Evaluation of hypofractionated adaptive radiotherapy using the MR Linac in localised pancreatic cancer: protocol summary of the Emerald-Pancreas phase 1/expansion study located at Oxford University Hospital, UK.

INTRODUCTION: Online adaptive MR-guided radiotherapy allows for dose escalation to pancreatic cancer while sparing surrounding critical organs. We seek to evaluate the safety of delivering hypofractionated five-fraction, three-fraction and single-fraction MR-guided stereotactic ablative radiotherapy (SABR) to the pancreas. METHODS AND ANALYSIS: This is a single-centre three-arm phase 1 non-randomised safety study. Patients with localised pancreatic cancer will receive either 50 Gy in five (biological equivalent dose (BED10)=100 Gy), 39 Gy in three (BED10=90 Gy) or 25 Gy in a single fraction (BED10=87.5 Gy) MR-guided daily online adaptive radiotherapy. Each fractionation regimen will be assessed as independent cohorts to determine tolerability, assessed continuously using Bayesian conjugate posterior beta distributions. The primary endpoint of the study is to establish the safety of five-fraction, three-fraction and single-fraction MR-guided hypofractionation SABR in localised pancreatic cancer by assessing dose-limiting toxicities. Secondary endpoints include overall survival, progression-free survival, local control rates, overall control rate, resection rates, long-term toxicities and freedom from second-line chemotherapy. This study plans to also explore imaging and immune biomarkers that may be useful to predict outcome and personalise treatment. The trial will recruit up to 60 patients with a safety run-in. ETHICS AND DISSEMINATION: The trial is approved by the West Midlands-Black Country Research Ethics Committee 22/WM/0122. The results will be disseminated via conference presentations, peer-reviewed scientific journals and submission to regulatory authorities. The data collected for the study, including individual participant data, will be made available to researchers on request to the study team and with appropriate reason, via octo-enquiries@oncology.ox.ac.uk. The shared data will be deidentified participant data and will be available for 3 years following publication of the study. Data will be shared with investigator support, after approval of a proposal and with a signed data access agreement. TRIAL REGISTRATION NUMBER: ISRCTN10557832.

Oxygen-enhanced MRI and radiotherapy in patients with oropharyngeal squamous cell carcinoma.

Background and purpose: This study aimed to assess the role of T1 mapping and oxygen-enhanced MRI in patients undergoing radical dose radiotherapy for HPV positive oropharyngeal cancer, which has not yet been examined in an OE-MRI study. Materials and methods: Variable Flip Angle T1 maps were acquired on a 3T MRI scanner while patients (n = 12) breathed air and/or 100 % oxygen, before and after fraction 10 of the planned 30 fractions of chemoradiotherapy ('visit 1' and 'visit 2', respectively). The analysis aimed to assess to what extent (1) native R1 relates to patient outcome; (2) OE-MRI response relates to patient outcome; (3) changes in mean R1 before and after radiotherapy related to clinical outcome in patients with oropharyngeal squamous cell carcinoma. Results: Due to the radiotherapy being largely successful, the sample sizes of non-responder groups were small, and therefore it was not possible to properly assess the predictive nature of OE-MRI. The tumour R1 increased in some patients while decreasing in others, in a pattern that was overall consistent with the underlying OE-MRI theory and previously reported tumour OE-MRI responses. In addition, we discuss some practical challenges faced when integrating this technique into a clinical trial, with the aim that sharing this is helpful to researchers planning to use OE-MRI in future clinical studies. Conclusion: Altogether, these results suggest that further clinical OE-MRI studies to assess hypoxia and radiotherapy response are worth pursuing, and that there is important work to be done to improve the robustness of the OE-MRI technique in human applications in order for it to be useful as a widespread clinical technique.

An insight into the current perceptions of UK radiographers on the future impact of AI on the profession: A cross-sectional survey.

