Multi-institutional evaluation of a Pareto navigation guided automated radiotherapy planning solution for prostate cancer.

BACKGROUND: Current automated planning solutions are calibrated using trial and error or machine learning on historical datasets. Neither method allows for the intuitive exploration of differing trade-off options during calibration, which may aid in ensuring automated solutions align with clinical preference. Pareto navigation provides this functionality and offers a potential calibration alternative. The purpose of this study was to validate an automated radiotherapy planning solution with a novel multi-dimensional Pareto navigation calibration interface across two external institutions for prostate cancer. METHODS: The implemented 'Pareto Guided Automated Planning' (PGAP) methodology was developed in RayStation using scripting and consisted of a Pareto navigation calibration interface built upon a 'Protocol Based Automatic Iterative Optimisation' planning framework. 30 previous patients were randomly selected by each institution (IA and IB), 10 for calibration and 20 for validation. Utilising the Pareto navigation interface automated protocols were calibrated to the institutions' clinical preferences. A single automated plan (VMATAuto) was generated for each validation patient with plan quality compared against the previously treated clinical plan (VMATClinical) both quantitatively, using a range of DVH metrics, and qualitatively through blind review at the external institution. RESULTS: PGAP led to marked improvements across the majority of rectal dose metrics, with Dmean reduced by 3.7 Gy and 1.8 Gy for IA and IB respectively (p < 0.001). For bladder, results were mixed with low and intermediate dose metrics reduced for IB but increased for IA. Differences, whilst statistically significant (p < 0.05) were small and not considered clinically relevant. The reduction in rectum dose was not at the expense of PTV coverage (D98% was generally improved with VMATAuto), but was somewhat detrimental to PTV conformality. The prioritisation of rectum over conformality was however aligned with preferences expressed during calibration and was a key driver in both institutions demonstrating a clear preference towards VMATAuto, with 31/40 considered superior to VMATClinical upon blind review. CONCLUSIONS: PGAP enabled intuitive adaptation of automated protocols to an institution's planning aims and yielded plans more congruent with the institution's clinical preference than the locally produced manual clinical plans.

Evaluating a radiotherapy deep learning synthetic CT algorithm for PET-MR attenuation correction in the pelvis.

BACKGROUND: Positron emission tomography-magnetic resonance (PET-MR) attenuation correction is challenging because the MR signal does not represent tissue density and conventional MR sequences cannot image bone. A novel zero echo time (ZTE) MR sequence has been previously developed which generates signal from cortical bone with images acquired in 65 s. This has been combined with a deep learning model to generate a synthetic computed tomography (sCT) for MR-only radiotherapy. This study aimed to evaluate this algorithm for PET-MR attenuation correction in the pelvis. METHODS: Ten patients being treated with ano-rectal radiotherapy received a [Formula: see text]F-FDG-PET-MR in the radiotherapy position. Attenuation maps were generated from ZTE-based sCT (sCTAC) and the standard vendor-supplied MRAC. The radiotherapy planning CT scan was rigidly registered and cropped to generate a gold standard attenuation map (CTAC). PET images were reconstructed using each attenuation map and compared for standard uptake value (SUV) measurement, automatic thresholded gross tumour volume (GTV) delineation and GTV metabolic parameter measurement. The last was assessed for clinical equivalence to CTAC using two one-sided paired t tests with a significance level corrected for multiple testing of [Formula: see text]. Equivalence margins of [Formula: see text] were used. RESULTS: Mean whole-image SUV differences were -0.02% (sCTAC) compared to -3.0% (MRAC), with larger differences in the bone regions (-0.5% to -16.3%). There was no difference in thresholded GTVs, with Dice similarity coefficients [Formula: see text]. However, there were larger differences in GTV metabolic parameters. Mean differences to CTAC in [Formula: see text] were [Formula: see text] (± standard error, sCTAC) and [Formula: see text] (MRAC), and [Formula: see text] (sCTAC) and [Formula: see text] (MRAC) in [Formula: see text]. The sCTAC was statistically equivalent to CTAC within a [Formula: see text] equivalence margin for [Formula: see text] and [Formula: see text] ([Formula: see text] and [Formula: see text]), whereas the MRAC was not ([Formula: see text] and [Formula: see text]). CONCLUSION: Attenuation correction using this radiotherapy ZTE-based sCT algorithm was substantially more accurate than current MRAC methods with only a 40 s increase in MR acquisition time. This did not impact tumour delineation but did significantly improve the accuracy of whole-image and tumour SUV measurements, which were clinically equivalent to CTAC. This suggests PET images reconstructed with sCTAC would enable accurate quantitative PET images to be acquired on a PET-MR scanner.

