Dosimetric characterization of a new surface-conforming electron MLC prototype.

The purpose is to reduce normal tissue radiation toxicity for electron therapy through the creation of a surface-conforming electron multileaf collimator (SCEM). The SCEM combines the benefits of skin collimation, electron conformal radiotherapy, and modulated electron radiotherapy. An early concept for the SCEM was constructed. It consists of leaves that protrude towards the patient, allowing the leaves to conform closely to irregular patient surfaces. The leaves are made of acrylic to decrease bremsstrahlung, thereby decreasing the out-of-field dose. Water tank scans were performed with the SCEM in place for various field sizes for all available electron energies (6, 9, 12, and 15 MeV) with a 0.5 cm air gap to the water surface at 100 cm source-to-surface distance (SSD). These measurements were compared with Cerrobend cutouts with the field size-matched at 100 and 110 cm SSD. Output factor measurements were taken in solid water for each energy at dmax for both the cerrobend cutouts and SCEM at 100 cm SSD. Percent depth dose (PDD) curves for the SCEM shifted shallower for all energies and field sizes. The SCEM also produced a higher surface dose relative to Cerrobend cutouts, with the maximum being a 9.8% increase for the 3 cm × 9 cm field at 9 MeV. When compared to the Cerrobend cutouts at 110 cm SSD, the SCEM showed a significant decrease in the penumbra, particularly for lower energies (i.e., 6 and 9 MeV). The SCEM also showed reduced out-of-field dose and lower bremsstrahlung production than the Cerrobend cutouts. The SCEM provides significant improvement in the penumbra and out-of-field dose by allowing collimation close to the skin surface compared to Cerrobend cutouts. However, the added scatter from the SCEM increases shallow PDD values. Future work will focus on reducing this scatter while maintaining the penumbra and out-of-field benefits the SCEM has over conventional collimation.

Development and multi-institutional validation of a convolutional neural network to detect vertebral body mis-alignments in 2D x-ray setup images.

BACKGROUND: Misalignment to the incorrect vertebral body remains a rare but serious patient safety risk in image-guided radiotherapy (IGRT). PURPOSE: Our group has proposed that an automated image-review algorithm be inserted into the IGRT process as an interlock to detect off-by-one vertebral body errors. This study presents the development and multi-institutional validation of a convolutional neural network (CNN)-based approach for such an algorithm using patient image data from a planar stereoscopic x-ray IGRT system. METHODS: X-rays and digitally reconstructed radiographs (DRRs) were collected from 429 spine radiotherapy patients (1592 treatment fractions) treated at six institutions using a stereoscopic x-ray image guidance system. Clinically-applied, physician approved, alignments were used for true-negative, "no-error" cases. "Off-by-one vertebral body" errors were simulated by translating DRRs along the spinal column using a semi-automated method. A leave-one-institution-out approach was used to estimate model accuracy on data from unseen institutions as follows: All of the images from five of the institutions were used to train a CNN model from scratch using a fixed network architecture and hyper-parameters. The size of this training set ranged from 5700 to 9372 images, depending on exactly which five institutions were contributing data. The training set was randomized and split using a 75/25 split into the final training/ validation sets. X-ray/ DRR image pairs and the associated binary labels of "no-error" or "shift" were used as the model input. Model accuracy was evaluated using images from the sixth institution, which were left out of the training phase entirely. This test set ranged from 180 to 3852 images, again depending on which institution had been left out of the training phase. The trained model was used to classify the images from the test set as either "no-error" or "shifted", and the model predictions were compared to the ground truth labels to assess the model accuracy. This process was repeated until each institution's images had been used as the testing dataset. RESULTS: When the six models were used to classify unseen image pairs from the institution left out during training, the resulting receiver operating characteristic area under the curve values ranged from 0.976 to 0.998. With the specificity fixed at 99%, the corresponding sensitivities ranged from 61.9% to 99.2% (mean: 77.6%). With the specificity fixed at 95%, sensitivities ranged from 85.5% to 99.8% (mean: 92.9%). CONCLUSION: This study demonstrated the CNN-based vertebral body misalignment model is robust when applied to previously unseen test data from an outside institution, indicating that this proposed additional safeguard against misalignment is feasible.

Hydrogen sulfide decreases photodynamic therapy outcome through the modulation of the cellular redox state.