INTRODUCTION: As a profession, radiographers have always been keen on adapting and integrating new technologies. The increasing integration of artificial intelligence (AI) into clinical practice in the last five years has been met with scepticism by some, who predict the demise of the profession, whilst others suggest a bright future with AI, full of opportunities and synergies. Post COVID-19 pandemic need for economic recovery and a backlog of medical imaging and reporting may accelerate the adoption of AI. It is therefore timely to appreciate practitioners' perceptions of AI used in clinical practice and their perception of the short-term impact on the profession. AIM: This study aims to explore the perceptions of AI in the UK radiography workforce and to investigate its current AI applications and future technological expectations of radiographers. METHODS: An online survey (QualtricsⓇ) was created by a team of radiography AI experts. The survey was disseminated via social media and professional networks in the UK. Demographic information and perceptions of the impact of AI on several aspects of the radiography profession were gathered, including the current use of AI in practice, future expectations and the perceived impact of AI on the profession. RESULTS: 411 responses were collected (80% diagnostic radiographers (DR); 20% therapeutic radiographers (TR)). Awareness of AI used in clinical practice is low, with DR respondents suggesting AI will have the most value/potential in cross sectional imaging and image reporting. TR responses linked AI as having most value in treatment planning, contouring, and image acquisition/matching. Respondents felt that AI will impact radiographers' daily work (DR, 79.6%; TR, 88.9%) by standardising some aspects of patient care and technical factors of radiography practice. A mixed response about impact on careers was reported. CONCLUSIONS: Respondents were unsure about the ways in which AI is currently used in practice and how AI will impact on careers in the future. It was felt that AI integration will lead to increased job opportunities to contribute to decision making as an end user. Job security was not identified as a cause for concern.

Using Variable Flip Angle (VFA) and Modified Look-Locker Inversion Recovery (MOLLI) T1 mapping in clinical OE-MRI.

BACKGROUND AND PURPOSE: The imaging technique known as Oxygen-Enhanced MRI is under development as a noninvasive technique for imaging hypoxia in tumours and pulmonary diseases. While promising results have been shown in preclinical experiments, clinical studies have mentioned experiencing difficulties with patient motion, image registration, and the limitations of single-slice images compared to 3D volumes. As clinical studies begin to assess feasibility of using OE-MRI in patients, it is important for researchers to communicate about the practical challenges experienced when using OE-MRI on patients to help the technique advance. MATERIALS AND METHODS: We report on our experience with using two types of T1 mapping (MOLLI and VFA) for a recently completed OE-MRI clinical study on oropharyngeal squamous cell carcinoma. RESULTS: We report: (1) the artefacts and practical difficulties encountered in this study; (2) the difference in estimated T1 from each method used - the VFA T1 estimation was higher than the MOLLI estimation by 27% on average; (3) the standard deviation within the tumour ROIs - there was no significant difference in the standard deviation seen within the tumour ROIs from the VFA versus MOLLI; and (4) the OE-MRI response collected from either method. Lastly, we collated the MRI acquisition details from over 45 relevant manuscripts as a convenient reference for researchers planning future studies. CONCLUSION: We have reported our practical experience from an OE-MRI clinical study, with the aim that sharing this is helpful to researchers planning future studies. In this study, VFA was a more useful technique for using OE-MRI in tumours than MOLLI T1 mapping.

Beauty Is in the AI of the Beholder: Are We Ready for the Clinical Integration of Artificial Intelligence in Radiography? An Exploratory Analysis of Perceived AI Knowledge, Skills, Confidence, and Education Perspectives of UK Radiographers.

