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Personalized treatment strategies based on non‑invasive biomarkers have potential to improve patient management in patients with newly diagnosed glioblastoma (GBM). The residual tumour burden after surgery in GBM patients is a prognostic imaging biomarker. However, in clinical patient management, its assessment is a manual and time‑consuming process that is at risk of inter‑rater variability. Furthermore, the prediction of patient outcome prior to radiotherapy may identify patient subgroups that could benefit from escalated radiotherapy doses. Therefore, in this study, we investigate the capabilities of traditional radiomics and 3D convolutional neural networks for automatic detection of the residual tumour status and to prognosticate time‑to‑recurrence (TTR) and overall survival (OS) in GBM using postoperative [11C] methionine positron emission tomography (MET‑PET) and gadolinium‑enhanced T1‑w magnetic resonance imaging (MRI). On the independent test data, the 3D‑DenseNet model based on MET‑PET achieved the best performance for residual tumour detection, while the logistic regression model with conventional radiomics features performed best for T1c‑w MRI (AUC: MET‑PET 0.95, T1c‑w MRI 0.78). For the prognosis of TTR and OS, the 3D‑DenseNet model based on MET‑PET integrated with age and MGMT status achieved the best performance (Concordance‑Index: TTR 0.68, OS 0.65). In conclusion, we showed that both deep‑ learning and conventional radiomics have potential value for supporting image‑based assessment and prognosis in GBM. After prospective validation, these models may be considered for treatment personalization.

Background and purpose: Radiotherapy (RT) is an adjuvant treatment option for glioma patients. Side effects include tissue atrophy, which might be a contributing factor to neurocognitive decline after treatment. The goal of this study was to determine potential atrophy of the hippocampus, amygdala, thalamus, putamen, pallidum and caudate nucleus in glioma patients having undergone magnetic resonance imaging (MRI) before and after RT. Materials and methods: Subcortical volumes were measured using T1-weighted MRI from patients before RT (N = 91) and from longitudinal follow-ups acquired in three-monthly intervals (N = 349). The volumes were normalized to the baseline values, while excluding structures touching the clinical target volume (CTV) or abnormal tissue seen on FLAIR imaging. A multivariate linear effects model was used to determine if time after RT and mean RT dose delivered to the corresponding structures were significant predictors of tissue atrophy. Results: The hippocampus, amygdala, thalamus, putamen, and pallidum showed significant atrophy after RT as function of both time after RT and mean RT dose delivered to the corresponding structure. Only the caudate showed no dose or time dependant atrophy. Conversely, the hippocampus was the structure with the highest atrophy rate of 5.2 % after one year and assuming a mean dose of 30 Gy. Conclusion: The hippocampus showed the highest atrophy rates followed by the thalamus and the amygdala. The subcortical structures here found to decrease in volume indicative of radiosensitivity should be the focus of future studies investigating the relationship between neurocognitive decline and RT. © 2022 The Authors

Background and purpose: Radiotherapy is a standard treatment option for high-grade gliomas. Cognitive impairment is a side effect associated with radiotherapy particularly in long-term survivors. Recent findings suggest involvement of the cerebellum in cognitive function. The goal of this study was therefore to investigate dose dependent cerebellar atrophy using prospective, longitudinal MR data from adult glioma patients who received radiotherapy. Materials and methods: Cerebellar volumes were measured using T1-weighted MR images from 91 glioma patients before radiotherapy and every three months thereafter. We calculated the average cerebellar volume change per year per Gy, based on the mean cerebellar dose, using linear regression analysis. Subsequently, patient age was investigated as a confounding factor using multiple linear regression analysis. The impact of chemotherapy was assessed separately in a subgroup of patients receiving a cerebellar dose ≤ 1 Gy. Cerebellar mean dose and cerebellar volume changes were compared between patients treated with proton (N = 38) and photon therapy (N = 52). Results: Cerebellar volume decreased 2.4 % per 10 Gy per year (p < 0.001). The cerebellar volume loss was progressive over time without signs of recovery within the observational period of two years. Neither patient age (p = 0.27) nor chemotherapy (p = 0.43) had a significant impact on cerebellar atrophy. Compared to patients treated with photons, the cerebellar dose was significantly lower in patients treated with proton therapy (p < 0.001, r = 0.62) which also translated to a significantly lower cerebellar volume reduction per year (p = 0.016, r = 0.25). Conclusion: Cerebellar volume decreased significantly and irreversibly after radiotherapy as function of time and dose. Further work is now needed to correlate these results with cognitive function and motor performance.

