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Background: In vivo dosimetry (IVD) is rarely performed in brachytherapy (BT), allowing potential dose misadministration to go unnoticed. This study presents a clinical routine-calibration method of detectors for IVD in high (HDR) and pulsed dose rate (PDR) Ir-192 BT., Purpose: To evaluate the dosimetric precision and feasibility of an in-clinic calibration routine of detectors for IVD in afterloading BT., Methods: Calibrations were performed in a PMMA phantom with two needles inserted 20 mm apart. The source was loaded in one of the needles at 15 dwells for 10 s. The detector was placed in the other needle, and its signal was recorded. The mean signal at each dwell position was fitted to the expected dose rate with the calibration factor and the detector's longitudinal position being free parameters. The method was tested with an inorganic scintillation detector using one Ir-192 FlexiSource HDR and two Ir-192 GammaMedPlus PDR sources and followed by validation measurements in water., Results: The standard measurement uncertainty (k = 1) of the calibration factor in absolute terms (Gy/s) was 3.2/3.4% for the HDR/PDR source. The uncertainty was dominated by source strength uncertainty, and the precision of the method was <1%. The mean ± 1SD of the difference in measured and expected dose rate during validation was 1.5 ± 4.7% (HDR) and 0.0 ± 4.1% (PDR) with a positional uncertainty in the setup of 0.33/0.23 mm (HDR/PDR) (k = 1)., Conclusion: A precise and feasible in-clinic calibration method for IVD and source strength consistency tests in BT was presented., (Copyright © 2024 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.)

Purpose: The aim of this work was to investigate the ability of a biological oxygen enhancement ratio-weighted dose, D OER , to describe acute skin toxicity variations observed in mice after proton pencil beam scanning irradiations with changing doses and beam time structures., Methods and Materials: In five independent experiments, the right hind leg of a total of 621 CDF1 mice was irradiated previously in the entrance plateau of a pencil beam scanning proton beam. The incidence of acute skin toxicity (of level 1.5-2.0-2.5-3.0-3.5) was scored for 47 different mouse groups that mapped toxicity as function of dose for conventional and FLASH dose rate, toxicity as function of field dose rate with and without repainting, and toxicity when splitting the treatment into 1 to 6 identical deliveries separated by 2 minutes. D OER was calculated for all mouse groups using a simple oxygen kinetics model to describe oxygen depletion. The three independent model parameters (oxygen-depletion rate, oxygen-recovery rate, oxygen level without irradiation) were fitted to the experimental data. The ability of D OER to describe the toxicity variations across all experiments was investigated by comparing D OER -response curves across the five independent experiments., Results: After conversion from the independent variable tested in each experiment to D OER , all five experiments had similar MDD OER 50 (D OER giving 50% toxicity incidence) with standard deviations of 0.45 - 1.6 Gy for the five toxicity levels. D OER could thus describe the observed toxicity variations across all experiments., Conclusions: D OER described the varying FLASH-sparing effect observed for a wide range of conditions. Calculation of D OER for other irradiation conditions can quantitatively estimate the FLASH-sparing effect for arbitrary irradiations for the investigated murine model. With appropriate fitting parameters D OER also may be able to describe FLASH effect variations with dose and dose rate for other assays and endpoints., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Purpose: Preclinical studies have shown a preferential normal tissue sparing effect of FLASH radiation therapy with ultra-high dose rates. The aim of the present study was to use a murine model of acute skin toxicity to investigate the biologic effect of varying dose rates, time structure, and introducing pauses in the dose delivery., Methods and Materials: The right hind limbs of nonanaesthetized mice were irradiated in the entrance plateau of a pencil beam scanning proton beam with 39.3 Gy. Experiment 1 was with varying field dose rates (0.7-80 Gy/s) without repainting, experiment 2 was with varying field dose rates (0.37-80 Gy/s) with repainting, and in experiment 3, the dose was split into 2, 3, 4, or 6 identical deliveries with 2-minute pauses. In total, 320 mice were included, with 6 to 25 mice per group. The endpoints were skin toxicity of different levels up to 25 days after irradiation., Results: The dose rate 50 , which is the dose rate to induce a response in 50% of the animals, depended on the level of skin toxicity, with the higher toxicity levels displaying a FLASH effect at 0.7-2 Gy/s. Repainting resulted in higher toxicity for the same field dose rate. Splitting the dose into 2 deliveries reduced the FLASH effect, and for 3 or more deliveries, the FLASH effect was almost abolished for lower grades of toxicity., Conclusions: The dose rate that induced a FLASH effect varied for different skin toxicity levels, which are characterized by a differing degree of sensitivity to radiation dosage. Conclusions on a threshold for the dose rate needed to obtain a FLASH effect can therefore be influenced by the dose sensitivity of the used endpoint. Splitting the total dose into more deliveries compromised the FLASH effect. This can have an impact for fractionation as well as for regions where 2 or more FLASH fields overlap within the same treatment session., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background and Purpose: In vivo dosimetry is not standard in brachytherapy and some errors go undetected. The aim of this study was to evaluate the accuracy of multi-channel vaginal cylinder pulsed dose-rate brachytherapy using in vivo dosimetry., Materials and Methods: In vivo dosimetry data was collected during the years 2019-2022 for 22 patients (32 fractions) receiving multi-channel cylinder pulsed dose-rate brachytherapy. An inorganic scintillation detector was inserted in a cylinder channel. Each fraction was analysed as independent data sets. In vivo dosimetry-based source-tracking was used to determine the relative source-to-detector position. Measured dose was compared to planned and re-calculated source-tracking based doses. Assuming no change in organ and applicator geometry throughout treatment, the planned and source-tracking based dose distributions were compared in select volumes via γ-index analysis and dose-volume-histograms., Results: The mean ± SD planned vs. measured dose deviations in the first pulse were 0.8 ± 5.9 %. In 31/32 fractions the deviation was within the combined in vivo dosimetry uncertainty (averaging 9.7 %, k =  2) and planning dose calculation uncertainty (1.6 %, k =  2). The dwell-position offsets were < 2 mm for 88 % of channels, with the largest being 5.1 mm (4.0 mm uncertainty, k =  2). 3 %/2 mm γ pass-rates averaged 97.0 % (clinical target volume (CTV)), 100.0 % (rectum), 99.9 % (bladder). The mean ± SD deviation was -1. 1  ± 2.9 % for CTV D98, and -0.2 ± 0.9 % and -1.2 ± 2.5 %, for bladder and rectum D2cm 3 respectively, indicating good agreement between intended and delivered dose., Conclusions: In vivo dosimetry verified accurate and stable dose delivery in multi-channel vaginal cylinder based pulsed dose-rate brachytherapy., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: While these relations have had no influence on the findings of this work, the authors find it appropriate to inform on the following financial and advisory connections: The study has been funded by: - Aarhus University open access agreement (granted to all Aarhus University affiliated research). - Novo Nordisk Fonden (for the research group and not specifically for this study). Author-specific relations: Jacob G Johansen: - Research collaboration with ELEKTA (not this study). - Member of ORIGIN (https://origin2020.eu/) advisory board. - Member of BRAPHYS work-group under GEC-ESTRO. - No-voting consultant in AAPM Working Group on Medical Errors in brachytherapy (WGMEB). Kari Tanderup: - Grant from Danish Cancer Society (not specifically for this study). Research collaboration with ELEKTA (not this study). The remaining authors have not relations of interest., (© 2024 The Authors.)

