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Introduction: Manual segmentation of medical images is labor intensive and especially challenging for images with poor contrast or resolution. The presence of disease exacerbates this further, increasing the need for an automated solution. To this extent, SynthSeg is a robust deep learning model designed for automatic brain segmentation across various contrasts and resolutions. This study validates the SynthSeg robust brain segmentation model on computed tomography (CT), using a multi-center dataset., Methods: An open access dataset of 260 paired CT and magnetic resonance imaging (MRI) from radiotherapy patients treated in 5 centers was collected. Brain segmentations from CT and MRI were obtained with SynthSeg model, a component of the Freesurfer imaging suite. These segmentations were compared and evaluated using Dice scores and Hausdorff 95 distance (HD95), treating MRI-based segmentations as the ground truth. Brain regions that failed to meet performance criteria were excluded based on automated quality control (QC) scores., Results: Dice scores indicate a median overlap of 0.76 (IQR: 0.65-0.83). The mean volume difference is 7.79% (CI: 6.41%-9.18%), with CT segmentations typically smaller than MRI-based. The median HD95 is 2.95 mm (IQR: 1.73-5.39). QC score based thresholding improves median dice by 0.1 and median HD95 by 0.05 mm. Morphological differences related to sex and age, as detected by MRI, were also replicated with CT, with an approximate 17% difference between the CT and MRI results for sex and 10% difference between the results for age., Conclusion: SynthSeg can be utilized for CT-based automatic brain segmentation, but only in applications where precision is not essential. CT performance is lower than MRI based on the integrated QC scores, but low-quality segmentations can be excluded with QC-based thresholding. Additionally, performing CT-based neuroanatomical studies is encouraged, as the results show correlations in sex- and age-based analyses similar to those found with MRI., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: To assess the efficacy of magnetic resonance (MR) lymphography with gadobutrol contrast for sentinel lymph node (SLN) mapping in early-stage oral squamous cell carcinoma (OSCC). Methods: This pilot study compared the identification of SLNs by MR lymphography using a gadolinium-based contrast agent (gadobutrol) to conventional [ 99m Tc]Tc-nanocolloid lymphoscintigraphy (including single-photon emission computed tomography/computed tomography (SPECT/CT)) in 10 early-stage OSCC patients undergoing SLN biopsy. The patients initially underwent conventional lymphoscintigraphy following the peritumoral administration of indocyanine green [ 99m Tc]Tc-nanocolloid (120 megabecquerel; ~0.5 mL). Subsequently, 0.5-1.0 mL gadobutrol was peritumorally injected, and MR imaging was acquired for 30 min. The following day, the identified SLNs were harvested and subjected to a histopathological assessment. The MR lymphography and [ 99m Tc]Tc-nanocolloid lymphoscintigraphy results were evaluated and compared with respect to those of the SLN identification. The reference standard consisted of a histopathological evaluation of the harvested SLNs, complementary neck dissection specimens, and follow-up data. Results: The MR lymphography detected 16 out of 27 SLNs identified by [ 99m Tc]Tc-nanocolloid lymphoscintigraphy, revealing an additional SLN that did not harbor metastasis. MR lymphography failed to identify any SLNs in one patient. Of the seven histopathologically positive SLNs detected by [ 99m Tc]Tc-nanocolloid lymphoscintigraphy, three were identified by MR lymphography. All patients remained disease-free after a median follow-up of 16 months. Compared to [ 99m Tc]Tc-nanocolloid lymphoscintigraphy, MR lymphography using gadobutrol achieved an SLN identification rate of 59%, a sensitivity of 75%, and a negative predictive value of 86%. Conclusions: MR lymphography using gadobutrol demonstrates limited reliability for SLN mapping in early-stage OSCC.

In this study, we present a method that enables voxel-by-voxel comparison of in vivo imaging to immunohistochemistry (IHC) biomarkers. As a proof of concept, we investigated the spatial correlation between dynamic contrast enhanced (DCE-)CT parameters and IHC biomarkers Ki-67 (proliferation), HIF-1α (hypoxia), and CD45 (immune cells). 54 whole-mount tumor slices of 15 laryngeal and hypopharyngeal carcinomas were immunohistochemically stained and digitized. Heatmaps of biomarker positivity were created and registered to DCE-CT parameter maps. The adiabatic approximation to the tissue homogeneity model was used to fit the following DCE parameters: K trans (transfer constant), V e (extravascular and extracellular space), and V i (intravascular space). Both IHC and DCE maps were downsampled to 4 × 4 × 3 mm[3] voxels. The mean values per tumor were used to calculate the between-subject correlations between parameters. For the within-subject (spatial) correlation, values of all voxels within a tumor were compared using the repeated measures correlation (r rm ). No between-subject correlations were found between IHC biomarkers and DCE parameters, whereas we found multiple significant within-subject correlations: V e and Ki-67 (r rm = -0.17, P < .001), V e and HIF-1α (r rm = -0.12, P < .001), K trans and CD45 (r rm = 0.13, P < .001), V i and CD45 (r rm = 0.16, P < .001), and V i and Ki-67 (r rm = 0.08, P = .003). The strongest correlation was found between IHC biomarkers Ki-67 and HIF-1α (r rm = 0.35, P < .001). This study shows the technical feasibility of determining the 3 dimensional spatial correlation between histopathological biomarker heatmaps and in vivo imaging. It also shows that between-subject correlations do not reflect within-subject correlations of parameters., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Background and Purpose: In head and neck squamous cell carcinoma (HNSCC) patients, the radiation dose to nearby organs at risk can be reduced by restricting elective neck irradiation from lymph node levels to individual lymph nodes. However, manual delineation of every individual lymph node is time-consuming and error prone. Therefore, automatic magnetic resonance imaging (MRI) segmentation of individual lymph nodes was developed and tested using a convolutional neural network (CNN)., Materials and Methods: In 50 HNSCC patients (UMC-Utrecht), individual lymph nodes located in lymph node levels Ib-II-III-IV-V were manually segmented on MRI by consensus of two experts, obtaining ground truth segmentations. A 3D CNN (nnU-Net) was trained on 40 patients and tested on 10. Evaluation metrics were Dice Similarity Coefficient (DSC), recall, precision, and F1-score. The segmentations of the CNN was compared to segmentations of two observers. Transfer learning was used with 20 additional patients to re-train and test the CNN in another medical center., Results: nnU-Net produced automatic segmentations of elective lymph nodes with median DSC: 0.72, recall: 0.76, precision: 0.78, and F1-score: 0.78. The CNN had higher recall compared to both observers (p = 0.002). No difference in evaluation scores of the networks in both medical centers was found after re-training with 5 or 10 patients., Conclusion: nnU-Net was able to automatically segment individual lymph nodes on MRI. The detection rate of lymph nodes using nnU-Net was higher than manual segmentations. Re-training nnU-Net was required to successfully transfer the network to the other medical center., Competing Interests: This study was possible due to the sponsored international fellowship of the first author by the following unrestricted grants: 1. Stichting Hanarth Fonds. 2. Prins Bernard Cultuur fonds, 3. Stichting de drie lichten, 4. Hendrik Muller Fonds, 5. Girard de Mielet van Coehoorn Stichting.The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Background: This study aimed to determine the prognostic value of radiological magnetic resonance imaging (MRI) variables and dynamic contrast enhanced (DCE)-MRI for local control (LC), disease control (DC), and overall survival (OS) in laryngeal and hypopharyngeal cancer patients after radiotherapy., Methods: 320 patients treated with radiotherapy were retrospectively included. Pretreatment MRIs were evaluated for the following anatomical tumor characteristics: cartilage invasion, extralaryngeal spread, and involvement of the anterior commissure, pre-epiglottic space, and paralaryngeal space.Pretreatment DCE-MRI was available in 89 patients. The median and 95th percentile of the 60-second area under the contrast-distribution-curve (AUC60 median and AUC60 p95 ) were determined in the tumor volume., Results: Univariable log-rank test determined that extralaryngeal spread, tumor volume and T-stage were prognostic for worse LC, DC, and OS. A low AUC60 p95 (<31.7 mmol·s/L) and thyroid cartilage invasion were prognostic for worse OS.In multivariable analysis, a Cox proportional hazard model showed that a AUC60 p95  ≥ 31.7 mmol·s/L was prognostic for better OS (HR=0.25, P <.001). Tumor volume was prognostic for DC (HR=3.42, P <.001) and OS (HR=3.27, P <.001). No anatomical MRI variables were significantly prognostic for LC, DC, or OS in multivariable analysis when corrected for confounders., Conclusion: Low pretreatment AUC60 p95 is prognostic for a worse OS, suggesting that poor tumor perfusion leads to worse survival. Large tumor volume is also prognostic for worse DC and OS. Anatomical MRI parameters are not prognostic for any of the evaluated treatment outcomes when corrected for confounders like age, T-stage, N-stage, and tumor volume., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Author(s).)

The brain relies on an effective clearance mechanism to remove metabolic waste products for the maintenance of homeostasis. Recent studies have focused on elucidating the forces that drive the motion of cerebrospinal fluid (CSF), responsible for removal of these waste products. We demonstrate that vascular responses evoked using controlled manipulations of partial pressure of carbon dioxide (PaCO 2 ) levels, serve as an endogenous driver of CSF clearance from the brain. To demonstrate this, we retrospectively surveyed our database, which consists of brain metastases patients from whom blood oxygen level-dependent (BOLD) images were acquired during targeted hypercapnic and hyperoxic respiratory challenges. We observed a correlation between CSF inflow signal around the fourth ventricle and CO 2 -induced changes in cerebral blood volume. By contrast, no inflow signal was observed in response to the nonvasoactive hyperoxic stimulus, validating our measurements. Moreover, our results establish a link between the rate of the hemodynamic response (to elevated PaCO 2 ) and peritumoral edema load, which we suspect may affect CSF flow, consequently having implications for brain clearance. Our expanded perspective on the factors involved in neurofluid flow underscores the importance of considering both cerebrovascular responses, as well as the brain mechanical properties, when evaluating CSF dynamics in the context of disease processes., (© 2024 The Authors. NMR in Biomedicine published by John Wiley & Sons Ltd.)

