Respiration-controlled radiotherapy in lung cancer: Systematic evaluation of the optimal application practice.

Background and purpose: Definitive radiochemotherapy (RCT) for non-small cell lung cancer (NSCLC) in UICC/TNM I-IVA (singular, oligometastatic) is one of the treatment methods with a potentially curative concept. However, tumour respiratory motion during RT requires exact pre-planning. There are various techniques of motion management like creating internal target volume (ITV), gating, inspiration breath-hold and tracking. The primary goal is to cover the PTV with the prescribed dose while at the same time maximizing dose reduction of surrounding normal tissues (organs at risk, OAR). In this study, two standardized online breath-controlled application techniques used alternately in our department are compared with respect to lung and heart dose. Materials and methods: Twenty-four patients who were indicated for thoracic RT received planning CTs in voluntary deep inspiration breath-hold (DIBH) and in free shallow breathing, prospectively gated in expiration (FB-EH). A respiratory gating system by Varian (Real-time Position Management, RPM) was used for monitoring. OAR, GTV, CTV and PTV were contoured on both planning CTs. The PTV margin to the CTV was 5 mm in the axial and 6-8 mm in the cranio-caudal direction. The consistency of the contours was checked by elastic deformation (Varian Eclipse Version 15.5). RT plans were generated and compared in both breathing positions using the same technique, IMRT over fixed irradiation directions or VMAT. The patients were treated in a prospective registry study with the approval of the local ethics committee. Results: The PTV in expiration (FB-EH) was on average significantly smaller than the PTV in inspiration (DIBH): for tumours in the lower lobe (LL) 431.5 vs. 477.6 ml (Wilcoxon test for connected samples; p = 0.004), in the upper lobe (UL) 659.5 vs. 686.8 ml (p = 0.005). The intra-patient comparison of plans in DIBH and FB-EH showed superiority of DIBH for UL-tumours and equality of DIBH and FB-EH for LL-tumours. The dose for OAR in UL-tumours was lower in DIBH than in FB-EH (mean lung dose p = 0.011; lungV20, p = 0.002; mean heart dose p = 0.016). The plans for LL-tumours in FB-EH showed no difference in OAR compared to DIBH (mean lung dose p = 0.683; V20Gy p = 0.33; mean heart dose p = 0.929). The RT setting was controlled online for each fraction and was robustly reproducible in FB-EH. Conclusion: RT plans for treating lung tumours implemented depend on the reproducibility of the DIBH and advantages of the respiratory situation with respect to OAR. The primary tumour localization in UL correlates with advantages of RT in DIBH, compared to FB-EH. For LL-tumours there is no difference between RT in FB-EH and RT in DIBH with respect to heart or lung exposure and therefore, reproducibility is the dominant criterion. FB-EH is recommended as a very robust and efficient technique for LL-tumours.

Cardiac fibroblast activation detected by Ga-68 FAPI PET imaging as a potential novel biomarker of cardiac injury/remodeling.

BACKGROUND: Fibroblast activation protein (FAP) as a specific marker of activated fibroblasts can be visualized by positron emission tomography (PET) using Ga-68-FAP inhibitors (FAPI). Gallium-68-labeled FAPI is increasingly used in the staging of various cancers. In addition, the first cases of theranostic approaches have been reported. In this work, we describe the phenomenon of myocardial FAPI uptake in patients who received a Ga-68 FAPI PET for tumor staging. METHOD AND RESULTS: Ga-68 FAPI PET examinations for cancer staging were retrospectively analyzed with respect to cardiac tracer uptake. Standardized uptake values (SUV) were correlated to clinical covariates in a univariate regression model. From 09/2018 to 11/2019 N = 32 patients underwent FAPI PET at our institution. Six out of 32 patients (18.8%) demonstrated increased localized myocardial tracer accumulation, with remote FAPI uptake being significantly higher in patients with vs without localized focal myocardial uptake (SUVmax 2.2 ± .6 vs 1.5 ± .4, P < .05 and SUVmean 1.6 ± .4 vs 1.2 ± .3, P < .05, respectively). Univariate regression demonstrated a significant correlation of coronary artery disease (CAD), age and left ventricular ejection fraction (LVEF) with remote SUVmean uptake, the latter with a very strong correlation with remote uptake (R2 = .74, P < .01). CONCLUSION: Our study indicates an association of CAD, age, and LVEF with FAPI uptake. Further studies are warranted to assess if fibroblast activation can be reliably measured and may be used for risk stratification regarding early detection or progression of CAD and left ventricular remodeling.

