-
Journal of Otolaryngology - Head & Neck... 2024Neck dissections (ND) are a routine procedure in head and neck oncology. Given the postoperative functional impact that some patients experience, it is imperative to...
BACKGROUND
Neck dissections (ND) are a routine procedure in head and neck oncology. Given the postoperative functional impact that some patients experience, it is imperative to identify and track quality of life (QoL) symptomatology to tailor each patient's therapeutic needs. To date, there is no validated French-Canadian questionnaire for this patient-population. We therefore sought to translate and validate the Neck Dissection Impairment Index (NDII) in Canadian French.
METHODS
A 3-phased approach was used. Phase 1: The NDII was translated from English to Canadian French using a "forward and backward" translational technique following international guidelines. Phase 2: A cognitive debriefing session was held with 10 Canadian French-speaking otolaryngology patients to evaluate understandability and acceptability. Phase 3: The final version was administered prospectively to 30 patients with prior history of ND and 30 control patients. These patients were asked to complete the questionnaire 2 weeks after their first response. Test-retest reliability was calculated with Spearman's correlation. Internal consistency was elicited using Cronbach's alpha.
RESULTS
NDII was successfully translated and validated to Canadian French. Cronbach's alpha revealed high internal consistency (0.92, lower 95% confidence limit 0.89). The correlation for test-retest validity were strong or very strong (0.61-0.91).
CONCLUSION
NDII is an internationally recognized QoL tool for the identification of ND-related impairments. This validated Canadian French version will allow clinicians to adequately assess the surgery-related QoL effect of neck surgery in the French-speaking population, while allowing French institutions to conduct and/or participate in multisite clinical trials requiring the NDII as an outcome measure.
Topics: Humans; Quality of Life; Neck Dissection; Female; Male; Middle Aged; Canada; Surveys and Questionnaires; Translations; Head and Neck Neoplasms; Reproducibility of Results; Aged; Adult; Prospective Studies; Surgical Oncology
PubMed: 38899627
DOI: 10.1177/19160216241263852 -
Journal of Cellular and Molecular... Jun 2024Hypoxia poses a significant challenge to the effectiveness of radiotherapy in head and neck squamous cell carcinoma (HNSCC) patients, and it is imperative to discover...
Hypoxia poses a significant challenge to the effectiveness of radiotherapy in head and neck squamous cell carcinoma (HNSCC) patients, and it is imperative to discover novel approaches to overcome this. In this study, we investigated the underlying mechanisms contributing to x-ray radioresistance in HPV-negative HNSCC cells under mild hypoxic conditions (1% oxygen) and explored the potential for autophagy modulation as a promising therapeutic strategy. Our findings show that HNSCC cells exposed to mild hypoxic conditions exhibit increased radioresistance, which is largely mediated by the hypoxia-inducible factor (HIF) pathway. We demonstrate that siRNA knockdown of HIF-1α and HIF-1β leads to increased radiosensitivity in HNSCC cells under hypoxia. Hypoxia-induced radioresistance was not attributed to differences in DNA double strand break repair kinetics, as these remain largely unchanged under normoxic and hypoxic conditions. Rather, we identify autophagy as a critical protective mechanism in HNSCC cells following irradiation under mild hypoxia conditions. Targeting key autophagy genes, such as BECLIN1 and BNIP3/3L, using siRNA sensitizes these cells to irradiation. Whilst autophagy's role in hypoxic radioresistance remains controversial, this study highlights the importance of autophagy modulation as a potential therapeutic approach to enhance the effectiveness of radiotherapy in HNSCC.
Topics: Humans; Autophagy; Radiation Tolerance; Cell Line, Tumor; Squamous Cell Carcinoma of Head and Neck; Cell Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Beclin-1; Head and Neck Neoplasms; Membrane Proteins; DNA Repair; RNA, Small Interfering; Proto-Oncogene Proteins; X-Rays; DNA Breaks, Double-Stranded; Tumor Suppressor Proteins
PubMed: 38899556
DOI: 10.1111/jcmm.18482 -
Chinese Neurosurgical Journal Jun 2024Glioblastoma are highly malignant type of primary brain tumors. Treatment for glioblastoma multiforme (GBM) generally involves surgery combined with chemotherapy and...
