Flemish network on rare connective tissue diseases (CTD): patient pathways in systemic sclerosis. First steps taken.

Despite the low prevalence of each rare disease, the total burden is high. Patients with rare diseases encounter numerous barriers, including delayed diagnosis and limited access to high-quality treatments. In order to tackle these challenges, the European Commission launched the European Reference Networks (ERNs), cross-border networks of healthcare providers and patients representatives. In parallel, the aims and structure of these ERNs were translated at the federal and regional levels, resulting in the creation of the Flemish Network of Rare Diseases. In line with the mission of the ERNs and to ensure equal access to care, we describe as first patient pathways for systemic sclerosis (SSc), as a pilot model for other rare connective and musculoskeletal diseases. Consensus was reached on following key messages: 1. Patients with SSc should have multidisciplinary clinical and investigational evaluations in a tertiary reference expert centre at baseline, and subsequently every three to 5 years. Intermediately, a yearly clinical evaluation should be provided in the reference centre, whilst SSc technical evaluations are permissionably executed in a centre that follows SSc-specific clinical practice guidelines. In between, monitoring can take place in secondary care units, under the condition that qualitative examinations and care including interactive multidisciplinary consultations can be provided. 2. Patients with early diffuse cutaneous SSc, (progressive) interstitial lung disease and/or pulmonary arterial hypertension should undergo regular evaluations in specialised tertiary care reference institutions. 3. Monitoring of patients with progressive interstitial lung disease and/or pulmonary (arterial) hypertension will be done in agreement with experts of ERN LUNG.

[Use of patient radiation shielding in diagnostic and interventional radiology]. / Einsatz von Patienten-Strahlenschutzmitteln in der diagnostischen und interventionellen Radiologie.

The use of patient contact shielding provides an opportunity to reduce patient radiation exposure. Recently, the use has been the subject of controversy. The Radiation Protection Committee has published a recommendation on the use of patient radiation shields by considering the recent findings on dose savings but also the risks of incorrect use. In this article, a specification for the more frequently used types of X­ray examination is given, which describes whether and which radiation contact shielding should be used. This is accompanied by a rationale for the use or non-use of patient radiation protection agents. Problems and possible errors are explained, as well as how to deal with special situations such as pregnant women and children.

Response of diamond detectors in ultra-high dose-per-pulse electron beams for dosimetry at FLASH radiotherapy.

Objective.With increasing investigation of the so-called FLASH effect, the need for accurate real time dosimetry for ultra-high dose rates is also growing. Considering the ultra-high dose-per-pulse (DPP) necessary to produce the ultra-high dose rates for investigations of the FLASH effect, real time dosimetry is a major challenge. In particular, vented ionization chambers, as used for dosimetry in conventional radiotherapy, show significant deviations from linearity with increasing DPP. This is due to recombination losses in the sensitive air volume. Solid state detectors could be an alternative. Due to their good stability of the response with regard to the accumulated dose, diamond detectors such as the microDiamond could be suitable here. The aims of this work are to investigate the response of microDiamond and adapted microDiamond prototypes in ultra-high DPP electron beams, to understand the underlying effects and to draw conclusions for further detector developments.Approach.For the study, an electron beam with a DPP up to 6.5 Gy and a pulse duration of 2.5µs was used to fulfill the conditions under which the FLASH effect was observed. As a dose rate-independent reference, alanine dosimeters were used.Main Results.It has been shown that the commercially available microDiamond detectors have limitations in terms of linearity at ultra-high DPP. But this is not an intrinsic limitation of the detector principle. The deviations from linearity were correlated with the series resistance and the sensitivity. It could be shown that the linear range can be extended towards ultra-high DPP range by reducing the sensitivity in combination with a low series resistance of the detectors.Significance.The work shows that synthetic single crystal diamond detectors working as Schottky photodiodes are in principle suitable for FLASH-RT dosimetry at electron linear accelerators.

A long-term neuropsychological evaluation in Fabry disease.

