Gy Group Research Articles

Molecular Mechanism of Male Sterility Induced by 60Co γ-Rays on Plutella xylostella (Linnaeus).

Plutella xylostella (Linnaeus) is one of the notorious pests causing substantial loses to numerous cruciferous vegetables across many nations. The sterile insect technique (SIT) is a safe and effective pest control method, which does not pollute the environment and does not produce drug resistance. We used proteomics technology and bioinformatics analysis to investigate the molecular mechanisms responsible for the effects of different doses of radiation treatment on the reproductive ability of male P. xylostella. A total of 606 differentially expressed proteins (DEPs) were identified in the 200 Gy/CK group, 1843 DEPs were identified in the 400 Gy/CK group, and 2057 DEPs were identified in the 400 Gy/200 Gy group. The results showed that after 200 Gy irradiation, the testes resisted radiation damage by increasing energy supply, amino acid metabolism and transport, and protein synthesis, while transcription-related pathways were inhibited. After 400 Gy irradiation, the mitochondria and DNA in the testis tissue of P. xylostella were damaged, which caused cell autophagy and apoptosis, affected the normal life activities of sperm cells, and greatly weakened sperm motility and insemination ability. Meanwhile, Western blotting showed that irradiation affects tyrosine phosphorylation levels, which gradually decrease with increasing irradiation dose.

Differential impacts of ionizing radiation on a sexually dimorphic trait in male and female Acheta domesticus

Purpose In many Orthopteran species, including crickets, forewings exhibit substantial sexual dimorphism driven by sexual selection. In the cricket, Acheta domesticus, females are the ‘choosy’ sex and males exhibit multiple sexual signals to attract and successfully mate. Male forewings have highly specialized structures critical for acoustic signaling and mating. In contrast, female forewings currently serve no known purpose in this flightless species. Forewings also differ morphologically with male forewings containing complex acoustic producing and resonating regions and females lacking any defined structures. Due to their importance to mating as well as their structural complexity, impacts of environmental stress that target cricket forewing development may therefore have more severe consequences in males than females. Here, we investigate the sensitivity of a sexually dimorphic trait, forewing morphology, to an early life environmental stressor. Materials and Methods We applied ionizing radiation (0-–27.8 Gy) as a stressor as dose can be precisely applied as well as its relevance in both environmental contamination and use in the Sterile Insect Technique. Results A canonical variate analysis indicated that wing shape was significantly altered in males at all doses; .58 Gy, 2.3 Gy, 4.6 Gy, 16.2 Gy, and 23.2 Gy. In females, shape was significantly altered at 27.8 Gy and 23.2 Gy groups and to a lesser extent at .58 Gy and 16.2 Gy. Linear regression analysis of centroid size indicated a dose dependent decline in wing size in both sexes, with males exhibiting more decline. Fluctuating asymmetry, a measure of environmental sensitivity, revealed that males were more sensitive to shape changes due to stress than females. This difference in sensitivity is likely due to the complexity of male forewings. Conclusion These results expand understanding of sex dimorphism in stress responses and sensitivity to ionizing radiation.

Efficacy and safety of high dose twice-daily thoracic radiotherapy versus standard dose for limited stage small-cell lung cancer: A multicentre, open-label randomised, phase 3 trial.

8587 Background: We aimed to assess the efficacy and safety of high-dose, hyperfractionated thoracic radiotherapy of 54 Gy in 30 fractions compared with standard dose(45 Gy in 30 fractions) as a first-line treatment for LS-SCLC. Methods: The study was an open-label, randomised, phase 3 trial, done at 16 public hospitals in China.Key inclusion criteria were patients aged 18-70 years, with previously histologically or cytologically confirmed LS-SCLC, previously untreated or received 1-2 courses of intravenous cisplatin (75 mg/m²of body-surface area, on day 1 or divided into two days of each cycle) or carboplatin (area under the curve of 5 mg/mL per min, day 1 of each cycle)and intravenous etoposide (100 mg/m²of body-surface area, on days 1-3 of each cycle), and an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.Eligible patients were randomly assigned (1:1) to receive receive volumetric-modulated arc radiotherapy (VMAT) of 45 Gy in 30 fractions or the simultaneous integrated boost VMAT (SIB-VMAT) of 54 Gy in 30 fractions to the primary lung tumour and lymph node metastases starting 0-42 days after the first chemotherapy course. Both groups of patients received thoracic radiotherapy twice per day and 10 fractions per week.Prophylactic cranial radiation (PCI, 25Gy in 10 fractions) was implemented to patients with responsive disease. The primary endpoint was overall survival. Safety was analysed in the as-treated population. This study is complete and registered with ClinicalTrials.gov,NCT03214003. Results: Between June 30, 2017, and April 6, 2021, 224 eligible patients were enrolled and randomly assigned to 54 Gy (n = 108) or 45 Gy (n = 116).Median follow-up for the primary analysis was 45 months (IQR 41-48). Median overall survival was significantly improved in the 54 Gy group (62.4 months ) compared with the 45 Gy group (43.1 months; p = 0.001). Median progression-free survival was significantly improved in the 54 Gy group (30.5 months) compared with the 45 Gy group (16.7 months; p = 0.044). The most common grade 3-4 adverse events were neutropenia (30 [28%] of 108 patients in the 54 Gy group vs 27 [23%] of 116 patients in the 45 Gy group), neutropenic infections (6 [6%] vs 2 [2%]), thrombocytopenia (13 [12%] vs 12 [10%]), anaemia (6 [6%] vs 4 [3%]), and oesophagitis (1 [1%] vs 3 [3%]). There were one treatment-related deaths in 54 Gy group (myocardial infarction). Conclusions: Compared with standard thoracic radiotherapy dose of 45 Gy, the high dose dose of 54 Gy improved overall survival and progression-free survival without increasing toxicities in patients with LS-SCLC, supporting twice-daily hyperfractionated thoracic radiotherapy of 54 Gy with concurrent chemotherapy is an alternative treatment option for LS-SCLC. Clinical trial information: NCT03214003 .

