Microbiome profiling and Co-metabolism pathway analysis in cervical cancer patients with acute radiation enteritis.

Background: Intestinal bacteria significantly contribute to the metabolism of intestinal epithelial tissues. As the occurrence and development of radiation enteritis (RE) depend on the "co-metabolism" microenvironment formed by the host and intestinal microbiota, which involves complex influencing factors and strong correlations, ordinary techniques struggle to fully explain the underlying mechanisms. However, given that it is based on systems biology, metabolomics analysis is well-suited to address these issues. This study aimed to analyze the metabolomic changes in urine, serum, and fecal samples during volumetric modulated arc therapy (VMAT) for cervical cancer and screen for characteristic metabolites of severe acute radiation enteritis (SARE) and RE. Methods: We enrolled 50 patients who received radiotherapy for cervical cancer. Urine, serum, and fecal samples of patients were collected at one day before radiotherapy and the second week, fourth week, and sixth week after the start of radiotherapy. Control group samples were collected during the baseline period. Differential metabolites were identified by metabolomics analysis; co-metabolic pathways were clarified. We used the mini-SOM library for incorporating characteristic metabolites, and established metabolite classification models for predicting SARE and RE. Results: Urine and serum sample data showed remarkable clustering effect; metabolomics data of the fecal supernatant were evidently disturbed. Patient sample analyses during VMAT revealed the following. Urine samples: Downregulation of the pyrimidine and riboflavin metabolism pathways as well as initial upregulation followed by downregulation of arginine and proline metabolism pathways and the arginine biosynthesis pathway. Fecal samples: Upregulation of linoleic acid and phenylalanine metabolic pathways and initial downregulation followed by upregulation of arachidonic acid (AA) metabolic pathways. Serum samples: Initial upregulation followed by downregulation of the arginine biosynthesis pathway and downregulation of glutathione, AA, and arginine and proline metabolic pathways. Conclusion: Patients with cervical cancer exhibited characteristic metabolic pathways and characteristic metabolites predicting RE and SARE were screened out. An effective RE mini-SOM classification model was successfully established.

Analysis of clinical and physical dosimetric factors that determine the outcome of severe acute radiation pneumonitis in lung cancer patients.

OBJECTIVE: We conducted a retrospective statistical analysis of clinical and physical dosimetric factors of lung cancer patients who had previously undergone lung and/or mediastinal radiotherapy and died of or survived severe acute radiation pneumonitis (SARP). Our study was the first to reveal the heterogeneity in clinical factors, physical dosimetric factors, and SARP onset time that determined the clinical outcomes of lung cancer patients who developed SARP. MATERIALS AND METHODS: The clinical characteristics, physical dosimetry factors, and SARP onset time of deceased and surviving patients were retrospectively analyzed. SPSS 20.0 was used for data analysis. Student's t-test was used for intergroup comparison, and a Mann-Whitney U test was used for data with skewed distribution. Qualitative data were represented using frequencies (%), and Fisher's exact test or χ2 test was used for intergroup comparison of nonparametric data. Binary logistic analysis was used for univariate and multivariate analyses. Differences with a P < 0.05 were considered statistically significant. RESULTS: Univariate analysis revealed that the potential predictors of SARP death were as follows: ipsilateral lung V5 and V30, contralateral lung V5, V10, and V30, total lung V5, V10, and V30, mean lung dose, mean heart dose, and maximum spinal cord dose. Multivariate analysis showed that ipsilateral lung V5 and total lung V5 were predictors that determined the final outcome of SARP patients. In addition, we analyzed the time from the completion of radiotherapy to SARP onset, and found significant difference between the two groups. CONCLUSIONS: There was no decisive correlation between clinical characteristics and SARP outcome (i.e., death or survival) in lung radiotherapy patients. Ipsilateral lung V5 and total lung V5 were independent predictors of death in SARP patients.

Establishment of a prediction model for severe acute radiation enteritis associated with cervical cancer radiotherapy.

BACKGROUND: Cervical cancer is one of the most common gynecological malignant tumors. Radiation enteritis (RE) leads to radiotherapy intolerance or termination of radiotherapy, which negatively impacts the therapeutic effect and seriously affects the quality of life of patients. If the incidence of RE in patients can be predicted in advance, and targeted clinical preventive treatment can be carried out, the side effects of radiotherapy in cervical cancer patients can be significantly reduced. Furthermore, accurate prediction of RE is essential for the selection of individualized radiation dose and the optimization of the radiotherapy plan. AIM: To analyze the relationships between severe acute RE (SARE) of cervical cancer radiotherapy and clinical factors and dose-volume parameters retrospectively. METHODS: We included 50 cervical cancer patients who received volumetric modulated arc therapy (VMAT) from September 2017 to June 2018 in the Department of Radiotherapy at The First Affiliated Hospital Soochow University. Clinical and dose-volume histogram factors of patients were collected. Logistic regression analysis was used to evaluate the predictive value of each factor for SARE. A nomogram to predict SARE was developed (SARE scoring system ≥ 3 points) based on the multiple regression coefficients; validity was verified by an internal verification method. RESULTS: Gastrointestinal and hematological toxicity of cervical cancer VMAT gradually increased with radiotherapy and reached the peak at the end of radiotherapy. The main adverse reactions were diarrhea, abdominal pain, colitis, anal swelling, and blood in the stool. There was no significant difference in the incidence of gastrointestinal toxicity between the radical and postoperative adjuvant radiotherapy groups (P > 0.05). There were significant differences in the small intestine V20, V30, V40, and rectal V40 between adjuvant radiotherapy and radical radiotherapy after surgery (P < 0.05). Univariate and multivariate analyses revealed anal bulge rating (OR: 14.779, 95%CI: 1.281-170.547, P = 0.031) and disease activity index (DAI) score (OR: 53.928, 95%CI: 3.822-760.948, P = 0.003) as independent predictors of SARE. CONCLUSION: Anal bulge rating (> 0.500 grade) and DAI score (> 2.165 points) can predict SARE. The nomogram shows potential value in clinical practice.