Impact of attenuation correction of radiotherapy hardware for positron emission tomography-magnetic resonance in ano-rectal radiotherapy patients.

BACKGROUND: Positron Emission Tomography-Magnetic Resonance (PET-MR) scanners could improve ano-rectal radiotherapy planning through improved Gross Tumour Volume (GTV) delineation and enabling dose painting strategies using metabolic measurements. This requires accurate quantitative PET images acquired in the radiotherapy treatment position. PURPOSE: This study aimed to evaluate the impact on GTV delineation and metabolic parameter measurement of using novel Attenuation Correction (AC) maps that included the radiotherapy flat couch, coil bridge and anterior coil to see if they were necessary. METHODS: Seventeen ano-rectal radiotherapy patients received a 18 F $\mathrm{^{18}F}$ -FluoroDeoxyGlucose PET-MR scan in the radiotherapy position. PET images were reconstructed without ( CTAC std $\mathrm{CTAC_{std}}$ ) and with ( CTAC cba $\mathrm{CTAC_{cba}}$ ) the radiotherapy hardware included. Both AC maps used the same Computed Tomography image for patient AC. Semi-manual and threshold GTVs were delineated on both PET images, the volumes compared and the Dice coefficient calculated. Metabolic parameters: Standardized Uptake Values SUV max $\mathrm{SUV_{max}}$ , SUV mean $\mathrm{SUV_{mean}}$ and Total Lesion Glycolysis (TLG) were compared using paired t-tests with a Bonferroni corrected significance level of p = 0.05 / 8 = 0.006 $p = 0.05/8 = 0.006$ . RESULTS: Differences in semi-manual GTV volumes between CTAC cba $\mathrm{CTAC_{cba}}$ and CTAC std $\mathrm{CTAC_{std}}$ were approaching statistical significance (difference - 15.9 % ± 1.6 % $-15.9\%\pm 1.6\%$ , p = 0.007 $p = 0.007$ ), with larger differences in low FDG-avid tumours ( SUV mean < 8.5 g mL - 1 $\mathrm{SUV_{mean}} < 8.5\;\mathrm{g\: mL^{-1}}$ ). The CTAC cba $\mathrm{CTAC_{cba}}$ and CTAC std $\mathrm{CTAC_{std}}$ GTVs were concordant with Dice coefficients 0.89 ± 0.01 $0.89 \pm 0.01$ (manual) and 0.98 ± 0.00 $0.98 \pm 0.00$ (threshold). Metabolic parameters were significantly different, with SUV max $\mathrm{SUV_{max}}$ , SUV mean $\mathrm{SUV_{mean}}$ and TLG differences of - 11.5 % ± 0.3 % $-11.5\%\ \pm 0.3\%$ ( p < 0.001 $p < 0.001$ ), - 11.6 % ± 0.3 % $-11.6\% \pm 0.3\%$ ( p < 0.001 $p < 0.001$ ) and - 13.7 % ± 0.6 % $-13.7\%\ \pm 0.6\%$ ( p = 0.003 $p = 0.003$ ) respectively. The TLG difference resulted in 1/8 rectal cancer patients changing prognosis group, based on literature TLG cut-offs, when using CTAC cba $\mathrm{CTAC_{cba}}$ rather than CTAC std $\mathrm{CTAC_{std}}$ . CONCLUSIONS: This study suggests that using AC maps with the radiotherapy hardware included is feasible for patient imaging. The impact on tumour delineation was mixed and needs to be evaluated in larger cohorts. However using AC of the radiotherapy hardware is important for situations where accurate metabolic measurements are required, such as dose painting and treatment prognostication.

