Clinical characteristics of pediatric allogeneic hematopoietic stem cell transplantation-associated thrombotic microangiopathy (TA-TMA): a retrospective single-center analysis.

OBJECTIVES: To investigate the clinical features of thrombotic microangiopathy associated with allogeneic hematopoietic stem cell transplantation in children. METHODS: A retrospective analysis of continuous clinical data from HSCT received in the Department of Hematology and Oncology of Wuhan Children's Hospital from August 1, 2016 to December 31, 2021. RESULTS: During this period, 209 patients received allo-HSCT in our department, 20 (9.6%) of whom developed TA-TMA. TA-TMA was diagnosed at a median of 94 (7-289) days post-HSCT. Eleven (55%) patients had early TA-TMA within 100 days post-HSCT, while the other 9 (45%) patients had TA-TMA thereafter. The most common symptom of TA-TMA was ecchymosis (55%), while the main signs were refractory hypertension (90%) and multi-cavity effusion (35%). Five (25%) patients had central nervous system symptoms (convulsions and lethargy). All 20 patients had progressive thrombocytopenia, with 16 patients receiving transfusion of platelets that was ineffective. Ruptured red blood cells were visible in only two patients with peripheral blood smears. Cyclosporine A or Tacrolimus (CNI) dose was reduced once TA-TMA was diagnosed. Nineteen cases were treated with low-molecular-weight heparin, 17 patients received plasma exchange, and 12 patients were treated with rituximab. TA-TMA-related mortality percentage in this study was 45% (9/20). CONCLUSION: Platelet decline and/or ineffective transfusion post-HSCT should be considered an early indicator of TA-TMA in pediatric patients. TA-TMA in pediatric patients may occur without evidence of peripheral blood schistocytes. Aggressive treatment is required once diagnosis is confirmed, but the long-term prognosis is poor.

[Clinical Analysis of Salvage Treatment of Glucocorticoid Resistant Graft-Versus-Host Disease with Vedolizumab in Children].

OBJECTIVE: To investigate the efficacy and safety of VDZ (Vedolizumab) in the salvage treatment of glucocorticoid resistance to gastrointestinal graft-versus-host disease (GR-GI GVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) in children. METHODS: The clinical data of 5 patients with refractory GI GVHD who received allo-HSCT in Wuhan Children's Hospital from December 2020 to December 2021 were retrospectively analyzed with VDZ salvage therapy. RESULTS: Among the 5 children with refractory GI GVHD, there were 1 male and 4 female, including 2 cases of extremely severe aplastic anemia, 1 case of acute myeloid leukemia (M2, high-risk), 1 case of fanconi anemia and 1 case of myelodysplastic syndrome. The median age of transplant recipients was 54.4 (12-164) months. The median treatment time from transplantation to VDZ was 1.4 (0.6-6.8) months. On average, 3.5 (2-5) doses of VDZ were received. After receiving treatment, 2 patients achieved a complete response (CR), 2 patients achieved a very good partial response (VGPR), 1 patient was non-responsive (NR) after a short-term partial response (PR). Compared with that before VDZ treatment, the amount of diarrhea, stool color, blood and traits of the children after medication were effectively improved. The median follow-up time was 9.3 (7.23-12.83) months. No disseminated or severe bacterial/fungal infections occurred during VDZ treatment and follow-up, and 2 children died of leukemia recurrence and pulmonary bronchiolitis obliterans. CONCLUSION: VDZ salvage treatment of refractory GI GVHD in children has obvious short-term efficacy and good safety.

Electron ultra-high dose rate FLASH irradiation study using a clinical linac: Linac modification, dosimetry, and radiobiological outcome.

