Abdominal Irradiation Research Articles

Trichostatin A mitigates acute and late effects of radiation in intestine by regulation of DNA damage repair and Wnt/TGFβ/Smad signaling

Purpose Radiation accidents and misuse of nuclear weapons elevate the risk of development of acute life-threatening injuries as well as their late effects are noted in survivors. Currently, no countermeasure agents are available for the management of radiation-induced GI injury (RIGI) in humans. In the present study, the radiomitigative potential of Trichostatin A (TSA) was evaluated against acute and late RIGI. Methods 15 Gy gamma radiation was delivered to the whole abdomen of C57BL/6 mice, followed by intravenous TSA (150 ng/kg) administration after 1 h and 24 h. Acute changes were checked 24 h and 3.5 days post irradiation. Mice were monitored for development of fibrosis, survival for 1 year and alteration in different signaling pathways. Result 15 Gy abdominal irradiation activated the DNA damage marker (γ-H2AX) by nearly 3.2 ± 0.29 fold and regulated the repair proteins, XRCC1 and PARP1 in the intestine, which was differentially regulated by TSA. The Wnt signaling pathway and stem cell proliferation in the intestine were also positively regulated by TSA. The TSA administered mice demonstrated improved intestinal morphology. 12.5% of TSA administered mice survived upto 1 year whereas 100% of 15 Gy exposed mice died by 6 months. The surviving mice that had received TSA showed reduced intestinal fibrosis than 15 Gy group, possibly via downregulation of TGFβ/Smad signaling. Conclusion The findings suggest that TSA have the potential to mitigate both acute and late effects of radiation in the intestine and can be explored as promising agent in the management of RIGI.

Deep learning based ultra-low dose fan-beam computed tomography image enhancement algorithm: Feasibility study in image quality for radiotherapy.

We investigated the feasibility of deep learning-based ultra-low dose kV-fan-beam computed tomography (kV-FBCT) image enhancement algorithm for clinical application in abdominal and pelvic tumor radiotherapy. A total of 76 patients of abdominal and pelvic tumors were prospectively selected. The Catphan504 was acquired with the same conditions as the standard phantom test set. We used a CycleGAN-based model for image enhancement. Normal dose CT (NDCT), ultra-low dose CT (LDCT) and deep learning enhanced CT (DLR) were evaluated by subjective and objective analyses in terms of imaging quality, HU accuracy, and image signal-to-noise ratio (SNR). The image noise of DLR was significantly reduced, and the contrast-to-noise ratio (CNR) was significantly improved compared to the LDCT. The most significant improvement was the acrylic which represented soft tissue in CNR from 1.89 to 3.37, improving by 76%, nearly approaching the NDCT, and in low-density resolution from 7.64 to 12.6, improving by 64%. The spatial frequencies of MTF10 and MTF50 in DLR were 4.28 and 2.35 cycles/mm in DLR, respectively, which are higher than LDCT 3.87 and 2.12 cycles/mm, and even slightly higher than NDCT 4.15 and 2.28 cycles/mm. The accuracy and stability of HU values of DLR were similar to NDCT. The image quality evaluation of the two doctors agreed well with DLR and NDCT. A two-by-two comparison between groups showed that the differences in image scores of LDCT compared with NDCT and DLR were all statistically significant (p<0.05), and the subjective scores of DLR were close to NDCT. The image quality of DLR was close to NDCT with reduced radiation dose, which can fully meet the needs of conventional image-guided adaptive radiotherapy (ART) and achieve the quality requirements of clinical radiotherapy. The proposed method provided a technical basis for LDCT-guided ART.

USP15 regulates radiation-induced DNA damage and intestinal injury through K48-linked deubiquitination and stabilisation of ATM

BackgroundRadiation-induced intestinal injury (RIII) interrupts the scheduled processes of abdominal and pelvic radiotherapy (RT) and compromises the quality of life of cancer survivors. However, the specific regulators and mechanisms underlying the effects of RIII remain unknown. The biological effects of RT are caused primarily by DNA damage, and ataxia telangiectasia mutated (ATM) is a core protein of the DNA damage response (DDR). However, whether ATM is regulated by deubiquitination signaling remains unclear.MethodsWe established animal and cellular models of RIII. The effects of ubiquitin-specific protease 15 (USP15) on DNA damage and radion-induced intestinal injury were evaluated. Mass spectrometry analysis, truncation tests, and immunoprecipitation were used to identify USP15 as a binding partner of ATM and to investigate the ubiquitination of ATM. Finally, the relationship between the USP15/ATM axes was further determined via subsequent experiments.ResultsIn this study, we identified the deubiquitylating enzyme USP15 as a regulator of DNA damage and the pathological progression of RIII. Irradiation upregulates the expression of USP15, whereas pharmacological inhibition of USP15 exacerbates radiation-induced DNA damage and RIII both in vivo and in vitro. Mechanistically, USP15 interacts with, deubiquitinates, and stabilises ATM via K48-linked deubiquitination. Notably, ATM overexpression blocks the effect of USP15 genetic inhibition on DNA damage and RIII progression.ConclusionsThese findings describe ATM as a novel deubiquitination target of USP15 upon radiation-induced DNA damage and intestinal injury, and provides experimental support for USP15/ATM axis as a potential target for developing strategies that mitigate RIII.

