Low Pretreatment CD4+:CD8+ T Cell Ratios and CD39+CD73+CD19+ B Cell Proportions Are Associated with Improved Relapse-Free Survival in Head and Neck Squamous Cell Carcinoma.

The ectonucleotidases CD39 and CD73 are present on immune cells and play important roles in cancer progression by suppressing antitumour immunity. As such, CD39 and CD73 on peripheral blood mononuclear cells (PBMCs) are emerging as potential biomarkers to predict disease outcomes and treatment responses in cancer patients. This study aimed to examine T and B cells, including CD39 and CD73 expressing subsets, by flow cytometry in PBMCs from 28 patients with head and neck squamous cell carcinoma (HNSCC) and to assess the correlation with the treatment modality, human papillomavirus (HPV) status, and relapse-free survival (RFS). The PBMCs were examined pre-, mid-, and post-radiotherapy with concurrent cisplatin chemotherapy or anti-epidermal growth factor receptor antibody (cetuximab) therapy. Combination radiotherapy caused changes to T and B cell populations, including CD39 and CD73 expressing subsets, but no such differences were observed between concurrent chemotherapy and cetuximab. Pretreatment PBMCs from HPV+ patients contained increased proportions of CD39-CD73-CD4+ T cells and reduced proportions of CD39-/+CD73+CD4+ T cells compared to the equivalent cells from HPV- patients. Notably, the pretreatment CD4+:CD8+ T cell ratios and CD39+CD73+CD19+ B cell proportions below the respective cohort medians corresponded with an improved RFS. Collectively, this study supports the notion that CD39 and CD73 may contribute to disease outcomes in HNSCC patients and may assist as biomarkers, either alone or as part of immune signatures, in HNSCC. Further studies of CD39 and CD73 on PBMCs from larger cohorts of HNSCC patients are warranted.

Standardising Breast Radiotherapy Structure Naming Conventions: A Machine Learning Approach.

In progressing the use of big data in health systems, standardised nomenclature is required to enable data pooling and analyses. In many radiotherapy planning systems and their data archives, target volumes (TV) and organ-at-risk (OAR) structure nomenclature has not been standardised. Machine learning (ML) has been utilised to standardise volumes nomenclature in retrospective datasets. However, only subsets of the structures have been targeted. Within this paper, we proposed a new approach for standardising all the structures nomenclature by using multi-modal artificial neural networks. A cohort consisting of 1613 breast cancer patients treated with radiotherapy was identified from Liverpool & Macarthur Cancer Therapy Centres, NSW, Australia. Four types of volume characteristics were generated to represent each target and OAR volume: textual features, geometric features, dosimetry features, and imaging data. Five datasets were created from the original cohort, the first four represented different subsets of volumes and the last one represented the whole list of volumes. For each dataset, 15 sets of combinations of features were generated to investigate the effect of using different characteristics on the standardisation performance. The best model reported 99.416% classification accuracy over the hold-out sample when used to standardise all the nomenclatures in a breast cancer radiotherapy plan into 21 classes. Our results showed that ML based automation methods can be used for standardising naming conventions in a radiotherapy plan taking into consideration the inclusion of multiple modalities to better represent each volume.

Infrastructure platform for privacy-preserving distributed machine learning development of computer-assisted theragnostics in cancer.

INTRODUCTION: Emerging evidence suggests that data-driven support tools have found their way into clinical decision-making in a number of areas, including cancer care. Improving them and widening their scope of availability in various differing clinical scenarios, including for prognostic models derived from retrospective data, requires co-ordinated data sharing between clinical centres, secondary analyses of large multi-institutional clinical trial data, or distributed (federated) learning infrastructures. A systematic approach to utilizing routinely collected data across cancer care clinics remains a significant challenge due to privacy, administrative and political barriers. METHODS: An information technology infrastructure and web service software was developed and implemented which uses machine learning to construct clinical decision support systems in a privacy-preserving manner across datasets geographically distributed in different hospitals. The infrastructure was deployed in a network of Australian hospitals. A harmonized, international ontology-linked, set of lung cancer databases were built with the routine clinical and imaging data at each centre. The infrastructure was demonstrated with the development of logistic regression models to predict major cardiovascular events following radiation therapy. RESULTS: The infrastructure implemented forms the basis of the Australian computer-assisted theragnostics (AusCAT) network for radiation oncology data extraction, reporting and distributed learning. Four radiation oncology departments (across seven hospitals) in New South Wales (NSW) participated in this demonstration study. Infrastructure was deployed at each centre and used to develop a model predicting for cardiovascular admission within a year of receiving curative radiotherapy for non-small cell lung cancer. A total of 10,417 lung cancer patients were identified with 802 being eligible for the model. Twenty features were chosen for analysis from the clinical record and linked registries. After selection, 8 features were included and a logistic regression model achieved an area under the receiver operating characteristic (AUROC) curve of 0.70 and C-index of 0.65 on out-of-sample data. CONCLUSION: The infrastructure developed was demonstrated to be usable in practice between clinical centres to harmonize routinely collected oncology data and develop models with federated learning. It provides a promising approach to enable further research studies in radiation oncology using real world clinical data.

