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In recent years, a significant research effort has been underway to explore the effects of low-dose radiation (LDR). Animal models play a key role in various fields of research, including biomedicine, pharmaceutical, environmental, and behavioral studies. The use of animal models has been an invaluable tool in radiation research for understanding radiation biology, assessing radiation risks, and developing strategies for radiation protection and medical management. In the present review, the initial part focuses on the deleterious effects of high-dose radiation, and in correlation to that, in the later part of the review, the emphasis has been given to experimental approaches to explore the beneficial effects of LDR using animal models. This review could help explore the innovative approach for future research targeting the therapeutic role of LDR in various diseases, including depression, Cancer, Parkinson’s disease, and Alzheimer’s disease.

Abstract Background Concurrent chemoradiotherapy (CCRT) is the standard treatment for locally advanced esophageal squamous cell carcinoma (ESCC). However, the optimal radiotherapy regimen, particularly in terms of total dose and planned range of irradiation field, remains unclear. This phase III clinical trial aimed to compare the survival benefits between different radiation doses and different target fields. Methods This trial compared two aspects of radiation treatment, total dose and field, using a two‐by‐two factorial design. The high‐dose (HD) group received 59.4 Gy radiation, and the standard‐dose (SD) group received 50.4 Gy. The involved field irradiation (IFI) group and elective nodal irradiation (ENI) group adopted different irradiation ranges. The participants were assigned to one of the four groups (HD+ENI, HD+IFI, SD+ENI and SD+IFI). The primary endpoint was overall survival (OS), and the secondary endpoints included progression‐free survival (PFS). The synergy indexwas used to measure the interaction effect between dose and field. Results The interaction analysis did not reveal significant synergistic effects between the dose and irradiation field. In comparison to the target field, patients in IFI or ENI showed similar OS (hazard ratio [HR] = 0.99, 95% CI: 0.80‐1.23, p = 0.930) and PFS (HR = 1.02, 95% CI: 0.82–1.25). The HD treatment did not show significantly prolonged OS compared with SD (HR = 0.90, 95% CI: 0.72–1.11, p = 0.318), but it suggested improved PFS (25.2 months to 18.0 months). Among the four groups, the HD+IFI group presented the best survival, while the SD+IFI group had the worst prognosis. No significant difference in the occurrence of severe adverse events was found in dose or field comparisons. Conclusions IFI demonstrated similar treatment efficacy to ENI in CCRT of ESCC. The HD demonstrated improved PFS, but did not significantly improve OS. The dose escalation based on IFI (HD+IFI) showed better therapeutic efficacy than the current recommendation (SD+ENI) and is worth further validation.

In recent years, a significant research effort has been underway to explore the effects of low-dose radiation (LDR). Animal models play a key role in various fields of research, including biomedicine, pharmaceutical, environmental, and behavioral studies. The use of animal models has been an invaluable tool in radiation research for understanding radiation biology, assessing radiation risks, and developing strategies for radiation protection and medical management. In the present review, the initial part focuses on the deleterious effects of high-dose radiation, and in correlation to that, in the later part of the review, the emphasis has been given to experimental approaches to explore the beneficial effects of LDR using animal models. This review could help explore the innovative approach for future research targeting the therapeutic role of LDR in various diseases, including depression, Cancer, Parkinson's disease, and Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Organisms frequently suffer negative effects from large doses of ionizing radiation. However, radiation is not as hazardous at lower doses as was once believed. The current study aims to evaluate the possible radio‐adaptive effect induced by low‐dose radiation (LDR) in modulating high‐dose radiation (HDR) and N‐nitrosodiethylamine (NDEA)‐induced lung injury in male albino rats. Sixty‐four male rats were randomly divided into four groups: Group 1 (control): normal rats; Group 2 (D): rats given NDEA in drinking water; Group 3 (DR): rats administered with NDEA then exposed to fractionated HDR; and Group 4 (DRL): rats administered with NDEA then exposed to LDR + HDR. In the next stage, malondialdehyde (MDA), glutathione reduced (GSH), catalase (CAT), and superoxide dismutase (SOD) levels in the lung tissues were measured. Furthermore, the enzyme‐linked immunoassay analysis technique was performed to assess the Toll‐like receptor 4 (TLR4), interleukin‐1 receptor‐associated kinase 4 (IRAK4), and mitogen‐activated protein kinases (MAPK) expression levels. Histopathological and DNA fragmentation analyses in lung tissue, in addition to hematological and apoptosis analyses of the blood samples, were also conducted. Results demonstrated a significant increase in antioxidant defense and a reduction in MDA levels were observed in LDR‐treated animals compared to the D and DR groups. Additionally, exposure to LDR decreased TLR4, IRAK4, and MAPK levels, decreased apoptosis, and restored all the alterations in the histopathological, hematological parameters, and DNA fragmentation, indicating its protective effects on the lung when compared with untreated rats. Taken together, LDR shows protective action against the negative effects of subsequent HDR and NDEA. This impact may be attributable to the adaptive response induced by LDR, which decreases DNA damage in lung tissue and activates the antioxidative, antiapoptotic, and anti‐inflammatory systems in the affected animals, enabling them to withstand the following HDR exposure. Significance statement: The present work was designed to evaluate the adaptive response of low doses of gamma radiation against high doses of gamma radiation‐induced toxicity in lung tissue. [ABSTRACT FROM AUTHOR]