Comprehensive dose evaluation of a Deep Learning based synthetic Computed Tomography algorithm for pelvic Magnetic Resonance-only radiotherapy.

BACKGROUND AND PURPOSE: Magnetic Resonance (MR)-only radiotherapy enables the use of MR without the uncertainty of MR-Computed Tomography (CT) registration. This requires a synthetic CT (sCT) for dose calculations, which can be facilitated by a novel Zero Echo Time (ZTE) sequence where bones are visible and images are acquired in 65 seconds. This study evaluated the dose calculation accuracy for pelvic sites of a ZTE-based Deep Learning sCT algorithm developed by GE Healthcare. MATERIALS AND METHODS: ZTE and CT images were acquired in 56 pelvic radiotherapy patients in the radiotherapy position. A 2D U-net convolutional neural network was trained using pairs of deformably registered CT and ZTE images from 36 patients. In the remaining 20 patients the dosimetric accuracy of the sCT was assessed using cylindrical dummy Planning Target Volumes (PTVs) positioned at four different central axial locations, as well as the clinical treatment plans (for prostate (n = 10), rectum (n = 4) and anus (n = 6) cancers). The sCT was rigidly and deformably registered, the plan recalculated and the doses compared using mean differences and gamma analysis. RESULTS: Mean dose differences to the PTV D98% were ≤ 0.5% for all dummy PTVs and clinical plans (rigid registration). Mean gamma pass rates at 1%/1 mm were 98.0 ± 0.4% (rigid) and 100.0 ± 0.0% (deformable), 96.5 ± 0.8% and 99.8 ± 0.1%, and 95.4 ± 0.6% and 99.4 ± 0.4% for the clinical prostate, rectum and anus plans respectively. CONCLUSIONS: A ZTE-based sCT algorithm with high dose accuracy throughout the pelvis has been developed. This suggests the algorithm is sufficiently accurate for MR-only radiotherapy for all pelvic sites.

Cone beam computed tomography for dose calculation quality assurance for magnetic resonance-only radiotherapy.

BACKGROUND AND PURPOSE: Magnetic Resonance (MR)-only prostate radiotherapy using synthetic Computed Tomography (sCT) algorithms with high dose accuracy has been clinically implemented. MR images can suffer from geometric distortions so Quality Assurance (QA) using an independent, geometrically accurate, image could be required. The first-fraction Cone Beam CT (CBCT) has demonstrated potential but has not been evaluated in a clinical MR-only pathway. This study evaluated the clinical use of CBCT for dose accuracy QA of MR-only radiotherapy. MATERIALS AND METHODS: A total of 49 patients treated with MR-only prostate radiotherapy were divided into two cohorts. Cohort 1 (20 patients) received a back-up CT, whilst Cohort 2 (29 patients) did not. All patients were planned using the sCT and received daily CBCT imaging with MR-CBCT soft-tissue matching. Each CBCT was calibrated using a patient-specific stepwise Hounsfield Units-to-mass density curve. The treatment plan was recalculated on the first-fraction CBCT using the clinically applied soft-tissue match and the doses compared. For Cohort 1 the sCT was rigidly registered to the back-up CT, the plan recalculated and doses compared. RESULTS: Mean sCT-CBCT dose difference across both cohorts was - 0.6 ± 0.1 % (standard error of the mean, range - 2.3 % , 2.3 % ), with 47/49 patients within [ - 2 % , 1 % ]. The sCT-CBCT dose difference was systematically lower than the sCT-CT by - 0.7 ± 0.6 % ( ± 95 % limits of agreement). The mean sCT-CBCT gamma pass rate ( 2 % / 2 mm ) was 96.1 ± 0.4 % ( 85.4 % , 99.7 % ). CONCLUSIONS: CBCT-based dose accuracy QA for MR-only radiotherapy appears clinically feasible. There was a small systematic sCT-CBCT dose difference implying asymmetric tolerances of [ - 2 % , 1 % ] would be appropriate.