Photodynamic therapy (PDT) is a non-surgical treatment that has been approved for its human medical use in many cancers. PDT involves the interaction of a photosensitizer (PS) with light. The amino acid 5- aminolevulinic acid (ALA) can be used as a pro-PS, leading to the synthesis of Protoporphyrin IX. Hydrogen sulfide (H2S) is an endogenously produced gas that belongs to the gasotransmitter family, which can diffuse through biological membranes and have relevant physiological effects such as cardiovascular functions, vasodilatation, inflammation, cell cycle and neuro-modulation. It was also proposed to have cytoprotective effects. We aimed to study the modulatory effects of H2S on ALAPDT in the mammary adenocarcinoma cell line LM2. Exposure of the cells to NaHS (donor of H2S) in concentrations up to 10 mM impaired the response to ALA-PDT in a dose-dependent manner. The addition of 3 doses of NaHS showed the highest effect. This decreased response to the photodynamic treatment was correlated to an increase in the GSH levels, catalase activity, a dose dependent reduction of PpIX and increased intracellular ALA, decreased levels of oxidized proteins and a decrease of PDT-induced ROS. NaHS also reduced the levels of singlet oxygen in an in vitro assay. H2S also protected other cells of different origins against PDT mediated by ALA and other PSs. These results suggest that H2S has a role in the modulation of the redox state of the cells, and thus impairs the response to ALA-PDT through multifactor pathways. These findings could contribute to developing new strategies to improve the effectiveness of PDT particularly mediated by ALA or other ROS-related treatments.

End to end comparison of surface-guided imaging versus stereoscopic X-rays for the SRS treatment of multiple metastases with a single isocenter using 3D anthropomorphic gel phantoms.

INTRODUCTION: Two end-to-end tests evaluate the accuracy of a surface-guided radiation therapy (SGRT) system (CRAD Catalyst HD) for position verification in comparison to a stereoscopic x-ray imaging system (Brainlab Exactrac ) for single-isocenter, multiple metastases stereotactic radiosurgery (SRS) using 3D polymer gel inserts. MATERIALS AND METHODS: A 3D-printed phantom (Prime phantom, RTsafe PC, Athens, Greece) with two separate cylindrical polymer gel inserts were immobilized in open-face masks and treated with a single isocentric, multitarget SRS plan. Planning was done in Brainlab (Elements) to treat five metastatic lesions in one fraction, and initial setup was done using cone beam computed tomography. Positional verification was done using orthogonal X-ray imaging (Brainlab Exactrac) and/or a surface imaging system (CRAD Catalyst HD, Uppsala, Sweden), and shift discrepancies were recorded for each couch angle. Forty-two hours after irradiation, the gel phantom was scanned in a 1.5 Tesla MRI, and images were fused with the patient computed tomography data/structure set for further analysis of spatial dose distribution. RESULTS: Discrepancies between the CRAD Catalyst HD system and Brainlab Exactrac were <1 mm in the translational direction and <0.5° in the angular direction at noncoplanar couch angles. Dose parameters (DMean% , D95% ) and 3D gamma index passing rates were evaluated for both setup modalities for each planned target volume (PTV) at a variety of thresholds: 3%/2 mm (Exactrac≥93.1% and CRAD ≥87.2%), 5%/2 mm (Exactrac≥95.6% and CRAD ≥94.6%), and 5%/1 mm (Exactrac≥81.8% and CRAD ≥83.7%). CONCLUSION: Dose metrics for a setup with surface imaging was found to be consistent with setup using x-ray imaging, demonstrating high accuracy and reproducibility for treatment delivery. Results indicate the feasibility of using surface imaging for position verification at noncoplanar couch angles for single-isocenter, multiple-target SRS using end-to-end quality assurance (QA) testing with 3D polymer gel dosimetry.

Antiparasitic Derivatives of the Furoquinoline Alkaloids Kokusaginine And Flindersiamine.

We report the synthesis of 16 new compounds obtained from kokusaginine and flindersiamine, the main alkaloids isolated from the bark of Balfourodendron riedelianum. The activity of the compounds against axenic cultures of Trypanosoma cruzi epimastigtotes and trypomastigotes, as well as intracellular amastigotes, is described, together with their cytotoxic activity against three different human cell lines. The synthetic strategy for the preparation of the new compounds was based on the reactivity at the C4 position of the furoquinoline core towards nucleophiles. The new derivatives were synthesized by a Buchwald-Hartwig reaction, in most cases under green, solvent-free conditions. Compounds 1 c and 1 e displayed better in-vitro activity against trypomastigotes than benznidazole and nifurtimox (positive controls) with IC50 <4 µM. In addition, both compounds were not cytotoxic against the three human cell lines K562 (erytroleukimia), LM2 (breast cancer), and HaCat (keratinocyte). Interestingly, when evaluated against intracellular amastigotes, compound 1 c was able to significantly reduce the number of this parasite form, compared to the negative control.

Photosensitization of a subcutaneous tumour by the natural anthraquinone parietin and blue light.

