Radical Radiotherapy Research Articles

Green Synthesis of Silver Nanoparticles using Moringa oleifera: Implementation to Photoantimicrobial of Candida albicans with LED Light

Green synthesis of silver nanoparticles using Moringa oleifera (AgNPs/MO) was carried out to produce nanoscale antifungal agents which are used as photosensitizing agents in photoantimicrobial therapy. This study focused on investigating the potential of AgNPs/MO producing some toxic radical compounds that inhibit the growth of Candida albicans biofilms. The inhibition mechanism uses the principle of photoinactivation treatment which combines a photosensitizer with an LED light source at a power of 100 mW for 60 - 300 s of exposure. Quantitative data analyzed were the number of viable cells and radical compounds, formed by malondialdehyde (MDA) level. It is investigated through staining the XTT (2,3-Bis-(2-Methoxy-4-Nitro-5-Sulfophenyl)-2H-Tetrazolium-5-Carboxanilide) and TBARS (Thiobarbituric Acid Reactive Substances). The results show that the maximum wavelength of AgNPs is 440 nm while the Moringa oleifera has 2 peaks at 425 and 635 nm. The maximum effect occurred in the group of photosensitizer AgNPs/MO combined LED with percentage inactivation about 76.80 % for blue LEDs and 76.20 % for red LEDs. The group of LED irradiation without photosensitizer obtained about 51.85 % for blue LEDs and 50.04 % for red LEDs. The MDA level group of AgNPs/MO combined LED also produced MDA levels of 1.772 nmol/mL for blue LED and 1.617 nmol/mL for red LED. Meanwhile, the application of photoantimicrobial using only LEDs produced MDA levels of only 1.353 nmol/mL for blue LEDs and 1.347 nmol/mL for red LEDs. This research has shown that the green synthesis of AgNPs/MO has a good potential to inhibit the growth of Candida albicans biofilms as a photosensitizer agent. HIGHLIGHTS Silver nanoparticles (AgNPs) combined with Moringa oleifera (MO) extract have been shown to have potential as a photosensitizer to inhibit the growth of Candida albicans Green synthesis AgNPs/MO have a characteristic spectrum at 440 nm which is close to the blue light spectrum. Green synthesis AgNPs/MO combined with LED light irradiation energy can reduce the cell viability of Candida albicans up to 76.80 % through the XTT assay staining test method and produce 1.772 nmol/mL of Malondialdehyde that reacts with ROS compounds to cause cell damage. GRAPHICAL ABSTRACT

Understanding the impact of distance and disadvantage on lung cancer care and outcomes: a study protocol

BackgroundLung cancer is the third most common cancer in the UK and the leading cause of cancer mortality globally. NHS England guidance for optimum lung cancer care recommends management and treatment by a specialist team, with experts concentrated in one place, providing access to specialised diagnostic and treatment facilities. However, the complex and rapidly evolving diagnostic and treatment pathways for lung cancer, together with workforce limitations, make achieving this challenging. This place-based, behavioural science-informed qualitative study aims to explore how person-related characteristics interact with a person’s location relative to specialist services to impact their engagement with the optimal lung pathway, and to compare and contrast experiences in rural, coastal, and urban communities. This study also aims to generate translatable evidence to inform the evidence-based design of a patient engagement intervention to improve lung cancer patients’ and informal carers’ participation in and experience of the lung cancer care pathway.MethodsA qualitative cross-sectional interview study with people diagnosed with lung cancer < 6 months before recruitment (in receipt of surgery, radical radiotherapy, or living with advanced disease) and their informal carers. Participants will be recruited purposively from Barts Health NHS Trust and United Lincolnshire Hospitals NHS Trusts to ensure a diverse sample across urban and rural settings. Semi-structured interviews will explore factors affecting individuals’ capability, opportunity, and motivation to engage with their recommended diagnostic and treatment pathway. A framework approach, informed by the COM-B model, will be used to thematically analyse facilitators and barriers to patient engagement.DiscussionThe study aligns with the current policy priority to ensure that people with cancer, no matter where they live, can access the best quality treatments and care. The evidence generated will be used to ensure that lung cancer services are developed to meet the needs of rural, coastal, and urban communities. The findings will inform the development of an intervention to support patient engagement with their recommended lung cancer pathway.Protocol registrationThe study received NHS Research Ethics Committee (Ref: 23/SC/0255) and NHS Health Research Authority (IRAS ID 328531) approval on 04/08/2023. The study was prospectively registered on Open Science Framework (16/10/2023; https://osf.io/njq48).

Association of Definitive Radiotherapy for Esophageal Cancer and the Incidence of Secondary Head and Neck Cancers: A SEER Population-Based Study.