Are cone beam CT image matching skills transferrable from planning CT to planning MRI for MR-only prostate radiotherapy?

OBJECTIVES: Treatment verification for MR-only planning has focused on fiducial marker matching, however, these are difficult to identify on MR. An alternative is using the MRI for soft-tissue matching with cone beam computed tomography images (MR-CBCT). However, therapeutic radiographers have limited experience of MRI. This study aimed to assess transferability of therapeutic radiographers CT-CBCT prostate image matching skills to MR-CBCT image matching. METHODS: 23 therapeutic radiographers with 3 months-5 years' experience of online daily CT-CBCT soft-tissue matching prostate cancer patients participated. Each observer completed a baseline assessment of 10 CT-CBCT prostate soft-tissue image matches, followed by 10 MR-CBCT prostate soft-tissue image match assessment. A MRI anatomy training intervention was delivered and the 10 MR-CBCT prostate soft-tissue image match assessment was repeated. Limits of agreement were calculated as the disagreement of the observers with mean of all observers. RESULTS: Limits of agreement at CT-CBCT baseline were 2.8 mm, 2.8 mm, 0.7 mm (vertical, longitudinal, lateral). MR-CBCT matches prior to training were 3.3 mm, 3.1 mm, 0.9 mm, and after training 2.6 mm, 2.4 mm, 1.1 mm (vertical, longitudinal, lateral). Results show similar limits of agreement across the assessments, and variation reduced following the training intervention. CONCLUSION: This suggests therapeutic radiographers' prostate CBCT image matching skills are transferrable to a MRI planning scan, since MR-CBCT matching has comparable observer variation to CT-CBCT matching. ADVANCES IN KNOWLEDGE: This is the first publication assessing interobserver MR-CBCT prostate soft tissue matching in an MR-only pathway.

Additional Treatments to the Local tumour for metastatic prostate cancer-Assessment of Novel Treatment Algorithms (IP2-ATLANTA): protocol for a multicentre, phase II randomised controlled trial.

INTRODUCTION: Survival in men diagnosed with de novo synchronous metastatic prostate cancer has increased following the use of upfront systemic treatment, using chemotherapy and other novel androgen receptor targeted agents, in addition to standard androgen deprivation therapy (ADT). Local cytoreductive and metastasis-directed interventions are hypothesised to confer additional survival benefit. In this setting, IP2-ATLANTA will explore progression-free survival (PFS) outcomes with the addition of sequential multimodal local and metastasis-directed treatments compared with standard care alone. METHODS: A phase II, prospective, multicentre, three-arm randomised controlled trial incorporating an embedded feasibility pilot. All men with new histologically diagnosed, hormone-sensitive, metastatic prostate cancer, within 4 months of commencing ADT and of performance status 0 to 2 are eligible. Patients will be randomised to Control (standard of care (SOC)) OR Intervention 1 (minimally invasive ablative therapy to prostate±pelvic lymph node dissection (PLND)) OR Intervention 2 (cytoreductive radical prostatectomy±PLND OR prostate radiotherapy±pelvic lymph node radiotherapy (PLNRT)). Metastatic burden will be prespecified using the Chemohormonal Therapy Versus Androgen Ablation Randomized Trial for Extensive Disease (CHAARTED) definition. Men with low burden disease in intervention arms are eligible for metastasis-directed therapy, in the form of stereotactic ablative body radiotherapy (SABR) or surgery. Standard systemic therapy will be administered in all arms with ADT±upfront systemic chemotherapy or androgen receptor agents. Patients will be followed-up for a minimum of 2 years. PRIMARY OUTCOME: PFS. Secondary outcomes include predictive factors for PFS and overall survival; urinary, sexual and rectal side effects. Embedded feasibility sample size is 80, with 918 patients required in the main phase II component. Study recruitment commenced in April 2019, with planned follow-up completed by April 2024. ETHICS AND DISSEMINATION: Approved by the Health Research Authority (HRA) Research Ethics Committee Wales-5 (19/WA0005). Study results will be submitted for publication in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT03763253; ISCRTN58401737.