Final survival data from a randomized phase II trial comparing high-dose with standard-dose twice-daily (BID) thoracic radiotherapy (TRT) in limited stage small-cell lung cancer (LS SCLC).

8512 Background: Concurrent chemotherapy and TRT is standard treatment of LS SCLC. BID TRT of 45 Gy/30 fractions is the most recommended schedule. Trials report 5-year survival rates of up to 36%, illustrating that some are cured but also need for better treatment. Many treatment failures are due to relapses within TRT fields, and it has been proposed that higher TRT doses might improve local control and consequently survival. However, high-dose once-daily (QD) TRT of 66-70 Gy do not prolong survival. We investigated whether high-dose BID TRT of 60 Gy/40 fractions was tolerable and improved survival compared with the established 45 Gy schedule (NCT02041845). Primary analyses presented at ASCO 2020 showed that the trial was highly positive for the primary endpoint, 2-year survival (60 Gy: 74.2%, 45 Gy: 48.1%, OR 3.09 [95% CI 1.62-5.89]; p=0.0005). We now present updated and final survival data. Methods: Patients ≥18 years with PS 0-2, confirmed SCLC, LS according to the IASLC definition after PET CT staging received 4 courses of platinum/etoposide and were randomized to receive 60 Gy or 45 Gy to PET CT positive lesions. TRT started concurrently with the 2nd chemotherapy course. Responders were offered QD prophylactic cranial irradiation of 25-30 Gy. All patients were followed for 5 years or until death. Results: 170 eligible patients were randomized at 22 Scandinavian hospitals from 2014-2018 (60 Gy: n=89, 45 Gy: n=81). Median age was 65, 31.2% were ≥70 years, 57.1% women, 89.4% had PS 0-1, 83.5% stage III disease, 7.6% pleural effusion and 20.0% ≥5% weight loss last three months before enrollment. Baseline patient and disease characteristics and TRT planning target volumes were well balanced between treatment arms. Completion rates of chemotherapy (60 Gy: 92.1%, 45 Gy: 87.7%) and TRT (60 Gy: 96.6%, 45 Gy: 91.4%) were similar. Patients on the high-dose arm did not experience more grade 3-4 esophagitis (60 Gy: 21.2%, 45 Gy: 18.2%; p=0.83) or pneumonitis (60 Gy: 3.4%, 45 Gy: 0.0%; p=0.39), other grade 3-4 toxicity or treatment related deaths. The 60 Gy group had numerically longer PFS (median PFS 60 Gy: 18.6 months [95% CI 11.6-25.6], 45 Gy: 10.9 months [95% CI 8.7-13.2], HR 0.76 [95% CI 0.53-1.08]; p=0.13). Results for the primary endpoint remain unchanged. The higher TRT dose significantly prolonged survival (median OS 60 Gy: 43.5 months [95% CI 30.4-56.6], 45 Gy: 22.6 months [95% CI 17.2-28.0], HR 0.69 [0.48-0.99]; p=0.043) and provided higher 4.5 year survival rate (60 Gy: 41.6% [95% CI 30.4-56.6], 45 Gy: 28.4% [95% CI 18.9-39.5], OR: 1.79 [95% CI 0.95-3.41]). 5-year survival rates will be presented at the meeting. Conclusions: Compared with LS SCLC patients who received standard TRT, patients receiving high-dose BID TRT of 60 Gy did not experience more toxicity, had a substantial prolongation of survival and a much higher long term survival rate. Clinical trial information: NCT02041845 .

Variable Dose Rates in Realistic Radiation Exposures: Effects on Small Molecule Markers of Ionizing Radiation in the Murine Model.

Novel biodosimetry assays for use in preparedness and response to potential malicious attacks or nuclear accidents would ideally provide accurate dose reconstruction independent of the idiosyncrasies of a complex exposure to ionizing radiation. Complex exposures will consist of dose rates spanning the low dose rates (LDR) to very high-dose rates (VHDR) that need to be tested for assay validation. Here, we investigate how a range of relevant dose rates affect metabolomic dose reconstruction at potentially lethal radiation exposures (8 Gy in mice) from an initial blast or subsequent fallout exposures compared to zero or sublethal exposures (0 or 3 Gy in mice) in the first 2 days, which corresponds to an integral time individuals will reach medical facilities after a radiological emergency. Biofluids (urine and serum) were collected from both male and female 9-10-week-old C57BL/6 mice at 1 and 2 days postirradiation (total doses of 0, 3 or 8 Gy) after a VHDR of 7 Gy/s. Additionally, samples were collected after a 2-day exposure consisting of a declining dose rate (1 to 0.004 Gy/min) recapitulating the 7:10 rule-of-thumb time dependency of nuclear fallout. Overall similar perturbations were observed in both urine and serum metabolite concentrations irrespective of sex or dose rate, with the exception of xanthurenic acid in urine (female specific) and taurine in serum (VHDR specific). In urine, we developed identical multiplex metabolite panels (N6, N6,N6-trimethyllysine, carnitine, propionylcarnitine, hexosamine-valine-isoleucine, and taurine) that could identify individuals receiving potentially lethal levels of radiation from the zero or sublethal cohorts with excellent sensitivity and specificity, with creatine increasing model performance at day 1. In serum, individuals receiving a 3 or 8 Gy exposure could be identified from their pre-irradiation samples with excellent sensitivity and specificity, however, due to a lower dose response the 3 vs. 8 Gy groups could not be distinguished from each other. Together with previous results, these data indicate that dose-rate-independent small molecule fingerprints have potential in novel biodosimetry assays.