Impact of radiotherapy (RT) for esophageal cancer (EC) patients on the development of secondary head and neck cancer (SHNC) remains equivocal. The objective of this study was to investigate the link between definitive RT used for EC treatment and subsequent SHNC. This study was conducted using the Surveillance, Epidemiology, and End Results (SEER) database to collect the data of primary EC patients. Fine-Gray competing risk regression and standardized incidence ratio (SIR) and propensity score matching (PSM) method were used to match SHNC patients with only primary head and neck cancer (HNC) patients. Overall survival (OS) rates were applied by Kaplan-Meier analysis. In total, 14,158 EC patients from the SEER database were included, of which 9,239 patients (65.3%) received RT and 4,919 patients (34.7%) received no radiation therapy (NRT). After a 12-month latency period, 110 patients (1.2%) in the RT group and 36 patients (0.7%) in the NRT group experienced the development of SHNC. In individuals with primary EC, there was an increased incidence of SHNC compared to the general US population (SIR = 5.95, 95% confidence interval (CI): 5.15 - 6.84). Specifically, the SIR for SHNC was 8.04 (95% CI: 6.78 - 9.47) in the RT group and 3.51 (95% CI: 2.64 - 4.58) in the NRT group. Patients who developed SHNC after RT exhibited significantly lower OS compared to those after NRT. Following PSM, the OS of patients who developed SHNC after RT remained significantly lower than that of matched patients with only primary HNC. An association was discovered between RT for EC and increased long-term risk of SHNC. This work enables radiation oncologists to implement mitigation strategies to reduce the long-term risk of SHNC in patients who have received RT following primary EC.

Rhodamine-B for the mark, release, and recapture experiments in gamma-irradiated male Aedes aegypti (Diptera: Culicidae): Persistence, dispersal, and its effect on survival.

Rhodamine-B (Rh-B) marking shows a great potential for use in mark-release-recapture (MRR) studies for rear-and-release mosquito control strategies, including the radiation-based sterile insect technique. However, its applicability and evaluation in body-stain-irradiated males of Aedes aegypti have received little attention. The present study evaluated the use of Rh-B to mark gamma-irradiated male A. aegypti. Male A. aegypti were irradiated at the pupal stage at a dose of 70 Gy. After emergence, males were fed 0.1, 0.2, 0.3, or 0.4% Rh-B in 10% glucose solution for 4 days. Groups of unirradiated males that received the same feeding treatments were used as control groups. We evaluated the persistence of Rh-B and the longevity of males after Rh-B feeding. Furthermore, the use of Rh-B in irradiated A. aegypti for MRR experiments was evaluated at an urban site. No difference was observed in the Rh-B persistence among all concentrations at the 24-h postmarking period ranging from 91.25 ± 1.61% to 96.25 ± 1.61% and from 90.00 ± 2.28% to 93.13 ± 2.77% for the unirradiated and irradiated groups, respectively. Rh-B persistence significantly decreased over time, and persistence was significantly longer with increased concentrations in both the unirradiated and irradiated groups. Longevity was considerably decreased by Rh-B feeding and irradiation. However, no significant difference in longevity was found among males fed various concentrations of Rh-B. Through MRR experiments, irradiated-Rh-B marked males were mostly detected within a radius of 20 m and 40 m from the center-release point. The mean distance traveled of the released males from the three MRR events was calculated to be 42.6 m. This study confirms that Rh-B body marking through sugar feeding is applicable for irradiated male A. aegypti, with only a slight effect on longevity. Furthermore, considering the significant reduction in persistence over time, further study is needed to assess the impact of this reduction on the calculation of field biological parameters resulting from MRR experiments.

Utility of 64Cu-Sarcophagine-Bombesin PET/CT in Men with Biochemically Recurrent Prostate Cancer and Negative or Equivocal Findings on 68Ga-PSMA-11 PET/CT.

Despite a high detection rate of 68Ga-prostate-specific membrane antigen (PSMA) PET/CT in biochemical recurrence (BCR) of prostate cancer, a significant proportion of men have negative 68Ga-PSMA-11 PET/CT results. Gastrin-releasing peptide receptor, targeted by the copper-chelated bombesin analog 64Cu-sarcophagine-bombesin (SAR-BBN) PET/CT, is also overexpressed in prostate cancer. In this prospective imaging study, we investigate the detection rate of 64Cu-SAR-BBN PET/CT in patients with BCR and negative or equivocal 68Ga-PSMA-11 PET/CT results. Methods: Men with confirmed adenocarcinoma of the prostate, prior definitive therapy, and BCR (defined as a prostate-specific antigen [PSA] level > 0.2 ng/mL) with negative or equivocal 68Ga-PSMA-11 PET/CT results within 3 mo were eligible for enrollment. 64Cu-SAR-BBN PET/CT scans were acquired at 1 and 3 h after administration of 200 MBq of 64Cu-SAR-BBN, with further delayed imaging undertaken optionally at 24 h. PSA (ng/mL) was determined at baseline. All PET (PSMA and bombesin) scans were assessed visually. Images were read with masking of the clinical results by 2 experienced nuclear medicine specialists, with a third reader in cases of discordance. Accuracy was defined using a standard of truth that included biopsy confirmation, confirmatory imaging, or response to targeted treatment. Results: Twenty-five patients were enrolled. Prior definitive therapy was radical prostatectomy (n = 24, 96%) or radiotherapy (n = 1, 4%). The median time since definitive therapy was 7 y (interquartile range [IQR], 4-11 y), and the Gleason score was 7 or less (n = 15, 60%), 8 (n = 3, 12%), or 9 (n = 7, 28%). The median PSA was 0.69 ng/mL (IQR, 0.28-2.45 ng/mL). Baseline PSMA PET scans were negative in 19 patients (76%) and equivocal in 6 (24%). 64Cu-SAR-BBN PET-avid disease was identified in 44% (11/25): 12% (3/25) with local recurrence, 20% (5/25) with pelvic node metastases, and 12% (3/25) with distant metastases. The κ-score between readers was 0.49 (95% CI, 0.16-0.82). Patients were followed up for a median of 10 mo (IQR, 9-12 mo). Bombesin PET/CT results were true-positive in 5 of 25 patients (20%), false-positive in 2 of 25 (8%), false-negative in 7 of 25 (28%), and unverified in 11 of 25 (44%). Conclusion: 64Cu-SAR-BBN PET/CT demonstrated sites of disease recurrence in 44% of BCR cases with negative or equivocal 68Ga-PSMA-11 PET/CT results. Further evaluation to confirm diagnostic benefit is warranted.