Purpose: This prospective trial investigates the association of time to recurrence (TTR) in glioblastoma with [11C]methionine (MET) tracer uptake before postoperative radiochemotherapy (RCT) aiming to guide radiotherapy boost regions. Experimental Design: Between 2013 and 2016, 102 patients with glioblastoma were recruited. RCT was performed with concurrent and adjuvant temozolomide to a total dose of 60 Gy. Tumor residues in postresection PET and MRI were together defined as gross tumor volumes for radiotherapy treatment planning. [11C]methionine (MET)-PET/MRI was performed before RCT and at each follow-up. Results: The primary hypothesis of a longer TTR for patients without increased tracer accumulation in postoperative MET-PET was confirmed in 89 patients. With 18.9 months (95% confidence interval, 9.3–28.5 months), median TTR was significantly (P < 0.001) longer for patients without (n = 29, 32.6%) as compared with 6.3 months (3.6–8.9) for patients with MET accumulation (n = 60, 67.4%) in pre-RCT PET. Although MRI often did not detect all PET-positive regions, an unfavorable impact of residual tumor in postsurgical MRI (n = 38, 42.7%) on TTR was observed [4.6 (4.2–5.1) vs. 15.5 months (6.0–24.9), P < 0.001]. Significant multivariable predictors for TTR were MRI positivity, PET-positive volume, and O6-methylguanine DNA methyltransferase (MGMT) hypermethylation. Conclusions: Postsurgical amino acid PET has prognostic value for TTR after RCT in glioblastoma. Because of the added value of the metabolic beyond the pure structural information, it should complement MRI in radiotherapy planning if available with reasonable effort, at least in the context of maximal therapy. Furthermore, the spatial correlation of regions of recurrence with PET-positive volumes could provide a bioimaging basis for further trials, for example, testing local radiation dose escalation.

Background and purpose Radio(chemo)therapy is standard in the adjuvant treatment of glioblastoma. Inevitably, brain tissue surrounding the target volume is also irradiated, potentially causing acute and late side-effects. Diffusion imaging has been shown to be a sensitive method to detect early changes in the cerebral white matter (WM) after radiation. The aim of this work was to assess possible changes in the mean diffusivity (MD) of WM after radio(chemo)therapy using Diffusion-weighted imaging (DWI) and to compare these effects between patients treated with proton and photon irradiation. Materials and methods 70 patients with glioblastoma underwent adjuvant radio(chemo)therapy with protons (n = 20) or photons (n = 50) at the University Hospital Dresden. MRI follow-ups were performed at three-monthly intervals and in this study were evaluated until 33 months after the end of therapy. Relative white matter MD changes between baseline and all follow-up visits were calculated in different dose regions. Results We observed a significant decrease of MD (p < 0.05) in WM regions receiving more than 20 Gy. MD reduction was progressive with dose and time after radio(chemo)therapy (maximum: −7.9 ± 1.2% after 24 months, ≥50 Gy). In patients treated with photons, significant reductions of MD in the entire WM (p < 0.05) were seen at all time points. Conversely, in proton patients, whole brain MD did not change significantly. Conclusions Irradiation leads to measurable MD reduction in white matter, progressing with both increasing dose and time. Treatment with protons reduces this effect most likely due to a lower total dose in the surrounding white matter. Further investigations are needed to assess whether those MD changes correlate with known radiation induced side-effects.

Purpose or Objective: Radio(chemo)therapy is part of the standard treatment of high-grade glioma patients and has been associated with cerebral atrophy [1,2]. Preclinical work also suggests radiation induced atrophy of the cerebellum [3,4]. Investigating cerebellar atrophy in patients treated with radiation is a further step in understanding radiation-induced deficits in both motor function and cognition. The aim of this study was to investigate cerebellar volume changes in a cohort of glioblastoma patients treated with photon or proton radio(chemo)therapy. Material and Methods: Data was acquired on a 3T Philips Ingenuity TF PET/MRI scanner (Philips Healthcare, Best, The Netherlands) as part of a prospective, longitudinal study investigating the effect of 11C-methionine PET/MR for tailoring the treatment of patients with glioblastoma (NCT01873469). In total, 71 patients with cerebral GBM (21 treated with proton therapy) had a baseline MR and at least one follow-up MRI, obtained in 3 monthly intervals after irradiation, available, including 3D T1-weighted (T1w) imaging (1×1×1 mm3) before and after intravenous injection of contrast agent (CE). Patients were treated with a total dose of 60 Gy(RBE=1.1) delivered in 2Gy fractions. On average 3.6 follow-ups were available covering a time period of 413 days ± 432 days (mean ± SD). The cerebellum was cut out from each MRI by warping [5] the MNI152 brain atlas and a corresponding cerebellar mask to each brain extracted T1w MRI. Sigmoid and transverse sinuses mimicking cerebellar tissue were removed using the CE T1w MRI. The cerebellum was segmented into grey matter (GM), white matter (WM) and cerebrospinal fluid (CSF) [6]. Its volume was calculated as the sum of all GM and WM probabilities and normalized to the baseline value for each patient. The mean relative cerebellar volume change per year was estimated for each patient with a linear regression. The resulting rate of volume change per year was plotted against the mean d

