A methodology to extract outcomes from routine healthcare data for patients with locally advanced non-small cell lung cancer.

BACKGROUND: Outcomes for patients in UK with locally advanced non-small cell lung cancer (LA NSCLC) are amongst the worst in Europe. Assessing outcomes is important for analysing the effectiveness of current practice. However, data quality is inconsistent and regular large scale analysis is challenging. This project investigates the use of routine healthcare datasets to determine progression free survival (PFS) and overall survival (OS) of patients treated with primary radical radiotherapy for LA NSCLC. METHODS: All LA NSCLC patients treated with primary radical radiotherapy in a 2 year period were identified and paired manual and routine data generated for an initial pilot study. Manual data was extracted information from hospital records and considered the gold standard. Key time points were date of diagnosis, recurrence, death or last clinical encounter. Routine data was collected from various data sources including, Hospital Episode Statistics, Personal Demographic Service, chemotherapy data, and radiotherapy datasets. Relevant event dates were defined by proxy time points and refined using backdating and time interval optimization. Dataset correlations were then tested on key clinical outcome indicators to establish if routine data could be used as a reliable proxy measure for manual data. RESULTS: Forty-three patients were identified for the pilot study. The manual data showed a median age of 67 years (range 46- 89 years) and all patients had stage IIIA/B disease. Using the manual data, the median PFS was 10.78 months (range 1.58-37.49 months) and median OS was 16.36 months (range 2.69-37.49 months). Based on routine data, using proxy measures, the estimated median PFS was 10.68 months (range 1.61-31.93 months) and estimated median OS was 15.38 months (range 2.14-33.71 months). Overall, the routine data underestimated the PFS and OS of the manual data but there was good correlation with a Pearson correlation coefficient of 0.94 for PFS and 0.97 for OS. CONCLUSIONS: This is a novel approach to use routine datasets to determine outcome indicators in patients with LA NSCLC that will be a surrogate to analysing manual data. The ability to enable efficient and large scale analysis of current lung cancer strategies has a huge potential impact on the healthcare system.

A comparison of the dose distributions from three proton treatment planning systems in the planning of meningioma patients with single-field uniform dose pencil beam scanning.

With the number of new proton centers increasing rapidly, there is a need for an assessment of the available proton treatment planning systems (TPSs). This study compares the dose distributions of complex meningioma plans produced by three proton TPSs: Eclipse, Pinnacle3, and XiO. All three systems were commissioned with the same beam data and, as best as possible, matched configuration settings. Proton treatment plans for ten patients were produced on each system with a pencil beam scanning, single-field uniform dose approach, using a fixed horizontal beamline. All 30 plans were subjected to identical dose constraints, both for the target coverage and organ at risk (OAR) sparing, with a consistent order of priority. Beam geometry, lateral field margins, and lateral spot resolutions were made consistent across all systems. Few statistically significant differences were found between the target coverage and OAR sparing of each system, with all optimizers managing to produce plans within clinical tolerances (D2 < 107% of prescribed dose, D5 < 105%, D95 > 95%, D99 > 90%, and OAR maximum doses) despite strict constraints and overlapping structures.

A 3D in vitro cancer model as a platform for nanoparticle uptake and imaging investigations.

In order to maximize the potential of nanoparticles (NPs) in cancer imaging and therapy, their mechanisms of interaction with host tissue need to be fully understood. NP uptake is known to be dramatically influenced by the tumor microenvironment, and an imaging platform that could replicate in vivo cellular conditions would make big strides in NP uptake studies. Here, a novel NP uptake platform consisting of a tissue-engineered 3D in vitro cancer model (tumoroid), which mimics the microarchitecture of a solid cancer mass and stroma, is presented. As the tumoroid exhibits fundamental characteristics of solid cancer tissue and its cellular and biochemical parameters are controllable, it provides a real alternative to animal models. Furthermore, an X-ray fluorescence imaging system is developed to demonstrate 3D imaging of GNPs and to determine uptake efficiency within the tumoroid. This platform has implications for optimizing the targeted delivery of NPs to cells to benefit cancer diagnostics and therapy.