The role of shared decision-making in enhancing patient experience: Insights from a cohort of curative head and neck cancer patients

IntroductionShared decision-making (SDM) is on the NHS policy agenda, and the preferred model for preference-sensitive decisions. This study establishes baseline patient-perceived SDM in a radical head and neck cohort, and explores patients’ views on SDM in a large, specialist trust. MethodsAn SDM questionnaire was distributed to all radical head and neck radiotherapy patients (N = 165), June–December 2023. This combined a well-validated instrument for measuring SDM from the patient perspective, SDM-Q-9, with additional questions exploring patient views. Thematic analysis was used to construct and interpret themes. Results65/165 (39%) questionnaires were returned. SDM-Q-9 mean standardised score was 78.6 (SD 26.3). There was a moderate ceiling effect (26%). Scores were not sensitive to sex (p = 0.64) or age (ρ = 0.1). Higher levels of SDM were perceived by participants who stated SDM was very important (51/65, 79%) than somewhat or not at all important (82.4 vs. 62.7; p = 0.02; Cohen d = 0.75). Individuals who discussed their personal priorities with the clinician (46/65, 70.8%), were more likely to be very satisfied with their involvement in SDM (89.1% vs. 52.9%). Thematic analysis generated three themes: Control, Desire for Transparency and Understanding, and Doctor as the Expert. ConclusionPatient-perceived SDM levels are high for head and neck patients. Participants who value SDM also perceive higher levels of SDM. Patient satisfaction increases when individuals discuss their personal priorities. The modest response rate and self-selection bias affect the generalisability of the results. Only radiotherapy patients were included; those who chose alternative treatment may perceive different levels of SDM. The moderate ceiling effect may limit the use of SDM-Q-9 to measure impact of future interventions to improve SDM. Implications for practiceSDM-Q-9 should be combined with an objective, observer measure of SDM.

Radiotherapy and chemoradiotherapy for postoperative recurrence in patients with esophageal squamous cell carcinoma.

The optimal treatment for esophageal squamous cell carcinoma (ESCC) patients with postoperative recurrence remains controversial. We aimed to evaluate the effects of radiotherapy (RT) and chemoradiotherapy (CRT) on postoperative recurrence in ESCC patients. Recurrence ESCC patients who received salvage RT and CRT from January 2015 to January 2019 were retrospectively reviewed. Post-recurrence survival (PRS) and prognostic factors were evaluated by Kaplan-Meier and Cox proportional hazards models, respectively. Subgroup analyses were performed based on pathological lymph node (LN) status (negative/positive) to evaluate the differences in salvage treatments and toxic reaction. A total of 170 patients were enrolled, with a median age of 60 years (range 43-77). No significant difference was found in the median PRS between the salvage RT and CRT groups (p > 0.05). Multivariate analysis revealed that TNM stage III and IV, macroscopic medullary type, and distant metastasis recurrence pattern were independent prognostic factors (all p < 0.05) for PRS. Salvage treatment was not associated with PRS (p = 0.897). However, in patients with negative LN, CRT was associated with prolonged survival (p = 0.043) and had no significant differences in toxic reactions compared to RT (p = 0.924). In addition, RT showed better prognoses (p = 0.020) and lower toxic reactions (p = 0.030) than CRT in patients with positive LNs. Based on prognosis and toxic reactions, ESCC recurrence patients with negative LNs could benefit from CRT, but RT should be recommended for patients with positive LNs.

Surgery or radiotherapy improves survival in elderly patients with early non-small cell lung cancer: A population-based analysis.

There is a lack of evidence to support a consensus on whether surgery or radiotherapy is optimal for elderly or very elderly patients with early-stage non-small cell lung cancer (NSCLC). We aimed to assess the impact of surgery or radiotherapy on survival in elderly (≥70 years) and very elderly (≥80 years) patients with early-stage NSCLC. Patients aged ≥70 years diagnosed with early-stage NSCLC between January 1, 1975, and December 31, 2018, were identified in the Surveillance, Epidemiology, and End Results (SEER) database. Overall survival (OS) and cancer-specific survival (CSS) were assessed based on surgery, radiotherapy, and no-treatment groups. Data for 15,224 NSCLC patients aged ≥70 years were collected, which consisted of 6949 (45.6%) patients who underwent surgery alone, 5014 (32.9%) who underwent radiotherapy alone, and 3261 (21.5%) who received no treatment. Surgery significantly improved patient survival compared with no treatment (MST: 74 months vs. 7 months, HR: 0.201, 95% CI: 0.186-0.217, P < 0.001), as did radiotherapy (MST: 28 months vs. 7 months, HR: 0.440; 95% CI: 0.413-0.469, P < 0.001). Surgery also resulted in improved survival compared with radiotherapy (74 months vs. 28 months, HR: 0.455; 95% CI: 0.430-0.482, P < 0.001). A similar conclusion was made from the analysis of CSS. A subgroup analysis further confirmed the survival benefits. The results of this large-scale retrospective study indicate that both surgery and radiotherapy significantly enhance survival outcomes in patients aged ≥70 or ≥80 years with early-stage NSCLC. The survival benefits of surgery were particularly notable.