A retrospective study of adjuvant proton radiotherapy for breast cancer after lumpectomy: a comparison of conventional-dose and hypofractionated dose

PurposeThis study aimed to compare the adverse reactions of conventional-dose and hypofractionated dose of proton therapy for breast cancer.Materials and methodsBreast cancer patients treated with proton radiotherapy in conventional-dose or hypofractionated dose were studied retrospectively.ResultFrom January 2017 to December 2019, our center treated 50 patients following lumpectomy with proton radiotherapy. According to the AJCC 8th Edition standard, there were stage I in 26 patients, stage II in 22 patients, and stage III in 2 patients. A total of 14 patients received intensity-modulated proton therapy at a dose of 50 Gy in 25 fractions, followed by a 10 Gy 4 fractionated boost to the lumpectomy cavity, while 36 received 40.05 Gy in 15 fractions, simultaneous integrated boost (SIB) 48 Gy to the lumpectomy cavity. Median follow-up time for 40.05 Gy group was 35.6 months (15–43 months). Median follow-up time for 50 Gy group was 46.8 months (36–68 months). For acute toxicity, the grade 1 and 2 radiodermatitis in conventional-dose group were 35.7% and 57.1%, respectively. In hypofractionated dose group, the grade 1 and 2 radiodermatitis were 91.7% and 8.3%, respectively. The radiodermatitis is hypofractionneted dose better than conventional-dose significantly. Grade 1 radiation-induced esophagitis in conventional-dose group and hypofractionated dose group were 85.71% and 60%, respectively. For late toxicity, no patients developed radiation-induced pneumonitis and rib fracture in conventional-dose group. Three patients presented grade 1 pneumonitis; one patient presented graded 2 pneumonitides and two patients presented rib fracture in hypofractionated dose group. One presented hypothyroidism in hypofractionated dose group. All patients were satisfied with breast shape. The one- and two-year OS and DFS for conventional-dose group were 100 and 100; 100 and 92.9%, respectively. The one- and two-year OS and DFS for hypofractionated dose group were 100 and 100; 100 and 100%, respectively.ConclusionProton radiation therapy can significantly reduce the normal tissue dose in breast cancer patients' hearts, lungs, and other organs. Hypofractionated proton therapy shortens the treatment course with mild radiation-related adverse effects, and has a better effect on addressing the acute adverse reactions than conventional proton radiotherapy.

Stereotactic Body Radiation Therapy for Pulmonary Metastasis from Colorectal Adenocarcinoma: Biologically Effective Dose 150 Gy is Preferred for Tumour Control

AimsTo compare the local control rate of pulmonary metastatic lesions in colorectal adenocarcinoma treated with stereotactic body radiation therapy (SBRT) using a biologically effective dose with an α/β ratio of 10 (BED10) of 150 Gy. Materials and methodsWe analysed 231 pulmonary metastatic lesions from colorectal adenocarcinoma treated with SBRT in 135 patients. The patients were referred for the control of oligometastatic or oligoprogressive disease in the lungs. A dose of 40–60 Gy in three to eight fractions was delivered. The local control per tumour (LCpT) by BED10 was evaluated. The local control per patient (LCpP), pulmonary progression-free survival (PPFS), any progression-free survival (APFS) and overall survival were also reported as clinical outcomes. ResultsA significant difference was observed in the LCpT between the BED10 groups (P < 0.001). The 1-, 2- and 3-year LCpT were 38.9%, 25.9% and 25.9% in BED10 < 100 group; 84.1%, 62.6% and 60.4% in 100 ≤ BED10 < 150 Gy group; and 97.3%, 94.9% and 85.2% in BED10 ≥ 150 Gy group, respectively. BED10 ≥ 150 Gy remained significant in the multivariate analysis of LCpT. The 3-year LCpP, PPFS, APFS and overall survival rates were 62.7%, 26.5%, 24.8% and 67.7%, respectively. Oligoprogression (versus oligometastasis), multiple pulmonary nodules and extrapulmonary metastasis were associated with a poor prognosis. ConclusionA BED10 ≥ 150 Gy may be required to achieve sufficient local control. The indications for SBRT and the extent of metastatic disease should be assessed for proper estimation of the clinical outcomes.