Flexible Polymer X-ray Detectors with Non-fullerene Acceptors for Enhanced Stability: Toward Printable Tissue Equivalent Devices for Medical Applications.

There is growing interest in the development of novel materials and devices capable of ionizing radiation detection for medical applications. Organic semiconductors are promising candidates to meet the demands of modern detectors, such as low manufacturing costs, mechanical flexibility, and a response to radiation equivalent to human tissue. However, organic semiconductors have typically been employed in applications that convert low energy photons into high current densities, for example, solar cells and LEDs, and thus existing design rules must be re-explored for ionizing radiation detection where high energy photons are converted into typically much lower current densities. In this work, we report the optoelectronic and X-ray dosimetric response of a tissue equivalent organic photodetector fabricated with solution-based inks prepared from polymer donor poly(3-hexylthiophene) (P3HT) blended with either a non-fullerene acceptor (5Z,5'Z)-5,5'-((7,7'-(4,4,9,9-tetraoctyl-4,9-dihydro-s-indaceno[1,2-b:5,6-b']dithiophene-2,7-diyl)bis(benzo[c][1,2,5]thiadiazole-7,4-diyl))bis(methanylylidene))bis(3-ethyl-2-thioxothiazolidin-4-one) (o-IDTBR) or a fullerene acceptor, [6,6]-phenyl-C61-butyric acid methyl ester (PCBM). Indirect detection of X-rays was achieved via coupling of organic photodiodes with a plastic scintillator. Both detectors displayed an excellent response linearity with dose, with sensitivities to 6 MV photons of 263.4 ± 0.6 and 114.2 ± 0.7 pC/cGy recorded for P3HT:PCBM and P3HT:o-IDTBR detectors, respectively. Both detectors also exhibited a fast temporal response, able to resolve individual 3.6 µs pulses from the linear accelerator. Energy dependence measurements highlighted that the photodetectors were highly tissue equivalent, though an under-response in devices compared to water by up to a factor of 2.3 was found for photon energies of 30-200 keV due to the response of the plastic scintillator. The P3HT:o-IDTBR device exhibited a higher stability to radiation, showing just an 18.4% reduction in performance when exposed to radiation doses of up to 10 kGy. The reported devices provide a successful demonstration of stable, printable, flexible, and tissue-equivalent radiation detectors with energy dependence similar to other scintillator-based detectors used in radiotherapy.

Implementation of the Australian Computer-Assisted Theragnostics (AusCAT) network for radiation oncology data extraction, reporting and distributed learning.

INTRODUCTION: There is significant potential to analyse and model routinely collected data for radiotherapy patients to provide evidence to support clinical decisions, particularly where clinical trials evidence is limited or non-existent. However, in practice there are administrative, ethical, technical, logistical and legislative barriers to having coordinated data analysis platforms across radiation oncology centres. METHODS: A distributed learning network of computer systems is presented, with software tools to extract and report on oncology data and to enable statistical model development. A distributed or federated learning approach keeps data in the local centre, but models are developed from the entire cohort. RESULTS: The feasibility of this approach is demonstrated across six Australian oncology centres, using routinely collected lung cancer data from oncology information systems. The infrastructure was used to validate and develop machine learning for model-based clinical decision support and for one centre to assess patient eligibility criteria for two major lung cancer radiotherapy clinical trials (RTOG-9410, RTOG-0617). External validation of a 2-year overall survival model for non-small cell lung cancer (NSCLC) gave an AUC of 0.65 and C-index of 0.62 across the network. For one centre, 65% of Stage III NSCLC patients did not meet eligibility criteria for either of the two practice-changing clinical trials, and these patients had poorer survival than eligible patients (10.6 m vs. 15.8 m, P = 0.024). CONCLUSION: Population-based studies on routine data are possible using a distributed learning approach. This has the potential for decision support models for patients for whom supporting clinical trial evidence is not applicable.