Daily Diagnostic Quality Computed Tomography-on-Rails (CTOR) Image Guidance for Abdominal Stereotactic Body Radiation Therapy (SBRT).

Stereotactic body radiation therapy (SBRT) for abdominal targets faces a variety of challenges, including motion caused by the respiration and digestion and a relatively poor level of contrast between the tumor and the surrounding tissues. Breath-hold treatments with computed tomography-on-rails (CTOR) image guidance is one way of addressing these challenges, allowing for both the tumor and normal tissues to be well-visualized. Using isodose lines (IDLs) from CT simulations as a guide, the anatomical information can be used to shift the alignment or trigger a replan, such that normal tissues receive acceptable doses of radiation. This study aims to describe the workflow involved when using CTOR for pancreas and liver SBRT and demonstrates its effectiveness through several case studies. In these case studies, using the anatomical information gained through diagnostic-quality CT guidance to make slight adjustments to the alignment, resulted in reductions in the maximum dose to the stomach. High-quality imaging, such as CTOR, and the use of IDLs to estimate the doses to OARs, enable the safe delivery of SBRT, without the added complexity and resource commitment required by daily online adaptive planning.

Rectal Epithelial Stem Cell Kinetics in Acute Radiation Proctitis

The intestinal tract is a typical radiosensitive tissue, and radiation rectal injury is a severe side effect that limits the prescribed dose in radiotherapy of the abdominal and pelvic region. Understanding the post-irradiation kinetics of Lgr5-positive stem cells is crucial in comprehending this adverse process. In this study, we utilized Lgr5-EGFP knock-in mice expressing EGFP and LGR5 antibody fluorescence staining of wild-type mice. At the state of radiation injury, the qPCR analysis showed a significant decrease in the expression level of Lgr5 in the rectal epithelial tissue. The dose-response relationship analysis showed that at low to moderate doses up to 10 gray (Gy), Lgr5-clustered populations were observed at the base of the crypt, whereas at sublethal doses (20 Gy and 29 Gy), the cells exhibited a dot-like scatter pattern, termed Lgr5-dotted populations. During recovery, 30 days post-irradiation, Lgr5-clustered populations gradually re-emerged while Lgr5-dotted populations declined, implying that some of the Lgr5-dotted stem cell populations re-clustered, aiding regenerations. Based on statistical analysis of the dose-response relationship using wild-type mice, the threshold dose for destroying these stem cell structures is 18 Gy. These findings may help set doses in mouse abdominal irradiation experiments for radiation intestinal injury and for understanding the histological process of injury development.

Vasoactive intestinal peptide promotes secretory differentiation and mitigates radiation-induced intestinal injury

BackgroundVasoactive intestinal peptide (VIP) is a neuronal peptide with prominent distribution along the enteric nervous system. While effects of VIP on intestinal motility, mucosal vasodilation, secretion, and mucosal immune cell function are well-studied, the direct impact of VIP on intestinal epithelial cell turnover and differentiation remains less understood. Intestinal stem and progenitor cells are essential for the maintenance of intestinal homeostasis and regeneration, and their functions can be modulated by factors of the stem cell niche, including neuronal mediators. Here, we investigated the role of VIP in regulating intestinal epithelial homeostasis and regeneration following irradiation-induced injury.MethodsJejunal organoids were derived from male and female C57Bl6/J, Lgr5-EGFP-IRES-CreERT2 or Lgr5-EGFP-IRES-CreERT2/R26R-LSL-TdTomato mice and treated with VIP prior to analysis. Injury conditions were induced by exposing organoids to 6 Gy of irradiation (IR). To investigate protective effects of VIP in vivo, mice received 12 Gy of abdominal IR followed by intraperitoneal injections of VIP.ResultsWe observed that VIP promotes epithelial differentiation towards a secretory phenotype predominantly via the p38 MAPK pathway. Moreover, VIP prominently modulated epithelial proliferation as well as the number and proliferative activity of Lgr5-EGFP+ progenitor cells under homeostatic conditions. In the context of acute irradiation injury in vitro, we observed that IR injury renders Lgr5-EGFP+ progenitor cells more susceptible to VIP-induced modulations, which coincided with the strong promotion of epithelial regeneration by VIP. Finally, the observed effects translate into an in vivo model of abdominal irradiation, where VIP showed to prominently mitigate radiation-induced injury.ConclusionsVIP prominently governs intestinal homeostasis by regulating epithelial progenitor cell proliferation and differentiation and promotes intestinal regeneration following acute irradiation injury.