The accuracy of Magnetic Resonance - Cone Beam Computed Tomography soft-tissue matching for prostate radiotherapy.

BACKGROUND AND PURPOSE: Magnetic Resonance (MR)-Only radiotherapy requires a method for matching image with on-treatment Cone Beam Computed Tomography (CBCT). This study aimed to investigate the accuracy of MR-CBCT soft-tissue matching for prostate MR-only radiotherapy. MATERIALS AND METHODS: Three patient cohorts were used, with all patients receiving MR and CT scans. For the first cohort (10 patients) the first fraction CBCT was automatically rigidly registered to the CT and MR scans and the MR-CT registration predicted using the MR-CBCT and CT-CBCT registrations. This was compared to the automatic MR-CT registration. For the second and third cohorts (five patients each) the first fraction CBCT was independently matched to the CT and MR by four radiographers, the MR-CBCT and CT-CBCT matches compared and the inter-observer variability assessed. The second cohort used a CT-based structure set and the third a MR-based structure set with the MR relabelled as a 'CT'. RESULTS: The mean difference between predicted and actual MR-CT registrations was Δ R All = - 0.1 ± 0.2 mm (s.e.m.). Radiographer MR-CBCT registrations were not significantly different to CT-CBCT, with mean differences in soft-tissue match ⩽ 0.2 mm and all except one difference ⩽ 3.3 mm . This was less than the MR-CBCT inter-observer limits of agreement [ 3.5 , 2.4 , 0.9 ] mm (vertical, longitudinal, lateral), which were similar ( ⩽ 0.5 mm ) to CT-CBCT. CONCLUSIONS: MR-CBCT soft-tissue matching is not significantly different to CT-CBCT. Relabelling the MR as a 'CT' does not appear to change the automatic registration. This suggests that MR-CBCT soft-tissue matching is feasible and accurate.

The effects of antimicrobial peptides WAM-1 and LL-37 on multidrug-resistant Acinetobacter baumannii.

Increasing multidrug resistance (MDR) in Acinetobacter baumannii warrants therapeutic alternatives, and the bactericidal nature of antimicrobial peptides (AMPs) offers a possible approach. In this study, we examined the interaction of cathelicidin AMPs WAM-1, a marsupial AMP, and LL-37, a human AMP, with A. baumannii clinical isolates. We characterized the antibiotic resistance of the isolates, the bacteriostatic and bactericidal effects of these AMPs, synergistic activity with antibiotics, and their effects on biofilm formation and dispersal. All clinical isolates were resistant to commonly prescribed antibiotics, with four of seven isolates showing MDR. WAM-1 and LL-37 showed variable activity in clinical isolates, with WAM-1 having a stronger bacteriostatic effect than LL-37 and showing rapid bactericidal activity against clinical isolates. Furthermore, synergistic bactericidal activity was observed with WAM-1 and commonly prescribed antibiotics. Both peptides were able to inhibit biofilm formation in all clinical isolates at some concentrations, and WAM-1 dispersed mature biofilm in most isolates. LL-37 was unable to disperse mature biofilms in any strains. Further studies must be done to elucidate the true value of these alternative treatments, but these results suggest that MDR A. baumannii's susceptibility to AMPs may result in innovative therapeutics to prevent or treat these infections.

Improving Staging in Bladder Cancer: The Increasing Role of Multiparametric Magnetic Resonance Imaging.