Web-Based Patient-Reported Outcome Measures for Personalized Treatment and Care (PROMPT-Care): Multicenter Pragmatic Nonrandomized Trial.

BACKGROUND: Despite the acceptability and efficacy of e-patient-reported outcome (ePRO) systems, implementation in routine clinical care remains challenging. OBJECTIVE: This pragmatic trial implemented the PROMPT-Care (Patient Reported Outcome Measures for Personalized Treatment and Care) web-based system into existing clinical workflows and evaluated its effectiveness among a diverse population of patients with cancer. METHODS: Adult patients with solid tumors receiving active treatment or follow-up care in four cancer centers were enrolled. The PROMPT-Care intervention supported patient management through (1) monthly off-site electronic PRO physical symptom and psychosocial well-being assessments, (2) automated electronic clinical alerts notifying the care team of unresolved clinical issues following two consecutive assessments, and (3) tailored online patient self-management resources. Propensity score matching was used to match controls with intervention patients in a 4:1 ratio for patient age, sex, and treatment status. The primary outcome was a reduction in emergency department presentations. Secondary outcomes were time spent on chemotherapy and the number of allied health service referrals. RESULTS: From April 2016 to October 2018, 328 patients from four public hospitals received the intervention. Matched controls (n=1312) comprised the general population of patients with cancer, seen at the participating hospitals during the study period. Emergency department visits were significantly reduced by 33% (P=.02) among patients receiving the intervention compared with patients in the matched controls. No significant associations were found in allied health referrals or time to end of chemotherapy. At baseline, the most common patient reported outcomes (above-threshold) were fatigue (39%), tiredness (38.4%), worry (32.9%), general wellbeing (32.9%), and sleep (24.1%), aligning with the most frequently accessed self-management domain pages of physical well-being (36%) and emotional well-being (23%). The majority of clinical feedback reports were reviewed by nursing staff (729/893, 82%), largely in response to the automated clinical alerts (n=877). CONCLUSIONS: Algorithm-supported web-based systems utilizing patient reported outcomes in clinical practice reduced emergency department presentations among a diverse population of patients with cancer. This study also highlighted the importance of (1) automated triggers for reviewing above-threshold results in patient reports, rather than passive manual review of patient records; (2) the instrumental role nurses play in managing alerts; and (3) providing patients with resources to support guided self-management, where appropriate. Together, these factors will inform the integration of web-based PRO systems into future models of routine cancer care. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12616000615482; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=370633. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.1186/s12885-018-4729-3.

Comparison of peripheral blood mononuclear cell isolation techniques and the impact of cryopreservation on human lymphocytes expressing CD39 and CD73.

CD39 and CD73 are ecto-nucleotidases present on human peripheral blood mononuclear cells (PBMCs) and are emerging biomarkers on these cells in various disorders including cancer. Many factors influence PBMC quality, so it is essential to validate sample processing methods prior to incorporation in clinical studies. This study examined the impact of both PBMC cryopreservation and PBMC isolation using SepMate density gradient centrifugation on CD39 and CD73 expressing subsets. First, PBMCs were isolated from the peripheral blood of 11 healthy donors by routine Ficoll-Paque density gradient centrifugation, cryopreserved and compared with freshly isolated PBMCs by flow cytometry. The proportions of T and B cells expressing combinations of CD39 and CD73 were relatively stable over 6-month cryopreservation, although some T cell combinations revealed small but significant changes. Second, peripheral blood was collected from six healthy donors to compare PBMCs isolated by SepMate or Ficoll-Paque density gradient centrifugation. Compared with Ficoll-Paque, the more rapid SepMate method yielded 9.1% less PBMCs but did not alter cell viability or proportions of T and B cells expressing combinations of CD39 and CD73. The present study reveals that cryopreservation is suitable for studying T and B cells expressing combinations of CD39 and CD73. However, caution should be exercised when observing small differences in these cryopreserved subsets between different cohorts. Further, SepMate and Ficoll-Paque methods of PBMC isolation show similar results for T and B cell subset analysis; however, SepMate is a faster and easier approach.

Thulium oxide nanoparticles as radioenhancers for the treatment of metastatic cutaneous squamous cell carcinoma.