ANTECEDENTES: Proteína de activación de fibroblastos (FAP) como marcador específico de fibroblastos maduros activados se puede visualizar mediante tomografía por emisión de positrones (PET) usando inhibidores de Ga-68-FAP (FAPI). El FAPI marcado con galio 68 se usa cada vez más en la estatificación de varios tipos de cáncer.Además, se han reportado los primeros casos de abordajes teranósticos. En este trabajo describimos el fenómeno de la captación de FAPI miocárdica en pacientes que recibieron Ga-68 FAPI PET para estatificación tumoral. MéTODO Y RESULTADOS: Los exámenes de PET Ga-68 FAPI para estadificación de cáncer se analizaron retrospectivamente con respecto a la captación del marcador cardíaco. Los valores de absorción estandarizados (SUV) se correlacionaron con covariables clínicas en un modelo de regresión univariante. Del 09/2018 al 11/2019 con una n = 32 pacientes fueron sometidos a PET FAPI en nuestra institución. Seis de 32 pacientes (18.8%) demostraron un aumento de acumulación del marcador localizado en el miocardio, con la captación remota de FAPI siendo significativamente mayor en pacientes con aumento de la captación vs sin captación focalizada de miocardio (SUVmax 2.2 ± 0.6 vs. 1.5 ± 0.4, p <0.05 y SUV mean 1.6 ± 0.4 vs. 1.2 ± 0.3, p <0.05, respectivamente). La regresión univariante demostró una correlación significativa de la enfermedad de la arteria coronaria (CAD), la edad y la fracción de eyección ventricular izquierda (FEVI) con absorción SUV remota, esta última con una muy fuerte correlación con la captación remota (R² = 0.74, p <0.01). CONCLUSIóN: Nuestro estudio indica una asociación de CAD, edad y FEVI con la captación de FAPI. Se necesitan más estudios para evaluar si la activación de fibroblastos se puede medir de manera confiable y se puede usar para la estratificación de riesgo con respecto a la detección temprana o la progresión de la CAD y la remodelación ventricular izquierda.

CONTEXTE: La protéine d'activation des fibroblastes (FAP) activés et matures peut être visualisée par tomographie à émission de positons (TEP) à l'aide d'inhibiteurs de l'activation des fibroblastes (FAPI). FAPI marqué au gallium 68 est de plus en plus utilisé dans la stratification de divers cancers. De plus, les premiers exemples d'approches théranostiques ont été rapportés. Dans ce travail nous décrivons la captation myocardique de FAPI chez les patients qui bénéficié d'une TEP au Ga-68 FAPI pour stratification tumorale. MéTHODE ET RéSULTATS: Les examens TEP Ga-68 FAPI pour la stratification oncologique ont été analysés rétrospectivement pour l'absorption du traceur au niveau cardiaque. Les valeurs d'absorption normalisées (SUV) font été corrélées aux variables cliniques selon un modèle de régression univarié. A partir de septembre 2018 jusqu'en novembre 2019, 32 patients ont bénéficié d'une TEP FAPI dans notre établissement. Six de nos 32 patients (18,8%) ont démontré une augmentation focale de captation du tracer au niveau myocardique. Les foyers systémiques se sont révélés significativement plus élevé chez les patients avec foyers myocardiques localisés (SUV max 2,2 ± 0,6 vs 1,5 ± 0,4, p <0,05 et SUV mean 1,6 ± 0,4 vs 1,2 ± 0,3, p <0,05, respectivement). Nous avons observé une corrélation significative entre la maladie coronarienne, l'âge, la fraction d'éjection du ventricule gauche et la présence de foyer myocardiques FAPI (R² = 0,74, p <0,01) CONCLUSION: Notre étude indique une association entre la maladie cardiovasculaire coronarienne, l'âge et la FEVG et la captation myocardique de FAPI. Des études additionnelles sont nécessaires pour déterminer si l'activation des fibroblastes peut être mesurée de manière fiable et utilisée pour la détection et la progression de la maladie coronarienne et le remodelage du ventricule gauche.

Combined radiotherapy and concurrent tumor treating fields (TTFields) for glioblastoma: Dosimetric consequences on non-coplanar IMRT as initial results from a phase I trial.