6471 Adult Height in Male Survivors of Childhood Cancer Treated with Aromatase Inhibitors and Growth Hormone

Abstract Disclosure: N.I. Pollock: None. M. Song: None. A. Wolf: None. Y. Li: None. C. Hawkes: None. N. Motamedi: None. M.R. Denburg: None. S. Mostoufi-Moab: None. Title: Adult Height in Male Survivors of Childhood Cancer Treated with Aromatase Inhibitors and Growth Hormone Objectives: Aromatase inhibitor (AI) therapy in combination with growth hormone (GH), or as monotherapy, may have a role in improving height outcomes in male pediatric patients with GH deficiency (GHD). The effectiveness of AI therapy in the childhood cancer survivors is not known. In this retrospective study, we assess adult height (AH) in childhood cancer survivors treated with AI combined with GH therapy compared to those treated with GH alone. Methods: This was a single center retrospective cohort study of male survivors of childhood cancer treated with GH for diagnosis of GHD between 2007 and 2023. We compared AH outcomes in males treated with GH alone or in combination with off-label use of AI. Demographic and clinical characteristics, including anthropometric measurements, endocrinopathies, and cancer history, were obtained from the medical record. AH was noted as height documented at fusion of growth plates or following 18 years of age. Differences in demographic, clinical, and treatment characteristics were assessed using univariate tests of association. Multivariable regression with stepwise selection was used to examine risk factors associated with AH. All statistical analyses were performed using Stata 18.0. Results: Ninety-two patients were included; 70 were treated with GH monotherapy and 22 with combination AI/GH. Median age at AI initiation was 13.6 years (IQR 12.3-14.3) versus 11.2 years (IQR 8.6-12.9) for GH (unpaired t-test p-value &amp;lt;0.01; 95% CI -4.01, -1.91). A greater proportion of patients in the AI/GH group had been treated with stem cell transplantation, abdominal radiation, total body irradiation, and cis-retinoic acid (Fisher’s exact p-value &amp;lt;0.01). There was no statistically significant difference in AH or AH Z-score between treatment groups, with the median AH Z-score in the AI/GH group -1.95 (IQR -3.11, -0.75) versus -1.39 (IQR -2.65, 0.11) in the GH group. In multivariable linear regression, history of radiation to the spine (β= -5.9, 95% CI -11.2, -0.6), height Z-score (β= 0.3, 95% CI 0.11, 0.46), BMI Z-score (β= 3.2, 95% CI 0.95, 5.5), and advanced bone age at GH or AI treatment initiation (β= -10.1, 95% CI -17.3, -2.9) were significantly associated with AH. Conclusions: Adjunctive treatment with AI and GH was not associated with increased AH outcomes in male survivors of childhood cancer compared to GH monotherapy. Future work is needed to determine optimal adjunctive medical therapy to maximize FAH impacted by cancer therapy for this patient population. Presentation: 6/3/2024

Redefining FLASH Radiation Therapy: The Impact of Mean Dose Rate and Dose Per Pulse in the Gastrointestinal Tract

The understanding of how varying radiation beam parameter settings affect the induction and magnitude of the FLASH effect remains limited. We sought to systematically evaluate how the magnitude of radiation-induced gastrointestinal toxicity depends on the interplay between mean dose rate (MDR) and dose per pulse (DPP). C57BL/6J mice received total abdominal irradiation (TAI, 11-14 Gy single fraction) through either conventional (CONV) irradiation (low-DPP and low MDR, CONV) or through various combinations of DPP and MDR up to ultra-high-dose-rate beam conditions. DPPs ranging from 1 to 6 Gy were evaluated, while the total dose and MDR (>100 Gy/s) were kept constant; the effects of MDR were evaluated for the range of 0.3 to 1440 Gy/s, while the total dose and DPP were kept constant. Radiation-induced gastrointestinal toxicity was quantified in nontumor-bearing mice through the regenerating crypt assay and survival assessment. Tumor response was evaluated through tumor growth delay. Within each tested total dose using a constant MDR (>100 Gy/s), increasing DPP led to an increase in sparing (an increase in the number of regenerating crypts), with a more prominent effect seen at 12- and 14-Gy TAI. Interestingly, at DPPs of >4 Gy, a similar level of crypt sparing was demonstrated irrespective of the MDR used (from 0.3 to 1440 Gy/s). At a fixed high-DPP of 4.7 Gy, survival was equivalently improved relative to CONV irrespective of MDR. However, at a lower DPP of 0.93 Gy, an MDR of 104 Gy/s produced a greater survival effect compared with 0.3 Gy/s. We also confirmed that high-DPP, regardless of MDR, produced the same magnitude of tumor growth delay relative to CONV using a clinically relevant melanoma mouse model. This study demonstrates the strong influence that the beam parameter settings have on the magnitude of the FLASH effect. Both high-DPP and ultra-high-dose-rate appeared independently sufficient to produce FLASH sparing of gastrointestinal toxicity while isoeffective tumor response was maintained across all conditions.

