Probing the glioma microvasculature: a case series of the comparison between perfusion MRI and intraoperative high-frame-rate ultrafast Doppler ultrasound.

BACKGROUND: We aimed to describe the microvascular features of three types of adult-type diffuse glioma by comparing dynamic susceptibility contrast (DSC) perfusion magnetic resonance imaging (MRI) with intraoperative high-frame-rate ultrafast Doppler ultrasound. METHODS: Case series of seven patients with primary brain tumours underwent both DSC perfusion MRI and intra-operative high-frame-rate ultrafast Doppler ultrasound. From the ultrasound images, three-dimensional vessel segmentation was obtained of the tumour vascular bed. Relative cerebral blood volume (rCBV) maps were generated with leakage correction and normalised to the contralateral normal-appearing white matter. From tumour histograms, median, mean, and maximum rCBV ratios were extracted. RESULTS: Low-grade gliomas (LGGs) showed lower perfusion than high-grade gliomas (HGGs), as expected. Within the LGG subgroup, oligodendroglioma showed higher perfusion than astrocytoma. In HGG, the median rCBV ratio for glioblastoma was 3.1 while astrocytoma grade 4 showed low perfusion with a median rCBV of 1.2. On the high-frame-rate ultrafast Doppler ultrasound images, all tumours showed a range of rich and organised vascular networks with visually apparent abnormal vessels, even in LGG. CONCLUSIONS: This unique case series revealed in vivo insights about the microvascular architecture in both LGGs and HGGs. Ultrafast Doppler ultrasound revealed rich vascularisation, also in tumours with low perfusion at DSC MRI. These findings warrant further investigations using advanced MRI postprocessing, in particular for characterising adult-type diffuse glioma. RELEVANCE STATEMENT: Our findings challenge the current assumption behind the estimation of relative cerebral blood volume that the distribution of blood vessels in a voxel is random. KEY POINTS: • Ultrafast Doppler ultrasound revealed rich vascularity irrespective of perfusion dynamic susceptibility contrast MRI state. • Rich and organised vascularisation was also observed even in low-grade glioma. • These findings challenge the assumptions for cerebral blood volume estimation with MRI.

Evaluating the Predictive Value of Glioma Growth Models for Low-Grade Glioma After Tumor Resection.

Tumor growth models have the potential to model and predict the spatiotemporal evolution of glioma in individual patients. Infiltration of glioma cells is known to be faster along the white matter tracts, and therefore structural magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) can be used to inform the model. However, applying and evaluating growth models in real patient data is challenging. In this work, we propose to formulate the problem of tumor growth as a ranking problem, as opposed to a segmentation problem, and use the average precision (AP) as a performance metric. This enables an evaluation of the spatial pattern that does not require a volume cut-off value. Using the AP metric, we evaluate diffusion-proliferation models informed by structural MRI and DTI, after tumor resection. We applied the models to a unique longitudinal dataset of 14 patients with low-grade glioma (LGG), who received no treatment after surgical resection, to predict the recurrent tumor shape after tumor resection. The diffusion models informed by structural MRI and DTI showed a small but significant increase in predictive performance with respect to homogeneous isotropic diffusion, and the DTI-informed model reached the best predictive performance. We conclude there is a significant improvement in the prediction of the recurrent tumor shape when using a DTI-informed anisotropic diffusion model with respect to istropic diffusion, and that the AP is a suitable metric to evaluate these models. All code and data used in this publication are made publicly available.

Reproducibility of APT-weighted CEST-MRI at 3T in healthy brain and tumor across sessions and scanners.