Human papillomavirus (HPV) is an important risk factor for oropharyngeal squamous cell carcinoma (OPSCC). HPV-positive (HPV+) cases are associated with a different pathophysiology, microstructure, and prognosis compared to HPV-negative (HPV-) cases. This review aimed to investigate the potential of magnetic resonance imaging (MRI) to discriminate between HPV+ and HPV- tumours and predict HPV status in OPSCC patients. A systematic literature search was performed on 15 December 2022 on EMBASE, MEDLINE ALL, Web of Science, and Cochrane according to PRISMA guidelines. Twenty-eight studies ( n = 2634 patients) were included. Five, nineteen, and seven studies investigated structural MRI (e.g., T1, T2-weighted), diffusion-weighted MRI, and other sequences, respectively. Three out of four studies found that HPV+ tumours were significantly smaller in size, and their lymph node metastases were more cystic in structure than HPV- ones. Eleven out of thirteen studies found that the mean apparent diffusion coefficient was significantly higher in HPV- than HPV+ primary tumours. Other sequences need further investigation. Fourteen studies used MRI to predict HPV status using clinical, radiological, and radiomics features. The reported areas under the curve (AUC) values ranged between 0.697 and 0.944. MRI can potentially be used to find differences between HPV+ and HPV- OPSCC patients and predict HPV status with reasonable accuracy. Larger studies with external model validation using independent datasets are needed before clinical implementation.

Objective: This study aims to determine the added value of a geometrically accurate diffusion-weighted (DW-) MRI sequence on the accuracy of gross tumor volume (GTV) delineations, using pathological tumor delineations as a ground truth., Methods: Sixteen patients with laryngeal or hypopharyngeal carcinoma were included. After total laryngectomy, the specimen was cut into slices. Photographs of these slices were stacked to create a 3D digital specimen reconstruction, which was registered to the in vivo imaging. The pathological tumor (tumor HE ) was delineated on the specimen reconstruction. Six observers delineated all tumors twice: once with only anatomical MR imaging, and once (a few weeks later) when DW sequences were also provided. The majority voting delineation of session one (GTV MRI ) and session two (GTV DW-MRI ), as well as the clinical target volumes (CTVs), were compared to the tumor HE ., Results: The mean tumor HE volume was 11.1 cm 3 , compared to a mean GTV MRI volume of 18.5 cm 3 and a mean GTV DW-MRI volume of 15.7 cm 3 . The median sensitivity (tumor coverage) was comparable between sessions: 0.93 (range: 0.61-0.99) for the GTV MRI and 0.91 (range: 0.53-1.00) for the GTV DW-MRI . The CTV volume also decreased when DWI was available, with a mean CTV MR of 47.1 cm 3 and a mean CTV DW-MRI of 41.4 cm 3 . Complete tumor coverage was achieved in 15 and 14 tumors, respectively., Conclusion: GTV delineations based on anatomical MR imaging tend to overestimate the tumor volume. The availability of the geometrically accurate DW sequence reduces the GTV overestimation and thereby CTV volumes, while maintaining acceptable tumor coverage., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: The increasing incidence of brain metastases (BMs) and improved survival rates underscore the necessity to investigate the effects of treatments on individuals. The aim of this study was to evaluate the individual trajectories of subjective and objective cognitive performance after radiotherapy in patients with BMs., Methods: The study population consisted of adult patients with BMs referred for radiotherapy. A semi-structured interview and comprehensive neurocognitive assessment (NCA) were used to assess both subjective and objective cognitive performance before, 3 months and ≥ 11 months after radiotherapy. Reliable change indices were used to identify individual, clinically meaningful changes., Results: Thirty-six patients completed the 3-month follow-up, and 14 patients completed the ≥ 11-months follow-up. Depending on the domain, subjective cognitive decline was reported by 11-22% of patients. In total, 50% of patients reported subjective decline in at least one cognitive domain. Intracranial progression 3 months postradiotherapy was a risk-factor for self-reported deterioration ( P  = .031). Objective changes were observed across all domains, with a particular vulnerability for decline in memory at 3 months postradiotherapy. The majority of patients (81%) experienced both a deterioration as well as improvement (eg, mixed response) in objective cognitive functioning. Results were similar for the long-term follow-up (3 to ≥11 months). No risk factors for objective cognitive change 3 months postradiotherapy were identified., Conclusions: Our study revealed that the majority of patients with BMs will show a mixed cognitive response following radiotherapy, reflecting the complex impact. This underscores the importance of patient-tailored NCAs 3 months postradiotherapy to guide optimal rehabilitation strategies., Competing Interests: The authors declare no conflict of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

Objective: This study explores the feasibility of ex-vivo high-field magnetic resonance (MR) imaging to create digital a three-dimensional (3D) representations of tongue cancer specimens, referred to as the "MR-based digital specimen" (MR-DS). The aim was to create a method to assist surgeons in identifying and localizing inadequate resection margins during surgery, a critical factor in achieving locoregional control., Methods: Fresh resection specimens of nine tongue cancer patients were imaged in a 7 Tesla small-bore MR, using a high-resolution multislice and 3D T2-weighted Turbo Spin Echo. Two independent radiologists (R1 and R2) outlined the tumor and mucosa on the MR-images whereafter the outlines were configured to an MR-DS. A color map was projected on the MR-DS, mapping the inadequate margins according to R1 and R2. We compared the hematoxylin-eosin-based digital specimen (HE-DS), which is a histopathological 3D representation derived from HE stained sections, with its corresponding MR-images. In line with conventional histopathological assessment, all digital specimens were divided into five anatomical regions (anterior, posterior, craniomedial, caudolateral and deep central). Over- and underestimation 95 th -percentile Hausdorff-distances were calculated between the radiologist- and histopathologist-determined tumor outlines. The MR-DS' diagnostic accuracy for inadequate margin detection (i.e. sensitivity and specificity) was determined in two ways: with conventional histopathology and HE-DS as reference., Results: Using conventional histopathology as a reference, R1 achieved 77% sensitivity and 50% specificity, while R2 achieved 65% sensitivity and 57% specificity. When referencing to the HE-DS, R1 achieved 94% sensitivity and 61% specificity, while R2 achieved 88% sensitivity and 71% specificity. Range of over- and underestimation 95HD was 0.9 mm - 11.8 mm and 0.0 mm - 5.3 mm, respectively., Conclusion: This proof of concept for volumetric assessment of resection margins using MR-DSs, demonstrates promising potential for further development. Overall, sensitivity is higher than specificity for inadequate margin detection, because of the radiologist's tendency to overestimate tumor size., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 de Koning, Dankbaar, de Keizer, Willemsen, van der Toorn, Breimer, van Es, de Bree, Noorlag and Philippens.)

Background and Purpose: Individual elective lymph node irradiation instead of elective neck irradiation is a new concept for head-and-neck cancer (HNC) patients developed for the Magnetic Resonance Image guided linear accelerator (MR-linac). To prepare this, the detectability, volume changes and intra-fraction motion of elective lymph nodes on the MR-linac was assessed., Materials and Methods: A total of 15 HNC patients underwent diagnostic pre-treatment MRI. Additionally, two MR-linac scans were obtained with a 10-minute time difference in the first week of radiation treatment. Elective lymph node contours inside lymph node levels (Ib-V) were segmented on the pre-treatment MRI and the MR-linac scans and compared on number and maximal transversal diameter. Intra-fraction motion of elective lymph nodes on the MR-linac was estimated using Center of Mass (COM) distances and incremental isotropic expansion of lymph node segmentations., Results: Of all 679 detected lymph nodes on the pre-treatment MRI, eight lymph nodes were not detectable on the first MR-linac scan and 16 new lymph nodes were detected. Lymph node diameters between the pre-treatment MRI scan and the MR-linac scan varied from -0.19 to + 0.13 mm. COM distances varied from 1.2 to 1.7 mm and lymph node contours had to be expanded with 3 mm., Conclusions: Nearly all elective lymph nodes were detectable on the 1.5T MR-linac scan with no major changes in target volumes compared to the pre-treatment MRI. Simulated intra-fraction motion during the MR-linac scans was smaller than the 5-mm margin that will be used in the first elective lymph node radiation treatment., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 Published by Elsevier B.V. on behalf of European Society of Radiotherapy & Oncology.)

Arterial spin labeling (ASL) MRI is a routine clinical imaging technique that provides quantitative cerebral blood flow (CBF) information. A related technique is blood oxygenation level-dependent (BOLD) MRI during hypercapnia, which can assess cerebrovascular reactivity (CVR). ASL is weighted towards arteries, whereas BOLD is weighted towards veins. Their associated parameters in heterogeneous tissue types or under different hemodynamic conditions remains unclear. Baseline multi-delay ASL MRI and BOLD MRI during hypercapnia were performed in fourteen patients with brain metastases. In the ROI analysis, the CBF and CVR values were positively correlated in regions showing sufficient reserve capacity (i.e. non-steal regions, r rm  = 0.792). Additionally, longer hemodynamic lag times were related to lower baseline CBF ( r rm  = -0.822) and longer arterial arrival time (AAT; r rm  = 0.712). In contrast, in regions exhibiting vascular steal an inverse relationship was found with higher baseline CBF related to more negative CVR ( r rm  = -0.273). These associations were confirmed in voxelwise analyses. The relationship between CBF, AAT and CVR measures seems to be dependent on the vascular status of the underlying tissue. Healthy tissue relationships do not hold in tissues experiencing impaired or exhausted autoregulation. CVR metrics can possibly identify at-risk areas before perfusion deficiencies become visible on ASL MRI, specifically within vascular steal regions., Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: The APRICOT study described in the current manuscript, as well as the first author (Eva van Grinsven), were supported by research funding from the Dutch Cancer Society “Koningin Wilhelmina Fonds (KWF)” (#11110). Alex Bhogal is supported by a Dutch research council talent grant (NWO VENI: The ischemic fingerprint, [VI.VENI.194.056]. The funding sources had no role in conducting this research or preparation of this manuscript. No other declarations of interests apply.