To understand the ultra-early reaction of normal organ lipids during irradiation, we investigated the response of lipids, including polyunsaturated fatty acid (PUFA) chains, which are particularly susceptible to damage by ROS, in mice's kidneys, lungs, brains, and livers within 5 min of single high-dose irradiation. In this study, we set up three groups of C56BL/6 male mice and conducted whole-body irradiation with 0 Gy, 10 Gy, and 20 Gy single doses. Kidney, lung, brain, and liver tissues were collected within 5 min of irradiation. PUFA-targeted and whole lipidomic analyses were conducted using liquid chromatography–tandem mass spectrometry (LC-MS/MS). The results showed that PUFA chains of kidney phosphatidylcholine (PC), phosphatidylethanolamine (PE), and triacylglycerol (TG) significantly increased within 5 min of 10 Gy and 20 Gy irradiation. The main components of increased PUFA chains in PC and PE were C18:2, C20:4, and C22:6, and in TG the main component was C18:2. The kidney lipidomes also showed significant changes from the perspective of lipid species, mainly dominated by an increase in PC, PE, TG, and signal lipids, while lipidomes of the lung, brain, and liver were slightly changed. Our results revealed that acute PUFA chains increase and other lipidomic changes in the kidney upon whole-body irradiation within 5 min of irradiation. The significantly increased lipids also showed a consistent preference for possessing PUFA chains. The lipidomic changes varied from organ to organ, which indicates that the response upon irradiation within a short time is tissue-specific. [ABSTRACT FROM AUTHOR]

Simple Summary: The standard of care (SoC) for patients with unresectable stage III non-small-cell lung cancer is concurrent chemoradiation followed by durvalumab. Because of co-morbidities, however, the concurrent approach is only amenable for about one-third of patients. While sequential regimens are usually regarded as palliative, these schedules applied in a dose-escalated mode may be part of a curative approach. As the combination of high-dose radiation and durvalumab remains a question of ongoing research, this retrospective study aims at evaluating pulmonary side effects after sequential chemoradiotherapy with high-dose irradiation compared to SoC. Radiation dose escalation showed no excess pulmonary toxicity such as pneumonitis but tendentially better intrathoracic control, suggesting that this alternative approach is safe and feasible. Introduction: The standard of care (SoC) for unresectable stage III non-small-cell lung cancer (NSCLC) is durvalumab maintenance therapy after concurrent chemoradiation in patients with PD-L1 > 1%. However, the concurrent approach is only amenable for about one-third of patients due to co-morbidities. Although sequential regimens are usually not regarded as curative, these schedules applied in a dose-escalated manner may be similarly radical as SoC. As combining high-dose radiation and durvalumab remains a question of debate this retrospective bi-center study aims to evaluate pulmonary toxicity after high-dose chemoradiotherapy beyond 70 Gy compared to SoC. Patients and Methods: Patients with NSCLC stage III received durvalumab after either sequential high-dose chemoradiation or concomitant SoC. Chemotherapy consisted of platinum combined with either pemetrexed, taxotere, vinorelbine, or gemcitabine. The primary endpoint was short-term pulmonary toxicity occurring within six months after the end of radiotherapy (RT). Results: A total of 78 patients were eligible for this analysis. 18F-FDG-PET-CT, cranial MRT, and histological/cytological verification were mandatory in the diagnostic work-up. The high-dose and SoC group included 42/78 (53.8%) and 36/78 (46.2%) patients, respectively, which were matched according to baseline clinical variables. While the interval between the end of RT and the start of durvalumab was equal in both groups (p = 0.841), more courses were administered in the high-dose cohort (p = 0.031). Pulmonary toxicity was similar in both groups (p = 0.599), whereas intrathoracic disease control was better in the high-dose group (local control p = 0.081, regional control p = 0.184). Conclusion: The data of this hypothesis-generating study suggest that sequential high-dose chemoradiation followed by durvalumab might be similar to SoC in terms of pulmonary toxicity and potentially more effective with respect to intra-thoracic disease control. Larger trials with a prospective design are warranted to validate these results. [ABSTRACT FROM AUTHOR]