Computed tomography and radiation dose images-based deep-learning model for predicting radiation pneumonitis in lung cancer patients after radiation therapy

PurposeTo develop a deep learning model that combines CT and radiation dose (RD) images to predict the occurrence of radiation pneumonitis (RP) in lung cancer patients who received radical (chemo)radiotherapy. MethodsCT, RD images and clinical parameters were obtained from 314 retrospectively-collected patients (training set) and 35 prospectively-collected patients (test-set-1) who were diagnosed with lung cancer and received radical radiotherapy in the dose range of 50 Gy and 70 Gy. Another 194 (60 Gy group, test-set-2) and 158 (74 Gy group, test-set-3) patients from the clinical trial RTOG 0617 were used for external validation. A ResNet architecture was used to develop a prediction model that combines CT and RD features. Thereafter, the CT and RD weights were adjusted by using 40 patients from test-set-2 or 3 to accommodate cohorts with different clinical settings or dose delivery patterns. Visual interpretation was implemented using a gradient-weighted class activation map (grad-CAM) to observe the area of model attention during the prediction process. To improve the usability, ready-to-use online software was developed. ResultsThe discriminative ability of a baseline trained model had an AUC of 0.83 for test-set-1, 0.55 for test-set-2, and 0.63 for test-set-3. After adjusting CT and RD weights of the model using a subset of the RTOG-0617 subjects, the discriminatory power of test-set-2 and 3 improved to AUC 0.65 and AUC 0.70, respectively. Grad-CAM showed the regions of interest to the model that contribute to the prediction of RP. ConclusionA novel deep learning approach combining CT and RD images can effectively and accurately predict the occurrence of RP, and this model can be adjusted easily to fit new cohorts.

Efficacy and safety of different radiotherapy doses in neoadjuvant chemoradiotherapy in patients with locally advanced rectal cancer: A retrospective study.

This study aims to compare the efficacy and safety of neoadjuvant chemoradiotherapy (nCRT) with different radiotherapy doses (45Gy and 50.4Gy) in patients with locally advanced rectal cancer (LARC). Herein, 120 patients with LARC were retrospectively enrolled between January 2016 and June 2021. All patients underwent two courses of induction chemotherapy (XELOX), chemoradiotherapy, and total mesorectum excision (TME). A total of 72 patients received a radiotherapy dose of 50.4 Gy, while 48 patients received a dose of 45 Gy. Surgery was then performed within 5-12 weeks following nCRT. There was no statistically significant difference between the baseline characteristics of the two groups. The rate of good pathological response in the 50.4Gy group was 59.72% (43/72), while in the 45Gy group achieved 64.58% (31/48) (P>0.05). The disease control rate (DCR) in the 50.4Gy group was 88.89% (64/72), compared to 89.58% (43/48) in the 45Gy group (P>0.05). The incidence of adverse reactions for radioactive proctitis, myelosuppression, and intestinal obstruction or perforation differed significantly between the two groups (P<0.05). The anal retention rate in the 50.4Gy group was significantly higher in contrast to the 45Gy group (P<0.05). Patients receiving a radiotherapy dose of 50.4Gy have a better anal retention rate but also a higher incidence of adverse events such as radioactive proctitis, myelosuppression, and intestinal obstruction or perforation, and a comparable prognosis to patients treated with a radiotherapy dose of 45Gy.

Combined iodine-125 seed strand, portal vein stent, transarterial chemoembolization, lenvatinib and anti-PD-1 antibodies therapy for hepatocellular carcinoma and Vp4 portal vein tumor thrombus: A propensity-score analysis.

To evaluate the safety and efficacy of interventional therapy (iodine-125[125I] seed strand and portal vein stent [PVS] implantation plus transarterial chemoembolization [TACE]) combined with systemic therapy (lenvatinib plus anti-PD-1 antibody) as first-line treatment for hepatocellular carcinoma (HCC) patients with Vp4 portal vein tumor thrombus (PVTT). From December 2018 to October 2021, 87 HCC patients with Vp4 PVTT were included in this single-center retrospective study. Forty-seven patients underwent interventional therapy combined with lenvatinib and anti-PD-1 antibody (group A), while 40 cases underwent interventional therapy combined with lenvatinib only (group B). Overall response rate (ORR), stent occlusion rates (SOR), median overall survival (OS), median progression-free survival (PFS) and median stent patency time (SPT) were compared between the 2 groups. The mean intended dose (r = 10 mm; z = 0; 240 days) was 64.9 ± 1.0 Gy and 64.5 ± 1.1 Gy in group A and B, respectively (p = 0.133). ORR and SOR were significantly different between group A and B (ORR, 55.3% vs 17.5%, p < 0.001; SOR, 12.8% vs 35.0%, p = 0.014). In the propensity-score matching (PSM) cohort, the median OS, median PFS and median SPT were significantly longer in group A compared with group B (32 PSM pairs; OS, 17.7 ± 1.7 vs 12.0 ± 0.8 months, p = 0.010; PFS, 17.0 ± 4.3 vs 8.0 ± 0.7 months, p < 0.001; SPT, not-reached vs 12.5 ± 1.1 months, p = 0.028). This interventional therapy combined with lenvatinib and anti-PD-1 antibody is safe and effective for HCC patients with Vp4 PVTT.

Curcumin Increases Radiosensitivity of Radioresistant Nasopharyngeal Cancer.