Objective: Patients with brain metastases (BrMs) are a heterogeneous population, with almost 50% experiencing cognitive impairment before brain radiotherapy. Defining pre-radiotherapy cognitive profiles will aid in understanding of the cognitive vulnerabilities and offer valuable insight and guidance for tailoring interventions., Methods: The study population consisted of 58 adult patients with BrMs referred for radiotherapy. A semi-structured interview and comprehensive battery including 10 neuropsychological tests were used to assess subjective and objective cognitive performance prior to radiotherapy., Results: A majority (69%) of patients report decline in cognitive performance compared to their premorbid level (i.e. pre-cancer). Objective testing revealed memory (52%), processing speed (33%) and emotion recognition (29%) deficits were most frequent. 21% of patients had no cognitive deficits while 55% had deficits (-1.5SD) in at least two cognitive domains. Hierarchical cluster analysis based on patient deficit profiles identified four clusters: (I) no or limited cognitive deficits selectively restricted to processing speed or executive function, (II) psychomotor speed deficits, (III) memory deficits and (IV) extensive cognitive deficits including memory. No patient or clinical-related (e.g. age, number of BrMs, previous treatment) differences were found between clusters., Conclusions: Patterns of cognitive performance in patients with BrMs are heterogeneous, with most experiencing at least some degree of neurocognitive dysfunction. We identified four meaningful cognitive clusters. Stability of these clusters over time and in different samples should be assessed to advance understanding of the cognitive vulnerability of this patient population., (© 2023 The Authors. Psycho-Oncology published by John Wiley & Sons Ltd.)

Brain metastases occur in ten to thirty percent of the adult cancer population. Treatment consists of different (palliative) options, including stereotactic radiosurgery (SRS). Sensitive MRI biomarkers are needed to better understand radiotherapy-related effects on cerebral physiology and the subsequent effects on neurocognitive functioning. In the current study, we used physiological imaging techniques to assess cerebral blood flow (CBF), oxygen extraction fraction (OEF), cerebral metabolic rate of oxygen (CMRO 2 ) and cerebrovascular reactivity (CVR) before and three months after SRS in nine patients with brain metastases. The results showed improvement in OEF, CBF and CMRO 2 within brain tissue that recovered from edema (all p ≤ 0.04), while CVR remained impacted. We observed a global post-radiotherapy increase in CBF in healthy-appearing brain tissue ( p = 0.02). A repeated measures correlation analysis showed larger reductions within regions exposed to higher radiotherapy doses in CBF ( r rm = -0.286, p < 0.001), CMRO 2 ( r rm = -0.254, p < 0.001), and CVR ( r rm = -0.346, p < 0.001), but not in OEF ( r rm = -0.004, p = 0.954). Case analyses illustrated the impact of brain metastases progression on the post-radiotherapy changes in both physiological MRI measures and cognitive performance. Our preliminary findings suggest no radiotherapy effects on physiological parameters occurred in healthy-appearing brain tissue within 3-months post-radiotherapy. Nevertheless, as radiotherapy can have late side effects, larger patient samples allowing meaningful grouping of patients and longer follow-ups are needed.

Introduction: Diffusion-weighted imaging (DWI) on MRI-linear accelerator (MR-linac) systems can potentially be used for monitoring treatment response and adaptive radiotherapy in head and neck cancers (HNC) but requires extensive validation. We performed technical validation to compare six total DWI sequences on an MR-linac and MR simulator (MR sim) in patients, volunteers, and phantoms., Methods: Ten human papillomavirus-positive oropharyngeal cancer patients and ten healthy volunteers underwent DWI on a 1.5 T MR-linac with three DWI sequences: echo planar imaging (EPI), split acquisition of fast spin echo signals (SPLICE), and turbo spin echo (TSE). Volunteers were also imaged on a 1.5 T MR sim with three sequences: EPI, BLADE (vendor tradename), and readout segmentation of long variable echo trains (RESOLVE). Participants underwent two scan sessions per device and two repeats of each sequence per session. Repeatability and reproducibility within-subject coefficient of variation (wCV) of mean ADC were calculated for tumors and lymph nodes (patients) and parotid glands (volunteers). ADC bias, repeatability/reproducibility metrics, SNR, and geometric distortion were quantified using a phantom., Results: In vivo repeatability/reproducibility wCV for parotids were 5.41%/6.72%, 3.83%/8.80%, 5.66%/10.03%, 3.44%/5.70%, 5.04%/5.66%, 4.23%/7.36% for EPI MR-linac , SPLICE, TSE, EPI MR sim , BLADE, RESOLVE. Repeatability/reproducibility wCV for EPI MR-linac , SPLICE, TSE were 9.64%/10.28%, 7.84%/8.96%, 7.60%/11.68% for tumors and 7.80%/9.95%, 7.23%/8.48%, 10.82%/10.44% for nodes. All sequences except TSE had phantom ADC biases within ± 0.1x10 -3 mm 2 /s for most vials (EPI MR-linac , SPLICE, and BLADE had 2, 3, and 1 vials out of 13 with larger biases, respectively). SNR of b = 0 images was 87.3, 180.5, 161.3, 171.0, 171.9, 130.2 for EPI MR-linac , SPLICE, TSE, EPI MR sim , BLADE, RESOLVE., Conclusion: MR-linac DWI sequences demonstrated near-comparable performance to MR sim sequences and warrant further clinical validation for treatment response assessment in HNC., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Haralick texture features are used to quantify the spatial distribution of signal intensities within an image. In this study, the heterogeneity of proliferation (Ki-67 expression) and immune cells (CD45 expression) within tumors was quantified and used to classify histologic characteristics of larynx and hypopharynx carcinomas. Of 21 laryngectomy specimens, 74 whole-mount tumor slides were scored on histologic characteristics. Ki-67 and CD45 immunohistochemistry was performed, and all sections were digitized. The tumor area was annotated in QuPath. Haralick features independent of the diaminobenzidine intensity were extracted from the isolated diaminobenzidine signal to quantify intratumor heterogeneity. Haralick features from both Ki-67 and CD45 were used as input for a principal component analysis. A linear support vector machine was fitted to the first 4 principal components for classification and validated with a leave-one-patient-out cross-validation method. Significant differences in individual Haralick features were found between cohesive and noncohesive tumors for CD45 (angular second motion: P =.03, inverse difference moment: P =.009, and entropy: P =.02) and between the larynx and hypopharynx tumors for both CD45 (angular second motion: P =.03, inverse difference moment: P =.007, and entropy: P =.005) and Ki-67 (correlation: P =.003). Therefore, these features were used for classification. The linear classifier resulted in a classification accuracy of 85% for site of origin and 81% for growth pattern. A leave-one-patient-out cross-validation resulted in an error rate of 0.27 and 0.35 for both classifiers, respectively. In conclusion, we show a method to quantify intratumor heterogeneity of immunohistochemistry biomarkers using Haralick features. This study also shows the feasibility of using these features to classify tumors by histologic characteristics. The classifiers created in this study are a proof of concept because more data are needed to create robust classifiers, but the method shows potential for automated tumor classification., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: We aim to characterize the serial quantitative apparent diffusion coefficient (ADC) changes of the target disease volume using diffusion-weighted imaging (DWI) acquired weekly during radiation therapy (RT) on a 1.5T MR-Linac and correlate these changes with tumor response and oncologic outcomes for head and neck squamous cell carcinoma (HNSCC) patients as part of a programmatic R-IDEAL biomarker characterization effort., Methods: Thirty patients with pathologically confirmed HNSCC who received curative-intent RT at the University of Texas MD Anderson Cancer Center, were included in this prospective study. Baseline and weekly Magnetic resonance imaging (MRI) (weeks 1-6) were obtained, and various ADC parameters (mean, 5 th , 10 th , 20 th , 30 th , 40 th , 50 th , 60 th , 70 th , 80 th , 90 th and 95 th percentile) were extracted from the target regions of interest (ROIs). Baseline and weekly ADC parameters were correlated with response during RT, loco-regional control, and the development of recurrence using the Mann-Whitney U test. The Wilcoxon signed-rank test was used to compare the weekly ADC versus baseline values. Weekly volumetric changes (Δvolume) for each ROI were correlated with ΔADC using Spearman's Rho test. Recursive partitioning analysis (RPA) was performed to identify the optimal ΔADC threshold associated with different oncologic outcomes., Results: There was an overall significant rise in all ADC parameters during different time points of RT compared to baseline values for both gross primary disease volume (GTV-P) and gross nodal disease volumes (GTV-N). The increased ADC values for GTV-P were statistically significant only for primary tumors achieving complete remission (CR) during RT. RPA identified GTV-P ΔADC 5 th percentile >13% at the 3 rd week of RT as the most significant parameter associated with CR for primary tumor during RT (p <0.001). Baseline ADC parameters for GTV-P and GTV-N didn't significantly correlate with response to RT or other oncologic outcomes. There was a significant decrease in residual volume of both GTV-P & GTV-N throughout the course of RT. Additionally, a significant negative correlation between mean ΔADC and Δvolume for GTV-P at the 3 rd and 4 th week of RT was detected (r = -0.39, p = 0.044 & r = -0.45, p = 0.019, respectively)., Conclusion: Assessment of ADC kinetics at regular intervals throughout RT seems to be correlated with RT response. Further studies with larger cohorts and multi-institutional data are needed for validation of ΔADC as a model for prediction of response to RT.

Objectives: This study aimed to validate a digital image analysis (DIA) workflow for automatic positive cell detection and positive region delineation for immunohistochemical hypoxia markers with a nuclear (hypoxia-inducible factor 1α [HIF-1α]) and a cytoplasmic (pimonidazole [PIMO]) staining pattern., Materials and Methods: 101 tissue fragments from 44 laryngeal tumor biopsies were immunohistochemically stained for HIF-1α and PIMO. QuPath was used to determine the percentage of positive cells and to delineate positive regions automatically. For HIF-1α, only cells with strong staining were considered positive. Three dedicated head and neck pathologists scored the percentage of positive cells using three categories (0: <1%; 1: 1%-33%; 2: >33%;). The pathologists also delineated the positive regions on 14 corresponding PIMO and HIF-1α-stained fragments. The consensus between observers was used as the reference standard and was compared to the automatic delineation., Results: Agreement between categorical positivity scores was 76.2% and 65.4% for PIMO and HIF-1α, respectively. In all cases of disagreement in HIF-1α fragments, the DIA underestimated the percentage of positive cells. As for the region detection, the DIA correctly detected most positive regions on PIMO fragments (false positive area=3.1%, false negative area=0.7%). In HIF-1α, the DIA missed some positive regions (false positive area=1.3%, false negative area=9.7%)., Conclusions: Positive cell and region detection on biopsy material is feasible, but further optimization is needed before unsupervised use. Validation at varying DAB staining intensities is hampered by lack of reliability of the gold standard (i.e., visual human interpretation). Nevertheless, the DIA method has the potential to be used as a tool to assist pathologists in the analysis of IHC staining., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

