The Effects of Melatonin Administration on Intestinal Injury Caused by Abdominal Irradiation from Mice.

Intestinal injury caused by ionizing radiation (IR) is a main clinical issue for patients with cancer receiving abdominal or pelvic radiotherapy. Melatonin (N-acetyl-5-methoxytryptamine) is a neurohormone that the pineal gland in the brain normally secretes. The study aimed to disclose the potential function of melatonin in intestinal injury induced by IR and its mechanism. Pretreatment with melatonin enhanced the 30-day survival rate of the irradiated mice and promoted the recovery of the intestinal epithelium and hematopoietic function following abdominal irradiation (ABI). Melatonin altered the gene profile of the small intestines from mice following ABI. The enriched biological process terms for melatonin treatment prior to radiation were mainly involved in the immune process. LPS/IL-1-mediated inhibition of RXR Function, TWEAK signaling, and Toll-like receptor signaling were the most activated canonical pathways targeted by melatonin. An upstream analysis network showed that Tripartite motif-containing 24 (TRIM24) was the most significantly inhibited and S100 calcium binding protein A9 (S100A9) activated. TRIM24 activated atherogenesis and cell viability in breast cancer cell lines and S100A9 inhibited the metabolism of amino acids. Melatonin has radioprotective effects on ABI-caused intestinal injury. The mechanisms behind the beneficial effects of melatonin were involved in activation of the immunity. It is necessary to conduct further experiments to explore the underlying mechanisms.

Therapeutic radiation exposure of the abdomen during childhood induces chronic adipose tissue dysfunction.

BACKGROUNDChildhood cancer survivors who received abdominal radiotherapy (RT) or total body irradiation (TBI) are at increased risk for cardiometabolic disease, but the underlying mechanisms are unknown. We hypothesize that RT-induced adipose tissue dysfunction contributes to the development of cardiometabolic disease in the expanding population of childhood cancer survivors.METHODSWe performed clinical metabolic profiling of adult childhood cancer survivors previously exposed to TBI, abdominal RT, or chemotherapy alone, alongside a group of healthy controls. Study participants underwent abdominal s.c. adipose biopsies to obtain tissue for bulk RNA sequencing. Transcriptional signatures were analyzed using pathway and network analyses and cellular deconvolution.RESULTSIrradiated adipose tissue is characterized by a gene expression signature indicative of a complex macrophage expansion. This signature includes activation of the TREM2-TYROBP network, a pathway described in diseases of chronic tissue injury. Radiation exposure of adipose is further associated with dysregulated adipokine secretion, specifically a decrease in insulin-sensitizing adiponectin and an increase in insulin resistance-promoting plasminogen activator inhibitor-1. Accordingly, survivors exhibiting these changes have early signs of clinical metabolic derangement, such as increased fasting glucose and hemoglobin A1c.CONCLUSIONChildhood cancer survivors exposed to abdominal RT or TBI during treatment exhibit signs of chronic s.c. adipose tissue dysfunction, manifested as dysregulated adipokine secretion that may negatively impact their systemic metabolic health.FUNDINGThis study was supported by Rockefeller University Hospital; National Institute of General Medical Sciences (T32GM007739); National Center for Advancing Translational Sciences (UL1 TR001866); National Cancer Institute (P30CA008748); American Cancer Society (133831-CSDG-19-117-01-CPHPS); American Diabetes Association (1-17-ACE-17); and an anonymous donor (MSKCC).

Mitigation on bowel loops daily variations by 1.5-T MR-guided daily-adaptive SBRT for abdomino-pelvic lymph-nodal oligometastases.