PURPOSE: Ultra-high dose rate FLASH irradiation (FLASH-IR) has been shown to cause less normal tissue damage compared with conventional irradiation (CONV-IR), this is known as the "FLASH effect." It has attracted immense research interest because its underlying mechanism is scarcely known. The purpose of this study was to determine whether FLASH-IR and CONV-IR induce differential inflammatory cytokine expression using a modified clinical linac. MATERIALS AND METHODS: An Elekta Synergy linac was used to deliver 6 MeV CONV-IR and modified to deliver FLASH-IR. Female FvB mice were randomly assigned to three different groups: a non-irradiated control, CONV-IR, or FLASH-IR. The FLASH-IR beam was produced by single pulses repeated manually with a 20-s interval (Strategy 1), or single-trigger multiple pulses with a 10 ms interval (Strategy 2). Mice were immobilized in the prone position in a custom-designed applicator with Gafchromic films positioned under the body. The prescribed doses for the mice were 6 to 18 Gy and verified using Gafchromic films. Cytokine expression of three pro-inflammatory cytokines (tumor necrosis factor-α [TNF-α], interferon-γ [IFN-γ], interleukin-6 [IL-6]) and one anti-inflammatory cytokine (IL-10) in serum samples and skin tissue were examined within 1 month post-IR. RESULTS: The modified linac delivered radiation at an intra-pulse dose rate of around 1 × 106 Gy/s and a dose per pulse over 2 Gy at a source-to-surface distance (SSD) of 13 to 15 cm. The achieved dose coverage was 90%-105% of the maximum dose within -20 to 20 mm in the X direction and 95% within -30 to 30 mm in the Y direction. The absolute deviations between the prescribed dose and the actual dose were 2.21%, 6.04%, 2.09%, and 2.73% for 6, 9, 12, and 15 Gy as measured by EBT3 films, respectively; and 4.00%, 4.49%, and 2.30% for 10, 14, and 18 Gy as measured by the EBT XD films, respectively. The reductions in the CONV-IR versus the FLASH-IR group were 4.89%, 10.28%, -7.8%, and -22.17% for TNF-α, IFN-γ, IL-6, and IL-10 in the serum on D6, respectively; 37.26%, 67.16%, 56.68%, and -18.95% in the serum on D31, respectively; and 62.67%, 35.65%, 37.75%, and -12.20% for TNF-α, IFN-γ, IL-6, and IL-10 in the skin tissue, respectively. CONCLUSIONS: Ultra-high dose rate electron FLASH caused lower pro-inflammatory cytokine levels in serum and skin tissue which might mediate differential tissue damage between FLASH-IR and CONV-IR.

Normal tissue complication probability models for prospectively scored late rectal and urinary morbidity after proton therapy of prostate cancer.

BACKGROUND AND PURPOSE: Photons and protons have fundamentally different properties, i.e. protons have a reduced dose bath but a higher relative biological effectiveness. Photon-based normal tissue complication probability (NTCP) models may therefore not immediately be applicable to proton therapy (PT). The aim was to derive parameters of the Lyman-Kutcher-Burman (LKB) NTCP model using prospectively recorded late morbidity data from PT, focusing on rectal morbidity and prostate cancer. MATERIALS AND METHODS: Prospectively collected data were available for 1151 prostate cancer patients treated with passive scattering PT and prescribed target doses of 78-82 Gy (RBE = 1.1) in 2 Gy fractions. Morbidity data (CTCAE v3.0) consisted of two alternative late grade 2 rectal bleeding endpoints: Medical Grade2A (GR2A) and procedural Grade2B (GR2B), as well as late grade 3 + urinary morbidity. GR2A + 2B were observed in 156/1047 patients (15%), GR2B in 45/1047 patients (4%), and urinary grade 3 + in 51/1151 patients (4%). LKB NTCP model parameters (D50, m, and n) were derived by maximum likelihood estimation. RESULTS: For the rectum/rectal wall the volume parameter n was low (0.07-0.14) for both GR2A + 2B and GR2B, as was the m parameter (range: 0.16-0.20). For the bladder/bladder wall both parameters were high (n-range: 0.20-0.36; m-range: 0.32-0.36). D50 parameters were higher for GR2B of the rectum/rectal wall (95.9-98.0 Gy) and bladder/bladder wall (118.1-119.9 Gy), but lower for GR2A2B (71.7-73.6 Gy). CONCLUSION: PT specific LKB NTCP model parameters were derived from a population of more than 1000 patients. The D50 parameter differed for all structures and endpoints and deviated from typical photon-based LKB model values.

NRG Oncology Survey of Monte Carlo Dose Calculation Use in US Proton Therapy Centers.