Introduction: The long-term complication rate in head-and-neck squamous cell carcinoma (HNSCC) patients caused by radiotherapy (RT) can be decreased by restricting elective neck irradiation (ENI) from large adjacent lymph node levels to only individual elective lymph nodes. The primary objective of this study is to treat the first HNSCC patients with individual elective lymph node irradiation by means of a Magnetic Resonance-linac (MR-linac) in order to assess the feasibility., Methods and Analysis: In this phase I feasibility study, 20 patients will be included with histologically proven cT2-4N0-1M0 HNSCC originating from the oropharynx, hypopharynx or larynx, planned for treatment with primary radiotherapy and bilateral elective neck irradiation (ENI). Patients will be treated with 35 fractions in six weeks, according to the DAHANCA schedule. Individual lymph nodes inside the conventional lymph node levels will be categorized in low-risk, intermediate-risk and high-risk based on cytology, histology and imaging parameters. Low-risk and intermediate-risk lymph nodes will irradiated in 20 and 23 fractions respectively, with a fraction dose of 2 Gy (=40/46 Gy EQD2). The high-risk lymph nodes and the primary tumor will be irradiated in 35 fractions of 2 Gy (=70 Gy equivalent dose in 2 Gy fractions (EQD2)). To limit treatment burden, 20 fractions will be applied on the MR-linac. The last 15 fractions (sequential boost at the primary tumor, intermediate-risk and high-risk lymph nodes) will be applied on a conventional linear accelerator. The main study endpoint is the percentage of fractions that are successfully completed on the MR-linac., Ethics and Dissemination: With individual elective lymph node irradiation we expect less toxicity and a better quality of life for HNSCC patients. However, as the treatment time on the MR-linac will be longer (30-45 vs 15 min per fraction) we need to examine if patients can endure this new treatment concept., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Author(s).)

Radiation therapy is a major component of cancer treatment pathways worldwide. The main aim of this treatment is to achieve tumor control through the delivery of ionizing radiation while preserving healthy tissues for minimal radiation toxicity. Because radiation therapy relies on accurate localization of the target and surrounding tissues, imaging plays a crucial role throughout the treatment chain. In the treatment planning phase, radiological images are essential for defining target volumes and organs-at-risk, as well as providing elemental composition (e.g., electron density) information for radiation dose calculations. At treatment, onboard imaging informs patient setup and could be used to guide radiation dose placement for sites affected by motion. Imaging is also an important tool for treatment response assessment and treatment plan adaptation. MRI, with its excellent soft tissue contrast and capacity to probe functional tissue properties, holds great untapped potential for transforming treatment paradigms in radiation therapy. The MR in Radiation Therapy ISMRM Study Group was established to provide a forum within the MR community to discuss the unmet needs and fuel opportunities for further advancement of MRI for radiation therapy applications. During the summer of 2021, the study group organized its first virtual workshop, attended by a diverse international group of clinicians, scientists, and clinical physicists, to explore our predictions for the future of MRI in radiation therapy for the next 25 years. This article reviews the main findings from the event and considers the opportunities and challenges of reaching our vision for the future in this expanding field., (© 2022 The Authors. Magnetic Resonance in Medicine published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

Background and Purpose: To decrease the impact of radiotherapy to healthy tissues in the head and neck region, we propose to restrict the elective neck irradiation to elective lymph nodes at risk of containing micro metastases instead of the larger lymph node volumes. To assess whether this new concept is achievable in the clinic, we determined the number, volume changes and displacement of elective lymph nodes during the course of radiotherapy., Materials and Methods: MRI scans of 10 head and neck cancer (HNC) patients were acquired before radiotherapy and in week 2, 3, 4 and 5 during radiotherapy. The weekly delineations of elective lymph nodes inside the lymph node levels (Ib/II/III/IVa/V) were rigidly registered and analyzed regarding number and volume. The displacement of elective lymph nodes was determined by center of mass (COM) distances, vector-based analysis and the isotropic contour expansion of the lymph nodes of the pre-treatment scan or the scan of the previous week in order to geographically cover 95% of the lymph nodes in the scans of the other weeks., Results: On average, 31 elective lymph nodes in levels Ib-V on each side of the neck were determined. This number remained constant throughout radiotherapy in most lymph node levels. The volume of the elective lymph nodes reduced significantly in all weeks, up to 50% in week 5, compared to the pre-treatment scan. The largest median COM displacements were seen in level V, for example 5.2 mm in week 5 compared to the pre-treatment scan. The displacement of elective lymph nodes was mainly in cranial direction. Geographical coverage was obtained when the lymph node volumes were expanded with 7 mm in case the pre-treatment scan was used and 6.5 mm in case the scan of the previous week was used., Conclusion: Elective lymph nodes of HNC patients remained visible on MRI and decreased in size during radiotherapy. The displacement of elective lymph nodes differ per lymph node level and were mainly directed cranially. Weekly adaptation does not seem to improve coverage of elective lymph nodes. Based on our findings we expect elective lymph node irradiation is achievable in the clinic., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2022 Reinders, Stijnman, de Ridder, Doornaert, Raaijmakers and Philippens.)

Background and Purpose: In (ultra-)hypofractionation, the contribution of intrafraction motion to treatment accuracy becomes increasingly important. Our purpose was to evaluate intrafraction motion and resulting geometric uncertainties for breast tumor (bed) and individual axillary lymph nodes, and to compare prone and supine position for the breast tumor (bed)., Materials and Methods: During 1-3 min of free breathing, we acquired transverse/sagittal interleaved 1.5 T cine magnetic resonance imaging (MRI) of the breast tumor (bed) in prone and supine position and coronal/sagittal cine MRI of individual axillary lymph nodes in supine position. A total of 31 prone and 23 supine breast cine MRI (in 23 women) and 52 lymph node cine MRI (in 24 women) were included. Maximum displacement, breathing amplitude, and drift were analyzed using deformable image registration. Geometric uncertainties were calculated for all displacements and for breathing motion only., Results: Median maximum displacements (range over the three orthogonal orientations) were 1.1-1.5 mm for the breast tumor (bed) in prone and 1.8-3.0 mm in supine position, and 2.2-2.4 mm for lymph nodes. Maximum displacements were significantly smaller in prone than in supine position, mainly due to smaller breathing amplitude: 0.6-0.9 mm in prone vs. 0.9-1.4 mm in supine. Systematic and random uncertainties were 0.1-0.4 mm in prone position and 0.2-0.8 mm in supine position for the tumor (bed), and 0.4-0.6 mm for the lymph nodes., Conclusion: Intrafraction motion of breast tumor (bed) and individual lymph nodes was small. Motion of the tumor (bed) was smaller in prone than in supine position., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Authors.)

Immobilization masks are used to prevent patient movement during head and neck (H&N) radiotherapy. Motion restriction is beneficial both during treatment, as well as in the pre-treatment simulation phase, where magnetic resonance imaging (MRI) is often used for target definition. However, the shape and size of the immobilization masks hinder the use of regular, close-fitting MRI receive arrays. In this work, we developed a mask-compatible 8-channel H&N array that consists of a single-channel baseplate, on which the mask can be secured, and a flexible 7-channel anterior element that follows the shape of the mask. The latter uses high impedance coils to achieve its flexibility and radiolucency. A fully-functional prototype was manufactured, its radiolucency was characterized, and the gain in imaging performance with respect to current clinical setups was quantified. Dosimetry measurements showed an overall dose change of -0.3%. Small, local deviations were up to -2.7% but had no clinically significant impact on a full treatment plan, as gamma pass rates (3%/3 mm) only slightly reduced from 97.9% to 97.6% (clinical acceptance criterion: ≥95%). The proposed H&N array improved the imaging performance with respect to three clinical setups. The H&N array more than doubled (+123%) and tripled (+246%) the signal-to-noise ratio with respect to the clinical MRI-simulation and MR-linac setups, respectively. G -factors were also lower with the proposed H&N array. The improved imaging performance resulted in a clearly visible signal-to-noise ratio improvement of clinically used TSE and DWI acquisitions. In conclusion, the 8-channel H&N array improves the imaging performance of MRI-simulation and MR-linac acquisitions, while dosimetry suggests that no clinically significant dose changes are induced., (© 2022 Institute of Physics and Engineering in Medicine.)

In recent years, MRI-guided radiotherapy (MRgRT) has taken an increasingly important position in image-guided radiotherapy (IGRT). Magnetic resonance imaging (MRI) offers superior soft tissue contrast in anatomical imaging compared to computed tomography (CT), but also provides functional and dynamic information with selected sequences. Due to these benefits, in current clinical practice, MRI is already used for target delineation and response assessment in patients with head and neck squamous cell carcinoma (HNSCC). Because of the close proximity of target areas and radiosensitive organs at risk (OARs) during HNSCC treatment, MRgRT could provide a more accurate treatment in which OARs receive less radiation dose. With the introduction of several new radiotherapy techniques (i.e., adaptive MRgRT, proton therapy, adaptive cone beam computed tomography (CBCT) RT, (daily) adaptive radiotherapy ensures radiation dose is accurately delivered to the target areas. With the integration of a daily adaptive workflow, interfraction changes have become visible, which allows regular and fast adaptation of target areas. In proton therapy, adaptation is even more important in order to obtain high quality dosimetry, due to its susceptibility for density differences in relation to the range uncertainty of the protons. The question is which adaptations during radiotherapy treatment are oncology safe and at the same time provide better sparing of OARs. For an optimal use of all these new tools there is an urgent need for an update of the target definitions in case of adaptive treatment for HNSCC. This review will provide current state of evidence regarding adaptive target definition using MR during radiotherapy for HNSCC. Additionally, future perspectives for adaptive MR-guided radiotherapy will be discussed.