PURPOSE: We report preliminary dosimetric data concerning the use of 1.5-T MR-guided daily-adaptive radiotherapy for abdomino-pelvic lymph-nodal oligometastases. We aimed to assess the impact of this technology on mitigating daily variations for both target coverage and organs-at-risk (OARs) sparing. METHODS: A total of 150 sessions for 30 oligometastases in 23 patients were analyzed. All patients were treated with MR-guided stereotactic body radiotherapy (SBRT) for a total dose of 35 Gy in five fractions. For each fraction, a quantitative analysis was performed for PTV volume, V35Gy and Dmean. Similarly, for OARs, we assessed daily variations of volume, Dmean, Dmax. Any potential statistically significant change between baseline planning and daily-adaptive sessions was assessed using the Wilcoxon signed-rank test, assuming a p value < 0.05 as significant. RESULTS: Average baseline PTV, bowel, bladder, and single intestinal loop volumes were respectively 8.9 cc (range 0.7-41.2 cc), 1176 cc (119-3654 cc), 95 cc (39.7-202.9 cc), 18.3 cc (9.1-37.7 cc). No significant volume variations were detected for PTV (p = 0.21) bowel (p = 0.36), bladder (p = 0.47), except for single intestinal loops, which resulted smaller (p = 0.026). Average baseline V35Gy and Dmean for PTV were respectively 85.6% (72-98.8%) and 35.6 Gy (34.6-36.1 Gy). We recorded a slightly positive trend in favor of daily-adaptive strategy vs baseline planning for improved target coverage, although not reaching statistical significance (p = 0.11 and p = 0.18 for PTV-V35Gy and PTV-Dmean). Concerning OARs, a significant difference was observed in favor of daily-adapted treatments in terms of single intestinal loop Dmax [23.05 Gy (13.2-26.9 Gy) at baseline vs 20.5 Gy (12.1-24 Gy); p value = 0.0377] and Dmean [14.4 Gy (6.5-18 Gy) at baseline vs 13.0 Gy (6.7-17.6 Gy); p value = 0.0003]. Specifically for bladder, the average Dmax was 18.6 Gy (0.4-34.3 Gy) at baseline vs 18.3 Gy (0.7-34.3 Gy) for a p value = 0.28; the average Dmean was 7.0 Gy (0.2-16.6 Gy) at baseline vs 6.98 Gy (0.2-16.4 Gy) for a p value = 0.66. Concerning the bowel, no differences in terms of Dmean [4.78 Gy (1.3-10.9 Gy) vs 5.6 Gy (1.4-10.5 Gy); p value = 0.23] were observed between after daily-adapted sessions. A statistically significant difference was observed for bowel Dmax [26.4 Gy (7.7-34 Gy) vs 25.8 Gy (7.8-33.1 Gy); p value = 0.0086]. CONCLUSIONS: Daily-adaptive MR-guided SBRT reported a significantly improved single intestinal loop sparing for lymph-nodal oligometastases. Also, bowel Dmax was significantly reduced with daily-adaptive strategy. A minor advantage was also reported in terms of PTV coverage, although not statistically significant.

A Machine Learning Model Approach to Risk-Stratify Patients With Gastrointestinal Cancer for Hospitalization and Mortality Outcomes.

PURPOSE: Patients with gastrointestinal (GI) cancer frequently experience unplanned hospitalizations, but predictive tools to identify high-risk patients are lacking. We developed a machine learning model to identify high-risk patients. METHODS AND MATERIALS: In the study, 1341 consecutive patients undergoing GI (abdominal or pelvic) radiation treatment (RT) from March 2016 to July 2018 (derivation) and July 2018 to January 2019 (validation) were assessed for unplanned hospitalizations within 30 days of finishing RT. In the derivation cohort of 663 abdominal and 427 pelvic RT patients, a machine learning approach derived random forest, gradient boosted decision tree, and logistic regression models to predict 30-day unplanned hospitalizations. Model performance was assessed using area under the receiver operating characteristic curve (AUC) and prospectively validated in 161 abdominal and 90 pelvic RT patients using Mann-Whitney rank-sum test. Highest quintile of risk for hospitalization was defined as "high-risk" and the remainder "low-risk." Hospitalizations for high- versus low-risk patients were compared using Pearson's χ2 test and survival using Kaplan-Meier log-rank test. RESULTS: Overall, 13% and 11% of patients receiving abdominal and pelvic RT experienced 30-day unplanned hospitalization. In the derivation phase, gradient boosted decision tree cross-validation yielded AUC = 0.823 (abdominal patients) and random forest yielded AUC = 0.776 (pelvic patients). In the validation phase, these models yielded AUC = 0.749 and 0.764, respectively (P < .001 and P = .002). Validation models discriminated high- versus low-risk patients: in abdominal RT patients, frequency of hospitalization was 39% versus 9% in high- versus low-risk groups (P < .001) and 6-month survival was 67% versus 92% (P = .001). In pelvic RT patients, frequency of hospitalization was 33% versus 8% (P = .002) and survival was 86% versus 92% (P = .15) in high- versus low-risk patients. CONCLUSIONS: In patients with GI cancer undergoing RT as part of multimodality treatment, machine learning models for 30-day unplanned hospitalization discriminated high- versus low-risk patients. Future applications will test utility of models to prompt interventions to decrease hospitalizations and adverse outcomes.

Intraindividual variation of dose parameters in oncologic CT imaging.