Background and Purpose: Oxygen dynamics may be important for the tissue-sparing effect observed at ultra-high dose rates (FLASH sparing effect). This study investigated the correlation between local instantaneous dose rate and radiation-induced oxygen pressure reduction during proton pencil beam scanning (PBS) irradiations of a sample and quantified the oxygen consumption g-value., Materials and Methods: A 0.2 ml phosphorescent sample (1 μM PtG4 Oxyphor probe in saline) was irradiated with a 244 MeV proton PBS beam. Four irradiations were performed with variations of a PBS spot pattern with 5 × 7 spots. During irradiation, the partial oxygen pressure (pO 2 ) was measured with 4.5 Hz temporal resolution with a phosphorometer (Oxyled) that optically excited the probe and recorded the subsequently emitted light. A calibration was performed to calculate the pO 2 level from the measured phosphorescence lifetime. A fiber-coupled scintillator simultaneously measured the instantaneous dose rate in the sample with 50 kHz sampling rate. The oxygen consumption g-value was determined on a spot-by-spot level and using the total pO 2 change for full spot pattern irradiation., Results: A high correlation was found between the local instantaneous dose rate and pO 2 reduction rate, with a correlation coefficient of 0.96-0.99. The g-vales were 0.18 ± 0.01 mmHg/Gy on a spot-by-spot level and 0.17 ± 0.01 mmHg/Gy for full spot pattern irradiation., Conclusions: The pO 2 reduction rate was directly related to the local instantaneous dose rate per delivered spot in PBS deliveries. The methodology presented here can be applied to irradiation at ultra-high dose rates with modifications in the experimental setup., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Author(s).)

Objective: A favorable effect of ultra-high dose rate (FLASH) radiation on normal tissue-sparing has been indicated in several preclinical studies. In these studies, the adverse effects of radiation damage were reduced without compromising tumor control. Most studies of proton FLASH investigate these effects within the entrance of a proton beam. However, the real advantage of proton therapy lies in the Spread-out Bragg Peak (SOBP), which allows for giving a high dose to a target with a limited dose to healthy tissue at the entrance of the beam. Therefore, a clinically relevant investigation of the FLASH effect would be of healthy tissues within a SOBP. Our study quantified the tissue-sparing effect of FLASH radiation on acute and late toxicity within an SOBP in a murine model., Material/methods: Radiation-induced damage was assessed for acute and late toxicity in the same mice following irradiation with FLASH (Field dose rate of 60 Gy/s) or conventional (CONV, 0.34 Gy/s) dose rates. The right hindleg of unanesthetized female CDF1 mice was irradiated with single-fraction doses between 19.9-49.7 Gy for CONV and 30.4-65.9 Gy for FLASH with 5-8 mice per dose. The leg was placed in the middle of a 5 cm SOBP generated from a mono-energetic beam using a 2D range modulator. Acute skin toxicity quantified by hair loss, moist desquamation and toe separation was monitored daily within 29 days post-treatment. Late toxicity of fibrotic development measured by leg extendibility was monitored biweekly until 30 weeks post-treatment., Results: Comparison of acute skin toxicity following radiation indicated a tissue-sparing effect of FLASH compared to conventional single-fraction radiation with a mean protection ratio of 1.40 (1.35-1.46). Fibrotic development similarly indicated normal tissue sparing with a 1.18 (1.17-1.18) protection ratio. The acute skin toxicity tissue sparing was similar to data from entrance-beam irradiations of Sørensen et al. (4)., Conclusion: Full dose-response curves for acute and late toxicity after CONV and FLASH radiation were obtained. Radiation within the SOBP retains the normal-tissue-sparing effect of FLASH with a dose-modifying factor of 40% for acute skin damage and 18% for fibrotic development., Competing Interests: BS and PP are co-inventors on a patent-application application number 63257211 and EFS ID: 44064136. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Kristensen, Poulsen, Kanouta, Rohrer, Ankjærgaard, Andersen, Johansen, Simeonov, Weber, Grau and Sørensen.)

Background: Dosimetry in pre-clinical FLASH studies is essential for understanding the beam delivery conditions that trigger the FLASH effect. Resolving the spatial and temporal characteristics of proton pencil beam scanning (PBS) irradiations with ultra-high dose rates (UHDR) requires a detector with high spatial and temporal resolution., Purpose: To implement a novel camera-based system for time-resolved two-dimensional (2D) monitoring and apply it in vivo during pre-clinical proton PBS mouse irradiations., Methods: Time-resolved 2D beam monitoring was performed with a scintillation imaging system consisting of a 1 mm thick transparent scintillating sheet, imaged by a CMOS camera. The sheet was placed in a water bath perpendicular to a horizontal PBS proton beam axis. The scintillation light was reflected through a system of mirrors and captured by the camera with 500 frames per second (fps) for UHDR and 4 fps for conventional dose rates. The raw images were background subtracted, geometrically transformed, flat field corrected, and spatially filtered. The system was used for 2D spot and field profile measurements and compared to radiochromic films. Furthermore, spot positions were measured for UHDR irradiations. The measured spot positions were compared to the planned positions and the relative instantaneous dose rate to equivalent fiber-coupled point scintillator measurements. For in vivo application, the scintillating sheet was placed 1 cm upstream the right hind leg of non-anaesthetized mice submerged in the water bath. The mouse leg and sheet were both placed in a 5 cm wide spread-out Bragg peak formed from the mono-energetic proton beam by a 2D range modulator. The mouse leg position within the field was identified for both conventional and FLASH irradiations. For the conventional irradiations, the mouse foot position was tracked throughout the beam delivery, which took place through repainting. For FLASH irradiations, the delivered spot positions and relative instantaneous dose rate were measured., Results: The pixel size was 0.1 mm for all measurements. The spot and field profiles measured with the scintillating sheet agreed with radiochromic films within 0.4 mm. The standard deviation between measured and planned spot positions was 0.26 mm and 0.35 mm in the horizontal and vertical direction, respectively. The measured relative instantaneous dose rate showed a linear relation with the fiber-coupled scintillator measurements. For in vivo use, the leg position within the field varied between mice, and leg movement up to 3 mm was detected during the prolonged conventional irradiations., Conclusions: The scintillation imaging system allowed for monitoring of UHDR proton PBS delivery in vivo with 0.1 mm pixel size and 2 ms temporal resolution. The feasibility of instantaneous dose rate measurements was demonstrated, and the system was used for validation of the mouse leg position within the field., (© 2024 The Authors. Medical Physics published by Wiley Periodicals LLC on behalf of American Association of Physicists in Medicine.)

Purpose: To use quantities measurable during in vivo dosimetry to build unique channel identifiers, that enable detection of brachytherapy errors., Materials and Methods: Treatment plan of 360 patients with prostate cancer who underwent high-dose-rate brachytherapy (range, 16-25 catheters; mean, 17) were used. A single point virtual dosimeter was placed at multiple positions within the treatment geometry, and the source-dosimeter distance and dwell time were determined for each dwell position in each catheter. These values were compared across all catheters, dwell position by dwell position, simulating a treatment delivery. A catheter was considered uniquely identified if, for a given dwell position, no other catheters had the same measured values. The minimum number of dwell positions needed to identify a specific catheter and the optimal dosimeter location uniquely were determined. The radial (r) and vertical (z) dimensions of the source-dosimeter distance were also examined for their utility in discriminating catheters., Results: Using a virtual dosimeter with no uncertainties, all catheters were identified in 359 of the 360 cases with 9 dwell position measurements. When only the dwell time were measured, all catheters were uniquely identified after 1 dwell position. With a 2-mm spatial accuracy (r,z), all catheters were identified in 94% of the plans. Simultaneous measurement of source-dosimeter distance and dwell time ensured full catheter identification in all plans ranging from 2 to 6 dwell positions. The number of dwell positions needed to uniquely identify all catheters was lower when the distance from the implant center was higher., Conclusions: The most efficient fingerprinting approach involved combining source-dosimeter distance (i.e., source tracking) and dwell time. The further the dosimeter is placed from the center of the implant the better it can uniquely identify catheters., (Copyright © 2024. Published by Elsevier Inc.)