Purpose: Tumor and target volume manual delineation remains a challenging task in head and neck cancer radiation therapy. The purpose of this study was to conduct a multi-institutional evaluation of manual delineations of gross tumor volume (GTV), high-risk clinical target volume (CTV), parotids, and submandibular glands on treatment simulation magnetic resonance scans of patients with oropharyngeal cancer., Methods and Materials: We retrospectively collected pretreatment T1-weighted, T1-weighted with gadolinium contrast, and T2-weighted magnetic resonance imaging scans for 4 patients with oropharyngeal cancer under an institution review board-approved protocol. We provided the scans to 26 radiation oncologists from 7 international cancer centers that participated in this delineation study. We also provide the patients' clinical history and physical examination findings, along with a medical photographic image and radiologic results. We used both the Simultaneous Truth and Performance Level Estimation algorithm and pair-wise comparisons of the contours, using overlap/distance metrics. Lastly, to assess experience and CTV delineation institutional practices, we had participants complete a brief questionnaire., Results: Large variability was measured between observers' delineations for GTVs and CTVs. The mean Dice similarity coefficient values across all physicians' delineations for GTVp, GTVn, CTVp, and CTVn were 0.77, 0.67, 0.77, and 0.69, respectively, for Simultaneous Truth and Performance Level Estimation algorithm comparison, and 0.67, 0.60, 0.67, and 0.58, respectively, for pair-wise analysis. Normal tissue contours were defined more consistently when considering overlap/distance metrics. The median radiation oncology clinical experience was 7 years. The median experience delineating on magnetic resonance imaging was 3.5 years. The GTV-to-CTV margin used was 10 mm for 6 of 7 participant institutions. One institution used 8 mm, and 3 participants (from 3 different institutions) used a margin of 5 mm., Conclusions: The data from this study suggests that appropriate guidelines, contouring quality assurance sessions, and training are still needed for the adoption of magnetic resonance-based treatment planning for head and neck cancers. Such efforts should play a critical role in reducing delineation variation and ensure standardization of target design across clinical practices., (Copyright © 2022. Published by Elsevier Inc.)

Objective: Tumor hypoxia results in worse local control and patient survival. We performed a digital, single-cell-based analysis to compare two biomarkers for hypoxia (hypoxia-inducible factor 1-alpha [HIF-1α] and pimonidazole [PIMO]) and their effect on outcome in laryngeal cancer patients treated with accelerated radiotherapy with or without carbogen breathing and nicotinamide (AR versus ARCON)., Materials and Methods: Immunohistochemical staining was performed for HIF-1α and PIMO in consecutive sections of 44 laryngeal cancer patients randomized between AR and ARCON. HIF-1α expression and PIMO-binding were correlated using digital image analysis in QuPath. High-density areas for each biomarker were automatically annotated and staining overlap was analyzed. Kaplan-Meier survival analyses for local control, regional control and disease-free survival were performed to predict a response benefit of ARCON over AR alone for each biomarker., Results: 106 Tissue fragments of 44 patients were analyzed. A weak, significant positive correlation was observed between HIF-1α and PIMO positivity on fragment level, but not on patient level. A moderate strength correlation (r = 0.705, p < 0.001) was observed between the number of high-density staining areas for both biomarkers. Staining overlap was poor. HIF-1α expression, PIMO-binding or a combination could not predict a response benefit of ARCON over AR., Conclusion: Digital image analysis to compare positive cell fractions and staining overlap between two hypoxia biomarkers using open-source software is feasible. Our results highlight that there are distinct differences between HIF-1α and PIMO as hypoxia biomarkers and therefore suggest co-existence of different forms of hypoxia within a single tumor., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Recurrences remain an important problem in laryngeal squamous cell carcinoma. Little has been described about histological characteristics of the primary laryngeal tumor that may be associated with recurrences. Identifying risk factors for recurrences might help in adapting treatment or follow-up. Using real-life population-based data, we aimed to identify histological features of the primary tumor associated with recurrences and overall survival., Material and Methods: Demographic, clinical and treatment information on all first primary invasive laryngeal tumors diagnosed in 2010-2014 (N = 3705) were extracted from the population-based nationwide Netherlands cancer registry (NCR) and linked to PALGA, the nationwide Dutch pathology registry, to obtain data on histological factors and recurrences. For a random 1502 patients histological information i.e., keratinization, perineural invasion (PNI+), vascular invasion (VI+), growth pattern, degree of differentiation, extracapsular spread (ECS+), cartilage- and bone invasion and extralaryngeal extension, was manually extracted from narrative pathology reports and analyzed for locoregional recurrence and overall survival using cox regression analysis., Results: In total, 299 patients developed a locoregional recurrence and 555 patients died. Keratinization (HR = 0.96 (95%CI: 0.68-1.34) p = 0.79), two or three adverse characteristics (PNI+, VI+, non-cohesive growth) (HR = 1.38 (95% CI: 0.63-3.01) p = 0.42), and ECS+ (HR = 1.38 (95% CI: 0.48-4.02) p = 0.55) were not associated to recurrence. For death, also no significant association was found., Conclusion: In this population-based real-life dataset on laryngeal carcinoma in the Netherlands, histological factors were not associated with locoregional recurrences or overall survival, but future studies should investigate the role of these features in treatment decisions., (© 2022. The Author(s).)

Background and Purpose: Accelerated partial breast irradiation (APBI) may benefit from the MR-Linac for target definition, patient setup, and motion monitoring. In this planning study, we investigated whether prone or supine position is dosimetrically beneficial for APBI on an MR-Linac and we evaluated patient comfort., Materials and Methods: Twenty-patients (9 postoperative, 11 preoperative) with a DCIS or breast tumor <3 cm underwent 1.5 T MRI in prone and supine position. The tumor or tumor bed was delineated as GTV and a 2 cm CTV-margin and 0.5 cm PTV-margin were added. 1.5 T MR-Linac treatment plans (5 × 5.2 Gy) with 11 beams were created for both positions in each patient. We evaluated the number of plans that achieved the planning constraints and performed a dosimetric comparison between prone and supine position using the Wilcoxon signed-rank test (p-value <0.01 for significance). Patient experience during scanning was evaluated with a questionnaire., Results: All 40 plans met the target coverage and OAR constraints, regardless of position. Heart D mean was not significantly different (1.07 vs. 0.79 Gy, p-value: 0.027). V5Gy to the ipsilateral lung (4.4% vs. 9.8% median, p-value 0.009) and estimated delivery time (362 vs. 392 s, p-value: 0.003) were significantly lower for prone position. PTV coverage and dose to other OAR were comparable between positions. The majority of patients (13/20) preferred supine position., Conclusion: APBI on the MR-Linac is dosimetrically feasible in prone and supine position. Mean heart dose was similar in both positions. Ipsilateral lung V5Gy was lower in prone position., Competing Interests: Conflicts of interest The department of radiotherapy of the UMC Utrecht is part of the Elekta MR-Linac Research Consortium. Several authors have received financial support from Elekta for visiting consortium meetings. The funding sources had no role in the preparation, review, or approval of the manuscript, and decision to submit the manuscript for publication., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Purpose: We aimed to evaluate changes in dynamic contrast-enhanced (DCE) and diffusion-weighted (DW) magnetic resonance imaging (MRI) scans acquired before and after single-dose ablative neoadjuvant partial breast irradiation (NA-PBI), and explore the relation between semiquantitative MRI parameters and radiologic and pathologic responses., Methods and Materials: We analyzed 3.0T DCE and DW-MRI of 36 patients with low-risk breast cancer who were treated with single-dose NA-PBI, followed by breast-conserving surgery 6 or 8 months later. MRI was acquired before NA-PBI and 1 week, 2, 4, and 6 months after NA-PBI. Breast radiologists assessed the radiologic response and breast pathologists scored the pathologic response after surgery. Patients were grouped as either pathologic responders or nonresponders (<10% vs ≥10% residual tumor cells). The semiquantitative MRI parameters evaluated were time to enhancement (TTE), 1-minute relative enhancement (RE 1min ), percentage of enhancing voxels (%EV), distribution of washout curve types, and apparent diffusion coefficient (ADC)., Results: In general, the enhancement increased 1 week after NA-PBI (baseline vs 1 week median - TTE: 15s vs 10s; RE 1min : 161% vs 197%; %EV: 47% vs 67%) and decreased from 2 months onward (6 months median - TTE: 25s; RE 1min : 86%; %EV: 12%). Median ADC increased from 0.83 × 10 -3 mm 2 /s at baseline to 1.28 × 10 -3 mm 2 /s at 6 months. TTE, RE 1min , and %EV showed the most potential to differentiate between radiologic responses, and TTE, RE 1min , and ADC between pathologic responses., Conclusions: Semiquantitative analyses of DCE and DW-MRI showed changes in relative enhancement and ADC 1 week after NA-PBI, indicating acute inflammation, followed by changes indicating tumor regression from 2 to 6 months after radiation therapy. A relation between the MRI parameters and radiologic and pathologic responses could not be proven in this exploratory study., (© 2021 The Authors.)

Purpose: High-field magnetic resonance-linear accelerators (MR-Linacs), linear accelerators combined with a diagnostic magnetic resonance imaging (MRI) scanner and online adaptive workflow, potentially give rise to novel online anatomic and response adaptive radiation therapy paradigms. The first high-field (1.5T) MR-Linac received regulatory approval in late 2018, and little is known about clinical use, patient tolerability of daily high-field MRI, and toxicity of treatments. Herein we report the initial experience within the MOMENTUM Study (NCT04075305), a prospective international registry of the MR-Linac Consortium., Methods and Materials: Patients were included between February 2019 and October 2020 at 7 institutions in 4 countries. We used descriptive statistics to describe the patterns of care, tolerability (the percentage of patients discontinuing their course early), and safety (grade 3-5 Common Terminology Criteria for Adverse Events v.5 acute toxicity within 3 months after the end of treatment)., Results: A total 943 patients participated in the MOMENTUM Study, 702 of whom had complete baseline data at the time of this analysis. Patients were primarily male (79%) with a median age of 68 years (range, 22-93) and were treated for 39 different indications. The most frequent indications were prostate (40%), oligometastatic lymph node (17%), brain (12%), and rectal (10%) cancers. The median number of fractions was 5 (range, 1-35). Six patients discontinued MR-Linac treatments, but none due to an inability to tolerate repeated high-field MRI. Of the 415 patients with complete data on acute toxicity at 3-month follow-up, 18 (4%) patients experienced grade 3 acute toxicity related to radiation. No grade 4 or 5 acute toxicity related to radiation was observed., Conclusions: In the first 21 months of our study, patterns of care were diverse with respect to clinical utilization, body sites, and radiation prescriptions. No patient discontinued treatment due to inability to tolerate daily high-field MRI scans, and the acute radiation toxicity experience was encouraging., (Copyright © 2021. Published by Elsevier Inc.)