Impact of motion management strategies on abdominal organ at risk delineation for magnetic resonance-guided radiotherapy

Background and purposeThe impact of respiratory motion management strategies for abdominal radiotherapy, such as abdominal compression (AC) and breath hold (BH), on abdominal organ at risk (OAR) delineation on magnetic resonance imaging (MRI) is unknown. This feasibility study compared the inter- and intra- observer delineation variation on MRI acquired with AC, BH for three critical abdominal OAR. Materials and methodsT2-weighted (W) 3D MRI in free-breathing (FB) and with AC, and T1W 3D mDixon exhale BH were acquired. Four observers blinded to motion management strategy used, delineated stomach, liver, and duodenum on all MRI. One case per strategy was repeated over 6 weeks later to quantify intra-observer variation. Simultaneous truth and performance level estimation (STAPLE) contours for each OAR were generated, median and IQR mean distance to agreement (mDTA) and maximum Hausdorff distance (HD) between observer and STAPLE contours were calculated. Observers scored organ visibility on each MRI using a four-point Likert scale. ResultsA total of 27 scans including repeats were delineated. Pooled mDTA for all OARs was 1.3 mm (0.5 mm) with AC, 1.4 mm (1.0 mm) with BH, and 1.3 mm (0.5 mm) in FB. Intra-observer mDTA was highest for all organs in FB with 10.8 mm for duodenum, 1.8 mm for liver, and 2.7 mm for stomach. The pooled mean perceptual quality score value was highest for AC across organs. ConclusionsNo motion management strategy demonstrated superior similarity across OAR, emphasizing the need for personalised approaches based on individual clinical and patient factors.

Impact of geometric correction on echo-planar imaging-based apparent diffusion coefficient maps for abdominal radiotherapy

Objective. The apparent diffusion coefficient (ADC) extracted from diffusion-weighted magnetic resonance imaging (DWI) is a potential biomarker in radiotherapy (RT). DWI is often implemented with an echo-planar imaging (EPI) read-out due to speed, but unfortunately low geometric accuracy follows. This study aimed to investigate the influence of geometric distortions on the ADCs extracted from the gross tumor volume (GTV) and on the shape of the GTV in abdominal EPI-DWI. Approach. Twenty-one patients had EPI-DWI scans on a 1.5 T MRI sim before treatment and on a 1.5 T MRI-Linac at one of the first treatment fractions. Off-resonance correction with and without eddy current correction were applied to ADC maps. The clinical GTVs were deformed based on the same (but inverted) corrections to assess the local-regional geometric influence of distortions. Mean surface distance (MSD), Hausdorff distance (HD), and Dice similarity coefficient (DSC) were calculated to compare the original and distorted GTVs, and ADC values were calculated based on a mono-exponential model. Phantom measurements were performed to validate the applied correction method. Main results. The median (range) ADC change within the GTV after full distortion correction was 1.3% (0.02%–6.9%) for MRI-Sim and 1.5% (0.1%–6.4%) for MRI-Linac. The additional effect of the eddy current correction was small in both systems. The median (range) MSD, HD, and DSC comparing the original and off-resonance distorted GTVs for all patients were 0.43 mm (0.11–0.94 mm), 4.00 mm (1.00–7.81 mm) and 0.93 (0.82–0.99), respectively. Significance. Overall effect of distortion correction was small in terms of derived ADC values, indicating that distortion correction is unimportant for prediction of outcomes based on ADC. However, large local geometric changes occurred after off-resonance distortion correction for some patients, suggesting that if the spatial information from ADC maps is to be used for dose painting strategies, corrections should be applied.

Discordance in acute gastrointestinal toxicity between synchrotron-based proton and linac-based electron ultra-high dose rate irradiation.