Integrated-mode proton radiography with 2D lateral projections.

Integrated-mode proton radiography leading to water equivalent thickness (WET) maps is an avenue of interest for motion management, patient positioning, andin vivorange verification. Radiographs can be obtained using a pencil beam scanning setup with a large 3D monolithic scintillator coupled with optical cameras. Established reconstruction methods either (1) involve a camera at the distal end of the scintillator, or (2) use a lateral view camera as a range telescope. Both approaches lead to limited image quality. The purpose of this work is to propose a third, novel reconstruction framework that exploits the 2D information provided by two lateral view cameras, to improve image quality achievable using lateral views. The three methods are first compared in a simulated Geant4 Monte Carlo framework using an extended cardiac torso (XCAT) phantom and a slanted edge. The proposed method with 2D lateral views is also compared with the range telescope approach using experimental data acquired with a plastic volumetric scintillator. Scanned phantoms include a Las Vegas (contrast), 9 tissue-substitute inserts (WET accuracy), and a paediatric head phantom. Resolution increases from 0.24 (distal) to 0.33 lp mm-1(proposed method) on the simulated slanted edge phantom, and the mean absolute error on WET maps of the XCAT phantom is reduced from 3.4 to 2.7 mm with the same methods. Experimental data from the proposed 2D lateral views indicate a 36% increase in contrast relative to the range telescope method. High WET accuracy is obtained, with a mean absolute error of 0.4 mm over 9 inserts. Results are presented for various pencil beam spacing ranging from 2 to 6 mm. This work illustrates that high quality proton radiographs can be obtained with clinical beam settings and the proposed reconstruction framework with 2D lateral views, with potential applications in adaptive proton therapy.

A likelihood-based particle imaging filter using prior information.

BACKGROUND: Particle imaging can increase precision in proton and ion therapy. Interactions with nuclei in the imaged object increase image noise and reduce image quality, especially for multinucleon ions that can fragment, such as helium. PURPOSE: This work proposes a particle imaging filter, referred to as the Prior Filter, based on using prior information in the form of an estimated relative stopping power (RSP) map and the principles of electromagnetic interaction, to identify particles that have undergone nuclear interaction. The particles identified as having undergone nuclear interactions are then excluded from the image reconstruction, reducing the image noise. METHODS: The Prior Filter uses Fermi-Eyges scattering and Tschalär straggling theories to determine the likelihood that a particle only interacts electromagnetically. A threshold is then set to reject those particles with a low likelihood. The filter was evaluated and compared with a filter that estimates this likelihood based on the measured distribution of energy and scattering angle within pixels, commonly implemented as the 3σ filter. Reconstructed radiographs from simulated data of a 20-cm water cylinder and an anthropomorphic chest phantom were generated with both protons and helium ions to assess the effect of the filters on noise reduction. The simulation also allowed assessment of secondary particle removal through the particle histories. Experimental data were acquired of the Catphan CTP 404 Sensitometry phantom using the U.S. proton CT (pCT) collaboration prototype scanner. The proton and helium images were filtered with both the prior filtering method and a state-of-the-art method including an implementation of the 3σ filter. For both cases, a dE-E telescope filter, designed for this type of detector, was also applied. RESULTS: The proton radiographs showed a small reduction in noise (1 mm of water-equivalent thickness [WET]) but a larger reduction in helium radiographs (up to 5-6 mm of WET) due to better secondary filtering. The proton and helium CT images reflected this, with similar noise at the center of the phantom (0.02 RSP) for the proton images and an RSP noise of 0.03 for the proposed filter and 0.06 for the 3σ filter in the helium images. Images reconstructed from data with a dose reduction, up to a factor of 9, maintained a lower noise level using the Prior Filter over the state-of-the-art filtering method. CONCLUSIONS: The proposed filter results in images with equal or reduced noise compared to those that have undergone a filtering method typical of current particle imaging studies. This work also demonstrates that the proposed filter maintains better performance against the state of the art with up to a nine-fold dose reduction.

