Scanned Ion Beam Therapy for Thoracic Tumors

Although frequently cured of Hodgkin lymphoma, adolescents and young adults can develop radiation induced second cancers. These patients could potentially benefit from scanned ion radiotherapy yet likely would require motion mitigation strategies. In theory, four-dimensional (4D) optimization of ion beam fields for individual motion states of respiration can enable superior sparing of healthy tissue near moving targets, compared to other motion mitigation strategies. Furthermore, carbon-ion therapy can sometimes provide greater relative biological effectiveness (RBE) for cell sterilization in a target but nearly equivalent RBE in tissue upstream of the target, compared to proton therapy. Thus, we expected that for some patients with Hodgkin lymphoma, carbon-ion therapy would reduce the predicted risk of second cancer incidence in the breast compared with proton therapy. The purpose of this work was to determine whether 4D-optimized carbon-ion therapy would significantly reduce the predicted risk of radiation induced second cancers in the breast for female Hodgkin lymphoma patients while preserving tumor control compared with proton therapy. To achieve our goals, we first investigated whether 4D-optimized carbon beam tracking could reduce dose to volumes outside a moving target compared with 3D-optimized carbon beam tracking while preserving target dose coverage. To understand the reliability of scanned carbon beam tracking, we studied the robustness of dose distributions in thoracic targets to uncertainties in patient motion. Finally, we investigated whether using carbon-ion therapy instead of proton therapy would significantly reduce the predicted risk of second cancer in the breast for a sample of Hodgkin lymphoma patients. We found that 4D-optimized ion beam tracking therapy can reduce the maximum dose to critical structures near a moving target by as much as 53%, compared to 3D-optimized ion beam tracking therapy. We validated these findings experimentally using a scanned carbon ion synchrotron and a motion phantom. We found scanned carbon beam tracking to be sensitive to a number of motion uncertainties, most notably phase delays in tracking, systematic spatial errors, and interfractional motion changes. Our findings indicate that a lower risk of second cancer in the breast might be expected for some Hodgkin lymphoma patients using carbon-ion therapy instead of proton therapy. For our reference scenario, we found the ratio of risk to be 0.77 ± 0.35 for radiogenic breast cancer after carbon-ion therapy versus proton therapy. Our findings were dependent on the RBE values for tumor induction and the radiosensitivity of breast tissue, as well as the physical dose distribution.

Development of a SPECT -based three-dimensional treatment planner for radionuclide therapy with iodine -131

Accurate calculation of absorbed dose to target tumors and normal tissues in the body is an important requirement for establishing fundamental dose-response relationships for radioimmunotherapy. Two major obstacles have been the difficulty in obtaining an accurate patient-specific 3-D activity map in-vivo and calculating the resulting absorbed dose. This study investigated a methodology for 3-D internal dosimetry, which integrates the 3-D biodistribution of the radionuclide acquired from SPECT with a dose-point kernel convolution technique to provide the 3-D distribution of absorbed dose. Accurate SPECT images were reconstructed with appropriate methods for noise filtering, attenuation correction, and Compton scatter correction. The SPECT images were converted into activity maps using a calibration phantom. The activity map was convolved with an $\sp{131}$I dose-point kernel using a 3-D fast Fourier transform to yield a 3-D distribution of absorbed dose. The 3-D absorbed dose map was then processed to provide the absorbed dose distribution in regions of interest. This methodology can provide heterogeneous distributions of absorbed dose in volumes of any size and shape with nonuniform distributions of activity. Comparison of the activities quantitated by our SPECT methodology to true activities in an Alderson abdominal phantom (with spleen, liver, and spherical tumor) yielded errors of $-$16.3% to 4.4%. Volume quantitation errors ranged from $-$4.0 to 5.9% for volumes greater than 88 ml. The percentage differences of the average absorbed dose rates calculated by this methodology and the MIRD S-values were 9.1% for liver, 13.7% for spleen, and 0.9% for the tumor. Good agreement (percent differences were less than 8%) was found between the absorbed dose due to penetrating radiation calculated from this methodology and TLD measurement. More accurate estimates of the 3-D distribution of absorbed dose can be used as a guide in specifying the minimum activity to be administered to patients to deliver a prescribed absorbed dose to tumor without exceeding the toxicity limits of normal tissues. ^

