Incorporating adverse event relatedness into dose-finding clinical trial designs

Dose-finding designs estimate the dose level of a drug based on observed adverse events. Relatedness of the adverse event to the drug has been generally ignored in all proposed design methodologies. These designs assume that the adverse events observed during a trial are definitely related to the drug, which can lead to flawed dose-level estimation. We incorporate adverse event relatedness into the so-called continual reassessment method. Adverse events that have ‘doubtful’ or ‘possible’ relationships to the drug are modelled using a two-parameter logistic model with an additive probability mass. Adverse events ‘probably’ or ‘definitely’ related to the drug are modelled using a cumulative logistic model. To search for the maximum tolerated dose, we use the maximum estimated toxicity probability of these two adverse event relatedness categories. We conduct a simulation study that illustrates the characteristics of the design under various scenarios. This article demonstrates that adverse event relatedness is important for improved dose estimation. It opens up further research pathways into continual reassessment design methodologies.

Gambling on gambling in Baccarat : financial implications of raising bet limits and table differentials

The house advantage for Baccarat is known, hence the theoretical win can be determined. What is impractical to theoretically determine is the frequency and financial implications of extreme events, for example, prolonged winning streaks coupled with various betting patterns. The simulation herein provides such granularity. We explore the effect of following the „hot hand‟, that is, rapidly escalating bets when players are on a winning streak. To minimize their exposure, casino management sets a table bet maximum as well as a table differential. These figures can and do serve as a means to differentiate one casino from another. As the allowable bet maximum increases so does the total amount bet, which increases the theoretical winnings, thus suggesting that a high bet limit and differential is beneficial for the house. However, the greater are these amounts, the greater the number of shoes that end with players losing relative to a constant betting scenario (the number of times a player wins at all can drop from ~47% of the time to less than a quarter); but there will, on occasion, be more extreme payouts to players. This simulation is therefore intended to help casino managers set betting limits that maximize total winnings while bearing in mind both the likelihood and magnitude of negative outcomes to the casino.

Prostate radiotherapy treatment plan quality : effects of hip prostheses

Introduction This study aimed to examine the geometric and dosimetric results when radiotherapy treatment plans are designed for prostate cancer patients with hip prostheses. Methods Ten EBRT treatment plans for localised prostate cancer, in the presence of hip prostheses, were analysed and compared with a reference set of 196 treatment plans for localised prostate cancer in patients without prostheses. Crowe et al.’s TADA code [1] was used to extract treatment plan parameters and evaluate doses to target volumes and critical structures against recommended goals [2] and constraints [3, 4]. Results The need to avoid transmitting the radiation beam through the hip prostheses limited the range of gantry angles available for use in both the rotational (VMAT) and the non-rotational (3DCRT and IMRT) radiotherapy treatments. This geometric limitation (exemplified in the VMAT data shown in Fig. 1) reduced the overall quality of the treatment plans for patients with prostheses compared to the reference plans. All plans with prostheses failed the PTV dose homogeneity requirement [2], whereas only 4 % of the plans without prostheses failed this test. Several treatment plans for patients with hip prostheses also failed the QUANTEC requirements that less than 50 % of the rectum receive 50 Gy and less than 35 % of the rectum receive 60 Gy to keep the grade 3 toxicity rate below 10 % [3], or the Hansen and Roach requirement that less than 25 % of the bladder receive 75 Gy [4]. Discussion and conclusions The results of this study exemplify the difficulty of designing prostate radiotherapy treatment plans, where beams provide adequate doses to targeted tissues while avoiding nearby organs at risk, when the presence of hip prostheses limits the available treatment geometries. This work provides qualitative evidence of the compromised dose distributions that can result, in such cases.