Isotoxic dose escalated radiotherapy for glioblastoma based on diffusion-weighted MRI and tumor control probability-an in-silico study.

OBJECTIVES: Glioblastoma (GBM) is the most common malignant primary brain tumor with local recurrence after radiotherapy (RT), the most common mode of failure. Standard RT practice applies the prescription dose uniformly across tumor volume disregarding radiological tumor heterogeneity. We present a novel strategy using diffusion-weighted (DW-) MRI to calculate the cellular density within the gross tumor volume (GTV) in order to facilitate dose escalation to a biological target volume (BTV) to improve tumor control probability (TCP). METHODS: The pre-treatment apparent diffusion coefficient (ADC) maps derived from DW-MRI of ten GBM patients treated with radical chemoradiotherapy were used to calculate the local cellular density based on published data. Then, a TCP model was used to calculate TCP maps from the derived cell density values. The dose was escalated using a simultaneous integrated boost (SIB) to the BTV, defined as the voxels for which the expected pre-boost TCP was in the lowest quartile of the TCP range for each patient. The SIB dose was chosen so that the TCP in the BTV increased to match the average TCP of the whole tumor. RESULTS: By applying a SIB of between 3.60 Gy and 16.80 Gy isotoxically to the BTV, the cohort's calculated TCP increased by a mean of 8.44% (ranging from 7.19 to 16.84%). The radiation dose to organ at risk is still under their tolerance. CONCLUSIONS: Our findings indicate that TCPs of GBM patients could be increased by escalating radiation doses to intratumoral locations guided by the patient's biology (i.e., cellularity), moreover offering the possibility for personalized RT GBM treatments. ADVANCES IN KNOWLEDGE: A personalized and voxel level SIB radiotherapy method for GBM is proposed using DW-MRI, which can increase the tumor control probability and maintain organ at risk dose constraints.

International Multicenter Study of Clinical Outcomes of Sinonasal Melanoma Shows Survival Benefit for Patients Treated with Immune Checkpoint Inhibitors and Potential Improvements to the Current TNM Staging System.

Objectives Sinonasal mucosal melanoma (SNMM) is an extremely rare and challenging sinonasal malignancy with a poor prognosis. Standard treatment involves complete surgical resection, but the role of adjuvant therapy remains unclear. Crucially, our understanding of its clinical presentation, course, and optimal treatment remains limited, and few advancements in improving its management have been made in the recent past. Methods We conducted an international multicenter retrospective analysis of 505 SNMM cases from 11 institutions across the United States, United Kingdom, Ireland, and continental Europe. Data on clinical presentation, diagnosis, treatment, and clinical outcomes were assessed. Results One-, three-, and five-year recurrence-free and overall survival were 61.4, 30.6, and 22.0%, and 77.6, 49.2, and 38.3%, respectively. Compared with disease confined to the nasal cavity, sinus involvement confers significantly worse survival; based on this, further stratifying the T3 stage was highly prognostic ( p < 0.001) with implications for a potential modification to the current TNM staging system. There was a statistically significant survival benefit for patients who received adjuvant radiotherapy, compared with those who underwent surgery alone (hazard ratio [HR] = 0.74, 95% confidence interval [CI]: 0.57-0.96, p = 0.021). Immune checkpoint blockade for the management of recurrent or persistent disease, with or without distant metastasis, conferred longer survival (HR = 0.50, 95% CI: 0.25-1.00, p = 0.036). Conclusions We present findings from the largest cohort of SNMM reported to date. We demonstrate the potential utility of further stratifying the T3 stage by sinus involvement and present promising data on the benefit of immune checkpoint inhibitors for recurrent, persistent, or metastatic disease with implications for future clinical trials in this field.

A probability model for anatomical robust optimisation in head and neck cancer proton therapy.