Background: In respiratory gated radiotherapy, low latency between target motion into and out of the gating window and actual beam-on and beam-off is crucial for the treatment accuracy. However, there is presently a lack of guidelines and accurate methods for gating latency measurements., Purpose: To develop a simple and reliable method for gating latency measurements that work across different radiotherapy platforms., Methods: Gating latencies were measured at a Varian ProBeam (protons, RPM gating system) and TrueBeam (photons, TrueBeam gating system) accelerator. A motion-stage performed 1 cm vertical sinusoidal motion of a marker block that was optically tracked by the gating system. An amplitude gating window was set to cover the posterior half of the motion (0-0.5 cm). Gated beams were delivered to a 5 mm cubic scintillating ZnSe:O crystal that emitted visible light when irradiated, thereby directly showing when the beam was on. During gated beam delivery, a video camera acquired images at 120 Hz of the moving marker block and light-emitting crystal. After treatment, the block position and crystal light intensity were determined in all video frames. Two methods were used to determine the gate-on (τ on ) and gate-off (τ off ) latencies. By method 1, the video was synchronized with gating log files by temporal alignment of the same block motion recorded in both the video and the log files. τ on was defined as the time from the block entered the gating window (from gating log files) to the actual beam-on as detected by the crystal light. Similarly, τ off was the time from the block exited the gating window to beam-off. By method 2, τ on and τ off were found from the videos alone using motion of different sine periods (1-10 s). In each video, a sinusoidal fit of the block motion provided the times T min of the lowest block position. The mid-time, T mid-light , of each beam-on period was determined as the time halfway between crystal light signal start and end. It can be shown that the directly measurable quantity T mid-light - T min  = (τ off +τ on )/2, which provided the sum (τ off +τ on ) of the two latencies. It can also be shown that the beam-on (i.e., crystal light) duration ΔT light increases linearly with the sine period and depends on τ off - τ on : ΔT light  = constant•period+(τ off - τ on ). Hence, a linear fit of ΔT light as a function of the period provided the difference of the two latencies. From the sum (τ off +τ on ) and difference (τ off - τ on ), the individual latencies were determined., Results: Method 1 resulted in mean (±SD) latencies of τ on  = 255 ± 33 ms, τ off  = 82 ± 15 ms for the ProBeam and τ on  = 84 ± 13 ms, τ off  = 44 ± 11 ms for the TrueBeam. Method 2 resulted in latencies of τ on  = 255 ± 23 ms, τ off  = 95 ± 23 ms for the ProBeam and τ on  = 83 ± 8 ms, τ off  = 46 ± 8 ms for the TrueBeam. Hence, the mean latencies determined by the two methods agreed within 13 ms for the ProBeam and within 2 ms for the TrueBeam., Conclusions: A novel, simple and low-cost method for gating latency measurements that work across different radiotherapy platforms was demonstrated. Only the TrueBeam fully fulfilled the AAPM TG-142 recommendation of maximum 100 ms latencies., (© 2023 The Authors. Medical Physics published by Wiley Periodicals LLC on behalf of American Association of Physicists in Medicine.)

Background and Purpose: Proton therapy is sensitive to range uncertainties, which typically are accounted for by margins or robust optimization, based on tissue-independent uncertainties. However, range uncertainties have been shown to depend on the specific tissues traversed. The aim of this study was to investigate the differences between range margins based on stopping power ratio (SPR) uncertainties which were tissue-specific (applied voxel-wise) or fixed (tissue-independent or composite)., Materials and Methods: Uncertainties originating from imaging, computed tomography (CT) number estimation, and SPR estimation were calculated for low-, medium-, and high-density tissues to quantify the tissue-specific SPR uncertainties. Four clinical treatment plans (four different tumor sites) were created and recomputed after applying either tissue-specific or fixed SPR uncertainties. Plans with tissue-specific and fixed uncertainties were compared, based on dose-volume-histogram parameters for both targets and organs-at-risk., Results: The total SPR uncertainties were 7.0% for low-, 1.0% for medium-, and 1.3% for high-density tissues. Differences between the proton plans with tissue-specific and fixed uncertainties were mainly found in the vicinity of the target. Composite uncertainties were found to capture the tissue-specific uncertainties more accurately than the tissue-independent uncertainties., Conclusion: Different SPR uncertainties were found for low-, medium-, and high-density tissues indicating that range margins based on tissue-specific uncertainties may be more exact than the standard approach of using tissue-independent uncertainties. Differences between applying tissue-specific and fixed uncertainties were found, however, a fixed uncertainty might still be sufficient, but with a magnitude that depends on the body region., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors. Published by Elsevier B.V. on behalf of European Society of Radiotherapy & Oncology.)

Background: The spatial and temporal dose rate distribution of pencil beam scanning (PBS) proton therapy is important in ultra-high dose rate (UHDR) or FLASH irradiations. Validation of the temporal structure of the dose rate is crucial for quality assurance and may be performed using detectors with high temporal resolution and large dynamic range., Purpose: To provide time-resolved in vivo dose rate measurements using a scintillator-based detector during proton PBS pre-clinical mouse experiments with dose rates ranging from conventional to UHDR., Methods: All irradiations were performed at the entrance plateau of a 250 MeV PBS proton beam. A detector system with four fiber-coupled ZnSe:O inorganic scintillators and 20 μs temporal resolution was used for dose rate measurements. The system was first characterized in terms of precision and stem signal. The detector precision was determined through repeated irradiations with the same field. The stem signal contribution was quantified by irradiating two of the detector probes alongside a bare fiber (fiber without a coupled scintillator). Next, the detector system was calibrated against an ionization chamber (IC) with all four detector probes and the IC placed in a water bath at 2 cm depth. A scan pattern covering 9.6 × 9.6 cm was used. Multiple irradiations with different requested nozzle currents provided instantaneous dose rates at the detector positions in the range of 7-1270 Gy/s. The correspondence of the detector signal (in Volts) to the instantaneous dose rate (in Gy/s) was found. The instantaneous dose rate was calculated from the beam current and the spot-to-detector distance assuming a Gaussian beam profile at distances up to 8 mm from the spot. Afterwards, the calibrated system was used in vivo, in mouse experiments, where mouse legs were irradiated with a constant dose and varying field dose rates of 0.7-87.5 Gy/s. The instantaneous dose rate was measured for each delivered spot and the delivered dose was determined as the integrated instantaneous dose rate. The spot dose profile and PBS dose rate map were calculated. The dose contamination to neighbouring mice were measured together with the upper limit of the dose to the mouse body., Results: The detectors showed high precision with ≤0.4% fluctuations in the measured dose. The stem signal exceeded 10% for spots <5 mm from the optical fiber and >18 mm from the scintillator. It contributed up to 0.2% to the total dose, which was considered negligible. All four detectors showed a non-linear relation between signal and instantaneous dose rate, which was modelled with a polynomial response function. In the mouse experiments, the measured scintillator dose showed 1.8% fluctuations, independent of the field dose rate. The in vivo measured spot dose profile had tails that deviated from a Gaussian profile with measurable dose contributions from spots up to 85 mm from the detector. Neighbour mouse irradiation contributed ∼1% of the total mouse dose. The upper limit of the mouse body dose was 6% of the mouse leg dose., Conclusions: A fiber-coupled inorganic scintillator-based detector system can provide high precision in vivo measurements of the instantaneous dose rate if correction for the non-linear dose rate dependency is applied., (© 2022 The Authors. Medical Physics published by Wiley Periodicals LLC on behalf of American Association of Physicists in Medicine.)

