Focused ultrasound (FUS) has become an important non-invasive therapy for solid tumor ablation via thermal effects. The cavitation effect induced by FUS is thereby avoided but applied for lithotripsy, support drug delivery and the induction of blood vessel destruction for cancer therapy. In this study, head and neck cancer (FaDu), glioblastoma (T98G), and prostate cancer (PC-3) cells were exposed to FUS by using an in vitro FUS system followed by single-dose X-ray radiation therapy (RT) or water bath hyperthermia (HT). Sensitization effects of short FUS shots with cavitation (FUS-Cav) or without cavitation (FUS) to RT or HT (45 °C, 30 min) were evaluated. FUS-Cav significantly increases the sensitivity of cancer cells to RT and HT by reducing long-term clonogenic survival, short-term cell metabolic activity, cell invasion, and induction of sonoporation. Our results demonstrated that short FUS treatment with cavitation has good potential to sensitize cancer cells to RT and HT non-invasively.

No description available.

ABSTRACT Erythema is a well-documented early indicator of tissue injury resulting from exposure to high doses of ionizing radiation. Close monitoring of radiation-induced injury to the skin can help identify opportunities for early interventions that may prevent or reduce more severe reactions. The gold standard for monitoring erythema is visual assessment (VA) by a trained clinician. This method has been criticized for being subjective and designed with very broad categorical descriptors. This work introduces a newly developed VA scale called the clinician erythema assessment for radiation therapy (CEA-RT).The reliability and accuracy of the CEA-RT scale was tested among 20 radiation therapists who trained to use the scale on digital images of radiation induced erythema. CEA-RT demonstrated to be highly reliable when therapist’s grades were compared to themselves, but moderately accurate when therapist’s grades were compared to each. A follow-up study with real patients and fewer but more extensively trained raters was proposed to demonstrate the grading accuracy of the CEA-RT scale. As an alternatively to VA, spectroscopy has the ability to monitor erythema by measuring the change in concentration of hemoglobin (Hb) within the vessels of the skin. These changes in Hb concentration are linked to the degree of erythema. This thesis also investigated the use of hyperspectral imaging (HSI) and diffuse reflectance spectroscopy (DRS) as potential technological alternatives for evaluating erythema. In a second study, Erythema was artificially induced in 3 volunteers who participated in a pilot study designed to assess the ability of an experimental HSI camera to detect skin changes. The data extracted from the hyperspectral images was found to effectively yield spectral profiles and Dawson’s erythema indices (EI) in agreement with the erythema grades assigned by the gold standard therefore showing HSI to be a viable alternative of assessing erythema. Finally, a third study compared DRS measurements to VA using the CEA-RT scale. The DRS system was previously used to measure in vivo erythema but did not compare spectral measurements to an accepted standard. Ten patient volunteers received daily DRS and VA evaluations for a period of 2 to 4 weeks. The results demonstrated that the Dawson’s EI calculated from the spectral data correlated well with the gold standard (VA grades) and that DRS is able to detect changes in the skin throughout the course of radiation treatments. / Thesis / Master of Science (MSc)

We aimed to evaluate possible factors influencing the long-term survival of teeth after tumor therapy to the head and neck region with and without radiation. Between January 2019 and January 2020, patients who underwent for head and neck cancer and received dental treatment before and after at the Department of Prosthetic Dentistry of the Martin Luther University Halle- Wittenberg were enrolled in the study. Clinical examination with assessment of dental status and stimulated salivary flow rate (SFR) was performed and information about disease progression and therapy was retrieved from medical records. Of 118 patients (male: 70.3%; mean age: 63.2 12.4 years), 95 received radiotherapy (RT), and 47 were administered radio-chemotherapy (RCT). The teeth of irradiated patients exhibited a lower 5-year survival probability (74.2%) than those of nonirradiated patients (89.4%). The risk of loss (RL) after RT increased with nicotine use, presence of intraoral defects, reduced SFR, RCT and regarding mandibular teeth, and decreased with crowning following. Lower SFR increased the RL even without RT. Consideration of patient’s treatment history, individual risk profile, and clinical findings during the prosthetic planning phase could enable earlier, more targeted dental treatment after (e.g., timely crowning).