BACKGROUND: Glioblastoma is a rapidly proliferating tumor. Patients bear an inferior prognosis with a median survival time of 14-16 months. Proliferation and repopulation are a major resistance promoting factor for conventionally fractionated radiotherapy. Tumor-Treating-Fields (TTFields) are an antimitotic modality applying low-intensity (1-3 V/cm), intermediate-frequency (100-300 kHz) alternating electric-fields. More recently interference of TTFields with DNA-damage-repair and synergistic effects with radiotherapy were reported in the preclinical setting. This study aims at examining the dosimetric consequences of TTFields applied during the course of radiochemotherapy. METHODS: Cone-beam-computed-tomography (CBCT)-data from the first seven patients of the PriCoTTF-phase-I-trial were used in a predefined way for dosimetric verification and dose-accumulation of the non-coplanar-intensity-modulated-radiotherapy (IMRT)-treatment-plans as well as geometric analysis of the transducer-arrays by which TTFields are applied throughout the course of treatment. Transducer-array-position and contours were obtained from the low-dose CBCT's routinely made for image-guidance. Material-composition of the electrodes was determined and a respective Hounsfield-unit was assigned to the electrodes. After 6D-fusion with the planning-CT, the dose-distribution was recalculated using a Boltzmann-equation-solver (Acuros XB) and a Monte-Carlo-dose-calculation-engine. RESULTS: Overdosage in the scalp in comparison to the treatment plan without electrodes stayed below 8.5% of the prescribed dose in the first 2 mm below and also in deeper layers outside 1cm2 at highest dose as obtained from dose-volume-histogram comparisons. In the clinical target volume (CTV), underdosage was limited to 2.0% due to dose attenuation by the electrodes in terms of D95 and the effective-uniform-dose. Principal-component-analysis (PCA) showed that the first principal-position-component of the variation of repeated array-placement in the direction of the largest variations and the perpendicular second-component spanning a tangential plane on the skull had a standard deviation of 1.06 cm, 1.23 cm, 0.96 cm, and 1.11 cm for the frontal, occipital, left and right arrays for the first and 0.70 cm, 0.71 cm, 0.79 cm, and 0.68 cm, respectively for the second-principal-component. The variations did not differ from patient-to-patient (p > 0.8, Kruskal-Wallis-tests). This motion led to a diminution of the dosimetric effects of the electrodes. CONCLUSION: From a dosimetric point of view, dose deviations in the CTV due to transducer-arrays were not clinically significant in the first 7 patients and confirmed feasibility of combined adjuvant radiochemotherapy and concurrent TTFields. PriCoTTF Trial: A phase I/II trial of TTFields prior and concomitant to radiotherapy in newly diagnosed glioblastoma. DRKS-ID: DRKS00016667. Date of Registration in DRKS: 2019/02/26. Investigator Sponsored/Initiated Trial (IST/IIT): yes. Ethics Approval/Approval of the Ethics Committee: Approved. (leading) Ethics Committee Nr.: 18-8316-MF, Ethik-Kommission der Medizinischen. Fakultät der Universität Duisburg-Essen. EUDAMED-No. (for studies acc. to Medical Devices act): CIV-18-08-025247.

Radiation exposure of image-guided intrathecal administration of nusinersen to adult patients with spinal muscular atrophy.

PURPOSE: To examine diagnostic reference levels (DRL) and achievable doses (AD) of image-guided and size-specific dose estimates (SSDE) and organ and effective doses of CT-guided intrathecal nusinersen administration to adult patients with spinal muscular atrophy (SMA). METHODS: This study involved a total of 60 image-guided intrathecal nusinersen treatments between August 2017 and June 2018. Patient cohort comprised 14 adult patients with the following SMA types: type 2 (n = 9) and type 3 (n = 5) with a mean age of 33.6 years (age range 25-57 years). DRL, AD, SSDE, organ, and effective doses were assessed with a dose-monitoring program based on the Monte Carlo simulation techniques. RESULTS: DRL and AD for computed tomography are summarised as follows: in terms of CT-dose index (CTDIvol), DRL 56.4 mGy and AD 36.7 mGy; in terms of dose-length product (DLP), DRL 233.1 mGy cm and AD 120.1 mGy cm. DRL and AD for fluoroscopic guidance were distributed as follows: in terms of dose-area product (DAP), DRL 239.1 µGy m2 and AD 135.2 mGy cm2. Mean SSDE was 9.2 mGy. Mean effective dose of the CT-guided injections was 2.5 mSv (median 2.0 mSv, IQR 1.3-3.2 mSv). Highest organ doses in the primary beam of radiation were the small intestine 12.9 mSv, large intestine 9.5 mSv, and ovaries 3.6 mSv. CONCLUSION: Radiation exposure of SMA patients measured as DRLs is generally not higher compared with patients without SMA despite severe anatomical hazards. Dose monitoring data may allow clinicians to stratify radiation risk, identify organs at risk, and adopt measures for specific radiation dose reduction.