Purpose: Preclinical studies indicate a normal tissue sparing effect when ultra-high dose rate (FLASH) radiation is used, while tumor response is maintained. This differential response has promising perspectives for improved clinical outcome. This study investigates tumor control and normal tissue toxicity of pencil beam scanning (PBS) proton FLASH in a mouse model., Methods and Materials: Tumor bearing hind limbs of non-anaesthetized CDF1 mice were irradiated in a single fraction with a PBS proton beam using either conventional (CONV) dose rate (0.33-0.63 Gy/s field dose rate, 244 MeV) or FLASH (71-89 Gy/s field dose rate, 250 MeV). 162 mice with a C3H mouse mammary carcinoma subcutaneously implanted in the foot were irradiated with physical doses of 40-60 Gy (8-14 mice per dose point). The endpoints were tumor control (TC) assessed as no recurrent tumor at 90 days after treatment, the level of acute moist desquamation (MD) to the skin of the foot within 25 days post irradiation, and radiation induced fibrosis (RIF) within 24 weeks post irradiation., Results: TCD 50 (dose for 50% tumor control) was similar for CONV and FLASH with values (and 95% confidence intervals) of 49.1 (47.0-51.4) Gy for CONV and 51.3 (48.6-54.2) Gy for FLASH. RIF analysis was restricted to mice with tumor control. Both endpoints showed distinct normal tissue sparing effect of proton FLASH with MDD 50 (dose for 50% of mice displaying moist desquamation) of <40.1 Gy for CONV and 52.3 (50.0-54.6) Gy for FLASH, (dose modifying factor at least 1.3) and FD 50 (dose for 50% of mice displaying fibrosis) of 48.6 (43.2-50.8) Gy for CONV and 55.6 (52.5-60.1) Gy for FLASH (dose modifying factor of 1.14)., Conclusions: FLASH had the same tumor control as CONV, but reduced normal tissue damage assessed as acute skin damage and radiation induced fibrosis., Competing Interests: Conflict of interest statement This study presented in this manuscript is partly funded by Varian. Two co-authors are co-inventors on a patent-application filled with application number 63257211 and EFS ID: 44064136, which contains parts of the data included in the manuscript., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: There is increased interest in in vivo dosimetry for 192 Ir brachytherapy (BT) treatments using high atomic number (Z) inorganic scintillators. Their high light output enables construction of small detectors with negligible stem effect and simple readout electronics. Experimental determination of absorbed-dose energy dependence of detectors relative to water is prevalent, but it can be prone to high detector positioning uncertainties and does not allow for decoupling of absorbed-dose energy dependence from other factors affecting detector response ., Purpose: To investigate which measurement conditions and detector properties could affect their absorbed-dose energy dependence in BT in vivo dosimetry., Methods: We used a general-purpose Monte Carlo (MC) code PENELOPE for the characterization of high-Z inorganic scintillators with the focus on ZnSe ( Z ¯ = 32 $\bar{Z}=32$ ) Z. Two other promising media CsI ( Z ¯ = 54 $\bar{Z}=54$ ) and Al 2 O 3 ( Z ¯ = 11 $\bar{Z}=11$ ) were included for comparison in selected scenarios. We determined absorbed-dose energy dependence of crystals relative to water under different scatter conditions (calibration phantom 12 × 12 × 30 cm 3 , characterization phantoms 20 × 20 × 20 cm 3 , 30 × 30 × 30 cm 3 , 40 × 40 × 40 cm 3 , and patient-like elliptic phantom 40 × 30 × 25 cm 3 ). To mimic irradiation conditions during prostate treatments, we evaluated whether the presence of pelvic bones and calcifications affect ZnSe response. ZnSe detector design influence was also investigated., Results: In contrast to low-Z organic and medium-Z inorganic scintillators, ZnSe and CsI media have substantially greater absorbed-dose energy dependence relative to water. The response was phantom-size dependent and changed by 11% between limited- and full-scatter conditions for ZnSe, but not for Al 2 O 3 . For a given phantom size, a part of the absorbed-dose energy dependence of ZnSe is caused not due to in-phantom scatter but due to source anisotropy. Thus, the absorbed-dose energy dependence of high-Z scintillators is a function of not only the radial distance but also the polar angle. Pelvic bones did not affect ZnSe response, whereas large and intermediate size calcifications reduced it by 9% and 5%, respectively, when placed midway between the source and the detector., Conclusions: Unlike currently prevalent low- and medium-Z scintillators, high-Z crystals are sensitive to characterization and in vivo measurement conditions. However, good agreement between MC data for ZnSe in the present study and experimental data for ZnSe:O by Jørgensen et al. (2021) suggests that detector signal is proportional to the average absorbed dose to the detector cavity. This enables an easy correction for non-TG43-like scenarios (e.g., patient sizes and calcifications) through MC simulations. Such information should be provided to the clinic by the detector vendors., (© 2022 American Association of Physicists in Medicine.)

Introduction: In vivo dosimetry (IVD) can be used for source tracking (ST), i.e., estimating source positions, during brachytherapy. The aim of this study was to exploit IVD-based ST to perform 3D dose reconstruction for high-dose-rate prostate brachytherapy and to evaluate the robustness of the treatments against observed geometric variations., Materials and Methods: Twenty-three fractions of high-dose-rate prostate brachytherapy were analysed. The treatment planning was based on MRI. Time-resolved IVD was performed using a fibre-coupled scintillator. ST was retrospectively performed using the IVD measurements. The ST identified 2D positional shifts of each treatment catheter and thereby inferred updated source positions. For each fraction, the dose was recalculated based on the source-tracked catheter positions and compared with the original plan dose using differences in dose volume histogram indices., Results: Of 352 treatment catheters, 344 had shifts of less than 5 mm. Shifts between 5 and 10 mm were observed for 3 catheters, and shifts greater than 10 mm for 2 catheters. The ST failed for 3 catheters. The maximum relative difference in clinical target volume (prostate + 3 mm isotropic margin) D 90% was 5%. In one fraction, the bladder D 2cm 3 dose increased by 18% (1.4 Gy) due to a single source position being inside the bladder rather than nearby as planned. The max increase in urethra dose was 1.5 Gy (15%)., Conclusion: IVD-based 3D dose reconstruction for high-dose-rate prostate brachytherapy is feasible. The dosimetric impact of the observed catheter shifts was limited. Dose reconstruction can therefore aid in determining the dosimetric impact of geometric variations and errors in brachytherapy., Competing Interests: Conflict of interest Nothing to report., (Copyright © 2022. Published by Elsevier B.V.)