Background and Purpose: Conventional elective neck irradiation (ENI) in head and neck cancer consists of radiotherapy (RT) to the regional lymph node (LN) levels contoured on computed tomography. Hybrid Magnetic Resonance (MR) - RT modalities, such as combined magnetic resonance imaging - linear accelerators (MRLs), might enable new ENI strategies in which individual non-suspect lymph nodes (i-LNs) are targeted. In this treatment planning study, new MR-based strategies targeting i-LNs (i-ENI) were compared to conventional treatment., Materials and Methods: All i-LNs were delineated on MR images of ten retrospectively selected patients with T2-4aN0M0 laryngeal cancer. Three strategies were considered. Strategy A: Conventional ENI delivered with a conventional linear accelerator (35x 1.55 Gy). Strategy B: MRL-based i-ENI (35x 1.55 Gy) to the individual lymph nodes including a background dose to the conventional elective neck volumes (35x 1.03 Gy). Strategy C: Same as Strategy B, but without background dose. In all plans the dose prescription to the primary tumor was 35x 2 Gy. Mean dose ( D mean ) reductions in the organs at risk (OAR) were compared using the Wilcoxon signed rank test., Results: Compared to conventional ENI (strategy A), significant D mean reductions of 6.0 Gy and 8.0 Gy were observed in the submandibular glands, of 9.4 Gy and 13 Gy in the carotid arteries and of 9.9 Gy and 19.4 Gy in the thyroid for strategy B and C, respectively. Large inter-patient variations of D mean reductions were observed in all OARs., Conclusion: MRL-based i-ENI is a new promising concept that could reduce the mean dose to OARs in the neck significantly for patients with laryngeal cancer., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 The Author(s).)

Quantitative imaging biomarkers (QIBs) derived from MRI techniques have the potential to be used for the personalised treatment of cancer patients. However, large-scale data are missing to validate their added value in clinical practice. Integrated MRI-guided radiotherapy (MRIgRT) systems, such as hybrid MRI-linear accelerators, have the unique advantage that MR images can be acquired during every treatment session. This means that high-frequency imaging of QIBs becomes feasible with reduced patient burden, logistical challenges, and costs compared to extra scan sessions. A wealth of valuable data will be collected before and during treatment, creating new opportunities to advance QIB research at large. The aim of this paper is to present a roadmap towards the clinical use of QIBs on MRIgRT systems. The most important need is to gather and understand how the QIBs collected during MRIgRT correlate with clinical outcomes. As the integrated MRI scanner differs from traditional MRI scanners, technical validation is an important aspect of this roadmap. We propose to integrate technical validation with clinical trials by the addition of a quality assurance procedure at the start of a trial, the acquisition of in vivo test-retest data to assess the repeatability, as well as a comparison between QIBs from MRIgRT systems and diagnostic MRI systems to assess the reproducibility. These data can be collected with limited extra time for the patient. With integration of technical validation in clinical trials, the results of these trials derived on MRIgRT systems will also be applicable for measurements on other MRI systems., Competing Interests: Conflict of interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr. van der Heide receives industry grant support from Philips Healthcare and Elekta AB and ITEA project (‘Starlit’). Dr. Fuller received/receives funding and salary support related to this project from: the National Institutes of Health (NIH) National Institute of Biomedical Imaging and Bioengineering (NIBIB) Research Education Programs for Residents and Clinical Fellows Grant (R25EB025787-01); the National Institute for Dental and Craniofacial Research Establishing Outcome Measures Award (1R01DE025248/R56DE025248) and Academic Industrial Partnership Grant (R01DE028290); National Cancer Institute (NCI) Early Phase Clinical Trials in Imaging and Image-Guided Interventions Program (1R01CA218148); an NIH/NCI Cancer Center Support Grant (CCSG) Pilot Research Program Award from the UT MD Anderson CCSG Radiation Oncology and Cancer Imaging Program (P30CA016672); and an NCI-NSF Smart Connected Health Program (R01 CA257814). Direct infrastructure support is provided to Dr. Fuller by the multidisciplinary Stiefel Oropharyngeal Research Fund of the University of Texas MD Anderson Cancer Center Charles and Daneen Stiefel Center for Head and Neck Cancer and the Cancer Center Support Grant (P30CA016672) and the MD Anderson Program in Image-guided Cancer Therapy. Dr. Fuller has received direct industry grant support, in-kind support, honoraria, and travel funding from Elekta AB related to this project. Ms. McDonald receives salary and funding support from the NIH NIDCR Ruth L. Kirschstein National Research Service Award (NRSA) Individual Predoctoral Fellowship (F31DE029093) and a Dr. John J. Kopchick Fellowship through the UT MD Anderson UTHealth Graduate School of Biomedical Sciences. All remaining authors have declared no conflicts of interest., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: In this systematic review, we aim to identify prognostic imaging variables of recurrent laryngeal or hypopharyngeal carcinoma after chemoradiotherapy., Methods: A systematic search was performed in PubMed and EMBASE (1990-2020). The crude data and effect estimates were extracted for each imaging variable. The level of evidence of each variable was assessed and pooled risk ratios (RRs) were calculated., Results: Twenty-two articles were included in this review, 17 on computed tomography (CT) and 5 on magnetic resonance imaging (MRI) variables. We found strong evidence for the prognostic value of tumor volume at various cut-off points (pooled RRs ranging from 2.09 to 3.03). Anterior commissure involvement (pooled RR 2.19), posterior commissure involvement (pooled RR 2.44), subglottic extension (pooled RR 2.25), and arytenoid cartilage extension (pooled RR 2.10) were also strong prognostic factors., Conclusion: Pretreatment tumor volume and involvement of several subsites are prognostic factors for recurrent laryngeal or hypopharyngeal carcinoma after chemoradiotherapy., (© 2021 The Authors. Head & Neck published by Wiley Periodicals LLC.)

Purpose: This prospective study is, to our knowledge, the first report of daily adaptive radiation therapy (ART) for head and neck cancer (HNC) using a 1.5T magnetic resonance imaging-linear accelerator (MR-linac) with particular focus on safety and feasibility and dosimetric results of an online rigid registration-based adapt to position (ATP) workflow., Methods and Materials: Ten patients with HNC received daily ART on a 1.5T/7MV MR-linac, 6 using ATP only and 4 using ATP with 1 offline adapt-to-shape replan. Setup variability with custom immobilization masks was assessed by calculating the mean systematic error (M), standard deviation of the systematic error (Σ), and standard deviation of the random error (σ) of the isocenter shifts. Quality assurance was performed with a cylindrical diode array using 3%/3 mm γ criteria. Adaptive treatment plans were summed for each patient to compare the delivered dose with the planned dose from the reference plan. The impact of dosimetric variability between adaptive fractions on the summation plan doses was assessed by tracking the number of optimization constraint violations at each individual fraction., Results: The random errors (mm) for the x, y, and z isocenter shifts, respectively, were M = -0.3, 0.7, 0.1; Σ = 3.3, 2.6, 1.4; and σ = 1.7, 2.9, 1.0. The median (range) γ pass rate was 99.9% (90.9%-100%). The differences between the reference and summation plan doses were -0.61% to 1.78% for the clinical target volume and -11.74% to 8.11% for organs at risk (OARs), although an increase greater than 2% in OAR dose only occurred in 3 cases, each for a single OAR. All cases had at least 2 fractions with 1 or more constraint violations. However, in nearly all instances, constraints were still met in the summation plan despite multiple single-fraction violations., Conclusions: Daily ART on a 1.5T MR-linac using an online ATP workflow is safe and clinically feasible for HNC and results in delivered doses consistent with planned doses., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Background and Purpose: Diffusion-weighted imaging (DWI) for treatment response monitoring is feasible on hybrid magnetic resonance linear accelerator (MR-linac) systems. The MRI scanner of the Elekta Unity system has an adjusted design compared to diagnostic scanners. We investigated its impact on measuring the DWI-derived apparent diffusion coefficient (ADC) regarding three aspects: the choice of b-values, the spatial variation of the ADC, and scanning during radiation treatment. The aim of this study is to give recommendations for accurate ADC measurements on Unity systems., Materials and Methods: Signal-to-noise ratio (SNR) measurements with increasing b-values were done to determine the highest bvalue that can be measured reliably. The spatial variation of the ADC was assessed on six Unity systems with a cylindrical phantom of 40 cm diameter. The influence of gantry rotation and irradiation was investigated by acquiring DWI images before and during treatment of 11 prostate cancer patients., Results: On the Unity system, a maximum b-value of 500 s/mm 2 should be used for ADC quantification, as a trade-off between SNR and diffusion weighting. Accurate ADC values were obtained within 7 cm from the iso-center, while outside this region ADC values deviated more than 5%. The ADC was not influenced by the rotating linac or irradiation during treatment., Conclusion: We provide Unity system specific recommendations for measuring the ADC. This will increase the consistency of ADC values acquired in different centers on the Unity system, enabling large cohort studies for biomarker discovery and treatment response monitoring., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background and Purpose: To enable accurate magnetic resonance imaging (MRI)-based dose calculations, synthetic computed tomography (sCT) images need to be generated. We aim at assessing the feasibility of dose calculations from MRI acquired with a heterogeneous set of imaging protocol for paediatric patients affected by brain tumours., Materials and Methods: Sixty paediatric patients undergoing brain radiotherapy were included. MR imaging protocols varied among patients, and data heterogeneity was maintained in train/validation/test sets. Three 2D conditional generative adversarial networks (cGANs) were trained to generate sCT from T1-weighted MRI, considering the three orthogonal planes and its combination (multi-plane sCT). For each patient, median and standard deviation (σ) of the three views were calculated, obtaining a combined sCT and a proxy for uncertainty map, respectively. The sCTs were evaluated against the planning CT in terms of image similarity and accuracy for photon and proton dose calculations., Results: A mean absolute error of 61 ± 14 HU (mean±1σ) was obtained in the intersection of the body contours between CT and sCT. The combined multi-plane sCTs performed better than sCTs from any single plane. Uncertainty maps highlighted that multi-plane sCTs differed at the body contours and air cavities. A dose difference of -0.1 ± 0.3% and 0.1 ± 0.4% was obtained on the D > 90% of the prescribed dose and mean γ 2%,2mm pass-rate of 99.5 ± 0.8% and 99.2 ± 1.1% for photon and proton planning, respectively., Conclusion: Accurate MR-based dose calculation using a combination of three orthogonal planes for sCT generation is feasible for paediatric brain cancer patients, even when training on a heterogeneous dataset., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background and Purpose: The relation between radiotherapy (RT) dose to the brain and morphological changes in healthy tissue has seen recent increased interest. There already is evidence for changes in the cerebral cortex and white matter, as well as selected subcortical grey matter (GM) structures. We studied this relation in all deep GM structures, to help understand the aetiology of post-RT neurocognitive symptoms., Materials and Methods: We selected 31 patients treated with RT for grade II-IV glioma. Pre-RT and 1 year post-RT 3D T1-weighted MRIs were automatically segmented, and the changes in volume of the following structures were assessed: amygdala, nucleus accumbens, caudate nucleus, hippocampus, globus pallidus, putamen, and thalamus. The volumetric changes were related to the mean RT dose received by each structure. Hippocampal volumes were entered into a population-based nomogram to estimate hippocampal age., Results: A significant relation between RT dose and volume loss was seen in all examined structures, except the caudate nucleus. The volume loss rates ranged from 0.16 to 1.37%/Gy, corresponding to 4.9-41.2% per 30 Gy. Hippocampal age, as derived from the nomogram, was seen to increase by a median of 11 years., Conclusion: Almost all subcortical GM structures are susceptible to radiation-induced volume loss, with higher volume loss being observed with increasing dose. Volume loss of these structures is associated with neurological deterioration, including cognitive decline, in neurodegenerative diseases. To support a causal relationship between radiation-induced deep GM loss and neurocognitive functioning in glioma patients, future studies are needed that directly correlate volumetrics to clinical outcomes., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2020 The Author(s).)

