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INTRODUCTION: The HERBERT study evaluated a high-dose-rate endorectal brachytherapy boost (HDREBT) after EBRT in medically inoperable/elderly patients with rectal cancer. The response-rates are promising but not without risk of toxicity. The current analysis provides a comprehensive overview of patient reported, physician reported and endoscopically observed toxicity. MATERIAL AND METHODS: A brachytherapy dose finding study was performed in 38 inoperable/elderly patients with T2-T4N0-1 rectal cancer. Patients received EBRT (13 × 3 Gy) followed by three weekly HDREBT applications (5-8 Gy). Toxicity was assessed via three methods: patient and physician (CTCAEv3) reported rectal symptoms and endoscopically. Wilcoxon's signed rank test, paired t-test and Spearman's correlation were used. RESULTS: Patient reported bowel symptoms showed a marked increase at the end of EBRT and two weeks after HDREBT. Acute grade 2 and 3 proctitis occurred in 68.4% and 13.2% respectively while late grade 2 and ≥3 proctitis occurred in 48% and 40%. Endoscopic evaluation mainly showed erythema and telangiectasia. In three patients frank haemorrhage or ulceration occurred. Most severe toxicity was observed 12-18 months after treatment. CONCLUSION: For elderly patients with rectal cancer, definitive radiotherapy can provide good tumour response but has a substantial risk of toxicity. The potential benefit and risks of a HDREBT boost above EBRT alone must be further evaluated.

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Inflicted traumatic brain injury (ITBI) - a possible result of child abuse - is difficult to diagnose, yet the diagnosis bears great impact on patients and their relatives. The purpose of this paper is to describe ophthalmologic findings that can be seen in relation to ITBI. For exemplification, three different cases are described in detail. ITBI is diagnosed through a multidisciplinary approach by exclusion of other causes that could explain the clinical findings, and by linking factors that together raise a high suspicion of ITBI. The typical triad of ITBI includes intracerebral haemorrhage, encephalopathy and retinal haemorrhages. Therefore, detailed fundus examination by an ophthalmologist is important when ITBI is suspected. A pattern of bilateral, multiple retinal haemorrhages present in different retinal layers and widespread from posterior pole to the retinal periphery, is highly suspicious for ITBI, and contributes to the final diagnosis.

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UNLABELLED: INTRODUCTION AND PURPOSE OF THE STUDY: With this study we aimed to describe a "true world" picture of severe paediatric 'community-acquired' septic shock and establish the feasibility of a future prospective trial on early goal-directed therapy in children. During a 6-month to 1-year retrospective screening period in 16 emergency departments (ED) in 12 different countries, all children with severe sepsis and signs of decreased perfusion were included. RESULTS: A 270,461 paediatric ED consultations were screened, and 176 cases were identified. Significant comorbidity was present in 35.8 % of these cases. Intensive care admission was deemed necessary in 65.7 %, mechanical ventilation in 25.9 % and vasoactive medications in 42.9 %. The median amount of fluid given in the first 6 h was 30 ml/kg. The overall mortality in this sample was 4.5 %. Only 1.2 % of the survivors showed a substantial decrease in Paediatric Overall Performance Category (POPC). 'Severe' outcome (death or a decrease ≥2 in POPC) was significantly related (p < 0.01) to: any desaturation below 90 %, the amount of fluid given in the first 6 h, the need for and length of mechanical ventilation or vasoactive support, the use of dobutamine and a higher lactate or lower base excess but not to any variables of predisposition, infection or host response (as in the PIRO (Predisposition, Infection, Response, Organ dysfunction) concept). CONCLUSION: The outcome in our sample was very good. Many children received treatment early in their disease course, so avoiding subsequent intensive care. While certain variables predispose children to become septic and shocked, in our sample, only measures of organ dysfunction and concomitant treatment proved to be significantly related with outcome. We argue why future studies should rather be large multinational prospective observational trials and not necessarily randomised controlled trials.