Photodynamic therapy (PDT) is an anticancer treatment involving administration of a tumour-localizing photosensitizer, followed by activation by light of a suitable wavelength. In previous work, we showed that the natural anthraquinone (AQ) Parietin (PTN), was a promising photosensitizer for photodynamic therapy of leukemic cells in vitro. The present work aimed to analyze the photosensitizing ability of PTN in the mammary carcinoma LM2 cells in vitro and in vivo in a model of subcutaneously implanted tumours. Photodynamic therapy mediated by parietin (PTN-PDT) (PTN 30 µM, 1 h and 1.78 J/cm2 of blue light) impaired cell growth and migration of LM2 cells in vitro. PTN per se induced a significant decrease in cell migration, and it was even more marked after illumination (migration index was 0.65 for PTN and 0.30 for PTN-PDT, *p < 0.0001, ANOVA test followed by Tukey's multiple comparisons test), suggesting that both PTN and PTN-PDT would be potential inhibitors of metastasis. Fluorescence microscopy observation indicated cytoplasmic localization of the AQ and no fluorescence at all was recorded in the nuclei. When PTN (1.96 mg) dissolved in dimethyl sulfoxide was topically applied on the skin of mice subcutaneously implanted with LM2 cells, PTN orange fluorescence was strongly noticed in the stratum corneum and also in the inner layers of the tumour up to approximately 5 mm. After illumination with 12.74 J/cm2 of blue light, one PDT dose at day 1, induced a significant tumour growth delay at day 3, which was not maintained in time. Therefore, we administered a second PTN-PDT boost on day 3. Under these conditions, the delay of tumour growth was 28% both on days 3 and 4 of the experiment (*p < 0.05 control vs. PTN-PDT, two-way ANOVA, followed by Sidak's multiple comparisons test). Histology of tumours revealed massive tumour necrosis up to 4 mm of depth. Intriguingly, a superficial area of viable tumour in the 1 mm superficial area, and a quite conserved intact skin was evidenced. We hypothesize that this may be due to PTN aggregation in contact with the skin and tumour milieu of the most superficial tumour layers, thus avoiding its photochemical properties. On the other hand, normal skin treated with PTN-PDT exhibited slight histological changes. These preliminary findings encourage further studies of natural AQs administered in different vehicles, for topical treatment of cutaneous malignancies.

Effects of varying statistical uncertainty using a Monte Carlo based treatment planning system for VMAT.

PURPOSE: To determine the severity of the effects on VMAT dose calculations caused by varying statistical uncertainties (SU) per control point in a Monte Carlo based treatment planning system (TPS) and to assess the impact of the uncertainty during dose volume histogram (DVH) evaluation. METHODS: For this study, 13 archived patient plans were selected for recalculation. Treatment sites included prostate, lung, and head and neck. These plans were each recalculated five times with varying uncertainty levels using Elekta's Monaco Version 5.11.00 Monte Carlo Gold Standard XVMC dose calculation algorithm. The statistical uncertainty per control point ranged from 2 to 10% at intervals of 2%, while the grid spacing was set at 3 mm for all calculations. Indices defined by the RTOG describing conformity, coverage, and homogeneity were recorded for each recalculation. RESULTS: For all indices tested, one-way ANOVA tests failed to reject the null hypothesis that there is no significant difference between SU levels (p>0.05). Using the Bland-Altman analysis method, it was determined that we can expect the indices (with the exception of CIRTOG) to be within 1% of the lowest uncertainty calculation when calculating at 4% SU per control point. Beyond that, we can expect the indices to be within 3% of the lowest uncertainty calculation. CONCLUSION: Increasing the SU per control point exponentially decreased the amount of time required for dose calculations, while creating minimal observable differences in DVHs and isodose lines.

Urological Cancer Treatment by a Multidisciplinary Teamthroughout the Covid-19 Pandemic: What Have We Learned? / Tratamiento del cáncer urológico por un equipo multidisciplinario durante la pandemia de Covid-19: ¿Qué hemos aprendido?

Introduction It is known that cancer care is best approached by a multidisciplinary team (MDT). This became specifically true in the Covid-19 pandemic in which choices for urological cancer treatment are influenced by many factors. In some cases, delayed treatment may have consequences regarding the patient's oncological outcomes. The aim of the present article is to report our experience throughout the Covid-19 pandemic treating patients with urological neoplasms at a high-volume center. Methods We used a convenience sampling method. Cases were evaluated and discussed on an individual basis at the MDT meetings, and, after a consensus regarding delaying or scheduling treatment, patients were scheduled according to the risk of postponing the procedures. The Medically Necessary, Time-Sensitive (MeNTS) scoring system was measured in each patient; all patients answered the Centers for Disease Control and Prevention (CDC) Covid-19 self-screening questionnaire prior to surgery. The Covid-19-free survival rate was estimated. Results A total of 194 patients were assessed by themultidisciplinary team and finally treated, with median follow-up of 4 (interquartile range [IQR]: 2.75 to 6) months. Only two patients had Covid-19 confirmed by real-time polymerase chain reaction (RT-PCR). In total, 54 patients underwent oncological surgery, 129 were treated with radiotherapy, and 11 were treated with intravenous chemotherapy. Themedian age was 66 years (IQR: 59 to 94 years), and the median MeNTS score in the surgically-treated cohort was 35 points (IQR: 31 to 47 points). Conclusions The evaluation and treatment of urological cancer should be conducted by an MDT; this is of utmost importance, especially during the Covid-19 pandemic. The data collected in our institution showed that most patients could be safely treated by taking all necessary precautions and discussing each case individually in the MDT meetings and performing a close follow-up.