Introduction: The use of artificial intelligence (AI) in medical imaging and radiotherapy has been met with both scepticism and excitement. However, clinical integration of AI is already well-underway. Many authors have recently reported on the AI knowledge and perceptions of radiologists/medical staff and students however there is a paucity of information regarding radiographers. Published literature agrees that AI is likely to have significant impact on radiology practice. As radiographers are at the forefront of radiology service delivery, an awareness of the current level of their perceived knowledge, skills, and confidence in AI is essential to identify any educational needs necessary for successful adoption into practice. Aim: The aim of this survey was to determine the perceived knowledge, skills, and confidence in AI amongst UK radiographers and highlight priorities for educational provisions to support a digital healthcare ecosystem. Methods: A survey was created on Qualtrics® and promoted via social media (Twitter®/LinkedIn®). This survey was open to all UK radiographers, including students and retired radiographers. Participants were recruited by convenience, snowball sampling. Demographic information was gathered as well as data on the perceived, self-reported, knowledge, skills, and confidence in AI of respondents. Insight into what the participants understand by the term "AI" was gained by means of a free text response. Quantitative analysis was performed using SPSS® and qualitative thematic analysis was performed on NVivo®. Results: Four hundred and eleven responses were collected (80% from diagnostic radiography and 20% from a radiotherapy background), broadly representative of the workforce distribution in the UK. Although many respondents stated that they understood the concept of AI in general (78.7% for diagnostic and 52.1% for therapeutic radiography respondents, respectively) there was a notable lack of sufficient knowledge of AI principles, understanding of AI terminology, skills, and confidence in the use of AI technology. Many participants, 57% of diagnostic and 49% radiotherapy respondents, do not feel adequately trained to implement AI in the clinical setting. Furthermore 52% and 64%, respectively, said they have not developed any skill in AI whilst 62% and 55%, respectively, stated that there is not enough AI training for radiographers. The majority of the respondents indicate that there is an urgent need for further education (77.4% of diagnostic and 73.9% of therapeutic radiographers feeling they have not had adequate training in AI), with many respondents stating that they had to educate themselves to gain some basic AI skills. Notable correlations between confidence in working with AI and gender, age, and highest qualification were reported. Conclusion: Knowledge of AI terminology, principles, and applications by healthcare practitioners is necessary for adoption and integration of AI applications. The results of this survey highlight the perceived lack of knowledge, skills, and confidence for radiographers in applying AI solutions but also underline the need for formalised education on AI to prepare the current and prospective workforce for the upcoming clinical integration of AI in healthcare, to safely and efficiently navigate a digital future. Focus should be given on different needs of learners depending on age, gender, and highest qualification to ensure optimal integration.

Mitochondrial Inhibitor Atovaquone Increases Tumor Oxygenation and Inhibits Hypoxic Gene Expression in Patients with Non-Small Cell Lung Cancer.

PURPOSE: Tumor hypoxia fuels an aggressive tumor phenotype and confers resistance to anticancer treatments. We conducted a clinical trial to determine whether the antimalarial drug atovaquone, a known mitochondrial inhibitor, reduces hypoxia in non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients with NSCLC scheduled for surgery were recruited sequentially into two cohorts: cohort 1 received oral atovaquone at the standard clinical dose of 750 mg twice daily, while cohort 2 did not. Primary imaging endpoint was change in tumor hypoxic volume (HV) measured by hypoxia PET-CT. Intercohort comparison of hypoxia gene expression signatures using RNA sequencing from resected tumors was performed. RESULTS: Thirty patients were evaluable for hypoxia PET-CT analysis, 15 per cohort. Median treatment duration was 12 days. Eleven (73.3%) atovaquone-treated patients had meaningful HV reduction, with median change -28% [95% confidence interval (CI), -58.2 to -4.4]. In contrast, median change in untreated patients was +15.5% (95% CI, -6.5 to 35.5). Linear regression estimated the expected mean HV was 55% (95% CI, 24%-74%) lower in cohort 1 compared with cohort 2 (P = 0.004), adjusting for cohort, tumor volume, and baseline HV. A key pharmacodynamics endpoint was reduction in hypoxia-regulated genes, which were significantly downregulated in atovaquone-treated tumors. Data from multiple additional measures of tumor hypoxia and perfusion are presented. No atovaquone-related adverse events were reported. CONCLUSIONS: This is the first clinical evidence that targeting tumor mitochondrial metabolism can reduce hypoxia and produce relevant antitumor effects at the mRNA level. Repurposing atovaquone for this purpose may improve treatment outcomes for NSCLC.

Stereotactic body radiotherapy for moderately central and ultra-central oligometastatic disease: Initial outcomes.