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An integrated MRI-accelerator system provides MRI images before and during irradiation. Our purpose is to investigate the feasibility of treatment plan adaptation using solely MRI data, which lack density information. In this study we used CT data to quantify the tissue density effect. Treatment planning was performed for five prostate cancer patients. We simulated correction of a 3, 5, 7 and 10 mm prostate shift relative to the body contour in the anterior, posterior, superior and inferior directions. We applied the original treatment plan to each corrected prostate shift and recalculated the dose distribution using the same monitor units (MU). We calculated the dose differences with and without density information. The latter mimics geometrically correct MRI data. Physical path lengths, available in MRI data, are used to perform MU rescaling per beam and are shown to be of more importance than tissue densities for treatment plan adaptation in prostate cancer. As the change in the physical path length of the central beam axis is representative of the entire beam, MU rescaling based on central beam axis information works fine. In conclusion, MRI data could be used for treatment plan adaptation in prostate cancer provided that the images are geometrically correct.

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External beam radiation treatment for patients with cervical cancer is hindered by the relatively large motion of the target volume. A hybrid MRI-accelerator system makes it possible to acquire online MR images during treatment in order to correct for motion and deformation. To fully benefit from such a system, online delineation of the target volumes is necessary. The aim of this study is to investigate the accuracy of rigid, non-rigid and semi-automatic registrations of MR images for interfractional contour propagation in patients with cervical cancer. Registration using mutual information was performed on both bony anatomy and soft tissue. A B-spline transform was used for the non-rigid method. Semi-automatic registration was implemented with a point set registration algorithm on a small set of manual landmarks. Online registration was simulated by application of each method to four weekly MRI scans for each of 33 cervical cancer patients. Evaluation was performed by distance analysis with respect to manual delineations. The results show that soft-tissue registration significantly (P < 0.001) improves the accuracy of contour propagation compared to registration based on bony anatomy. A combination of user-assisted and non-rigid registration provides the best results with a median error of 3.2 mm (1.4-9.9 mm) compared to 5.9 mm (1.7-19.7 mm) with bone registration (P < 0.001) and 3.4 mm (1.3-19.1 mm) with non-rigid registration (P = 0.01). In a clinical setting, the benefit may be further increased when outliers can be removed by visual inspection of the online images. We conclude that for external beam radiation treatment of cervical cancer, online MRI imaging will allow target localization based on soft tissue visualization, which provides a significantly higher accuracy than localization based on bony anatomy. The use of limited user input to guide the registration increases overall accuracy. Additional non-rigid registration further reduces the propagation error and negates errors caused by small observer variations.

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At the UMC Utrecht, The Netherlands, we have constructed a prototype MRI accelerator. The prototype is a modified 6 MV Elekta (Crawley, UK) accelerator next to a modified 1.5 T Philips Achieva (Best, The Netherlands) MRI system. From the initial design onwards, modifications to both systems were aimed to yield simultaneous and unhampered operation of the MRI and the accelerator. Indeed, the simultaneous operation is shown by performing diagnostic quality 1.5 T MRI with the radiation beam on. No degradation of the performance of either system was found. The integrated 1.5 T MRI system and radiotherapy accelerator allow simultaneous irradiation and MR imaging. The full diagnostic imaging capacities of the MRI can be used; dedicated sequences for MRI-guided radiotherapy treatments will be developed. This proof of concept opens the door towards a clinical prototype to start testing MRI-guided radiation therapy (MRIgRT) in the clinic.