Metastases from cutaneous squamous cell carcinoma (cSCC) occur in 2%-5% of cases. Surgery is the standard treatment, often combined with adjuvant radiotherapy. Concurrent carboplatin treatment with post-operative radiotherapy may be prescribed, although it has not shown benefit in recent clinical trials in high-risk cSCC patients. The novel high-Z nanoparticle thulium (III) oxide has been shown to enhance radiation dose delivery to brain tumors by specific uptake of these nanoparticles into the cancerous tissue. As the dose-enhancement capacity of thulium oxide nanoparticles following radiotherapy against metastatic cSCC cells is unknown, its efficacy as a radiosensitizer was evaluated, with and without carboplatin. Novel and validated human patient-derived cell lines of metastatic cSCC were used. The sensitivity of the cells to radiation was investigated using short-term proliferation assays as well as clonogenic survival as the radiobiological endpoint. Briefly, cells were irradiated with 125 kVp orthovoltage x-rays (0-6 Gy) with and without thulium oxide nanoparticles (99.9% trace metals basis; 50 µg ml-1) or low dose carboplatin pre-sensitization. Cellular uptake of the nanoparticles was first confirmed by microscopy and found to have no impact on short-term cell survival for the cSCC cells, highlighting the biocompatibility of thulium oxide nanoparticles. Clonogenic cell survival assays confirmed radio-sensitization when exposed to thulium nanoparticles, with the cell sensitivity increasing by a factor of 1.24 (calculated at the 10% survival fraction) for the irradiated cSCC cells. The combination of carboplatin with thulium oxide nanoparticles with irradiation did not result in significant further reductions in survival compared to nanoparticles alone. This is the first study to provide in vitro data demonstrating the independent radiosensitization effect of high-Z nanoparticles against metastatic cSCC with or without carboplatin. Further preclinical investigations with radiotherapy plus high-Z nanoparticles for the management of metastatic cSCC are warranted.

Establishment of novel long-term cultures from EpCAM positive and negative circulating tumour cells from patients with metastatic gastroesophageal cancer.

Circulating tumour cell (CTC) enumeration and profiling has been established as a valuable clinical tool in many solid malignancies. A key challenge in CTC research is the limited number of cells available for study. Ex vivo CTC culture permits expansion of these rare cell populations for detailed characterisation, functional assays including drug sensitivity testing, and investigation of the pathobiology of metastases. We report for the first time the establishment and characterisation of two continuous CTC lines from patients with gastroesophageal cancer. The two cell lines (designated UWG01CTC and UWG02CTC) demonstrated rapid tumorigenic growth in immunodeficient mice and exhibit distinct genotypic and phenotypic profiles which are consistent with the tumours of origin. UWG02CTC exhibits an EpCAM+, cytokeratin+, CD44+ phenotype, while UWG01CTC, which was derived from a patient with metastatic neuroendocrine cancer, displays an EpCAM-, weak cytokeratin phenotype, with strong expression of neuroendocrine markers. Further, the two cell lines show distinct differences in drug and radiation sensitivity which match differential cancer-associated gene expression pathways. This is strong evidence implicating EpCAM negative CTCs in metastasis. These novel, well characterised, long-term CTC cell lines from gastroesophageal cancer will facilitate ongoing research into metastasis and the discovery of therapeutic targets.

Two-dimensional solid-state array detectors: A technique for in vivo dose verification in a variable effective area.

PURPOSE: We introduce a technique that employs a 2D detector in transmission mode (TM) to verify dose maps at a depth of dmax in Solid Water. TM measurements, when taken at a different surface-to-detector distance (SDD), allow for the area at dmax (in which the dose map is calculated) to be adjusted. METHODS: We considered the detector prototype "MP512" (an array of 512 diode-sensitive volumes, 2 mm spatial resolution). Measurements in transmission mode were taken at SDDs in the range from 0.3 to 24 cm. Dose mode (DM) measurements were made at dmax in Solid Water. We considered radiation fields in the range from 2 × 2 cm2 to 10 × 10 cm2 , produced by 6 MV flattened photon beams; we derived a relationship between DM and TM measurements as a function of SDD and field size. The relationship was used to calculate, from TM measurements at 4 and 24 cm SDD, dose maps at dmax in fields of 1 × 1 cm2 and 4 × 4 cm2 , and in IMRT fields. Calculations were cross-checked (gamma analysis) with the treatment planning system and with measurements (MP512, films, ionization chamber). RESULTS: In the square fields, calculations agreed with measurements to within ±2.36%. In the IMRT fields, using acceptance criteria of 3%/3 mm, 2%/2 mm, 1%/1 mm, calculations had respective gamma passing rates greater than 96.89%, 90.50%, 62.20% (for a 4 cm SSD); and greater than 97.22%, 93.80%, 59.00% (for a 24 cm SSD). Lower rates (1%/1 mm criterion) can be explained by submillimeter misalignments, dose averaging in calculations, noise artifacts in film dosimetry. CONCLUSIONS: It is possible to perform TM measurements at the SSD which produces the best fit between the area at dmax in which the dose map is calculated and the size of the monitored target.