The objective of this study is to identify essential aspects influencing radiation dose in computed tomography [CT] of the chest, abdomen and pelvis by intraindividual comparison of imaging parameters and patient related factors. All patients receiving at least two consecutive CT examinations for tumor staging or follow-up within a period of 22 months were included in this retrospective study. Different CT dose estimates (computed tomography dose index [CTDIvol], dose length product [DLP], size-specific dose estimate [SSDE]) were correlated with patient's body mass index [BMI], scan length and technical parameters (tube current, tube voltage, pitch, noise level, level of iterative reconstruction). Repeated-measures-analysis was initiated with focus on response variables (CTDIvol, DLP, SSDE) and possible factors (age, BMI, noise, scan length, peak kilovoltage [kVp], tube current, pitch, adaptive statistical iterative reconstruction [ASIR]). A univariate-linear-mixed-model with repeated-measures-analysis followed by Bonferroni adjustments was used to find associations between CT imaging parameters, BMI and dose estimates followed by a subsequent multivariate-mixed-model with repeated-measures-analysis with Bonferroni adjustments for significant parameters. A p-value <0.05 was considered statistically significant. We found all dose estimates in all imaging regions were substantially affected by tube current. The iterative reconstruction significantly influenced all dose estimates in the thoracoabdominopelvic scans as well as DLP and SSDE in chest-CT. Pitch factor affected all dose parameters in the thoracoabdominopelvic CT group. These results provide further evidence that tube current has a pivotal role and potential in radiation dose management. The use of iterative reconstruction algorithms can substantially decrease radiation dose especially in thoracoabdominopelvic and chest-CT-scans. Pitch factor should be kept at a level of ≥1.0 in order to reduce radiation dose.

Utility of adjuvant whole abdominal radiation therapy in ovarian clear cell cancer (OCCC): a pragmatic cohort study of women with classic immuno-phenotypic signature.

BACKGROUND: To evaluate the initial experience and clinical utility of first-line adjuvant intensity-modulated whole abdominal radiation therapy (WART) in women with ovarian clear cell cancer (OCCC) referred to an academic center. METHODS: Progression-free and overall survival was analyzed in a pragmatic observational cohort study of histologically pure OCCC patients over-expressing HNF-1ß treated between 2013 and end-December 2018. An in-house intensity-modulated WART program was developed from a published pre-clinical model. Radiation dose-volume data was curated to American Association of Physics in Medicine (AAPM) Task Group 263 recommendations. A dedicated database prospectively recorded presenting characteristics and outcomes in a standardized fashion. RESULTS: Five women with FIGO (2018) stage IA to IIIA2 OCCC were treated with first-line WART. Median age was 58 years (range 47-68 years). At diagnosis CA-125 was elevated in 4 cases (median 56 kU/L: range 18.4-370 kU/L) before primary de-bulking surgery. Severe premorbid endometriosis was documented in 3 patients. At a median follow-up of 77 months (range 16-83 mo.), all patients remain alive and progression-free on clinical, biochemical (CA-125), and 18Fluoro-deoxyglucose (FDG) PET/CT re-evaluation. Late radiation toxicity was significant (G3) in 1 case who required a limited bowel resection and chronic nutritional support at 9 months post-WART; 2 further patients had asymptomatic (G2) osteoporotic fragility fractures of axial skeleton at 12 months post-radiation treated with anti-resorptive agents (denosumab). CONCLUSIONS: The clinical utility of intensity-modulated WART in OCCC over-expressing HNF-1ß was suggested in this small observational cohort study. The hypothesis that HNF-1ß is a portent of platinum-resistance and an important predictive biomarker in OCCC needs further confirmation. Curating multi-institutional cohort studies utilizing WART by means of "Big Data" may improve OCCC care standards in the future.

Radiation doses from head, neck, chest and abdominal CT examinations: an institutional dose report.

PURPOSE: We aimed to obtain typical values for head, neck, chest, and abdominal computed tomography (CT) examinations from routine patients in 2018, and to review our data with national and international diagnostic reference levels (DRLs). METHODS: Single-phase head, neck, chest, and abdominal CT scans of adults performed in 64-slice CT in 2018 were included in this study. Radiation dose parameters of CT scans were obtained from the picture archiving and communication system of our hospital. Volumetric CT dose index (CTDIvol) and dose length product (DLP) values were recorded. Effective dose (ED) and scan length was calculated. A 16 cm diameter phantom is referenced for head CT, and 32 cm diameter phantom is referenced for neck, chest, and abdominal CT. Descriptive statistics of the variables were given according to the normality testing. RESULTS: Median CTDIvol value was 53 mGy for the head, 13.1 mGy for the neck, 8.3 mGy for the chest, and 8.6 mGy for the abdomen. Median DLP value was 988 mGy.cm for the head, 299 mGy.cm for the neck, 314 mGy.cm for the chest, and 457 mGy.cm for the abdomen. Median ED value was 2.07 mSv for the head, 1.76 mSv for the neck, 4.4 mSv for the chest, and 6.8 mSv for the abdomen. Considering national DRLs, median CTDIvol values of head, chest, and abdomen were lower, whereas median DLP and ED values of head and chest were higher. For the abdomen, the median DLP and ED values were lower. CONCLUSION: Overall radiation dose parameters obtained in this study points out the need for optimization of head CT examinations in our institution.

