DNA damage (Molinari et al (1996) Oncogene 13: 2077-2086; Okorokov et al (1997) EMBO J 16: 6008-6017). In the present study we have asked if mutants of p53 retain the ability to undergo similar proteolytic cleavage, and compared sequence-specific 'DNA contact' with 'structural' mutants commonly found in human cancer. In addition, a series of phosphorylation site mutants were generated to investigate the possible effects of phosphorylation/dephosphorylation on the proteolytic cleavage of p53. All mutants tested bound to a mismatched DNA target in vitro. Moreover, studies in vitro and in vivo indicate that p53 mutants with intact conformational structure (as determined by immunoreactivity with PAb246 and PAb1620) retain the ability to undergo proteolytic cleavage similar, if not identical, to the wild-type p53 protein. Our results suggest that the capacity for p53 to bind mismatched DNA is independent of structural conformation of the central core domain. Proteolytic cleavage, however, is crucially dependent upon a wild-type conformation of the protein.

Synchronous nyctohemeral rhythms in human blood melatonin and in human post-mortem pineal enzyme.

Serum melatonin was measured by radioimmunoassay at 4-hourly intervals for 24 h in five normal men, and shown to exhibit nyctohemeral variations. The highest concentrations of serum melatonin occurred at 02.00 hours and the lowest concentrations at 14.00 hours. The synthetic enzymes for melatonin, serotonin-N-acetyl transferase (SNAT) and hydroxyindole-O-methyltransferase (HIOMT) were measured in post-mortem pineal organs from thirty-six men and women, and the activity of both enzymes was directly related to the time of death of the subject, resulting in a similar nyctohemeral curve as that observed with serum melatonin. The SNAT and HIOMT enzymes were stable when measured in pineal organs held under the usual post-mortem conditions. The observations indicated a nyctohemeral rhythm in human pineal function and suggests that any clinical interpretation of pineal dysfunction in disease states should take into consideration this normal rhythm.

The human immunodeficiency virus type 1 regulatory protein Tat inhibits interferon-induced iNos activity in a murine macrophage cell line.

Human immunodeficiency virus type 1 (HIV-1) infection is frequently associated with concurrent infection by opportunistic pathogens, against which production of nitric oxide by host macrophages provides a first line of defence. We have investigated whether regulatory HIV-1 proteins, such as Tat, can modulate the activity of the inducible nitric oxide synthase (iNos) gene when expressed in stable transfectant lines of RAW264.7 cells. A bioassay for Tat, based on transactivation of an HIV-1 LTR-CAT reporter gene, allowed selection of Tat-expressing cells. Parental and Tat-expressing macrophages accumulated identical levels of nitrite following lipopolysaccharide (LPS) stimulation. Interferon gamma (IFN-gamma) stimulation however, resulted in reduced levels of nitrite accumulation as a direct consequence of Tat expression. Conditioned media from Tat-expressing cells reduced the level of nitrite accumulation in parental cells following IFN-gamma stimulation but not stimulation with LPS. These results implicate HIV-1 Tat as a modulator of the IFN-gamma-specific signal transduction pathways leading to iNos expression.