Introduccion La atención del cáncer se aborda mejor con un equipo multidisciplinario (EMD), aspecto que se tornó más importante en la pandemia por Covid-19, en que las opciones para tratar el cáncer urológico están influenciadas por muchos factores. En algunos casos, el tratamiento retrasado puede tener consecuencias en los resultados oncológicos del paciente. El objetivo de este estudio es describir nuestra experiencia en un centro de referencia y de alto volumen para el tratamiento de neoplasias urológicas durante la pandemia por Covid-19. Métodos Realizamos un muestreo por conveniencia. Posteriormente, los casos fueron evaluados y discutidos de forma individual en las reuniones del EMD. Posterior a la obtención de un consenso sobre el tratamiento del paciente, los pacientes fueron programados según el riesgo individual de posponer el manejo. Se midió la puntuación de cada paciente en el sistema Medically Necessary Time-Sensitive (MeNTS, "Médicamente necesario, sensibles al tiempo"). Todos los pacientes respondieron el cuestionario de autoevaluación del Centers for Disease Control and Prevention (CDC) COVID-19 antes de la cirugía. Se estimó la tasa de supervivencia libre de Covid-19. Resultados Un total de 194 pacientes fueron evaluados por el EMD y finalmente tratados, con una mediana de seguimiento de 4 (rango intercuartil [RIC]: 2,75 a 6) meses. Solo dos tenían Covid-19 confirmado por reacción en cadena de la polimerasa en tiempo real (RCP-TR). Un total de 54 pacientes fueron sometidos a cirugía oncológica, 129 fueron tratados con radioterapia, y 11 fueron tratados con quimioterapia intravenosa. La mediana de edad fue de 66 años (RIC: 59 a 94 años), la puntuación mediana en el MeNTS de la cohorte tratada quirúrgicamente fue de 35 puntos (RIC: 31 a 47 puntos). Conclusiones La evaluación y el tratamiento del cáncer urológico debe ser realizado por un EMD durante la pandemia de Covid-19. Los datos recopilados en nuestra institución mostraron que la mayoría de los pacientes podrían ser tratados de manera segura, discutiendo cada caso individualmente y haciendo un seguimiento cercano.

A customizable aluminum compensator system for total body irradiation.

PURPOSE: To develop a simplified aluminum compensator system for total body irradiation (TBI) that is easy to assemble and modify in a short period of time for customized patient treatments. METHODS: The compensator is composed of a combination of 0.3 cm thick aluminum bars, two aluminum T-tracks, spacers, and metal bolts. The system is mounted onto a plexiglass block tray. The design consists of 11 fixed sectors spanning from the patient's head to feet. The outermost sectors utilize 7.6 cm wide aluminum bars, while the remaining sectors use 2.5 cm wide aluminum bars. There is a magnification factor of 5 from the compensator to the patient treatment plane. Each bar of aluminum is interconnected at each adjacent sector with a tongue and groove arrangement and fastened to the T-track using a metal washer, bolt, and nut. Inter-bar leakage of the compensator was tested using a water tank and diode. End-to-end measurements were performed with an ion chamber in a solid water phantom and also with a RANDO phantom using internal and external optically stimulated luminescent detectors (OSLDs). In-vivo patient measurements from the first 20 patients treated with this aluminum compensator were compared to those from 20 patients treated with our previously used lead compensator system. RESULTS: The compensator assembly time was reduced to 20-30 min compared to the 2-4 h it would take with the previous lead design. All end-to-end measurements were within 10% of that expected. The median absolute in-vivo error for the aluminum compensator was 3.7%, with 93.8% of measurements being within 10% of that expected. The median error for the lead compensator system was 5.3%, with 85.1% being within 10% of that expected. CONCLUSION: This design has become the standard compensator at our clinic. It allows for quick assembly and customization along with meeting the Task Group 29 recommendations for dose uniformity.

Photodynamic therapy of cutaneous T-cell lymphoma cell lines mediated by 5-aminolevulinic acid and derivatives.