BACKGROUND: Delivery of SBRT to central thoracic tumours within 2 cm of the proximal bronchial tree (PBT), and especially ultra-central tumours which directly abut the PBT, has been controversial due to concerns about high risk of toxicity and treatment-related death when delivering high doses close to critical mediastinal structures. We present dosimetric and clinical outcomes from a group of oligometastatic patients treated with a risk-adapted SBRT approach. METHODS: Between September 2015 and October 2018, 27 patients with 28 central thoracic oligometastases (6 moderately central, 22 ultra-central) were treated with 60 Gy in 8 fractions under online CBCT guidance. PTV dose was compromised where necessary to meet mandatory OAR constraints. Patients were followed up for toxicity and disease status. RESULTS: Mandatory OAR constraints were met in all cases; this required PTV coverage compromise in 23 cases, with V100% reduced to <70% in 11 cases. No acute or late toxicities of Grade ≥ 3 were reported. One and 2 year in-field control rates were 95.2% and 85.7% respectively, progression-free survival rates were 42.8% and 23.4% respectively, and overall survival rates were 82.7% and 69.5% respectively. No significant differences were seen in control or survival rates by extent of PTV underdosage or between moderately and ultra-central cases. CONCLUSION: It appears that compromising PTV coverage to meet OAR constraints allows safe and effective delivery of SBRT to moderately and ultra-central tumours, with low toxicity rates and high in-field control rates. This treatment can be delivered on standard linear accelerators with widely available imaging technology.

Oxygen-enhanced MRI MOLLI T1 mapping during chemoradiotherapy in anal squamous cell carcinoma.

BACKGROUND AND PURPOSE: Oxygen-enhanced magnetic resonance imaging (MRI) and T1-mapping was used to explore its effectiveness as a prognostic imaging biomarker for chemoradiotherapy outcome in anal squamous cell carcinoma. MATERIALS AND METHODS: T2-weighted, T1 mapping, and oxygen-enhanced T1 maps were acquired before and after 8-10 fractions of chemoradiotherapy and examined whether the oxygen-enhanced MRI response relates to clinical outcome. Patient response to treatment was assessed 3 months following completion of chemoradiotherapy. A mean T1 was extracted from manually segmented tumour regions of interest and a paired two-tailed t-test was used to compare changes across the patient population. Regions of subcutaneous fat and muscle tissue were examined as control ROIs. RESULTS: There was a significant increase in T1 of the tumour ROIs across patients following the 8-10 fractions of chemoradiotherapy (paired t-test, p < 0.001, n = 7). At baseline, prior to receiving chemoradiotherapy, there were no significant changes in T1 across patients from breathing oxygen (n = 9). In the post-chemoRT scans (8-10 fractions), there was a significant decrease in T1 of the tumour ROIs across patients when breathing 100% oxygen (paired t-test, p < 0.001, n = 8). Out of the 12 patients from which we successfully acquired a visit 1 T1-map, only 1 patient did not respond to treatment, therefore, we cannot correlate these results with clinical outcome. CONCLUSIONS: These clinical data demonstrate feasibility and potential for T1-mapping and oxygen enhanced T1-mapping to indicate perfusion or treatment response in tumours of this nature. These data show promise for future work with a larger cohort containing more non-responders, which would allow us to relate these measurements to clinical outcome.

Response of FDG avid pelvic bone marrow to concurrent chemoradiation for anal cancer.