Expression of cancer stem cell markers is prognostic in metastatic gastroesophageal adenocarcinoma.

Gastroesophageal adenocarcinoma is a common and highly lethal malignancy. Cancer stem cells (CSCs) have a key role in the development and progression of metastatic disease. While expression of CSC markers CD44, CD133 and aldehyde dehydrogenase 1 (ALDH1) in locoregional gastroesophageal cancer is known to be associated with poorer clinical outcomes, the significance of CSC marker expression in distal metastatic disease is unknown. We investigated the clinicopathological and prognostic associations of the CSC markers, CD44, CD133, and ALDH1, on metastatic deposits from gastroesophageal adenocarcinomas, and evaluated the association of CSC expression with urokinase-type plasminogen activator receptor (uPAR) expression. Of the 36 patients included in the study, 16 (44%) were positive for CD44, 13 (36%) were positive for CD133, and 26 (72%) were positive for ALDH1. CD44 expression was significantly associated with poorer overall survival (OS) in univariate [hazard ratio (HR) 2.9, 95% confidence interval (CI) 1.3-6.9, p=0.008] and multivariate analyses (HR 2.5, 95%CI 1.1-6.2, p=0.04). ALDH1 expression was significantly associated with poorer OS in univariate (HR 2.4, 95% CI 1.01-5.7, p=0.04) analysis but was not significant in multivariate analysis. Both CD44 and ALDH1 expression were significantly associated with uPAR expression. We found no association between CD133 expression and OS. CD44 expression on metastatic disease from gastroesophageal adenocarcinomas is an independent prognostic marker associated with poorer OS. These results expand current evidence to support the role of CSCs as biomarkers in metastatic gastroesophageal cancer.

Safety and Efficacy of Oxaliplatin Doublet Adjuvant Chemotherapy in Elderly Patients With Stage III Colon Cancer.

BACKGROUND: Colon cancer is common in the elderly, but owing to under representation in clinical trials, the benefit of standard therapies is uncertain in this age group. We aimed to clarify the efficacy and complications of adjuvant oxaliplatin and fluoropyrimidine chemotherapy for patients 70 years and older with stage III colon cancer. PATIENTS AND METHODS: All patients with stage III colon adenocarcinoma were identified from an Australian cancer registry (2006-2013). Multivariable Cox hazard regression was used to determine prognostic factors for all-cause mortality. Chemotherapy complications were quantified using discontinuation rates, hospital admissions, and mortality for 12 months after starting chemotherapy. RESULTS: A total of 2164 patients fulfilled our inclusion criteria, including 1080 (49.9%) patients ≥ 70 years. Patients ≥ 70 years were less likely to receive adjuvant chemotherapy (60.7% vs. 89.6%) or oxaliplatin doublet chemotherapy (18.8% vs. 71.2%). Older patients receiving oxaliplatin were more likely to cease treatment early (18.7% vs. 7.6%) and require hospital admission (67.0% vs. 53.5%). The addition of oxaliplatin provided an overall survival benefit for patients < 70 years (hazard ratio, 0.44; 95% confidence interval, 0.3-0.6; P < .0001) and for patients ≥ 70 years (hazard ratio, 0.64; 95% confidence interval, 0.5-0.9; P = .005). CONCLUSIONS: Despite a modestly increased rate of hospital admission and early chemotherapy cessation, we demonstrate a persistent survival benefit for the addition of oxaliplatin to a fluoropyrimidine as adjuvant treatment for stage III colon cancer in elderly patients.

Cryopreservation for delayed circulating tumor cell isolation is a valid strategy for prognostic association of circulating tumor cells in gastroesophageal cancer.