Background: Differences in imaging parameters influence computer-extracted parenchymal enhancement measures from breast MRI., Purpose: To investigate the effect of differences in dynamic contrast-enhanced MRI acquisition parameter settings on quantitative parenchymal enhancement of the breast, and to evaluate harmonization of contrast-enhancement values with respect to flip angle and repetition time., Study Type: Retrospective., Phantom/populations: We modeled parenchymal enhancement using simulations, a phantom, and two cohorts (N = 398 and N = 302) from independent cancer centers., Sequence Field/strength: 1.5T dynamic contrast-enhanced T 1 -weighted spoiled gradient echo MRI. Vendors: Philips, Siemens, General Electric Medical Systems., Assessment: We assessed harmonization of parenchymal enhancement in simulations and phantom by varying the MR parameters that influence the amount of T 1 -weighting: flip angle (8°-25°) and repetition time (4-12 msec). We calculated the median and interquartile range (IQR) of the enhancement values before and after harmonization. In vivo, we assessed overlap of quantitative parenchymal enhancement in the cohorts before and after harmonization using kernel density estimations. Cohort 1 was scanned with flip angle 20° and repetition time 8 msec; cohort 2 with flip angle 10° and repetition time 6 msec., Statistical Tests: Paired Wilcoxon signed-rank-test of bootstrapped kernel density estimations., Results: Before harmonization, simulated enhancement values had a median (IQR) of 0.46 (0.34-0.49). After harmonization, the IQR was reduced: median (IQR): 0.44 (0.44-0.45). In the phantom, the IQR also decreased, median (IQR): 0.96 (0.59-1.22) before harmonization, 0.96 (0.91-1.02) after harmonization. Harmonization yielded significantly (P < 0.001) better overlap in parenchymal enhancement between the cohorts: median (IQR) was 0.46 (0.37-0.58) for cohort 1 vs. 0.37 (0.30-0.44) for cohort 2 before harmonization (57% overlap); and 0.35 (0.28-0.43) vs. .0.37 (0.30-0.44) after harmonization (85% overlap)., Data Conclusion: The proposed practical harmonization method enables an accurate comparison between patients scanned with differences in imaging parameters., Level of Evidence: 3 TECHNICAL EFFICACY STAGE: 4., (© 2020 The Authors. Journal of Magnetic Resonance Imaging published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

Purpose: Our purpose was to present and evaluate expert consensus on contouring primary breast tumors on magnetic resonance imaging (MRI) in the setting of neoadjuvant partial breast irradiation in trials., Methods and Materials: Expert consensus on contouring guidelines for target definition of primary breast tumors on contrast-enhanced MRI in trials was developed by an international team of experienced breast radiation oncologists and a dedicated breast radiologist during 3 meetings. At the first meeting, draft guidelines were developed through discussing and contouring 2 cases. At the second meeting 6 breast radiation oncologists delineated gross tumor volume (GTV) in 10 patients with early-stage breast cancer (cT1N0) according to draft guidelines. GTV was expanded isotropically (20 mm) to generate clinical target volume (CTV), excluding skin and chest wall. Delineations were reviewed for disagreement and guidelines were clarified accordingly. At the third meeting 5 radiation oncologists redelineated 6 cases using consensus-based guidelines. Interobserver variation of GTV and CTV was assessed using generalized conformity index (CI). CI was calculated as the sum of volumes each pair of observers agreed upon, divided by the sum of encompassing volumes for each pair of observers., Results: For the 2 delineation sessions combined, mean GTV ranged between 0.19 and 2.44 cm 3 , CI for GTV ranged between 0.28 and 0.77, and CI for CTV between 0.77 and 0.94. The largest interobserver variation in GTV delineations was observed in cases with extended tumor spiculae, blood vessels near or markers within the tumor, or with increased enhancement of glandular breast tissue. Consensus-based guidelines stated to delineate all visible tumors on contrast enhanced-MRI scan 1 to 2 minutes after contrast injection and if a marker was inserted in the tumor to include this., Conclusions: Expert-based consensus on contouring primary breast tumors on MRI in trials has been reached. This resulted in low interobserver variation for CTV in the context of a uniform 20 mm GTV to CTV expansion margin., (Copyright © 2020 American Society for Radiation Oncology. All rights reserved.)

Current research in radiotherapy (RT) for breast cancer is evaluating neoadjuvant as opposed to adjuvant partial breast irradiation (PBI) with the aim of reducing the volume of breast tissue irradiated and therefore the risk of late treatment-related toxicity. The development of magnetic resonance (MR)-guided RT, including dedicated MR-guided RT systems [hybrid machines combining an MR scanner with a linear accelerator (MR-linac) or 60 Co sources], could potentially reduce the irradiated volume even further by improving tumour visibility before and during each RT treatment. In this position paper, we discuss MR guidance in relation to each step of the breast RT planning and treatment pathway, focusing on the application of MR-guided RT to neoadjuvant PBI., (Copyright © 2020 Groot Koerkamp, Vasmel, Russell, Shaitelman, Anandadas, Currey, Vesprini, Keller, De-Colle, Han, Braunstein, Mahmood, Lorenzen, Philippens, Verkooijen, Lagendijk, Houweling, van den Bongard and Kirby.)

Background: With overall survival of brain tumors improving, radiation induced brain injury is becoming an increasing issue. One of the effects of radiation therapy (RT) is thinning of the cerebral cortex, which could be one of the factors contributing to cognitive impairments after treatment. In healthy brain, cortex thickness varies between 1 and 4.5 mm. In this study, we assess the effect of RT on the thickness of the cerebral cortex and relate the changes to the local dose., Methods: We identified 28 glioma patients with optimal scan quality. Clinical CTs and MRIs at baseline and 1 year post-RT were collected and coregistered. The scans were processed via an automated image processing pipeline, which enabled measuring changes of the cortical thickness, which were related to local dose., Results: Three areas were identified where significant dose-dependent thinning occurred, with thinning rates of 5, 6, and 26 μm/Gy after 1 year, which corresponds to losses of 5.4%, 7.2%, and 21.6% per 30 Gy per year. The first area was largely located in the right inferior parietal, supramarginal, and superior parietal regions, the second in the right posterior cingulate and paracentral regions, and the third almost completely in the right lateral orbital frontal region., Conclusions: We have identified three areas susceptible to dose-dependent cortical thinning after radiation therapy. Should future prospective studies conclude that irradiation of these areas lead to cognitive decline, they need to be spared in order to prevent this debilitating consequence of treatment., (© The Author(s) 2020. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

Quantitative imaging biomarkers show great potential for use in radiotherapy. Quantitative images based on microscopic tissue properties and tissue function can be used to improve contouring of the radiotherapy targets. Furthermore, quantitative imaging biomarkers might be used to predict treatment response for several treatment regimens and hence be used as a tool for treatment stratification, either to determine which treatment modality is most promising or to determine patient-specific radiation dose. Finally, patient-specific radiation doses can be further tailored to a tissue/voxel specific radiation dose when quantitative imaging is used for dose painting. In this review, published standards, guidelines and recommendations on quantitative imaging assessment using CT, PET and MRI are discussed. Furthermore, critical issues regarding the use of quantitative imaging for radiation oncology purposes and resultant pending research topics are identified., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Purpose: To assess the pathologic and radiologic response in patients with low-risk breast cancer treated with magnetic resonance (MR) guided neoadjuvant partial breast irradiation (NA-PBI) and to evaluate toxicity and patient-reported outcomes (PROs)., Methods and Materials: For this single-arm prospective trial, women with unifocal, non-lobular tumors with a maximum diameter of 20 mm (age, 50-70 years) or 30 mm (age, ≥70 years) and tumor-negative sentinel node(s) were eligible. Patients were treated with a single ablative dose of NA-PBI followed by breast-conserving surgery after an interval of 6 to 8 months. Target volumes were defined on radiation therapy planning computed tomography scan and additional magnetic resonance imaging. Prescribed doses to gross tumor volume and clinical target volume (gross tumor volume plus 20 mm margin) were 20 Gy and 15 Gy, respectively. Primary outcome was pathologic complete response (pCR). Secondary outcomes were radiologic response (on magnetic resonance imaging), toxicity (Common Terminology Criteria for Adverse Events), PROs (European Organisation for Research and Treatment of Cancer QLQ-BR23, Hospital Anxiety and Depression Scale), and cosmesis (assessed by patient, radiation oncologist, and BCCT.core software)., Results: Thirty-six patients were treated with NA-PBI, and pCR was reported in 15 patients (42%; 95% confidence interval, 26%-59%). Radiologic complete response was observed in 15 patients, 10 of whom had pCR (positive predictive value, 67%; 95% confidence interval, 39%-87%). After a median follow-up of 21 months (range, 12-41), all patients experienced grade 1 fibrosis in the treated breast volume. Transient grade 2 and 3 toxicity was observed in 31% and 3% of patients, respectively. Local recurrences were absent. No deterioration in PROs or cosmetic results was observed., Conclusions: NA-PBI has the potential to induce pCR in a substantial proportion of patients, with acceptable toxicity. This treatment seems a feasible alternative to standard postoperative irradiation and could even result in postponement or omission of surgery if pCR can be accurately predicted in selected low-risk patients., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background and Purpose: When using an immobilization mask, a magnetic resonance imaging (MRI) head receive coil cannot be used and patients may experience discomfort during the examination. We therefore wish to assess the added value of an immobilization mask during all MRI scans intended for cranial stereotactic radiotherapy (SRT) planning., Materials and Methods: An MRI was acquired with and without a thermoplastic immobilization mask in ten patients eligible for SRT. A planning computed tomography (CT) scan was also made, to which the two MRIs were independently registered. Additionally, the MRI without immobilization was registered to the MRI in mask. On each sequence, gross tumour volume (GTV), the right eye, brain stem and chiasm were delineated. The absolute differences in centre-of-gravity coordinates and Dice coefficients of the volumes of the delineated structures between the two MRIs were compared., Results: Differences in GTV volume between the two MRIs were low, with median Dice coefficients between 0.88 and 0.91. Similarly, the median absolute differences in centre-of-gravity coordinates between the GTVs, organs at risk and landmarks delineated on the two MRIs were within 0.5 mm. The 95% confidence intervals of the median absolute differences in the three GTV coordinates was within 1 mm, which corresponds to the target volume safety margin used to account for possible errors during the SRT treatment chain., Conclusions: The effect of scanning a patient without the immobilization mask falls within acceptable bounds of error for the geometrical accuracy of the SRT treatment chain. Consequently, placing the head in treatment position during all MRI scans for patients undergoing radiotherapy of brain metastasis is deemed unnecessary., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2020 The Author(s).)