CONTEXT: In bladder cancer (BCa) patients, accurate local and regional tumor staging is required when planning treatment. Clinical understaging frequently occurs and leads to undertreatment of the disease, with a negative impact on survival. An improvement in staging accuracy could be attained by advances in imaging. Magnetic resonance imaging (MRI) is currently the best imaging technique for locoregional staging for several malignancies because of its superior soft tissue contrast resolution with the advantage of avoiding exposure to ionizing radiation. Important improvements in MRI technology have led to the introduction of multiparametric MRI (mpMRI), which combines anatomic and functional evaluation. OBJECTIVE: To review the fundamentals of mpMRI in BCa and to provide a contemporary overview of the available data on the role of this emerging imaging technology. EVIDENCE ACQUISITION: A nonsystematic literature search using the Medline and Cochrane Library databases was performed up to March 2016. Additional articles were retrieved by cross-matching references of selected articles. Only articles reporting complete data with regard to image acquisition protocols, locoregional staging, monitoring response to therapy, and detection of locoregional recurrence after primary treatment in BCa patients were selected. EVIDENCE SYNTHESIS: Standardization of acquisition and reporting protocols for bladder mpMRI is paramount. Combining anatomic and functional sequences improves the accuracy of local tumor staging compared with conventional imaging alone. Diffusion-weighted imaging may distinguish BCa type and grade. Functional sequences are capable of monitoring response to chemotherapy and radiation therapy. Diffusion-weighted imaging enhanced by lymphotropic nanoparticles showed high accuracy in pelvic lymph node staging compared with conventional cross-sectional imaging. CONCLUSIONS: In BCa patients, mpMRI appears a promising tool for accurate locoregional staging, predicting tumor aggressiveness and monitoring response to therapy. Further large-scale studies are needed to confirm these findings. PATIENT SUMMARY: Better imaging through improved technology will improve outcomes in bladder cancer patients. We reviewed the emerging use of multiparametric magnetic resonance imaging for staging and monitoring bladder cancer. Multiparametric magnetic resonance imaging appears more accurate than current methods for local and nodal staging and monitoring tumor response to treatment, but requires further investigation.

3'-Deoxy-3'-¹8F-fluorothymidine positron emission tomography as an early predictor of disease progression in patients with advanced and metastatic pancreatic cancer.

PURPOSE: 3'-Deoxy-3'-(18)F-fluorothymidine (FLT) positron emission tomography (PET) has limited utility in abdominal imaging due to high physiological hepatic uptake of tracer. We evaluated FLT PET/CT combined with a temporal-intensity information-based voxel-clustering approach termed kinetic spatial filtering (FLT PET/CTKSF) for early prediction of response and survival outcomes in locally advanced and metastatic pancreatic cancer patients receiving gemcitabine-based chemotherapy. METHODS: Dynamic FLT PET/CT data were collected before and 3 weeks after the first cycle of chemotherapy. Changes in tumour FLT PET/CT variables were determined. The primary end point was RECIST 1.1 response on contrast-enhanced CT after 3 months of therapy. RESULTS: Twenty patients were included. Visual distinction between tumours and normal pancreas was seen in FLT PETKSF images. All target lesions (>2 cm), including all primary pancreatic tumours, were visualised. Of the 11 liver metastases, 3 (<2 cm) were not visible after kinetic filtering. Of the 20 patients, 7 progressed (35%). Maximum standardised uptake value at 60 min post-injection (SUV60,max) significantly increased in patients with disease progression (p = 0.04). Receiver-operating characteristic curve analysis indicated that a threshold of SUV60,max increase of ≥ 12% resulted in sensitivity, specificity and positive predictive value (PPV) of 71, 100 and 100%, respectively [area under the curve (AUC) 0.90, p = 0.0001], to predict patients with disease progression. Changes in SUV60,max were not predictive of survival. CONCLUSION: FLT PET/CT detected changes in proliferation, with early increase in SUV60,max predicting progressive disease with a high specificity and PPV. Therefore, FLT PET/CT could be used as an early response biomarker for gemcitabine-based chemotherapy, to select a poor prognostic group who may benefit from novel therapeutic agents in advanced and metastatic pancreatic cancer.

Isolation and culture of adult ciliary epithelial cells, previously identified as retinal stem cells, and retinal progenitor cells.

The protocols described in this unit provide detailed information on how to isolate and expand, in culture, ciliary epithelial cells (CECs), previously identified as retinal stem cells, from the adult mouse eye, and embryonic retinal progenitor cells (RPCs) from the developing retina. CECs are initially cultured in floating conditions as neurospheres and then expanded in monolayer cultures. RPCs are cultured in floating conditions. Detailed protocols for retinal differentiation, as well as exogenous gene expression using lentivirus are also described.