Preclincial evaluation of Gold-DTDTPA Nanoparticles As Theranostic Agents In Prostate Cancer Radiotherapy

AIM: Gold nanoparticles have attracted significant interest in cancer diagnosis and treatment. Herein, we evaluated the theranostic potential of dithiolated diethylenetriamine pentaacetic acid (DTDTPA) conjugated AuNPs (Au@DTDTPA) for CT-contrast enhancement and radiosensitization in prostate cancer.

MATERIALS & METHODS: In vitro assays determined Au@DTDTPA uptake, cytotoxicity, radiosensitizing potential and DNA damage profiles. Human PC3 xenograft tumor models were used to determine CT enhancement and radiation modulating effects in vivo.

RESULTS: Cells exposed to nanoparticles and radiation observed significant additional reduction in survival compared with radiation only. Au@DTDTPA produced a CT enhancement of 10% and a significant extension in tumor growth delay from 16.9 days to 38.3 compared with radiation only.

CONCLUSION: This study demonstrates the potential of Au@DTDTPA to enhance CT-image contrast and simultaneously increases the radiosensitivity of prostate tumors.

Time-resolved dosimetric verification of respiratory-gated radiotherapy exposures using a high-resolution 2D ionisation chamber array

The aim of this work was to track and verify the delivery of respiratory-gated irradiations, performed with three versions of TrueBeam linac, using a novel phantom arrangement that combined the OCTAVIUS® SRS 1000 array with a moving platform. The platform was programmed to generate sinusoidal motion of the array. This motion was tracked using the real-time position management (RPM) system and four amplitude gating options were employed to interrupt MV beam delivery when the platform was not located within set limits. Time-resolved spatial information extracted from analysis of x-ray fluences measured by the array was compared to the programmed motion of the platform and to the trace recorded by the RPM system during the delivery of the x-ray field. Temporal data recorded by the phantom and the RPM system were validated against trajectory log files, recorded by the linac during the irradiation, as well as oscilloscope waveforms recorded from the linac target signal. Gamma analysis was employed to compare time-integrated 2D x-ray dose fluences with theoretical fluences derived from the probability density function for each of the gating settings applied, where gamma criteria of 2%/2 mm, 1%/1 mm and 0.5%/0.5 mm were used to evaluate the limitations of the RPM system. Excellent agreement was observed in the analysis of spatial information extracted from the SRS 1000 array measurements. Comparisons of the average platform position with the expected position indicated absolute deviations of  <0.5 mm for all four gating settings. Differences were observed when comparing time-resolved beam-on data stored in the RPM files and trajectory logs to the true target signal waveforms. Trajectory log files underestimated the cycle time between consecutive beam-on windows by 10.0  ±  0.8 ms. All measured fluences achieved 100% pass-rates using gamma criteria of 2%/2 mm and 50% of the fluences achieved pass-rates  >90% when criteria of 0.5%/0.5 mm were used. Results using this novel phantom arrangement indicate that the RPM system is capable of accurately gating x-ray exposure during the delivery of a fixed-field treatment beam.

Multicenter randomized phase II clinical trial comparing neoadjuvant oxaliplatin, capecitabine, and preoperative radiotherapy with or without cetuximab followed by total mesorectal excision in patients with high-risk rectal cancer (EXPERT-C).

PURPOSE: To evaluate the addition of cetuximab to neoadjuvant chemotherapy before chemoradiotherapy in high-risk rectal cancer. PATIENTS AND METHODS: Patients with operable magnetic resonance imaging-defined high-risk rectal cancer received four cycles of capecitabine/oxaliplatin (CAPOX) followed by capecitabine chemoradiotherapy, surgery, and adjuvant CAPOX (four cycles) or the same regimen plus weekly cetuximab (CAPOX+C). The primary end point was complete response (CR; pathologic CR or, in patients not undergoing surgery, radiologic CR) in patients with KRAS/BRAF wild-type tumors. Secondary end points were radiologic response (RR), progression-free survival (PFS), overall survival (OS), and safety in the wild-type and overall populations and a molecular biomarker analysis. RESULTS: One hundred sixty-five eligible patients were randomly assigned. Ninety (60%) of 149 assessable tumors were KRAS or BRAF wild type (CAPOX, n = 44; CAPOX+C, n = 46), and in these patients, the addition of cetuximab did not improve the primary end point of CR (9% v 11%, respectively; P = 1.0; odds ratio, 1.22) or PFS (hazard ratio [HR], 0.65; P = .363). Cetuximab significantly improved RR (CAPOX v CAPOX+C: after chemotherapy, 51% v 71%, respectively; P = .038; after chemoradiation, 75% v 93%, respectively; P = .028) and OS (HR, 0.27; P = .034). Skin toxicity and diarrhea were more frequent in the CAPOX+C arm. CONCLUSION: Cetuximab led to a significant increase in RR and OS in patients with KRAS/BRAF wild-type rectal cancer, but the primary end point of improved CR was not met.