Fabry disease (FD) is a X-linked multi-systemic metabolic disorder with mainly renal, cardiac and neurological dysfunction. The neuropsychological impact is still unclear, with previous study results ranging from disturbance of speed of information processing and executive functions to a normal cognitive profile. The aim of our study was to gain further insight into the neuropsychological involvement of FD. Patients with genetically proven FD were enrolled at the Ghent University Hospital by their treating neurologist. We evaluated the cognitive status of each patient by a thorough neuropsychological test battery and these exact same neuropsychological assessments were repeated after a follow-up period of 2-4 years and at a second follow-up moment 1-4 years after the first follow-up. Thirteen patients with FD were included (8 female) with mean age of 41.5 years (SD ± 13.9) at baseline. All patients had normal neuropsychological test results on the subtests included in the cognitive battery at baseline, according to age-, gender- and education matched normative data. At the first follow-up moment (2-4 years after baseline), six patients were included (3 male), mean age 45.3 years. At the second follow-up (1-4 years after first follow-up), four patients (2 male) were included, with mean age 45 years. Both at the first and second follow-up moments, all patients obtained normal scores on the subtests. The cognitive functioning appeared to be in the normal range at baseline and did not decline over a follow-up period of 3-8 years, suggesting that cognition in FD patients may be well-preserved in time.

Patient positioning verification for proton therapy using proton radiography.

We present a proof of principle, experimental validation of the potential of proton 'Range Probes' (RP) for patient positioning verification in proton therapy. In this work, we have evaluated experimentally the accuracy of RP by using tissue-like samples and an in-house developed multilayer ionization chamber (MLIC). In addition we build on our previous, simulation based work to present first experimental measurements of RP through anthropomorphic phantoms to detect either rotational or translational positioning errors. For this, a technique has been proposed to characterize the residual integral depth dose curve (RIDDC) after range mixing. This parametrization has been used to evaluate the similarity between Monte Carlo calculated error scenarios of the database and the measured RIDDC, while considering the intrinsic uncertainties of both modalities in order to deduce the positioning error. Finally, the additional dose applied to the patient when using clinical RP with known fluence has been estimated by measuring the local dose of a single RP. In tissue phantoms, the prediction accuracy of the water equivalent path length was 0.70%, with the highest deviations being found in low density samples (up to 5.67%). In addition, the results of the patient positioning verification measurements demonstrated that using carefully selected RPs, 1D translational or rotational errors could be detected with an accuracy of 1 mm and 2°, respectively, and that these would be associated with a low additional dose burden to the patient. In summary, these promising results suggest that the RP method could be a simple, fast and low-dose tool for verifying patient set-up during proton therapy treatment.

OCCUPATIONAL EXPOSURE FROM F-18-FDG PET/CT: IMPLEMENTATION TO ROUTINE CLINICAL PRACTICE.

The purpose of this study was to assess the occupational radiation exposure arising from positron emission tomography combined with X-ray computed tomography (PET/CT) procedures. From 2009 through the end of 2014, in a team of six technologists, personal dosimetry was performed using electronic personal dosemeters and film badge dosemeters. The technologists registered the separate exposure after each PET/CT operational step, which included radiopharmaceutical arrival, dispensing in individual syringes, injection and patient positioning.From the total of 3024 PET/CT procedures, 2142 were available for analysis. The personal dose equivalent for the technologists performing PET/CT ranged from 11.5 nSv/MBq to 23.8 nSv/MBq. Whole-body radiation dose originated mainly from radiopharmaceutical injection (41.5%) and patient positioning (51.1%). The sources of occupational exposure were successfully identified for PET/CT procedures. Record keeping using on-site occupational dosimetry is a useful tool for exposure optimisation.

Test study of boron nitride as a new detector material for dosimetry in high-energy photon beams.