BACKGROUND
Glioblastoma are highly malignant type of primary brain tumors. Treatment for glioblastoma multiforme (GBM) generally involves surgery combined with chemotherapy and radiotherapy. However, the development of tumoral chemo- and radioresistance induces complexities in clinical practice. Multiple signaling pathways are known to be involved in radiation-induced cell survival. However, the role of alpha-thalassemia X-linked mutant retardation syndrome (ATRX), a chromatin remodeling protein, in GBM radioresistance remains unclear.
METHODS
In the present study, the ATRX mutation rate in patients with glioma was obtained from The Cancer Genome Atlas, while its expression analyzed using bioinformatics. Datasets were also obtained from the Gene Expression Omnibus, and ATRX expression levels following irradiation of GBM were determined. The effects of ATRX on radiosensitivity were investigated using a knockdown assays.
RESULTS
The present study demonstrated that the ATRX mutation rate in patients with GBM was significantly lower than that in patients with low-grade glioma, and that patients harboring an ATRX mutation exhibited a prolonged survival, compared with to those harboring the wild-type gene. Single-cell RNA sequencing demonstrated that ATRX counts increased 2 days after irradiation, with ATRX expression levels also increasing in U-251MG radioresistant cells. Moreover, the results of in vitro irradiation assays revealed that ATRX expression was increased in U-251MG cells, while ATRX knockdown was associated with increased levels of radiosensitivity.
CONCLUSIONS
High ATRX expression levels in primary GBM may contribute to high levels of radioresistance. Thus ATRX is a potential target for overcoming the radioresistance in GBM.
PubMed: 38898533
DOI: 10.1186/s41016-024-00371-6 -
Sensors (Basel, Switzerland) Jun 2024Radon, a radioactive inert gas that comes from the decay of naturally occurring radioactive species, poses a substantial health risk due to its involvement in lung...
Radon, a radioactive inert gas that comes from the decay of naturally occurring radioactive species, poses a substantial health risk due to its involvement in lung cancer carcinogenesis. This work proposes a metrological approach for determining radon exhalation rates from diverse building materials. This methodology employs an electrostatic collection chamber for alpha spectrometry of radon isotopic decay products. Experimental evaluations were conducted particularly focusing on volcanic gray tuff from Sant'Agata de' Goti (Campania region, Italy), a material commonly utilized in construction, to assess radon exhalation rates. The study aligns with Legislative Decree 101/2020, a transposition of European Directive 59/2013/Euratom, highlighting the need to identify materials with a high risk of radon exhalation. Moreover, this work supports the goals of the Italian National Radon Action Plan related to the aforementioned decree, aiming to develop methodologies for estimating radon exhalation rates from building materials and improving radioprotection practices.
PubMed: 38894424
DOI: 10.3390/s24113633 -
International Journal of Molecular... May 2024Astronauts on exploratory missions will be exposed to galactic cosmic rays (GCR), which can induce neuroinflammation and oxidative stress (OS) and may increase the risk...
Astronauts on exploratory missions will be exposed to galactic cosmic rays (GCR), which can induce neuroinflammation and oxidative stress (OS) and may increase the risk of neurodegenerative disease. As key regulators of inflammation and OS in the CNS, microglial cells may be involved in GCR-induced deficits, and therefore could be a target for neuroprotection. This study assessed the effects of exposure to helium (He) and iron (Fe) particles on inflammation and OS in microglia in vitro, to establish a model for testing countermeasure efficacy. Rat microglia were exposed to a single dose of 20 cGy (300 MeV/n) He or 2 Gy Fe (600 MeV/n), while the control cells were not exposed (0 cGy). Immediately following irradiation, fresh media was applied to the cells, and biomarkers of inflammation (cyclooxygenase-2 [COX-2], nitric oxide synthase [iNOS], phosphorylated IκB-α [pIκB-α], tumor necrosis factor-α [TNFα], and nitrite [NO]) and OS (NADPH oxidase [NOX2]) were assessed 24 h later using standard immunochemical techniques. Results showed that radiation did not increase levels of NO or protein levels of COX-2, iNOS, pIκB-α, TNFα, or NOX2 compared to non-irradiated control conditions in microglial cells ( > 0.05). Therefore, microglia in isolation may not be the primary cause of neuroinflammation and OS following exposures to helium or iron GCR particles.