Long-term outcome of definitive radiotherapy for locally advanced non-small cell lung cancer: A real-world single-center study in the pre-durvalumab era.

There was limited research data on large-scale locally advanced non-small cell lung cancer (LA-NSCLC) radical radiotherapy (RT) reported in China. This study examined overall survival (OS), progression-free survival (PFS), treatment effectiveness, and toxicity in patients with LA-NSCLC treated with definitive RT in the pre-durvalumab era. A retrospective analysis of demographic information, clinical characteristics, treatment patterns, and clinical outcomes of 789 patients with LA-NSCLC who underwent radical RT at our center between January 2005 and December 2015 was performed. The Kaplan-Meier method and log-rank test were used for survival comparisons, and Cox regression was used for multivariate analysis. There were 328 patients with stage IIIA disease and 461 with stage IIIB disease. By the last follow-up, there were 365 overall deaths and 576 cases of recurrence, metastasis, or death. The median survival time was 31 months. The OS rates at 1, 2, 5, and 10 years were 83.7%, 59.5%, 28.8%, and 18.9%, respectively. PFS rates at 1, 2, 5, and 10 years were 48%, 24.5%, 11.9%, and 5.5%, respectively. Rates of ≥grade 3 acute radiation pneumonitis or esophagitis were 7.6% and 1.9%, respectively. Rates of ≥grade 3 chronic radiation pneumonitis and esophagitis were 11% and 0.4%, respectively. Multivariate analysis showed that the Karnofsky Performance Status (KPS) score, smoking status, and combined chemotherapy were prognostic factors for OS (p < 0.05). Multivariate analysis revealed that combined chemotherapy and radiation dose were prognostic factors for PFS (p < 0.05). Our center's data showed that the survival prognosis of locally advanced patients receiving RT and chemotherapy in China was consistent with international levels during the same period. Patients with a KPS score of 80 or higher, who had never smoked or received combined RT, had a more favorable prognosis than those with a KPS of less than 80, who had smoked, or only received RT. The combination of RT and chemotherapy, with a reasonable radiation dose, was the key to improving the therapeutic effect.

An SEM study on the effect of 9.3-µm CO2 laser on dentinal tubules for hypersensitivity treatment.

In-vitro studies were performed on dentin of extracted human molars to investigate the effectiveness of 9.3μm CO2 laser irradiation to occlude dentinal tubules. The observed occlusion of dentinal tubules with the irradiation was compared with application of three reagents: 2% Sodium Fluoride gel, an aqueous solution of hydroxyapatite nanoparticles and an equal mix of the two. We show that 9.3μm CO2 laser irradiation occludes dentinal tubules, and the use of laser irradiation produces better occlusion of the opened tubules compared to the use of topical reagents. Nine extracted and cleaned human molars were cut to obtain dentin disks of thickness of 3-5mm. Each disc was divided into four quarters, and each quarter served as two samples corresponding to irradiated and non-irradiated group counterparts. Five disks were used to study the effect of various laser irradiation energies on the dentinal tubules to find a good pulse fluence for occlusion of the dentinal tubules, and four disks were used for studying the effects of reagents and irradiation at the pulse fluences found in the first part of the study. The samples were irradiated with a beam diameter of 1mm (1/e2) at 15Hz pulse repetition rate, scanned automatically using a set of scanning mirrors. Samples were imaged using Scanning Electron Microscope (SEM) which were processed to determine tubule diameter. Safety of the irradiation treatment was investigated on 6 samples by measuring pulpal temperature rise. The effect of three topical reagents corresponding to 2% Sodium Fluoride gel (F), Hydroxyapatite nanoparticles (HA) and an equal mix of F and HA (HAF) on dentinal tubule occlusion was evaluated and compared with the laser irradiation. In all examined cases, laser irradiation at a fluence of 0.81J/cm2 resulted in a temperature increase less than 3°C which is safe, and no surface cracking was observed. There is a threshold pulse fluence of 0.27J/cm2 above which, laser produced surface melting. At a pulse fluence of 0.81J/cm2 a layer of recast of melted dentin was formed. Under this layer, peritubular dentin melting and occluding of the dentinal tubules was observed. Application of either F or HA or HAF did not produce visible occlusion effect on open tubules after washing and microbrushing with excess distilled water. 9.3μm CO2 laser irradiation on extracted human molar dentin at pulse fluence of 0.81J./cm2 resulted in tubule area reduction by 97% without rising pulpal temperatures to unsafe levels.