PURPOSE/OBJECTIVES: Monte Carlo (MC) dose calculation has appeared in primary commercial treatment-planning systems and various in-house platforms. Dual-energy computed tomography (DECT) and metal artifact reduction (MAR) techniques complement MC capabilities. However, no publications have yet reported how proton therapy centers implement these new technologies, and a national survey is required to determine the feasibility of including MC and companion techniques in cooperative group clinical trials. MATERIALS/METHODS: A 9-question survey was designed to query key clinical parameters: scope of MC utilization, validation methods for heterogeneities, clinical site-specific imaging guidance, proton range uncertainties, and how implants are handled. A national survey was distributed to all 29 operational US proton therapy centers on 13 May 2019. RESULTS: We received responses from 25 centers (86% participation). Commercial MC was most commonly used for primary plan optimization (16 centers) or primary dose evaluation (18 centers), while in-house MC was used more frequently for secondary dose evaluation (7 centers). Based on the survey, MC was used infrequently for gastrointestinal, genitourinary, gynecology and extremity compared with other more heterogeneous disease sites (P < .007). Although many centers had published DECT research, only 3/25 centers had implemented DECT clinically, either in the treatment-planning system or to override implant materials. Most centers (64%) treated patients with metal implants on a case-by-case basis, with a variety of methods reported. Twenty-four centers (96%) used MAR images and overrode the surrounding tissue artifacts; however, there was no consensus on how to determine metal dimension, materials density, or stopping powers. CONCLUSION: The use of MC for primary dose calculation and optimization was prevalent and, therefore, likely feasible for clinical trials. There was consensus to use MAR and override tissues surrounding metals but no consensus about how to use DECT and MAR for human tissues and implants. Development and standardization of these advanced technologies are strongly encouraged for vendors and clinical physicists.

Prevalence and Temporal Trends Analysis of Screening and Diagnostic Instruments in Posttraumatic Stress Disorder: Text Mining Study.

BACKGROUND: Various instruments for patient screening and diagnosis have been developed for and applied in posttraumatic stress disorder (PTSD). OBJECTIVE: This study comprehensively investigates the prevalence and temporal trends of the most widely used instruments in PTSD-related studies. METHODS: A total of 1345 files of registered clinical trials from ClinicalTrials.gov and 9422 abstracts from the PubMed database from 2005 to 2020 were downloaded for this study. The instruments applied in clinical trials were manually annotated, and instruments in abstracts were recognized using exact string matching. The prevalence score of an instrument in a certain period was calculated as the number of studies divided by the number of instances of the instrument. By calculating the yearly prevalence index of each instrument, we conducted a trends analysis and compared the trends in index change between instruments. RESULTS: A total of 4178 instrument synonyms were annotated, which were mapped to 1423 unique instruments. In the 16 years from 2005 to 2020, only 10 instruments were used more than once per year; the 4 most used instruments were the PTSD Checklist, the Clinician-Administered PTSD Disorder Scale, the Patient Health Questionnaire, and the Beck Depression Inventory. There were 18 instruments whose yearly prevalence index score exceeded 0.1 at least once during the 16 years. The changes in trends and time points of partial instruments in clinical trials and PubMed abstracts were highly consistent. The average time duration of a PTSD-related trial was 1495.5 days or approximately 4 years from submission to ClinicalTrial.gov to publication in a journal. CONCLUSIONS: The application of widely accepted and appropriate instruments can help improve the reliability of research results in PTSD-related clinical studies. With extensive text data obtained from real clinical trials and published articles, we investigated and compared the usage of instruments in the PTSD research community.

Fast MCsquare-Based Independent Dose Verification Platform for Pencil Beam Scanning Proton Therapy.

PURPOSE: To commission MCsquare (a multi-cores CPU-based dose calculation engine) for pencil beam scanning (PBS) proton therapy, integrate it into RayStation treatment plan system (TPS) to create a dedicated platform for fast independent dose verification. METHOD: A MCsquare-based independent dose verification platform (MC2InRS) was developed to realize automatic dose re-calculation for clinical use, including data preparation, dose calculation, 2D/3D gamma analysis. MCsquare was commissioned based on in-air lateral dose profiles, integrated depth dose, and the absolute dose of different beam energies for Proteus®ONE. MC2InRS was validated with measurement data using various targets and depths in a water phantom. This study also investigated 15 clinical cases to demonstrate the feasibility and effectiveness of MC2InRS platform in clinic practice. RESULTS: Between simulation and measurement, the distal range differences at 80% (R80) and 20% (R20) dose levels for each energy were below 0.05 mm, and 0.1 mm, respectively, and the absolute dose differences were below 0.5%. 29 out of 36 QA planes reached a 100% gamma passing rate (GPR) for 2%/2mm criteria, and a minimum of 98.3% gamma was obtained in water phantom between simulation and measurement. For the 15 clinical cases investigated, the average 2D GPR (2%/2mm) was 95.4%, 99.3% for MCsquare vs. measurement, MCsquare vs. TPS, respectively. The average 3D GPR (2%/2mm) was 98.9%, 95.3% for MCsquare vs. TPS in water, and computed tomography (CT), respectively. CONCLUSION: MC2InRS, a fast, independent dose verification platform, has been developed to perform dose verification with high accuracy and efficiency for Pencil Bream Scanning (PBS). Its potential to be applied in routine clinical practice has also been discussed.