Analysis of nutritional risk, skeletal muscle depletion, and lipid metabolism phenotype in acute radiation enteritis.

BACKGROUND: Radiation enteritis, which often occurs during radiation-induced acute intestinal symptoms (RIAIS), is the most common and important complication during radiotherapy for cervical cancer. RIAIS caused by abdominal and pelvic radiotherapy will affect nutrient intake, digestion, absorption, and metabolism, leading to malnutrition or poorer nutritional status. In patients with malignant tumors, malnutrition can adversely affect the curative effect and response of radiotherapy by reducing radiosensitivity, affecting the precision of radiotherapy placement and increasing the incidence of radiotherapy-related adverse reactions. AIM: To analyze nutritional risk, skeletal muscle depletion, and lipid metabolism phenotype in acute radiation enteritis. METHODS: Fifty patients with cervical cancer received external beam radiotherapy, and 15 patients received brachytherapy after external beam radiotherapy. Body weight, body composition parameters, nutritional risk screening (NRS) 2002 score, and blood biochemical indices of patients with cervical cancer during periradiation were tested by a one-way repeated measures analysis of variance. Metabolomics analysis was used to identify characteristic lipid metabolism pathways. Clinical factors that affect linoleic acid changes were screened using the generalized evaluation equation. RESULTS: Among the 50 patients, 37 had RIAIS, including 34 patients with grade 1-2 RIAIS and 3 patients with grade 3 RIAIS. The NRS 2002 score of patients who underwent cervical cancer radiotherapy continued to increase during the periradiation period, and 42 patients who underwent cancer radiotherapy had nutritional deficits (NRS 2002 score ≥ 3 points) at the end of radiotherapy. Correlation analyses revealed that body weight and body mass index changes were closely associated with body fat content (R2 = 0.64/0.51). The results of the univariate analysis showed that radiotherapy time, percentage reduction of serum albumin, and percentage reduction of serum prealbumin were the key factors affecting skeletal muscle exhaustion (P < 0.05). Metabolomic analysis of fecal supernatants of cervical cancer patients during the periradiation period revealed the involvement of linoleic acid, cholic acid, arachidonic acid, and N-acetyl-L-benzene alanine in the metabolic pathway of linoleic acid. CONCLUSION: Cervical cancer radiotherapy patients faced nutritional risks, decreased serum albumin synthesis, and increased risk of skeletal muscle exhaustion. Linoleic acid was a biomarker of high nutritional risk.

Clinical evaluation of deep learning-based clinical target volume three-channel auto-segmentation algorithm for adaptive radiotherapy in cervical cancer.

OBJECTIVES: Accurate contouring of the clinical target volume (CTV) is a key element of radiotherapy in cervical cancer. We validated a novel deep learning (DL)-based auto-segmentation algorithm for CTVs in cervical cancer called the three-channel adaptive auto-segmentation network (TCAS). METHODS: A total of 107 cases were collected and contoured by senior radiation oncologists (ROs). Each case consisted of the following: (1) contrast-enhanced CT scan for positioning, (2) the related CTV, (3) multiple plain CT scans during treatment and (4) the related CTV. After registration between (1) and (3) for the same patient, the aligned image and CTV were generated. Method 1 is rigid registration, method 2 is deformable registration, and the aligned CTV is seen as the result. Method 3 is rigid registration and TCAS, method 4 is deformable registration and TCAS, and the result is generated by a DL-based method. RESULTS: From the 107 cases, 15 pairs were selected as the test set. The dice similarity coefficient (DSC) of method 1 was 0.8155 ± 0.0368; the DSC of method 2 was 0.8277 ± 0.0315; the DSCs of method 3 and 4 were 0.8914 ± 0.0294 and 0.8921 ± 0.0231, respectively. The mean surface distance and Hausdorff distance of methods 3 and 4 were markedly better than those of method 1 and 2. CONCLUSIONS: The TCAS achieved comparable accuracy to the manual delineation performed by senior ROs and was significantly better than direct registration.