Sodium Tanshinone IIA Sulfonate Protects Primary Cardiomyocytes Against Radiation-Induced Myocardial Injury via the p38 Pathway.

Sodium tanshinone IIA sulfonate (STS), which is extracted from a Chinese medicinal herb, possesses many pharmacologic functions, such as coronary dilation, anti-inflammatory properties, and antiapoptotic and antioxidant effects. It remains unknown whether STS can protect cardiomyocytes injured after radiation therapy. An in vitro Sprague-Dawley (SD) rat neonatal cardiomyocyte system was established. Primary cardiomyocytes (PCMs) from neonatal SD rats were isolated under sterile conditions. PCM cells were divided into a control group (0 Gy/hour) and 5 experimental radiation therapy groups (0.25 Gy/hour, 0.5 Gy/hour, 1 Gy/hour, 2 Gy/hour, and 4 Gy/hour). Cell viability, the content of malondialdehyde (MDA), the lactate dehydrogenase (LDH) leakage rate, and superoxide dismutase (SOD) and glutathione (GSH) activities were recorded separately in each group after 7 days of culture. Western blot was used to detect the levels of p38, caspase-3 protein, and X protein (BAX) associated with B-cell lymphoma 2 (Bcl-2) in PCMs. X-rays inhibited cell growth, decreased cell viability, and induced an oxidative stress response in PCMs. STS and SB203580 (the inhibitor of P38 mitogen-activated protein kinase pathway) alleviated X-ray-induced damage to PCMs. An enzyme-linked immunosorbent assay showed that X-rays increased the cTnT level. STS and SB203580 ameliorated the X-ray-induced increase in cTnT leakage. X-rays enhanced the expression of p38/p-p38 and caspase-3 while reducing the expression of Bcl-2/BAX in PCMs, as demonstrated by western blotting. STS and SB203580 mitigated the changes in protein expression triggered by X-ray radiation. In conclusions, STS was shown to exert significant cardioprotective, anti-inflammatory, and antioxidant effects in PCMs by inhibiting the p38 mitogen-activated protein kinase pathway.

Analysis of Molecular Mechanisms of Chronic Irradiation Effects on Electrical Signals in Wheat Plants

The effect of ionizing radiation (IR) on plants is mainly realized by altering the status of signaling systems and modifying stress signals. Variation potential (VP) is one of the types of electrical signals in plants. IR contributes to an increase in the amplitude of the VP, but the mechanisms of such influence are practically unknown. A possible way to implement changes arising from the action of IR is the regulation of gene expression. In the present work, the changes in the gene expression of participants in the generation and propagation of VP in irradiated plants are investigated. The experiments were performed on 14–15-day-old soft wheat plants (Triticum aestivum L.) grown under chronic irradiation (source 90Sr-90Y) with a dose rate of 31.3 μGy/h. The maximum accumulated dose was about 11.3 mGy. The irradiated plants showed no changes in the expression of calcium (TPC1), anionic (ALMT1 and CLC1), potassium (AKT1) channels, H+-ATPase (HA1), and NADPH oxidase (RBOHs) genes. A decrease in the expression of the SKOR potassium channel gene was revealed. The potassium channel blocker, tetraethylammonium chloride, caused an increase in response amplitude in control plants comparable to the increase in amplitude in the irradiated group. The obtained results indicate that one of the ways IR influences the electrical signals of plants is to inhibit the expression of the potassium channel.

Comparative efficacy of radical prostatectomy and radiotherapy in the treatment of high-risk prostate cancer.

Both radical prostatectomy and radiation therapy are effective in controlling the condition of patients with hormone-resistant prostate cancer (HRPCa). However, there is limited research on the prognosis and quality of life of HRPCa patients after different treatment modalities. To explore the efficacy of radical prostatectomy (RP) and radiotherapy (RT), when treating high-risk prostate cancer (HRPCa). Overall 103 HRPCa patients were included and were divided into RP group and RT group according to different treatment methods. The propensity score matching method (PSM) was used to balance the baseline data of the two groups and match 34 patients in each group. The prognosis, quality of life, and basic efficacy of patients were compared. After intervention, the disease-free survival rate of the RT group was higher than that of the RP group (79.41% vs. 55.88%, p= 0.038). Quality of life scores between the two treatment methods had no difference before intervention (p> 0.05), but higher in RT group than that of the RP group after intervention (p< 0.05). After treatment, there was no statistically significant difference in total effective rate of treatment between two groups (44.12% vs. 58.82%, p> 0.05), but the disease control rate was significantly higher in RT group (94.12% vs. 76.47%, p= 0.040). Radical radiotherapy is effective in the clinical treatment of HRPCa patients, with a higher disease-free survival rate and improved quality of life after treatment, and is worth promoting.

Relative Biological Effectiveness of Carbon Ion Beams for Induction of Medulloblastoma with Radiation-specific Chromosome 13 Deletion in Ptch1+/- Mice.