A new PET prototype for proton therapy: comparison of data and Monte Carlo simulations

Ion beam therapy is a valuable method for the treatment of deep-seated and radio-resistant tumors thanks to the favorable depth-dose distribution characterized by the Bragg peak. Hadrontherapy facilities take advantage of the specific ion range, resulting in a highly conformal dose in the target volume, while the dose in critical organs is reduced as compared to photon therapy. The necessity to monitor the delivery precision, i.e. the ion range, is unquestionable, thus different approaches have been investigated, such as the detection of prompt photons or annihilation photons of positron emitter nuclei created during the therapeutic treatment. Based on the measurement of the induced β+ activity, our group has developed various in-beam PET prototypes: the one under test is composed by two planar detector heads, each one consisting of four modules with a total active area of 10 × 10 cm2. A single detector module is made of a LYSO crystal matrix coupled to a position sensitive photomultiplier and is read-out by dedicated frontend electronics. A preliminary data taking was performed at the Italian National Centre for Oncological Hadron Therapy (CNAO, Pavia), using proton beams in the energy range of 93–112 MeV impinging on a plastic phantom. The measured activity profiles are presented and compared with the simulated ones based on the Monte Carlo FLUKA package.

Estudo dos parâmetros dosimétricos de sementes de Iodo-125 desenvolvidas pelo IPEN-CNEN/SP utilizadas em braquiterapia por simulação computacional pelo método de Monte Carlo

As expectativas da Organização Mundial de Saúde para o ano de 2030 são que o número de mortes por câncer seja de aproximadamente 13,2 milhões, evidenciando a elevada parcela desta doença no problema de saúde mundial. Com relação ao câncer de próstata, de acordo com o Instituto Nacional do Câncer, o número de casos diagnosticados no mundo em 2012 foi de aproximadamente 1,1 milhão, enquanto que no Brasil os dados indicam a incidência de 68 mil novos casos. O tratamento deste tipo de neoplasia pode ser realizado com cirurgia (prostatectomia) ou radioterapia. Dentre a radioterapia, podemos destacar a técnica de braquiterapia, a qual consiste na introdução (implante) de pequenas fontes radioativas (sementes) no interior da próstata, onde será entregue um valor elevado de dose no volume de tratamento e baixa dose nos tecidos ao redor. No Brasil, a classe médica estima uma demanda de aproximadamente 8000 sementes/mês, sendo o custo unitário de cada semente de pelo menos U$ 26,00. A Associação Americana de Físicos na Medicina publicou alguns documentos descrevendo quais parâmetros e análises devem ser realizadas para avaliações da distribuição de dose, como por exemplo, os parâmetros Constante de taxa de dose, Função radial e Função de anisotropia. Estes parâmetros podem ser obtidos através de medidas experimentais da distribuição de dose ou por simulações computacionais. Neste trabalho foram determinados os parâmetros dosimétricos da semente OncoSeed-6711 da empresa Oncura-GEHealthcare e da semente desenvolvida pelo Grupo de Dosimetria de Fontes de Braquiterapia do Centro de Tecnologia das Radiações (CTR IPEN-CNEN/SP) por simulação computacional da distribuição de dose utilizando o código MCNP5, baseado no Método de Monte Carlo. A semente 6711 foi modelada, assim como um sistema dosimétrico constituído por um objeto simulador cúbico de 30x30x30 cm3 preenchido com água. Os valores obtidos da semente 6711 foram comparados com alguns apresentados na literatura, onde o parâmetro Constante de taxa de dose apresentou erro relativo em relação ao valor publicado no TG- 43 de 0,1%, sendo que os outros parâmetros analisados também apresentaram boa concordância com os valores publicados na literatura. Deste modo, pode-se considerar que os parâmetros utilizados nas simulações (espectro, modelagem geométrica e avaliação de resultados) estão compatíveis com outros estudos, sendo estes parâmetros também utilizados nas simulações da semente do IPEN. Considerando as análises de incerteza estatística, os valores obtidos da semente do IPEN são semelhantes aos valores da semente 6711.