The delta-amino acid 5-aminolevulinic acid (ALA), is the precursor of the endogenous photosensitiser Protoporphyrin IX (PpIX), and is currently approved for Photodynamic Therapy (PDT) of certain superficial cancers. However, ALA-PDT is not very effective in diseases in which T-cells play a significant role. Cutaneous T-cell lymphomas (CTCL) is a group of non-Hodgkin malignant diseases, which includes mycosis fungoides (MF) and Sézary syndrome (SS). In previous work, we have designed new ALA esters synthesised by three-component Passerini reactions, and some of them showed higher performance as compared to ALA. This work aimed to determine the efficacy as pro-photosensitisers of five new ALA esters of 2-hydroxy-N-arylacetamides (1f, 1 g, 1 h, 1i and 1 k) of higher lipophilicity than ALA in Myla cells of MF and HuT-78 cells of SS. We have also tested its effectiveness against ALA and the already marketed ALA methyl ester (Me-ALA) and ALA hexyl ester (He-ALA). Both cell Myla and SS cells were effectively and equally photoinactivated by ALA-PDT. Besides, the concentration of ALA required to induce half the maximal porphyrin synthesis was 209 µM for Myla and 169 µM for HuT-78 cells. As a criterion of efficacy, we calculated the concentration of the ALA derivatives necessary to induce half the plateau porphyrin values obtained from ALA. These values were achieved at concentrations 4 and 12 times lower compared to ALA, according to the derivative used. For He-ALA, concentrations were 24 to 25 times lower than required for ALA for inducing comparable porphyrin synthesis in both CTCL cells. The light doses for inducing 50% of cell death (LD50) for He-ALA, 1f, 1 g, 1 h and 1i were around 18 and 25 J/cm2 for Myla and HuT-78 cells respectively, after exposure to 0.05 mM concentrations of the compounds. On the other hand, the LD50s for the compound 1 k were 40 and 57 J/cm2 for Myla and HuT-78, respectively. In contrast, 0.05 mM of ALA and Me-ALA did not provoke photokilling since the concentration employed was far below the porphyrin saturation point for these compounds. Our results suggest the potential use of ALA derivatives for topical application in PDT treatment of MF and extracorporeal PDT for the depletion of activated T-cells in SS.

On the evaluation of mobile target trajectory between four-dimensional computer tomography and four-dimensional cone-beam computer tomography.

PURPOSE: For mobile lung tumors, four-dimensional computer tomography (4D CT) is often used for simulation and treatment planning. Localization accuracy remains a challenge in lung stereotactic body radiation therapy (SBRT) treatments. An attractive image guidance method to increase localization accuracy is 4D cone-beam CT (CBCT) as it allows for visualization of tumor motion with reduced motion artifacts. However, acquisition and reconstruction of 4D CBCT differ from that of 4D CT. This study evaluates the discrepancies between the reconstructed motion of 4D CBCT and 4D CT imaging over a wide range of sine target motion parameters and patient waveforms. METHODS: A thorax motion phantom was used to examine 24 sine motions with varying amplitudes and cycle times and seven patient waveforms. Each programmed motion was imaged using 4D CT and 4D CBCT. The images were processed to auto segment the target. For sine motion, the target centroid at each phase was fitted to a sinusoidal curve to evaluate equivalence in amplitude between the two imaging modalities. The patient waveform motion was evaluated based on the average 4D data sets. RESULTS: The mean difference and root-mean-square-error between the two modalities for sine motion were -0.35 ± 0.22 and 0.60 mm, respectively, with 4D CBCT slightly overestimating amplitude compared with 4D CT. The two imaging methods were determined to be significantly equivalent within ±1 mm based on two one-sided t tests (p < 0.001). For patient-specific motion, the mean difference was 1.5 ± 2.1 (0.8 ± 0.6 without outlier), 0.4 ± 0.3, and 0.8 ± 0.6 mm for superior/inferior (SI), anterior/posterior (AP), and left/right (LR), respectively. CONCLUSION: In cases where 4D CT is used to image mobile tumors, 4D CBCT is an attractive localization method due to its assessment of motion with respect to 4D CT, particularly for lung SBRT treatments where accuracy is paramount.

Novel meso-substituted porphyrin derivatives and its potential use in photodynamic therapy of cancer.

BACKGROUND: Photodynamic therapy (PDT) is an anticancer treatment that utilizes the interaction of light and a photosensitiser (PS), promoting tumour cell death mediated by generation of reactive oxygen species. In this study, we evaluated the in vitro photoactivity of four meso-substituted porphyrins and a porphyrin coupled to a fullerene. METHODS: The cell line employed was the LM3 mammary adenocarcinoma, and the PS with the best photokilling activity was administered to mice bearing the LM3 subcutaneously implanted adenocarcinoma. The TEMCP4+ porphyrin and its analogue TEMCC4+ chlorine contain four identical carbazoyl substituents at the meso positions of the tetrapyrrolic macrocycle and have A4 symmetry. The TAPP derivative also has A4 symmetry, and it is substituted at the meso positions by aminopropoxy groups. The DAPP molecule has ABAB symmetry with aminopropoxy and the trifluoromethyl substituents in trans positions. The TCP-C604+ dyad is formed by a porphyrin unit covalently attached to the fullerene C60. RESULTS: The PSs are taken up by the cells with the following efficiency: TAPP> TEMCP4+ = TEMCC4+ > DAPP >TCP-C604+, and the amount of intracellular PS correlates fairly with the photodamage degree, but also the quantum yields of singlet oxygen influence the PDT outcome. TAPP, DAPP, TEMCC4+ and TEMCP4+ exhibit high photoactivity against LM3 mammary carcinoma cells, being TAPP the most active. After topical application of TAPP on the skin of mice bearing LM3 tumours, the molecule is localized mainly in the stratum corneum, and at a lower extent in hair follicles and sebaceous glands. Systemic administration of TAPP produces a tumour: normal skin ratio of 31.4, and high accumulation in intestine and lung. CONCLUSION: The results suggest a potential use of topical TAPP for the treatment of actinic keratosis and skin adnexal neoplasms. In addition, selectivity for tumour tissue after systemic administration highlights the selectivity of and potentiality of TAPP as a new PS.

Robustness of single-isocenter multiple-metastasis stereotactic radiosurgery end-to-end testing across institutions.

The accuracy of stereotactic radiosurgery (SRS) to multiple metastases with a single-isocenter using high definition dynamic radiosurgery (HDRS) was evaluated across institutions. An SRS plan was delivered at six HDRS-capable institutions to an anthropomorphic phantom consisting of point, film, and 3D-gel dosimeters. Direct dose comparison and gamma analysis were used to evaluate the accuracy. Point measurements averaged across institutions were within 1.2±0.5%. The average gamma passing rate in the film was 96.6±2.2% (3%/2 mm). For targets within 4 cm of the isocenter, the 3D dosimetric gel gamma passing rate averaged across institutions was >90% (3%/2 mm). The targeting accuracy of high definition dynamic radiosurgery assessed by geometrical offset of the center of dose distributions across multiple institutions in this study was within 1 mm for targets within 4 cm of isocenter. Across variations in clinical practice, comparable dosimetry and localization is possible with this treatment planning and delivery technique.

Apoptotic cell death induced by dendritic derivatives of aminolevulinic acid in endothelial and foam cells co-cultures.

Photodynamic therapy (PDT) is an effective procedure for the treatment of lesions diseases based on the selectivity of a photosensitising compound with the ability to accumulate in the target cell. Atherosclerotic plaque is a suitable target for PDT because of the preferential accumulation of photosensitisers in atherosclerotic plaques. Dendrimers are hyperbranched polymers conjugated to drugs. The dendrimers of ALA hold ester bonds that inside the cells are cleaved and release ALA, yielding PpIX production. The dendrimer 6m-ALA was chosen to perform this study since in previous studies it induced the highest porphyrin macrophage: endothelial cell ratio (Rodriguez et al. in Photochem Photobiol Sci 14:1617-1627, 2015). We transformed Raw 264.7 macrophages to foam cells by exposure to oxidised LDLs, and we employed a co-culture model of HMEC-1 endothelial cells and foam cells to study the affinity of ALA dendrimers for the foam cells. In this work it was proposed an in vitro model of atheromatous plaque, the aim was to study the selectivity of an ALA dendrimer for the foam cells as compared to the endothelial cells in a co-culture system and the type of cell death triggered by the photodynamic treatment. The ALA dendrimer 6m-ALA showed selectivity PDT response for foam cells against endothelial cells. A light dose of 1 J/cm2 eliminate foam cells, whereas less than 50% of HMEC-1 is killed, and apoptosis cell death is involved in this process, and no necrosis is present. We propose the use of ALA dendrimers as pro-photosensitisers to be employed in photoangioplasty to aid in the treatment of obstructive cardiovascular diseases, and these molecules can also be employed as a theranostic agent.

Quantifying false positional corrections due to facial motion using SGRT with open-face Masks.