Comparison of eye-lens doses imparted during interventional and non-interventional neuroimaging techniques for assessment of intracranial aneurysms.

BACKGROUND: A neurointerventional examination of intracranial aneurysms often involves the eye lens in the primary beam of radiation. OBJECTIVE: To assess and compare eye-lens doses imparted during interventional and non-interventional imaging techniques for the examination of intracranial aneurysms. METHODS: We performed a phantom study on an anthropomorphic phantom (ATOM dosimetry phantom 702-D; CIRS, Norfolk, Virginia, USA) and assessed eye-lens doses with thermoluminescent dosimeters (TLDs) type 100 (LiF:Mg, Ti) during (1) interventional (depiction of all cerebral arteries with triple 3D-rotational angiography and twice 2-plane DSA anteroposterior and lateral projections) and (2) non-interventional (CT angiography (CTA)) diagnosis of intracranial aneurysms. Eye-lens doses were calculated following recommendations of the ICRP 103. Image quality was analysed in retrospective by two experienced radiologists on the basis of non-interventional and interventional pan-angiography examinations of patients with incidental aneurysms (n=50) on a five-point Likert scale. RESULTS: The following eye-lens doses were assessed: (1) interventional setting (triple 3D-rotational angiography and twice 2-plane DSA anteroposterior and lateral projections) 12 mGy; (2) non-interventional setting (CTA) 4.1 mGy. Image quality for depiction of intracranial aneurysms (>3 mm) was evaluated as good by both readers for both imaging techniques. CONCLUSIONS: Eye-lens doses are markedly higher during the interventional than during the non-interventional diagnosis of intracranial aneurysms. For the eye-lens dose, CTA offers considerable radiation dose savings in the diagnosis of intracranial aneurysms.

Comparison of radiation doses imparted during 128-, 256-, 384-multislice CT-scanners and cone beam computed tomography for intra- and perioperative cochlear implant assessment.

PURPOSE: To examine radiation-doses imparted during multislice (MSCT) and cone-beam computed-tomography (CBCT) for perioperative examination of cochlear-implant insertion. METHODS: Radiation-doses were assessed during standardized petrous-bone CT-protocols at different MSCT ((I) single-source CT-scanner Somatom-Definition-AS+, (II) 2nd generation of dual-source CT-scanner Somatom-Definition-Flash, (III) 3rd generation of dual-source CT-scanner Somatom-Force and at the CBCT Ziehm-Vision-RFD3D ((IV) (a) RFD-3D (Standard-modifier), (b) RFD-3D (Low-dose-modifier)). Image quality was examined by two radiologists appraising electrode-array placement, quality-control of cochlear-implant surgery and complications based on real patients' examinations (n=78). RESULTS: In MSCT-setting following radiation-doses were assessed (CTDIw; DLP): (I) 21.5mGy; 216mGycm; (II) 19.7mGy; 195mGycm; (III) 12.7mGy; 127mGycm; in the CBCT setting radiation doses were distributed as follows: (IV) (a) 1.9mGy; 19.4mGycm; (b) 1.2mGy; 12.9mGycm. Overall, image quality was evaluated as good for both, MSCT- and CBCT-examinations, with a good interrater reliability (r=0.81). CONCLUSION: CBCT bears considerable dose-saving potential for the perioperative examination of cochlear-implant insertion while maintaining adequate image quality.

Perception of emotional prosody in adults with attention deficit hyperactivity disorder.

OBJECTIVE: Attention deficit hyperactivity disorder (ADHD) is associated with social conflicts. The purpose of this study was to explore domains of social cognition in adult patients with ADHD. METHODS: The assessment of social cognition was based on established neuropsychological tests: the Tübinger Affect Battery (TAB) for prosody and the Cambridge Behaviour Scale (CBS) for empathy. The performance of adults with ADHD (N = 28) was compared with the performance of a control group (N = 29) matched according to basic demographic variables. RESULTS: Treatment-naïve adults with ADHD showed deficits in emotional prosody (P = 0.02) and in the ability to empathize (P < 0.02) independent of executive functioning. In particular, their ability to perceive angry feelings was found to be compromised (P = 0.04). When emotional prosody was considered in relation to facial expressions, patients and controls showed no impairments (P > 0.2). No gender differences concerning social cognitive skills were detected. CONCLUSIONS: ADHD is associated with social cognition impairments involving both emotional prosody and empathy.

Efficacy of high-pitch CT protocols for radiation dose reduction.