Introduction: Curatively intended chemo-radio-immunotherapy for non-small cell lung cancer (NSCLC) stage III may lead to post-therapeutic pulmonary function (PF) impairment. We hypothesized that the decrease in global PF corresponds to the increase in tissue density in follow-up CTs. Hence, the study aim was to correlate the dynamics in radiographic alterations to carbon monoxide diffusing capacity (DL CO ) and FEV 1 , which may contribute to a better understanding of radiation-induced lung disease. Methods: Eighty-five patients with NSCLC III were included. All of them received two cycles of platinum-based induction chemotherapy followed by high dose radiation. Thereafter, durvalumab was administered for one year in 63/85 patients (74%). Pulmonary function tests (PFTs) were performed three months and six months after completion of radiotherapy (RT) and compared to baseline. At the same time points, patients underwent diagnostic CT (dCT). These dCTs were matched to the planning CT (pCT) using RayStation® Model Based Segmentation and deformable image registration. Differential volumes defined by specific isodoses were generated to correlate them with the PFTs. Results: In general, significant correlations between PFTs and differential volumes were found in the mid-dose range, especially for the volume of the lungs receiving between 65% and 45% of the dose prescribed (V 65 − 45 % ) and DL CO ( p < 0.01 ). This volume range predicted DL CO after RT (p-value 0.03) as well. In multivariate analysis, DL CO (p-value 0.040) and FEV 1 (p-value 0.014) predicted pneumonitis. Conclusions: The current analysis revealed a strong relation between the dynamics of DL CO and CT morphology changes in the mid-dose range, which convincingly indicates the importance of routinely used PFTs in the context of a curative treatment approach. [ABSTRACT FROM AUTHOR]

Background: Concurrent chemoradiotherapy (CCRT) is the standard treatment for locally advanced esophageal squamous cell carcinoma (ESCC). However, the optimal radiotherapy regimen, particularly in terms of total dose and planned range of irradiation field, remains unclear. This phase III clinical trial aimed to compare the survival benefits between different radiation doses and different target fields., Methods: This trial compared two aspects of radiation treatment, total dose and field, using a two-by-two factorial design. The high-dose (HD) group received 59.4 Gy radiation, and the standard-dose (SD) group received 50.4 Gy. The involved field irradiation (IFI) group and elective nodal irradiation (ENI) group adopted different irradiation ranges. The participants were assigned to one of the four groups (HD+ENI, HD+IFI, SD+ENI and SD+IFI). The primary endpoint was overall survival (OS), and the secondary endpoints included progression-free survival (PFS). The synergy indexwas used to measure the interaction effect between dose and field., Results: The interaction analysis did not reveal significant synergistic effects between the dose and irradiation field. In comparison to the target field, patients in IFI or ENI showed similar OS (hazard ratio [HR] = 0.99, 95% CI: 0.80-1.23, p = 0.930) and PFS (HR = 1.02, 95% CI: 0.82-1.25). The HD treatment did not show significantly prolonged OS compared with SD (HR = 0.90, 95% CI: 0.72-1.11, p = 0.318), but it suggested improved PFS (25.2 months to 18.0 months). Among the four groups, the HD+IFI group presented the best survival, while the SD+IFI group had the worst prognosis. No significant difference in the occurrence of severe adverse events was found in dose or field comparisons., Conclusions: IFI demonstrated similar treatment efficacy to ENI in CCRT of ESCC. The HD demonstrated improved PFS, but did not significantly improve OS. The dose escalation based on IFI (HD+IFI) showed better therapeutic efficacy than the current recommendation (SD+ENI) and is worth further validation., (© 2024 The Author(s). Cancer Communications published by John Wiley & Sons Australia, Ltd on behalf of Sun Yat‐sen University Cancer Center.)