BACKGROUND AND PURPOSE: To determine if suppression of active bone marrow, as defined on FDG PETCT, is seen in on-treatment imaging of anal cancer patients receiving concurrent chemoradiation. METHODS AND MATERIALS: Scans from 26 patients participating in the ART trial (full title: Anal squamous cell carcinoma: Investigation of functional imaging during chemoRadioTherapy), a single center observational study with FDG PETCT prior to radiotherapy and at fraction 8-10 of concurrent chemoradiation were analysed. Active bone marrow was contoured in both the pelvis and un-irradiated thoracic spine. SUV and volume of active bone marrow after 8-10 fractions of treatment were compared to baseline. Dose metrics to pelvic active bone marrow were extracted and compared to reduction in SUV/active bone marrow volume and to blood count nadir using linear regression. RESULTS: Suppression of active bone marrow is seen in the pelvis by a reduction in mean SUV and volume of active bone marrow after 8-10 fractions of treatment. Suppression is not seen in un-irradiated thoracic spine. Dose metrics were associated with reduced SUV and reduced volume of active bone marrow. Volume of active bone marrow receiving <20 Gy was associated with WCC/ANC nadir. 20 Gy was identified as the most likely clinically meaningful dose threshold for toxicity. Volume of active bone marrow receiving <20 Gy correlated to WCC and ANC with an increase of 100 cc being associated with an increase of 0.4 and 0.3 respectively. CONCLUSION: The effect of concurrent chemoradiation in suppression of active bone marrow is seen in on-treatment FDG PETCT scans. Chemotherapy appears well tolerated after 2 weeks of treatment.

Impact of abdominal compression on setup error and image matching during radical abdominal radiotherapy.

PURPOSE: To determine the impact of abdominal compression (AC) on setup error and image matching time. MATERIALS AND METHODS: This study included 72 liver, pancreas and abdominal node patients treated radically from 2016 to 2019 in a single centre. Patients received either SBRT or conventional radical fractionation (CRF). Compressed patients were supine, arms up with kneefix and AC equipment. Uncompressed patients were supine, arms up with kneefix. All patients received daily online-matched CBCTs before treatment. Initial setup error was determined for all patients. Registration error was assessed for 10 liver and 10 pancreas patients. Image matching times were determined using beam on times. Statistical tests conducted were an F-test to compare variances in setup error, Student's t-tests for setup error and average image analysis, and a Wilcoxon Mann Whitney test for imaging matching time analysis. RESULTS: Initial setup displacement was similar between compressed and uncompressed patients. Displacements > 1 cm occurred more frequently in the longitudinal direction for most patients. SBRT patients required more additional manual positioning following imaging. Mean absolute registration error in the SI direction was 5.4 mm and 3.3 mm for uncompressed and compressed pancreas patients respectively and 1.7 mm and 0.8 mm for uncompressed and compressed liver patients respectively. Compressed patients required less time for image matching and fewer images per fraction on average. Repeat imaging occurred more frequently in SBRT and uncompressed patients. CONCLUSIONS: Although abdominal compression has no significant impact on setup error, it can reduce imaging matching times resulting in improved treatment accuracy.

Comparison of investigator-delineated gross tumour volumes and quality assurance in pancreatic cancer: Analysis of the on-trial cases for the SCALOP trial.

BACKGROUND AND PURPOSE: We performed a retrospective central review of tumour outlines in patients undergoing radiotherapy in the SCALOP trial. MATERIALS AND METHODS: The planning CT scans were reviewed retrospectively by a central review team, and the accuracy of investigators' GTV (iGTV) and PTV (iPTV) was compared to the trials team-defined gold standard (gsGTV and gsPTV) using the Jaccard Conformity Index (JCI) and Geographical Miss Index (GMI). The prognostic value of JCI and GMI was also assessed. The RT plans were also reviewed against protocol-defined constraints. RESULTS: 60 patients with diagnostic-quality planning scans were included. The median whole volume JCI for GTV was 0.64 (IQR: 0.43-0.82), and the median GMI was 0.11 (IQR: 0.05-0.22). For PTVs, the median JCI and GMI were 0.80 (IQR: 0.71-0.88) and 0.04 (IQR: 0.02-0.12) respectively. Tumour was completely missed in 1 patient, and⩾50% of the tumour was missed in 3. Patients with JCI for GTV⩾0.7 had 7.12 (95% CIs: 1.83-27.67, p=0.005) higher odds of progressing by 9months in multivariate analysis. Major deviations in RT planning were noted in 4.5% of cases. CONCLUSIONS: Radiotherapy workshops and real-time central review of contours are required in RT trials of pancreatic cancer.