Carbon ion radiotherapy (CIRT) for pediatric cancer is currently limited because of the unknown risk of induction of secondary cancers. Medulloblastoma of Ptch1+/- mice offers a unique experimental system for radiation-induced carcinogenesis, in which tumors are classified into spontaneous and radiation-induced subtypes based on their features of loss of heterozygosity (LOH) that affect the wild-type Ptch1 allele. The present study aims to investigate in young Ptch1+/- mice the carcinogenic effect, and its age dependence, of the low-linear energy transfer (LET, ∼13 keV/µm) carbon ions, to which normal tissues in front of the tumor are exposed during therapy. We irradiated Ptch1+/- mice at postnatal day (P) 1, 4, or 10 with 290 MeV/u carbon ions (0.05-0.5 Gy; LET, 13 keV/µm) and monitored them for medulloblastoma development. Loss of heterozygosity of seven genetic markers on chromosome 13 (where Ptch1 resides) was studied to classify the tumors. Carbon ion exposure induced medulloblastoma most effectively at P1. The LOH patterns of tumors were either telomeric or interstitial, the latter occurring almost exclusively in the irradiated groups, allowing the use of interstitial LOH as a biomarker of radiation-induced tumors. Radiation-induced tumors developed during a narrow age window (most strongly at P1 and only moderately at P4, with suppressed tumorigenesis at P10). Calculated using previous results using 137Cs gamma rays, the values for relative biological effectiveness (RBE) regarding radiation-induced tumors were 4.1 (3.4, 4.8) and 4.3 (3.3, 5.2) (mean and 95% confidence interval) for exposure at P1 and 4, respectively. Thus, the RBE of carbon ions for medulloblastoma induction in Ptch1+/- mice was higher than the generally recognized RBE of 1-2 for cell killing, chromosome aberrations, and skin reactions.

Dietary restriction and fasting alleviate radiation-induced intestinal injury by inhibiting cGAS/STING activation

Radiation injury to the intestine is one of the most common complications in patients undergoing abdominal or pelvic cavity radiotherapy, limiting the clinical application of this treatment. Evidence shows the potential benefits of dietary restriction in improving metabolic profiles and age-related diseases. The present study investigated the effects and mechanisms of dietary restriction in radiation-induced intestinal injury. The mice were randomly divided into the control group, 10 Gy total abdominal irradiation (TAI) group, and groups pretreated with 30% caloric restriction (CR) for 7 days or 24 h fasting before TAI. After radiation, the mice were returned to ad libitum. The mice were sacrificed 3.5 days after radiation, and tissue samples were collected. CR and fasting reduced radiation-induced intestinal damage and promoted intestinal recovery by restoring the shortened colon length, improving the impaired intestinal structure and permeability, and remodeling gut microbial structure. CR and fasting also significantly reduced mitochondrial damage and DNA damage, which in turn reduced activation of the cyclic GMP-AMP synthase/stimulator of interferon gene (cGAS/STING) pathway and the production of type I interferon and other chemokines in the jejunum. Since the cGAS/STING pathway is linked with innate immunity, we further showed that CR and fasting induced polarization to immunosuppressive M2 macrophage, decreased CD8+ cytotoxic T lymphocytes, and downregulated proinflammatory factors in the jejunum. Our findings indicated that CR and fasting alleviate radiation-induced intestinal damage by reducing cGAS/STING-mediated harmful immune responses.

Effects of PreOperative radiotherapy in a preclinical glioblastoma model: a paradigm-shift approach.

PreOperative radiotherapy (RT) is commonly used in the treatment of brain metastasis and different cancer types but has never been used in primary glioblastoma (GBM). Here, we aim to establish, describe, and validate the use of PreOperative RT for the treatment of GBM in a preclinical model. Rat brains were locally irradiated with 30-Gy, hypofractionated in five doses 2 weeks before or after the resection of intracranial GBM. Kaplan-Meier analysis determined survival. Hematoxylin-eosin staining was performed, and nuclei size and p21 senescence marker were measured in both resected and recurrent rodent tumors. Immunohistochemistry assessed microglia/macrophage markers, and RNAseq analyzed gene expression changes in recurrent tumors. Akoya Multiplex Staining on two human patients from our ongoing Phase I/IIa trial served as proof of principle. PreOperative RT group median survival was significantly higher than PostOperative RT (p < 0.05). Radiation enlarged cytoplasm and nuclei in PreOperative RT resected tumors (p < 0.001) and induced senescence in PostOperative RT recurrent tumors (p < 0.05). Gene Set Enrichment Analysis (GSEA) suggested a more proliferative profile in PreOperative RT group. PreOperative RT showed lower macrophage/microglia recruitment in recurrent tumors (p < 0.01) compared to PostOperative RT. Akoya Multiplex results indicated TGF-ß accumulation in the cytoplasm of TAMs and CD4 + lymphocyte predominance in PostOperative group. This is the first preclinical study showing feasibility and longer overall survival using neoadjuvant radiotherapy before GBM resection in a mammalian model. This suggests strong superiority for new clinical radiation strategies. Further studies and trials are required to confirm our results.

