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Translational Cancer Research May 2024Despite the promise of concurrent radiotherapy (RT) and immunotherapy in head and neck cancer (HNC), multiple randomized trials of this combination have had...
Despite the promise of concurrent radiotherapy (RT) and immunotherapy in head and neck cancer (HNC), multiple randomized trials of this combination have had disappointing results. To evaluate potential immunologic mechanisms of RT resistance, we compared pre-treatment HNCs that developed RT resistance to a matched cohort that achieved curative status. Gene set enrichment analysis demonstrated that a pre-treatment pro-immunogenic tumor microenvironment (TME), including type II interferon [interferon gamma (IFNγ)] and tumor necrosis factor alpha (TNFα) signaling, predicted cure while type I interferon [interferon alpha (IFNα)] enrichment was associated with an immunosuppressive TME found in tumors that went on to recur. We then used immune deconvolution of RNA sequencing datasets to evaluate immunologic cell subset enrichment. This identified M2 macrophage signaling associated with type I IFN pathway expression in RT-recurrent disease. To further dissect mechanism, we then evaluated differential gene expression between pre-treatment and RT-resistant HNCs from sampled from the same patients at the same anatomical location in the oral cavity. Here, recurrent samples exhibited upregulation of type I IFN-stimulated genes (ISGs) including members of the IFN-induced protein with tetratricopeptide repeats (IFIT) and IFN-induced transmembrane (IFITM) gene families. While several ISGs were upregulated in each recurrent cancer, IFIT2 was significantly upregulated in all recurrent tumors when compared with the matched pre-RT specimens. Based on these observations, we hypothesized sustained type I IFN signaling through ISGs, such as IFIT2, may suppress the intra-tumoral immune response thereby promoting radiation resistance.
PubMed: 38881922
DOI: 10.21037/tcr-23-2104 -
Radiotherapy and Oncology : Journal of... Jun 2024Preclinical research demonstrated that the exposure of microbubbles (intravascular gas microspheres) to focussed ultrasound within the targeted tumour upregulates...
BACKGROUND AND PURPOSE
Preclinical research demonstrated that the exposure of microbubbles (intravascular gas microspheres) to focussed ultrasound within the targeted tumour upregulates pro-apoptotic pathways and enhances radiation-induced tumour cell death. This study aimed to assess the safety and efficacy of magnetic resonance (MR)-guided focussed ultrasound-stimulated microbubbles (MRgFUS-MB) for head and neck cancers (HN).
MATERIALS AND METHODS
This prospective phase 1 clinical trial included patients with newly diagnosed or recurrent HN cancer (except nasopharynx malignancies) for whom locoregional radiotherapy with radical- or palliative-intent as deemed appropriate. Patients with contraindications for microbubble administration or contrast-enhanced MR were excluded. MR-coupled focussed ultrasound sonicated intravenously administered microbubbles within the MR-guided target volume. Patients receiving 5-10 and 33-35 radiation fractions were planned for 2 and 3 MRgFUS-MB treatments, respectively. Primary endpoint was toxicity per CTCAEv5.0. Secondary endpoint was tumour response at 3 months per RECIST 1.1 criteria.
RESULTS
Twelve patients were enrolled between Jun/2020 and Nov/2023, but 1 withdrew consent. Eleven patients were included in safety analysis. Median follow-up was 7 months (range, 0.3-38). Most patients had oropharyngeal cancer (55 %) and received 20-30 Gy/5-10 fractions (63 %). No systemic toxicity or MRgFUS-MB-related adverse events occurred. The most severe acute adverse events were radiation-related grade 3 toxicities in 6 patients (55 %; dermatitis in 3, mucositis in 1, dysphagia in 6). No radiation necrosis or grade 4/5 toxicities were reported. 8 patients were included in the 3-month tumour response assessment: 4 had partial response (50 %), 3 had complete response (37.5 %), and 1 had progressive disease (12.5 %).
CONCLUSIONS
MRgFUS-MB treatment was safe and associated with high rates of tumour response at 3 months.