ARCII: A phase II trial of the HIV protease inhibitor Nelfinavir in combination with chemoradiation for locally advanced inoperable pancreatic cancer.

BACKGROUND AND PURPOSE: Nelfinavir can enhance intrinsic radiosensitivity, reduce hypoxia and improve vascularity. We conducted a phase II trial combining nelfinavir with chemoradiotherapy (CRT) for locally advanced inoperable pancreatic cancer (LAPC). MATERIALS AND METHODS: Radiotherapy (50.4Gy/28 fractions; boost to 59.4Gy/33 fractions) was administered with weekly gemcitabine and cisplatin. Nelfinavir started 3-10days before and was continued during CRT. The primary end-point was 1-year overall survival (OS). Secondary end-points included histological downstaging, radiological response, 1-year progression free survival (PFS), overall survival (OS) and treatment toxicity. An imaging sub-study (n=6) evaluated hypoxia ((18)F-Fluoromisonidazole-PET) and perfusion (perfusion CT) during induction nelfinavir. RESULTS: The study closed after recruiting 23 patients, due to non-availability of Nelfinavir in Europe. The 1-year OS was 73.4% (90% CI: 54.5-85.5%) and median OS was 17.4months (90% CI: 12.8-18.8). The 1-year PFS was 21.8% (90% CI: 8.9-38.3%) and median PFS was 5.5months (90% CI: 4.1-8.3). All patients experienced Grade 3/4 toxicity, but many were asymptomatic laboratory abnormalities. Four of 6 patients on the imaging sub-study demonstrated reduced hypoxia and increased perfusion post-nelfinavir. CONCLUSIONS: CRT combined with nelfinavir showed acceptable toxicity and promising survival in pancreatic cancer.

Clinical Trial of Oral Nelfinavir before and during Radiation Therapy for Advanced Rectal Cancer.

PURPOSE: Nelfinavir, a PI3K pathway inhibitor, is a radiosensitizer that increases tumor blood flow in preclinical models. We conducted an early-phase study to demonstrate the safety of nelfinavir combined with hypofractionated radiotherapy (RT) and to develop biomarkers of tumor perfusion and radiosensitization for this combinatorial approach. EXPERIMENTAL DESIGN: Ten patients with T3-4 N0-2 M1 rectal cancer received 7 days of oral nelfinavir (1,250 mg b.i.d.) and a further 7 days of nelfinavir during pelvic RT (25 Gy/5 fractions/7 days). Perfusion CT (p-CT) and DCE-MRI scans were performed pretreatment, after 7 days of nelfinavir and prior to the last fraction of RT. Biopsies taken pretreatment and 7 days after the last fraction of RT were analyzed for tumor cell density (TCD). RESULTS: There were 3 drug-related grade 3 adverse events: diarrhea, rash, and lymphopenia. On DCE-MRI, there was a mean 42% increase in medianKtrans, and a corresponding median 30% increase in mean blood flow on p-CT during RT in combination with nelfinavir. Median TCD decreased from 24.3% at baseline to 9.2% in biopsies taken 7 days after RT (P= 0.01). Overall, 5 of 9 evaluable patients exhibited good tumor regression on MRI assessed by tumor regression grade (mrTRG). CONCLUSIONS: This is the first study to evaluate nelfinavir in combination with RT without concurrent chemotherapy. It has shown that nelfinavir-RT is well tolerated and is associated with increased blood flow to rectal tumors. The efficacy of nelfinavir-RT versus RT alone merits clinical evaluation, including measurement of tumor blood flow.

Endobiliary Stent Position Changes during External-beam Radiotherapy.