Proton FLASH has been investigated using cyclotron and synchrocyclotron beamlines but not synchrotron beamlines. We evaluated the impact of dose rate (ultra-high [UHDR] vs. conventional [CONV]) and beam configuration (shoot-through [ST] vs. spread-out-Bragg-peak [SOBP]) on acute radiation-induced gastrointestinal toxicity (RIGIT) in mice. We also compared RIGIT between synchrotron-based protons and linac-based electrons with matched mean dose rates. We administered abdominal irradiation (12-14 Gy single fraction) to female C57BL/6J mice with an 87 MeV synchrotron-based proton beamline (2 cm diameter field size as a lateral beam). Dose rates were 0.2 Gy/s (S-T pCONV), 0.3 Gy/s (SOBP pCONV), 150 Gy/s (S-T pFLASH), and 230 Gy/s (SOBP pFLASH). RIGIT was assessed by the jejunal regenerating crypt assay and survival. We also compared responses to proton [pFLASH and pCONV] with responses to electron CONV (eCONV, 0.4 Gy/s) and electron FLASH (eFLASH, 188-205 Gy/s). The number of regenerating jejunal crypts at each matched dose was lowest for pFLASH (similar between S-T and SOBP), greater and similar between pCONV (S-T and SOBP) and eCONV, and greatest for eFLASH. Correspondingly, mice that received pFLASH SOBP had the lowest survival rates (50% at 50 days), followed by pFLASH S-T (80%), and pCONV SOBP (90%), but 100% of mice receiving pCONV S-T survived (log-rank P = 0.047 for the four groups). Our findings are consistent with an increase in RIGIT after synchrotron-based pFLASH versus pCONV. This negative proton-specific FLASH effect versus linac-based electron irradiation underscores the importance of understanding the physical and biological factors that will allow safe and effective clinical translation.

MICROBIOME AND INFLAMMASOME ALTERATIONS FOUND DURING RADIATION DOSE FINDING IN A SINCLAIR MINIPIG MODEL OF GASTROINTESTINAL ACUTE RADIATION SYNDROME.

Both abdominal radiotherapy and a nuclear event can result in gastrointestinal symptoms, including acute radiation syndrome (GI-ARS). GI-ARS is characterized by compromised intestinal barrier integrity increasing the risk for infectious complications. Physiologically relevant animal models are crucial for elucidating host responses and therapeutic targets. We aimed to determine the radiation dose requirements for creating GI-ARS in the Sinclair minipig. Male, sexually mature swine were randomly divided into sham (n = 6) and three lower hemibody radiation dosage groups of 8, 10, and 12 Gy (n = 5/group) delivered using linear accelerator-derived x-rays (1.9 Gy/min). Animals were monitored for GI-ARS symptoms for 14 days with rectal swab and blood collection at days 0-3, 7, 10, and 14 followed by necropsy for western blotting and histology. Dose-dependent increases in weight loss, diarrhea severity, and mortality (log-rank test, P = 0.041) were seen. Villi length was significantly reduced in all irradiated animals compared to controls ( P < 0.001). Serum citrulline decreased and bacterial translocation increased after irradiation compared to controls. Increased NLRP3 levels in post-mortem jejunum were seen ( P = 0.0043) as well as increased IL-1β levels in the 12 Gy group ( P = 0.041). Radiation dose and survival were associated with significant gut microbial community shifts in beta diversity. Moreover, decedents had increased Porphyromonas, Campylobacter, Bacteroides , Parvimonas , and decreased Fusobacterium and decreased Aerococcus, Lactobacillus, Prevotella, and Streptococcus . Our novel Sinclair minipig model showed dose-dependent clinical symptoms of GI-ARS. These findings provide invaluable insights into the intricate interplay between GI-ARS, intestinal inflammation, and gut microbiota alterations offering potential targets for therapeutic and diagnostic interventions after radiation exposure.

Loss of Nrf2 aggravates ionizing radiation-induced intestinal injury by activating the cGAS/STING pathway via Pirin