Background: Electronic brachytherapy (eBT) is considered a safe treatment with good outcomes. However, eBT lacks standardized and independent dose verification, which could impede future use., Purpose: To validate the 3D dose-to-water distribution of an electronic brachytherapy (eBT) source using a small-volume plastic scintillation detector (PSD)., Methods: The relative dose distribution of a Papillon 50 (P50) (Ariane Medical Systems, UK) eBT source was measured in water with a PSD consisting of a cylindrical scintillating BCF-12 fiber (length: 0.5 mm, Ø: 1 mm) coupled to a photodetector via an optical fiber. The measurements were performed with the PSD mounted on a motorized stage in a water phantom (MP3) (PTW, Germany). This allowed the sensitive volume of the PSD to be moved to predetermined positions relative to the P50 applicator, which pointed vertically downward while just breaching the water surface. The percentage depth-dose (PDD) was measured from 0 to 50 mm source-to-detector distance (SDD) in 1-3 mm steps. Dose profiles were measured along two perpendicular axes at five different SDDs with step sizes down to 0.5 mm. Characterization of the PSD consisted of determining the energy correction through Monte Carlo (MC) simulation and by measuring the stability and dose rate linearity using a well-type ionization chamber as a reference. The measured PDD and profiles were validated with corresponding MC simulations., Results: The measured and simulated PDD curves agreed within 2% (except at 0 mm and 43 mm depth) after the PSD measurements were corrected for energy dependency. The absorbed dose decreased by a factor of 2 at 7 mm depth and by a factor of 10 at 26 mm depth. The measured dose profiles showed dose gradients at the profile edges of more than 50%/mm at 5 mm depth and 15%/mm at 50 mm depth. The measured profile widths increased 0.66 mm per 1 mm depth, while the simulated profile widths increased 0.74 mm per 1 mm depth. An azimuthal dependency of > 10% was observed in the dose at 10 mm distance from the beam center. The total uncertainty of the measured relative dose is < 2.5% with a positional uncertainty of 0.4 mm. The measurements for a full 3D dose characterization (PDD and profiles) can be carried out within 8 h, the limiting factor being cooling of the P50., Conclusion: The PSD and MP3 water phantoms provided a method to independently verify the relative 3D dose distribution in water of an eBT source., (© 2022 The Authors. Medical Physics published by Wiley Periodicals LLC on behalf of American Association of Physicists in Medicine.)

Purpose: Key factors in FLASH treatments are the ultra-high dose rate (UHDR) and the time structure of the beam delivery. Measurement of the time structure in pencil beam scanning (PBS) proton FLASH treatments is challenging for many types of detectors since high temporal resolution is needed. In this study, a fast scintillator detector system was developed and used to measure the individual spot durations as well as the time when the beam moves between two positions (transition duration) during PBS proton FLASH and UHDR treatments. The spot durations were compared with machine log-file recordings., Methods: A detector system based on inorganic scintillating crystals was developed. The system consisted of four detector probes made of a sub-millimeter ZnSe:O crystal that was coupled via an optical fiber to an optical reader with 50 kHz sampling rate. The detector system was used in two experiments, both performed with a PBS proton beam with 250 MeV beam energy and 215 nA requested nozzle beam current. The sampling rate enabled multiple measurements during each spot delivery and during the beam transition between spots. First, the detector was tested in a phantom experiment, where a total of 305 scan sequences were delivered to the four detectors. The number of spots delivered without beam interruption in a single scan sequence ranged from one to 35. The spot duration and transition duration were measured for each individual spot. Secondly, the detector system was used in vivo in preclinical experiments with FLASH irradiation of mouse legs placed in the entrance plateau of the beam. A single detector was placed 1 cm downstream of the irradiated mouse leg. The mouse dose ranged from 30.5 to 44.2 Gy and the field consisted of 35 spots. The spot durations as well as the mean dose rate (field dose divided by the measured field duration) for each mouse were determined using the detector and then compared with the corresponding log files., Results: The phantom experiment showed that the logged total duration of an uninterrupted spot sequence was consistently shorter than the measured duration with a difference of -0.252 ms (95% confidence interval: [-0.255, -0.249 ms]). This corresponded to 0.05%-0.07% of the spot sequence duration in the mice experiments. For individual spots, the mean ± 1SD difference between logged and measured spot duration was -0.39 ± 0.05 ms for the first spot in a sequence, 0.13 ± 0.04 ms for the last spot in a sequence, and -0.0017 ± 0.09 ms for the intermediate spots in a sequence. The measured spot transition durations were 0.20 ± 0.04 ms (5.1 mm horizontal steps) and 0.50 ± 0.04 ms (5.0 mm vertical steps). For the mouse experiments, the mean dose rate calculated from the measured field duration was 84.1-92.5 Gy/s. It agreed with log files with a root mean square difference of 0.02 Gy/s., Conclusions: Fiber-coupled scintillator detectors were designed with sufficient temporal resolution to measure the spot and transition duration during PBS proton UHDR deliveries. Their small volume makes them feasible for in vivo use in preclinical FLASH studies. The logged spot durations were in excellent agreement with measurements but showed small systematic errors in the logged duration for the first and last spot in a sequence., (© 2022 American Association of Physicists in Medicine.)

Purpose: High-dose rate (HDR) and pulsed-dose rate (PDR) brachytherapy would benefit from an independent treatment verification system to monitor treatment delivery and to detect errors in real time. This paper characterizes and provides an uncertainty budget for a detector based on a fiber-coupled high-Z inorganic scintillator capable of performing time-resolved in vivo dosimetry during HDR and PDR brachytherapy., Method: The detector was composed of a detector probe and an optical reader. The detector probe consisted of either a 0.5 × 0.4 × 0.4 mm 3 (HDR) or a 1.0 × 0.4 × 0.4 mm 3 (PDR) cuboid ZnSe:O crystal glued onto an optical-fiber cable. The outer diameter of the detector probes was 1 mm, and fit inside standard brachytherapy catheters. The signal from the detector probe was read out at 20 Hz by a photodiode and a data acquisition device inside the optical reader. In order to construct an uncertainty budget for the detector, six characteristics were determined: (1) temperature dependence of the detector probe, (2) energy dependence as a function of the probe-to-source position in 2D (determined with 2 mm resolution using a robotic arm), (3) the signal-to-noise ratio (SNR), (4) short-term stability over 8 h, and (5) long-term stability of three optical readers and four probes used for in vivo monitoring in HDR and PDR treatments over 21 months (196 treatments and 189 detector calibrations, and (6) dose-rate dependence., Results: The total uncertainty of the detector at a 20 mm probe-to-source distance was < 5.1% and < 5.8% for the HDR and PDR versions, respectively. Regarding the above characteristics, (1) the sensitivity of the detector decreased by an average of 1.4%/°C for detector probe temperatures varying from 22 to 37°C; (2) the energy dependence of the detector was nonlinear and depended on both probe-to-source distance and the angle between the probe and the brachytherapy source; (3) the median SNRs were 187 and 34 at a 20 mm probe-to-source distance for the HDR and PDR versions, respectively (corresponding median source activities of 4.8 and 0.56 Ci, respectively); (4) the detector response varied by 0.6% in 11 identical irradiations over 8 h; (5) the sensitivity of the four detector probes decreased systematically by 0-1.2%/100 Gy of dose delivered to the probes, and random fluctuations of 4.8% in the sensitivity were observed for the three probes used in PDR and 1.9% for the probe used in HDR; and (6) the detector response was linear with dose rate., Conclusion: ZnSe:O detectors can be used effectively for in vivo dosimetry and with high accuracy for HDR and PDR brachytherapy applications., (© 2021 American Association of Physicists in Medicine.)