PURPOSE: Endobiliary stents can be used as surrogates for pancreatic localization when using cone-beam computed tomography (CBCT) during external-beam radiotherapy (EBRT). This work reports on interfraction stent position changes during EBRT for locally advanced pancreatic cancer (LAPC). MATERIALS AND METHODS: Six patients with endobiliary stents who underwent EBRT for LAPC were assessed. Measurements from the most superior aspect of the stent (sup stent) and the most inferior aspect of the stent (inf stent) to the most inferior, posterior aspect of the L1 vertebra central spinous process were determined from daily treatment CBCTs and compared with those determined from the planning computed tomography (CT) scan. Changes in stent-L1 measurements were interpreted as changes in relative stent position. RESULTS: Three patients showed mean interfraction stent position changes of ≥1 cm when treatment measurements were compared with planning measurements. The sup stent for patient A moved to the right (2.66 ± 2.77 cm) and inferiorly (3.0 ± 3.12 cm), and the inf stent moved to the right (1.92 ± 2.02 cm) inferiorly (3.23 ± 3.34 cm) and posteriorly (1.41 ± 1.43 cm). The inf stent for patient B moved superiorly (2.23 ± 0.49 cm) and posteriorly (1.72 ± 0.59 cm). The sup and inf stent for patient F moved inferiorly (0.98 ± 0.35 cm and 1.21 ± 0.38 cm, respectively). The remaining three patients C, D, and E showed interfraction position changes of <1 cm. CONCLUSION: Endobiliary stent migration and deformation were observed in a small subset of patients. Further investigation is required before confirming their use as surrogates for LAPC target localization during image-guided EBRT.

BUT: L'endoprothèse endobiliaire peut être utilisée substitut à la localisation pancréatique dans l'utilisation de la tomographie par ordinateur à faisceau conique (TOFC) en radiothérapie externe. La présente étude fait état du déplacement interfraction de l'endoprothèse durant la radiothérapie externe pour le cancer du pancréas localement avancé (CPLA). MATÉRIEL ET MÉTHODOLOGIE: Six patients porteurs d'une endoprothèse endobiliaire ayant reçu des traitements de radiothérapie externe pour un CPLA ont été évalués. Les mesures pour l'aspect le plus supérieur de l'endoprothèse (sup stent) et son aspect le plus inférieur (inf stent) par rapport à l'aspect le plus supérieur et inférieur de l'apophyse épineuse centrale de la vertèbre L1 ont été déterminés à partir des traitements quotidiens de TOFC et comparés à celles établies lors de la tomographie de planification. Les changements dans la mesure endoprothèse-L1 ont été interprétés comme des changements dans la position relative de l'endoprothèse. RÉSULTATS: Trois patients ont présenté un déplacement interfraction de l'endoprothèse de ≥1 cm lorsque les mesures de traitement ont été comparées aux mesures de planification. Pour le patient A, la mesure sup stent montre un déplacement vers la droite (2,66±2,77 cm) et le bas (3,0±3,12 cm), tandis que la mesure inf stent se déplaçait vers la droite (1,92±2,02 cm), le bas (3,23±3,34 cm) et l'arrière (1,41±1,43 cm). La mesure inf stent pour le patient B montre un déplacement vers le haut (2,23±0,49 cm) et l'arrière (1,72±0,59 cm). Les mesures sup et inf stent du patient F montrent un déplacement vers le bas (0,98±0,35 cm et 1,21±0,38 cm, respectivement). Chez les trois autres patients (C, D et E), le déplacement interfraction est inférieur à 1 cm. CONCLUSION: La migration et la déformation de l'endoprothèse endobiliaire ont été observées chez un petit sous-ensemble de patients. D'autres études seront nécessaires avant de pouvoir confirmer leur utilisation comme substitut à la localisation des cibles CPLA durant la radiothérapie externe guidée par l'image.

Identification of vitamin B1 metabolism as a tumor-specific radiosensitizing pathway using a high-throughput colony formation screen.