[Artificial intelligence based Chinese clinical trials eligibility criteria classification].

Subject recruitment is a key component that affects the progress and results of clinical trials, and generally conducted with eligibility criteria (includes inclusion criteria and exclusion criteria). The semantic category analysis of eligibility criteria can help optimizing clinical trials design and building automated patient recruitment system. This study explored the automatic semantic categories classification of Chinese eligibility criteria based on artificial intelligence by academic shared task. We totally collected 38 341 annotated eligibility criteria sentences and predefined 44 semantic categories. A total of 75 teams participated in competition, with 27 teams having submitted system outputs. Based on the results, we found out that most teams adopted mixed models. The mainstream resolution was applying pre-trained language models capable of providing rich semantic representation, which were combined with neural network models and used to fine-tune the models with reference to classifier tasks, and finally improved classification performance could be obtained by ensemble modeling. The best-performing system achieved a macro F1 score of 0.81 by using a pre-trained language model, i.e. bidirectional encoder representations from transformers (BERT) and ensemble modeling. With the error analysis we found out that from the point of data processing steps the data pre-processing and post-processing were very important for classification, while from the point of data volume these categories with less data volume showed lower classification performance. Finally, we hope that this study could provide a valuable dataset and state-of-the-art result for the research of Chinese medical short text classification.

Semantic categorization of Chinese eligibility criteria in clinical trials using machine learning methods.

BACKGROUND: Semantic categorization analysis of clinical trials eligibility criteria based on natural language processing technology is crucial for the task of optimizing clinical trials design and building automated patient recruitment system. However, most of related researches focused on English eligibility criteria, and to the best of our knowledge, there are no researches studied the Chinese eligibility criteria. Thus in this study, we aimed to explore the semantic categories of Chinese eligibility criteria. METHODS: We downloaded the clinical trials registration files from the website of Chinese Clinical Trial Registry (ChiCTR) and extracted both the Chinese eligibility criteria and corresponding English eligibility criteria. We represented the criteria sentences based on the Unified Medical Language System semantic types and conducted the hierarchical clustering algorithm for the induction of semantic categories. Furthermore, in order to explore the classification performance of Chinese eligibility criteria with our developed semantic categories, we implemented multiple classification algorithms, include four baseline machine learning algorithms (LR, NB, kNN, SVM), three deep learning algorithms (CNN, RNN, FastText) and two pre-trained language models (BERT, ERNIE). RESULTS: We totally developed 44 types of semantic categories, summarized 8 topic groups, and investigated the average incidence and prevalence in 272 hepatocellular carcinoma related Chinese clinical trials. Compared with the previous proposed categories in English eligibility criteria, 13 novel categories are identified in Chinese eligibility criteria. The classification result shows that most of semantic categories performed quite well, the pre-trained language model ERNIE achieved best performance with macro-average F1 score of 0.7980 and micro-average F1 score of 0.8484. CONCLUSION: As a pilot study of Chinese eligibility criteria analysis, we developed the 44 semantic categories by hierarchical clustering algorithms for the first times, and validated the classification capacity with multiple classification algorithms.

Postoperative or Salvage Proton Radiotherapy for Prostate Cancer After Radical Prostatectomy.