Amide proton transfer (APT)-weighted chemical exchange saturation transfer (CEST) imaging is a recent MRI technique making its way into clinical application. In this work, we investigated whether APT-weighted CEST imaging can provide reproducible measurements across scan sessions and scanners. Within-session, between-session and between scanner reproducibility was calculated for 19 healthy volunteers and 7 patients with a brain tumor on two 3T MRI scanners. The APT-weighted CEST effect was evaluated by calculating the Lorentzian Difference (LD), magnetization transfer ratio asymmetry (MTRasym), and relaxation-compensated inverse magnetization transfer ratio (MTRREX) averaged in whole brain white matter (WM), enhancing tumor and necrosis. Within subject coefficient of variation (COV) calculations, Bland-Altman plots and mixed effect modeling were performed to assess the repeatability and reproducibility of averaged values. The group median COVs of LD APT were 0.56% (N = 19), 0.84% (N = 6), 0.80% (N = 9) in WM within-session, between-session and between-scanner respectively. The between-session COV of LD APT in enhancing tumor (N = 6) and necrotic core (N = 3) were 4.57% and 5.67%, respectively. There were no significant differences in within session, between session and between scanner comparisons of the APT effect. The COVs of LD and MTRREX were consistently lower than MTRasym in all experiments, both in healthy tissues and tumor. The repeatability and reproducibility of APT-weighted CEST was clinically acceptable across scan sessions and scanners. Although MTRasym is simple to acquire and compute and sufficient to provide robust measurement, it is beneficial to include LD and MTRREX to obtain higher reproducibility for detecting minor signal difference in different tissue types.

Microvasculature Features Derived from Hybrid EPI MRI in Non-Enhancing Adult-Type Diffuse Glioma Subtypes.

In this study, we used the vessel size imaging (VSI) MRI technique to characterize the microvasculature features of three subtypes of adult-type diffuse glioma lacking enhancement. Thirty-eight patients with confirmed non-enhancing glioma were categorized into three subtypes: Oligo (IDH-mut&1p/19q-codeleted), Astro (IDH-mut), and GBM (IDH-wt). The VSI technique provided quantitative maps of cerebral blood volume (CBV), microvasculature (µCBV), and vessel size for each patient. Additionally, tissue samples of 21 patients were histopathologically analyzed, and microvasculature features were quantified. Both MRI- and histology-derived features were compared across the three glioma subtypes with ANOVA or Kruskal-Wallis tests. Group averages of CBV, µCBV, and vessel size were significantly different between the three glioma subtypes (p < 0.01). Astro (IDH-mut) had a significantly lower CBV and µCBV compared to Oligo (IDH-mut&1p/19q-codeleted) (p = 0.004 and p = 0.001, respectively), and a higher average vessel size compared to GBM (IDH-wt) (p = 0.01). The histopathological analysis showed that GBM (IDH-wt) possessed vessels with more irregular shapes than the two other subtypes (p < 0.05). VSI provides a good insight into the microvasculature characteristics of the three adult-type glioma subtypes even when lacking enhancement. Further investigations into the specificity of VSI to differentiate glioma subtypes are thus warranted.

Combined molecular subtyping, grading, and segmentation of glioma using multi-task deep learning.

BACKGROUND: Accurate characterization of glioma is crucial for clinical decision making. A delineation of the tumor is also desirable in the initial decision stages but is time-consuming. Previously, deep learning methods have been developed that can either non-invasively predict the genetic or histological features of glioma, or that can automatically delineate the tumor, but not both tasks at the same time. Here, we present our method that can predict the molecular subtype and grade, while simultaneously providing a delineation of the tumor. METHODS: We developed a single multi-task convolutional neural network that uses the full 3D, structural, preoperative MRI scans to predict the IDH mutation status, the 1p/19q co-deletion status, and the grade of a tumor, while simultaneously segmenting the tumor. We trained our method using a patient cohort containing 1508 glioma patients from 16 institutes. We tested our method on an independent dataset of 240 patients from 13 different institutes. RESULTS: In the independent test set, we achieved an IDH-AUC of 0.90, an 1p/19q co-deletion AUC of 0.85, and a grade AUC of 0.81 (grade II/III/IV). For the tumor delineation, we achieved a mean whole tumor Dice score of 0.84. CONCLUSIONS: We developed a method that non-invasively predicts multiple, clinically relevant features of glioma. Evaluation in an independent dataset shows that the method achieves a high performance and that it generalizes well to the broader clinical population. This first-of-its-kind method opens the door to more generalizable, instead of hyper-specialized, AI methods.