Effects of small field output factors on IMRT optimisation and dose calculation

Introduction Given the known challenges of obtaining accurate measurements of small radiation fields, and the increasing use of small field segments in IMRT beams, this study examined the possible effects of referencing inaccurate field output factors in the planning of IMRT treatments. Methods This study used the Brainlab iPlan treatment planning system to devise IMRT treatment plans for delivery using the Brainlab m3 microMLC (Brainlab, Feldkirchen, Germany). Four pairs of sample IMRT treatments were planned using volumes, beams and prescriptions that were based on a set of test plans described in AAPM TG 119’s recommendations for the commissioning of IMRT treatment planning systems [1]: • C1, a set of three 4 cm volumes with different prescription doses, was modified to reduce the size of the PTV to 2 cm across and to include an OAR dose constraint for one of the other volumes. • C2, a prostate treatment, was planned as described by the TG 119 report [1]. • C3, a head-and-neck treatment with a PTV larger than 10 cm across, was excluded from the study. • C4, an 8 cm long C-shaped PTV surrounding a cylindrical OAR, was planned as described in the TG 119 report [1] and then replanned with the length of the PTV reduced to 4 cm. Both plans in each pair used the same beam angles, collimator angles, dose reference points, prescriptions and constraints. However, one of each pair of plans had its beam modulation optimisation and dose calculation completed with reference to existing iPlan beam data and the other had its beam modulation optimisation and dose calculation completed with reference to revised beam data. The beam data revisions consisted of increasing the field output factor for a 0.6 9 0.6 cm2 field by 17 % and increasing the field output factor for a 1.2 9 1.2 cm2 field by 3 %. Results The use of different beam data resulted in different optimisation results with different microMLC apertures and segment weightings between the two plans for each treatment, which led to large differences (up to 30 % with an average of 5 %) between reference point doses in each pair of plans. These point dose differences are more indicative of the modulation of the plans than of any clinically relevant changes to the overall PTV or OAR doses. By contrast, the maximum, minimum and mean doses to the PTVs and OARs were smaller (less than 1 %, for all beams in three out of four pairs of treatment plans) but are more clinically important. Of the four test cases, only the shortened (4 cm) version of TG 119’s C4 plan showed substantial differences between the overall doses calculated in the volumes of interest using the different sets of beam data and thereby suggested that treatment doses could be affected by changes to small field output factors. An analysis of the complexity of this pair of plans, using Crowe et al.’s TADA code [2], indicated that iPlan’s optimiser had produced IMRT segments comprised of larger numbers of small microMLC leaf separations than in the other three test cases. Conclusion: The use of altered small field output factors can result in substantially altered doses when large numbers of small leaf apertures are used to modulate the beams, even when treating relatively large volumes.

Development of a dose assessment tool for the auditing of radiotherapy treatment dosimetric quality

The reporting and auditing of patient dose is an important component of radiotherapy quality assurance. The manual extraction of dose-volume metrics is time consuming and undesirable when auditing the dosimetric quality of a large cohort of patient plans. A dose assessment application was written to overcome this, allowing the calculation of various dose-volume metrics for large numbers of plans exported from treatment planning systems. This application expanded on the DICOM-handling functionality of the MCDTK software suite. The software extracts dose values in the volume of interest by using a ray casting point-in-polygon algorithm, where the polygons have been defined by the contours in the RTSTRUCT file...

Origins of the observed asymmetry in out-of-field dose from a linac fitted with an external micro-MLC

Objective Recently, Taylor et al. reported that use of the BrainLAB m3 microMLC, for stereotactic radiosurgery, results in a decreased out-of-field dose in the direction of leaf-motion compared to the outof- field dose measured in the direction orthogonal to leaf-motion [1]. It was recommended that, where possible, patients should be treated with their superior–inferior axes aligned with the microMLCs leafmotion direction, to minimise out-of-field doses [1]. This study aimed, therefore, to examine the causes of this asymmetry in outof- field dose and, in particular, to establish that a similar recommendation need not be made for radiotherapy treatments delivered by linear accelerators without external micro-collimation systems. Methods Monte Carlo simulations were used to study out-of-field dose from different linear accelerators (the Varian Clinacs 21iX and 600C and the Elekta Precise) with and without internal MLCs and external microMLCs [2]. Results Simulation results for the Varian Clinac 600C linear accelerator with BrainLAB m3 microMLC confirm Taylor et als [1] published experimental data. The out-of-field dose in the leaf motion direction is deposited by lower energy (more obliquely scattered) photons than the out-of-field dose in the orthogonal direction. Linear accelerators without microMLCs produce no asymmetry in out-offield dose. Conclusions The asymmetry in out-of-field dose previously measured by Taylor et al. [1] results from the shielding characteristics of the BrainLAB m3 microMLC device and is not produced by the linear accelerator to which it is attached.