Objective.Develop an anatomical model based on the statistics of the population data and evaluate the model for anatomical robust optimisation in head and neck cancer proton therapy.Approach.Deformable image registration was used to build the probability model (PM) that captured the major deformation from patient population data and quantified the probability of each deformation. A cohort of 20 nasopharynx patients was included in this retrospective study. Each patient had a planning CT and 6 weekly CTs during radiotherapy. We applied the model to 5 test patients. Each test patient used the remaining 19 training patients to build the PM and estimate the likelihood of a certain anatomical deformation to happen. For each test patient, a spot scanning proton plan was created. The PM was evaluated using proton spot location deviation and dose distribution.Main results. Using the proton spot range, the PM can simulate small non-rigid variations in the first treatment week within 0.21 ± 0.13 mm. For overall anatomical uncertainty prediction, the PM can reduce anatomical uncertainty from 4.47 ± 1.23 mm (no model) to 1.49 ± 1.08 mm at week 6. The 95% confidence interval (CI) of dose metric variations caused by actual anatomical deformations in the first week is -0.59% ∼ -0.31% for low-risk CTD95, and 0.84-3.04 Gy for parotidDmean. On the other hand, the 95% CI of dose metric variations simulated by the PM at the first week is -0.52 ∼ -0.34% for low-risk CTVD95, and 0.58 ∼ 2.22 Gy for parotidDmean.Significance.The PM improves the estimation accuracy of anatomical uncertainty compared to the previous models and does not depend on the acquisition of the weekly CTs during the treatment. We also provided a solution to quantify the probability of an anatomical deformation. The potential of the model for anatomical robust optimisation is discussed.

Improving workflow for adaptive proton therapy with predictive anatomical modelling: A proof of concept.

PURPOSE: To demonstrate predictive anatomical modelling for improving the clinical workflow of adaptive intensity-modulated proton therapy (IMPT) for head and neck cancer. METHODS: 10 radiotherapy patients with nasopharyngeal cancer were included in this retrospective study. Each patient had a planning CT, weekly verification CTs during radiotherapy and predicted weekly CTs from our anatomical model. Predicted CTs were used to create predicted adaptive plans in advance with the aim of maintaining clinically acceptable dosimetry. Adaption was triggered when the increase in mean dose (Dmean) to the parotid glands exceeded 3 Gy(RBE). We compared the accumulated dose of two adaptive IMPT strategies: 1) Predicted plan adaption: One adaptive plan per patient was optimised on a predicted CT triggered by replan criteria. 2) Standard replan: One adaptive plan was created reactively in response to the triggering weekly CT. RESULTS: Statistical analysis demonstrates that the accumulated dose differences between two adaptive strategies are not significant (p > 0.05) for CTVs and OARs. We observed no meaningful differences in D95 between the accumulated dose and the planned dose for the CTVs, with mean differences to the high-risk CTV of -1.20 %, -1.23 % and -1.25 % for no adaption, standard and predicted plan adaption, respectively. The accumulated parotid Dmean using predicted plan adaption is within 3 Gy(RBE) of the planned dose and 0.31 Gy(RBE) lower than the standard replan approach on average. CONCLUSION: Prediction-based replanning could potentially enable adaptive therapy to be delivered without treatment gaps or sub-optimal fractions, as can occur during a standard replanning strategy, though the benefit of using predicted plan adaption over the standard replan was not shown to be statistically significant with respect to accumulated dose in this study. Nonetheless, a predictive replan approach can offer advantages in improving clinical workflow efficiency.

DIR-based models to predict weekly anatomical changes in head and neck cancer proton therapy.