Dietary Methionine Supplementation Exacerbates Gastrointestinal Toxicity in a Mouse Model of Abdominal Irradiation.

BACKGROUND AND PURPOSE: Identification of appropriate dietary strategies for prevention of weight and muscle loss in cancer patients is crucial for successful treatment and prolonged patient survival. High-protein oral nutritional supplements decrease mortality and improve indices of nutritional status in cancer patients; however, high-protein diets are often rich in methionine, and experimental evidence indicates that a methionine-supplemented diet (MSD) exacerbates gastrointestinal toxicity after total body irradiation. Here, we sought to investigate whether MSD can exacerbate gastrointestinal toxicity after local abdominal irradiation, an exposure regimen more relevant to clinical settings. MATERIALS AND METHODS: Male CBA/CaJ mice fed either a methionine-adequate diet or MSD (6.5 mg methionine/kg diet vs 19.5 mg/kg) received localized abdominal X-irradiation (220 kV, 13 mA) using the Small Animal Radiation Research Platform, and tissues were harvested 4, 7, and 10 days after irradiation. RESULTS: MSD exacerbated gastrointestinal toxicity after local abdominal irradiation with 12.5 Gy. This was evident as impaired nutrient absorption was paralleled by reduced body weight recovery. Mechanistically, significant shifts in the gut ecology, evident as decreased microbiome diversity, and substantially increased bacterial species that belong to the genus Bacteroides triggered proinflammatory responses. The latter were evident as increases in circulating neutrophils with corresponding decreases in lymphocytes and associated molecular alterations, exhibited as increases in mRNA levels of proinflammatory genes Icam1, Casp1, Cd14, and Myd88. Altered expression of the tight junction-related proteins Cldn2, Cldn5, and Cldn6 indicated a possible increase in intestinal permeability and bacterial translocation to the liver. CONCLUSIONS: We report that dietary supplementation with methionine exacerbates gastrointestinal syndrome in locally irradiated mice. This study demonstrates the important roles registered dieticians should play in clinical oncology and further underlines the necessity of preclinical and clinical investigations in the role of diet in the success of cancer therapy.

The Impact of Radiation Energy on Dose Homogeneity and Organ Dose in the Göttingen Minipig Total-Body Irradiation Model.

Animal models of total-body irradiation (TBI) are used to elucidate normal tissue damage and evaluate the efficacy of medical countermeasures (MCM). The accuracy of these TBI models depends on the reproducibility of the radiation dose-response relationship for lethality, which in turn is highly dependent on robust radiation physics and dosimetry. However, the precise levels of radiation each organ absorbs can change dramatically when different photon beam qualities are used, due to the interplay between their penetration and the natural variation of animal sizes and geometries. In this study, we evaluate the effect of varying the radiation energy, namely cobalt-60 (Co-60); of similar penetration to a 4-MV polyenergetic beam), 6 MV and 15 MV, in the absorbed dose delivered by TBI to individual organs of eight Göttingen minipigs of varying weights (10.3-24.1 kg) and dimensions (17.5-25 cm width). The main organs, i.e. heart, lungs, esophagus, stomach, bowels, liver, kidneys and bladder, were contoured by an experienced radiation oncologist, and the volumetric radiation dose distribution was calculated using a commercial treatment planning system commissioned and validated for Co-60, 6-MV and 15-MV teletherapy units. The dose is normalized to the intended prescription at midline in the abdomen. For each animal and each energy, the body and organ dose volume histograms (DVHs) were computed. The results show that more penetrating photon energies produce dose distributions that are systematically and consistently more homogeneous and more uniform, both within individual organs and between different organs, across all animals. Thoracic organs (lungs, heart) received higher dose than prescribed while pelvic organs (bowel, bladder) received less dose than prescribed, due to smaller and wider separations, respectively. While these trends were slightly more pronounced in the smallest animals (10.3 kg, 19 cm abdominal width) and largest animals (>20 kg, ∼25 cm abdominal width), they were observed in all animals, including those in the 9-15 kg range typically used in MCM models. Some organs received an average absorbed dose representing <80% of prescribed dose when Co-60 was used, whereas all organs received average doses of >87% and >93% when 6 and 15 MV were used, respectively. Similarly, average dose to the thoracic organs reached as high as 125% of the intended dose with Co-60, compared to 115% for 15 MV. These results indicate that Co-60 consistently produces less uniform dose distributions in the Göttingen minipig compared to 6 and 15 MV. Moreover, heterogeneity of dose distributions for Co-60 is accentuated by anatomical and geometrical variations across various animals, leading to different absorbed dose delivered to organs for different animals. This difference in absorbed radiation organ doses, likely caused by the lower penetration of Co-60 and 6 MV compared to 15 MV, could potentially lead to different biological outcomes. While the link between the dose distribution and variation of biological outcome in the Göttingen minipig has never been explicitly studied, more pronounced dose heterogeneity within and between organs treated with Co-60 teletherapy units represents an additional confounding factor which can be easily mitigated by using a more penetrating energy.