Colony formation is the gold standard assay for determining reproductive cell death after radiation treatment, since effects on proliferation often do not reflect survival. We have developed a high-throughput radiosensitivity screening method based on clonogenicity and screened a siRNA library against kinases. Thiamine pyrophosphokinase-1 (TPK1), a key component of Vitamin B1/thiamine metabolism, was identified as a target for radiosensitization. TPK1 knockdown caused significant radiosensitization in cancer but not normal tissue cell lines. Other means of blocking this pathway, knockdown of thiamine transporter-1 (THTR1) or treatment with the thiamine analogue pyrithiamine hydrobromide (PyrH) caused significant tumor specific radiosensitization. There was persistent DNA damage in cells irradiated after TPK1 and THTR1 knockdown or PyrH treatment. Thus this screen allowed the identification of thiamine metabolism as a novel radiosensitization target that affects DNA repair. Short-term modulation of thiamine metabolism could be a clinically exploitable strategy to achieve tumor specific radiosensitization.

Challenges in using ¹8F-fluorodeoxyglucose-PET-CT to define a biological radiotherapy boost volume in locally advanced pancreatic cancer.

BACKGROUND: The best method of identifying regions within pancreatic tumours that might benefit from an increased radiotherapy dose is not known. We investigated the utility of pre-treatment FDG-PET in predicting the spatial distribution of residual metabolic activity following chemoradiotherapy (CRT) in locally advanced pancreatic cancer (LAPC). METHODS: 17 patients had FDG-PET/CT scans at baseline and six weeks post-CRT. Tumour segmentation was performed at 40% and 50% of SUVmax at baseline and 60%, 70%, 80% and 90% post-CRT. FDG-PET scans were non-rigidly registered to the radiotherapy planning CT using the CT component of the FDG-PET/CT. Percentage overlap of the post-CRT volumes with the pre-CRT volumes with one another and the gross tumour volume (GTV) was calculated. RESULTS: SUVmax decreased during CRT (median pre- 8.0 and post- 3.6, p < 0.0001). For spatial correlation analysis, 9 pairs of scans were included (Four were excluded following complete metabolic response, one patient had a non-FDG avid tumour, one had no post-CRT imaging, one had diffuse FDG uptake that could not be separated from normal tissues and one had an elevated blood glucose). The Pre40% and 50% of SUVmax volumes covered a mean of 50.8% and 30.3% of the GTV respectively. The mean% overlap of the 90%, 80%, 70%, 60% of SUVmax post-CRT with the Pre40% and Pre50% volumes were 83.3%, 84.0%, 83.7%, 77.9% and 77.8%, 69.9%, 74.5%, 64.8% respectively. CONCLUSIONS: Regions of residual metabolic activity following CRT can be predicted from the baseline FDG-PET and could aid definition of a biological target volume for non-uniform dose prescriptions.

A treatment planning comparison of four target volume contouring guidelines for locally advanced pancreatic cancer radiotherapy.

BACKGROUND AND PURPOSE: Contouring of target volumes varies significantly in radiotherapy of pancreatic ductal adenocarcinoma (PDAC). There is a lack of consensus as to whether elective lymph nodes (eLN's) should be included or not in the planning target volume (PTV). In the present study we analyzed the dosimetric coverage of the eLN's and organs at risk (OAR) by comparing four different contouring guidelines. METHODS AND MATERIALS: PTVs were delineated with (Oxford and RTOG guidelines) or without (Michigan and SCALOP guidelines) including the eLNs in eleven patients with PDAC. eLNs included the peripancreatic, paraaortic, paracaval, celiac trunk, superior mesenteric and portal vein clinical target volumes (CTVs). A 3D-CRT plan (50.40 Gy in 28 fractions) was performed to analyze and compare the dosimetric coverage of all eLNs and OAR between the 4 contouring guidelines. RESULTS: The size of Oxford and RTOG PTVs was comparable and significantly larger than the SCALOP and Michigan PTVs. Interestingly the eLNs received a significant amount of incidental dose irradiation by PTV-based plans that only aimed to treat the tumor without the eLNs. The dosimetric coverage of eLN presented a large variability according to the respective contouring methods. The difference in the size of the 4 PTVs was reflected to the dose distribution at the OAR. CONCLUSIONS: Our study provides important information regarding the impact of different contouring guidelines on the dose distribution to the eLNs and the OAR in patients with locally advanced PDAC treated with radiotherapy.