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.

Fiducial Marker Guided Prostate Radiotherapy: A Review

Image guided radiotherapy (IGRT) is an essential tool in the accurate delivery of modern radiotherapy techniques. Prostate radiotherapy positioned using skin marks or bony anatomy may be adequate for delivering a relatively homogenous whole pelvic radiotherapy dose but these are not reliable when using reduced margins, dose escalation or hypo-fractionated stereotactic radiotherapy. Fiducial markers (FMs) for prostate IGRT have been in use since the 1990's. They require surgical implantation and provide a surrogate for the position of the prostate gland. A variety of FMs are available and they can be used in a number of ways. This review aims to establish the evidence for using prostate FMs in terms of feasibility, implantation procedures, types of FMs used, FM migration, imaging modalities used and the clinical impact of FMs. A search strategy was defined and a literature search was carried out in Medline. Inclusion and exclusion criteria were applied which resulted in 50 papers being included in this review. The evidence demonstrates that FMs provide a more accurate surrogate for the position of the prostate than either external skin marks or bony anatomy. A combination of FM alignment and soft tissue analysis is currently the most effective and widely available approach to ensuring accuracy in prostate IGRT. FM implantation is safe and well tolerated. FM migration is possible but minimal. Standardisation of all techniques and procedures in relation to the use of prostate FMs is required. Finally a clinical trial investigating a non-surgical alternative to prostate FMS is introduced.

Multiple training interventions significantly improve reproducibility of PET/CT-based lung cancer radiotherapy target volume delineation using an IAEA study protocol

BACKGROUND AND PURPOSE: To assess the impact of a standardized delineation protocol and training interventions on PET/CT-based target volume delineation (TVD) in NSCLC in a multicenter setting.

MATERIAL AND METHODS: Over a one-year period, 11 pairs, comprised each of a radiation oncologist and nuclear medicine physician with limited experience in PET/CT-based TVD for NSCLC from nine different countries took part in a training program through an International Atomic Energy Agency (IAEA) study (NCT02247713). Teams delineated gross tumor volume of the primary tumor, during and after training interventions, according to a provided delineation protocol. In-house developed software recorded the performed delineations, to allow visual inspection of strategies and to assess delineation accuracy.

RESULTS: Following the first training, overall concordance indices for 3 repetitive cases increased from 0.57±0.07 to 0.66±0.07. The overall mean surface distance between observer and expert contours decreased from -0.40±0.03 cm to -0.01±0.33 cm. After further training overall concordance indices for another 3 repetitive cases further increased from 0.64±0.06 to 0.80±0.05 (p=0.01). Mean surface distances decreased from -0.34±0.16 cm to -0.05±0.20 cm (p=0.01).

CONCLUSION: Multiple training interventions improve PET/CT-based TVD delineation accuracy in NSCLC and reduces interobserver variation.

Radiotherapy and Immunotherapy Combinations in Non-small Cell Lung Cancer: A Promising Future?

The goal of re-programming the host immune system to target malignancy with durable anti-tumour clinical responses has been speculated for decades. In the last decade such speculation has been transformed into reality with unprecedented and durable responses to immune checkpoint inhibitors seen in solid tumours. This mini-review considers the mechanism of action of immune modulating agents and the potential for combination with radiotherapy in the treatment of non-small cell lung cancer.