The aim of this test study is to check whether boron nitride (BN) might be applied as a detector material in high-energy photon-beam dosimetry. Boron nitride exists in various crystalline forms. Hexagonal boron nitride (h-BN) possesses high mobility of the electrons and holes as well as a high volume resistivity, so that ionizing radiation in the clinical range of the dose rate can be expected to produce a measurable electrical current at low background current. Due to the low atomic numbers of its constituents, its density (2.0 g cm-3) similar to silicon and its commercial availability, h-BN appears as possibly suitable for the dosimetry of ionizing radiation. Five h-BN plates were contacted to triaxial cables, and the detector current was measured in a solid-state ionization chamber circuit at an applied voltage of 50 V. Basic dosimetric properties such as formation by pre-irradiation, sensitivity, reproducibility, linearity and temporal resolution were measured with 6 MV photon irradiation. Depth dose curves at quadratic field sizes of 10 cm and 40 cm were measured and compared to ionization chamber measurements. After a pre-irradiation with 6 Gy, the devices show a stable current signal at a given dose rate. The current-voltage characteristic up to 400 V shows an increase in the collection efficiency with the voltage. The time-resolved detector current behavior during beam interrupts is comparable to diamond material, and the background current is negligible. The measured percentage depth dose curves at 10 cm × 10 cm field size agreed with the results of ionization chamber measurements within ±2%. This is a first study of boron nitride as a detector material for high-energy photon radiation. By current measurements on solid ionization chambers made from boron nitride chips we could demonstrate that boron nitride is in principle suitable as a detector material for high-energy photon-beam dosimetry.

Targeting BET proteins improves the therapeutic efficacy of BCL-2 inhibition in T-cell acute lymphoblastic leukemia.

Inhibition of anti-apoptotic BCL-2 (B-cell lymphoma 2) has recently emerged as a promising new therapeutic strategy for the treatment of a variety of human cancers, including leukemia. Here, we used T-cell acute lymphoblastic leukemia (T-ALL) as a model system to identify novel synergistic drug combinations with the BH3 mimetic venetoclax (ABT-199). In vitro drug screening in primary leukemia specimens that were derived from patients with high risk of relapse or relapse and cell lines revealed synergistic activity between venetoclax and the BET (bromodomain and extraterminal) bromodomain inhibitor JQ1. Notably, this drug synergism was confirmed in vivo using T-ALL cell line and patient-derived xenograft models. Moreover, the therapeutic benefit of this drug combination might, at least in part, be mediated by an acute induction of the pro-apoptotic factor BCL2L11 and concomitant reduction of BCL-2 upon BET bromodomain inhibition, ultimately resulting in an enhanced binding of BIM (encoded by BCL2L11) to BCL-2. Altogether, our work provides a rationale to develop a new type of targeted combination therapy for selected subgroups of high-risk leukemia patients.

Experimental determination of the lateral dose response functions of detectors to be applied in the measurement of narrow photon-beam dose profiles.

This study aims at the experimental determination of the detector-specific 1D lateral dose response function K(x) and of its associated rotational symmetric counterpart K(r) for a set of high-resolution detectors presently used in narrow-beam photon dosimetry. A combination of slit-beam, radiochromic film, and deconvolution techniques served to accomplish this task for four detectors with diameters of their sensitive volumes ranging from 1 to 2.2 mm. The particular aim of the experiment was to examine the existence of significant negative portions of some of these response functions predicted by a recent Monte-Carlo-simulation (Looe et al 2015 Phys. Med. Biol. 60 6585-607). In a 6 MV photon slit beam formed by the Siemens Artiste collimation system and a 0.5 mm wide slit between 10 cm thick lead blocks serving as the tertiary collimator, the true cross-beam dose profile D(x) at 3 cm depth in a large water phantom was measured with radiochromic film EBT3, and the detector-affected cross-beam signal profiles M(x) were recorded with a silicon diode, a synthetic diamond detector, a miniaturized scintillation detector, and a small ionization chamber. For each detector, the deconvolution of the convolution integral M(x) = K(x) ∗ D(x) served to obtain its specific 1D lateral dose response function K(x), and K(r) was calculated from it. Fourier transformations and back transformations were performed using function approximations by weighted sums of Gaussian functions and their analytical transformation. The 1D lateral dose response functions K(x) of the four types of detectors and their associated rotational symmetric counterparts K(r) were obtained. Significant negative curve portions of K(x) and K(r) were observed in the case of the silicon diode and the diamond detector, confirming the Monte-Carlo-based prediction (Looe et al 2015 Phys. Med. Biol. 60 6585-607). They are typical for the perturbation of the secondary electron field by a detector with enhanced electron density compared with the surrounding water. In the cases of the scintillation detector and the small ionization chamber, the negative curve portions of K(x) practically vanish. It is planned to use the measured functions K(x) and K(r) to deconvolve clinical narrow-beam signal profiles and to correct the output factor values obtained with various high-resolution detectors.