PubMed: 38879128
DOI: 10.1016/j.radonc.2024.110380 -
IEEE Journal of Biomedical and Health... Jun 2024GB (Glioblastoma WHO Grade 4) is the most aggressive type of brain tumor in adults that has a short survival rate even after aggressive treatment with surgery and...
GB (Glioblastoma WHO Grade 4) is the most aggressive type of brain tumor in adults that has a short survival rate even after aggressive treatment with surgery and radiation therapy. The changes in magnetic resonance imaging (MRI) for patients with GB after radiotherapy are indicative of either radiation-induced necrosis (RN) or recurrent brain tumor (rBT). Screening for rBT and RN at an early stage is crucial for facilitating faster treatment and better outcomes for the patients. Differentiating rBT from RN is challenging as both may present with similar radiological and clinical characteristics on MRI. Moreover, learning-based rBT versus RN classification using MRI may suffer from class imbalance due to a lack of patient data. While synthetic data generation using generative models has shown promise to address class imbalances, the underlying data representation may be different in synthetic or augmented data. This study proposes computational modeling with statistically rigorous repeated random sub-sampling to balance the subset sample size for rBT and RN classification. The proposed pipeline includes multiresolution radiomic feature (MRF) extraction followed by feature selection with statistical significance testing (p<0.05). The five-fold cross validation results show the proposed model with MRF features classifies rBT from RN with an area under the curve (AUC) of 0.892±0.055. Moreover, considering the dependence between survival time and censoring time (where patients are not followed up until death), the feasibility of using MRF radiomic features as a non-invasive biomarker to identify patients who are at higher risk of recurrence or radiation necrosis is demonstrated. The cross-validated results show that the MRF model provides the best overall survival prediction with an AUC of 0.77±0.032. Comparison with state-of-the-art methods suggest the proposed method is effective in RN versus rBT classification and patient survivability prediction.
PubMed: 38875078
DOI: 10.1109/JBHI.2024.3406256 -
Journal of Applied Clinical Medical... Jun 2024The study aimed to investigate the optimal isodose line (IDL) in linear accelerator-based stereotactic radiotherapy for single brain metastasis, using HyperArc. We...
PURPOSE
The study aimed to investigate the optimal isodose line (IDL) in linear accelerator-based stereotactic radiotherapy for single brain metastasis, using HyperArc. We compared the dosimetric parameters for target and normal brain tissue among six plans with different IDLs.
METHODS
This study included 30 patients with single brain metastasis. We retrospectively generated six plans for each tumor with different IDLs (80%, 70%, 60%, 50%, 40%, and 33%) using HyperArc. All treatment plans were normalized to the prescription dose of 35 Gy in five fractions which was covered by 95% of the planning target volume (PTV), defined by adding a 1.0 mm margin to the gross tumor volume (GTV). The dosimetric parameters were compared among the six plans.
RESULTS
For GTV > 0.1 cm, the ratio of brain-GTV volumes receiving 25 Gy to PTV (V/PTV) was significantly lower at IDL 40%-70% than at IDL 80% and 33% (p < 0.01, retrospectively). For GTV < 0.1 cm, V/PTV decreased continuously as IDL decreased. The values of D and D for GTV increased with decreasing IDL. An IDL of 50% or less was required to achieve D of greater than 43 Gy and D of greater than 50 Gy. The mean values of D and D for IDL 50% were 44.3 and 51.9 Gy.
CONCLUSION
The optimal IDL is 40%-50% for GTV > 0.1 cm. These lower IDLs could increase D and D of GTV while lowering V of normal brain tissue, which may help reduce the risk of radiation necrosis and improve local control.
PubMed: 38863310
DOI: 10.1002/acm2.14408 -
Breast Cancer (Tokyo, Japan) Jun 2024The safety and outcome of breast reconstruction after radiotherapy are controversial, and the aesthetic aspects have not been studied extensively. We compared the...
BACKGROUND
The safety and outcome of breast reconstruction after radiotherapy are controversial, and the aesthetic aspects have not been studied extensively. We compared the results of vascular anastomosis, the incidence of postoperative complications, and aesthetic appearance between patients who had and had not received radiotherapy who then had undergone delayed breast reconstruction with autologous free flaps from the abdomen, thighs, and buttocks.