Objective. We proposed two anatomical models for head and neck patients to predict anatomical changes during the course of radiotherapy.Approach. Deformable image registration was used to build two anatomical models: (1) the average model (AM) simulated systematic progressive changes across the patient cohort; (2) the refined individual model (RIM) used a patient's CT images acquired during treatment to update the prediction for each individual patient. Planning CTs and weekly CTs were used from 20 nasopharynx patients. This dataset included 15 training patients and 5 test patients. For each test patient, a spot scanning proton plan was created. Models were evaluated using CT number differences, contours, proton spot location deviations and dose distributions.Main results. If no model was used, the CT number difference between the planning CT and the repeat CT at week 6 of treatment was on average 128.9 Hounsfield Units (HU) over the test population. This can be reduced to 115.5 HU using the AM, and to 110.5 HU using the RIM3(RIM, updated at week (3). When the predicted contours from the models were used, the average mean surface distance of parotid glands can be reduced from 1.98 (no model) to 1.16 mm (AM) and 1.19 mm (RIM3) at week 6. Using the proton spot range, the average anatomical uncertainty over the test population reduced from 4.47 ± 1.23 (no model) to 2.41 ± 1.12 mm (AM), and 1.89 ± 0.96 mm (RIM3). Based on the gamma analysis, the average gamma index over the test patients was improved from 93.87 ± 2.48 % (no model) to 96.16 ± 1.84% (RIM3) at week 6.Significance. The AM and the RIM both demonstrated the ability to predict anatomical changes during the treatment. The RIM can gradually refine the prediction of anatomical changes based on the AM. The proton beam spots provided an accurate and effective way for uncertainty evaluation.

Pre-treatment analysis of non-rigid variations can assist robust intensity-modulated proton therapy plan selection for head and neck patients.

PURPOSE: To incorporate small non-rigid variations of head and neck patients into the robust evaluation of intensity-modulated proton therapy (IMPT) for the selection of robust treatment plans. METHODS: A cohort of 20 nasopharynx cancer patients with weekly kilovoltage CT (kVCT) and 15 oropharynx cancer patients with weekly cone-beam CT (CBCT) were retrospectively included. Anatomical variations between week 0/week 1 of treatment were acquired using deformable image registration (DIR) for all 35 patients and then applied to the planning CT of four patients who have kVCT scanned each week to simulate potential small non-rigid variations (sNRVs). The robust evaluations were conducted on IMPT plans with: (1) different number of beam fields from 3-field to 5-field; (2) different beam angles. The robust evaluation before treatment, including the sNRVs and setup uncertainty, referred to as sNRV+R evaluation was compared with the conventional evaluation (without sNRVs) in terms of robustness consistency with the gold standard evaluation based on weekly CT. RESULTS: Among four patients (490 scenarios), we observed a maximum difference in the sNRV+R evaluation to the nominal dose of: 9.37% dose degradation on D95 of clinical target volumes (CTVs), increase in mean dose (D mean $_{\text{mean}}$ ) of parotid 11.87 Gy, increase in max dose (D max $_{\text{max}}$ ) of brainstem 20.82 Gy. In contrast, in conventional evaluation, we observed a maximum difference to the nominal dose of: 7.58% dose degradation on D95 of the CTVs, increase in parotid D mean $_{\text{mean}}$ by 4.88 Gy, increase in brainstem D max $_{\text{max}}$ by 13.5 Gy. In the measurement of the robustness ranking consistency with the gold standard evaluation, the sNRV+R evaluation was better or equal to the conventional evaluation in 77% of cases, particularly, better on spinal cord, parotid glands, and low-risk CTV. CONCLUSION: This study demonstrated the additional dose discrepancy that sNRVs can make. The inclusion of sNRVs can be beneficial to robust evaluation, providing information on clinical uncertainties additional to the conventional rigid isocenter shift.

Clinical outcomes, Kadish-INSICA staging and therapeutic targeting of somatostatin receptor 2 in olfactory neuroblastoma.