A dosimetry and radiobiological model for intravascular brachytherapy treatment planning with radioisotope emitting stents

The aim of this study was to develop a practical, versatile and fast dosimetry and radiobiological model for calculation of the 3D dose distribution and radiobiological effectiveness of radioactive stents. The algorithm was written in Matlab 6.5 programming language and is based on the dose point kernel convolution. The dosimetry and radiobiological model was applied for evaluation of the 3D dose distribution of 32P, 90Y, 188Re and 177Lu stents. Of the four, 32P delivers the highest dose, while 90Y, 188Re and 177Lu require high levels of activity to deliver a significant therapeutic dose in the range of 15-30 Gy. Results of the radiobiological model demonstrated that the same physical dose delivered by different radioisotopes produces significantly different radiobiological effects. This type of theoretical dose calculation can be useful in the development of new stent designs, the planning of animal studies and clinical trials, and clinical decisions involving individualized treatment plans.

Gold nanoparticle induced vasculature damage in radiotherapy: Comparing protons, megavoltage photons, and kilovoltage photons

Purpose: The purpose of this work is to investigate the radiosensitizing effect of gold nanoparticle (GNP) induced vasculature damage for proton, megavoltage (MV) photon, and kilovoltage (kV) photon irradiation. Methods: Monte Carlo simulations were carried out using tool for particle simulation (TOPAS) to obtain the spatial dose distribution in close proximity up to 20 µm from the GNPs. The spatial dose distribution from GNPs was used as an input to calculate the dose deposited to the blood vessels. GNP induced vasculature damage was evaluated for three particle sources (a clinical spread out Bragg peak proton beam, a 6 MV photon beam, and two kV photon beams). For each particle source, various depths in tissue, GNP sizes (2, 10, and 20 nm diameter), and vessel diameters (8, 14, and 20 µm) were investigated. Two GNP distributions in lumen were considered, either homogeneously distributed in the vessel or attached to the inner wall of the vessel. Doses of 30 Gy and 2 Gy were considered, representing typical in vivo enhancement studies and conventional clinical fractionation, respectively. Results: These simulations showed that for 20 Au-mg/g GNP blood concentration homogeneously distributed in the vessel, the additional dose at the inner vascular wall encircling the lumen was 43% of the prescribed dose at the depth of treatment for the 250 kVp photon source, 1% for the 6 MV photon source, and 0.1% for the proton beam. For kV photons, GNPs caused 15% more dose in the vascular wall for 150 kVp source than for 250 kVp. For 6 MV photons, GNPs caused 0.2% more dose in the vascular wall at 20 cm depth in water as compared to at depth of maximum dose (Dmax). For proton therapy, GNPs caused the same dose in the vascular wall for all depths across the spread out Bragg peak with 12.7 cm range and 7 cm modulation. For the same weight of GNPs in the vessel, 2 nm diameter GNPs caused three times more damage to the vessel than 20 nm diameter GNPs. When the GNPs were attached to the inner vascular wall, the damage to the inner vascular wall can be up to 207% of the prescribed dose for the 250 kVp photon source, 4% for the 6 MV photon source, and 2% for the proton beam. Even though the average dose increase from the proton beam and MV photon beam was not large, there were high dose spikes that elevate the local dose of the parts of the blood vessel to be higher than 15 Gy even for 2 Gy prescribed dose, especially when the GNPs can be actively targeted to the endothelial cells. Conclusions: GNPs can potentially be used to enhance radiation therapy by causing vasculature damage through high dose spikes caused by the addition of GNPs especially for hypofractionated treatment. If GNPs are designed to actively accumulate at the tumor vasculature walls, vasculature damage can be increased significantly. The largest enhancement is seen using kilovoltage photons due to the photoelectric effect. Although no significant average dose enhancement was observed for the whole vasculature structure for both MV photons and protons, they can cause high local dose escalation (>15 Gy) to areas of the blood vessel that can potentially contribute to the disruption of the functionality of the blood vessels in the tumor.