Size-Specific Dose Estimates of Radiation Based on Body Weight and Body Mass Index for Chest and Abdomen-Pelvic CTs.

BACKGROUND: To correlate body weight, body mass index (BMI), and water-equivalent diameter (d w) and to assess size-specific dose estimates (SSDEs) based on body weight and BMI for chest and abdomen-pelvic CT examinations. METHODS: An in-house program was used to calculate d w, size-dependent conversion factor (f), and SSDE for 1178 consecutive patients undergoing chest and abdomen-pelvic CT examinations. Associations among body weight, BMI, and d w were determined, and linear equations were generated using linear regression analysis of the first 50% of the patient population. SSDEs (SSDEweight and SSDEBMI) were calculated based on body weight and BMI as d w surrogates on the second 50% of the patient population. Mean root-mean-square errors of SSDEweight and SSDEBMI were computed with SSDE from the axial images as reference values. RESULTS: Both body weight and BMI correlated strongly with d w for the chest (r = 0.85, 0.87, all p < 0.001) and abdomen-pelvis (r = 0.85, 0.86, all p < 0.001). Mean values of SSDEweight and SSDEBMI based on the linear equations for body weight, BMI, and d w were in close agreement with SSDE from the axial images, with overall mean root-mean-square errors of 0.62 mGy (6.10%) and 0.57 mGy (5.65%), for chest, and 0.76 mGy (5.61%) and 0.71 mGy (5.22%), for abdomen-pelvis, respectively. CONCLUSIONS: Both body weight and BMI, serving as d w surrogates, can be used to calculate SSDEs in the chest and abdomen-pelvis CT examinations, providing values comparable to SSDEs from the axial images, with an overall mean root-mean-square error of less than 0.76 mGy or 6.10%.

Feasibility and safety of 1.5 T MR-guided and daily adapted abdominal-pelvic SBRT for elderly cancer patients: geriatric assessment tools and preliminary patient-reported outcomes.

BACKGROUND: We present preliminary data of the first older cancer patients treated with Hybrid Linac for stereotactic body radiotherapy (SBRT) consisting of 1.5 T MRI-guided and daily-adapted treatment. The aim was to assess feasibility, safety and the role of G8 and Charlson Comorbidity Index (CCI) questionnaires in predicting patients' QoL, evaluated by patient-reported outcome measures (PROMs). METHODS: Two groups of patients with localized prostate cancer or abdominal-pelvic oligometastases were analyzed. SBRT schedule consisted of 35 Gy delivered in 5 fractions. The primary endpoint was to measure the impact of G8 and CCI on PROMs. Both G8 and the CCI were performed at baseline, while the EORTC Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) for PROMs assessment was prospectively performed at baseline and after SBRT. RESULTS: Forty older patients were analyzed. The median age was 73 years (range 65-85). For the entire population, the median G8 score was 15 (10-17) and the median CCI score was 6 (4-11). Concerning the PROMS, the EORTC-QLQ C30 questionnaire reported no difference between the pre- and post-SBRT evaluation in all patients, except for the fatigue item that declined after SBRT, especially in the group of patients with a G8 score < 15 and with age < 75 years (p = 0.049). No grade 3 or higher acute toxicity occurred. CONCLUSION: This is the first report documenting for older cancer patients that 1.5 T MRI-guided daily-adapted SBRT is feasible, safe and does not impact on the QoL at the end of treatment. Longer follow-up is advocated to report long-term outcomes. TRIAL REGISTRATION: Date of approval April 2019 and numbered MRI/LINAC no. 23748.

Design, Implementation, and in Vivo Validation of a Novel Proton FLASH Radiation Therapy System.