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BACKGROUND: Despite increasing attention to the epidemiology of pain, relatively little is known about the association between pain and health in children. In particular, no studies have examined this relationship in the general population of children in Canada. OBJECTIVES: To assess the association between self-reported pain experiences and health in school children in southeastern Ontario. Health measures included perceived health status, psychological complaints and satisfaction with school. METHODS: A total of 495 nine- to 13-year-old school children completed the Pain Experience Interview -- Short Form and health-related questions from the Health Behaviour in School-aged Children questionnaire. RESULTS: Of the 495 children in the present study, 8% rated their health as 'fair' to 'poor', 56% reported experiencing at least one of four psychological symptoms more than once a week and 24% said they disliked school. The strongest associations existed between headaches and poor self-rated health (OR=10.1; 95% CI 1.3 to 78.3), recurrent pain and psychological outcomes (OR=3.6; 95% CI 2.0 to 6.3), and recurrent pain and disliking school (OR=3.6; 95% CI 1.9 to 6.7). DISCUSSION: These findings indicate that common childhood pains are associated with childhood health. Further studies are needed to assess the causal relationship between pain and health in children, to obtain a more comprehensive understanding of the personal and economic impact of childhood pain, and to monitor changes in the lives of children living with chronic pain.

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In daily clinical practice, implanted fiducial markers are used to correct for prostate motion, but not for prostate deformation. The aim of this study is to investigate the variation in target and rectum dose due to the deformation of the prostate gland (without seminal vesicles). Therefore, we performed five to six MRI scans of eight healthy volunteers that exhibited large variation in rectal volume and thus prostate deformation. Prostate motion was corrected by a mask-based rigid registration which uses the delineation as well as the internal structures of the prostate gland. Per MRI scan, one IMRT plan with a PTV margin of 4 mm was created, resulting in 41 IMRT plans. The dose distribution of the IMRT plan based on the MRI scan with the minimum rectal volume was applied to the other rigidly registered MRI scans to evaluate the impact of prostate deformation. In conclusion, pre-treatment planning on the minimum rectal volume can cause a fraction dose increase (up to 15%) to the rectum due to prostate deformation. The impact on the total dose increase to the rectum depends on the intrapatient rectum variation during treatment, but is negligible with the currently used PTV margins in a fractionated treatment.

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When comparing delineations it is often useful to obtain a local measure of distance between the volume surfaces. Commonly used methods for analysing local distance exhibit fundamental drawbacks which may cause overestimation of the distance or lead to asymmetry in the measure. This paper describes a new method that aims to solve these problems. The new method finds corresponding points between two delineations by traversing a vector field based on the combined gradient of the distance transforms. The proposed method provides a fundamentally more reliable, symmetric measure of distance. This is supported by an illustrative example of observer variation in prostate delineation. An implementation of the method is available on request to the author.

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The aim of this study was to evaluate drug metabolism in rat small intestinal and colon precision-cut slices during 24 h of incubation and the applicability of these slices for enzyme induction studies. Various parameters were evaluated: intracellular levels of ATP (general viability marker), alkaline phosphatase activity (specific epithelial marker), villin expression (specific epithelial marker), and metabolic rates of 7-ethoxycoumarin (CYP1A), testosterone (CYP3A and CYP2B), and 7-hydroxycoumarin (glucuronide and sulfate conjugation) conversions. ATP and villin remained constant up to, respectively, 5 and 8 h in small intestine and up to 24 h in colon. The metabolic rate remained constant in small intestinal slices up to 8 h and decreased afterward to 24 to 92%, depending on the substrate studied. The inducibility of metabolism in small intestinal and colon slices was tested with several inducers at various concentrations and incubation times. The following inducers were used: 3-methylcholanthrene, beta-naphthoflavone, indirubin, and tert-butylhydroquinone (aryl hydrocarbon receptor ligands), dexamethasone (glucocorticoid receptor/pregnane X receptor ligand) and phenobarbital (constitutive androstane receptor ligand). After incubation with inducers, metabolic rates were evaluated with 7-ethoxycoumarin and testosterone (phase I) and 7-hydroxycoumarin (phase II) as substrate. All inducers elevated the metabolic rates consistent with the available published in vivo induction data. Induction of enzyme activity was already detectable after 5 h (small intestine) and after 8 h (colon) for 3-methylcholanthrene and beta-naphthoflavone and was clearly detectable for all tested inducers after 24 h (up to 20-fold compared with noninduced controls). In conclusion, small intestinal and colon precision-cut slices are useful for metabolism and enzyme induction studies.

