An Overview of Current Practice in External Beam Radiation Oncology with Consideration to Potential Benefits and Challenges for Nanotechnology

Over the past two decades, there has been a significant evolution in the technologies and techniques employed within the radiation oncology environment. Over the same period, extensive research into the use of nanotechnology in medicine has highlighted a range of potential benefits to its incorporation into clinical radiation oncology. This short communication describes key tools and techniques that have recently been introduced into specific stages of a patient’s radiotherapy pathway, including diagnosis, external beam treatment and subsequent follow-up. At each pathway stage, consideration is given towards how nanotechnology may be combined with clinical developments to further enhance their benefit, with some potential opportunities for future research also highlighted. Prospective challenges that may influence the introduction of nanotechnology into clinical radiotherapy are also discussed, indicating the need for close collaboration between academic and clinical staff to realise the full clinical benefit of this exciting technology

Dosimetry and dose planning in boron neutron capture therapy : Monte Carlo studies

Boron neutron capture therapy (BNCT) is a biologically targeted radiotherapy modality. So far, 249 cancer patients have received BNCT at the Finnish Research Reactor 1 (FiR1) in Finland. The effectiveness and safety of radiotherapy are dependent on the radiation dose delivered to the tumor and healthy tissues, and on the accuracy of the doses. At FiR 1, patient dose calculations are performed with the Monte Carlo (MC) based SERA treatment planning system. Initially, BNCT was applied to head and neck cancer, brain tumors, and malignant melanoma. To evaluate the applicability of the new target tumors for BNCT, calculation dosimetry studies are needed. So far, clinical BNCT has been performed with the neutrons from a nuclear reactor, while an accelerator based neutron sources applicable for hospital operation would be preferable. In this thesis, BNCT patient dose calculation practice in Finland was evaluated against reference calculations and experimental data in several cases. The suitability of the deuterium-deuterium (D-D) and deuterium-tritium (D-T) fusion reaction based compact neutron sources for BNCT were evaluated. In addition, feasibility of BNCT for noninvasive liver tumor treatments was examined. The deviation between SERA and the reference calculations was within 4% for the boron, nitrogen, and photon dose components elsewhere, except on the phantom or skin surface. These dose components produce 99% of the tumor dose and more than 90% of the healthy tissue dose at points of relevance for treatment at the FiR 1 facility. The reduced voxel cell size in the SERA edit mesh improves calculation accuracy on the surface. The erratic biased fast-neutron run option in SERA led to significant underestimation (up to 30 60%) of the fast-neutron dose, while more accurate fast-neutron dose calculations without the biased option are too time-consuming for clinical practice. Large (over 5%) deviation was found between the measured and calculated photon doses, which produces from 25% up to 50% or more of the healthy tissue dose at certain depths. The MC code version MCNP5 is applicable for ionization chamber response within an accuracy of 2% 1%, which is sufficient for BNCT. The fusion-based neutron generators are applicable for BNCT treatments, if yields of over 1013 neutrons per second could be obtained. The simulations indicate that noninvasive liver BNCT with epithermal neutron beams can deliver high tumor dose (about 70 weighted Gy units) into the shallow depths of the liver, while tumor doses at the deepest parts of the organ remains low (approximately 10 weighted Gy units), if the accumulation of boron in the tumor compared with that in the healthy liver is sixfold or less. The patient dose calculation practice is safe and accurate against reference methods for the major dose components induced by thermal neutrons. Final verification of the fast neutron and photon dose calculation is restricted to high levels of uncertainty in existing measurement methods.Boorineutronisädehoito (BNCT-hoito) on biologisesti kohdennettu sädehoitomuoto, joka perustuu booriatomien ja neutronien väliseen vuorovaikutukseen ja boorin kertymiseen kasvaimeen enemmän kuin terveeseen kudokseen. Tähän mennessä BNCT-hoidoilla on hoidettu 249 syöpäpotilasta Suomessa. Hoidot on toteutettu Suomen ensimmäisellä koereaktorilla (FiR 1), joka otettiin käyttöön vuonna 1962. Sädehoidon teho ja turvallisuus riippuvat kasvaimen ja terveen kudoksen saamasta säteilyannoksesta ja annoksen määrityksen tarkkuudesta. Suomessa BNCT- hoidoissa potilasannoslaskenta on toteutettu Monte Carlo -simulointimenetelmään perustuvalla SERA-annossuunnitteluohjelmalla. BNCT:tä on käytetty pään ja kaulan alueen kasvainten, aivokasvainten ja melanoomaan hoitona. Annoslaskentatutkimuksia tarvitaan selvittämään BNCT-hoidon soveltuvuutta uusien kohteiden hoitoon. Toistaiseksi BNCT on annettu neutroneilla, jotka tuotetaan ydinreaktoreissa, mutta hiukkaskiihdyttimet olisivat käytännöllisempiä neuronilähteitä, koska soveltuisivat sairaalaympäristöön. Tässä väitöskirjassa on verrattu erilaisia laskennallisia ja kokeellisia menetelmiä BNCT-annosmäärityksessä. Lisäksi on tutkittu laskennallisesti deuterium-deuterium (D-D) ja deuterium-tritium (D-T) fuusioon perustuvien neutronilähteiden soveltuvuutta BNCT-hoitoon, ja selvitetty onko saavutettavan annosjakauman puolesta mahdollista hoitaa maksakasvaimia ulkoisella BNCT:llä. SERA-ohjelmalla ja verrokkimenetelmillä laskettujen boori-, typpi-, ja fotoniannosten ero on korkeintaan 4 %, jos pinta-annosta ei oteta huomioon. Nämä annoskomponentit muodostavat 99 % kasvaimen annoksesta ja yli 90 % terveen kudoksen annoksesta hoidon kannalta merkittävillä syvyyksillä. Pinta-annoksen laskentatarkkuus paranee, kun SERA-ohjelman laskentahilan kokoa pienennetään. Erillinen nopeiden neutronien aiheuttaman annoksen laskentamalli SERA-ohjelmassa ei ole riittävän tarkka ja se aliarvioi nopeaneutroniannoksen jopa 30−60 %, mutta ilman erillistä mallia nopeiden neutronien annoksen laskeminen riittävällä tarkkuudella on liian hidasta käytännön potilastyössä. Suuri ero löydettiin myös lasketussa ja mitatussa fotoniannoksessa, joka aiheuttaa vähintään 25 %, mutta jopa 50 % terveen kudoksen annoksesta tietyillä syvyyksillä. Tulosten perusteella Monte Carlo -ohjelma MCNP5 soveltuu fotonimittauksissa käytetyn ionisaatiokammion vasteen mallintamiseen 2 % tarkkuudella, joka on riittävä BNCT:ssä ja mahdollisesti tulee parantamaan fotoniannoksen määrityksen tarkkuutta. D-D ja D-T fuusioneutronilähteet soveltuvat BNCT -hoitoihin, jos tuottavat yli 1013 neutronia sekunnissa. Epitermisillä neutroneilla annettu maksan ulkoinen BNCT -hoito aiheuttaa pinnallisiin kasvaimiin jopa 70 painotetun grayn sädeannoksen, mutta syvällä maksassa sijaitsevien kasvainten annos jää pieneksi (noin 10 painotettua grayta), jos kasvaimen booripitoisuus on enintään kuusinkertainen verrattuna terveen maksakudoksen booripitoisuuteen. Tärkeimpien, termisten neutronien synnyttämien, annoskomponenttien laskenta SERA-ohjelmalla on todettu tarkaksi verrokkimenetelmiin verrattuna. Nopeiden neutronien ja fotonien synnyttämän säteilyannoksen varmistamista rajoittaa mittausmenetelmien epätarkkuus. Käytössä oleva potilasannoslaskentamenetelmä on turvallinen ja tarkkuudeltaan hyvä

Bismuth-based nanoparticles as theranostic agents for x-ray Computed Tomography (CT) and radiation therapy