Introduction: Curatively intended chemo-radio-immunotherapy for non-small cell lung cancer (NSCLC) stage III may lead to post-therapeutic pulmonary function (PF) impairment. We hypothesized that the decrease in global PF corresponds to the increase in tissue density in follow-up CTs. Hence, the study aim was to correlate the dynamics in radiographic alterations to carbon monoxide diffusing capacity (DLCO) and FEV1, which may contribute to a better understanding of radiation-induced lung disease. Methods: Eighty-five patients with NSCLC III were included. All of them received two cycles of platinum-based induction chemotherapy followed by high dose radiation. Thereafter, durvalumab was administered for one year in 63/85 patients (74%). Pulmonary function tests (PFTs) were performed three months and six months after completion of radiotherapy (RT) and compared to baseline. At the same time points, patients underwent diagnostic CT (dCT). These dCTs were matched to the planning CT (pCT) using RayStation® Model Based Segmentation and deformable image registration. Differential volumes defined by specific isodoses were generated to correlate them with the PFTs. Results: In general, significant correlations between PFTs and differential volumes were found in the mid-dose range, especially for the volume of the lungs receiving between 65% and 45% of the dose prescribed (V65−45%) and DLCO (p<0.01). This volume range predicted DLCO after RT (p-value 0.03) as well. In multivariate analysis, DLCO (p-value 0.040) and FEV1 (p-value 0.014) predicted pneumonitis. Conclusions: The current analysis revealed a strong relation between the dynamics of DLCO and CT morphology changes in the mid-dose range, which convincingly indicates the importance of routinely used PFTs in the context of a curative treatment approach.

The optimal induction treatment in potentially-resectable stage IIIA-N2 NSCLC remains undefined. To compare neoadjuvant high-dose chemoradiotherapy (CRT) to neoadjuvant chemotherapy (CHT) in patients with resectable, stage IIIA-N2 non-small-cell lung cancer (NSCLC). Retrospective, multicentre study of 99 patients diagnosed with stage cT1-T3N2M0 NSCLC who underwent neoadjuvant treatment (high-dose CRT or CHT) followed by surgery between January 2005 and December 2014. 47 patients (47.5%) underwent CRT and 52 (52.5%) CHT, with a median follow-up of 41 months. Surgery consisted of lobectomy (87.2% and 82.7%, in the CRT and CHT groups, respectively) or pneumonectomy (12.8% vs. 17.3%). Nodal downstaging (to N1/N0) and Pathologic complete response (pCR; pT0pN0) rates were significantly higher in the CRT group (89.4% vs. 57.7% and 46.8% vs. 7.7%, respectively; p < 0.001)). Locoregional recurrence was significantly lower in the CRT group (8.5% vs. 13.5%; p = 0.047) but distant recurrence rates were similar in the two groups. Median PFS was 45 months (CHT) vs. "not reached" (CRT). Median OS was similar: 61 vs. 56 months (p = 0.803). No differences in grade ≥3 toxicity were observed. On the Cox regression analysis, advanced pT stage was associated with worse OS and PFS (p < 0.001) and persistent N2 disease (p = 0.002) was associated with worse PFS. Compared to neoadjuvant chemotherapy alone, a higher proportion of patients treated with preoperative CRT achieved nodal downstaging and pCR with better locoregional control. However, there were no differences in survival. More studies are needed to know the optimal treatment of these patients. [ABSTRACT FROM AUTHOR]

It has been well documented that the outcome of prostate cancer treatment depends on the dose administered. Hence, techniques have been developed that allow high-dose administration without increasing the complications, e.g. external radiotherapy combined with high-dose radiation (HDR) brachytherapy. In this article we analyse the technique and protocol of real-time HDR brachytherapy together with the preliminary results that support its use. Between June 1998 and December 2004, 100 patients with adenoma of the prostate were treated with 46 Gy of external irradiation to the pelvis and 2 HDR brachytherapy fractions (each of 1150 cGy) at the end of weeks 1 and 3 of a 5-week radiotherapy course. The 1997 American Joint Commission on Cancer (AJCC) system was used to establish disease stage. Patients with intermediaterisk (PSA 10–20 ng/ml or Gleason=7 or T2c) and high-risk (two intermediate risk factors or PSC >20 ng/ml or Gleason >7 or >T2c) without metastases were eligible for the brachytherapy. Biochemical failure was defined according to the American Society for Therapeutic Radiology and Oncology (ASTRO) consensus panel statement. SPSS statistical package was used to quantify survival (Kaplan-Meier method). Toxicity was scored according to RTOG guidelines. The mean age of patients was 67 years (range 49–78). Clinical stage was T2a in 22% of the patients, 26% T2b and 52% T3. Initial PSA was = 10 ng/ml in 22% of the patients and >10 ng/ml in 78%. Median follow-up was 28 months (range: 12–79). The 5-year overall survival and actuarial biochemical control were 99% and 87% respectively. No chronic severe complications were noted. The good results of local control, disease-free survival and few complications that the external radiotherapy combined with HDR brachytherapy have shown suggest that the method should be considered as first-choice in the treatment of prostate tumours of high-and intermediate-risk. [ABSTRACT FROM AUTHOR]

