BACKGROUND: Complete response prediction in locally advanced rectal cancer (LARC) patients is generally focused on the radiomics analysis of staging MRI. Until now, omics information extracted from gut microbiota and circulating tumor DNA (ctDNA) have not been integrated in composite biomarkers-based models, thereby omitting valuable information from the decision-making process. In this study, we aim to integrate radiomics with gut microbiota and ctDNA-based genomics tracking during neoadjuvant chemoradiotherapy (nCRT).
METHODS: The main hypothesis of the MOREOVER study is that the incorporation of composite biomarkers with radiomics-based models used in the THUNDER-2 trial will improve the pathological complete response (pCR) predictive power of such models, paving the way for more accurate and comprehensive personalized treatment approaches. This is due to the inclusion of actionable omics variables that may disclose previously unknown correlations with radiomics. Aims of this study are: - to generate longitudinal microbiome data linked to disease resistance to nCRT and postulate future therapeutic strategies in terms of both type of treatment and timing, such as fecal microbiota transplant in non-responding patients. - to describe the genomics pattern and ctDNA data evolution throughout the nCRT treatment in order to support the prediction outcome and identify new risk-category stratification agents. - to mine and combine collected data through integrated multi-omics approaches (radiomics, metagenomics, metabolomics, metatranscriptomics, human genomics, ctDNA) in order to increase the performance of the radiomics-based response predictive model for LARC patients undergoing nCRT on MR-Linac.
METHODS: The objective of the MOREOVER project is to enrich the phase II THUNDER-2 trial (NCT04815694) with gut microbiota and ctDNA omics information, by exploring the possibility to enhance predictive performance of the developed model. Longitudinal ctDNA genomics, microbiome and genomics data will be analyzed on 7 timepoints: prior to nCRT, during nCRT on a weekly basis and prior to surgery. Specific modelling will be performed for data harvested, according to the TRIPOD statements.
CONCLUSIONS: We expect to find differences in fecal microbiome, ctDNA and radiomics profiles between the two groups of patients (pCR and not pCR). In addition, we expect to find a variability in the stability of the considered omics features over time. The identified profiles will be inserted into dedicated modelling solutions to set up a multiomics decision support system able to achieve personalized treatments.

UNASSIGNED: Organ motion (OM) and volumetric changes pose challenges in radiotherapy (RT) for locally advanced cervical cancer (LACC). Magnetic Resonance-guided Radiotherapy (MRgRT) combines improved MRI contrast with adaptive RT plans for daily anatomical changes. Our goal was to analyze cervico-uterine structure (CUS) changes during RT to develop strategies for managing OM.
UNASSIGNED: LACC patients received chemoradiation by MRIdian system with a simultaneous integrated boost (SIB) protocol. Prescription doses of 55-50.6 Gy at PTV1 and 45-39.6 Gy at PTV2 were given in 22 and 25 fractions. Daily MRI scans were co-registered with planning scans and CUS changes were assessed.Six PTVs were created by adding 0.5, 0.7, 1, 1.3, 1.5, and 2 cm margins to the CUS, based on the simulation MRI. Adequate margins were determined to include 95 % of the CUSs throughout the entire treatment in 95 % of patients.
UNASSIGNED: Analysis of 15 LACC patients and 372 MR scans showed a 31 % median CUS volume decrease. Asymmetric margins of 2 cm cranially, 0.5 cm caudally, 1.5 cm posteriorly, 2 cm anteriorly, and 1.5 cm on both sides were optimal for PTV, adapting to CUS variations. Post-14th fraction, smaller margins of 0.7 cm cranially, 0.5 cm caudally, 1.3 cm posteriorly, 1.3 cm anteriorly, and 1.3 cm on both sides sufficed.
UNASSIGNED: CUS mobility varies during RT, suggesting reduced PTV margins after the third week. MRgRT with adaptive strategies optimizes dose delivery, emphasizing the importance of streamlined IGRT with reduced PTV margins using a tailored MRgRT workflow with hybrid MRI-guided systems.