Purpose: The aim of this study is to perform three-dimensional (3D) source position reconstruction by combining in vivo dosimetry measurements from two independent detector systems., Methods: Time-resolved dosimetry was performed in a water phantom during HDR brachytherapy irradiation with 192 Ir source using two detector systems. The first was based on three plastic scintillator detectors and the second on a single inorganic crystal (CsI:Tl). Brachytherapy treatments were simulated in water under TG-43U1 conditions, including a HDR prostate plan. Treatment needles were placed in distances covering a range of source movement of 120 mm around the detectors. The distance from each dwell position to each scintillator was determined based on the measured dose rates. The three distances given by the mPSD were recalculated to a position along the catheter (z) and a distance radially away from the mPSD (xy) for each dwell position (a circumference around the mPSD). The source x, y, and z coordinates were derived from the intersection of the mPSD's circumference with the sphere around the ISD based on the distance to this detector. We evaluated the accuracy of the source position reconstruction as a function of the distance to the source, the most likely location for detector positioning within a prostate volume, as well as the capacity to detect positioning errors., Results: Approximately 4000 source dwell positions were tracked for eight different HDR plans. An intersection of the mPSD torus and the ISD sphere was observed in 77.2% of the dwell positions, assuming no uncertainty in the dose rate determined distance. This increased to 100% if 1σ search regions were added. However, only 73(96)% of the expected dwell positions were found within the intersection band for 1(2) σ uncertainties. The agreement between the source's reconstructed and expected positions was within 3 mm for a range of distances to the source up to 50 mm. The experiments on a HDR prostate plan, showed that by having at least one of the detectors located in the middle of the prostate volume, reduces the measurement deviations considerably compared to scenarios where the detectors were located outside of the prostate volume. The analysis showed a detection probability that, in most cases, is far from the random detection threshold. Errors of 1(2) mm can be detected in ranges of 5-25 (25-50) mm from the source, with a true detection probability rate higher than 80%, while the false probability rate is kept below 20%., Conclusions: By combining two detector responses, we enabled the determination of the absolute source coordinates. The combination of the mPSD and the ISD in vivo dosimetry constitutes a promising alternative for real-time 3D source tracking in HDR brachytherapy., (© 2020 American Association of Physicists in Medicine.)

Purpose: To report on the accuracy of an in vivo dosimetry (IVD)-based source tracking (ST) method for high dose rate (HDR) prostate brachytherapy (BT)., Methods: The ST was performed on a needle-by-needle basis. A least square fit of the expected to the measured dose rate was performed using the active dwell positions in the given needle. Two fitting parameters were used to determine the position of each needle relative to the IVD detector: radial (away or toward the detector) and longitudinal (along the axis of the treatment needle). The accuracy of the ST was assessed in a phantom where the geometries of five HDR prostate BT treatments previously treated at our clinic were reproduced. For each of the five treatment geometries, one irradiation was performed with the detector placed in the middle of the implant. Furthermore, four additional irradiations were performed for one of the geometries where the detector was retracted caudally in four steps of 10-15 mm and up to 12 mm inferior of the most inferior active dwell position, which represented the prostate apex. The time resolved dose measurements were retrieved at a rate of 20 Hz using a detector based on an Al 2 O 3 :C radioluminescence crystal, which was placed inside a standard BT needle. Individual calibrations of the detector were performed prior to each of the nine irradiations., Results: Source tracking could be applied in all needles across all nine irradiations. For irradiations with the detector located in the middle region of the implant (a total of 89 needles), the mean ± standard deviation (SD, k = 1) accuracy was -0.01 mm ± 0.38 mm and 0.30 mm ± 0.38 mm in the radial and longitudinal directions, respectively. Caudal retraction of the detector did not lead to reduced accuracy as long as the detector was located superior to the most inferior active dwell positions in all needles. However, reduced accuracy was observed for detector positions inferior to the most inferior active dwell positions which corresponded to detector positions in and inferior to the prostate apex region. Detector positions in the prostate apex and 12 mm inferior to the prostate resulted in mean ± SD (k = 1) ST accuracy of 0.7 mm ± 1 mm and 2.8 mm ± 1.6 mm, respectively, in radial direction, and -1.7 mm ± 1 mm and -2.1 mm ± 1.1 mm, respectively, in longitudinal direction. The largest deviations for the configurations with those detector positions were 2.6 and 5.4 mm, respectively, in the radial direction and -3.5 and -3.8 mm, respectively, in the longitudinal direction., Conclusion: This phantom study demonstrates that ST based on IVD during prostate BT is adequately accurate for clinical use. The ST yields submillimeter accuracy on needle positions as long as the IVD detector is positioned superior to at least one active dwell position in all needles. Locations of the detector inferior to the prostate apex result in decreased ST accuracy while detector locations in the apex region and above are advantageous for clinical applications., (© 2021 American Association of Physicists in Medicine.)

Brachytherapy can deliver high doses to the target while sparing healthy tissues due to its steep dose gradient leading to excellent clinical outcome. Treatment accuracy depends on several manual steps making brachytherapy susceptible to operational mistakes. Currently, treatment delivery verification is not routinely available and has led, in some cases, to systematic errors going unnoticed for years. The brachytherapy community promoted developments in in vivo dosimetry (IVD) through research groups and small companies. Although very few of the systems have been used clinically, it was demonstrated that the likelihood of detecting deviations from the treatment plan increases significantly with time-resolved methods. Time-resolved methods could interrupt a treatment avoiding gross errors which is not possible with time-integrated dosimetry. In addition, lower experimental uncertainties can be achieved by using source-tracking instead of direct dose measurements. However, the detector position in relation to the patient anatomy remains a main source of uncertainty. The next steps towards clinical implementation will require clinical trials and systematic reporting of errors and near-misses. It is of utmost importance for each IVD system that its sensitivity to different types of errors is well understood, so that end-users can select the most suitable method for their needs. This report aims to formulate requirements for the stakeholders (clinics, vendors, and researchers) to facilitate increased clinical use of IVD in brachytherapy. The report focuses on high dose-rate IVD in brachytherapy providing an overview and outlining the need for further development and research., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: G. Paiva Fonseca and F. Verhaegen declares research collaborations with Varian Medical Systems., (© 2020 The Authors.)

Purpose: This paper presents a method to verify dwell times during High Dose Rate (HDR) Brachytherapy (BT) by means of in vivo dosimetry (IVD), and reports on an afterloader's stability in dwell time control., Methods: In vivo dosimetry was performed during 20 HDR prostate cancer treatments using a point detector based on a radio-luminescence crystal (Al 2 O 3 :C) coupled to a fiber-optic cable. The dose rate was recorded at either 10 Hz or 20 Hz during the treatments. The "time of transit" when the source moved between two dwell positions was identified using the difference in count rate between two measurements. The dwell times were then determined by subtracting two adjacent times of transit. The measured dwell times were matched with the planned dwell times and categorised into two groups: Dwell times matching a single dwell position (identified) and dwell times matching the sum of multiple dwell positions (unidentified). Deviations between measured and planned dwell times were calculated for the identified dwell positions., Results: A total of 3518 dwell positions were analysed. The amount of identified dwell positions were 82%, which increased to 89% if the short dwell times (<1 s) were omitted in the analysis. The largest deviation was -0.4 s seen for a single dwell position, and in 97.1% of the cases, the deviations were <0.15 s., Conclusion: The dwell times in BT are well controlled by the afterloader. It is shown that IVD facilitates the detection of dwell time offsets that could have a clinical impact., (Copyright © 2019 Associazione Italiana di Fisica Medica. Published by Elsevier Ltd. All rights reserved.)