PURPOSE: Recent studies suggest that ultrahigh-dose-rate, "FLASH," electron radiation therapy (RT) decreases normal tissue damage while maintaining tumor response compared with conventional dose rate RT. Here, we describe a novel RT apparatus that delivers FLASH proton RT (PRT) using double scattered protons with computed tomography guidance and provide the first report of proton FLASH RT-mediated normal tissue radioprotection. METHODS AND MATERIALS: Absolute dose was measured at multiple depths in solid water and validated against an absolute integral charge measurement using a Faraday cup. Real-time dose rate was obtained using a NaI detector to measure prompt gamma rays. The effect of FLASH versus standard dose rate PRT on tumors and normal tissues was measured using pancreatic flank tumors (MH641905) derived from the KPC autochthonous PanCa model in syngeneic C57BL/6J mice with analysis of fibrosis and stem cell repopulation in small intestine after abdominal irradiation. RESULTS: The double scattering and collimation apparatus was dosimetrically validated with dose rates of 78 ± 9 Gy per second and 0.9 ± 0.08 Gy per second for the FLASH and standard PRT. Whole abdominal FLASH PRT at 15 Gy significantly reduced the loss of proliferating cells in intestinal crypts compared with standard PRT. Studies with local intestinal irradiation at 18 Gy revealed a reduction to near baseline levels of intestinal fibrosis for FLASH-PRT compared with standard PRT. Despite this difference, FLASH-PRT did not demonstrate tumor radioprotection in MH641905 pancreatic cancer flank tumors after 12 or 18 Gy irradiation. CONCLUSIONS: We have designed and dosimetrically validated a FLASH-PRT system with accurate control of beam flux on a millisecond time scale and online monitoring of the integral and dose delivery time structure. Using this system, we found that FLASH-PRT decreases acute cell loss and late fibrosis after whole-abdomen and focal intestinal RT, whereas tumor growth inhibition is preserved between the 2 modalities.

MRI-Based Upper Abdominal Organs-at-Risk Atlas for Radiation Oncology.

PURPOSE: The purpose of our study was to provide a guide for identification and contouring of upper abdominal organs-at-risk (OARs) in the setting of online magnetic resonance imaging (MRI)-guided radiation treatment planning and delivery. METHODS AND MATERIALS: After a needs assessment survey, it was determined that an upper abdominal MRI-based atlas of normal OARs would be of benefit to radiation oncologists and radiation therapists. An anonymized diagnostic 1.5T MRI from a patient with typical upper abdominal anatomy was used for atlas development. Two MRI sequences were selected for contouring, a T1-weighted gadoxetic acid contrast-enhanced MRI acquired in the hepatobiliary phase and axial fast imaging with balanced steady-state precession. Two additional clinical MRI sequences from commercial online MRI-guided radiation therapy systems were selected for contouring and were included in the final atlas. Contours from each data set were completed and reviewed by radiation oncologists, along with a radiologist who specializes in upper abdominal imaging, to generate a consensus upper abdominal MRI-based OAR atlas. RESULTS: A normal OAR atlas was developed, including recommendations for contouring. The atlas and contouring guidance are described, and high-resolution MRI images and contours are displayed. OARs, such as the bile duct and biliary tree, which may be better seen on MRI than on computed tomography, are highlighted. The full DICOM/DICOM-RT MRI images from both the diagnostic and clinical online MRI-guided radiation therapy systems data sets have been made freely available, for educational purposes, at econtour.org. CONCLUSIONS: This MRI contouring atlas for upper abdominal OARs should provide a useful reference for contouring and education. Its routine use may help to improve uniformity in contouring in radiation oncology planning and OAR dose calculation. Full DICOM/DICOM-RT images are available online and provide a valuable educational resource for upper abdominal MRI-based radiation therapy planning and delivery.

Machine Learning Techniques Applied to Dose Prediction in Computed Tomography Tests.

Increasingly more patients exposed to radiation from computed axial tomography (CT) will have a greater risk of developing tumors or cancer that are caused by cell mutation in the future. A minor dose level would decrease the number of these possible cases. However, this framework can result in medical specialists (radiologists) not being able to detect anomalies or lesions. This work explores a way of addressing these concerns, achieving the reduction of unnecessary radiation without compromising the diagnosis. We contribute with a novel methodology in the CT area to predict the precise radiation that a patient should be given to accomplish this goal. Specifically, from a real dataset composed of the dose data of over fifty thousand patients that have been classified into standardized protocols (skull, abdomen, thorax, pelvis, etc.), we eliminate atypical information (outliers), to later generate regression curves employing diverse well-known Machine Learning techniques. As a result, we have chosen the best analytical technique per protocol; a selection that was thoroughly carried out according to traditional dosimetry parameters to accurately quantify the dose level that the radiologist should apply in each CT test.

Adjuvant intensity modulated whole-abdominal radiation therapy for high-risk patients with ovarian cancer FIGO stage III: final results of a prospective phase 2 study.