PURPOSE: Postprostatectomy radiation improves disease control, but limited data exist regarding outcomes, toxicities, and patient-reported quality of life with proton therapy. METHOD AND MATERIALS: The first 102 patients who were enrolled on an outcome tracking protocol between 2006 and 2017 and treated with double-scattered proton therapy after prostatectomy were retrospectively reviewed. Eleven (11%) received adjuvant radiation, while 91 (89%) received salvage radiation. Seventy-four received double-scattered proton therapy to the prostate bed only. Twenty-eight received a double-scattered proton therapy prostate-bed boost after prostate-bed and pelvic-node treatment. Eleven adjuvant patients received a median dose of 66.6 GyRBE (range, 66.0-70.2). Ninety-one salvage patients received a median dose of 70.2 GyRBE (range, 66.0-78.0). Forty-five patients received androgen deprivation therapy for a median 9 months (range, 1-30). Toxicities were scored using Common Terminology Criteria for Adverse Events v4.0 criteria, and patient-reported quality-of-life data were reviewed. RESULTS: The median follow-up was 5.5 years (range, 0.8-11.4 years). Five-year biochemical relapse-free and distant metastases-free survival rates were 72% and 91% for adjuvant patients, 57% and 97% for salvage patients, and 57% and 97% overall. Acute and late grade 3 or higher genitourinary toxicity rates were 1% and 7%. No patients had grade 3 or higher gastrointestinal toxicity. Acute and late grade 2 gastrointestinal toxicities were 5% and 2%. The mean values and SDs of the International Prostate Symptom Score, International Index of Erectile Function, and Expanded Prostate Cancer Index Composite bowel function and bother were 7.5 (SD = 5.9), 10.2 (SD = 8.3), 92.8 (SD = 11.1), and 91.2 (SD = 6.4), respectively, at baseline, and 12.1 (SD = 9.1), 10.1 (SD = 6.7), 87.3 (SD = 18), and 86.7 (SD = 13.8) at the 5-year follow-up. CONCLUSION: High-dose postprostatectomy proton therapy provides effective long-term biochemical control and freedom from metastasis, with low acute and long-term gastrointestinal and genitourinary toxicity.

Proton therapy delivery method affects dose-averaged linear energy transfer in patients.

The dosimetric advantages of proton therapy have led to its rapid proliferation in recent decades. This has been accompanied by a shift in technology from older units that deliver protons by passive scattering (PS) to newer units that increasingly use pencil-beam scanning (PBS). The biologic effectiveness of proton physical dose purportedly rises with increasing dose-weighted average linear energy transfer (LETD). The objective of this study was to determine the extent to which proton delivery methods affect LETD. We calculated LETDfrom simple, dosimetrically matched, and clinical treatment plans with TOPAS Monte-Carlo transport code. Simple treatment plans comprised single fields of PS and PBS protons in a water phantom. We performed simulations of matched and clinical treatment plans by using the treatment and anatomic data obtained from a cohort of children with craniopharyngioma who previously received PS or PBS proton therapy. We compared the distributions of LETDfrom PS and PBS delivery methods in clinically relevant ROIs. Wilcoxon signed-rank tests comparing single fields in water revealed that the LETDvalues from PBS were significantly greater than those from PS inside and outside the targeted volume (p < 0.01). Statistical tests comparing LETD-volume histograms from matched and clinical treatment plans showed that LETDwas generally greater for PBS treatment plans than for PS treatment plans (p < 0.05). In conclusion, the proton delivery method affects LETDboth inside and outside of the target volume. These findings suggest that PBS is more biologically effective than PS. Given the rapid expansion of PBS proton therapy, future studies are needed to confirm the applicability of treatment evaluation methods developed for PS proton therapy to those for modern PBS treatments to ensure their safety and effectiveness for the growing population of patients receiving proton therapy. This study uses data from two clinical trials: NCT01419067 and NCT02792582.

Image-Guided Hypofractionated Proton Therapy in Early-Stage Non-Small Cell Lung Cancer: A Phase 2 Study.