Gastroprotective and microbiome-modulating effects of ubiquinol in rats with radiation-induced enteropathy

Radiation enteritis is a frequently encountered issue for patients receiving radiotherapy and has a significant impact on cancer patients' quality of life. The gut microbiota plays a pivotal role in intestinal function, yet the impact of irradiation on gut microorganisms is not fully understood. This study explores the gastroprotective effect and gut microbiome-modulating potential of ubiquinol (Ubq), the reduced form of the powerful antioxidant CoQ-10. For this purpose, male albino rats were randomly assigned to four groups: Control, IRR (acute 7 Gy γ-radiation), Ubq_Post (Ubq for 7 days post-irradiation), and Ubq_Pre/Post (Ubq for 7 days pre and 7 days post-irradiation). The fecal microbiomes of all groups were profiled by 16S rRNA amplicon sequencing followed by bioinformatics and statistical analysis. Histopathological examination of intestinal tissue indicated severe damage in the irradiated group, which was mitigated by ubiquinol with enhanced regeneration, goblet cells, and intestinal alkaline phosphatase expression. Compared to the irradiated group, the Ubq-treated groups had a significant recovery of intestinal interleukin-1β, caspase-3, nitric oxide metabolites, and thio-barbituric reactive substances to near-healthy levels. Ubq_Pre/Post group displayed elevated peroxisome proliferator-activated receptor (PPAR-γ) level, suggesting heightened benefits. Serum insulin reduction in irradiated rats improved post-Ubq treatment, with a possible anti-inflammatory effect on the pancreatic tissue. Fecal microbiota profiling revealed a dysbiosis state with a reduction of bacterial diversity post-irradiation, which was re-modulated in the Ubq treated groups to profiles that are indistinguishable from the control group. These findings underscore Ubq's gastroprotective effects against radiation-induced enteritis and its potential in restoring the gut microbiota’s diversity and balance.

Adaptive radiotherapy for muscle invasive bladder cancer: a retrospective audit of two bladder filling protocols

BackgroundRadical radiotherapy for muscle-invasive bladder cancer (MIBC) is challenging due to large variations in bladder shape, size and volume during treatment, with drinking protocols often employed to mitigate geometric uncertainties. Utilising adaptive radiotherapy together with CBCT imaging to select a treatment plan that best fits the bladder target and reduce normal tissue irradiation is an attractive option to compensate for anatomical changes. The aim of this retrospective study was to compare a bladder empty (BE) protocol to a bladder filling (BF) protocol with regards to variations in target volumes, plan of the day (PoD) selection and plan dosimetry throughout treatment.MethodsForty patients were included in the study; twenty were treated with a BE protocol and twenty with a BF protocol to a total prescribed dose of 55 Gy in 20 fractions. Small, medium and large bladder plans were generated using three different CTV to PTV margins. Bladder (CTV) volumes were delineated on planning CTs and online pre-treatment CBCTs. Differences in CTV volumes throughout treatment, plan selection, PTV volumes and resulting dose metrics were compared for both protocols.ResultsMean bladder volume differed significantly on both the planning CTs and online pre-treatment CBCTs between the protocols (p < 0.05). Significant differences in bladder volumes were observed between the planning CT and pre-treatment CBCTs for BF (p < 0.05) but not for BE (p = 0.11). Both protocols saw a significant decrease in bladder volume between first and final treatment fractions (p < 0.05). Medium plans were preferentially selected for BE whilst when using the BF protocol the small plan was chosen most frequently. With no significant change to PTV coverage between the protocols, the volume of body receiving 25.0–45.8 Gy was found to be significantly smaller for BE patients (p < 0.05).ConclusionsThis work provides evidence in favour of a BE protocol compared to a BF protocol for radical radiotherapy for MIBC. The smaller treatment volumes observed in the BE protocol led to reduced OAR and total body doses and were also observed to be more consistent throughout the treatment course. These results highlight improvements in dosimetry for patients who undergo a BE protocol for MIBC.

Efficacy and safety of pyrotinib-based regimens in HER2 positive metastatic breast cancer: A retrospective real-world data study

ObjectivePyrotinib is a novel irreversible tyrosine kinase inhibitor that has shown efficacy for human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC). This study explored the efficacy and safety of pyrotinib in the treatment of HER2-positive MBC patients in the real world. MethodsFrom September 2018 to February 2022, 137 female patients with HER2-positive MBC treated in this center were enrolled in this study. The follow-up period ended on January 12, 2023. The primary endpoint of this study was progression-free survival (PFS). Overall survival (OS), objective response rate (ORR), disease control rate (DCR), clinical benefit rate (CBR), central nervous system (CNS)-PFS, CNS-ORR, CNS-CBR, CNS-DCR, and adverse event (AE) were the secondary endpoints. ResultsThe ORR, DCR and CBR were 41.98 % (55/131), 87.79 % (115/131) and 44.27 % (58/131) in this cohort, respectively. The median PFS for this cohort was 10.37 months [95 % confidence interval (CI): 9.205-11.535] and the median OS was 37.53 months (not reached). Univariate and multivariate analyses showed that trastuzumab sensitivity was an independent predictor of improved PFS [hazard ratio (HR): 0.579 (0.371-0.904, p=0.016)] and improved OS [0.410 (0.213-0.790, p=0.008)]. Patients treated with a pyrotinib-based regimen as second-line and third-or-post-line therapy had poorer PFS [second-line: 3.315 (1.832-6.000, p<0.001); third-or-post-line: 3.304 (1.749-6.243, p<0.001)] and OS [second-line: 4.631 (1.033-20.771, p=0.045); third-or-post-line: 5.738 (1.212-27.174, p=0.028)]. There were 38 brain metastases (BM) patients in this study, the CNS-mPFS [14.37 months (7.815-20.925) vs. 7.83 months (7.047-8.613), p=0.375] and mOS [not reached vs. 36.40 months (18.551-54.249), p=0.034] were better in brain radiotherapy (BRT) group than NBRT group. 18.98 % (26/137) of patients experienced grade 3 or higher diarrhea. No AE-related death was reported. ConclusionThis study confirms the promising antitumor activity and acceptable safety of real-world pyrotinib-based regimens for the treatment of HER2-positive MBC patients, particularly those who are trastuzumab-sensitive and who are receiving pyrotinib-based regimens as advanced first-line therapy. It has also been demonstrated that these regimens combined with BRT, provide better intracranial responses and long-term survival benefits for these patients with BM.