Three-dimensional dose verification for clinical treatments of small intracranial tumours

Cancers of the brain and central nervous system account for 1.6% of new cancers and 1.8% of cancer deaths globally. The highest rates of all developed nations are observed in Australia and New Zealand. There are known complexities associated with dose measurement of very small radiation fields. Here, 3D dosimetric verification of treatments for small intracranial tumours using gel dosimetry was investigated.

Book Reviews : "Off Limits: a parent’s guide to keeping kids safe from sexual abuse" and "Smart Parenting for Safer Kids"

Two important books on the topic of child sexual abuse prevention were recently published: Off Limits: A Parent’s Guide to Keeping Kids Safe from Sexual Abuse (Wurtele & Berkower, 2010) and Smart Parenting for Safer Kids (Briggs, 2010). The authors of both books are highly credentialed with long experience researching and writing about child sexual abuse prevention. Sandy Wurtele, PhD, is author of landmark child- and parent-focused sexual abuse prevention programs conducted in the USA over the past 30 years. She has published over 80 journal articles and book chapters on this topic. Her co-author, Feather Berkower, MSW, has been conducting workshops for adults on this topic for 25 years. Freda Briggs, PhD, has over 40 years’ experience in child protection in Australia and has also published numerous scholarly works on the topic. She was the inaugural recipient of the Australian Humanitarian Award in 1998, was Senior Australian of the Year in 2000, and was awarded an Order of Australia in 2005.

Catch limits, capacity utilization and cost reduction in Japanese fishery management

Japan's fishery harvest peaked in the late 1980s. To limit the race for fish, each fisherman could be provided with specific catch limits in the form of individual transferable quotas (ITQs). The market for ITQs would also help remove the most inefficient fishers. In this article we estimate the potential cost reduction associated with catch limits, and find that about 300 billion yen or about 3 billion dollars could be saved through the allocation and trading of individual-specific catch shares.

The relationship between ambient ultraviolet radiation (UVR) and objectively measured personal UVR exposure dose is modified by season and latitude

Despite the widespread use of ambient ultraviolet radiation (UVR) as a proxy measure of personal exposure to UVR, the relationship between the two is not well-defined. This paper examines the effects of season and latitude on the relationship between ambient UVR and personal UVR exposure. We used data from the AusD Study, a multi-centre cross-sectional study among Australian adults (18-75 years), where personal UVR exposure was objectively measured using polysulphone dosimeters. Data were analysed for 991 participants from 4 Australian cities of different latitude: Townsville (19.3 °S), Brisbane (27.5 °S), Canberra (35.3 °S) and Hobart (42.8 °S). Daily personal UVR exposure varied from 0.01 to 21 Standard Erythemal Doses (median=1.1, IQR: 0.5–2.1), on average accounting for 5% of the total available ambient dose. There was an overall positive correlation between ambient UVR and personal UVR exposure (r=0.23, p<0.001). However, the correlations varied according to season and study location: from strong correlations in winter (r=0.50) and at high latitudes (Hobart, r=0.50; Canberra, r=0.39), to null or even slightly negative correlations, in summer (r=0.01) and at low latitudes (Townsville, r=-0.06; Brisbane, r=-0.16). Multiple regression models showed significant effect modification by season and location. Personal exposure fraction of total available ambient dose was highest in winter (7%) and amongst Hobart participants (7%) and lowest in summer (1%) and in Townsville (4%). These results suggest season and latitude modify the relationship between ambient UVR and personal UVR exposure. Ambient UVR may not be a good indicator for personal exposure dose under some circumstances.