MRI-Based Assessment of Brain Tumor Hypoxia: Correlation with Histology.

Cerebral hypoxia significantly impacts the progression of brain tumors and their resistance to radiotherapy. This study employed streamlined quantitative blood-oxygen-level-dependent (sqBOLD) MRI to assess the oxygen extraction fraction (OEF)-a measure of how much oxygen is being extracted from vessels, with higher OEF values indicating hypoxia. Simultaneously, we utilized vessel size imaging (VSI) to evaluate microvascular dimensions and blood volume. A cohort of ten patients, divided between those with glioma and those with brain metastases, underwent a 3 Tesla MRI scan. We generated OEF, cerebral blood volume (CBV), and vessel size maps, which guided 3-4 targeted biopsies per patient. Subsequent histological analyses of these biopsies used hypoxia-inducible factor 1-alpha (HIF-1α) for hypoxia and CD31 for microvasculature assessment, followed by a correlation analysis between MRI and histological data. The results showed that while the sqBOLD model was generally applicable to brain tumors, it demonstrated discrepancies in some metastatic tumors, highlighting the need for model adjustments in these cases. The OEF, CBV, and vessel size maps provided insights into the tumor's hypoxic condition, showing intertumoral and intratumoral heterogeneity. A significant relationship between MRI-derived measurements and histological data was only evident in the vessel size measurements (r = 0.68, p < 0.001).

Noninvasive differentiation of molecular subtypes of adult nonenhancing glioma using MRI perfusion and diffusion parameters.

Background: Nonenhancing glioma typically have a favorable outcome, but approximately 19-44% have a highly aggressive course due to a glioblastoma genetic profile. The aim of this retrospective study is to use physiological MRI parameters of both perfusion and diffusion to distinguish the molecular profiles of glioma without enhancement at presentation. Methods: Ninety-nine patients with nonenhancing glioma were included, in whom molecular status (including 1p/19q codeletion status and IDH mutation) and preoperative MRI (T2w/FLAIR, dynamic susceptibility-weighted, and diffusion-weighted imaging) were available. Tumors were segmented semiautomatically using ITK-SNAP to derive whole tumor histograms of relative Cerebral Blood Volume (rCBV) and Apparent Diffusion Coefficient (ADC). Tumors were divided into three clinically relevant molecular profiles: IDH mutation (IDHmt) with (n = 40) or without (n = 41) 1p/19q codeletion, and (n = 18) IDH-wildtype (IDHwt). ANOVA, Kruskal-Wallis, and Chi-Square analyses were performed using SPSS. Results: rCBV (mean, median, 75th and 85th percentile) and ADC (mean, median, 15th and 25th percentile) showed significant differences across molecular profiles (P < .01). Posthoc analyses revealed that IDHwt and IDHmt 1p/19q codeleted tumors showed significantly higher rCBV compared to IDHmt 1p/19q intact tumors: mean rCBV (mean, SD) 1.46 (0.59) and 1.35 (0.39) versus 1.08 (0.31), P < .05. Also, IDHwt tumors showed significantly lower ADC compared to IDHmt 1p/19q codeleted and IDHmt 1p/19q intact tumors: mean ADC (mean, SD) 1.13 (0.23) versus 1.27 (0.15) and 1.45 (0.20), P < .001). Conclusions: A combination of low ADC and high rCBV, reflecting high cellularity and high perfusion respectively, separates IDHwt from in particular IDHmt 1p/19q intact glioma.

EASE: Clinical Implementation of Automated Tumor Segmentation and Volume Quantification for Adult Low-Grade Glioma.