To study the effects of curcumin on the proliferation, invasion, apoptosis, and radiosensitivity of the radioresistant nasopharyngeal carcinoma (NPC) C6661-IR strain as well as the potential radiosensitization mechanism. NPC cells were continuously irradiated with different intensities of radiation to induce radiation-resistant cell lines. A plate clone formation assay was used to evaluate the effect of curcumin on the radiosensitivity of NPC cells. 3-(4,5-Dimethylthiazol-2yl)-2,5-diphenyltetrazolium bromide thiazolyl blue (MTT) assay was conducted to detect changes in cell viability. Flow cytometry was employed to analyze apoptosis percentage as well as Transwell® assay and immunofluorescence assay to observe cell invasion. Western blotting was applied to detect the expression levels of Bax, Bcl-2, and pro/cleaved-caspase 3. MiR-205-5p mimics and si-TP53INP1 were synthesized and transfected into C6661-IR cells, and the cells were then incubated with 10 μm/L curcumin. Real-time quantitative reverse transcription PCR (RT-qPCR) was used to measure miR-205-5p levels and western blotting was conducted to detect the expression of TP53INP1. The optimal radiation dose of X-ray was 6 Gy, and this dose was used in all subsequent experiments. Curcumin treatment significantly inhibited the proliferation and invasion of C6661-IR cells, promoted apoptosis and enhanced radiosensitivity. Compared to the 0 Gy+Cur group and the 6 Gy+Cur group, the miR-205-5p levels were higher in the C6661-IR cells of the 0 Gy and 6 Gy groups. Moreover, miR-204-5p was found to directly target TP53INP1. Curcumin downregulated miR-205-5p levels and upregulated TP53INP1 expression (p < 0.05). Thus, modulation of miR-205-5p or TP53INP1 expression attenuates the biological effects of curcumin on C6661-IR cells. Curcumin inhibited the proliferation and invasion of C6661-IR, promoted apoptosis, and enhanced its radiosensitivity to X-rays by mediating miR-205-5p/TP53INP1 expression.

Facial Nerve Schwannoma Treatment with Stereotactic Radiosurgery (SRS) versus Resection followed by SRS: Outcomes and a Management Protocol.

Background Stereotactic radiosurgery (SRS) and resection are treatment options for patients with facial nerve schwannomas without mass effect. Objective This article evaluates outcomes of patients treated with SRS versus resection + SRS. Method We retrospectively compared 43 patients treated with SRS to 12 patients treated with resection + SRS. The primary study outcome was unfavorable combined endpoint, defined as worsening or new clinical symptoms, and/or tumor radiological progression. SRS (38.81 ± 5.3) and resection + SRS (67.14 ± 11.8) groups had similar clinical follow-ups. Results At the time of SRS, the tumor volumes of SRS (mean ± standard error; 1.83 ± 0.35 mL) and resection + SRS (2.51 ± 0.75 mL) groups were similar. SRS (12.15 ± 0.08 Gy) and resection + SRS (12.16 ± 0.14 Gy) groups received similar radiation doses. SRS group (42/43, 98%) had better local tumor control than the resection + SRS group (10/12, 83%, p = 0.04). Most of SRS (32/43, 74%) and resection + SRS (10/12, 83%) group patients reached a favorable combined endpoint following SRS ( p = 0.52). Considering surgical associated side effects, only 2/10 patients of the resection + SRS group reached a favorable endpoint ( p < 0.001). Patients of SRS group, who are > 34 years old ( p = 0.02), have larger tumors (> 4 mL, 0.04), internal auditory canal (IAC) segment tumor involvement ( p = 0.01) were more likely to reach an unfavorable endpoint. Resection + SRS group patients did not show such a difference. Conclusion While resection is still needed for larger tumors, SRS offers better clinical and radiological outcomes compared to resection followed by SRS for facial schwannomas. Younger age, smaller tumors, and non-IAC situated tumors are factors that portend a favorable outcome.

696 EFFECTS OF DIRECT IRRADIATION ON CARDIAC IMPIANTABLE ELECTRONIC DEVICES

Abstract Aims Cardiac implantable electronic devices (CIEDs) may sustain damages during a course of radiation therapy, especially when the beam is directed onto the pulse generator, with device electrical reset and/or sudden battery drain. 2010 HRS/ASA expert consensus, and all CIEDs manufacturers, recommend to avoid devices direct irradiation with an accumulated dose that exceed 5 grays (Gy). In our prospective study we tested the effects of direct irradiation on CIEDs with different radiation doses, also higher than 5 Gy. Methods 124 CIEDs of Medronic, Abbott, Biotronik, Boston Scientific, were collected during system upgrading or lead extraction procedures. All devices were considered if they had at least 80% of residual battery capacity. All CIEDs were programmed with same default electrical parameters. Depending by CIED type, pacing mode was configured in VVI, VVIR, VDDR or DDDR, and biventricular stimulation was activated, if present. ICDs electrical therapies were set-up with a pre-determined configuration. All devices were singularly placed in a 30 cm×30 cm plastic bowl containing 2 Lt of deionized water that was placed over 5 cm Rockwool to simulate the backscatter and irradiated by a linear accelerator (Elekta Synergy®). CIEDs were divided into two groups depending on irradiation dose delivered: 5 Gy and 10 Gy. Results No significant differences in battery drainage were observed after irradiation respect to baseline in 5 Gy as well 10 Gy group (7.8±3.1 vs. 7.4±2.1 [years] battery longevity, p=0.693; 7.6±3.1 vs. 7.3±2.1 [years] battery longevity, p=0.677, respectively) . Moreover, all CIEDS saved the baseline program setting, without device reset events. Conclusions Our data confirm that CIEDs direct irradiation of 5 Gy is safe, of note, direct irradiation up to 10 Gy seems to be similarly safe concerning the risk of CIEDs electrical reset and/or unexpected battery drain.