Modelling responses to spatially fractionated radiation fields using preclinical image-guided radiotherapy

OBJECTIVES: Radiotherapy is planned to achieve the optimal physical dose distribution to the target tumour volume whilst minimising dose to the surrounding normal tissue. Recent in vitro experimental evidence has demonstrated an important role for intercellular communication in radiobiological responses following non-uniform exposures. This study aimed to model the impact of these effects in the context of techniques involving highly modulated radiation fields or spatially fractionated treatments such as GRID therapy.

METHODS: Using the small animal radiotherapy research platform (SARRP) as a key enabling technology to deliver precision imaged-guided radiotherapy, it is possible to achieve spatially modulated dose distributions that model typical clinical scenarios. In this work, we planned uniform and spatially fractionated dose distributions using multiple isocentres with beam sizes of 0.5 - 5 mm to obtain 50% volume coverage in a subcutaneous murine tumour model, and applied a model of cellular response that incorporates intercellular communication to assess the potential impact of signalling effects with different ranges.

RESULTS: Models of GRID treatment plans which incorporate intercellular signalling showed increased cell killing within the low dose region. This results in an increase in the Equivalent Uniform Dose (EUD) for GRID exposures compared to standard models, with some GRID exposures being predicted to be more effective than uniform delivery of the same physical dose.

CONCLUSIONS: This study demonstrates the potential impact of radiation induced signalling on tumour cell response for spatially fractionated therapies and identifies key experiments to validate this model and quantify these effects in vivo.

ADVANCES IN KNOWLEDGE: This study highlights the unique opportunities now possible using advanced preclinical techniques to develop a foundation for biophysical optimisation in radiotherapy treatment planning.

LRP5 regulates human body fat distribution by modulating adipose progenitor biology in a dose- and depot-specific fashion

Summary Common variants in WNT pathway genes have been associated with bone mass and fat distribution, the latter predicting diabetes and cardiovascular disease risk. Rare mutations in the WNT co-receptors LRP5 and LRP6 are similarly associated with bone and cardiometabolic disorders. We investigated the role of LRP5 in human adipose tissue. Subjects with gain-of-function LRP5 mutations and high bone mass had enhanced lower-body fat accumulation. Reciprocally, a low bone mineral density-associated common LRP5 allele correlated with increased abdominal adiposity. Ex vivo LRP5 expression was higher in abdominal versus gluteal adipocyte progenitors. Equivalent knockdown of LRP5 in both progenitor types dose-dependently impaired β-catenin signaling and led to distinct biological outcomes: diminished gluteal and enhanced abdominal adipogenesis. These data highlight how depot differences in WNT/β-catenin pathway activity modulate human fat distribution via effects on adipocyte progenitor biology. They also identify LRP5 as a potential pharmacologic target for the treatment of cardiometabolic disorders. © 2015 The Authors.

Tissue distribution and depuration of the extracted hepatotoxic cyanotoxin microcystins in crucian carp (Carassius carassius) intraperitoneally injected at a sublethal dose