INTRODUCTION: Olfactory neuroblastoma (ONB) is a rare cancer of the sinonasal region. We provide a comprehensive analysis of this malignancy with molecular and clinical trial data on a subset of our cohort to report on the potential efficacy of somatostatin receptor 2 (SSTR2)-targeting imaging and therapy. METHODS: We conducted a retrospective analysis of 404 primary, locally recurrent, and metastatic olfactory neuroblastoma (ONB) patients from 12 institutions in the United States of America, United Kingdom and Europe. Clinicopathological characteristics and treatment approach were evaluated. SSTR2 expression, SSTR2-targeted imaging and the efficacy of peptide receptor radionuclide therapy [PRRT](177Lu-DOTATATE) were reported in a subset of our cohort (LUTHREE trial; NCT03454763). RESULTS: Dural infiltration at presentation was a significant predictor of overall survival (OS) and disease-free survival (DFS) in primary cases (n = 278). Kadish-Morita staging and Dulguerov T-stage both had limitations regarding their prognostic value. Multivariable survival analysis demonstrated improved outcomes with lower stage and receipt of adjuvant radiotherapy. Prophylactic neck irradiation significantly reduces the rate of nodal recurrence. 82.4% of the cohort were positive for SSTR2; treatment of three metastatic cases with SSTR2-targeted peptide-radionuclide receptor therapy (PRRT) in the LUTHREE trial was well-tolerated and resulted in stable disease (SD). CONCLUSIONS: This study presents pertinent clinical data from the largest dataset, to date, on ONB. We identify key prognostic markers and integrate these into an updated staging system, highlight the importance of adjuvant radiotherapy across all disease stages, the utility of prophylactic neck irradiation and the potential efficacy of targeting SSTR2 to manage disease.

Assessment of the impact of CT calibration procedures for proton therapy planning on pediatric treatments.

PURPOSE: Relative stopping powers (RSPs) for proton therapy are estimated using single-energy computed tomography (SECT), calibrated with standardized tissues of the adult male. It is assumed that those tissues are representative of tissues of all age and sex. Female, male, and pediatric tissues differ from one another in density and composition. In this study, we use tabulated pediatric tissues and computational phantoms to investigate the impact of this assumption on pediatric proton therapy. The potential of dual-energy CT (DECT) to improve the accuracy of these calculations is explored. METHODS: We study 51 human body tissues, categorized into male/female for the age groups newborn, 1-, 5-, 10-, and 15-year-old children, and adult, with given compositions and densities. CT numbers are simulated and RSPs are estimated using SECT and DECT methods. Estimated tissue RSPs from each method are compared to theoretical RSPs. The dose and range errors of each approach are evaluated on three computational phantoms (Ewing's sarcoma, salivary sarcoma, and glioma) derived from pediatric proton therapy patients. RESULTS: With SECT, soft tissues have mean estimation errors and standard deviation up to (1.96 ± 4.18)% observed in newborns, compared to (0.20 ± 1.15)% in adult males. Mean estimation errors for bones are up to (-3.35 ± 4.76)% in pediatrics as opposed to (0.10 ± 0.66)% in adult males. With DECT, mean errors reduce to (0.17 ± 0.13)% and (0.23 ± 0.22)% in newborns (soft tissues/bones). With SECT, dose errors in a Ewing's sarcoma phantom are exceeding 5 Gy (10% of prescribed dose) at the distal end of the treatment field, with volumes of dose errors >5 Gy of V diff > 5 = 4630.7  mm3 . Similar observations are made in the head and neck phantoms, with overdoses to healthy tissue exceeding 2 Gy (4%). A systematic Bragg peak shift resulting in either over- or underdosage of healthy tissues and target volumes depending on the crossed tissues RSP prediction errors is observed. Water equivalent range errors of single beams are between -1.53 and 5.50 mm (min, max) (Ewing's sarcoma phantom), -0.78 and 3.62 mm (salivary sarcoma phantom), and -0.43 and 1.41 mm (glioma phantom). DECT can reduce dose errors to <1 Gy and range errors to <1 mm. CONCLUSION: Single-energy computed tomography estimates RSPs for pediatric tissues with systematic shifts. DECT improves the accuracy of RSPs and dose distributions in pediatric tissues compared to the SECT calibration curve based on adult male tissues.

SSTR2 in Nasopharyngeal Carcinoma: Relationship with Latent EBV Infection and Potential as a Therapeutic Target.