PURPOSE: Studies have evaluated the viability of using open-face masks as an immobilization technique to treat intracranial and head and neck cancers. This method offers less stress to the patient with comparable accuracy to closed-face masks. Open-face masks permit implementation of surface guided radiation therapy (SGRT) to assist in positioning and motion management. Research suggests that changes in patient facial expressions may influence the SGRT system to generate false positional corrections. This study aims to quantify these errors produced by the SGRT system due to face motion. METHODS: Ten human subjects were immobilized using open-face masks. Four discrete SGRT regions of interest (ROIs) were analyzed based on anatomical features to simulate different mask openings. The largest ROI was lateral to the cheeks, superior to the eyebrows, and inferior to the mouth. The smallest ROI included only the eyes and bridge of the nose. Subjects were asked to open and close their eyes and simulate fear and annoyance and peak isocenter shifts were recorded. This was performed in both standard and SRS specific resolutions with the C-RAD Catalyst HD system. RESULTS: All four ROIs analyzed in SRS and Standard resolutions demonstrated an average deviation of 0.3 ± 0.3 mm for eyes closed and 0.4 ± 0.4 mm shift for eyes open, and 0.3 ± 0.3 mm for eyes closed and 0.8 ± 0.9 mm shift for eyes open. The average deviation observed due to changing facial expressions was 1.4 ± 0.9 mm for SRS specific and 1.6 ± 1.6 mm for standard resolution. CONCLUSION: The SGRT system can generate false positional corrections for face motion and this is amplified at lower resolutions and smaller ROIs. These errors should be considered in the overall tolerances and treatment plan when using open-face masks with SGRT and may warrant additional radiographic imaging.

Photodynamic therapy of tumour cells mediated by the natural anthraquinone parietin and blue light.

Photodynamic therapy (PDT) is a treatment for superficial tumours involving the administration of a photosensitiser followed by irradiation. The potential of the natural anthraquinone parietin (PTN) in PDT is still relatively unexploited. In the present work, PTN isolated from the lichen Teoloschistes nodulifer (Nyl.) Hillman (Telochistaceae) was evaluated as a potential photosensitiser on tumour cells employing UVA-Vis and blue light. Blue light of 2 J/cm2 induced 50% death of K562 leukaemic cells treated 1 h with 30 µM PTN (Protocol a). Higher light doses (8 J/cm2) were needed to achieve the same percentage of cell death employing lower PTN concentrations (3 µM) and higher exposure times (24 h) (Protocol b). Cell cycle analysis after both protocols of PTN-PDT revealed a high percentage of sub-G1 cells. PTN was found to be taken up by K562 cells mainly by passive diffusion. Other tumour cells such as ovary cancer IGROV-1 and LM2 mammary carcinoma, as well as the normal keratinocytes HaCaT, were also photosensitised with PTN-PDT. We conclude that PTN is a promising photosensitiser for PDT of superficial malignancies and purging of leukaemic cells, when illuminated with blue light. Thus, this light wavelength is proposed to replace the Vis-UVA lamps generally employed for the photosensitisation of anthraquinones.

An open-source tool to visualize potential cone collisions while planning SRS cases.

PURPOSE: To create an open-source visualization program that allows one to find potential cone collisions while planning intracranial stereotactic radiosurgery cases. METHODS: Measurements of physical components in the treatment room (gantry, cone, table, localization stereotactic radiation surgery frame, etc.) were incorporated into a script in MATLAB (MathWorks, Natick, MA) that produces three-dimensional visualizations of the components. A localization frame, used during simulation, fully contains the patient. This frame was used to represent a safety zone for collisions. Simple geometric objects are used to approximate the simulated components. The couch is represented as boxes, the gantry head and cone are represented by cylinders, and the patient safety zone can be represented by either a box or ellipsoid. These objects are translated and rotated based upon the beam geometry and the treatment isocenter to mimic treatment. A simple graphical user interface (GUI) was made in MATLAB (compatible with GNU Octave) to allow users to pass the treatment isocenter location, the initial and terminal gantry angles, the couch angle, and the number of angular points to visualize between the initial and terminal gantry angle. RESULTS: The GUI provides a fast and simple way to discover collisions in the treatment room before the treatment plan is completed. Twenty patient arcs were used as an end-to-end validation of the system. Seventeen of these appeared the same in the software as in the room. Three of the arcs appeared closer in the software than in the room. This is due to the treatment couch having rounded corners, whereas the software visualizes sharp corners. CONCLUSIONS: This simple GUI can be used to find the best orientation of beams for each patient. By finding collisions before a plan is being simulated in the treatment room, a user can save time due to replanning of cases.

Deep learning-based survival analysis for brain metastasis patients with the national cancer database.