BRCA1, BRCA2 and PALB2 mutations and CHEK2 c.1100delC in different South African ethnic groups diagnosed with premenopausal and/or triple negative breast cancer.

BACKGROUND: Current knowledge of the aetiology of hereditary breast cancer in the four main South African population groups (black, coloured, Indian and white) is limited. Risk assessments in the black, coloured and Indian population groups are challenging because of restricted information regarding the underlying genetic contributions to inherited breast cancer in these populations. We focused this study on premenopausal patients (diagnosed with breast cancer before the age of 50; n = 78) and triple negative breast cancer (TNBC) patients (n = 30) from the four South African ethnic groups. The aim of this study was to determine the frequency and spectrum of germline mutations in BRCA1, BRCA2 and PALB2 and to evaluate the presence of the CHEK2 c.1100delC allele in these patients. METHODS: In total, 108 South African breast cancer patients underwent mutation screening using a Next-Generation Sequencing (NGS) approach in combination with Multiplex Ligation-dependent Probe Amplification (MLPA) to detect large rearrangements in BRCA1 and BRCA2. RESULTS: In 13 (12 %) patients a deleterious mutation in BRCA1/2 was detected, three of which were novel mutations in black patients. None of the study participants was found to have an unequivocal pathogenic mutation in PALB2. Two (white) patients tested positive for the CHEK2 c.1100delC mutation, however, one of these also carried a deleterious BRCA2 mutation. Additionally, six variants of unknown clinical significance were identified (4 in BRCA2, 2 in PALB2), all in black patients. Within the group of TNBC patients, a higher mutation frequency was obtained (23.3 %; 7/30) than in the group of patients diagnosed before the age of 50 (7.7 %; 6/78). CONCLUSION: This study highlights the importance of evaluating germline mutations in major breast cancer genes in all of the South African population groups. This NGS study shows that mutation analysis is warranted in South African patients with triple negative and/or in premenopausal breast cancer.

Characterization of the genome-wide TLX1 binding profile in T-cell acute lymphoblastic leukemia.

The TLX1 transcription factor is critically involved in the multi-step pathogenesis of T-cell acute lymphoblastic leukemia (T-ALL) and often cooperates with NOTCH1 activation during malignant T-cell transformation. However, the exact molecular mechanism by which these T-cell specific oncogenes cooperate during transformation remains to be established. Here, we used chromatin immunoprecipitation followed by sequencing to establish the genome-wide binding pattern of TLX1 in human T-ALL. This integrative genomics approach showed that ectopic TLX1 expression drives repression of T cell-specific enhancers and mediates an unexpected transcriptional antagonism with NOTCH1 at critical target genes, including IL7R and NOTCH3. These phenomena coordinately trigger a TLX1-driven pre-leukemic phenotype in human thymic precursor cells, reminiscent of the thymus regression observed in murine TLX1 tumor models, and create a strong genetic pressure for acquiring activating NOTCH1 mutations as a prerequisite for full leukemic transformation. In conclusion, our results uncover a functional antagonism between cooperative oncogenes during the earliest phases of tumor development and provide novel insights in the multi-step pathogenesis of TLX1-driven human leukemia.

Dosimetric characteristics of the novel 2D ionization chamber array OCTAVIUS Detector 1500.