La radiothérapie stéréotaxique corporelle (SBRT) est une technique couramment employée pour le traitement de tumeurs aux poumons lorsque la chirurgie n’est pas possible ou refusée par le patient. Une complication de l’utilisation de cette méthode provient du mouvement de la tumeur causé par la respiration. Dans ce contexte, la radiothérapie asservie à la respiration (RGRT) peut être bénéfique. Toutefois, la RGRT augmente le temps de traitement en raison de la plus petite proportion de temps pour laquelle le faisceau est actif. En utilisant un faisceau de photons sans filtre égalisateur (FFF), ce problème peut être compensé par le débit de dose plus élevé d’un faisceau FFF. Ce mémoire traite de la faisabilité d’employer la technique de RGRT en combinaison avec l’utilisation un faisceau FFF sur un accélérateur Synergy S (Elekta, Stockholm, Suède) avec une ceinture pneumatique, le Bellows Belt (Philips, Amsterdam, Pays-Bas), comme dispositif de suivi du signal respiratoire. Un Synergy S a été modifié afin de pouvoir livrer un faisceau 6 MV FFF. Des mesures de profils de dose et de rendements en profondeur ont été acquises en cuve à eau pour différentes tailles de champs. Ces mesures ont été utilisées pour créer un modèle du faisceau 6 MV FFF dans le système de planification de traitement Pinnacle3 de Philips. Les mesures ont été comparées au modèle à l’aide de l’analyse gamma avec un critère de 2%, 2 mm. Par la suite, cinq plans SBRT avec thérapie en arc par modulation volumétrique (VMAT) ont été créés avec le modèle 6 MV du Synergy S, avec et sans filtre. Une comparaison des paramètres dosimétriques a été réalisée entre les plans avec et sans filtre pour évaluer la qualité des plans FFF. Les résultats révèlent qu’il est possible de créer des plans SBRT VMAT avec le faisceau 6 MV FFF du Synergy S qui sont cliniquement acceptables (les crières du Radiation Therapy Oncology Group 0618 sont respectés). Aussi, une interface physique de RGRT a été mise au point pour remplir deux fonctions : lire le signal numérique de la ceinture pneumatique Bellows Belt et envoyer une commande d’irradiation binaire au linac. L’activation/désactivation du faisceau du linac se fait par l’entremise d’un relais électromécanique. L’interface comprend un circuit électronique imprimé fait maison qui fonctionne en tandem avec un Raspberry Pi. Un logiciel de RGRT a été développé pour opérer sur le Raspberry Pi. Celui-ci affiche le signal numérique du Bellows Belt et donne l’option de choisir les limites supérieure et inférieure de la fenêtre d’irradiation, de sorte que lorsque le signal de la ceinture se trouve entre ces limites, le faisceau est actif, et inversement lorsque le signal est hors de ces limites. Le logiciel envoie donc une commande d’irradiation au linac de manière automatique en fonction de l’amplitude du signal respiratoire. Finalement, la comparaison entre la livraison d’un traitement standard sans RGRT avec filtre par rapport à un autre plan standard sans RGRT sans filtre démontre que le temps de traitement en mode FFF est réduit en moyenne de 54.1% pour un arc. De la même manière, la comparaison entre la livraison d’un traitement standard sans RGRT avec filtre par rapport à un plan de RGRT (fenêtre d’irradiation de 75%) sans filtre montre que le temps de traitement de RGRT en mode FFF est réduit en moyenne de 27.3% par arc. Toutefois, il n’a pas été possible de livrer des traitements de RGRT avec une fenêtre de moins de 75%. Le linac ne supporte pas une fréquence d’arrêts élevée. / Stereotactic body radiation therapy (SBRT) is a technique commonly employed for treatment of lung tumors when surgery is not possible or not accepted by the patient. One complication arising from the use of this method comes from the movement of the tumor during respiration. In this context, respiratory gated radiation therapy (RGRT) can be beneficial. By using a flattening filter free (FFF) photon beam, the increase in treatment time caused by a reduced beam-on time of respiratory gated methods can be compensated by the inherent increased dose rate of FFF beams. This thesis reports on the feasibility of using the RGRT technique in combination with the use of a FFF photon beam on a Synergy S (Elekta, Stockholm, Sweden) linear accelerator with a pneumatic belt, the Bellows Belt (Philips, Amsterdam, Netherlands), to monitor the patient’s respiratory signal. A Synergy S has been modified to deliver a 6 MV FFF photon beam. Dose profile and percentage depth dose measurements were taken in a water tank for different field sizes. Those measurements