Clinical Analysis of the Efficacy and Safety of Different Neoadjuvant Strategies in the Treatment of Locally Advanced Rectal Cancer

Objective In this study, we retrospectively analysed the efficacy and safety of three treatment models, namely, short-course radiotherapy sequential XELOX chemotherapy, neoadjuvant mFOLFOX6 concurrent radiotherapy and long-course concurrent radiotherapy with total mesorectal excision (TME) after treatment of locally advanced rectal cancer with high-risk factors. Methods We collected clinical data on 177 patients with locally advanced rectal cancer (cT3-4 and/or cN+) who were treated at the Department of Abdominal Oncology of the Affiliated Cancer Hospital of Guizhou Medical University from December 2017 to December 2022. All patients were associated with 2-3 risk factors [T4b, N2, Extramural Vascular Invasion (EMVI), Mesorectal Fascia (MRF) positivity], positive lateral lymph nodes. Among them, there were 45 cases in the short course radiotherapy sequential XELOX chemotherapy group (RT + XELOX group); 64 cases in the neoadjuvant mFOLFOX6 concurrent radiotherapy group (mFOLFOX6 + CRT group); and 68 cases in the long course concurrent radiotherapy group (CRT group). The RT + XELOX group and mFOLFOX6 + CRT group completed radiotherapy and 4 cycles of neoadjuvant chemotherapy, respectively, and then rested for 1-2 weeks before TME surgery; the CRT group completed concurrent radiotherapy and then rested for 6-8 weeks before TME surgery.Adjuvant chemotherapy was conducted after surgery in each of the three groups: 2 cycles of adjuvant chemotherapy with XELOX regimen in the RT + XELOX group, 4-6 cycles of adjuvant chemotherapy with mFOLFOX6 in the mFOLFOX6 + CRT group, and 8-12 cycles of adjuvant chemotherapy with mFOLFOX6 in the CRT group.The pathological complete response rate (pCR rate), tumour downstage rate, tumour complete resection rate (R0 resection rate), local recurrence rate, distant metastasis rate, overall survival rate, incidence of adverse reactions, surgical complications and completion rate of perioperative systemic chemotherapy were compared among patients in the three groups of cases after TME. Results The pCR rate (21.95% vs 17.24% vs 5.00%, p = 0.034) and and tumour downstage rate (78.05% vs 68.97% vs 53.33%, p = 0.029) were higher in the RT + XELOX group and mFOLFOX6 + CRT group compared to the CRT group. The RT + XELOX group had a lower 3-year distant metastasis rate (14.63% vs 36.67%, p = 0.048) and improved 3-year overall survival (76.57% vs 48.56%, p < 0.001) compared to the CRT group. There was no significant reduction in the 3-year distant metastasis rate in the mFOLFOX6 + CRT group versus the CRT group (27.59% vs 36.67%, p = 0.719), and the 3-year overall survival was similar (51.23% vs 48.56%, p = 0.35). Multi-logistic regression analysis and stratified analysis showed that patients in the RT + XELOX group and mFOLFOX6 + CRT group were more likely to achieve pCR than the CRT group (RT + XELOX group: OR 7.3, 95% CI [2.6-20.8], p < 0.001; mFOLFOX6 + CRT group OR 2.9, 95% CI [1.1-7.9], p = 0.036). The completion rates of perioperative systemic chemotherapy in the RT + XELOX, mFOLFOX6 + CRT, and CRT groups were 82.93% vs. 84.48% vs. 61.67% (χ2=9.95, p = 0.007), respectively. And there were significant differences in grade 3-4 leukopenia and thrombocytopenia (incidence of leukopenia: 15.50% vs. 7.81% vs. 1.47%, p = 0.045; incidence of thrombocytopenia: 13.33% vs 7.81% vs 1.47%, p = 0.027). There was no significant difference in the incidence of intraoperative and postoperative complications among the three groups (p > 0.05). Conclusions RT + XELOX group and mFOLFOX6 + CRT group significantly improved the near-term outcome (e.g., pCR rate) in patients with locally advanced rectal cancer with high-risk factors compared with CRT group. The RT + XELOX group also reduced the 3-year distant metastasis rate, increased the 3-year overall survival rate, and did not increase the incidence of perioperative surgical complications. It provides an effective means for the comprehensive treatment of locally advanced rectal cancer and has important clinical guidance and application value.