Various strategies have been developed to reduce radiation exposure of patients in CT examinations. The aim of this study was to evaluate the efficacy of high pitch in representative CT protocols examining lung embolism. We performed thermoluminescence measurements with an anthropomorphic phantom exposing it to CT algorithms for lung embolism in a 128-multislice, dual-source CT scanner: a standard CT protocol (sCT) and a CT protocol with a high pitch (+ F). Radiation doses for both CT algorithms were compared and the dose reduction potential of high pitch for individual organs was evaluated. As expected, the +F mode reduced the effective dose and organ doses in the primary beam of radiation (namely, lung, bone marrow, heart, breast, skin and skeleton) compared with sCT by up to 52% for an equivalent image quality. On the contrary, for organs at the margin of the primary beam (thymus, thyroid, liver, pancreas, kidneys, colon and small intestine), the +F mode reduced effective radiation doses by only 0-30%, compared with sCT. The dose reduction potential of the +F mode greatly depends on the position of the organ in the scan field. While for organs in the primary beam + F leads to a considerable dose reduction, it is less effective for tissues at the margin of the scanned area.

Dose comparison of classical 2-plane DSA and 3D rotational angiography for the assessment of intracranial aneurysms.

INTRODUCTION: The purpose of this experimental phantom study was to compare radiation doses imparted to patients undergoing classical two-plane digital subtraction angiography (2-plane DSA) and 3D rotational angiography in interventional neuroradiology. METHODS: Thermoluminescence dosimeter (TLD) measurements were performed at an anthropomorphic phantom using a digital interventional angiography system. Two-plane DSA included posterior/anterior (PA) and lateral (LAT) projections (frame-rate, 7.6 frames (PA) and 9.8 frames (LAT) for a scan time of approximately 8 s; image intensifier 27 cm (PA) and 25 cm (LAT)). For 3D rotational angiography, 122 images were acquired from one single image run with the imaging system rotating 240° around the phantom's head (image intensifier 37 cm). RESULTS: Effective dose was 0.4 mSv for 2-plane DSA compared to 0.1 mSv for 3D rotational angiography. Organ doses were approximately two to five times higher for classical 2-plane technique compared to the 3D rotational angiography, respectively: brain (11.4 vs. 2.4 mSv), eye lens (4.5 vs.1 mSv), salivary glands (7 vs. 1,7 mSv), oral mucosa (2.7 vs.0.9 mSv), thyroid (0.5 vs. 0.2 mSv), thymus (0.2 vs. 0.05 mSv), bone marrow within imaged region (1 vs. 0.2 mSv), oesophagus (0.07 vs. 0.03 mSv), endotracheal system (2.6 vs. 0.7 mSv) and skeletal components in the imaged region (0.7 vs. 0.2 mSv). CONCLUSION: Three-dimensional rotational angiography clearly reduces radiation doses compared to the classical 2-plane technique. Replacement of additional 2-plane DSA projections with 3D rotational angiography will lead to a remarkable decrease in patient radiation dose, without loss of image quality. Thus, we recommend routine application of 3D rotational angiography, in particular for diagnostic assessment of aneurysm morphology.

Impact of the scout view orientation on the radiation exposure and image quality in thoracic and abdominal CT.

OBJECTIVES: To assess the impact of the scout view orientation on radiation exposure and image quality in thoracoabdominal CT, when automated tube voltage selection (ATVS) and automated tube current modulation (ATCM) are used in combination with scan planning on a single scout view. METHODS: Fifty patients underwent two thoracoabdominal CT examinations, one planned on an anteroposterior scout view, one planned on a lateral scout view. Both examinations included contrast-enhanced imaging of chest (CH) and abdomen (AB) and non-contrast-enhanced imaging of the liver (LI). For all examinations the same imaging protocol was used on the same dual-source CT scanner. The radiation exposure was recorded and objective as well as visual image quality was assessed for all examinations. RESULTS: The median dose-length product was significantly lower in scans planned on a lateral scout view (CH: 179 vs. 218 mGy*cm, LI: 148 vs. 178 mGy*cm, AB: 324 vs. 370 mGy*cm, p < 0.0001). Objective image quality was marginal lower in scans planned on a lateral scout view, whereas the visual image quality was rated as equal. CONCLUSION: At the tested radiation doses, the orientation of the scout view has a significant impact on the radiation exposure but no clinically relevant impact on the image quality. KEY POINTS: • The scout view orientation has a significant impact on the radiation exposure. • The scout view orientation has no clinically relevant impact on image quality. • A lateral scout view should be preferred with regard to radiation exposure.