were used to create a model for the 6 MV FFF beam with the Pinnacle3 treatment planning system from Philips. Measurements were compared with the model using gamma index analysis with a 2%, 2 mm criterion. Then, five SBRT plans with volumetric modulated arc therapy (VMAT) were created in Pinnacle3 with the 6 MV Synergy S model, with and without a flattening filter. A comparison of dosimetric parameters was made between plans with and without a flattening filter to estimate the quality of the FFF plans. Results reveal that it is possible to create SBRT VMAT plans with the 6 MV FFF model of the Synergy S that are clinically acceptable (criteria of the Radiation Therapy Oncology Group 0618 were respected). Also, a RGRT hardware interface was created to fulfill two main functions: read the digital signal from the Bellows Belt pneumatic belt and send an on/off irradiation command to the linac. The activation/deactivation of the beam is regulated by an electromechanical relay. The interface is composed of a homemade printed circuit board that functions with a Raspberry Pi. A RGRT software was also developed to operate on the Raspberry Pi. This software shows the Bellows Belt’s digital signal and gives the option of choosing the upper and lower limits of the gating window. When the respiratory signal of the belt is between those limits, the beam is active, and vice versa when the signal is outside those limits. The software thus effectively sends an on/off irradiation command automatically to the linac depending on the amplitude of the respiratory signal. Finally, a comparison between the delivery of a standard plan without RGRT, with filter, and another standard plan without RGRT, without filter, shows that the treatment time for plans using the FFF beam is reduced by 54.1% on average for one arc. Similarly, a comparison between the delivery of a standard plan without RGRT, with filter, and a gated plan (gating window of 75%), without filter, shows that the treatment time for the gated treatments is reduced by 27.3% on average for one arc. However, it was not possible to deliver RGRT treatments with a gating window smaller than 75%. The linac does not support such a high frequency of beam halting.

Stereotaktische Strahlenchirurgie und -therapie (SRS/SRT) weisen sich durch sehr konformale und hochpräzise Dosisverteilungen aus. Im Kopfbereich ist SRS/SRT eine etablierte Behandlungsmethode. Um diese Technik in anderen Körperregionen anwenden zu können, wurden verschiedene Positionierungs- und Fixierungsmethoden, sowie der Einsatz von 9 verschiedene Bestrahlungstechniken untersucht. Es wurde auch die Genauigkeit von 2 Dosisalgorithmen evaluiert. Jeweils eine thermoplastische Maske für den Kopf- und den Kopf-Hals-Bereich, sowie ein Doppelvakuumsystem für extrakraniale Regionen wurden untersucht. Die Kopfmaske erreichte im Durchschnitt eine Genauigkeit von 1,8mm (Fehler 0,9mm), mit einem Oberkiefersupport auf 0,96mm +/- 0,25mm. Die Kopf-Hals-Maske zeigte mit 0,7mm +/- 0,4mm, dass ihre Verwendung in der SRS/SRT möglich ist. Für die Genauigkeit des Doppelvakuums wurde durchschnittlich 7,0mm +/-3,5mm ermittelt. Relativ zum Vakuumkissen wurde eine Genauigkeit von 1,6mm +/- 1,87mm gemessen. Evaluierungsmethoden waren IR-Marker, die mittels Zahnabdruck am Patienten fixiert wurden und fusionierte Wiederholungs-CTs, in denen die Verschiebung von Landmarken am Positionierungssystem und im Patienten vermessen wurden. Bei den Bestrahlungstechniken sind 3 Techniken durch gute Ergebnisse aufgefallen. Stehfeldtechnik, dynamischer Arc und IMRT zeigten mit einem 3mm-mMLC hohe Konformität und Homogenität auf. Die ersten beiden Techniken erreichten steile Dosisgradienten, wohingegen die IMRT bei komplexen Zielgebieten und nahen Risikostrukturen auffiel und immer die geforderte 90%-Umschließende erreichte. Die Verifizierung der Dosisalgorithmen erfolgte anhand von Filmen. 