BACKGROUND: The THUNDER-2 phase II single institutional trial investigates the benefits of MRI-guided radiotherapy (MRIgRT) in treating locally advanced rectal cancer (LARC). This study focuses on evaluating the impact of escalating radiation therapy dose in non-responder patients using the Early Tumour Regression Index (ERI) for predicting complete response (CR). The trial\'s primary endpoint is to increase the CR rate in non-responders by 10% and assess the feasibility of the delta radiomics-based MRIgRT predictive model. This interim analysis assesses the feasibility and safety of the proposed MRIgRT dose escalation strategy in terms of acute toxicity (gastrointestinal, genitourinary and haematological) and treatment adherence.
METHODS: Stage cT2-3, N0-2, or cT4 patients with anal sphincter involvement, N0-2a, M0, but without high-risk features were enrolled. MRIgRT treatment consisted of a standard dose of 55 Gy to the Gross Tumor Volume (GTV) and mesorectum, and 45 Gy to the mesorectum and drainage nodes in 25 fractions with concomitant chemotherapy. 0.35 T MRI was used for simulation imaging and daily alignment. ERI was calculated at the 10th fraction. Non-responders with an ERI above 13.1 received intensified dose escalation from the 11th fraction, resulting in a total dose of 60.1 Gy. Acute toxicity was assessed using the CTCAE v.5 scale.
RESULTS: From March 2021 to November 2022, 33 out of the total number of 63 patients to be enrolled (52.4%) were included, with one withdrawal unrelated to treatment. Sixteen patients (50%) underwent dose escalation. Treatment was well tolerated, with only one patient (3.1%) in the standard treatment group experiencing acute Grade 3 diarrhea, proctitis, and cystitis. No significant differences in toxicity were observed between the two groups (p = 0.5463).
CONCLUSIONS: MRIgRT treatment with dose escalation up to 60.1 Gy is well tolerated in LARC patients predicted as non-responders by ERI, confirming the feasibility and safety of this approach. The THUNDER-2 trial\'s primary and secondary endpoints will be fully analyzed when all planned patients will be enrolled.

UNASSIGNED: The stomach is one of the most deformable organs. Its shape can be easily affected by breathing movements, and daily diet, and it also varies when the body position is different. The susceptibility of stomach has made it challenging to treat gastric cancer using the conventional image-guided radiotherapy, i.e., the techniques based on kilovoltage X-ray imaging. The magnetic resonance imaging guided radiotherapy (MRgRT) is usually implemented using a hybrid system MR-LINAC. It is feasible to implement adaptive radiotherapy using MR-LINAC for deformable organs such as stomach. In this case report, we present our clinical experience to treat a gastric cancer patient using MR-LINAC.
UNASSIGNED: The patient is a 58-year-old male who started having black stools with no apparent cause a year ago. Gastroscopy result showed pancreatic cancer, pathology: adenocarcinoma on gastric cancer biopsy, adenocarcinoma on gastric body minor curvature biopsy. The patient was diagnosed with gastric cancer (adenocarcinoma, cTxN+M1, stage IV, HER-2 positive). The patient was treated in 25 fractions with radiotherapy using MR-LINAC with online adaptive treatment plans daily. The target area in daily MR images varied considerably when compared with the target area on the CT simulation images. During the course of treatment, there have even been instances where the planned target area where the patient received radiotherapy did not cover the lesion of the day.
UNASSIGNED: Online adaptive MRgRT can be a meaningful innovation for treating malignancies in the upper abdomen. The results in the current study are promising and are indicative for further optimizing online adaptive MRgRT in patients with inoperable tumors of the upper abdomen.

UNASSIGNED: The introduction of on-line magnetic resonance image-guided radiotherapy (MRIgRT) has led to an improvement in the therapeutic workflow of radiotherapy treatments thanks to the better visualization of therapy volumes assured by the higher soft tissue contrast. Magnetic Resonance contrast agents (MRCA) could improve the target delineation in on-line MRIgRT planning as well as reduce inter-observer variability and enable innovative treatment optimization protocols. The aim of this survey is to investigate the utilization of MRCA among centres that clinically implemented on-line MRIgRT technology.
UNASSIGNED: In September 2021, we conducted an online survey consisting of a sixteen-question questionnaire that was distributed to the all the hospitals around the world equipped with MR Linacs. The questionnaire was developed by two Italian 0.35 T and 1.5 T MR-Linac centres and was validated by four other collaborating centres, using a Delphi consensus methodology.
UNASSIGNED: The survey was distributed to 52 centres and 43 centres completed it (82.7%). Among these centres, 23 institutions (53.5%) used the 0.35T MR-Linac system, while the remaining 20 (46.5%) used the 1.5T MR-Linac system.According to results obtained, 25 (58%) of the centres implemented the use of MRCA for on-line MRIgRT. Gadoxetate (Eovist®; Primovist®) was reported to be the most used MRCA (80%) and liver the most common site of application (58%). Over 70% of responders agreed/strongly agreed to the need for international guidelines.
UNASSIGNED: The use of MRCA in clinical practice presents several pitfalls and future research will be necessary to understand the actual advantage derived from the use of MRCA in clinical practice, their toxicity profiles and better define the need of formulating guidelines for standardising the use of MRCA in MRIgRT workflow.