The mapping of mRNA alterations elucidates the etiology of radiation-induced pulmonary fibrosis.

The etiology of radiation-induced pulmonary fibrosis is not clearly understood yet, and effective interventions are still lacking. This study aimed to identify genes responsive to irradiation and compare the genome expression between the normal lung tissues and irradiated ones, using a radiation-induced pulmonary fibrosis mouse model. We also aimed to map the mRNA alterations as a predictive model and a potential mode of intervention for radiation-induced pulmonary fibrosis. Thirty C57BL/6 mice were exposed to a single dose of 16Gy or 20Gy thoracic irradiation, to establish a mouse model of radiation-induced pulmonary fibrosis. Lung tissues were harvested at 3 and 6months after irradiation, for histological identification. Global gene expression in lung tissues was assessed by RNA sequencing. Differentially expressed genes were identified and subjected to functional and pathway enrichment analysis. Immune cell infiltration was evaluated using the CIBERSORT software. Three months after irradiation, 317 mRNAs were upregulated and 254 mRNAs were downregulated significantly in the low-dose irradiation (16Gy) group. In total, 203 mRNAs were upregulated and 149 were downregulated significantly in the high-dose irradiation (20Gy) group. Six months after radiation, 651 mRNAs were upregulated and 131 were downregulated significantly in the low-dose irradiation group. A total of 106 mRNAs were upregulated and 4 downregulated significantly in the high-dose irradiation group. Several functions and pathways, including angiogenesis, epithelial cell proliferation, extracellular matrix, complement and coagulation cascades, cellular senescence, myeloid leukocyte activation, regulation of lymphocyte activation, mononuclear cell proliferation, immunoglobulin binding, and the TNF, NOD-like receptor, and HIF-1 signaling pathways were significantly enriched in the irradiation groups, based on the differentially expressed genes. Irradiation-responsive genes were identified. The differentially expressed genes were mainly associated with cellular metabolism, epithelial cell proliferation, cell injury, and immune cell activation and regulation.

Multi-Institutional Investigation of Dose-Escalated Photon Radiotherapy for Intracranial Ependymoma

<h3>Purpose/Objective(s)</h3> Adjuvant radiotherapy (RT) is an important modality of treatment for intracranial ependymoma. The most recently published Children's Oncology Group (COG) Study ACNS0121 recommended 54 Gy after gross total resection (GTR) for patients (pts) <18 months of age and 59.4 Gy for all other pts; however, the optimal RT dose remains unclear. Thus, we sought to characterize outcomes after dose-escalated photon radiotherapy (≥59.4 Gy) for intracranial ependymoma. <h3>Materials/Methods</h3> We conducted an Institutional Review Board-approved multi-institutional retrospective cohort analysis of pts who received surgery and radiation for grade II and III intracranial ependymoma between 1997-2021 before the age of 30 years. We recorded clinical and treatment characteristics, and outcomes. Progression-free survival (PFS) and overall survival (OS) were analyzed by Kaplan-Meier method and Tarone-Ware test. <h3>Results</h3> We identified 53 pts who were diagnosed at median age of 6.2 years (range: 0.9-29.9) and of which 20 (37.7%) were female. 20 (37.7%), 41 (77.4%), and 3 (5.7%) pts had anaplastic histology, infratentorial tumors, and metastatic disease at diagnosis, respectively. 15 (28.3%) pts received pre-RT chemotherapy and 10 pts (18.9%) had disease progression before RT. After median of 1 surgery (range: 1-5), 41 (77.4%) pts had a GTR before RT. 32 (60.4%) pts received ≥59.4 Gy. Median age at diagnosis was significantly lower for patients in the <59.4 Gy group compared to ≥59.4 Gy (3.9 vs. 8.7 years, p=0.01). Other factors were not significantly different between the two groups; however, fewer patients had anaplastic histology in the <59.4 Gy group compared to ≥59.4 Gy (23.8% vs. 46.9%, p=0.15). Median follow-up was 20.1 (range: 0.1-21.9) and 8.4 (range: 0.9-16.6) years for the <59.4 Gy and ≥59.4 Gy groups, respectively. PFS (8-year rates of 31.6% vs. 49.7%, p=0.24) and OS (8-year rates of 46.3% vs. 66.3%, p=0.19) were not significantly different between the <59.4 Gy and ≥59.4 Gy groups. Given anaplastic histology portends poor outcome, we examined outcomes for pts with grade 2 ependymoma, and found no significant difference in PFS (8-year rates of 40.0% vs. 61.5%, p=0.11) and OS (8-year rates of 46.7% vs. 64.8%, p=0.13) between the <59.4 Gy and ≥59.4 Gy groups. Median time to recurrence was 1.3 years (range: 0.3-14.7). Of the 29 recurrences in cohort, 7 (24.1%) occurred 5 years after RT. <h3>Conclusion</h3> In a modest sample size of pts undergoing photon-based RT for intracranial ependymoma, we found that there was a non-significant trend to PFS and OS being longer in pts receiving ≥59.4 Gy. Interestingly, 24.1% of recurrences in our cohort occurred 5 years or longer after RT, indicating that intracranial ependymoma can have a long disease course and long follow-up is important when studying outcomes. Future studies with larger cohorts and prospective design are still needed.