Ionizing radiation (IR)-induced intestinal injury remains a major limiting factor in abdominal radiation therapy, and its pathogenesis remains unclear. In this study, mouse models of IR-induced intestinal injury were established, and the effect of IR on nuclear factor erythroid 2-related factor 2 (Nrf2) was determined. More severe IR-induced intestinal damage was observed in Nrf2 knockout (KO) mice than in wild-type mice. Then, the negative regulation of cyclic GMP-AMP synthase/stimulator of interferon genes (cGAS/STING) signaling by Nrf2 was examined both in vivo and in vitro after IR. This was accompanied by alterations in the intestinal neutrophil and macrophage populations in mice. Subsequently, the effect of the cGAS/STING pathway on the intestinal toxicity of IR was also investigated. Moreover, the downregulation of cGAS/STING by Nrf2 via its target gene, Pirin, was confirmed using transfection assays. A rescue experiment with Pirin was also conducted using adeno-associated virus in Nrf2 KO mice. Finally, the protective effect of calcitriol against IR-induced intestinal injury, along with increased Nrf2 and Pirin levels and decreased cGAS, pSTING, and interferon-beta levels, were observed. Taken together, our results suggest that Nrf2 alleviates IR-induced intestinal injury through Pirin-mediated inhibition of the innate immunity-related cGAS/STING pathway.

Whole Abdominal Pencil Beam Scanned Proton FLASH Increases Acute Lethality

PurposeUltra-high dose-rate FLASH radiotherapy (RT) has emerged as a modality which promises to reduce normal tissue toxicity while maintaining tumor control. Previous studies of gastrointestinal toxicity using passively scattered FLASH proton therapy (PRT) have, however, yielded mixed results, suggesting that the requirements for gastrointestinal sparing by FLASH are an open question. Furthermore, the more clinically relevant pencil beam scanned (PBS) FLASH PRT has not yet been assessed in this context, despite differences in the spatiotemporal dose-rate distributions compared to passively scattered PRT. Here, we provide the first report on the effects of PBS FLASH PRT on acute gastrointestinal injury in mice after whole abdominal irradiation. Methods and MaterialsWhole abdominal irradiation was performed on C57BL/6J mice using the entrance channel of the Bragg curve of a 250 MeV PBS proton beam at field-averaged dose-rates of 0.6 Gy/s for conventional (CONV) and 80-100 Gy/s for FLASH PRT. A 2D strip ionization chamber array was used to measure the dose and dose rate for each mouse. Survival was assessed at 14 Gy. Intestines were harvested and processed as Swiss rolls for analysis using a novel artificial intelligence (AI)-based crypt assay to quantify crypt regeneration 4 days post-irradiation. ResultsSurvival was significantly reduced following 14 Gy FLASH PRT compared to CONV (P<0.001). Our AI-based crypt assays demonstrated no significant difference in intestinal crypts/cm or crypt depth between groups 4 days post-irradiation. Furthermore, we found no significant difference in EdU+ cells/crypt or Olfactomedin4+ intestinal stem cells with FLASH relative to CONV PRT. ConclusionsOverall, our data demonstrate significantly impaired survival following abdominal PBS FLASH PRT without apparent differences in intestinal histology 4 days post-irradiation.

Safety of Pelvic and Abdominal Radiation Therapy for Patients With Inflammatory Bowel Disease: A Dosimetric Analysis of Acute Bowel Toxicity

ObjectivesInflammatory bowel disease (IBD) has been considered a relative contraindication to radiation therapy (RT) due to the potential greater risk of RT-induced toxicities. This study aims to assess acute toxicity outcomes in patients with IBD treated with abdominal/pelvic RT. MethodsAfter institutional review board approval, patients with IBD who received RT to the abdomen/pelvis were identified from an institutional research repository and their electronic medical records were reviewed. The IBD cohort was matched 1:1 with controls according to all of the following: radiotherapy, gender, disease site, age, and year of RT. Acute toxicity was defined as toxicity occurring within 3 months of RT. Primary outcomes were assessed via univariable logistic regression models and predicted probability of acute toxicity and acute gastrointestinal (GI) toxicity were plotted for the most significant covariates. IBD and control control cohorts were compared on demographic and toxicity variables using chi-square/Fisher's exact tests and Kruskal-Wallis tests where appropriate. ResultsWe identified 62 patients with median age of 64 years (interquartile range [IQR] 54-70) who received RT from 2006-2022. Patients were treated with intensity-modulated RT (38; 61.3%), 3-dimensional conformal RT (12; 19.4%), and stereotactic body RT/brachytherapy (12; 19.4%). After RT, 28 (45.2%) and 23 (37.1%) patients experienced grade ≥2 acute (any) and acute GI toxicity, respectively. Higher overall RT dose and RT dose to small bowel were found to be signicantly associated with increased risk of grade ≥2 acute toxicities (OR=1.041 per unit Gy, 95% CI 1.005-1.084, p=0.034 and OR=1.046, 95% CI 1.018-1.082, p=0.003, respectively). Between IBD and control cohorts, there were no significant differences in grade ≥2 acute (any) and acute GI toxicities (p=0.710 and p=0.704, respectively). ConclusionIn patients with IBD treated with abdominal/pelvic RT for malignancy, RT was effective and well-tolerated. RT treatment planning should carefully consider the location(s) of IBD inflammation and dose to bowel structures, in particular, dose to small bowel.