8 Pläne wurden jeweils auf einem Film in Isozentrumsebene abgebildet und ein Vergleich mit der berechneten Dosis von Clarkson- und Pencil-Beam-Algorithmus mit Hilfe der Gamma-Evaluation durchgeführt. Beide Algorithmen sind für die SRS/SRT geeignet, der Pencil-Beam-Algorithmus zusätzlich für die IMRT verwendbar. / Stereotactic radiation surgery and therapy (SRS/SRT) are able to deliver conformal and precise dose distributions. For brain lesions SRS/SRT is a well-established technique. Its success increases interest to use it in other areas of the body. For this, evaluation of different patient positioning and treatment techniques, as well as dose algorithms have been performed. As patient fixation and positioning systems, 2 thermoplastic masks were evaluated for lesions located in the brain and the head and neck. In addition a double vacuum system for extra cranial treatments was used. The precision for the head mask was on average 1,8mm +/- 0,9mm, with an upper jaw support 0,9mm +/- 0,25mm. The head and neck mask realized a reproducibility of 0,7mm +/- 0,4mm and proved its use for SRS/SRT. For extra cranial positioning an average lesion misplacement of 7,0 mm +/-3,5 mm was measured. Relative to the vacuum cushion the accuracy was measured to be 1,6mm +/- 1,9mm. Infrared reflecting marker fixed precisely (+/- 0,6mm) with a dental impression and repeated CTs fused and landmark evaluated were successfully used to evaluate the patient fixation and positioning devices. 3 out of 9 treatment techniques had outstanding results. Static beams, dynamic arcs and IMRT all performed with a 3mm-mMLC showed a high conformity and homogeneity. The first two showed steep dose gradients and the later coped best with complex target shapes, close-by risk organs, and achieving 90% dose coverage. Verification of 2 algorithms was established with film. 8 plans were irradiated on film at isocenter and compared to calculations with Clarkson and pencil beam algorithm. Final evaluation was done using Gamma evaluation. Both algorithms showed their ability for SRS/SRT. The pencil beam algorithm is also capable of calculating IMRT plans. Summing the results the finding show that the use of some of the SRS-SRT techniques used for the head may be transferred for the use in extra cranial areas.

Cancer is one of the leading causes of death worldwide, and affects roughly 1.5 million new people in the United States every year. One of the leading tools in the detection and treatment of cancer is radiation. Tumors can be detected and identified using CT or PET scans, and can then be treated with external beam radiotherapy or brachytherapy. By taking advantage of the physical properties of gold and the biological properties of nanoparticles, gold nanoparticles (GNPs) can be used to improve both cancer radiotherapy and imaging. By infusing a tumor with GNPs, either using passive extravasation of nanoparticles by the tumor vasculature or active targeting of an antibody-conjugated nanoparticle to a specific tumor marker, the higher photon cross-section of gold will cause more radiation dose to be deposited in the tumor during photon-based radiotherapy. In principle, this would allow escalation of dose to the tumor while not increasing the dose to normal healthy tissue. Additionally, if a tumor infused with GNPs was irradiated by an external kilo-voltage source, the fluorescence emitted by the gold atoms would allow one to localize and quantify the GNP concentration. This work has two main aims: to quantify the GNP-mediated dose enhancement during GNRT on a nanometer scale, and to develop a refined imaging modality capable of quantifying GNP location and concentration within a small-animal-sized object. In order to quantify the GNP-mediated dose enhancement on a nanometer scale, a computational model was developed. This model combines both large-scale and small-scale calculations in order to accurately determine the heterogeneous dose distribution of GNPs. The secondary electron spectra were calculated using condensed history Monte Carlo, which is able to accurately take into account changes in beam quality throughout the tumor and calculate the average energy spectrum of the secondary charged particles created. Then, the dose distributions of these electron spectra were calculated on a nanometer scale using event-by-event Monte Carlo. The second aim is to develop an imaging system capable of reconstructing a tomographic image of GNP location and concentration in a small animal-sized object by capturing gold fluorescence photons emitted during irradiation of the object by an external beam. This would not only allow for localization of GNPs during gold nanoparticle-aided radiation therapy (GNRT), but also facilitate the use of GNPs as imaging agents for drug-delivery or other similar studies. The purpose of this study is to develop a cone-beam implementation of XFCT that meets realistic constrains on image resolution, detection limit, scan time, and dose. A Monte Carlo model of this imaging geometry was developed and used to test the methods of data acquisition and image reconstruction. The results of this study were then used to drive the production of a functioning benchtop, polychromatic cone-beam XFCT system.