MRNA Alteration Mapping of Radiation-Induced Pulmonary Fibrosis in C57BL/6 Mice

<h3>Purpose/Objective(s)</h3> Radiation-induced lung injury, including radiation-induced pneumonitis and pulmonary fibrosis, is a common serious dose-limiting toxicity of thoracic radiotherapy, and can be life-threatening. There is no definite conclusion of the etiology of radiation-induced pulmonary fibrosis (RIPF), and the effective interventions are still lacking. In this study, based on RIPF mouse model, we aim to identify genes responsive to irradiation, compare the difference in genome expression between normal lung tissues and the irradiated ones, and to provide the mRNA alteration mapping that can make the predictive model and potential interventions of RIPF. <h3>Materials/Methods</h3> Thirty C57BL/6 mice were randomized into 3 groups: control group (sham radiation), 16 Gy thoracic radiation group and 20 Gy radiation group to establish the RIPF mouse model. Lung tissues were harvested at 3 and 6 months after irradiation. The global gene expression of lung tissues was assessed by RNA sequencing. Differentially expressed genes were identified and subjected to function and pathway enrichment analysis. Infiltration of immune cells was evaluated by CIBERSORT. <h3>Results</h3> RIPF mouse model was successfully established in both 16 Gy and 20 Gy thoracic radiation groups. At 3 months after radiation, 317 mRNAs were significantly upregulated and 254 downregulated in the 16 Gy thoracic radiation group. 203 mRNAs were upregulated and 149 downregulated significantly in the 20 Gy group. At 6 months after radiation, 651 mRNAs were significantly upregulated and 131 downregulated in the 16 Gy group. 106 mRNAs were significantly upregulated and 4 downregulated in the 20 Gy group. Several functions and pathways including angiogenesis, epithelial cell proliferation, extracellular matrix, complement and coagulation cascades, TNF signaling pathway, NOD-like receptor signaling pathway, and HIF-1 signaling pathway were significantly enriched based on the differentially expressed genes in irradiation groups at 3 months after thoracic radiation. Cellular senescence, myeloid leukocyte activation, regulation of lymphocyte activation, mononuclear cell proliferation, immunoglobulin binding, and some other immune system associated pathways were also significantly enriched in irradiation groups at 6 months after radiation. We confirmed a dramatic increase of macrophage, neutrophil, dentric cell and natural killer cell, and a decrease of B cell in the two irradiation groups at 3 months. At 6 months, the infiltration of B cell in the 20 Gy group grew and became higher than the control group. <h3>Conclusion</h3> By RNA-seq, the irradiation responsive genes were identified. The differentially expressed genes were mainly associated with cell injury, cellular metabolism, epithelial and endothelial cell proliferation, and immune cell activation and regulation. Our results provided comprehensive clues on the mechanism of RIPF, which hopefully, may turn into the potential treatment target in preventing and reversing RIPF.

Using Hyperbaric Oxygen to Improve the Radiosensitivity of Human U251 Glioma Cells.

The aim of this study was to explore the use of hyperbaric oxygen to enhance the radiosensitivity of human glioma cells. Sub-cultured U251 human glioma cells were randomly divided into four groups: an untreated control group, cells treated with hyperbaric oxygen (HBO) only, cells treated with X-ray irradiation (X-ray) only, and cells treated with both HBO and X-ray. Cell morphology, cell proliferation activity, cell cycle distribution, and apoptosis were observed in these groups to evaluate the role of HBO in improving the radiosensitivity of glioma cells. With the increase in X-ray doses (0 Gy, 2 Gy, 4 Gy, 6 Gy, 8 Gy), the survival fraction (SF) of glioma cells gradually decreased. Significantly lower SF was observed for the cells treated with the HBO and X-ray together than in the X-ray group for each dose (all P < 0.05). The proliferation inhibition was significantly higher in the HBO combined with X-ray group than in the X-ray group for each dose (all P < 0.05) for the U251 cell line. The percentage of G2/M phase cells was significantly higher in the HBO combined with X-ray (2 Gy) group (26.70% ± 2.46%) and the HBO group (22.36% ± 0.91%) than in the control group (11.56% ± 2.01%) and X-ray (2 Gy) group (10.35% ± 2.69%) (all P < 0.05). U251 cell apoptosis was significantly higher in the HBO combined with X-ray (2 Gy) group than in the HBO group, the X-ray (2 Gy) group, and the control group (all P < 0.05). We conclude that HBO can enhance the proliferation inhibition and apoptosis of glioma U251 cells by blocking glioma cells in the G2/M phase and improve the radiosensitivity of U251 glioma cells.