Pelvic Radiation Therapy Increases Risk of Pouch Failure in Patients with Inflammatory Bowel Disease and Ileal Pouch.

The effect of radiation on the ileal pouch is less well studied in patients with inflammatory bowel disease (IBD) and ileal pouch-anal anastomosis. This retrospective study investigates the impact of external radiation therapy on the outcomes of ileal pouches. The study included 82 patients with IBD and ileal pouches, of whom 12 received pelvic radiation, 16 abdominal radiation, 14 radiation in other fields, and 40 served as controls with no radiation. Pouch-related outcomes, including pouch failure, worsening of symptoms, pouchitis, and development of strictures, along with changes in Pouch Disease Activity Index (PDAI) scores pre- and post-radiation were assessed. The pelvic radiation group exhibited a significantly higher rate of pouch failure (25%, p < 0.004) and worsening pouch-related symptoms (75%, p = 0.012) compared to other groups. Although not statistically significant, a higher incidence of pouchitis was observed in the pelvic radiation group (45.5%, p = 0.071). Strictures were more common in the pelvic radiation group (25%, p = 0.043). Logistic regression analysis revealed that pelvic radiation significantly increased the odds of pouch-related adverse outcomes (OR 5.66; 95% confidence interval: 1.61-21.5). Pelvic radiation significantly impacts the outcomes of ileal pouches in patients with IBD, increasing the risk of pouch failure, symptom exacerbation, and structural complications. These findings underscore the need for careful consideration of radiation therapy in this patient population and highlight the importance of closely monitoring and managing radiation-induced pouch dysfunction.

Histone deacetylase inhibitor, Trichostatin A mitigates ionizing radiation induced redox imbalance by regulating NRF2/GPX4/PINK1/PARKIN signaling in mice intestine.

Gastrointestinal-acute radiation syndrome (GI-ARS) caused by moderate to high doses of ionizing radiation exposurecontribute to early death in humans. GI injury is also a common adverse effect seen in cancer patients undergoing abdominal/pelvic radiotherapy. Currently, no countermeasure agents have been approved for medical management of GI-ARS. The present study aims to evaluate the mechanism of action of Trichostatin A(TSA), a pan histone deacetylaseinhibitor, against radiation-induced GI injury. TSA (150ng/kg bw) was administered to mice 1h and 24h after 15Gy abdominal irradiation. Expression of various markers of oxidative stress, mitochondrial dysfunction, and apoptosis were checked in the jejunum, and their possible regulation throughthe Nrf2 signaling pathway was evaluated. TSA administered post-irradiation (15Gy + TSA) elevated intestinal total antioxidant and glutathione levels by regulating the expression of Slc7A11 and antioxidant proteins, GCLC, GPX4, and TXNRD1. Improved mitochondrial membrane potential, ATP levels, downregulation of mitochondrial quality control proteins, (PINK1 and PARKIN), and differential regulation of the apoptotic proteins, (BAX, PUMA and BCL2) with reduced intestinal epithelial cell apoptosis in the TSA-adminstered groupwere observed. TSA also upregulated Nrf2 in the presence of its specific inhibitor, ML385, suggesting its involvement in regulating Nrf2 signaling during oxidative stress induced by radiation in intestine. H & E stained jejunumcross-sections revealed that TSA mitigated radiation-mediated intestinalinjury in mice. Present findingsindicate that TSA is beneficial in mitigating the damaging effects of ionizing radiation in the intestine.

Abdominal MR Multitasking for radiotherapy treatment planning: A motion-resolved and multicontrast 3D imaging approach.

Radiotherapy treatment planning (RTP) using MR has been used increasingly for the abdominal site. Multiple contrast weightings and motion-resolved imaging are desired for accurate delineation of the target and various organs-at-risk and patient-tailored planning. Current MR protocols achieve these through multiple scans with distinct contrast and variable respiratory motion management strategies and acquisition parameters, leading to a complex and inaccurate planning process. This study presents a standalone MR Multitasking (MT)-based technique to produce volumetric, motion-resolved, multicontrast images for abdominal radiotherapy treatment planning. The MT technique resolves motion and provides a wide range of contrast weightings by repeating a magnetization-prepared (saturation recovery and T2 preparations) spoiled gradient-echo readout series and adopting the MT image reconstruction framework. The performance of the technique was assessed through digital phantom simulations and in vivo studies of both healthy volunteers and patients with liver tumors. In the digital phantom study, the MT technique presented structural details and motion in excellent agreement with the digital ground truth. The in vivo studies showed that the motion range was highly correlated (R2 = 0.82) between MT and 2D cine imaging. MT allowed for a flexible contrast-weighting selection for better visualization. Initial clinical testing with interobserver analysis demonstrated acceptable target delineation quality (Dice coefficient = 0.85 ± 0.05, Hausdorff distance = 3.3 ± 0.72 mm). The developed MT-based, abdomen-dedicated technique is capable of providing motion-resolved, multicontrast volumetric images in a single scan, which may facilitate abdominal radiotherapy treatment planning.