BACKGROUND: Mesorectal motion (MM) is a source of uncertainty during neoadjuvant chemoradiotherapy (nCRT) delivery for locally advanced rectal cancer (LARC). Previously published experiences using cone-beam computed tomography imaging have already described significant movement. Aim of this analysis is to assess inter-fraction MM using the higher tissue contrast provided by hybrid magnetic resonance imaging (MRI) in LARC patients (pts) treated with MRI guided radiation therapy (MRgRT).
METHODS: The total mesorectum, its superior (Msup), middle (Mmid) and lower (Mlow) regions were contoured on the positioning MRIs acquired on simulation day and on each treatment day. Six PTVs were obtained adding 0.5, 0.7, 1, 1.3, 1.5 and 2 cm margin to the whole mesorectum, starting from the simulation MRI. Margins including 95% of the mesorectal structures during whole treatment in 95% of patients (pts) were considered adequate.
RESULTS: A total number of 312 fractions of 12 consecutive pts was retrospectively analyzed. The different mesorectum regions show specific motion variability. In particular, Msup shows larger variability in left, right and anterior directions, while the Mlow in caudal and posterior ones. The anterior margin is significantly larger in the Msup than in the other regions.
CONCLUSIONS: Different mesorectal regions move differently throughout the radiotherapy treatment, with the largest MM in the Msup anterior direction. Asymmetrical margins are recommended.

Objective. To investigate the feasibility to train artificial neural networks (NN) to recover lateral dose profiles from detector measurements in a magnetic field.Approach. A novel framework based on a mathematical convolution model has been proposed to generate measurement-less training dataset. 2D dose deposition kernels and detector lateral fluence response functions of two air-filled ionization chambers and two diode-type detectors have been simulated without magnetic field and for magnetic fieldB = 0.35 and 1.5 T. Using these convolution kernels, training dataset consisting pairs of dose profilesDx,yand signal profilesMx,ywere computed for a total of 108 2D photon fluence profilesψ(x,y)(80% training/20% validation). The NN were tested using three independent datasets, where the second test dataset has been obtained from simulations using realistic phase space files of clinical linear accelerator and the third test dataset was measured at a conventional linac equipped with electromagnets. Mainresults. The convolution kernels show magnetic field dependence due to the influence of the Lorentz force on the electron transport in the water phantom and detectors. The NN show good performance during training and validation with mean square error reaching a value of 1e-6 or smaller. The corresponding correlation coefficientsRreached the value of 1 for all models indicating an excellent agreement between expectedDx,yand predictedDpredx,y.The comparisons betweenDx,yandDpredx,yusing the three test datasets resulted in gamma indices (1 mm/1% global) <1 for all evaluated data points.Significance. Two verification approaches have been proposed to warrant the mathematical consistencies of the NN outputs. Besides offering a correction strategy not existed so far for relative dosimetry in a magnetic field, this work could help to raise awareness and to improve understanding on the distortion of detector\'s signal profiles by a magnetic field.

BACKGROUND: Neoadjuvant chemoradiation therapy (nCRT) is the standard treatment modality in locally advanced rectal cancer (LARC). Since response to radiotherapy (RT) is dose dependent in rectal cancer, dose escalation may lead to higher complete response rates. The possibility to predict patients who will achieve complete response (CR) is fundamental. Recently, an early tumour regression index (ERI) was introduced to predict pathological CR (pCR) after nCRT in LARC patients. The primary endpoints will be the increase of CR rate and the evaluation of feasibility of delta radiomics-based predictive MRI guided Radiotherapy (MRgRT) model.
METHODS: Patients affected by LARC cT2-3, N0-2 or cT4 for anal sphincter involvement N0-2a, M0 without high risk features will be enrolled in the trial. Neoadjuvant CRT will be administered using MRgRT. The initial RT treatment will consist in delivering 55 Gy in 25 fractions on Gross Tumor Volume (GTV) plus the corresponding mesorectum and 45 Gy in 25 fractions on the drainage nodes. Chemotherapy with 5-fluoracil (5-FU) or oral capecitabine will be administered continuously. A 0.35 Tesla MRI will be acquired at simulation and every day during MRgRT. At fraction 10, ERI will be calculated: if ERI will be inferior than 13.1, the patient will continue the original treatment; if ERI will be higher than 13.1 the treatment plan will be reoptimized, intensifying the dose to the residual tumor at the 11th fraction to reach 60.1 Gy. At the end of nCRT instrumental examinations are to be performed in order to restage patients. In case of stable disease or progression, the patient will undergo surgery. In case of major or complete clinical response, conservative approaches may be chosen. Patients will be followed up to evaluate toxicity and quality of life. The number of cases to be enrolled will be 63: all the patients will be treated at Fondazione Policlinico Universitario A. Gemelli IRCCS in Rome.
CONCLUSIONS: This clinical trial investigates the impact of RT dose escalation in poor responder LARC patients identified using ERI, with the aim of increasing the probability of CR and consequently an organ preservation benefit in this group of patients.
BACKGROUND: ClinicalTrials.gov Identifier: NCT04815694 (25/03/2021).