AIM: To demonstrate the feasibility of cryopreservation of peripheral blood mononuclear cells (PBMCs) for prognostic circulating tumor cell (CTC) detection in gastroesophageal cancer. METHODS: Using 7.5 mL blood samples collected in EDTA tubes from patients with gastroesopheagal adenocarcinoma, CTCs were isolated by epithelial cell adhesion molecule based immunomagnetic capture using the IsoFlux platform. Paired specimens taken during the same blood draw (n = 15) were used to compare number of CTCs isolated from fresh and cryopreserved PBMCs. Blood samples were processed within 24 h to recover the PBMC fraction, with PBMCs used for fresh analysis immediately processed for CTC isolation. Cryopreservation of PBMCs lasted from 2 wk to 25.2 mo (median 14.6 mo). CTCs isolated from pre-treatment cryopreserved PBMCs (n = 43) were examined for associations with clinicopathological variables and survival outcomes. RESULTS: While there was a significant trend to a decrease in CTC numbers associated with cryopreserved specimens (mean number of CTCs 34.4 vs 51.5, P = 0.04), this was predominately in samples with a total CTC count of > 50, with low CTC count samples less affected (P = 0.06). There was no significant association between the duration of cryopreservation and number of CTCs. In cryopreserved PBMCs from patient samples prior to treatment, a high CTC count (> 17) was associated with poorer overall survival (OS) (n = 43, HR = 4.4, 95%CI: 1.7-11.7, P = 0.0013). In multivariate analysis, after controlling for sex, age, stage, ECOG performance status, and primary tumor location, a high CTC count remained significantly associated with a poorer OS (HR = 3.7, 95%CI: 1.2-12.4, P = 0.03). CONCLUSION: PBMC cryopreservation for delayed CTC isolation is a valid strategy to assist with sample collection, transporting and processing.

A comparison of temporal Cherenkov separation techniques in pulsed signal scintillator dosimetry.

Cherenkov radiation is the primary source of unwanted light in a scintillator dosimetry system. In this work we compare two techniques for temporally separating Cherenkov radiation from a slow scintillator signal. These techniques are applicable to a pulsed radiation beam. We found that by analysing the rising edge of the light pulse to identify the fast Cherenkov light only removed 74% of the Cherenkov light. By integrating the tail of the signal where only scintillation light is present a more accurate result is achieved. The average of the results of the two methods provides up to a 90% improvement in the accuracy of the relative dose when compared to ionisation chamber, in certain measurements. This work demonstrates an alternative methodology for the removal of Cherenkov light using signal analysis, while preserving all the scintillation light signal and minimising the bulk of the experimental equipment.

Impact of a monolithic silicon detector operating in transmission mode on clinical photon beams.

PURPOSE: To investigate the effect on surface dose, as a function of different field sizes and distances from the solid water phantom to transmission detector (Dsd), of using the monolithic silicon detector MP512T in transmission mode. METHODS: The influence of operating the MP512T in transmission mode on the surface dose of a phantom for SSD 100cm was evaluated by using a Markus IC. The MP512T was fixed to an adjustable stand holder and was positioned at different Dsd, ranging from 0.3 to 24 cm. For each Dsd, measurements were carried out for irradiation field sizes of 5 × 5cm2, 8 × 8 cm2 and 10 × 10 cm2. Measurements were obtained under two different operational setups, (i) with the MP512T face-up and (ii) with the MP512T face-down. In addition, the transmission factors for the MP512T and the printed circuit board were only evaluated using a Farmer IC. RESULTS: For all Dsd and all field sizes, the MP512T led to the surface dose increasing by less than 25% when in the beam. For Dsd >18 cm the surface dose increase is less than 5%, and negligible for field size 5 × 5 cm2. The difference in the surface dose perturbation for the MP512T operating face up or operating face down is negligible (<2%) for all field sizes. The transmission factor of the MP512T ranged from 1.020 to 0.9950 for all measured Dsd and field sizes. CONCLUSION: The study demonstrated that positioning the MP512T in air between the Linac head and the phantom produced negligible perturbation of the surface dose for Dsd >18 cm, and was completely transparent for 6 MV photon beams.

Temporally separating Cherenkov radiation in a scintillator probe exposed to a pulsed X-ray beam.

Cherenkov radiation is generated in optical systems exposed to ionising radiation. In water or plastic devices, if the incident radiation has components with high enough energy (for example, electrons or positrons with energy greater than 175keV), Cherenkov radiation will be generated. A scintillator dosimeter that collects optical light, guided by optical fibre, will have Cherenkov radiation generated throughout the length of fibre exposed to the radiation field and compromise the signal. We present a novel algorithm to separate Cherenkov radiation signal that requires only a single probe, provided the radiation source is pulsed, such as a linear accelerator in external beam radiation therapy. We use a slow scintillator (BC-444) that, in a constant beam of radiation, reaches peak light output after 1 microsecond, while the Cherenkov signal is detected nearly instantly. This allows our algorithm to separate the scintillator signal from the Cherenkov signal. The relative beam profile and depth dose of a linear accelerator 6MV X-ray field were reconstructed using the algorithm. The optimisation method improved the fit to the ionisation chamber data and improved the reliability of the measurements. The algorithm was able to remove 74% of the Cherenkov light, at the expense of only 1.5% scintillation light. Further characterisation of the Cherenkov radiation signal has the potential to improve the results and allow this method to be used as a simpler optical fibre dosimeter for quality assurance in external beam therapy.