PURPOSE: The dosimetric properties of the OCTAVIUS Detector 1500 (OD1500) ionization chamber array (PTW-Freiburg, Freiburg, Germany) have been investigated. A comparative study was carried out with the OCTAVIUS Detector 729 and OCTAVIUS Detector 1000 SRS arrays. METHODS: The OD1500 array is an air vented ionization chamber array with 1405 detectors in a 27 × 27 cm(2) measurement area arranged in a checkerboard pattern with a chamber-to-chamber distance of 10 mm in each row. A sampling step width of 5 mm can be achieved by merging two measurements shifted by 5 mm, thus fulfilling the Nyquist theorem for intensity modulated dose distributions. The stability, linearity, and dose per pulse dependence were investigated using a Semiflex 31013 chamber (PTW-Freiburg, Freiburg, Germany) as a reference detector. The effective depth of measurement was determined by measuring TPR curves with the array and a Roos chamber type 31004 (PTW-Freiburg, Freiburg, Germany). Comparative output factor measurements were performed with the array, the Semiflex 31010 ionization chamber and the Diode 60012 (both PTW-Freiburg, Freiburg, Germany). The energy dependence of the OD1500 was measured by comparing the array's readings to those of a Semiflex 31010 ionization chamber for varying mean photon energies at the depth of measurement, applying to the Semiflex chamber readings the correction factor kNR for nonreference conditions. The Gaussian lateral dose response function of a single array detector was determined by searching the convolution kernel suitable to convert the slit beam profiles measured with a Diode 60012 into those measured with the array's central chamber. An intensity modulated dose distribution measured with the array was verified by comparing a OD1500 measurement to TPS calculations and film measurements. RESULTS: The stability and interchamber sensitivity variation of the OD1500 array were within ±0.2% and ±0.58%, respectively. Dose linearity was within 1% over the range from 5 to 1000 MU. The effective point of measurement of the OD1500 for dose measurements in RW3 phantoms was determined to be (8.7 ± 0.2) mm below its front surface. Output factors showed deviations below 1% for field sizes exceeding 4 × 4 cm(2). The dose per pulse dependence was smaller than 0.4% for doses per pulse from 0.2 to 1 mGy. The energy dependence of the array did not exceed ±0.9%. The parameter σ of the Gaussian lateral dose response function was determined as σ6MV = (2.07 ± 0.02) mm for 6 MV and σ15MV = (2.09 ± 0.02) mm for 15 MV. An IMRT verification showed passing rates well above 90% for a local 3 mm/3% criterion. CONCLUSIONS: The OD1500 array's dosimetric properties showed the applicability of the array for clinical dosimetry with the possibility to increase the spatial sampling frequency and the coverage of a dose distribution with the sensitive areas of ionization chambers by merging two measurements.

MicroRNA-193b-3p acts as a tumor suppressor by targeting the MYB oncogene in T-cell acute lymphoblastic leukemia.

The MYB oncogene is a leucine zipper transcription factor essential for normal and malignant hematopoiesis. In T-cell acute lymphoblastic leukemia (T-ALL), elevated MYB levels can arise directly through T-cell receptor-mediated MYB translocations, genomic MYB duplications or enhanced TAL1 complex binding at the MYB locus or indirectly through the TAL1/miR-223/FBXW7 regulatory axis. In this study, we used an unbiased MYB 3'untranslated region-microRNA (miRNA) library screen and identified 33 putative MYB-targeting miRNAs. Subsequently, transcriptome data from two independent T-ALL cohorts and different subsets of normal T-cells were used to select miRNAs with relevance in the context of normal and malignant T-cell transformation. Hereby, miR-193b-3p was identified as a novel bona fide tumor-suppressor miRNA that targets MYB during malignant T-cell transformation thereby offering an entry point for efficient MYB targeting-oriented therapies for human T-ALL.

Direct air activation measurements at a 15-MV medical linear accelerator.