PURPOSE: Due to the excellent outcomes with image-guided stereotactic body radiotherapy for patients with early-stage non-small cell lung cancer (NSCLC) and the low treatment-related toxicities using proton therapy (PT), we investigated treatment outcomes and toxicities when delivering hypofractionated PT. MATERIALS AND METHODS: Between 2009 and 2018, 22 patients with T1 to T2 N0M0 NSCLC (45% T1, 55% T2) received image-guided hypofractionated PT. The median age at diagnosis was 72 years (range, 58-90). Patients underwent 4-dimensional computed tomography simulation following fiducial marker placement, and daily image guidance was performed. Nine patients (41%) were treated with 48 GyRBE in 4 fractions for peripheral lesions, and 13 patients (59%) were treated with 60 GyRBE in 10 fractions for central lesions. Patients were assessed for CTCAEv4 toxicities with computed tomography imaging for tumor assessment. The primary endpoint was grade 3 to 5 toxicity at 1 year. RESULTS: The median follow-up for all patients was 3.5 years (range, 0.2-8.8 years). The overall survival rates at 3 and 5 years were 81% and 49%, respectively. Cause-specific survival rates at 3 and 5 years were 100% and 75%, respectively. The 3-year local, regional, and distant control rates were 86%, 85%, and 95%, respectively. Four patients experienced in-field recurrences between 18 and 45 months after treatment. One patient (5%) developed a late grade 3 bronchial stricture requiring hospitalization and stent. CONCLUSION: Image-guided hypofractionated PT for early-stage NSCLC provides promising local control and long-term survival with a low likelihood of toxicity. Regional nodal and distant relapses remain a problem.

Multivariate normal tissue complication probability models for rectal and bladder morbidity in prostate cancer patients treated with proton therapy.

BACKGROUND AND PURPOSE: Normal tissue complication probability (NTCP) models applied for model-based patient selection to proton therapy (PT) have usually been derived using dose/volume histogram (DVH) parameters from photon-based radiotherapy. This study aimed to derive PT-specific multivariate NTCP models that also accounted for the spatial dose distribution (rectum only) as well as non-dose/volume related factors. MATERIALS AND METHODS: The study included rectum and bladder DVHs, 2D rectal dose maps and relevant patient/treatment characteristics from 1151 prostate cancer cases treated with PT. Prospectively scored Grade 2 late rectal bleeding (CTCAE v3.0, also procedural interventions separately) (n = 156 (15%)) and Grade 3+ GU morbidity (n = 51 (4%)) were entered into a multivariate logistic regression analysis. Model evaluation included assessment of the area under the receiver operating characteristic curve (AUC). RESULTS: Anticoagulant use was a dominant predictor, chosen in four of the six rectum models and in the bladder model. Age was a dominant predictor in all procedural only rectum models while prostate volume, bladder D5% and V75Gy were predictors in the bladder model. The selection frequency of the dose/volume predictors varied widely, where the percentage of the anterior rectum surface receiving >=75 Gy was the most robust. AUC values ranged from 0.58 to 0.70 across all models, with no clear difference between the DVH- and spatial-based models for the rectum. CONCLUSION: Anticoagulant use and age were the most prominent predictors in the NTCP models. V75Gy of the rectal wall and the bladder was a predictor in the DVH-based models of the rectum and bladder respectively.

A Beam-Angle-Selection Method to Improve Inter-Fraction Motion Robustness for Lung Tumor Irradiation With Passive Proton Scattering.

In terms of dose distribution, protons are more sensitive to range variations than photons due to their unique properties. The aim of this study was to develop a method to identify patient-specific robust proton beam angles for lung tumor irradiation by investigating the association between water equivalent thickness (WET) variation and inter-fraction motion-induced target dose degradation. Using 3-dimensional computed tomography (3D-CT) images, the impact of WET variations on the target dose coverage of a series of coplanar proton beams was evaluated for 4 patients with lung cancer. Using ray tracing, WET maps, or WET baseline, were estimated for the internal target volume (ITV) at every 5° gantry interval in the axial plane. After calculating the WET baseline, the planning CT was shifted 5 mm in each anterior-posterior (AP), superior-inferior (SI), and left-right (LR) direction, yielding a total of 6 shifted CTs, and differential WET maps between the planning CT and each shifted CT were calculated. Target dose differences were associated with the average WET change between the original planning CT and the shifted CTs for all 360° gantry rotation beams. Target and OAR dose metrics in the ΔWET-guided plans were compared with those of the clinical plans. The WET variation maps showed areas of both high and low WET variations, with overall similar patterns yet individual differences reflecting tumor position differences. For all 4 patients investigated in this study, the coplanar plans demonstrated a strong correlation between WET changes and ITV dose reductions. Target dose coverage was more stable with the ΔWET-guided plan while OAR doses were comparable to the clinical plan. The WET variation maps have been used in this pilot study to identify proton beam angles that are either sensitive or robust to WET changes in proton passive scattering. This work demonstrates the feasibility of using WET variation maps to assist the planner in inter-fraction motion-robust proton beam angle selection.