Multi-institutional comparison of simulated treatment delivery errors in ssIMRT, manually planned VMAT and autoplan-VMAT plans for nasopharyngeal radiotherapy.

PURPOSE: To quantify the impact of simulated errors for nasopharynx radiotherapy across multiple institutions and planning techniques (auto-plan generated Volumetric Modulated Arc Therapy (ap-VMAT), manually planned VMAT (mp-VMAT) and manually planned step and shoot Intensity Modulated Radiation Therapy (mp-ssIMRT)). METHODS: Ten patients were retrospectively planned with VMAT according to three institution's protocols. Within one institution two further treatment plans were generated using differing treatment planning techniques. This resulted in mp-ssIMRT, mp-VMAT, and ap-VMAT plans. Introduced treatment errors included Multi Leaf Collimator (MLC) shifts, MLC field size (MLCfs), gantry and collimator errors. A change of more than 5% in most selected dose metrics was considered to have potential clinical impact. The original patient plan total Monitor Units (MUs) were correlated to the total number of dose metrics exceeded. RESULTS: The impact of different errors was consistent, with ap-VMAT plans (two institutions) showing larger dose deviations than mp-VMAT created plans (one institution). Across all institutions' VMAT plans the significant errors included; ±5° for the collimator angle, ±5mm for the MLC shift and +1, ±2 and ±5mm for the MLC field size. The total number of dose metrics exceeding tolerance was positively correlated to the VMAT total plan MUs (r=0.51, p<0.001), across all institutions and techniques. CONCLUSIONS: Differences in VMAT robustness to simulated errors across institutions occurred due to planning method differences. Whilst ap-VMAT was most sensitive to MLC errors, it also produced the best quality treatment plans. Mp-ssIMRT was most robust to errors. Higher VMAT treatment plan complexity led to less robust plans.

Development of a silicon diode detector for skin dosimetry in radiotherapy.

PURPOSE: The aim of in vivo skin dosimetry was to measure the absorbed dose to the skin during radiotherapy, when treatment planning calculations cannot be relied on. It is of particularly importance in hypo-fractionated stereotactic modalities, where excessive dose can lead to severe skin toxicity. Currently, commercial diodes for such applications are with water equivalent depths ranging from 0.5 to 0.8 mm. In this study, we investigate a new detector for skin dosimetry based on a silicon epitaxial diode, referred to as the skin diode. METHOD: The skin diode is manufactured on a thin epitaxial layer and packaged using the "drop-in" technology. It was characterized in terms of percentage depth dose, dose linearity, and dose rate dependence, and benchmarked against the Attix ionization chamber. The response of the skin diode in the build-up region of the percentage depth dose (PDD) curve of a 6 MV clinical photon beam was investigated. Geant4 radiation transport simulations were used to model the PDD in order to estimate the water equivalent measurement depth (WED) of the skin diode. Measured output factors using the skin diode were compared with the MOSkin detector and EBT3 film at 10 cm depth and at surface at isocenter of a water equivalent phantom. The intrinsic angular response of the skin diode was also quantified in charge particle equilibrium conditions (CPE) and at the surface of a solid water phantom. Finally, the radiation hardness of the skin diode up to an accumulated dose of 80 kGy using photons from a Co-60 gamma source was evaluated. RESULTS: The PDD curve measured with the skin diode was within 0.5% agreement of the equivalent Geant4 simulated curve. When placed at the phantom surface, the WED of the skin diode was estimated to be 0.075 ± 0.005 mm from Geant4 simulations and was confirmed using the response of a corrected Attix ionization chamber placed at water equivalent depth of 0.075 mm, with the measurement agreement to within 0.3%. The output factor measurements at 10 cm depth were within 2% of those measured with film and the MOSkin detector down to a field size of 2 × 2 cm2 . The dose-response for all detector samples was linear and with a repeatability within 0.2%. The skin diode intrinsic angular response showed a maximum deviation of 8% at 90 degrees and from 0 to 60 degree is less than 5%. The radiation sensitivity reduced by 25% after an accumulated dose of 20 kGy but after was found to stabilize. At 60 kGy total accumulated dose the response was within 2% of that measured at 20 kGy total accumulated dose. CONCLUSIONS: This work characterizes an innovative detector for in vivo and real-time skin dose measurements that is based on an epitaxial silicon diode combined with the Centre for Medical Radiation Physics (CMRP) "drop-in" packaging technology. The skin diode proved to have a water equivalent depth of measurement of 0.075 ± 0.005 mm and the ability to measure doses accurately relative to reference detectors.