Direct radiometric determination of (14)N (γ, n) (13)N air activation was achieved at a 15-MV medical linear accelerator operating in a high-energy photon mode. (13)N was identified by irradiating a gas-tight Marinelli beaker filled with nitrogen gas and later observing the 10-min half-life of the 511-keV positron-electron annihilation line using high-resolution gamma spectroscopy. Quantitative evaluation of the spectral signal yielded a (13)N production rate of 836.8 ± 32 Bq Gy(-1) in air per 40 × 40 cm(2) field cross section at 100 cm source-surface distance.

Patient radiation protection covers for head CT scans - a clinical evaluation of their effectiveness.

PURPOSE: Although the use of thyroid shields for patients for head CT examinations is reasonable and even required by German regulations, so far available shields are often not used due to difficult applicability. New shields that are easier to use and therefore may gain wider acceptance and more frequent use are now available. In this work two new patient shields are investigated regarding their dose reduction effectiveness and applicability and compared to a thyroid/sternum shield typically used as a part of personal protective equipment. MATERIALS AND METHODS: The reduction of organ doses for thyroid, sternum and mamma were measured with thermoluminescence detectors in an anthropomorphic female phantom. Additionally, the influence of the length or position of the overview scan at the beginning of the CT examination was taken into account. RESULTS: Depending on the patient shield, a reduction of the organ doses for thyroid of 5 - 24 %, for sternum of 25 - 48 % and for mamma of 25 - 70 % could be found. A shift of 25 mm in the cranial direction for the overview scan resulted in a reduction of these organ doses of 12 - 15 %. CONCLUSION: Patient shields for cranial CT examinations provide a considerable dose reduction. New models are easily applied and no decrease in image quality through reconstruction artifacts could be found. Therefore, it is advised to use shields which are applied upon the patient without the need to be wrapped around the neck and the overview scan should be positioned as close as possible to the examined region. KEY POINTS: • New shields provide a compromise between usability and radiation protection.• Patient shields reduce organ doses even when not directly exposed.• The overview scan contributes considerably to out of field organ doses.• Shielding factors are greatly influenced by the positioning of the examination field.

A new correction method serving to eliminate the parabola effect of flatbed scanners used in radiochromic film dosimetry.

PURPOSE: The purpose of this study is the correction of the lateral scanner artifact, i.e., the effect that, on a large homogeneously exposed EBT3 film, a flatbed scanner measures different optical densities at different positions along the x axis, the axis parallel to the elongated light source. At constant dose, the measured optical density profiles along this axis have a parabolic shape with significant dose dependent curvature. Therefore, the effect is shortly called the parabola effect. The objective of the algorithm developed in this study is to correct for the parabola effect. Any optical density measured at given position x is transformed into the equivalent optical density c at the apex of the parabola and then converted into the corresponding dose via the calibration of c versus dose. METHODS: For the present study EBT3 films and an Epson 10000XL scanner including transparency unit were used for the analysis of the parabola effect. The films were irradiated with 6 MV photons from an Elekta Synergy accelerator in a RW3 slab phantom. In order to quantify the effect, ten film pieces with doses graded from 0 to 20.9 Gy were sequentially scanned at eight positions along the x axis and at six positions along the z axis (the movement direction of the light source) both for the portrait and landscape film orientations. In order to test the effectiveness of the new correction algorithm, the dose profiles of an open square field and an IMRT plan were measured by EBT3 films and compared with ionization chamber and ionization chamber array measurement. RESULTS: The parabola effect has been numerically studied over the whole measuring field of the Epson 10000XL scanner for doses up to 20.9 Gy and for both film orientations. The presented algorithm transforms any optical density at position x into the equivalent optical density that would be measured at the same dose at the apex of the parabola. This correction method has been validated up to doses of 5.2 Gy all over the scanner bed with 2D dose distributions of an open square photon field and an IMRT distribution. CONCLUSIONS: The algorithm presented in this study quantifies and corrects the parabola effect of EBT3 films scanned in commonly used commercial flatbed scanners at doses up to 5.2 Gy. It is easy to implement, and no additional work steps are necessary in daily routine film dosimetry.