The growth rate of non-enhancing low-grade glioma has prognostic value for both malignant progression and survival, but quantification of growth is difficult due to the irregular shape of the tumor. Volumetric assessment could provide a reliable quantification of tumor growth, but is only feasible if fully automated. Recent advances in automated tumor segmentation have made such a volume quantification possible, and this work describes the clinical implementation of automated volume quantification in an application named EASE: Erasmus Automated SEgmentation. The visual quality control of segmentations by the radiologist is an important step in this process, as errors in the segmentation are still possible. Additionally, to ensure patient safety and quality of care, protocols were established for the usage of volume measurements in clinical diagnosis and for future updates to the algorithm. Upon the introduction of EASE into clinical practice, we evaluated the individual segmentation success rate and impact on diagnosis. In its first 3 months of usage, it was applied to a total of 55 patients, and in 36 of those the radiologist was able to make a volume-based diagnosis using three successful consecutive measurements from EASE. In all cases the volume-based diagnosis was in line with the conventional visual diagnosis. This first cautious introduction of EASE in our clinic is a valuable step in the translation of automatic segmentation methods to clinical practice.

Distinguishing pure histopathological growth patterns of colorectal liver metastases on CT using deep learning and radiomics: a pilot study.

Histopathological growth patterns (HGPs) are independent prognosticators for colorectal liver metastases (CRLM). Currently, HGPs are determined postoperatively. In this study, we evaluated radiomics for preoperative prediction of HGPs on computed tomography (CT), and its robustness to segmentation and acquisition variations. Patients with pure HGPs [i.e. 100% desmoplastic (dHGP) or 100% replacement (rHGP)] and a CT-scan who were surgically treated at the Erasmus MC between 2003-2015 were included retrospectively. Each lesion was segmented by three clinicians and a convolutional neural network (CNN). A prediction model was created using 564 radiomics features and a combination of machine learning approaches by training on the clinician's and testing on the unseen CNN segmentations. The intra-class correlation coefficient (ICC) was used to select features robust to segmentation variations; ComBat was used to harmonize for acquisition variations. Evaluation was performed through a 100 × random-split cross-validation. The study included 93 CRLM in 76 patients (48% dHGP; 52% rHGP). Despite substantial differences between the segmentations of the three clinicians and the CNN, the radiomics model had a mean area under the curve of 0.69. ICC-based feature selection or ComBat yielded no improvement. Concluding, the combination of a CNN for segmentation and radiomics for classification has potential for automatically distinguishing dHGPs from rHGP, and is robust to segmentation and acquisition variations. Pending further optimization, including extension to mixed HGPs, our model may serve as a preoperative addition to postoperative HGP assessment, enabling further exploitation of HGPs as a biomarker.

The Erasmus Glioma Database (EGD): Structural MRI scans, WHO 2016 subtypes, and segmentations of 774 patients with glioma.

The Erasmus Glioma Database (EGD) contains structural magnetic resonance imaging (MRI) scans, genetic and histological features (specifying the WHO 2016 subtype), and whole tumor segmentations of patients with glioma. Pre-operative MRI data of 774 patients with glioma (281 female, 492 male, 1 unknown, age range 19-86 years) treated at the Erasmus MC between 2008 and 2018 is available. For all patients a pre-contrast T1-weighted, post-contrast T1-weighted, T2-weighted, and T2-weighted FLAIR scan are available, made on a variety of scanners from four different vendors. All scans are registered to a common atlas and defaced. Genetic and histological data consists of the IDH mutation status (available for 467 patients), 1p/19q co-deletion status (available for 259 patients), and grade (available for 716 patients). The full WHO 2016 subtype is available for 415 patients. Manual segmentations are available for 374 patients and automatically generated segmentations are available for 400 patients. The dataset can be used to relate the visual appearance of the tumor on the scan with the genetic and histological features, and to develop automatic segmentation methods.

DeepDicomSort: An Automatic Sorting Algorithm for Brain Magnetic Resonance Imaging Data.