European aspects of standard setting in occupational hygiene and medicine

Occupational standards concerning the allowable concentrations of chemical compounds in the ambient air of workplaces have been established in several countries at national levels. With the integration of the European Union, a need exists for establishing harmonized Occupational Exposure Limits. For analytical developments, it is apparent that methods for speciation or fractionation of carcinogenic metal compounds will be of increasing practical importance for standard setting. Criteria of applicability under field conditions, cost-effectiveness, and robustness are practical driving forces for new developments. When the European Union issued a list of 62 chemical substances with Occupational Exposure Limits in 2000, 25 substances received a 'skin' notation. The latter indicates that toxicologically significant amounts may be taken up via the skin. Similar notations exist on national levels. For such substances, monitoring concentrations in ambient air will not be sufficient; biological monitoring strategies will gain further importance in the medical surveillance of workers who are exposed to such compounds. Proceedings in establishing legal frameworks for a biological monitoring of chemical exposures within Europe are paralleled by scientific advances in this field. A new aspect is the possibility of a differential adduct monitoring, using blood proteins of different half-life or lifespan. This technique allows differentiation between long-term mean exposure to reactive chemicals and short-term episodes, for example, by accidental overexposure. For further analytical developments, the following issues have been addressed as being particularly important: New dose monitoring strategies, sensitive and reliable methods for detection of DNA adducts, cytogenetic parameters in biological monitoring, methods to monitor exposure to sensitizing chemicals, and parameters for individual susceptibilities to chemical toxicants.

Prevention of Pollution of the Marine Environment from Vessels : The Potential and Limits of the International Maritime Organisation

--Critically discusses the role of International Maritime Organization (IMO) in the protection of the marine environment --Presents a clear, updated, concise and critical overview of the IMO marine environmental legal instruments --A fresh outlook on the north-south tensions in the IMO marine environmental discourses --Critically examines the principle of common but differentiated responsibilities in the context of IMO This book examines the role of The International Maritime Organization (IMO) in the prevention and control of pollution of the marine environment from vessels with a particular reference to the current north-south tensions regarding the strategy for combating climate change in the maritime sector as well as the prevention of marine pollution from the ship-breaking industry. The IMO, a United Nations specialized agency, has been entrusted with the duty to provide machinery for cooperation among governments for the prevention and control of pollution of the marine environment from vessels. The organization is responsible for drafting legal instruments as well as for facilitating technical cooperation for the protection of the marine environment. Although IMO legal instruments are mainly targeted at the prevention of pollution of the marine environment from vessels, there is a trend towards a liberal interpretation of this, and the organization has expanded its work to areas like shipbreaking, which is essentially a land-based industry.

Exact parametric confidence intervals for Bland-Altman limits of agreement

Purpose The previous literature on Bland-Altman analysis only describes approximate methods for calculating confidence intervals for 95% Limits of Agreement (LoAs). This paper describes exact methods for calculating such confidence intervals, based on the assumption that differences in measurement pairs are normally distributed. Methods Two basic situations are considered for calculating LoA confidence intervals: the first where LoAs are considered individually (i.e. using one-sided tolerance factors for a normal distribution); and the second, where LoAs are considered as a pair (i.e. using two-sided tolerance factors for a normal distribution). Equations underlying the calculation of exact confidence limits are briefly outlined. Results To assist in determining confidence intervals for LoAs (considered individually and as a pair) tables of coefficients have been included for degrees of freedom between 1 and 1000. Numerical examples, showing the use of the tables for calculating confidence limits for Bland-Altman LoAs, have been provided. Conclusions Exact confidence intervals for LoAs can differ considerably from Bland and Altman’s approximate method, especially for sample sizes that are not large. There are better, more precise methods for calculating confidence intervals for LoAs than Bland and Altman’s approximate method, although even an approximate calculation of confidence intervals for LoAs is likely to be better than none at all. Reporting confidence limits for LoAs considered as a pair is appropriate for most situations, however there may be circumstances where it is appropriate to report confidence limits for LoAs considered individually.

Second dose

Professor Nathan Efron'spersonal journey of retinopexy, cryopexy, vitrectomy and IOL surgery. An unexpected “ink in the sky” moment led to urgent surgery on a symptomatic left eye, with the asymptomatic right eye to follow…