Deep learning-based auto-segmentation of clinical target volumes for radiotherapy treatment of cervical cancer.

OBJECTIVES: Because radiotherapy is indispensible for treating cervical cancer, it is critical to accurately and efficiently delineate the radiation targets. We evaluated a deep learning (DL)-based auto-segmentation algorithm for automatic contouring of clinical target volumes (CTVs) in cervical cancers. METHODS: Computed tomography (CT) datasets from 535 cervical cancers treated with definitive or postoperative radiotherapy were collected. A DL tool based on VB-Net was developed to delineate CTVs of the pelvic lymph drainage area (dCTV1) and parametrial area (dCTV2) in the definitive radiotherapy group. The training/validation/test number is 157/20/23. CTV of the pelvic lymph drainage area (pCTV1) was delineated in the postoperative radiotherapy group. The training/validation/test number is 272/30/33. Dice similarity coefficient (DSC), mean surface distance (MSD), and Hausdorff distance (HD) were used to evaluate the contouring accuracy. Contouring times were recorded for efficiency comparison. RESULTS: The mean DSC, MSD, and HD values for our DL-based tool were 0.88/1.32 mm/21.60 mm for dCTV1, 0.70/2.42 mm/22.44 mm for dCTV2, and 0.86/1.15 mm/20.78 mm for pCTV1. Only minor modifications were needed for 63.5% of auto-segmentations to meet the clinical requirements. The contouring accuracy of the DL-based tool was comparable to that of senior radiation oncologists and was superior to that of junior/intermediate radiation oncologists. Additionally, DL assistance improved the performance of junior radiation oncologists for dCTV2 and pCTV1 contouring (mean DSC increases: 0.20 for dCTV2, 0.03 for pCTV1; mean contouring time decrease: 9.8 min for dCTV2, 28.9 min for pCTV1). CONCLUSIONS: DL-based auto-segmentation improves CTV contouring accuracy, reduces contouring time, and improves clinical efficiency for treating cervical cancer.

Celecoxib Alleviates Radiation-Induced Brain Injury in Rats by Maintaining the Integrity of Blood-Brain Barrier.

The underlying mechanisms of radiation-induced brain injury are poorly understood, although COX-2 inhibitors have been shown to reduce brain injury after irradiation. In the present study, the effect of celecoxib (a selective COX-2 inhibitor) pretreatment on radiation-induced injury to rat brain was studied by means of histopathological staining, evaluation of integrity of blood-brain barrier and detection of the expressions of inflammation-associated genes. The protective effect of celecoxib on human brain microvascular endothelial cells (HBMECs) against irradiation was examined and the potential mechanisms were explored. Colony formation assay and apoptosis assay were undertaken to evaluate the effect of celecoxib on the radiosensitivity of the HBMECs. ELISA was used to measure 6-keto-prostaglandin F1α (6-keto-PGF1α) and thromboxane B2 (TXB2) secretion. Western blot was employed to examine apoptosis-related proteins expressions. It was found that celecoxib protected rat from radiation-induced brain injury by maintaining the integrity of the blood-brain barrier and reducing inflammation in rat brain tissues. In addition, celecoxib showed a significant protective effect on HBMECs against irradiation, which involves inhibited apoptosis and decreased TXB2/6-keto-PGF1α ratio in brain vascular endothelial cells. In conclusion, celecoxib could alleviate radiation-induced brain injury in rats, which may be partially due to the protective effect on brain vascular endothelial cells from radiation-induced apoptosis.

The Construction of a Radiation-Induced Brain Injury Model and Preliminary Study on the Effect of Human Recombinant Endostatin in Treating Radiation-Induced Brain Injury.

BACKGROUND The aim of this study was to construct a radiation-induced brain injury (RBI) model and assess the effects of human recombinant endostatin in the treatment of RBI. MATERIAL AND METHODS In this study, the RBI model was used. Real-time quantitative polymerase chain reaction, immunohistochemistry, hematoxylin and eosin staining were conducted to detect the mRNA and protein expression of vascular endothelial growth factor (VEGF) and assess the effects of human recombinant endostatin in the treatment of RBI. RESULTS In this study, we successfully constructed a RBI model. VEGF mRNA expression was decreased after human recombinant endostatin treatment; however, VEGF protein secretion was increased in brain endothelial cells, and the secretion of VEGF protein was decreased in glial cells and nerve cells. Body weight changes indicated that human recombinant endostatin can increase the risk of weight loss. Brain water content results showed that human recombinant endostatin might aggravate cerebral edema in the acute stage of RBI, but it can reduce the progression of cerebral edema in the early delayed stage. Survival analysis showed that human recombinant endostatin improved the survival rate only in the early stage of RBI. CONCLUSIONS Radiation can induce vasogenic edema and is associated with the RBI occurrence and development. VEGF protein is highly relevant to the induction of edema and thrombosis in the acute phase of RBI and in the early delayed phase of RBI, including vascular repair and regeneration, thrombus ablation and other events. Human recombinant endostatin can reduce the progression of cerebral edema during the early onset of RBI.