An acute toxicity experiment was conducted by intraperitoneal injection with a sublethal dose of extracted microcystins (MCs), 50 mu g MC-LR (where L = leucine and R = arginine) equivalent/kg body weight (BW), to examine tissue distribution and depuration of MCs in crucian carp (Carassius carassius). Liver to body weight ratio increased at 3, 12, 24, and 48 h postinjection compared with that at 0 h (p < 0.05). MC concentrations in various tissues and aquaria water were analyzed at 1, 3, 12, 24, 48, and 168 h postinjection using liquid chromatography coupled with mass spectrometry (LC-MS). The highest concentration of MCs (MC-RR + MC-LR) was found in blood, 2 -270 ng/g dry weight (DW), followed by heart (3 -100 ng/g DW) and kidney (13 -88 ng/g DW). MC levels were relatively low in liver, gonad, intestine, spleen, and brain. MC contents in gills, gallbladder, and muscle were below the limit of detection. Significant negative correlation was present between MC-RR concentration in blood and that in kidney, confirming that blood was important in the transportation of MC-RR to kidney for excretion. Rapid accumulation and slow degradation of MCs were observed in gonad, liver, intestine, spleen, and brain. Only 0.07% of injected MCs were detected in liver. The recovery of MCs in liver of crucian carp seemed to be dose dependent.

Low-Dose Vascular Photodynamic Therapy Decreases Tumor Interstitial Fluid Pressure, which Promotes Liposomal Doxorubicin Distribution in a Murine Sarcoma Metastasis Model.

INTRODUCTION: Solid tumors are known to have an abnormal vasculature that limits the distribution of chemotherapy. We have recently shown that tumor vessel modulation by low-dose photodynamic therapy (L-PDT) could improve the uptake of macromolecular chemotherapeutic agents such as liposomal doxorubicin (Liporubicin) administered subsequently. However, how this occurs is unknown. Convection, the main mechanism for drug transport between the intravascular and extravascular spaces, is mostly related to interstitial fluid pressure (IFP) and tumor blood flow (TBF). Here, we determined the changes of tumor and surrounding lung IFP and TBF before, during, and after vascular L-PDT. We also evaluated the effect of these changes on the distribution of Liporubicin administered intravenously (IV) in a lung sarcoma metastasis model. MATERIALS AND METHODS: A syngeneic methylcholanthrene-induced sarcoma cell line was implanted subpleurally in the lung of Fischer rats. Tumor/surrounding lung IFP and TBF changes induced by L-PDT were determined using the wick-in-needle technique and laser Doppler flowmetry, respectively. The spatial distribution of Liporubicin in tumor and lung tissues following IV drug administration was then assessed in L-PDT-pretreated animals and controls (no L-PDT) by epifluorescence microscopy. RESULTS: L-PDT significantly decreased tumor but not lung IFP compared to controls (no L-PDT) without affecting TBF. These conditions were associated with a significant improvement in Liporubicin distribution in tumor tissues compared to controls (P < .05). DISCUSSION: L-PDT specifically enhanced convection in blood vessels of tumor but not of normal lung tissue, which was associated with a significant improvement of Liporubicin distribution in tumors compared to controls.

Effect of high dose selenium enriched yeast diets on the distribution of total selenium and selenium species within lamb tissues

The objective of this study was to determine the distribution of total selenium (Se) and of the proportion of total Se comprised as the selenized amino acids selenomethionine (SeMet) and selenocysteine (SeCys) within the post mortem tissues of lambs that were fed high dose selenized enriched yeast (SY), derived from a specific strain of Saccharomyces cerevisae CNCM (Collection Nationale de Culture de Micro-organism) I-3060. Thirty two Texel X Suffolk lambs (6.87 ± 0.23 kg BW) were offered both reconstituted milk replacer and a pelleted diet, both of which had been either supplemented with high SY (6.30 ± 0.18 mg Se/kg DM) or unsupplemented (0.13 ± 0.01 mg Se/kg of DM), depending on treatment designation, for a continuous period of 91 d. At enrollment and 28, 56 and 91 d following enrollment lambs were blood sampled. At the completion of the treatment period, five lambs from each treatment group were euthanased and samples of heart, liver, kidney and skeletal muscle (Longissimus Dorsi and Psoas Major) were retained for Se analysis. The inclusion of high SY increased (P < 0.001) whole blood Se concentration, reaching a maximum mean value of 815.2 ± 19.1 ng Se/mL compared with 217.8 ± 9.1 ng Se/mL in control animals. Tissue total Se concentrations were significantly (P < 0.001) higher in SY supplemented animals than in controls irrespective of tissue type; values were 26, 16, 8 and 3 times higher in skeletal muscle, liver, heart and kidney tissue of HSY lambs when compared to controls. however, the distribution of total Se and the proportions of total Se comprised as either SeMet or SeCys differed between tissue types. Selenocysteine was the predominant selenized amino acid in glandular tissues, such the liver and kidney. irrespective of treatment, although absolute values were markedly higher in HSY lambs. Conversely selenomethionine was the predominat selenized amino acid in cardiac and skeletal muscle (Longissimus Dorsi, and Psoas Major) tissues in HSY animals, although the same trend was not apparent for control lambs in which SeCys was the predominant selenized amino acid. It was concluded that there were increases in both whole blood and tissue total Se concentrations as a result of dietary supplementation with high dose of SY. Furthermore, distribution of total Se and Se species differed between both treatment designation and tissue type.