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AIMS: To investigate whether the analysis of immunoglobulin (Ig)/T cell receptor (TCR) rearrangements is useful in the diagnosis of lymphoproliferative disorders. METHODS: In a series of 107 consecutive cases with initial suspicion of non-Hodgkin's lymphoma (NHL), Southern blot (SB) analysis of Ig/TCR rearrangements was performed. RESULTS: In 98 of 100 histopathologically conclusive cases, Ig/TCR gene results were concordant. In one presumed diffuse large B cell lymphoma (DLCL) and one follicular lymphoma (FL) case no clonality could be detected by SB analysis, or by polymerase chain reaction (PCR) at second stage. In the DLCL, sampling error might have occurred; the FL was revised after an initial diagnosis of reactivity. In many of the histopathologically inconclusive cases Ig/TCR gene SB analysis was helpful, giving support for the histopathological suspicion. However, because of a lack of (clinical) follow up data this could not be confirmed in a few cases. CONCLUSIONS: Experienced haematopathologists or a pathologist panel can diagnose malignant versus reactive lesions in most cases without the need for Ig/TCR gene analysis and can select the 5-10% of cases that might benefit from molecular clonality studies.

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Several frequently applied polymerase chain reaction strategies for analysis of immunoglobulin heavy-chain gene rearrangements were compared by analyzing 70 B-cell lymphoproliferative disorders and 24 reactive lymphoid lesions. Southern blot analysis was used as the "gold standard" for clonality assessment. For polymerase chain reaction analysis, primers directed against framework (FR) 3 (FR3-A and FR3-B), FR2, and FR1 of the variable gene segments and against joining gene segments of the immunoglobulin heavy-chain gene were used. Polymerase chain reaction products were analyzed by high-resolution fingerprinting analysis using radiolabeled nucleotides, gene scanning using fluorochrome-labeled primers, and heteroduplex analysis. All of the assays generated polyclonal patterns in the reactive tissues. The sensitivity in detecting monoclonality as defined by Southern blotting varied between 60% (heteroduplex analysis with FR3 primers) and 77% (high-resolution fingerprinting analysis with FR2 primers). Comparison of the three FR3 assays revealed that gene scanning had the highest sensitivity (69%), probably because it could detect small aberrant monoclonal amplicons. False-negative results were especially frequent in follicular center lymphoma (n = 20), but also in diffuse large B-cell lymphoma (n = 18), both renowned for having mutated variable gene segments, potentially leading to primer mismatching. For example, in follicular center lymphoma, the FR3, FR2, and FR1 region primer sets detected clonality in only 35 to 40, 65, and 50%, respectively. Combining these techniques, 17 (85%) of 20 follicular center lymphoma samples showed monoclonality. Therefore, especially in follicular center lymphoma, diffuse large B-cell lymphoma, and, to a lesser extent, in other lymphomas, multiple variable gene segment primer sets must be used for a reliable assessment of clonality. Our results also suggest that gene scanning is somewhat more sensitive than other read-out systems. Heteroduplex analysis, however, is a reliable alternative within a diagnostic setting, avoiding the use of radioactivity or expensive automated sequencing equipment and fluorochrome-labeled (oligo)nucleotides.