METHODS
In total, 257 flaps in 241 patients were investigated; 194 and 63 flaps implanted in patients who did not receive radiotherapy and who received radiotherapy before breast reconstruction, respectively. Of the 257 flaps, 221, 20, 14, and 2 came from the abdomen, thighs, buttocks, and other anatomic locations, respectively. We evaluated aesthetic outcomes in 105 patients who had not received radiotherapy and 35 who had.
RESULTS
We found no significant differences between the two groups in the incidence of vascular reanastomosis, the time required for anastomosis, or the incidence of unplanned reoperation. Complications such as flap necrosis were rare in both groups. Aesthetic outcomes were significantly better in the patients who had not received radiotherapy.
CONCLUSIONS
Breast reconstruction with autologous free flaps can be performed safely in patients who have received radiotherapy, but the aesthetic result is slightly inferior to that in patients who had not received radiotherapy.
PubMed: 38862869
DOI: 10.1007/s12282-024-01593-3 -
Medical Oncology (Northwood, London,... Jun 2024Resistance to caspase-dependent apoptosis is often responsible for treatments failure in cancer. Necroptosis is a type of programmed necrosis that occurs under...
Resistance to caspase-dependent apoptosis is often responsible for treatments failure in cancer. Necroptosis is a type of programmed necrosis that occurs under caspase-deficient conditions that could overcome apoptosis resistance. Our purpose was to investigate the interrelationship between apoptotic and necroptotic death pathways and their influence on the response of breast cancer cells to radiotherapy in vitro. Human BC cell lines MCF-7 and MDA-MB-231 were treated with ionizing radiation, and then several markers of apoptosis, necroptosis, and survival were assessed in the presence and absence of necroptosis inhibition. MLKL knockdown was achieved by siRNA transfection. Our main findings emphasize the role of necroptosis in cellular response to radiation represented in the dose- and time-dependent elevated expression of necroptotic markers RIPK1, RIPK3, and MLKL. Knockdown of necroptotic marker MLKL by siRNA led to a significant elevation in MDA-MB-231 and MCF-7 survival with a dose modifying factor (DMF) of 1.23 and 1.61, respectively. Apoptotic markers Caspase 8 and TRADD showed transitory or delayed upregulation, indicating that apoptosis was not the main mechanism by which cells respond to radiation exposure. Apoptotic markers also showed a significant elevation following MLKL knockdown, suggesting its role either as a secondary or death alternative pathway. The result of our study emphasizes the critical role of the necroptotic pathway in regulating breast cancer cells responses to radiotherapy and suggests a promising utilization of its key modulator, MLKL, as a treatment strategy to improve the response to radiotherapy.
Topics: Humans; Apoptosis; Breast Neoplasms; Female; Necroptosis; Protein Kinases; Cell Line, Tumor; RNA, Small Interfering; Signal Transduction; MCF-7 Cells
PubMed: 38862702
DOI: 10.1007/s12032-024-02415-4 -
Nan Fang Yi Ke Da Xue Xue Bao = Journal... May 2024To evaluate the therapeutic effect of normal mouse serum on radiation pneumonitis in mice and explore the possible mechanism.
OBJECTIVE
To evaluate the therapeutic effect of normal mouse serum on radiation pneumonitis in mice and explore the possible mechanism.
METHODS
Mouse models of radiation pneumonitis induced by thoracic radiation exposure were given intravenous injections of 100 μL normal mouse serum or normal saline immediately after the exposure followed by injections once every other day for a total of 8 injections. On the 15th day after irradiation, histopathological changes of the lungs of the mice were examined using HE staining, the levels of TNF-α, TGF-β, IL-1α and IL-6 in the lung tissue and serum were detected using ELISA, and the percentages of lymphocytes in the lung tissue were analyzed with flow cytometry. High-throughput sequencing of exosome miRNA was carried out to explore the changes in the signaling pathways. The mRNA expression levels of the immune-related genes were detected by qRT-PCR, and the protein expressions of talin-1, tensin2, FAK, vinculin, α-actinin and paxillin in the focal adhesion signaling pathway were detected with Western blotting.