BACKGROUND: To assess late toxicity, quality of life and oncological outcome after consolidative whole abdominal radiotherapy (WART) following cytoreductive surgery and carboplatin/paclitaxel chemotherapy in high risk patients with advanced ovarian cancer FIGO stage III using IMRT (Intensity modulated radiation therapy). METHODS: The OVAR-IMRT-02 study is a multi-center single-arm phase-II-trial. Twenty patients with optimally debulked ovarian cancer stage FIGO III with complete remission after chemotherapy were treated with intensity modulated WART. A total dose of 30 Gy in 20 fractions was applied to the entire peritoneal cavity. Primary endpoint was treatment tolerability; secondary objectives were acute and chronic toxicities, quality of life, rates of therapy disruption/abortion, progression-free survival (PFS) and overall survival (OS). RESULTS: All patients completed treatment and 10/20 patients (50%) reached the final study follow-up of 36 months. Late side effects consisted of °1-°2 lower limb edema (44.5%), with one patient (5.6%) showing °3 edema. Three patients (16.7%) showed elevated gamma-Glutamyltransferase. There were no severe late side effects regarding renal or hepatic function or any gastrointestinal toxicity greater than °2. During WART, mean global health status decreased by 18.1 points (95%-CI: 7.1-29.0), but completely normalized after 6 months. The same trend was observed for the function scale scores. Kaplan-Meier-estimated 1-, 2- and 3-year PFS was 74, 51 and 40%, respectively. 1-, 2- and 3-year OS was 89, 83 and 83%, respectively. CONCLUSIONS: Intensity modulated WART after aggressive surgery and carboplatin/paclitaxel chemotherapy is associated with an acceptable risk of acute and late toxicity and minor impact on long-term quality of life. Together with the promising results for PFS and OS, intensity modulated WART could offer a new therapeutic option for consolidation treatment of patients with advanced ovarian cancer. TRIAL REGISTRATION: The study is registered with ClinicalTrials.gov ( NCT01180504 ). Registered 12 August 2010 - retrospectively registered.

Ultrasound-based repositioning and real-time monitoring for abdominal SBRT in DIBH.

AIM: Ultrasound-based repositioning and real-time-monitoring aim at the improvement of the precision of SBRT in deep inspiration breath-hold (DIBH). Accuracy of ultrasound-based daily repositioning was estimated by comparison with DIBH-cone-beam-CT. Intrafraction motion during beam-delivery was assessed by ultrasound-real-time-monitoring. PATIENTS/METHODS: Residual error after ultrasound-based interfractional repositioning (85 fractions, 16 SBRT-series; 14 patients) was assessed by marker-based (7 series) or liver-contour-based (9 series) matching in DIBH-CBCT. During beam-delivery, the percentage of 3D misalignment vector below 2 mm, between 2 and 5 mm, 5-7 mm and over 7 mm was estimated. Percentage of relevant target-displacements was analyzed as a function of DIBH-duration. RESULTS: Residual error after ultrasound-based positioning was 0.4 ±â€¯3.3 mm in LR (left-right), 0.2 ±â€¯4.3 mm in CC (cranio-caudal) and 1.0 ±â€¯3.0 mm in AP (anterior-posterior) directions (vector magnitude 5.4 ±â€¯3.3 mm, MV ±â€¯SD). Over 544 DIBHs, target displacement was 1.3 ±â€¯0.5 mm, 0.7 ±â€¯0.3 mm, 1.6 ±â€¯0.6 mm for CC, LR and AP directions, respectively (3D-vector 2.5 ±â€¯0.7 mm). 3D misalignment vector length was below 2 mm in 49.8%, between 2 and 7 mm in 46.3%, and over 7 mm in 3.9% of the beam-delivery-time. During the first 5 s of the DIBH, 3D-misalignment vector length was always below 10 mm. Percentage of target displacements over 10 mm was 0.2%, 0.5% and 0.8% for 10 s, 15 s and 20 s DIBH-duration. CONCLUSIONS: Ultrasound-based interfractional repositioning is an accurate method for daily localization of abdominal DIBH-SBRT targets. Residual motion is <7 mm in 96% of the beam-delivery-time. Deviations >10 mm occur rarely and can be avoided by gating the beam at a predefined threshold. Ideal DIBH-duration should not exceed 15 s.

2D ultrasound imaging based intra-fraction respiratory motion tracking for abdominal radiation therapy using machine learning.