On-board synthetic 4D MRI generation from 4D CBCT for radiotherapy of abdominal tumors: A feasibility study.

Magnetic resonance-guided radiotherapy with an MR-guided LINAC represents potential clinical benefits in abdominal treatments due to the superior soft-tissue contrast compared to kV-based images in conventional treatment units. However, due to the high cost associated with this technology, only a few centers have access to it. As an alternative, synthetic 4D MRI generation based on artificial intelligence methods could be implemented. Nevertheless, appropriate MRI texture generation from CT images might be challenging and prone to hallucinations, compromising motion accuracy. To evaluate the feasibility of on-board synthetic motion-resolved 4D MRI generation from prior 4D MRI, on-board 4D cone beam CT (CBCT) images, motion modeling information, and deep learning models using the digital anthropomorphic phantom XCAT. The synthetic 4D MRI corresponds to phases from on-board 4D CBCT. Each synthetic MRI volume in the 4D MRI was generated by warping a reference 3D MRI (MRIref, end of expiration phase from a prior 4D MRI) with a deformation field map (DFM) determined by (I) the eigenvectors from the principal component analysis (PCA) motion-modeling of the prior 4D MRI, and (II) the corresponding eigenvalues predicted by a convolutional neural network (CNN) model using the on-board 4D CBCT images as input. The CNN was trained with 1000 deformations of one reference CT (CTref, same conditions as MRIref) generated by applying 1000 DFMs computed by randomly sampling the original eigenvalues from the prior 4D MRI PCA model. The evaluation metrics for the CNN model were root-mean-square error (RMSE) and mean absolute error (MAE). Finally, different on-board 4D-MRI generation scenarios were assessed by changing the respiratory period, the amplitude of the diaphragm, and the chest wall motion of the 4D CBCT using normalized root-mean-square error (nRMSE) and structural similarity index measure (SSIM) for image-based evaluation, and volume dice coefficient (VDC), volume percent difference (VPD), and center-of-mass shift (COMS) for contour-based evaluation of liver and target volumes. The RMSE and MAE values of the CNN model reported 0.012±0.001 and 0.010±0.001, respectively for the first eigenvalue predictions. SSIM and nRMSE were 0.96±0.06 and 0.22±0.08, respectively. VDC, VPD, and COMS were 0.92±0.06, 3.08±3.73 %, and 2.3±2.1mm, respectively, for the target volume. The more challenging synthetic 4D-MRI generation scenario was for one 4D-CBCT with increased chest wall motion amplitude, reporting SSIM and nRMSE of 0.82 and 0.51, respectively. On-board synthetic 4D-MRI generation based on predicting actual treatment deformation from on-board 4D-CBCT represents a method that can potentially improve the treatment-setup localization in abdominal radiotherapy treatments with a conventional kV-based LINAC.

Polysaccharides isolated from Hibiscus sabdariffa L. mitigate intestinal radiation injury through relieving mucosal inflammation and reshaping gut microbiota in mice

Hibiscus sabdariffa L. (H. sabdariffa) shows considerable promise in alleviating oxidative stress injury through its rich content of phytochemicals, especially polysaccharides, yet its efficacy in treating intestinal radiation injury remains unclear. Here, we purified one water-soluble polysaccharides from H. sabdariffa (HSP1), and subsequently explored its role in relieving intestinal radiation injury via a mouse model of abdominal irradiation. The results demonstrated that HSP1 intervention effectively improved gut barrier function by restoring mucus secretion and upregulating tight junction proteins. Additionally, HSP1 mitigated oxidative stress through Nrf2/HO-1 pathway and reduced the inflammatory response through restraining the activation of pattern recognition receptors. Moreover, HSP1 modulated the balance of gut microbiota by suppressing pathogenic bacteria, while promoting the growth of beneficial symbiotic bacteria such as Lactobacillus, Ligilactobacillus, and Lachnospiraceae_NK4A136. Altogether, this study highlights the protective potential of HSP1 against intestinal radiation injury, providing primary data for further applications of H. sabdariffa polysaccharides as radioprotectors.