Safety and feasibility of stereotactic radiation therapy on porcine ventricular septum: a preliminary study

Objective: To explore the safety and feasibility of stereotactic radiation therapy (SBRT) strategy for irradiating porcine ventricular septum, see if can provide a preliminary experimental evidence for clinical SBRT in patients with hypertrophic obstructive cardiomyopathy (HOCM). Methods: Five male pigs (39-49 kg, 6 months old) were used in this study. Pigs were irradiated at doses of 25 Gy (n=2) or 40 Gy (n=3). Delineation of the target volume was achieved under the guidance of 3-dimensional CT image reconstruction, and SBRT was then performed on defined target volume of porcine ventricular septum. Blood biomarkers, electrocardiogram and echocardiography parameters were monitored before and after SBRT. Pathological examination (HE staining, Masson staining) was performed on the target and non-target myocardium at 6 months post SBRT. Results: SBRT was successful and all animals survived to the designed study endpoint (6 months) after SBRT. Serum cardiac troponin T (cTnT) level was significantly higher than the baseline level at 1 day post SBRT, and reduced at 1 week after SBRT, but was still higher than the baseline level(P<0.05). Serum N-terminal pro-B type natriuretic peptide (NT-proBNP) was also significantly increased at 1 day post SBRT (P<0.05) and returned to baseline level at 1 week post SBRT. The serum NT-proBNP level was (249±78), (594±37) and (234±46) pg/ml, respectively, and the cTnT was (14±7), (240±40) and (46±34) pg/ml, respectively at baseline, 1 day and 1 week after SBRT in the 40 Gy dose group. The serum NT-proBNP level was (184±20), (451±49) and (209±36) pg/ml, respectively, the cTnT values ​​were (9±1), (176±29) and (89±27) pg/ml, respectively at baseline, 1 day and 1 week after SBRT in the 25 Gy dose group. Both NT-proBNP and cTnT values tended to be higher post SBRT in the 40 Gy dose group as compared with the 25 Gy dose group, but the difference was not statistically significant (P>0.05). The left ventricular ejection fraction and the left ventricular end-diastolic diameter remained unchanged before and after SBRT (P>0.05). The interventricular septum thickness showed a decreasing trend at 6 months after SBRT, but the difference was not statistically significant ((9.54±0.24) mm vs. (9.82±8.00) mm, P>0.05). The flow velocity of the left ventricular outflow tract, and the valve function and morphology were not affected by SBRT. At 6 months after SBRT, HE staining revealed necrosis in the irradiated target area of ​​the myocardium in the 40 Gy dose group and the 25 Gy dose group, and the degree of necrosis in the irradiated interventricular septum was more obvious in the 40 Gy dose group as compared with the 25 Gy group. The combined histological analysis of the two groups showed that the necrotic area of ​​the irradiated target area accounted for (26±9)% of the entire interventricular septum area, which was higher than that of the non-irradiated area (0) (P<0.05). There was no damage or necrosis of myocardial tissue outside the target irradiation area in both groups. The results of Masson staining showed that the percentage area of myocardial fibrosis was significantly higher in the irradiated target area than non-irradiated area ((12.6±5.3)% vs. (2.5±0.8)%, P<0.05). Conclusion: SBRT is safe and feasible for irradiating porcine ventricular septum.

Histological and impedance changes of skeletal muscle by whole-body critical irradiation in a rat model

In this study, the electrical resistance of the whole body and histological changes of skeletal muscle were investigated in rats according to the increase in radiation dose. A total of 15 male Sprague-Dawley rats (5-weeks-old) were randomly divided into 5 groups (each, n = 3). Each group received 1 Gy, 5 Gy, 10 Gy and 20 Gy systemic exposure, and the non-irradiated group was used as a control for morphological comparison. After attaching an electrode clip to the forelimb of the rat, an AC frequency was applied before and 4 days after irradiation using an impedance/gain-phase analyzer, and the measurement system was automatically controlled with LabVIEW. Comparing to before irradiation after 4 days, the difference in the average impedance values at 1 Gy, 5 Gy, 10 Gy, and 20 Gy was 1188±989 ohm, 3076±2251 ohm, 7650±6836 ohm, and 10478±6250 ohm, respectively. By comparing the normal group and the experimental group, muscle fiber atrophy and collagen fibers around blood vessels were observed (p < 0.05, control group vs 5 Gy or more high-dose group). These results confirmed the previously reported morphological changes of skeletal muscle and our hypothesis that whole-body impedance measurement enables to reflect tissue changes after irradiation.

Advancements in the radiooncological treatment of high-risk prostate cancer: a quarter century of achievements.

BackgroundThe aim of the study was to evaluate the development of treatment of primary high-risk prostate cancer in regards to biochemical no evidence of disease (bNED), acute and late gastrointestinal (GI) and genitourinary (GU) side effects.Patients and methodsPrimary high-risk prostate cancer patients treated between 1994 and 2016 were included. Applied doses ranged from 60 to 80 Gy, with a dose of 1.8 or 2 Gy per fraction. Techniques were either 3D conformal or intensity modulated radiotherapy and volumetric intensity modulated arc therapy.Results142 patients were treated with doses up to 70 Gy (median dose 66 Gy; 66 Gy group), 282 with doses between 70 and 76 Gy (median dose 74 Gy; 74 Gy group), and 141 with doses >76 Gy (median dose 78 Gy; 78 Gy group). The median follow-up was 48 months. The bNED rates were 50% after 5 years and 44% after 9 years in the 66 Gy group; 65% and 54%, respectively, in the 74 Gy group; and 83% and 66%, respectively, in the 78 Gy group (p = 0.03 vs. 74 Gy and p < 0.0001 vs. 66 Gy). We found a higher rate of acute GI side effects in the 78 Gy group compared to the other groups, but not in maximum acute GU side effects and late maximum GI and GU effects.ConclusionsHigh-risk prostate cancer patients treated with doses of 78 Gy had significantly better bNED rates. Compared to the historical 66 Gy group, 50% more patients achieved bNED after a follow-up of 9 years.