Purpose: The purpose of this article is to demonstrate that brachytherapy source tracking can be realized with in vivo dosimetry. This concept could enable real-time treatment monitoring., Methods: In vivo dosimetry was incorporated in the clinical routine during high-dose-rate prostate brachytherapy at Aarhus University Hospital. The dosimetry was performed with a radioluminescent crystal positioned in a dedicated brachytherapy needle in the prostate. The dose rate was recorded every 50-100 ms during treatment and analyzed retrospectively. The measured total delivered dose and dose rates for each dwell position with dwell times >0.7 s were compared with expected values. Furthermore, the distance between the source and dosimeter, which was derived from the measured dose rates, was compared with expected values. The measured dose rate pattern in each needle was used to determine the most likely position of the needle relative to the dosimeter., Results: In total, 305 needles and 3239 dwell positions were analyzed based on 20 treatments. The measured total doses differed from the expected values by -4.7 ± 8.4% (1SD) with range (-17% to 12%). It was possible to determine needle shifts for 304 out of 305 needles. The mean radial needle shift between imaging and treatment was 0.2 ± 1.1 mm (1SD), and the mean longitudinal shift was 0.3 ± 2.0 mm (1SD)., Conclusion: Time-resolved in vivo dosimetry can be used to provide geometric information about the treatment progression of afterloading brachytherapy. This information may provide a clear indication of errors and uncertainties during a treatment and, therefore, enables real-time treatment monitoring., (Copyright © 2017 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.)

We review 25 patients with a spectrum of hindbrain (cerebellum, pons, and medulla) malformations from a cohort of children with high parental consanguinity rate. Twenty-three of the 25 patients were born to consanguineous parents. The patients were classified in four groups. Eleven patients of 6 families had malformation of the hindbrain and midbrain with molar tooth sign (10 patients of 5 families with typical Joubert syndrome), 5 patients showed severe supratentorial anomalies in addition to the hindbrain malformations, 5 patients had pontocerebellar or cerebellar hypoplasia with anterior horn cell disease in the spinal cord (spinal muscular atrophy), and 4 patients showed malformations affecting predominantly the hindbrain without substantial involvement of other systems. A locus for Joubert syndrome was previously identified on chromosome 9q34.3 in two families, and a second locus on chromosome 11p12-q13.3 in another family. A third Joubert syndrome locus has been mapped at 6q23 and a mutation in the AHI1 gene at this site has been found recently in a further family from this cohort. Delineation of homogeneous subgroups of patients with hindbrain malformations and molecular genetic analysis of these groups may lead to identification of further loci, genes and mutations responsible for the malformations., (Copyright (c) 2005 Wiley-Liss, Inc.)

A 1-year-old boy with extreme microcephaly and a complex brain malformation is reported. Magnetic resonance imaging revealed an abnormal gyral pattern with features of the agyria-pachygyria spectrum, partial agenesis of the corpus callosum, severely hypoplastic posterior cerebellar vermis, and an abnormal foliation pattern of the cerebellar hemispheres associated with a flat and wide isthmus and pons. Although this phenotype shares some features with malformations classified as microcephaly with a simplified gyral pattern, microlissencephaly, or lissencephaly with cerebellar hypoplasia, none of the several subgroups of these categories are identical to the cerebral dysgenesis found in this patient.

Two unrelated children and their siblings of Arab origin were diagnosed as having GM1 gangliosidosis on the basis of clinical features and markedly low levels of beta-galactosidase. The T2-weighted magnetic resonance images of the brain revealed certain characteristic features, including delayed myelination and abnormal appearance of the subcortical white matter, internal capsule, and basal ganglia. Their mutation analysis showed two novel mutations, which have not been described in an Arabic population.

Primary microcephaly is a heterogeneous group of cerebral malformations either with a relatively well-preserved or an abnormal gyral pattern. We describe the MRI findings and clinical features of 14 children with the combination of microcephaly and an abnormal gyral pattern. All children except one were Arabs and nine out of the 14 patients were born to consanguineous parents. Seven patients showed features of a simplified gyral pattern with relatively preserved posterior fossa structures. Two boys had a cortical malformation in the agyria-pachygyria spectrum; one of these two patients showed agenesis of the corpus callosum and severe cerebellar hypoplasia as well. The microcephaly was associated with polymicrogyria and leukoencephalopathy in two patients, with cortical dysplasia and hypogenesis of the corpus callosum in one patient, with agyria-pachygyria with callosal and pontocerebellar dysplasia in one patient, and a simplified gyral pattern with severe cerebellar hypoplasia in one case. One patient died in the neonatal period and three in infancy. All patients, who survived the neonatal period, had developmental delay, intellectual disability, and neurological deficits, and nine suffered from epilepsy.

Polymicrogyria is a brain malformation due to abnormal cortical organization. Two histological types, unlayered or four-layered can be distinguished. Polymicrogyria is a rare manifestation of chromosome 22q11 deletion syndrome. We report two boys with chromosome 22q11 deletion syndrome and polymicrogyria, and describe the neuropathological features of the malformation in one of them. Clinical examinations, EEG, brain MRI, chromosomal analysis with FISH, and neuropathological studies of surgically resected cortical tissue were performed. Both patients showed severe developmental delay with cardiovascular malformations and one of them had drug resistant epilepsy. Polymicrogyria was found in the frontal, parietal, and temporal areas, unilaterally in one patient and bilaterally in the other. Histology revealed four-layered polymicrogyria. The pathogenesis of polymicrogyria in 22q11 deletion syndrome is discussed., (Copyright 2004 Wiley-Liss, Inc.)

We report a girl who had Hirschsprung disease in association with distinct facial appearance, microcephaly, agenesis of the corpus callosum and mental retardation (Mowat-Wilson syndrome). Mutation analysis of the zinc finger homeo box 1 B (ZFHX1 B) gene revealed a de novo 7 bp deletion (TGGCCCC) at nucleotide 1773 (1773 delTGGCCCC) resulting in a frameshift and leading to a termination codon at amino acid residue 604 (604 X) in exon 8 C. The zinc finger homeo box 1 B (Smad interacting protein-1) is a transcription corepressor of Smad target genes with functions in the patterning of neural crest derived cells, CNS, and midline structures. Mutations in ZFHX1 B can lead to neurological disorders in addition to dysmorphic features, megacolon, and other malformations.

37 patients with penetrating injuries of the head or upper neck caused by gunshot wounds were admitted to the neurosurgical department during the ten-year period 1986 to 1995. There was a marked preponderance of males. 29 of the cases were attempted or successful suicides, four were homicides, and four were presumed to be accidents. The most common weapons used were pistol and rifle. Nine patients were under the influence of alcohol or drugs. There were eight survivors, seven of whom were operated on. Four of the patients suffered reduced vision, two of whom became blind. Two had hemiparesis, one had moderate mental dysfunction, and one recovered completely. None of the patients who were unconscious upon admission to hospital and had bilateral brain injury survived.