With the increasing size of datasets used in medical imaging research, the need for automated data curation is arising. One important data curation task is the structured organization of a dataset for preserving integrity and ensuring reusability. Therefore, we investigated whether this data organization step can be automated. To this end, we designed a convolutional neural network (CNN) that automatically recognizes eight different brain magnetic resonance imaging (MRI) scan types based on visual appearance. Thus, our method is unaffected by inconsistent or missing scan metadata. It can recognize pre-contrast T1-weighted (T1w),post-contrast T1-weighted (T1wC), T2-weighted (T2w), proton density-weighted (PDw) and derived maps (e.g. apparent diffusion coefficient and cerebral blood flow). In a first experiment,we used scans of subjects with brain tumors: 11065 scans of 719 subjects for training, and 2369 scans of 192 subjects for testing. The CNN achieved an overall accuracy of 98.7%. In a second experiment, we trained the CNN on all 13434 scans from the first experiment and tested it on 7227 scans of 1318 Alzheimer's subjects. Here, the CNN achieved an overall accuracy of 98.5%. In conclusion, our method can accurately predict scan type, and can quickly and automatically sort a brain MRI dataset virtually without the need for manual verification. In this way, our method can assist with properly organizing a dataset, which maximizes the shareability and integrity of the data.

The Association Between the Extent of Glioblastoma Resection and Survival in Light of MGMT Promoter Methylation in 326 Patients With Newly Diagnosed IDH-Wildtype Glioblastoma.

Background: The association between contrast enhanced (CE) and non-contrast enhanced (NCE) tumor resection and survival in patients with glioblastoma in relation to molecular subtypes is poorly understood. The aim of this study was to assess the association between CE and NCE tumor resection and survival in light of MGMT promoter methylation in newly diagnosed IDH-wildtype glioblastoma. Materials and methods: Patients with newly diagnosed IDH-wildtype glioblastoma who underwent surgery were eligible. CE and NCE tumor volumes were assessed on pre- and post-operative MRI scans and extent of resection was calculated. The association between CE and NCE tumor resection and survival was evaluated using multivariable Cox proportional hazards models and Kaplan Meier estimates. Results: Three hundred and twenty-six patients were included: 177 (54.3%) with and 149 (45.7%) without MGMT methylation. Multivariable Cox proportional hazards models stratified for MGMT methylation identified age ≤ 65y (HR 0.63; 95% CI, 0.49-0.81; p < 0.0001), chemoradiation (HR 0.13; 95% CI, 0.09-0.19; p < 0.0001), maximal CE tumor resection (HR 0.58; 95% CI, 0.39-0.87; p = 0.009), ≥ 30% NCE tumor resection (HR 0.71; 95% CI, 0.53-0.93; p = 0.014), and minimal residual CE tumor volume (HR 0.64; 95% CI, 0.46-0.88 p = 0.007) as being associated with longer overall survival. Kaplan Meier estimates showed that extensive surgery was more beneficial for patients with MGMT methylated glioblastoma. Conclusions: This study shows an association between maximal CE tumor resection, ≥30% NCE tumor resection, minimal residual CE tumor volume, and longer overall survival in patients with newly diagnosed IDH wildtype glioblastoma. Intraoperative imaging and stimulation mapping may be used to pursue safe and maximal resection. In future research, the safety aspect of maximizing tumor resection needs to be addressed.

Topographical Mapping of 436 Newly Diagnosed IDH Wildtype Glioblastoma With vs. Without MGMT Promoter Methylation.