Objective To implement Computed Tomography (CT)-based attenuation maps of radiotherapy (RT) positioning hardware and radiofrequency (RF) coils to enable hybrid positron emission tomography/magnetic resonance imaging (PET/MRI)-based RT treatment planning. Materials and Methods The RT positioning hardware consisted of a flat RT table overlay, coil holders for abdominal scans, coil holders for head and neck scans and an MRI compatible hip and leg immobilization system. CT images of each hardware element were acquired on a CT scanner. Based on the CT images, attenuation maps of the devices were created. Validation measurements were performed on a PET/MR scanner using a 68Ge phantom (48 MBq, 10 min scan time). Scans with each device in treatment position were performed. Then, reference scans containing only the phantom were taken. The scans were reconstructed online (at the PET/MRI scanner) and offline (via e7tools on a PC) using identical reconstruction parameters. Average reconstructed activity concentrations of the device and reference scans were compared. Results The device attenuation maps were successfully implemented. The RT positioning devices caused an average decrease of reconstructed PET activity concentration in the range between -8.3 ± 2.1 % (mean ± SD) (head and neck coil holder with coils) to -1.0 ± 0.5 % (abdominal coil holder). With attenuation correction taking into account RT hardware, these values were reduced to -2.0 ± 1.2 % and 0.6 ± 0.5 %, respectively. The results of the offline and online reconstructions were nearly identical, with a difference of up to 0.2 %. Conclusion The decrease in reconstructed activity concentration caused by the RT positioning devices is clinically relevant and can successfully be corrected using CT-based attenuation maps. Both the offline and online reconstruction methods are viable options.

Although olfactory dysfunction is one of the most well-established prodromal symptoms in Parkinson’s disease (PD), its correlation with clinical disease progression or dopaminergic dysfunction still remains unclear. We here evaluated the association of striatal dopamine metabolism and olfactory function in a homogenous cohort of 30 patients with early untreated de novo PD. Striatal dopamine metabolism was assessed by the extended 18Fluorodopa PET scanning protocol to measure 18Fluorodopa uptake (Kocc) and the effective dopamine distribution volume ratio (EDVR) as the inverse of dopamine turnover. Olfactory function was estimated by the “Sniffin’ Sticks” test including odor threshold (T), discrimination (D) and identification (I) assessment. We detected moderate correlations of the EDVR in the posterior putamen with the TDI composite score (r = 0.412; p = 0.024; Pearson’s correlation test) and the odor identification score (r = 0.444; p = 0.014). These correlations were confirmed by multivariate regression analyses using age, sex, symptom duration and disease severity as measured by UPDRSIII motor score as candidate covariates. No other associations were observed between olfaction measures and Kocc and EDVR in all striatal regions. Together, olfactory dysfunction in early PD is not correlated with striatal 18Fluorodopa uptake as a measure for dopaminergic degeneration, but with putaminal dopamine turnover as a marker for dopaminergic presynaptic compensatory processes in early PD. These results should be treated as hypothesis generating and require confirmation by larger multicenter studies.

Background and purpose: Radiotherapy is a standard treatment option for high-grade gliomas. Cognitive impairment is a side effect associated with radiotherapy particularly in long-term survivors. Recent findings suggest involvement of the cerebellum in cognitive function. The goal of this study was therefore to investigate dose dependent cerebellar atrophy using prospective, longitudinal MR data from adult glioma patients who received radiotherapy. Materials and methods: Cerebellar volumes were measured using T1-weighted MR images from 91 glioma patients before radiotherapy and every three months thereafter. We calculated the average cerebellar volume change per year per Gy, based on the mean cerebellar dose, using linear regression analysis. Subsequently, patient age was investigated as a confounding factor using multiple linear regression analysis. The impact of chemotherapy was assessed separately in a subgroup of patients receiving a cerebellar dose ≤ 1 Gy. Cerebellar mean dose and cerebellar volume changes were compared between patients treated with proton (N = 38) and photon therapy (N = 52). Results: Cerebellar volume decreased 2.4 % per 10 Gy per year (p < 0.001). The cerebellar volume loss was progressive over time without signs of recovery within the observational period of two years. Neither patient age (p = 0.27) nor chemotherapy (p = 0.43) had a significant impact on cerebellar atrophy. Compared to patients treated with photons, the cerebellar dose was significantly lower in patients treated with proton therapy (p < 0.001, r = 0.62) which also translated to a significantly lower cerebellar volume reduction per year (p = 0.016, r = 0.25). Conclusion: Cerebellar volume decreased significantly and irreversibly after radiotherapy as function of time and dose. Further work is now needed to correlate these results with cognitive function and motor performance.