Nasopharyngeal carcinoma (NPC) is a malignant epithelial tumor, most commonly located in the pharyngeal recess and endemic to parts of Asia. It is often detected at a late stage which is associated with poor prognosis (5-year survival rate of 63%). Treatment for this malignancy relies predominantly on radiotherapy and/or systemic chemotherapy, which can be associated with significant morbidity and impaired quality of life. In endemic regions NPC is associated with infection by Epstein-Barr virus (EBV) which was shown to upregulate the somatostatin receptor 2 (SSTR2) cell surface receptor. With recent advances in molecular techniques allowing for an improved understanding of the molecular aetiology of this disease and its relation to SSTR2 expression, we provide a comprehensive and up-to-date overview of this disease and highlight the emergence of SSTR2 as a key tumor biomarker and promising target for imaging and therapy.

Somatostatin receptor 2 expression in nasopharyngeal cancer is induced by Epstein Barr virus infection: impact on prognosis, imaging and therapy.

Nasopharyngeal cancer (NPC), endemic in Southeast Asia, lacks effective diagnostic and therapeutic strategies. Even in high-income countries the 5-year survival rate for stage IV NPC is less than 40%. Here we report high somatostatin receptor 2 (SSTR2) expression in multiple clinical cohorts comprising 402 primary, locally recurrent and metastatic NPCs. We show that SSTR2 expression is induced by the Epstein-Barr virus (EBV) latent membrane protein 1 (LMP1) via the NF-κB pathway. Using cell-based and preclinical rodent models, we demonstrate the therapeutic potential of SSTR2 targeting using a cytotoxic drug conjugate, PEN-221, which is found to be superior to FDA-approved SSTR2-binding cytostatic agents. Furthermore, we reveal significant correlation of SSTR expression with increased rates of survival and report in vivo uptake of the SSTR2-binding 68Ga-DOTA-peptide radioconjugate in PET-CT scanning in a clinical trial of NPC patients (NCT03670342). These findings reveal a key role in EBV-associated NPC for SSTR2 in infection, imaging, targeted therapy and survival.

Statistical limitations in proton imaging.

Proton imaging is a promising technology for proton radiotherapy as it can be used for: (1) direct sampling of the tissue stopping power, (2) input information for multi-modality RSP reconstruction, (3) gold-standard calibration against concurrent techniques, (4) tracking motion and (5) pre-treatment positioning. However, no end-to-end characterization of the image quality (signal-to-noise ratio and spatial resolution, blurring uncertainty) against the dose has been done. This work aims to establish a model relating these characteristics and to describe their relationship with proton energy and object size. The imaging noise originates from two processes: the Coulomb scattering with the nucleus, producing a path deviation, and the energy loss straggling with electrons. The noise is found to increases with thickness crossed and, independently, decreases with decreasing energy. The scattering noise is dominant around high-gradient edge whereas the straggling noise is maximal in homogeneous regions. Image quality metrics are found to behave oppositely against energy: lower energy minimizes both the noise and the spatial resolution, with the optimal energy choice depending on the application and location in the imaged object. In conclusion, the model presented will help define an optimal usage of proton imaging to reach the promised application of this technology and establish a fair comparison with other imaging techniques.

Radiobiological Implications of Nanoparticles Following Radiation Treatment.

Materials with a high atomic number (Z) are shown to cause an increase in the level of cell kill by ionizing radiation when introduced into tumor cells. This study uses in vitro experiments to investigate the differences in radiosensitization between two cell lines (MCF-7 and U87) and three commercially available nanoparticles (gold, gadolinium, and iron oxide) irradiated by 6 MV X-rays. To assess cell survival, clonogenic assays are carried out for all variables considered, with a concentration of 0.5 mg mL-1 for each nanoparticle material used. This study demonstrates differences in cell survival between nanoparticles and cell line. U87 shows the greatest enhancement with gadolinium nanoparticles (2.02 ± 0.36), whereas MCF-7 cells have higher enhancement with gold nanoparticles (1.74 ± 0.08). Mass spectrometry, however, shows highest elemental uptake with iron oxide and U87 cells with 4.95 ± 0.82 pg of iron oxide per cell. A complex relationship between cellular elemental uptake is demonstrated, highlighting an inverse correlation with the enhancement, but a positive relation with DNA damage when comparing the same nanoparticle between the two cell lines.