The authors present four patients with a history of high dose cranial irradiation, who were diagnosed years later to have symptomatic meningiomas requiring surgical management. Relevant literature pertaining to these rare tumours is reviewed and their unusual characteristics highlighted. Their aetio-pathogenesis and management strategies are discussed. [ABSTRACT FROM AUTHOR]

The bronchial tolerance to high doses of radiation is not fully understood. However, in the event of a radiological accident with unintended exposure of the central airways to high doses of radiation it would be important to be able to anticipate the clinical consequences given the magnitude of the absorbed dose to different parts of the bronchial tree. Stereotactic body radiation therapy (SBRT) is a radiation treatment technique involving a few large fractions of photon external-beam radiation delivered to a well-defined target in the body. Despite generally favourable results, with high local tumour control and low-toxicity profile, its utility for tumours located close to central thoracic structures has been questioned, considering reports of severe toxic symptoms such as haemoptysis (bleedings from the airways), bronchial necrosis, bronchial stenosis, fistulas and pneumonitis. In conjunction with patient- and tumour-related risk factors, recent studies have analysed the absorbed radiation dose to different thoracic structures of normal tissue to better understand their tolerance to these high doses per fraction. Although the specific mechanisms behind the toxicity are still partly unknown, dose to the proximal bronchial tree has been shown to correlate with high-grade radiation side effects. Still, there is no clear consensus on the tolerance dose of the different bronchial structures. Recent data indicate that a too high dose to a main bronchus may result in more severe clinical side effects as compared to a smaller sized bronchus. This review analyses the current knowledge on the clinical consequences of bronchial exposure to high dose hypofractionated radiation delivered with the SBRT technique, and the tolerance doses of the bronchi. It presents the current literature regarding types of high-grade clinical side effects, data on dose response and comments on other risk factors for high-grade toxic effects., (Creative Commons Attribution license.)

Quantification of chromosomal aberrations in the exposed personnel blood samples is considered as a 'gold standard' and sensitive biomarker in biological dosimetry. Despite technological developments, culture of cells for 48–52 h remains an unmet need in case of triage biodosimetry. Moreover, it is difficult to get sufficient number of metaphase spreads for scoring after high doses of exposures. The technique which causes condensation of chromatin before mitosis using biological or chemical agent is named as Premature Chromosome Condensation (PCC) assay. This assay is considered as an alternative to chromosome aberration assay, particularly at high acute doses of low and high LET radiation. To establish the PCC assay, blood samples were collected from healthy non-smoking individuals (n = 3) and exposed to various doses (0–20 Gy) of 6 MV X-rays at a dose rate of 5.6 Gy/min, using a high energy Linear accelerator (LINAC). Irradiated blood samples were subjected to Calyculin-A induced PCC. About 500 cells or more than 100 Ring Chromosomes (RC) were scored at each dose. Dicentric chromosomes (DC) and acentric fragments were also scored at each dose; the number of chromosomal aberrations in G1, M, G2/M and M/A phase of cell cycle were recorded and the frequency was used to construct the dose response curve. A dose dependent increase in RC and DC frequency were observed with a slope of 0.049 ± 0.002 and 0.30 ± 0.02 respectively. This study is first of its kind to construct a dose response curve for LINAC X-rays using a PCC assay. • This study is first of its kind to construct dose response curve for LINAC X-rays using PCC assay. • Chemically induced PCC is very reliable biodosimetry tool for accidental exposure. • PCC rings observed to be appropriate biomarker for high dose exposure. • Different types of PCC rings observed in various phases of cell cycle (G2/M, M, M/A) are shown. • It is shown that the dicentric chromosomes are suitable only for low dose exposure (<5 Gy). [ABSTRACT FROM AUTHOR]