Anatomical and functional imaging by means of computed tomography, magnetic resonance imaging, and positron emission tomography are, besides a thorough physical examination, of utmost importance for accurate staging of primary tumors in the head and neck region. This chapter deals with the particular advan-tages and disadvantages of those imaging techniques and gives practical guidance on how to employ these in radiation treatment planning.

Objectives To determine the value of 18F-FDG-PET/MRI in the diagnosis and management of patients with pelvic recurrence of rectal cancer. Methods Forty-four patients (16 women, 28 men) with a history of rectal cancer who received FDG-PET/MRI between June 2011 and February 2017 at our institution were retrospectively enrolled. Three patients received two FDG-PET/MRIs; thus a total of 47 examinations were included. Pelvic recurrence was confirmed either with histology (n = 27) or imaging follow-up (n = 17) (> 4 months). Two readers (one radiologist, one nuclear medicine physician) interpreted the images in consensus. Pelvic lesions were assessed regarding FDG uptake and morphology. Sensitivity, specificity, positive and negative predictive values as well as accuracy of PET/MRI in detecting recurrence were determined. Results In 47 FDG-PET/MRIs 30 suspicious pelvic lesions were identified, 29 of which were malignant. Two patients underwent resection and had histologically proven pelvic recurrence without showing suspicious findings on FDG-PET/MRI. Changes in management due to FDG-PET/MRI findings had been implemented in eight patients. Eighty per cent (16/20) of resected patients had histologically negative resection margins (R0), one patient had uncertain resection margins. Sensitivity of FDG-PET/MRI in detecting recurrence was 94%, specificity 94%, positive/negative predictive value and accuracy were 97%, 90% and 94%, respectively. Conclusions FDG-PET/MRI is a valuable tool in the diagnosis and staging of pelvic recurrence in patients with rectal cancer.

Despite combined modality treatment involving surgery and adjuvant radiotherapy, a relevant percentage of chordoma and chondrosarcoma patients develop a local recurrence. In a previous study, we identified optic apparatus and/or brainstem compression, histology and GTV volume as prognostic factors for the risk of local failure. The present study aims to analyze patterns of recurrence and correlate local control with a detailed dosimetric analysis.

Background and Purpose: To compare the structural and hemodynamic changes of healthy brain tissue in the cerebral hemisphere contralateral to the tumor following photon and proton radiochemotherapy. Materials and Methods: Sixty-seven patients (54.9±14.0 years) diagnosed with glioblastoma multiforme undergoing adjuvant photon (n=47) or proton (n=19) radiochemotherapy with temozolomide after tumor resection underwent T1-weighted and arterial spin labeling MRI. Changes in volume and perfusion before and 3 to 6 months after were compared between therapies. Results: A decrease in gray matter (GM) (-2.2%, P<0.001) and white matter (WM) (-1.2%, P<0.001) volume was observed in photon-therapy patients compared to the pre-radiotherapy baseline. In contrast, for the protontherapy group, no significant differences in GM (0.3%, P=0.64) or WM (-0.4%, P=0.58) volume were observed. GM volume decreased with 0.9% per 10 Gy dose increase (P<0.001) and differed between the radiation modalities (P<0.001). Perfusion decreased in photon-therapy patients (-10.1%, P=0.002), whereas the decrease in proton-therapy patients, while comparable in magnitude, did not reach statistical significance (-9.1%, P=0.12). There was no correlation between perfusion decrease and either dose (P=0.64) or radiation modality (P=0.94). Conclusion: Our results show that the tissue volume decrease depends on radiation dose delivered to the healthy hemisphere and differs between treatment modalities. In contrast, the decrease in perfusion was comparable for both irradiation modalities. We conclude that proton therapy may reduce brain-volume loss when compared to photon therapy.

Gray matter (GM) atrophy in healthy brain tissue following radiochemotherapy was shown in brain-tumor patients in several studies. Here, we aimed to study GM and white matter (WM) changes in glioblastoma patients undergoing photon (n=43) and proton (n=12) radiochemotherapy. In photon-therapy patients, a statistically significant decrease of both GM (~2%) and WM (1.3-2.3%) volume was found with a positive influence of the RT-dose on the GM volume loss. In proton-therapy patients, no significant changes in GM and WM volumes were observed after therapy. This indicates that the proton-therapy has the potential to reduce structural GM changes in healthy tissue.