<p>Cerebral radiation necrosis as a consequence of radiation therapy is often observed in patients several months to years after treatment. Complications include painful headaches, seizures, and in the worst-case death. Radiation necrosis is an irreversible condition with the options available to manage it all having noticeable downsides. As such, there is a critical need for better ways of either preventing the onset of necrosis and/or managing its symptoms. As radiation necrosis cannot be induced in humans for ethical reasons, a mouse model that mirrors the features of radiation necrosis observed in patients would allow for new techniques to be tested before being used in human clinical trials. This thesis will explain how our lab designed a murine model of cerebral radiation necrosis that uses a 320 keV cabinet irradiator to produce radiation necrosis and MRI and histology to evaluate the development of radiation necrosis at multiple time points.</p><p><br></p> <p> </p> <p>Our model required the development of a mouse positioning apparatus that could be used in the cabinet irradiator used as well as the machining of lead shields so that focal semi-hemispheric irradiations could be conducted with other critical structures spared. The MRI scans used as well as the algorithm used to draw radiation necrosis lesions were based off what has been used in previous Gamma Knife models of radiation necrosis. Our initial work showed that since the cabinet irradiator has a relatively flat dose distribution unlike the Gamma Knife, the radiation lesion volumes produced in the former either plateaued or decreased, unlike in the case of the latter where lesion volumes tended to decrease over time. Further work analyzed the effects of fractionation and found minimal sparing using four different fractionation schemes. The effects of strain and sex on the development of radiation necrosis were also analyzed, with strain being found to be a statistically significant parameter while sex was not. Future research should focus on testing the effects of new drugs and techniques for better dealing with radiation necrosis.<b></b></p>

Introducción: El cáncer de mama es más frecuente en mujeres y la segunda con mayor tasa de mortalidad en el Perú a pesar de la existencia de avanzadas técnicas oncológicas. Por ello, planteamos comparar la Radioterapia Externa (RE) con la Radioterapia intraoperatoria (RIO) en el tratamiento temprano. Esta última, técnica de concentración de dosis, cuenta con poca experiencia a nivel nacional. Objetivos: Comparar supervivencia global y libre de enfermedad a los 2 años, la incidencia de recurrencia local ipsilateral y toxicidad en pacientes con cáncer de mama temprano, que fueron sometidas a RIO o RE durante los años 2016-2018 en una clínica privada oncológica. Materiales y Métodos: Se realizó un estudio observacional, analítico de cohortes retrospectivo, con análisis bivariado para las variables dependientes; recurrencia local ipsilateral, toxicidad y sobrevida con las variables independientes. La diferencia entre estos grupos fue analizada con el modelo multivariado de regresión tipo Cox, para obtener el Hazard Ratio. El análisis de supervivencia se calculó mediante el método Kaplan-Meier, y la diferencia fue sometida a prueba log rank. Resultados: De un total de 482 pacientes con cáncer de mama temprano; 166 recibieron RIO y 316 recibieron RE convencional, con una mediana de seguimiento de 54 meses (RIC 27,1-63,4). La SG fue de 96,47% a los 2 años (98,8% RIO vs 95,25% RE), el análisis multivariado no mostró diferencia significativa. La SLE fue de 98,27% (97,97% RIO vs 98,73% RE). La recurrencia local ipsilateral de RE no fue inferior al de RIO y la toxicidad reportada como radiodermitis aguda fue mayor en el grupo que recibió RE (p<0,05). Discusión: Nuestro estudio es el primero en Perú que sugiere que dar RIO es al menos tan efectivo y con menor efecto colateral que la RE convencional. / Introduction: Breast cancer is more frequent in women and the second with the highest mortality rate in Peru despite the existence of advanced oncological techniques. For this reason, we propose to compare External Radiotherapy (EBRT) with intraoperative Radiotherapy (IORT) in early treatment. The IORT uses a dose concetration, has little experience at the national level. Objectives: To compare the global and disease-free survival at 