Peer Relationships in School-Age Children with Autism: Concurrent and Longitudinal Predictors

Thesis (Ph.D.)--University of Washington, 2016-08

3531: Neoadjuvant radiotherapy (RT) combined with capecitabine (Cape) and sorafenib (Sor) in patients (pts) with locally advanced, k-ras-mutated rectal cancer (LARC): A phase I/II trial SAKK 41/08

Background: K-ras mutation is found in up to 40% of LARC. Sor is a multitarget tyrosine kinase inhibitor including raf and VEGFR and has demonstrated radiosensitizing effects. Sor might improve outcome of standard preoperative radio-chemotherapy in patients with k-ras mutated LARC. Methods: Pts with k-ras mutated T3-4 and/or N+, M0 disease by MRI were included. Recommended doses from phase I part consisted of RT 1.8 Gy/day x25 with Cape 825mg/m2bid x 33 in combination with Sor 400mg/d. The primary endpoint for the phase II part was pathological complete response (pCR) prospectively defined as grade 3 (near complete regression) or 4 (complete regression) in the histological grading system according to Dworak (DC). A pCR rate of 8% or lower was considered uninteresting and of 22% or higher was promising. Secondary endpoints included sphincter preservation, R0 resection, downstaging and safety. Results: 54 pts were treated in 18 centers in Switzerland und Hungary, 40 pts were included into the single arm phase II part. Median dose intensity per day was 100.0% for RT, 98.6% for Cape and 100.0% for Sor respectively. pCR rate was 60.0% (95%CI: 43.3%, 75.1%) by central independent pathological review (15.0% DC grade 4; 45.0% DC grade 3). Sphincter preservation was achieved in 89.5%, R0 resection in 94.7% and downstaging in 81.6% of the pts. The most common grade 3 toxicities included diarrhea (15.0%), skin toxicity outside of the RT field (12.5%), pain (7.5%), skin toxicity in RT field, proctitis, fatigue and cardiac ischemia (each 5.0%). Laboratory AEs grade 3/4 were neutropenia (1 pt grade 4; 1 grade 3), creatinine elevation (1 pt grade 3). Conclusions: The combination of Sor to standard RCT with Cape in k-ras mutated LARC tumors is highly active with acceptable toxicity and deserves further investigation.

Influence of P53 on the radiotherapy response of hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide, and it has a poor prognosis and few therapeutic options. Radiotherapy is one of the most effective forms of cancer treatment, and P53 protein is one of the key molecules determining how a cell responds to radiotherapy. The aim of this study was to determine the therapeutic efficacy of iodine-131 in three human HCC cell lines.

CONCURRENT LOCALIZATION AND MAPPING WITH SONAR SENSORS AND CONSIDERATION OF VEHICLE MOTION

Simultaneous Localization and Mapping (SLAM) is a procedure used to determine the location of a mobile vehicle in an unknown environment, while constructing a map of the unknown environment at the same time. Mobile platforms, which make use of SLAM algorithms, have industrial applications in autonomous maintenance, such as the inspection of flaws and defects in oil pipelines and storage tanks. A typical SLAM consists of four main components, namely, experimental setup (data gathering), vehicle pose estimation, feature extraction, and filtering. Feature extraction is the process of realizing significant features from the unknown environment such as corners, edges, walls, and interior features. In this work, an original feature extraction algorithm specific to distance measurements obtained through SONAR sensor data is presented. This algorithm has been constructed by combining the SONAR Salient Feature Extraction Algorithm and the Triangulation Hough Based Fusion with point-in-polygon detection. The reconstructed maps obtained through simulations and experimental data with the fusion algorithm are compared to the maps obtained with existing feature extraction algorithms. Based on the results obtained, it is suggested that the proposed algorithm can be employed as an option for data obtained from SONAR sensors in environment, where other forms of sensing are not viable. The algorithm fusion for feature extraction requires the vehicle pose estimation as an input, which is obtained from a vehicle pose estimation model. For the vehicle pose estimation, the author uses sensor integration to estimate the pose of the mobile vehicle. Different combinations of these sensors are studied (e.g., encoder, gyroscope, or encoder and gyroscope). The different sensor fusion techniques for the pose estimation are experimentally studied and compared. The vehicle pose estimation model, which produces the least amount of error, is used to generate inputs for the feature extraction algorithm fusion. In the experimental studies, two different environmental configurations are used, one without interior features and another one with two interior features. Numerical and experimental findings are discussed. Finally, the SLAM algorithm is implemented along with the algorithms for feature extraction and vehicle pose estimation. Three different cases are experimentally studied, with the floor of the environment intentionally altered to induce slipping. Results obtained for implementations with and without SLAM are compared and discussed. The present work represents a step towards the realization of autonomous inspection platforms for performing concurrent localization and mapping in harsh environments.