Introduction: O6 -methylguanine-methyltransferase (MGMT) promoter methylation and isocitrate dehydrogenase (IDH) mutation status are important prognostic factors for patients with glioblastoma. There are conflicting reports about a differential topographical distribution of glioblastoma with vs. without MGMT promoter methylation, possibly caused by molecular heterogeneity in glioblastoma populations. We initiated this study to re-evaluate the topographical distribution of glioblastoma with vs. without MGMT promoter methylation in light of the updated WHO 2016 classification. Methods: Preoperative T2-weighted/FLAIR and postcontrast T1-weighted MRI scans of patients aged 18 year or older with IDH wildtype glioblastoma were collected. Tumors were semi-automatically segmented, and the topographical distribution between glioblastoma with vs. without MGMT promoter methylation was visualized using frequency heatmaps. Then, voxel-wise differences were analyzed using permutation testing with Threshold Free Cluster Enhancement. Results: Four hundred thirty-six IDH wildtype glioblastoma patients were included; 211 with and 225 without MGMT promoter methylation. Visual examination suggested that when compared with MGMT unmethylated glioblastoma, MGMT methylated glioblastoma were more frequently located near bifrontal and left occipital periventricular area and less frequently near the right occipital periventricular area. Statistical analyses, however, showed no significant difference in topographical distribution between MGMT methylated vs. MGMT unmethylated glioblastoma. Conclusions: This study re-evaluated the topographical distribution of MGMT promoter methylation in 436 newly diagnosed IDH wildtype glioblastoma, which is the largest homogenous IDH wildtype glioblastoma population to date. There was no statistically significant difference in anatomical localization between MGMT methylated vs. unmethylated IDH wildtype glioblastoma.

Predicting the 1p/19q Codeletion Status of Presumed Low-Grade Glioma with an Externally Validated Machine Learning Algorithm.

PURPOSE: Patients with 1p/19q codeleted low-grade glioma (LGG) have longer overall survival and better treatment response than patients with 1p/19q intact tumors. Therefore, it is relevant to know the 1p/19q status. To investigate whether the 1p/19q status can be assessed prior to tumor resection, we developed a machine learning algorithm to predict the 1p/19q status of presumed LGG based on preoperative MRI. EXPERIMENTAL DESIGN: Preoperative brain MR images from 284 patients who had undergone biopsy or resection of presumed LGG were used to train a support vector machine algorithm. The algorithm was trained on the basis of features extracted from post-contrast T1-weighted and T2-weighted MR images and on patients' age and sex. The performance of the algorithm compared with tissue diagnosis was assessed on an external validation dataset of MR images from 129 patients with LGG from The Cancer Imaging Archive (TCIA). Four clinical experts also predicted the 1p/19q status of the TCIA MR images. RESULTS: The algorithm achieved an AUC of 0.72 in the external validation dataset. The algorithm had a higher predictive performance than the average of the neurosurgeons (AUC 0.52) but lower than that of the neuroradiologists (AUC of 0.81). There was a wide variability between clinical experts (AUC 0.45-0.83). CONCLUSIONS: Our results suggest that our algorithm can noninvasively predict the 1p/19q status of presumed LGG with a performance that on average outperformed the oncological neurosurgeons. Evaluation on an independent dataset indicates that our algorithm is robust and generalizable.

Differences in spatial distribution between WHO 2016 low-grade glioma molecular subgroups.

BACKGROUND: Several studies reported a correlation between anatomic location and genetic background of low-grade gliomas (LGGs). As such, tumor location may contribute to presurgical clinical decision-making. Our purpose was to visualize and compare the spatial distribution of different WHO 2016 gliomas, frequently aberrated single genes and DNA copy number alterations within subgroups, and groups of postoperative tumor volume. METHODS: Adult grade II glioma patients (WHO 2016 classified) diagnosed between 2003 and 2016 were included. Tumor volume and location were assessed with semi-automatic software. All volumes of interest were mapped to a standard reference brain. Location heatmaps were created for each WHO 2016 glioma subgroup, frequently aberrated single genes and copy numbers (CNVs), as well as heatmaps according to groups of postoperative tumor volume. Differences between subgroups were determined using voxelwise permutation testing. RESULTS: A total of 110 IDH mutated astrocytoma patients, 92 IDH mutated and 1p19q co-deleted oligodendroglioma patients, and 22 IDH wild-type astrocytoma patients were included. We identified small regions in which specific molecular subtypes occurred more frequently. IDH-mutated LGGs were more frequently located in the frontal lobes and IDH wild-type tumors more frequently in the basal ganglia of the right hemisphere. We found no localizations of significant difference for single genes/CNVs in subgroups, except for loss of 9p in oligodendrogliomas with a predilection for the left parietal lobes. More extensive resections in LGG were associated with frontal locations. CONCLUSIONS: WHO low-grade glioma subgroups show differences in spatial distribution. Our data may contribute to presurgical clinical decision-making in LGG patients.