2 years, the incidence of ipsilateral local recurrence and toxicity in patients with early breast cancer, who underwent conventional IORT or EBRT to conservation surgery during the years 2016-2018 in a private cancer clinic. Materials and Methods: An observational, analytical, retrospective cohort study was carried out, with bivariate analysis for the dependent variables; Ipsilateral local recurrence, toxicity and survival with the independent variables. The difference between these groups was analyzed with the Cox-type multivariate regression model to obtain the Hazard Ratio. Survival analysis was calculated using the Kaplan-Meier method and the difference was subjected to a log rank test. Results: From a total of 482 patients with early breast cancer; 166 received IORT and 316 received conventional EBRT, with a median follow-up of 54 months (IQR 27,1-63,4). SG was 96.47% at 2 years (98,8% RIO vs 95,25% RE), the multivariate analysis did not show a significant difference. The DFS was 98,27% (97,97% RIO vs 98,73% RE), a significant difference according to multivariate analysis (HRa 6,44 CI95% 1,46-28-29). The ipsilateral local recurrence of EBRT was not inferior to that of IORT and the toxicity reported as acute radiodermatitis was higher in the group that received EBRT (p <0,05) Discussion: Our study is the first in Peru to suggest that administering IORT is at least as effective and with fewer side effects than conventional EBRT. / Tesis

The purpose of this thesis was to evaluate and compare the peripheral dose associated with VMAT lung SABR treatments for 10X, 6X, and 10X-FFF beams. Flattening Filter Free (FFF) radiotherapy photon beams exhibit high dose rates as compared to standard flattened photon beams. The high dose rates available with FFF beams make them ideal for high dose treatments, such as Volumetric Modulated Arc Therapy (VMAT)-delivery lung Stereotactic Ablative Radiotherapy (SABR), where treatment delivery is longer than that of standard treatments. They are also known to show reductions in treatment head scatter, multi-leaf collimator (MLC) transmission and treatment head leakage radiation, compared to flattened beams. The use of FFF beams for VMAT lung SABR has been shown to significantly reduce treatment delivery time, while maintaining plan quality and accuracy. Another potential advantage of the use of FFF beams for VMAT lung SABR is the reduction in peripheral (out-of-field) dose, due mainly to the reduction in head scatter and treatment head leakage. The peripheral doses delivered by VMAT Lung SABR treatments using 10X-FFF, 10X and 6X were investigated for the Varian TrueBeam medical linear accelerator. There were three components to this investigation; (1) Ion chamber measurement of peripheral dose for static open, static MLC and dynamic MLC fields, (2) Validation of Monte Carlo, Acuros XB and AAA algorithms for peripheral dose prediction, and (3) Evaluation of peripheral doses for VMAT lung SABR treatments using the validated Monte Carlo model. Measurements of out-of field doses for static open, static MLC and dynamic MLC fields showed that 10X-FFF delivered peripheral doses in the range of 30% to 50%, 3% to 40% and 5% to 20% lower than the peripheral doses for flattened beams. Dose calculation algorithm validation showed that AAA and Acuros XB significantly under predicted the dose in the peripheral region. Monte Carlo was found to be the most accurate dose calculation algorithm for peripheral dose prediction. The VMAT lung SABR dose distributions were calculated for both static gantry delivery and arc delivery using the validated Monte Carlo model. For static gantry Monte Carlo simulation, 10X-FFF was found to show a reduction in peripheral dose in the range of 7% to 21% and 7% to 17% when compared to 6X and 10X. For arc delivery Monte Carlo simulation, 10X-FFF was found to deliver a statistically significant reduction in mean peripheral dose compared to 6X in four of the six cases, and was not found to deliver a statistically significant reduction in mean peripheral dose compared to 10X in any of the six cases. For this type of VMAT lung SABR treatment, 10X-FFF offers a reduction in peripheral dose over 6X. In terms of the benefits of using 10X-FFF for this type of treatment, the reduction in peripheral dose is added to the already-established reduction in treatment times. / Graduate / 0756 / 0574