Topics: Animals; Microglia; Cosmic Radiation; Oxidative Stress; Rats; Inflammation; Biomarkers; Nitric Oxide Synthase Type II; Iron; Cyclooxygenase 2; Helium; Tumor Necrosis Factor-alpha; NADPH Oxidase 2
PubMed: 38892109
DOI: 10.3390/ijms25115923 -
International Journal of Molecular... May 2024Astatine (At) is a cyclotron-produced alpha emitter with a physical half-life of 7.2 h. In our previous study, the At-labeled prostate-specific membrane antigen (PSMA)...
Astatine (At) is a cyclotron-produced alpha emitter with a physical half-life of 7.2 h. In our previous study, the At-labeled prostate-specific membrane antigen (PSMA) compound ([At]PSMA-5) exhibited excellent tumor growth suppression in a xenograft model. We conducted preclinical biodistribution and toxicity studies for the first-in-human clinical trial. [At]PSMA-5 was administered to both normal male ICR mice ( = 85) and cynomolgus monkeys ( = 2). The mice were divided into four groups for the toxicity study: 5 MBq/kg, 12 MBq/kg, 35 MBq/kg, and vehicle control, with follow-ups at 1 day ( = 10 per group) and 14 days ( = 5 per group). Monkeys were observed 24 h post-administration of [At]PSMA-5 (9 MBq/kg). Blood tests and histopathological examinations were performed at the end of the observation period. Blood tests in mice indicated no significant myelosuppression or renal dysfunction. However, the monkeys displayed mild leukopenia 24 h post-administration. Despite the high accumulation in the kidneys and thyroid, histological analysis revealed no abnormalities. On day 1, dose-dependent single-cell necrosis/apoptosis was observed in the salivary glands of mice and intestinal tracts of both mice and monkeys. Additionally, tingible body macrophages in the spleen and lymph nodes indicated phagocytosis of apoptotic B lymphocytes. Cortical lymphopenia (2/10) in the thymus and a decrease in the bone marrow cells (9/10) were observed in the 35 MBq/kg group in mice. These changes were transient, with no irreversible toxicity observed in mice 14 days post-administration. This study identified no severe toxicities associated with [At]PSMA-5, highlighting its potential as a next-generation targeted alpha therapy for prostate cancer. The sustainable production of At using a cyclotron supports its applicability for clinical use.
Topics: Animals; Male; Prostatic Neoplasms; Mice; Tissue Distribution; Mice, Inbred ICR; Astatine; Alpha Particles; Humans; Macaca fascicularis; Glutamate Carboxypeptidase II; Radiopharmaceuticals
PubMed: 38891856
DOI: 10.3390/ijms25115667 -
Journal of Translational Medicine Jun 2024This study developed a nomogram model using CT-based delta-radiomics features and clinical factors to predict pathological complete response (pCR) in esophageal squamous...
BACKGROUND
This study developed a nomogram model using CT-based delta-radiomics features and clinical factors to predict pathological complete response (pCR) in esophageal squamous cell carcinoma (ESCC) patients receiving neoadjuvant chemoradiotherapy (nCRT).
METHODS
The study retrospectively analyzed 232 ESCC patients who underwent pretreatment and post-treatment CT scans. Patients were divided into training (n = 186) and validation (n = 46) sets through fivefold cross-validation. 837 radiomics features were extracted from regions of interest (ROIs) delineations on CT images before and after nCRT to calculate delta values. The LASSO algorithm selected delta-radiomics features (DRF) based on classification performance. Logistic regression constructed a nomogram incorporating DRFs and clinical factors. Receiver operating characteristic (ROC) and area under the curve (AUC) analyses evaluated nomogram performance for predicting pCR.