Technical Note: Angular dependence of a 2D monolithic silicon diode array for small field dosimetry.

PURPOSE: This study aims to investigate the 2D monolithic silicon diode array size of 52 × 52 mm2 (MP512) angular response. An angular correction method has been developed that improves the accuracy of dose measurement in a small field. METHODS: The MP512 was placed at the center of a cylindrical phantom, irradiated using 6 MV and 10 MV photons and incrementing the incidence of the beam angle in 15° steps from 0° to 180°, and then in 1° steps between 85° and 95°. The MP512 response was characterized for square field sizes varying between 1 × 1 cm2 and 10 × 10 cm2 . The angular correction factor was obtained as the ratio of MP512 response to EBT3 film measured doses as a function of the incidence angle (Ɵ) and was normalized at 0° incidence angle. Beam profiles of the corrected MP512 responses were compared with the EBT3 responses to verify the effectiveness of the method adopted. RESULTS: The intrinsic angular dependence of the MP512 shows maximum relative deviation from the response normalized to 0° of 18.5 ± 0.5% and 15.5 ± 0.5% for 6 MV and 10 MV, respectively, demonstrating that the angular response is sensitive to the energy. In contrast, the variation of angular response is less affected by field size. Comparison of cross-plane profiles measured by the corrected MP512 and EBT3 shows an agreement within ±2% for all field sizes when the beams irradiated the array at 0°, 45°, 135°, and 180° angles of incidence from the normal to the detector plane. At 90° incidence, corresponding to a depth dose measurement, up to a 6% discrepancy was observed for a 1 × 1 cm2 field of 6 MV. CONCLUSION: An angular correction factor can be adopted for small field sizes. Measurements discrepancies could be encountered when irradiating with very small fields parallel to the detector plane. Using this approach, the MP512 is shown to be a suitable detector for 2D dose mapping of small field size photon beams.

Sidedness is prognostic in locoregional colon cancer: an analysis of 9509 Australian patients.

BACKGROUND/AIM: Right sided colon cancer (RsCC) is proposed to be a distinct disease entity to left sided colon cancer (LsCC). We seek to confirm primary tumour location as an independent prognostic factor in locoregional colorectal cancer. METHODS: All patients with stage I - III primary adenocarcinoma of colon were identified from the New South Wales (NSW) clinical cancer registry (2006-2013). Primary tumour location (RsCC vs LsCC) survival analyses were conducted using the Kaplan-Meier method, and adjusted hazard ratios for 5-year all-cause mortality (OS) and 5-year cancer specific mortality (CSS) were obtained using Cox proportional hazards regression. RESULTS: We identified 9509 patients including 5051 patients with RsCC and 4458 with LsCC. Patients with RsCC were more likely to be older, female, have a higher Charlson comorbidity index, and have worse tumour prognostic factors. In univariate analysis of all stages combined, those patients with RsCC had a worse overall survival (OS, HR 1.20 95% CI 1.11-1.29, p < 0.0001), although this was not significant in the multivariate analysis (HR 0.96 95% CI 0.89-1.04, p = 0.35). Stage I patients with RsCC had a trend to improved OS (multivariate HR 0.84 95% CI 0.69-1.01, p = 0.07) and a significantly improved CSS (multivariate HR 0.51 95% CI 0.35-0.75, p = 0.0006). In stage II patients with RsCC there was a significantly improved OS (multivariate HR 0.85 95% CI 0.75-0.98, p = 0.02) and CSS (multivariate HR 0.59 95% CI 0.45-0.78, p = 0.0002) compared to LsCC. In stage III patients, those with RsCC had a worse OS (multivariate HR 1.13 95% CI 1.01-1.26, p = 0.032) and a trend to worse CSS (multivariate HR 1.12 95% CI 0.94-1.33, p = 0.22). CONCLUSIONS: Primary tumour location is an important prognostic factor in locoregional colon cancer with an effect that varies by stage. RsCC is associated with lower all-cause mortality in stage II, and higher all-cause mortality in stage III.