PURPOSE: Prognostic indices such as the Brain Metastasis Graded Prognostic Assessment have been used in clinical settings to aid physicians and patients in determining an appropriate treatment regimen. These indices are derivative of traditional survival analysis techniques such as Cox proportional hazards (CPH) and recursive partitioning analysis (RPA). Previous studies have shown that by evaluating CPH risk with a nonlinear deep neural network, DeepSurv, patient survival can be modeled more accurately. In this work, we apply DeepSurv to a test case: breast cancer patients with brain metastases who have received stereotactic radiosurgery. METHODS: Survival times, censorship status, and 27 covariates including age, staging information, and hormone receptor status were provided for 1673 patients by the NCDB. Monte Carlo cross-validation with 50 samples of 1400 patients was used to train and validate the DeepSurv, CPH, and RPA models independently. DeepSurv was implemented with L2 regularization, batch normalization, dropout, Nesterov momentum, and learning rate decay. RPA was implemented as a random survival forest (RSF). Concordance indices of test sets of 140 patients were used for each sample to assess the generalizable predictive capacity of each model. RESULTS: Following hyperparameter tuning, DeepSurv was trained at 32 min per sample on a 1.33 GHz quad-core CPU. Test set concordance indices of 0.7488 ± 0.0049, 0.6251 ± 0.0047, and 0.7368 ± 0.0047, were found for DeepSurv, CPH, and RSF, respectively. A Tukey HSD test demonstrates a statistically significant difference between the mean concordance indices of the three models. CONCLUSION: Our results suggest that deep learning-based survival prediction can outperform traditional models, specifically in a case where an accurate prognosis is highly clinically relevant. We recommend that where appropriate data are available, deep learning-based prognostic indicators should be used to supplement classical statistics.

Patient-specific dose quality assurance of single-isocenter multiple brain metastasis stereotactic radiosurgery using PTW Octavius 4D.

PURPOSE: Single-isocenter multiple brain metastasis stereotactic radiosurgery is an efficient treatment modality increasing in clinical practice. The need to provide accurate, patient-specific quality assurance (QA) for these plans is met by several options. This study reviews some of these options and explores the use of the Octavius 4D as a solution for patient-specific plan quality assurance. METHODS: The Octavius 4D Modular Phantom (O4D) with the 1000 SRS array was evaluated in this study. The array consists of 977 liquid-filled ion chambers. The center 5.5 cm × 5.5 cm area has a detector spacing of 2.5 mm. The ability of the O4D to reconstruct three-dimensional (3D) dose was validated against a 3D gel dosimeter, ion chamber, and film measurements. After validation, 15 patients with 2-11 targets had their plans delivered to the phantom. The criteria used for the gamma calculation was 3%/1 mm. The portion of targets which were measurable by the phantom was countable. The accompanying software compiled the measured doses allowing each target to be counted from the measured dose distribution. RESULTS: Spatial resolution was sufficient to verify the high dose distributions characteristic of SRS. Amongst the 15 patients there were 74 targets. Of the 74 targets, 61 (82%) of them were visible on the measured dose distribution. The average gamma passing rate was 99.3% (with sample standard deviation of 0.68%). CONCLUSIONS: The high resolution provided by the O4D with 1000 SRS board insert allows for very high-resolution measurement. This high resolution in turn can allow for high gamma passing rates. The O4D with the 1000 SRS array is an acceptable method of performing quality assurance for single-isocenter multiple brain metastasis SRS.

Dose Calculation Comparisons between Three Modern Treatment Planning Systems.

PURPOSE: Monaco treatment planning system (TPS) version 5.1 uses a Monte-Carlo (MC)-based dose calculation engine. The aim of this study is to verify and compare the Monaco-based dose calculations with both Pinnacle3 collapsed cone convolution superposition (CCCS) and Eclipse anisotropic analytical algorithm (AAA) calculations. MATERIALS AND METHODS: For this study, 18 previously treated lung and head-and-neck (HN) cancer patients were chosen to compare the dose calculations between Pinnacle, Monaco, and Eclipse. Plans were chosen from those that had been treated using the Elekta VersaHD or a Novalis Tx linac. All of the treated volumetric-modulated arc therapy plans used 6 MV or 10 MV photon beams. The original plans calculated with CCCS or AAA along with the recalculated ones using MC from the three TPS were exported into Velocity software for intercomparison. RESULTS: To compare the dose calculations, Planning target volume (PTV) heterogeneity indexes and conformity indexes were calculated from the dose volume histograms (DVH) of all plans. While mean lung dose (MLD), lung V5 and V20 values were recorded for lung plans, the computed dose to parotids, brainstem, and mandible were documented for HN plans. In plan evaluation, percent differences of the above dosimetric values in Monaco computation were compared against each of the other TPS computations. CONCLUSION: It could be concluded through this research that there can be differences in the calculation of dose across different TPSs. Although relatively small, these differences could become apparent when compared using DVH. These differences most likely arise from the different dose calculation algorithms used in each TPS. Monaco employs the MC allowing it to have much more detailed calculations that result in it being seen as the most accurate and the gold standard.