RESULTS
No significant differences existed between the training and validation datasets. The 4-feature delta-radiomics signature (DRS) demonstrated good predictive accuracy for pCR, with α-binormal-based and empirical AUCs of 0.871 and 0.869. T-stage (p = 0.001) and differentiation degree (p = 0.018) were independent predictors of pCR. The nomogram combined the DRS and clinical factors improved the classification performance in the training dataset (AUC = 0.933 and AUC = 0.941). The validation set showed similar performance with AUCs of 0.958 and 0.962.
CONCLUSIONS
The CT-based delta-radiomics nomogram model with clinical factors provided high predictive accuracy for pCR in ESCC patients after nCRT.
Topics: Humans; Nomograms; Male; Female; Middle Aged; Neoadjuvant Therapy; Esophageal Squamous Cell Carcinoma; Esophageal Neoplasms; Tomography, X-Ray Computed; Chemoradiotherapy; ROC Curve; Treatment Outcome; Aged; Carcinoma, Squamous Cell; Reproducibility of Results; Adult; Area Under Curve; Retrospective Studies; Radiomics
PubMed: 38890720
DOI: 10.1186/s12967-024-05392-4 -
Cell Death & Disease Jun 2024Radiation therapy (RT) remains a common treatment for cancer patients worldwide, despite the development of targeted biological compounds and immunotherapeutic drugs....
Radiation therapy (RT) remains a common treatment for cancer patients worldwide, despite the development of targeted biological compounds and immunotherapeutic drugs. The challenge in RT lies in delivering a lethal dose to the cancerous site while sparing the surrounding healthy tissues. Low linear energy transfer (low-LET) and high linear energy transfer (high-LET) radiations have distinct effects on cells. High-LET radiation, such as alpha particles, induces clustered DNA double-strand breaks (DSBs), potentially inducing cell death more effectively. However, due to limited range, alpha-particle therapies have been restricted. In human cancer, mutations in TP53 (encoding for the p53 tumor suppressor) are the most common genetic alteration. It was previously reported that cells carrying wild-type (WT) p53 exhibit accelerated senescence and significant rates of apoptosis in response to RT, whereas cells harboring mutant p53 (mutp53) do not. This study investigated the combination of the alpha-emitting atoms RT based on internal Radium-224 (Ra) sources and systemic APR-246 (a p53 reactivating compound) to treat tumors with mutant p53. Cellular models of colorectal cancer (CRC) or pancreatic ductal adenocarcinoma (PDAC) harboring mutant p53, were exposed to alpha particles, and tumor xenografts with mutant p53 were treated using Ra source and APR-246. Effects on cell survival and tumor growth, were assessed. The spread of alpha emitters in tumors was also evaluated as well as the spatial distribution of apoptosis within the treated tumors. We show that mutant p53 cancer cells exhibit radio-sensitivity to alpha particles in vitro and to alpha-particles-based RT in vivo. APR-246 treatment enhanced sensitivity to alpha radiation, leading to reduced tumor growth and increased rates of tumor eradication. Combining alpha-particles-based RT with p53 restoration via APR-246 triggered cell death, resulting in improved therapeutic outcomes. Further preclinical and clinical studies are needed to provide a promising approach for improving treatment outcomes in patients with mutant p53 tumors.
Topics: Alpha Particles; Humans; Tumor Suppressor Protein p53; Animals; Mice; Radiation-Sensitizing Agents; Mutation; Quinuclidines; Cell Line, Tumor; Mice, Nude; Xenograft Model Antitumor Assays; Apoptosis; Neoplasms
PubMed: 38890278
DOI: 10.1038/s41419-024-06830-3 -
Nutrition, Metabolism, and... May 2024Systemic inflammation and oxidation are primary contributors to the development of atherosclerosis. Oxidation of low-density lipoprotein (LDL) particles within the...
BACKGROUND AND AIMS
Systemic inflammation and oxidation are primary contributors to the development of atherosclerosis. Oxidation of low-density lipoprotein (LDL) particles within the vascular endothelium has been hypothesized to be an initial step in the formation of atherosclerotic plaques, with inflammatory cytokines serving as the signaling mechanism for concomitant macrophage activation. Supplementation with the antioxidative macular xanthophylls (lutein [L], zeaxanthin [Z], and meso-zeaxanthin [MZ]) has been shown to aid in the reduction of inflammatory physiologic responses; therefore, we hypothesized that in our study population, supplementation with these xanthophylls would facilitate a systemic reduction in markers of inflammation and cardiovascular lipid oxidation.