Ideal radiotherapy treatment involves the delivery of a pre-set dose of ionising radiations to a well specified target by radiologic imaging techniques. Conforming the dose to the target is crucial as ionising radiation causes damage to healthy tissues. Rapid imaging and dose delivery modalities, which have also been developed, have brought a great improvement in accuracy of targeted cancer treatments. However, current diagnostic and treatment procedures are still limited by insufficient accuracy in terms of the radiobiology of radiotherapy. Hence, a major area of endeavour is improving their accuracy and therapeutic effects. Recently, research has focused primarily on attempting to radio-sensitise targets. This process involves inclusion of high atomic number (Z) materials into targets prior to irradiation. To increase efficiency of this process, nanoparticles (NPs) consisting of high Z elements are used. Incorporation of these materials with medical imaging devices such as X-ray computed tomography (CT) scans leads to improved disease characterisation and monitoring of response to therapy. Moreover, nanoparticles can enhance dose effects in external beam radiotherapy. The rationale behind this work was to develop and characterise NPs and incorporate them into the processes employed by current diagnostic CT imaging devices in order to enhance sensitivity and increase the chance of identifying disease at a time when the patient can receive a positive prognosis. This enhancement is also important in advancing towards eliminating the need for invasive biopsies, which is currently the most accurate diagnostic method for cancer detection and therapy follow up. In addition, the same NPs can be used as dose enhancement agents to improve radiotherapy effects on cancerous tissues whilst minimising effects on healthy tissues. Therefore, this thesis had the two major aims: to use bismuth-based NPs as dual-function agents for cancer; diagnostic as well as therapeutic. Using a single system to enhance detection as well as boost therapeutic efficacy leads to the promising platform called “theranostics”. Optimisation of the diagnostic and therapeutic strategies simultaneously enhances cancer control and increases patient’s survival rates. Contrast agent studies were conducted using phantoms with CT scanners, while radiation dose enhancement was carried out using biological cell survival assays and two radiotherapy techniques; superficial radiotherapy (SXRT) (kV) and megavoltage (deep) (MV) therapy with a linear accelerator (LINAC). The results of the study provided evidence that bismuth (Bi) and its compounds (bismuth sulfide (Bi2S3) and bismuth oxyiodide (BiOI) NPs) can be synthesised and surface-modified using suitable biocompatible methods. Attention was also given also to nanoparticle-surface coating effects in optimising long term stability. Furthermore, the NPs were characterised using transmission electron microscopy (TEM), X-ray diffraction (XRD) and X-ray photoelectron spectroscopy (XPS), thermogravimetric analysis (TGA), Fourier transform infrared spectroscopy (FT-IR) and Zeta potential measurements in order to confirm nanoparticle size, compositions and surface modifications. It was established that bismuth-based NPs can be produced in small and well-defined sizes and are stable in water for a long period of time. Initially, experiments investigated the feasibility of employing high-Z Bi2S3-NPs as a contrast agent for CT compared to conventional contrast media (CM). An extended study determined the optimal clinical tube potentials for visualisation of Bi-based NPs with respect to iodinated CM. Results showed particular promise for maximising contrast enhancement across the studied range of 80 to 140 kilovoltage (kV). These results were supported by National Institute of Standards and Technology (NIST) mass attenuation data. A second, novel study was conducted to determine the benefit of the K-edge value for Bi and iodine (I), using bismuth oxyiodide (BiOI) NPs to enhance subject contrast in dual-energy (DE-CT) and spectral (MARS) CT imaging. Both CT scanners revealed the superiority of BiOI-NPs over the conventional iodinated contrast agents. A second series of studies was conducted to develop cell culture-related protocols to measure the response of different cell lines exposed to X-ray radiotherapy beams with energies in kVp and MV as well as to measure the effect of NPs containing high Z on the radiation responses. The first study was carried out to investigate and compare the effect of Bi2S3 and gold (Au)-NPs on the radiation response of mouse PC3 prostate and B16 melanoma cells. Equimolar concentrations of both Au and Bi2S3-NPs displayed equal dose enhancement with B16 cells, while the latter provided higher values with PC3 cells. At equimolar concentrations there are less Bi atoms compared to Au in their respective NPs. Both NPs at comparable concentrations (0.5-1 mM) elicited similar cytotoxicity in PC3 cells. This study demonstrates that the less expensive Bi2S3-NPs are a viable alternative to Au-NPs as a dose-enhancing agent in clinical applications. The second study investigated the cytotoxicity of Bi- and Bi2S3-NPs towards two human cell lines, A549 (lung adenocarcinoma epithelial) and DU145 (prostate carcinoma). Results revealed that Bi-NPs at comparable concentrations to Bi2S3- NPs (0.5-1 mM) caused higher cytotoxicity in both cell lines. The presence of both NPs led to decreasing the surviving fraction of cells when NPs were combined together with X-ray irradiation, compared to the control (irradiation alone). Cells irradiated with kVp energies showed the greatest radiosensitisation value compared to MV energies. Results also demonstrated that Bi-NPs generated a greater dose enhancement effect than Bi2S3-NPs in irradiated cells. The maximum Dose Enhancement Factor (DEF) obtained at the lower energy kV range for cells treated with Bi-NPs (0.25 mM) was 2.29 in A549 cells and 1.56 in DU145 cells, compared to the DEF values of 1.41 in A549 cells and 1.63 in DU145 cells when cells were treated with higher concentrations (1mM) of Bi2S3-NPs. Lower radiation dose enhancement was observed when using a high energy MV beam, with higher DEF values for Bi-NPs (0.25 mM) treatment (1.26 in A549 cells and 1.23 in DU145 cells) as compared to DEF values with similar concentrations of Bi2S3-NPs (1.09 in A549 cells and 1.07 in DU145 cells). Using a linear quadratic model to analyse the radiobiological effect of the dose enhancement by NPs it were found that there was systematic changes of the alpha (α) value which increased by treating with the NPs, while there were very small changes for the beta (β) value

