J. C. J. de Boer

A new approach to off-line setup corrections: Combining safety with minimum workload

Off-line patient setup correction protocols based on electronic portal images are an effective tool to reduce systematic patient setup errors. Recently, we have introduced the no action level (NAL) protocol which establishes a significant error reduction at a very small workload. However, this protocol did not include an explicit verification of the applied setup corrections. Systematic mistakes in the execution of setup corrections (e.g., a setup correction is always executed in the +X direction whereas a correction in the -X direction was prescribed) may introduce large systematic setup errors (irrespective of the setup protocol) and may seriously impair treatment outcome. We have therefore extended the NAL protocol with a correction verification (COVER) stage, solely aimed at detecting such mistakes. In short, COVER tests the magnitude of the postcorrection setup error in each relevant direction. If these residue errors are below the acceptance threshold T, no more electronic portal images are required and the protocol has finished. If not, the origin of this result should be investigated; if no obvious mistakes are present, the procedure is repeated for one more treatment fraction. If the residue setup errors are confirmed to be larger than T, the entire protocol is restarted. Using both Monte Carlo simulations and analytical calculations, we performed a risk analysis and evaluated the workload for various choices of T. A threshold T = 3 x sigma(r), where sigma(r) is the mean standard deviation of the random setup errors, ensured that (1) COVER introduces only a small additional workload (1.05 measurement per patient, while the absolute minimum is 1.0) and (2) serious correction mistakes are detected with high probability. Even if setup corrections are wrongly applied in each patient (worst case scenario), COVER ensures that the final distribution of systematic errors is not wider than the precorrection distribution of systematic errors; for realistic frequencies of correction mistakes (<< 1 per patient) this distribution becomes much more narrow. The combination of NAL and COVER thus provides a highly efficient as well as safe method to reduce systematic setup errors.

Physical characteristics of a commercial electronic portal imaging device

An electronic portal imaging device (EPID) for use in radiotherapy with high energy photons has been under development since 1985 and has been in clinical use since 1988. The x-ray detector consists of a metal plate/fluorescent screen combination, which is monitored by a charge-coupled device (CDD)-camera. This paper discusses the physical quantities governing image quality. A model which describes the signal and noise propagation through the detector is presented. The predicted contrasts and signal-to-noise ratios are found to be in agreement with measurements based on the EPID images. Based on this agreement the visibility of low contrast structures in clinical images has been calculated with the model. Sufficient visibility of relevant structures (4-10 mm water-equivalent thickness) has been obtained down to a delivered dose of 4 cGy at dose maximum. It is found that the described system is not limited by quantum noise but by camera read-out noise. In addition we predict that with a new type of CCD sensor the signal-to-noise ratio can be increased by a factor of 5 at small doses, enabling high quality imaging, for most relevant clinical situations, with a patient dose smaller than 4 cGy. The latter system would be quantum noise limited.

Characteristics relevant to portal dosimetry of a cooled CCD camera‐based EPID

Our EPIDs have recently been equipped with Peltier-cooled CCD cameras. The CCD cooling dramatically reduced deteriorating effects of radiation damage on image quality. Over more than 600 days of clinical operation, the radiation induced noise contribution has remained stable at a very low level (1 SD < or = 0.15% of the camera dynamic range), in marked contrast with the previously used noncooled cameras. The camera response (output signal versus incident EPID radiation exposure) can be accurately described with a quadratic function. This response reproduced well, both in short and long term (variation < 0.2% respectively < 0.4% (1 SD)), rendering the cooled camera well-suited for EPID dosimetry applications.

Molecular Basis of DNA Repair Mechanisms and Syndromes

Numerous chemical agents and various types of radiation (e.g. UV-light, X-rays) induce a wide range of lesions in DNA. Such damage can lead to changes in the nucleotide sequence varying from point mutations to gross chromosomal aberrations which can alter the expression or functioning of genes implicated in regulation of cell proliferation and differentiation, thereby forwarding the cell in the multistep process of carcinogenesis. To prevent these and other deleterious consequences of DNA injury, all living organisms are equipped with a complex network of DNA repair systems. One of the best studied repair processes is the nucleotide excision repair (NER) pathway which removes a wide diversity of DNA lesions including cyclobutane pyrimidine dimers and (6–4) photoproducts as well as chemical adducts and cross-links. In most — if not all — organisms two NER subpathways operate. One deals with the rapid and efficient removal of lesions that block transcription and thus need to be eliminated urgently (transcription-coupled repair, TCR). The other accomplishes the slower and less efficient global genome repair (GGR) of bulk DNA, including the nontranscribed strand of active genes.

Children’s outcomes at 2-year follow-up after 4 years of structured multi-professional medical-ethical decision-making in a neonatal intensive care unit

Objective:We reviewed our decisions about continuation/withdrawal of life-sustaining treatments in a group of critically ill newborns who were discussed in structured medical ethical decision-making meetings, and provide the surviving children’s outcomes at 2-year follow-up.Study Design:In an explorative observational study, 61 cases were evaluated. The children involved had been discussed in such a structured way from 2009 to 2012 in a level III-D neonatal intensive care unit.Results:Decisions made were: full treatment (n=6), earlier restriction cancelled (n=3), treatment restriction (n=30) and palliative care (n=22). Parents of six children disagreed with the decision proposed. Thirteen (54%) of the 24 children who survived (39%) had moderate to severe neurological problems; 8 (33%) had additional sequelae; only one 2-year-old child was healthy.Conclusions:Decisions made varied to a large extent. The poor outcomes should be disseminated among decision makers. Future studies must explore new ways to improve outcome prediction, extend follow-up periods and consider what living with severe handicaps really means for both child and family.

Development and application of efficient portal imaging solutions

markdownabstract__Abstract__ The central subject of this thesis is to derive clinically applicable methods to measure and improve the reproducibility of treatment delivery in radiotherapy by means of portal imaging. The most important criteria that such methods should meet, apart from being effective, is that (1) they are relatively simple to implement and (2) the additional workload required in daily practice is small. This approach was inspired by the observation that routine application of portal imaging in clinical practice, according to well-defined protocols, remains relatively rare. Below, we first sketch the general aims and practice of radiotherapy. From this brief overview, a number of aspects become apparent that are essential to the work described in the following chapters. In particular, the meaning of systematic and random geometrical errors in radiotherapy is emphasised.