Tissue distribution of a plasmid DNA encoding Hsp65 gene is dependent on the dose administered through intramuscular delivery

In order to assess a new strategy of DNA vaccine for a more complete understanding of its action in immune response, it is important to determine the in vivo biodistribution fate and antigen expression. In previous studies, our group focused on the prophylactic and therapeutic use of a plasmid DNA encoding the Mycobacterium leprae 65-kDa heat shock protein (Hsp65) and achieved an efficient immune response induction as well as protection against virulent M. tuberculosis challenge. In the present study, we examined in vivo tissue distribution of naked DNA-Hsp65 vaccine, the Hsp65 message, genome integration and methylation status of plasmid DNA. The DNA-Hsp65 was detectable in several tissue types, indicating that DNA-Hsp65 disseminates widely throughout the body. The biodistribution was dose-dependent. In contrast, RT-PCR detected the Hsp65 message for at least 15 days in muscle or liver tissue from immunized mice. We also analyzed the methylation status and integration of the injected plasmid DNA into the host cellular genome. The bacterial methylation pattern persisted for at least 6 months, indicating that the plasmid DNA-Hsp65 does not replicate in mammalian tissue, and Southern blot analysis showed that plasmid DNA was not integrated. These results have important implications for the use of DNA-Hsp65 vaccine in a clinical setting and open new perspectives for DNA vaccines and new considerations about the inoculation site and delivery system. © 2006 Coelho-Castelo et al; licensee BioMed Central Ltd.

Tissue distribution of a plasmid DNA encoding Hsp65 gene is dependent on the dose administered through intramuscular delivery

In order to assess a new strategy of DNA vaccine for a more complete understanding of its action in immune response, it is important to determine the in vivo biodistribution fate and antigen expression. In previous studies, our group focused on the prophylactic and therapeutic use of a plasmid DNA encoding the Mycobacterium leprae 65-kDa heat shock protein (Hsp65) and achieved an efficient immune response induction as well as protection against virulent M. tuberculosis challenge. In the present study, we examined in vivo tissue distribution of naked DNA-Hsp65 vaccine, the Hsp65 message, genome integration and methylation status of plasmid DNA. The DNA-Hsp65 was detectable in several tissue types, indicating that DNA-Hsp65 disseminates widely throughout the body. The biodistribution was dose-dependent. In contrast, RT-PCR detected the Hsp65 message for at least 15 days in muscle or liver tissue from immunized mice. We also analyzed the methylation status and integration of the injected plasmid DNA into the host cellular genome. The bacterial methylation pattern persisted for at least 6 months, indicating that the plasmid DNA-Hsp65 does not replicate in mammalian tissue, and Southern blot analysis showed that plasmid DNA was not integrated. These results have important implications for the use of DNA-Hsp65 vaccine in a clinical setting and open new perspectives for DNA vaccines and new considerations about the inoculation site and delivery system.