We have previously developed a robotic ultrasound imaging system for motion monitoring in abdominal radiation therapy. Owing to the slow speed of ultrasound image processing, our previous system could only track abdominal motions under breath-hold. To overcome this limitation, a novel 2D-based image processing method for tracking intra-fraction respiratory motion is proposed. Fifty-seven different anatomical features acquired from 27 sets of 2D ultrasound sequences were used in this study. Three 2D ultrasound sequences were acquired with the robotic ultrasound system from three healthy volunteers. The remaining datasets were provided by the 2015 MICCAI Challenge on Liver Ultrasound Tracking. All datasets were preprocessed to extract the feature point, and a patient-specific motion pattern was extracted by principal component analysis and slow feature analysis (SFA). The tracking finds the most similar frame (or indexed frame) by a k-dimensional-tree-based nearest neighbor search for estimating the tracked object location. A template image was updated dynamically through the indexed frame to perform a fast template matching (TM) within a learned smaller search region on the incoming frame. The mean tracking error between manually annotated landmarks and the location extracted from the indexed training frame is 1.80 ± 1.42 mm. Adding a fast TM procedure within a small search region reduces the mean tracking error to 1.14 ± 1.16 mm. The tracking time per frame is 15 ms, which is well below the frame acquisition time. Furthermore, the anatomical reproducibility was measured by analyzing the location's anatomical landmark relative to the probe; the position-controlled probe has better reproducibility and yields a smaller mean error across all three volunteer cases, compared to the force-controlled probe (2.69 versus 11.20 mm in the superior-inferior direction and 1.19 versus 8.21 mm in the anterior-posterior direction). Our method reduces the processing time for tracking respiratory motion significantly, which can reduce the delivery uncertainty.

Whole abdominopelvic intensity-modulated radiation therapy for peritoneal disseminated rhabdomyosarcoma with three-year follow-up: a case report.

BACKGROUND: The role of local radiotherapy in the treatment of metastatic rhabdomyosarcoma is important. However, with peritoneal dissemination, the application of local therapy is challenging. Although there are few reports addressing the efficacy of the whole abdominopelvic irradiation to peritoneal disseminated rhabdomyosarcoma patients, no precise curse of treatment nor the follow up result is explained in paper nor in the text. CASE PRESENTATION: Six years old rhabdomyosarcoma boy with peritoneal dissemination was treated at our facility under COG D9803 protocol (vincristine, dactinomycin, and cyclophosphamide (VAC)). He underwent tumor resection on the 14th week according to the protocol. During surgery, the 2-cm residual tumor was completely resected, but in the pelvis, numerous nodules that were suspected as peritoneal disseminated tumors were observed. We administered 30 Gy/20fr whole abdominopelvic radiotherapy using volumetric modulated arc therapy (VMAT) technique and a 6 Gy sequential boost to pelvis after the surgery and completed the protocol treatment. During the course of treatment, the patient experienced G4 hematological toxicity and received multiple transfusions, particularly after whole abdominopelvic irradiation. He has achieved complete remission and is alive without evidence of recurrence and severe late adverse effect for 3 years. In terms of growth, his height and weight are within the average values for Japanese boys at the same age. CONCLUSION: By using the VMAT technique, a patient with peritoneal disseminated rhabdomyosarcoma can be treated, and a dose of 30 Gy to the whole abdominopelvis with concurrent chemotherapy may be tolerable.

Texture-based, automatic contour validation for online adaptive replanning: A feasibility study on abdominal organs.

PURPOSE: Evaluation of contour accuracy in radiation therapy planning requires manual interaction and is one of the most limiting bottlenecks for online replanning. This study aims to develop an automatic approach to rapidly evaluate contour quality based on image texture features to facilitate the routine practice of online adaptive replanning (OLAR). METHOD: Fifty-five pancreas cancer patients were selected from a clinical database of patients treated at our institution from 2011 to 2018. For each patient, the pancreas head and duodenum were contoured in five images (one fraction per week) resulting in a total of 275 CT image sets with corresponding ground-truth contours. A second set of inaccurate contours was generated using deformable-image-registration-based contour propagation. Three subregions, core, inner shell and outer shell, were generated from the contour of each organ. Texture features were extracted from each subregion and descriptive features of each subregion were identified using the image set with corresponding ground-truth contours. A three-level decision tree model was constructed based on texture constraints empirically determined for the three subregions. The two datasets containing ground truth and inaccurate contours were merged. Randomized threefold cross-validation was performed and repeated three times. RESULTS: The first level of the decision tree utilizes textures derived from principal component analysis of a subset of extracted features from the core subregion (five PCs for pancreas head, seven PCs for duodenum). The second and third levels of the decision tree use gray-level co-occurrence matrix (GLCM)-based cluster prominence to reject inaccurate contours. The trained model identifies accurate and inaccurate contours with an average sensitivity/specificity of 85%/91% for the pancreas head and 92%/92% for the duodenum contours. The false-positive rate is 9% and 8% for pancreas head and duodenum, respectively. The execution time is less than 15 s using a standard desktop computer. CONCLUSION: Quantitative image features can be used to develop a model to rapidly validate the quality of an organ contour. Our model accurately classifies unseen contours as accurate or inaccurate with high sensitivity and specificity. As auto-segmentation continues to improve in quality and accuracy, this method may be integrated into a fully automatic pipeline for auto-segmentation, contour-quality evaluation and contour correction, which would replace the time-consuming manual review process, thereby facilitating the more routine practice of OLAR.