An active pixel sensor x-ray diffraction (APXRD) system for breast cancer diagnosis.

This paper describes the potential application of an active pixel sensor-based x-ray diffraction (APXRD) system in the field of breast cancer diagnosis. The design and initial testing of the system was reported previously (Bohndiek et al 2008b Phys. Med. Biol. 53 655-72). The system has potential both as a 'diffraction enhanced breast imager' (DEBI) and as a probe for quantitative analysis of breast biopsy samples. The resolution of the system in a DEBI arrangement is 1 mm and the contrast available using a material-specific x-ray diffraction image was found to be up to seven times greater than that of a transmission image. Scatter signatures from a series of biopsy-equivalent samples, ranging in composition from 100% fat to 100% fibrous tissue, were acquired with the APXRD system. Multivariate data analysis was used to produce a partial least squares (PLS) model sensitive to sample fat content. The final model is able to accurately predict the fat content of a series of unknown samples and is robust to significant added noise. This suggests that the APXRD system could provide a simple, semi-automated, quantitative measurement system for analysis of breast biopsy samples. Training on a range of scatter signatures from real breast biopsy samples covering various stages of disease is now needed to test this hypothesis.

The influence of nuclear interactions on ionization chamber perturbation factors in proton beams: FLUKA simulations supported by a Fano test.

PURPOSE: In all recent protocols for the reference dosimetry of clinical proton beams, ionization chamber perturbation factors are assumed to be unity. In this work, such factors were computed using the FLUKA Monte Carlo code for three ionization chamber types, with particular attention to the influence of nuclear interactions. METHODS: The accuracy of the transport algorithms implemented in FLUKA was first evaluated by performing a Fano cavity test. Ionization chamber perturbation factors were computed for the PTW-34001 Roos® and the PTW-34070 and PTW-34073 Bragg peak® chambers for proton beams of 60-250 MeV using the same transport parameters that were needed to pass the Fano test. RESULTS: FLUKA was found to pass the Fano test within 0.15%. Ionization chamber simulation results show that the presence of the air cavity and the wall results in dose perturbations of the order of 0.6% and 0.8%, respectively. The perturbation factors are shown to be energy dependent and nuclear interactions must be taken into account for accurate calculation of the ionization chamber's response. CONCLUSION: Ionization chamber perturbations can amount to 1% in high-energy proton beams and therefore need to be considered in dosimetry procedures.

Impact of varying planning parameters on proton pencil beam scanning dose distributions in four commercial treatment planning systems.

PURPOSE: In pencil beam scanning proton therapy, target coverage is achieved by scanning the pencil beam laterally in the x- and y-directions and delivering spots of dose to positions at a given radiological depth (layer). Dose is delivered to the spots on different layers by pencil beams of different energy until the entire volume has been irradiated. The aim of this study is to investigate the implementation of proton planning parameters (spot spacing, layer spacing and margins) in four commercial proton treatment planning systems (TPSs): Eclipse, Pinnacle3 , RayStation and XiO. MATERIALS AND METHODS: Using identical beam data in each TPS, plans were created on uniform material synthetic phantoms with cubic targets. The following parameters were systematically varied in each TPS to observe their different implementations: spot spacing, layer spacing and margin. Additionally, plans were created in Eclipse to investigate the impact of these parameters on plan delivery and optimal values are suggested. RESULTS: It was found that all systems except Eclipse use a variable layer spacing per beam, based on the Bragg peak width of each energy layer. It is recommended that if this cannot be used, then a constant value of 5 mm will ensure good dose homogeneity. Only RayStation varies the spot spacing according to the variable spot size with depth. If a constant spot spacing is to be used, a value of 5 mm is recommended as a good compromise between dose homogeneity, plan robustness and planning time. It was found that both Pinnacle3 and RayStation position spots outside of the defined volume (target plus margin). CONCLUSIONS: All four systems are capable of delivering uniform dose distributions to simple targets, but their implementation of the various planning parameters is different. In this paper comparisons are made between the four systems and recommendations are made as to the values that will provide the best compromise in dose homogeneity and planning time.