RESULTS
In the mouse models of radiation pneumonitis, injections of normal mouse serum significantly decreased the lung organ coefficient, lowered the levels of TNF-α, TGF-β, IL-1α and IL-6 in the serum and lung tissues, and ameliorated infiltration of CD45, CD4 and T lymphocytes in the lung tissue (all <0.05). The expression levels of and genes at both the mRNA and protein levels and the protein expressions of talin-1, tensin2, FAK, vinculin, α‑actinin and paxillin were all significantly down-regulated in the mouse models after normal mouse serum treatment.
CONCLUSION
Normal mouse serum ameliorates radiation pneumonitis in mice by inhibiting the expressions of key proteins in the Focal adhesion signaling pathway.
Topics: Animals; Mice; Signal Transduction; Radiation Pneumonitis; Focal Adhesions; Lung; Interleukin-6; Disease Models, Animal; Tumor Necrosis Factor-alpha; Transforming Growth Factor beta; MicroRNAs; Interleukin-1alpha
PubMed: 38862437
DOI: 10.12122/j.issn.1673-4254.2024.05.01 -
Clinical Neuroradiology Jun 2024To investigate the feasibility of using radiomics analysis of quantitative maps from synthetic MRI to preoperatively predict diffuse glioma grades, isocitrate...
PURPOSE
To investigate the feasibility of using radiomics analysis of quantitative maps from synthetic MRI to preoperatively predict diffuse glioma grades, isocitrate dehydrogenase (IDH) subtypes, and 1p/19q codeletion status.
METHODS
Data from 124 patients with diffuse glioma were used for analysis (n = 87 for training, n = 37 for testing). Quantitative T1, T2, and proton density (PD) maps were obtained using synthetic MRI. Enhancing tumour (ET), non-enhancing tumour and necrosis (NET), and peritumoral edema (PE) regions were segmented followed by manual fine-tuning. Features were extracted using PyRadiomics and then selected using Levene/T, BorutaShap and maximum relevance minimum redundancy algorithms. A support vector machine was adopted for classification. Receiver operating characteristic curve analysis and integrated discrimination improvement analysis were implemented to compare the performance of different radiomics models.
RESULTS
Radiomics models constructed using features from multiple tumour subregions (ET + NET + PE) in the combined maps (T1 + T2 + PD) achieved the highest AUC in all three prediction tasks, among which the AUC for differentiating lower-grade and high-grade diffuse gliomas, predicting IDH mutation status and predicting 1p/19q codeletion status were 0.92, 0.95 and 0.86 respectively. Compared with those constructed on individual T1, T2, and PD maps, the discriminant ability of radiomics models constructed on the combined maps separately increased by 11, 17 and 10% in predicting glioma grades, 35, 52 and 19% in predicting IDH mutation status, and 16, 15 and 14% in predicting 1p/19q codeletion status (p < 0.05).
CONCLUSION
Radiomics analysis of quantitative maps from synthetic MRI provides a new quantitative imaging tool for the preoperative prediction of grades and molecular subtypes in diffuse gliomas.
PubMed: 38858272
DOI: 10.1007/s00062-024-01421-3 -
Lin Chuang Er Bi Yan Hou Tou Jing Wai... Jun 2024To establish a staging system for guiding clinical treatment and prognostic risk assessment by retrospectively analyzing the cases with radionecrosis of the nasopharynx...