Radiopharmaceuticals

Radiopharmaceuticals - Current Research for Better Diagnosis and Therapy discusses the importance of radiopharmaceuticals and their environmental, pharmaceutical, diagnostic, therapeutic, and research applications. Chapters address such topics as the fundamentals of radiopharmaceutical chemistry and preparation, fabrication, materials manipulation, and characterization of radiopharmaceuticals, applications of radiopharmaceuticals in preclinical studies, radiopharmaceuticals in modern cancer therapy, and new trends in preparation, biodistribution, and pharmacokinetics of radiopharmaceuticals in diagnosis and research

Case series of breast fillers and how things may go wrong: radiology point of view

INTRODUCTION: Breast augmentation is a procedure opted by women to overcome sagging breast due to breastfeeding or aging as well as small breast size. Recent years have shown the emergence of a variety of injectable materials on market as breast fillers. These injectable breast fillers have swiftly gained popularity among women, considering the minimal invasiveness of the procedure, nullifying the need for terrifying surgery. Little do they know that the procedure may pose detrimental complications, while visualization of breast parenchyma infiltrated by these fillers is also deemed substandard; posing diagnostic challenges. We present a case series of three patients with prior history of hyaluronic acid and collagen breast injections. REPORT: The first patient is a 37-year-old lady who presented to casualty with worsening shortness of breath, non-productive cough, central chest pain; associated with fever and chills for 2-weeks duration. The second patient is a 34-year-old lady who complained of cough, fever and haemoptysis; associated with shortness of breath for 1-week duration. CT in these cases revealed non thrombotic wedge-shaped peripheral air-space densities. The third patient is a 37‐year‐old female with right breast pain, swelling and redness for 2- weeks duration. Previous collagen breast injection performed 1 year ago had impeded sonographic visualization of the breast parenchyma. MRI breasts showed multiple non- enhancing round and oval shaped lesions exhibiting fat intensity. CONCLUSION: Radiologists should be familiar with the potential risks and hazards as well as limitations of imaging posed by breast fillers such that MRI is required as problem-solving tool