The aim of the present work is to investigate the behavior of two diode-type detectors (PTW microDiamond 60019 and PTW microSilicon 60023) in transverse magnetic field under small field conditions. A formalism based on TRS 483 has been proposed serving as the framework for the application of these high-resolution detectors under these conditions. Measurements were performed at the National Metrology Institute of Germany (PTB, Braunschweig) using a research clinical linear accelerator facility. Quadratic fields corresponding to equivalent square field sizesSbetween 0.63 and 4.27 cm at the depth of measurement were used. The magnetic field strength was varied up to 1.4 T. Experimental results have been complemented with Monte Carlo simulations up to 1.5 T. Detailed simulations were performed to quantify the small field perturbation effects and the influence of detector components on the dose response. The does response of both detectors decreases by up to 10% at 1.5 T in the largest field size investigated. InS = 0.63 cm, this reduction at 1.5 T is only about half of that observed in field sizesS > 2 cm for both detectors. The results of the Monte Carlo simulations show agreement better than 1% for all investigated conditions. Due to normalization at the machine specific reference field, the resulting small field output correction factors for both detectors in magnetic fieldkQclin,QmsrBare smaller than those in the magnetic field-free case, where correction up to 6.2% at 1.5 T is required for the microSilicon in the smallest field size investigated. The volume-averaging effect of both detectors was shown to be nearly independent of the magnetic field. The influence of the enhanced-density components within the detectors has been identified as the major contributors to their behaviors in magnetic field. Nevertheless, the effect becomes weaker with decreasing field size that may be partially attributed to the deficiency of low energy secondary electrons originated from distant locations in small fields.

OBJECTIVE: The magnetic-field correction factors k B , Q of compact air-filled ionization chambers have been investigated experimentally and using Monte Carlo simulations up to 1.5 T. The role of the nonsensitive region within the air cavity and influence of the chamber construction on its dose response have been elucidated.
METHODS: The PTW Semiflex 3D 31021, PinPoint 3D 31022, and Sun Nuclear Cooperation SNC125c chambers were studied. The k B , Q factors were measured at the experimental facility of the German National Metrology Institute (PTB) up to 1.4 T using a 6 MV photon beam. The chambers were positioned with the chamber axis perpendicular to the beam axis (radial); and parallel to the beam axis (axial). In both cases, the magnetic field was directed perpendicular to both the beam axis and chamber axis. Additionally, the sensitive volumes of these chambers have been experimentally determined using a focused proton microbeam and finite element method. Beside the simulations of k B , Q factors, detailed Monte Carlo technique has been applied to analyse the secondary electron fluence within the air cavity, that is, the number of secondary electrons and the average path length as a function of the magnetic field strength.
RESULTS: A nonsensitive volume within the air cavity adjacent to the chamber stem for the PTW chambers has been identified from the microbeam measurements and FEM calculations. The dose response of the three investigated ionization chambers does not deviate by more than 4% from the field-free case within the range of magnetic fields studied in this work for both the radial and axial orientations. The simulated k B , Q for the fully guarded PTW chambers deviate by up to 6% if their sensitive volumes are not correctly considered during the simulations. After the implementation of the sensitive volume derived from the microbeam measurements, an agreement of better than 1% between the experimental and Monte Carlo k B , Q factors for all three chambers can be achieved. Detailed analysis reveals that the stem of the PTW chambers could give rise to a shielding effect reducing the number of secondary electrons entering the air cavity in the presence of magnetic field. However, the magnetic field dependence of their path length within the air cavity is shown to be weaker than for the SNC125c chamber, where the length of the air cavity is larger than its diameter. For this chamber it is shown that the number of electrons and their path lengths in the cavity depend stronger on the magnetic field.
CONCLUSIONS: For clinical measurements up to 1.5 T, the required k B , Q corrections of the three chambers could be kept within 3% in both the investigated chamber orientations. The results reiterate the importance of considering the sensitive volume of fully guarded chambers, even for the investigated compact chambers, in the Monte Carlo simulations of chamber response in magnetic field. The resulting magnetic field-dependent dose response has been demonstrated to depend on the chamber construction, such as the ratio between length and the diameter of the air cavity as well as the design of the chamber stem.