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PURPOSE: Primary cutaneous large B-cell lymphoma (PCLBCL) that presents on the leg has recently been recognized as a distinct disease entity. These lymphomas have a reduced disease-free survival and a worse prognosis as compared with the more common, morphologically similar PCLBCL that present on the head or trunk. Studies in noncutaneous diffuse large B-cell lymphomas suggest a relationship between the expression of bcl-2 protein and clinical behavior. In the present study, we investigated whether these two groups of PCLBCL differ in the expression of bcl-2 protein and the presence of t(4;18), known as one of the causes of bcl-2 overexpression. PATIENTS AND METHODS: Paraffin sections from pretreatment biopsies of 14 PCLBCLs of the head or trunk and nine PCLBCLs of the legs were investigated for expression of bcl-2 protein using immunohistochemistry, and for the presence of the 14;18 translocation using polymerase chain reaction (PCR) amplification with primers against both the major breakpoint region (mbr) and the minor cluster region (mcr) of bcl-2. For reasons of comparison, nine secondary cutaneous large B-cell lymphomas (SCLBCLs) were also studied. RESULTS: Expression of bcl-2 protein was found in all nine PCLBCLs of the leg and in all nine SCLBCLs, but not in any of the 14 PCLBCLs on the head and trunk. The t(14;18) was only detected in two of seven SCLBCLs, but not in the five PCLBCLs of the leg or the eight PCLBCLs on the head or trunk studied. CONCLUSION: The striking differences in bcl-2 expression between PCLBCL of the head or trunk and PCLBCL on the leg suggest that bcl-2 expression is site-related and may contribute to the different clinical behavior between these two groups of lymphomas. In addition, they underscore that PCLBCL on the head and trunk and PCLBCL on the leg are distinct disease entities, as recently recognized in the European Organization for Research and Treatment of Cancer (EORTC) classification for primary cutaneous lymphomas.

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Epidermal growth factor (EGF) and platelet-derived growth (PDGF) are suggested to be involved in the proliferation of human gliomas. We examined the effects of these growth factors on two human malignant glioma cell lines. Treatment of the A172 glioblastoma and the Hs683 glioma cell line with EGF and PDGF resulted in the tyrosine autophosphorylation, and hence activation, of the respective growth factor receptors. In addition, both cell lines responded to EGF and PDGF with increased deoxyribonucleic acid (DNA) synthesis. Because the intrinsic protein tyrosine kinase activity of this class of growth factor receptors is indispensable for their functioning, we tested the effects of specific protein tyrosine kinase inhibitors on growth factor-induced DNA synthesis and glioma cell proliferation. Genistein inhibited both EGF- and PDGF-stimulated autophosphorylation of the receptors and induction of DNA synthesis. However, genistein seemed to be cytotoxic to the cells. The tyrphostins RG 50875 and RG 13022 dose-dependently inhibited DNA synthesis induced by EGF, PDGF, and serum. RG 13022 completely blocked the EGF- and PDGF-induced DNA synthesis at a concentration of 50 mumol/L. The tyrphostins showed no selectivity in blocking either EGF or PDGF signaling. With concentrations up to mumol/L, no cytotoxic side effects of the tyrphostins were observed. Both tyrphostins also inhibit serum-driven cell growth in a dose-dependent manner. These results support the hypothesis that activated protein tyrosine kinase receptors are involved in the proliferation of A172 and Hs683 glioma cells. Selective inhibitors of protein tyrosine kinases, therefore, might have the potential to contribute to the treatment of growth factor-dependent gliomas.

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OBJECTIVES: To compare the health status of Riverdale residents with residents of the rest of Toronto. DESIGN: Cross-sectional telephone survey. SETTING: Toronto. TIME FRAME: October 1988-June 1989. PARTICIPANTS: Four hundred and fourteen residents of Riverdale, a residential-industrial area of Toronto, and 866 residents of the rest of Toronto, age 15 years and older in households with telephones. MAIN RESULTS: Respondents in Riverdale compared to respondents in the rest of Toronto were more likely to speak languages other than English, have less formal education, and be of Oriental ethnic origin. Perceived health status varied between the two areas, but no significant difference existed in diagnosed morbidity. Riverdale respondents were much more aware of food and soil contamination than respondents from the rest of Toronto.

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