Summary: This study was carried out to assess anatomic variations and pathologic changes associated with a potentially increased risk of complications during percutaneous nucleotomy. The MRI and CT examinations of 88 patients were reviewed with regard to the positional relationship between the trajectory to the disc and the bowel and iliac vessels respectively at the L4-L5 and L5-S1 levels. Pathologic conditions involving the anterior part of the annulus were assessed both by MRI and by CT-discography of 97 discs. The shortest distance from the needle course to the bowels was 29 mm. At ten other disc levels this distance was less than 40 mm. The position of the bowels is influenced by the size of the patient, the size and course of the psoas muscles and the amount of retroperitoneal fat. The bowels are at greaten distance from the trajectory at the L5-S1 than at the L4-L5 level. The risk of bowel puncture seems to be minimal. The iliac vessels were positioned behind the midportion of the disc in three patients. There was greater variation and a shorter distance to the trajectory at the L5-S1 than at the L4-L5 level. Anterior disc hernias, and particularly severe annular degeneration involving the anterior part of the annulus are frequently seen. These conditions include a weakening of the annulus and may increase the risk of anterior perforation during nucleotomy.

The 8th of November marks the centennial of the discovery of Röntgen rays. This discovery occurred serendipitously during an experiment with cathode rays by the physicist Wilhelm Conrad Röntgen in Würzburg, Germany. Not many other discoveries in basic natural science have had such an enormous impact and immediate application in medicine. Röntgen had a Dutch connection, since he spent 17 years of his childhood and youth in the Netherlands. In his final school report, the only subject in which the later Nobel prize winner in physics received poor marks was physics! Notes released 70 years after Röntgen received his prize revealed that the Nobel Committee for Physics actually had recommended that the prize be divided equally between Röntgen and Philipp Lenard, another eminent German physicist.

Aims: The investigation was carried out in order to compare the accuracy of CT and MR imaging in depicting whether disk hernias were contained by the posterior longitudinal ligament (PLL). This is crucial in the evaluation of patients who are possible candidates for percutaneous nucleotomy, which is considered effective only in contained hernias., Results: Of 124 pathologic disks examined in 114 patients, CT was more accurate than MR imaging in 7 patients due to misinterpretation of the integrity of the PLL by MR. These hernias were therefore erroneously classified as noncontained. There was consistency between the classification by CT and MR imaging in the other 117 disks, of which 109 were correct. Both methods overstaged a large hernia that was contained by the PLL, and failed to demonstrate that 7 others were noncontained., Conclusions: CT, which has higher sensitivity in depicting calcifications, representing further contraindications to percutaneous nucleotomy, is therefore recommended as the primary examination in these patients. Additional MR imaging should be considered if the results of CT are equivocal or at variance with the clinical presentation.

Aims: The findings at CT-diskography (CT-D), including recording of the pain introduced at contrast injection, were compared with plain CT and MR imaging in 111 disks in 101 patients aged 18 to 68 years., Results: Six disks which were normal at CT had normal CT-D and 5 of them had normal signal on MR imaging. The degree of annular degeneration and the depth of the annular tears were significantly associated with each other and with loss of disk height, but not with size or location of the hernias. Only the depth of the tears was significantly associated with loss of signal on MR. However, frequently complete annular tears and severe annular degeneration were seen in association with small bulges and hernias, even in disks with normal or slightly reduced signal on MR and with normal height. The type and intensity of the pain introduced were associated with each other and with the depth of the annular tears, but not with the degree of annular degeneration, size of the hernia or the MR signal intensity of the disks., Conclusions: Annular degeneration and tears on one hand, and the type and intensity of pain introduced on the other, seem to be related than separate phenomena.

Percutaneous nucleotomy is designed to treat small and medium-sized contained disk hernias. It is offered to patients who have not responded to conservative treatment for three months or more. The nucleotomy procedure is well tolerated by a majority of patients and the rate of complications is low. The patients can be treated as out-patients. Among a total material of 130 patients, a primary good response to the treatment was observed in 81 (62%). However, owing to recurrencies the success rate had fallen to 52% at 12-39 months (mean 22 months) after nucleotomy. In selected patients with symptoms from one disk level only, and with no evidence of spinal stenosis, or of osteophyte formation or a narrowing of the disk space by more than 25%, the results were better. Here the success rate was 61% (70% in males and 50% in females).

The purpose of this study was to evaluate 2 years' experience with percutaneous automated nucleotomy. Adult patients with small to medium sized disk hernias corresponding to clinical symptoms, and without evidence of free fragments or stenosis were treated on an outpatient basis. All patients had sciatica and conservative treatment had failed for at least 3 months. Using the Nucleotome R system, access to the disk was achieved in all but 6 of 172 disks in 152 patients. Degenerative disk disease or pain was the reason for technical failures. Four other procedures were discontinued because of pain and moderate hemorrhage. Except for one case of diskitis, no serious complications occurred. Of the patients in a prospective study, 63 had a follow-up period of 4 months or more. The overall clinical success rate was 62%, and was not significantly influenced by patient sex or age, duration of symptoms, level treated, disk degeneration or amount of nucleus material removed. The results are promising; however, this study indicates a need for refined patient selection in order to decrease the number of failures.

A double-blind comparative study of the nonionic contrast medium iopentol and the ionic contrast medium metrizoate for urography was carried out in 200 adult outpatients. Significantly less discomfort and other side effects were observed following iopentol than following metrizoate. No serious adverse reactions and no clinically significant alterations in heart rate or blood pressure were observed. A questionnaire was used to record delayed symptoms, from 30 min after contrast medium injection and for one week. The response rate was 92% and delayed adverse events were reported by 45%. The incidence of delayed reactions was significantly lower following iopentol than following metrizoate, i.e., delayed arm pain, fatigue, headache, diarrhea, nasal congestion, and rash. Delayed arm pain was probably due to contrast medium induced thrombosis in 1% following iopentol and in 8% following metrizoate. Most other symptoms were probably related to a combination of nocebo effect and coincidentally occurring symptoms. The urograms with both media were of similar high quality. Iopentol was found a suitable contrast medium for urography.

The routine use of CT in 51 consecutive patients with squamous cell carcinoma of the larynx revealed cartilage involvement or extralaryngeal tumor growth consistent with a T4 tumor which made 14 patients candidates for laryngectomy. Only 5 of these had a T4 classification by clinical examination while 8 cases were upstaged from T3. Except for one supraglottic tumor upstaged from T2 to T4, CT did not change the classification for T1 and T2 tumors, whose localization was mainly glottic, and there were 2 false-negative examinations. It is concluded that CT is mandatory only in advanced tumors of the glottic region or when the anterior commissure is involved. However, in suspected malignancies of the sub- or supraglottic regions CT should always be carried out because these patients are at an increased risk of unexpected deep tumor growth.

In a double-blind investigation, 30 knee arthrographies were performed by injection of either Amipaque 290 mg I/ml or Urografin 60% (292 mg I/ml). Both contrast media are well tolerated, and give excellent initial contrast quality, which deteriorates rapidly. This occurs more slowly with Amipaque, which has lower osmolality and causes less joint effusion.

A case of bilateral clefts in the pedicles of the L1 vertebra, diagnosed by computed tomography, is presented. The differentiation from other clefts located laterally in the neural arch is briefly summarized, and the possible origin of this entity is discussed. It is improbable that the clefts represent persistent neurocentral synchondroses.