METHODS AND RESULTS
In this double-blind placebo-controlled supplementation study, participants were randomly allocated to receive the active intervention containing L (10 mg) + MZ (10 mg) + Z (2 mg) or placebo (containing sunflower oil). Serum concentrations of carotenoids (assessed by HPLC), inflammatory cytokines (IL-6, IL-1β, TNF-α) and oxidized LDL (OxLDL; by solid-phase sandwich ELISA) were measured at baseline and at 6-months. Results showed that over the supplementation period, compared to placebo, the active group demonstrated statistically significant increases in serum concentrations of L, Z, & MZ (p < 0.05), reductions in inflammatory cytokines IL-1β (p < 0.001) and TNF-α (p = 0.003), as well as a corresponding reduction in serum OxLDL (p = 0.009).
CONCLUSIONS
Our data show that L, Z, & MZ supplementation results in decreased serum IL-1β, TNF-α, and OxLDL. This suggests that these carotenoids are acting systemically to attenuate oxidative lipid products and inflammation, thus reducing their contribution to atherosclerotic plaque formation.
PubMed: 38890092
DOI: 10.1016/j.numecd.2024.05.009 -
Advances in Radiation Oncology Jul 2024Ultrahypofractionated (UHF) radiation therapy (RT) has become a treatment alternative for patients with localized prostate cancer. In more advanced cases, seminal...
Ultrahypofractionated Radiation Therapy for Prostate Cancer Including Seminal Vesicles in the Target Volume: A Treatment-planning Study Based on the HYPO-RT-PC Fractionation Schedule.
PURPOSE
Ultrahypofractionated (UHF) radiation therapy (RT) has become a treatment alternative for patients with localized prostate cancer. In more advanced cases, seminal vesicles (SVs) are routinely included in the target volume. The Scandinavian HYPO-RT-PC trial, which compared 42.7 Gy in 7 fractions (fr) to conventional fractionation (CF), did not include SVs in the clinical target volume. The primary objective of the present work was to implement a ultrahypofractionated-simultaneous integrated boost (UHF-SIB) for prostate cancer RT, incorporating SVs into the target volume based on this fractionation schedule. A secondary objective was to analyze the unintentional dose coverage of SVs from state-of-the-art volumetric modulated arc therapy treatments to the prostate gland only.
METHODS AND MATERIALS
Two different equieffective UHF-SIB treatment schedules to SVs were derived based on the CF clinical schedule (50.0 Gy/25 fr to elective SVs and 70.0 Gy/35 fr to verified SV-invasion (SVI)) using the linear quadric model with α/β = 2 Gy and 3 Gy. The dose to the prostate was 42.7 Gy/7 fr in both schedules, with 31.2 Gy/37.8 Gy (α/β = 2 Gy) and 32.7 Gy/40.1 Gy (α/β = 3 Gy) to elective SV/verified SVI. Volumetric modulated arc therapy plans to the proximal 10 mm and 20 mm were optimized, and dose-volume metrics for target volumes and organs at risk were evaluated.
RESULTS
Dose metrics were overall lower for UHF-SIB compared with CF. QUANTEC-based volume criteria were 2% to 7% lower for the rectum and 2% to 4% lower for the bladder in the UHF-SIB. The D to elective SV was 7 to 12 Gy lower with UHF-SIB, and the corresponding data for verified SVI were approximately 2 to 3 Gy. The SV(10 mm) V for prostate-only treatments (42.7 Gy) were as follows: median (IQR), 99% (87-100) and 78% (58-99) for the clinical target volume and planning target volume, respectively.
CONCLUSIONS
UHF RT based on the HYPO-RT-PC fractionation schedule, with a SIB technique, to the prostate and the base of the SV can be planned with lower doses (EQD2) to organs at risk, compared with CF. The unintentional dose to the proximal parts of SVs in prostate-only treatment can be substantial.
PubMed: 38883997
DOI: 10.1016/j.adro.2024.101531