Fast and accurate sensitivity analysis of IMPT treatment plans using Polynomial Chaos Expansion.

The highly conformal planned dose distribution achievable in intensity modulated proton therapy (IMPT) can severely be compromised by uncertainties in patient setup and proton range. While several robust optimization approaches have been presented to address this issue, appropriate methods to accurately estimate the robustness of treatment plans are still lacking. To fill this gap we present Polynomial Chaos Expansion (PCE) techniques which are easily applicable and create a meta-model of the dose engine by approximating the dose in every voxel with multidimensional polynomials. This Polynomial Chaos (PC) model can be built in an automated fashion relatively cheaply and subsequently it can be used to perform comprehensive robustness analysis. We adapted PC to provide among others the expected dose, the dose variance, accurate probability distribution of dose-volume histogram (DVH) metrics (e.g. minimum tumor or maximum organ dose), exact bandwidths of DVHs, and to separate the effects of random and systematic errors. We present the outcome of our verification experiments based on 6 head-and-neck (HN) patients, and exemplify the usefulness of PCE by comparing a robust and a non-robust treatment plan for a selected HN case. The results suggest that PCE is highly valuable for both research and clinical applications.

Robustness Recipes for Minimax Robust Optimization in Intensity Modulated Proton Therapy for Oropharyngeal Cancer Patients.

PURPOSE: We aimed to derive a "robustness recipe" giving the range robustness (RR) and setup robustness (SR) settings (ie, the error values) that ensure adequate clinical target volume (CTV) coverage in oropharyngeal cancer patients for given gaussian distributions of systematic setup, random setup, and range errors (characterized by standard deviations of Σ, σ, and ρ, respectively) when used in minimax worst-case robust intensity modulated proton therapy (IMPT) optimization. METHODS AND MATERIALS: For the analysis, contoured computed tomography (CT) scans of 9 unilateral and 9 bilateral patients were used. An IMPT plan was considered robust if, for at least 98% of the simulated fractionated treatments, 98% of the CTV received 95% or more of the prescribed dose. For fast assessment of the CTV coverage for given error distributions (ie, different values of Σ, σ, and ρ), polynomial chaos methods were used. Separate recipes were derived for the unilateral and bilateral cases using one patient from each group, and all 18 patients were included in the validation of the recipes. RESULTS: Treatment plans for bilateral cases are intrinsically more robust than those for unilateral cases. The required RR only depends on the ρ, and SR can be fitted by second-order polynomials in Σ and σ. The formulas for the derived robustness recipes are as follows: Unilateral patients need SR = -0.15Σ(2) + 0.27σ(2) + 1.85Σ - 0.06σ + 1.22 and RR=3% for ρ = 1% and ρ = 2%; bilateral patients need SR = -0.07Σ(2) + 0.19σ(2) + 1.34Σ - 0.07σ + 1.17 and RR=3% and 4% for ρ = 1% and 2%, respectively. For the recipe validation, 2 plans were generated for each of the 18 patients corresponding to Σ = σ = 1.5 mm and ρ = 0% and 2%. Thirty-four plans had adequate CTV coverage in 98% or more of the simulated fractionated treatments; the remaining 2 had adequate coverage in 97.8% and 97.9%. CONCLUSIONS: Robustness recipes were derived that can be used in minimax robust optimization of IMPT treatment plans to ensure adequate CTV coverage for oropharyngeal cancer patients.