To establish a staging system for guiding clinical treatment and prognostic risk assessment by retrospectively analyzing the cases with radionecrosis of the nasopharynx and skull base (RNSB) after radiotherapy for nasopharyngeal carcinoma. A total of 86 cases of RNSB from January 2019 to December 2022 visited Department of Otorhinolaryngology Head and Neck, the People's Hospital of Guangxi Zhuang Autonomous Region. Seventeen patients gave up the treatment, and 69 patients who underwent treatment were included for analysis. By analyzing the results of electronic nasopharyngolaryngoscopy combined with magnetic resonance (MR), CT, and other imaging examinations, a staging system for RNSB was proposed. The relationship between the staging system and the surgical effectiveness and clinical prognosis was further analyzed. According to the severity and extent of destruction of soft tissue, bone, and the adjacent neurovascular structures, the RNSB was categorized into closed type (=5) and open type (=64), of which the open type was subdivided into five types: type Ⅰ(=4), type Ⅱ(=6), type Ⅲ(=39, of which 21 cases were type Ⅲa and 18 cases were type Ⅲb), type Ⅳ(=12), and type Ⅴ(=8). The clinical stage of RNSB were classified based on nasopharyngolaryngoscopy and imaging examinations, receiving the second course of radiotherapy or not, the involvement of the infection site, the extent of bone destruction, the degree of internal carotid artery involvement, and the degree of brain tissue necrosis: stageⅠ(1-2 scores), 11 cases at stageⅡ(3-4 scores), 24 cases at stage Ⅲ(5-6 scores), and 30 cases at stage Ⅳ( ≥ 7 scores or more). Twenty-two patients chose conservative treatment (2 patients at stage Ⅰ, 3 patients at stage Ⅱ, 7 patients at stage Ⅲ, and 10 patients at stage Ⅳ). Forty-seven patients chose nasal endoscopic surgical treatment (2 patients at stage Ⅰ, 8 patients at stage Ⅱ, 17 patients at stage Ⅲ, and 20 patients at stage Ⅳ), of which 16 cases had received free mucosal flap and/or stented septum mucosal flap repair. Patients at stages Ⅰ, Ⅱ, and Ⅲ achieved satisfactory efficacy after surgical treatment. In addition, higher clinical stage was found to correlate with the worse prognosis and higher incidence of perioperative complications, which included failure of healing because of surgical site infection, cerebrospinal fluid nasal leakage, progressive osteonecrosis, nasopharyngeal hemorrhage, and death. The staging system proposed in our study can be used for early detection of RNSB during regular follow-up, and is also valuable for clinical treatment guidance and prognosis assessment.
Topics: Humans; Male; Female; Skull Base; Nasopharyngeal Neoplasms; Retrospective Studies; Middle Aged; Necrosis; Radiation Injuries; Nasopharynx; Adult; Aged; Magnetic Resonance Imaging; Prognosis; Tomography, X-Ray Computed
PubMed: 38858113
DOI: 10.13201/j.issn.2096-7993.2024.06.007 -
Biochimica Et Biophysica Acta.... Jun 2024Neuroinflammation is a hallmark of several neurodegenerative disorders that has been extensively studied in recent years. Microglia, the primary immune cells of the...
Neuroinflammation is a hallmark of several neurodegenerative disorders that has been extensively studied in recent years. Microglia, the primary immune cells of the central nervous system (CNS), are key players in this physiological process, demonstrating a remarkable adaptability in responding to various stimuli in the eye and the brain. Within the complex network of neuroinflammatory signals, the fatty acid N-ethanolamines, in particular N-arachidonylethanolamine (anandamide, AEA), emerged as crucial regulators of microglial activity under both physiological and pathological states. In this study, we interrogated for the first time the impact of the signaling of these bioactive lipids on microglial cell responses to a sub-lethal acute UVB radiation, a physical stressor responsible of microglia reactivity in either the retina or the brain. To this end, we developed an in vitro model using mouse microglial BV-2 cells. Upon 24 h of UVB exposure, BV-2 cells showed elevated oxidative stress markers and, cyclooxygenase (COX-2) expression, enhanced phagocytic and chemotactic activities, along with an altered immune profiling. Notably, UVB exposure led to a selective increase in expression and activity of fatty acid amide hydrolase (FAAH), the main enzyme responsible for degradation of fatty acid ethanolamides. Pharmacological FAAH inhibition via URB597 counteracted the effects of UVB exposure, decreasing tumor necrosis factor α (TNF-α) and nitric oxide (NO) release and reverting reactive oxidative species (ROS), interleukin-1β (IL-1β), and interleukin-10 (IL-10) levels to the control levels. Our findings support the potential of enhanced fatty acid amide signaling in mitigating UVB-induced cellular damage, paving the way to further exploration of these lipids in light-induced immune responses.
PubMed: 38857757
DOI: 10.1016/j.bbalip.2024.159524