Objectives: Pretreatment identification of radio-insensitive head and neck squamous cell carcinomas (HNSCC) would affect treatment modality selection. The apparent diffusion coefficient (ADC) of a tumor could be a predictor of local recurrence. However, little is known about its prognostic value next to known factors such as clinical T-stage. The aim of the present study is to determine the added value of pretreatment ADC to clinical T-stage as a prognostic factor for local recurrence., Methods: This retrospective cohort study included 217 patients with HNSCC treated with (chemo)radiotherapy between April 2009 and December 2015. All patients underwent diffusion-weighted MRI prior to treatment. Median ADC values of all tumors were obtained using a semi-automatic delineation method. Univariate models containing ADC and T-stage were compared with a multivariable model containing both variables., Results: Fifty-eight patients experienced a local recurrence within 3 years. On average, the ADC value in the group of patients with a recurrence was 1.01 versus 1.00 (10 -3  mm 2 /s) in the group without a recurrence. Univariate analysis showed no significant association between tumor ADC and local recurrence within 3 years after (chemo)radiotherapy (p = 0.09). Cox regression showed that clinical T-stage was an independent predictor of local recurrence and adding ADC to the model did not increase its performance., Conclusion: Pretreatment ADC has no added value as a prognostic factor for local recurrence to clinical T-stage., Key Points: • Pretreatment identification of head and neck squamous cell carcinoma patients who do not benefit from (chemo)radiotherapy could improve personalized cancer care. • The apparent diffusion coefficient (ADC) obtained from diffusion-weighted MRI has been reported to be a prognostic factor for local recurrence. • In this study, ADC has no added value as a prognostic factor compared with clinical T-stage.

Background: The SIOPE-Brain Tumor Group recently published a guideline on craniospinal target volume delineation for highly conformal radiotherapy. In order to spare critical structures like e.g., the lens or cochlea, highly conformal techniques can underdose the cerebrospinal fluid (CSF) in the dural reflections around cranial and sacral nerves. The purpose of this study is to generate evidence for CSF extension within the dural sheaths of the cranial and sacral nerves in order to improve accuracy in target volume delineation. Material and methods: Ten healthy volunteers, age 21 till 41 years, underwent an MRI-scan of the skull-base and sacral plexus. To evaluate CSF extension, cT2-weighted images with fat suppression, low signal to noise ratio and little to no motion-related artifacts were used. Two observers measured the extension of CSF from the inner table of the skull for the cranial nerves, and outside the spinal canal for the sacral nerves. Results: CSF extension (mean distance [95% CI]) was visible within the dural sheaths surrounding the majority of the cranial nerves: optic nerve (40 mm [38-42]), trigeminal nerve (16 mm [15-19]), facial-vestibulocochlear nerve (11 mm [11-12]), glossopharyngeal-vagus-accessory nerve (7 mm [7-9]) and hypoglossal nerve (8 mm [7-9]). No CSF was observed outside the spinal canal at sacral level. No significant difference between both observers was measured. Conclusion: This study generates evidence for significant CSF extension outside the inner table of the skull. Despite the vicinity of the lens and cochlea, we therefore recommend the inclusion of both optic nerves and internal auditory canals in the clinical target volume for craniospinal irradiation when using highly conformal delivery techniques.

Purpose: To develop and evaluate a patch-based convolutional neural network (CNN) to generate synthetic computed tomography (sCT) images for magnetic resonance (MR)-only workflow for radiotherapy of head and neck tumors. A patch-based deep learning method was chosen to improve robustness to abnormal anatomies caused by large tumors, surgical excisions, or dental artifacts. In this study, we evaluate whether the generated sCT images enable accurate MR-based dose calculations in the head and neck region., Methods: We conducted a retrospective study on 34 patients with head and neck cancer who underwent both CT and MR imaging for radiotherapy treatment planning. To generate the sCTs, a large field-of-view T2-weighted Turbo Spin Echo MR sequence was used from the clinical protocol for multiple types of head and neck tumors. To align images as well as possible on a voxel-wise level, CT scans were nonrigidly registered to the MR (CT reg ). The CNN was based on a U-net architecture and consisted of 14 layers with 3 × 3 × 3 filters. Patches of 48 × 48 × 48 were randomly extracted and fed into the training. sCTs were created for all patients using threefold cross validation. For each patient, the clinical CT-based treatment plan was recalculated on sCT using Monaco TPS (Elekta). We evaluated mean absolute error (MAE) and mean error (ME) within the body contours and dice scores in air and bone mask. Also, dose differences and gamma pass rates between CT- and sCT-based plans inside the body contours were calculated., Results: sCT generation took 4 min per patient. The MAE over the patient population of the sCT within the intersection of body contours was 75 ± 9 Hounsfield Units (HU) (±1 SD), and the ME was 9 ± 11 HU. Dice scores of the air and bone masks (CT reg vs sCT) were 0.79 ± 0.08 and 0.70 ± 0.07, respectively. Dosimetric analysis showed mean deviations of -0.03% ± 0.05% for dose within the body contours and -0.07% ± 0.22% inside the >90% dose volume. Dental artifacts obscuring the CT could be circumvented in the sCT by the CNN-based approach in combination with Turbo Spin Echo (TSE) magnetic resonance imaging (MRI) sequence that typically is less prone to susceptibility artifacts., Conclusions: The presented CNN generated sCTs from conventional MR images without adding scan time to the acquisition. Dosimetric evaluation suggests that dose calculations performed on the sCTs are accurate, and can therefore be used for MR-only radiotherapy treatment planning of the head and neck., (© 2019 The Authors. Medical Physics published by Wiley Periodicals, Inc. on behalf of American Association of Physicists in Medicine.)

In brain/head-and-neck radiotherapy (RT), thermoplastic immobilization masks guarantee reproducible patient positioning in treatment position between MRI, CT, and irradiation. Since immobilization masks do not fit in the diagnostic MR head/head-and-neck coils, flexible surface coils are used for MRI imaging in clinical practice. These coils are placed around the head/neck, in contact with the immobilization masks. However, the positioning of these flexible coils is technician dependent, thus leading to poor image reproducibility. Additionally, flexible surface coils have an inferior signal-to-noise-ratio (SNR) compared to diagnostic coils. The aim of this work was to create a new immobilization setup which fits into the diagnostic MR coils in order to enhance MR image quality and reproducibility. For this purpose, a practical immobilization setup was constructed. The performances of the standard clinical and the proposed setups were compared with four tests: SNR, image quality, motion restriction, and reproducibility of inter-fraction subject positioning. The new immobilization setup resulted in 3.4 times higher SNR values on average than the standard setup, except directly below the flexible surface coils where similar SNR was observed. Overall, the image quality was superior for brain/head-and-neck images acquired with the proposed RT setup. Comparable motion restriction in feet-head/left-right directions (maximum motion ≈1 mm) and comparable inter-fraction repositioning accuracy (mean inter-fraction movement 1 ± 0.5 mm) were observed for the standard and the new setup.

Background: Magnetic Resonance linear accelerator (MR-linac) systems represent a new type of technology that allows for online MR-guidance for high precision radiotherapy (RT). Currently, the first MR-linac installations are being introduced clinically. Since the imaging performance of these integrated MR-linac systems is critical for their application, a thorough commissioning of the MRI performance is essential. However, guidelines on the commissioning of MR-guided RT systems are not yet defined and data on the performance of MR-linacs are not yet available., Materials & Methods: Here we describe a comprehensive commissioning protocol, which contains standard MRI performance measurements as well as dedicated hybrid tests that specifically assess the interactions between the Linac and the MRI system. The commissioning results of four MR-linac systems are presented in a multi-center study., Results: Although the four systems showed similar performance in all the standard MRI performance tests, some differences were observed relating to the hybrid character of the systems. Field homogeneity measurements identified differences in the gantry shim configuration, which was later confirmed by the vendor., Conclusion: Our results highlight the importance of dedicated hybrid commissioning tests and the ability to compare the machines between institutes at this very early stage of clinical introduction. Until formal guidelines and tolerances are defined the tests described in this study may be used as a practical guideline. Moreover, the multi-center results provide initial bench mark data for future MR-linac installations., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: This prospective study aims to test if MRI including diffusion weighted images can replace FDG PET-CT in the diagnosis of patients with suspicion of local recurrent head and neck squamous cell carcinomas after (chemo)radiation., Methods: Seventy-five patients suspected of local recurrence underwent a MRI and a FDG PET-CT. Qualitative assessment of the images was performed. Reference standard was the results of biopsy or the absence of a recurrence during follow up., Results: Seventy patients were included. Fifty percent had local recurrence. FDG PET-CT had accuracy of 71% compared to 73% for MRI. The sensitivity and specificity were 97% compared to 69% and 46% compared to 77% for FDG PET-CT and MRI respectively., Conclusions: MRI showed similar diagnostic accuracy, superior specificity but inferior sensitivity compared to FDG PET-CT. Based on current results, we consider MRI including diffusion weighted sequences unable to replace FDG PET-CT as a single imaging modality when local recurrent disease of HNSCC after (C)RT is suspected., (Copyright © 2018 Elsevier B.V. All rights reserved.)