Comparative dosimetric analysis of normal brain tissue in patients with Nasopharyngeal carcinoma at different stages after radiation therapy.

INTRODUCTION: Radiotherapy (RT) is the main treatment for patients with nasopharyngeal carcinoma (NPC). NPC patients at different stages have varying levels of damage to normal brain tissue after RT. No study has yet thoroughly analyzed the variations in radiation dosages in the brain for different stages of NPC patients treated with RT. This study aims to examine these variations. METHODS: 1446 NPC patients' CT and RTdose data were retrospectively reviewed. Analysis of the radiation dosage was executed on these 803 patients. The RTdose images for several patient groups were averaged after registering each patient's RTdose data to the CT brain template created in our earlier study. The voxel-based (VB) analysis was used to examine the dose variations in the brains of three groups of NPC patients: the early-stage group, the stage III group, and the stage IV group. RESULTS: As the disease progresses from early to advanced stages, the intensity and volume of radiation in the brain increase. The normal brain tissue accepted a substantially larger dosage in more advanced NPC patients. Differences in brain regions between stage III and early-stage patients were minimal compared to any other two groups. Brain regions exhibited substantial variations between the stage IV group and all other patient groups were broadly distributed. CONCLUSION: Our findings highlight the critical role of NPC staging in the therapeutic strategy, emphasizing the heterogeneity of radiation-induced tissue damage across disease stages and implying the need to develop stage-specific RT plans.

Specific-CT brain template construction and retrospective dosimetric comparison study in brain for nasopharyngeal carcinoma patients treated with IMRT or VMAT.

The current Radiotherapy (RT) technology still inevitably irradiated normal brain tissue, causing implicit radiation-induced injury. This study investigates the precise localization and the corresponding radiation dosage of brain regions susceptible to damage in nasopharyngeal carcinoma (NPC) patients following RT. Utilizing the Advanced Normalization Tools (ANTs) package, a computed tomography (CT) brain template was created in the standard Montreal Neurological Institute (MNI) space, based on 803 Chinese NPC patients (T0~T4) who underwent RT. With this template, all patients' CT and RTdose data were registered to the MNI space, and the RTdose distribution characteristics in normal brain tissues were compared for NPC patients treated with Intensity-modulated radiotherapy (IMRT) or Volumetric Modulated Arc Therapy (VMAT), with patients' age and gender as covariates. Analysis of the average dosages indicated that certain areas within the Limbic, Temporal, and Posterior Lobes, the Brainstem, and the Cerebellum Posterior Lobe were exposed to doses exceeding 50 Gy. Inter-group analysis revealed that IMRT delivered higher doses than VMAT to brain regions anterior to the nasopharyngeal tumor, whereas VMAT affected the posterior regions more. Interestingly, VMAT showed a drawback in preserving the normal brain tissues for T4-stage patients. This revealed that the two treatment modalities have unique characteristics in preserving normal brain tissue, each with advantages. With better localization precision, the created CT brain template in MNI space may be beneficial for NPC patients' toxicity and dosimetric analyses.

Single isocenter versus dual isocenter treatment using flattening filter-free and jaw-tracking volumetrically modulated arc therapy for boot-shaped lung cancer: Evaluation of dosimetric and feasibility.

BACKGROUND: To determine whether a dual-isocenter volumetrically modulated arc therapy (VMAT) technique results in lower normal pulmonary dosage compared to a traditional single isocenter technique for boot-shaped lung cancer. METHODS: A cohort of 15 patients with advanced peripheral or central lung cancer who had metastases in the mediastinum and supraclavicular lymph nodes was randomly selected for this retrospective study. VMAT plans were generated for each patient using two different beam alignment techniques with the 6-MV flattening filter-free (FFF) photon beam: single-isocenter jaw-tracking VMAT based on the Varian TrueBeam linear accelerator (S-TV), and dual-isocenter VMAT based on both TrueBeam (D-TV) and Halcyon linear accelerator (D-HV). For all 45 treatment plans, planning target volume (PTV) dose coverage, conformity/homogeneity index (CI/HI), mean heart dose (MHD), mean lung dose (MLD) and the total lung tissue receiving 5, 20, 30 Gy (V5, V20, V30) were evaluated. The monitor units (MUs), delivery time, and plan quality assurance (QA) results were recorded. RESULTS: The quality of the objectives of the three plans was comparable to each other. In comparison with S-TV, D-TV and D-HV improved the CI and HI of the PTV (p < 0.05). The MLD was 13.84 ± 1.44 Gy (mean ± SD) for D-TV, 14.22 ± 1.30 Gy and 14.16 ± 1.42 Gy for S-TV and D-HV, respectively. Lungs-V5Gy was 50.78 ± 6.24%, 52.00 ± 7.32% and 53.36 ± 8.48%, Lungs-V20Gy was 23.72 ± 2.27%, 26.18 ± 2.86% and 24.96 ± 3.09%, Lungs-V30Gy was 15.69 ± 1.76%, 17.20 ± 1.72% and 16.52 ± 2.07%. Compared to S-TV, D-TV provided statistically significant better protection for the total lung, with the exception of the lungs-V5. All plans passed QA according the gamma criteria of 3%/3 mm. CONCLUSIONS: Taking into account the dosimetric results and published clinical data on radiation-induced pulmonary injury, dual-isocenter jaw-tracking VMAT may be the optimal choice for treating boot-shaped lung cancer.

A detailed dosimetric comparative study of IMRT and VMAT in normal brain tissues for nasopharyngeal carcinoma patients treated with radiotherapy.

Background: Radiotherapy (RT) is the primary treatment for nasopharyngeal carcinoma (NPC). However, it can cause implicit RT-induced injury by irradiating normal brain tissue. To date, there have been no detailed reports on the radiated exact location in the brain, the corresponding radiation dose, and their relationship. Methods: We analyzed 803 Chinese NPC patients treated with RT and used a CT brain template in a Montreal Neurological Institute (MNI) space to compare the group differences in RT dose distribution for different RT technologies (IMRT or VMAT). Results: Brain regions that received high doses (>50 Gy) of radiation were mainly located in parts of the temporal and limbic lobes, where radioactive damage often occurs. Brain regions that accepted higher doses with IMRT were mainly located near the anterior region of the nasopharyngeal tumor, while brain regions that accepted higher doses with VMAT were mainly located near the posterior region of the tumor. No significant difference was detected between IMRT and VMAT for T1 stage patients. For T2 stage patients, differences were widely distributed, with VMAT showing a significant dose advantage in protecting the normal brain tissue. For T3 stage patients, VMAT showed an advantage in the superior temporal gyrus and limbic lobe, while IMRT showed an advantage in the posterior cerebellum. For T4 stage patients, VMAT showed a disadvantage in protecting the normal brain tissue. These results indicate that IMRT and VMAT have their own advantages in sparing different organs at risk (OARs) in the brain for different T stages of NPC patients treated with RT. Conclusion: Our approach for analyzing dosimetric characteristics in a standard MNI space for Chinese NPC patients provides greater convenience in toxicity and dosimetry analysis with superior localization accuracy. Using this method, we found interesting differences from previous reports: VMAT showed a disadvantage in protecting the normal brain tissue for T4 stage NPC patients.

Research Value of Intensity Modulated Radiation Therapy in Alleviating Parotid Gland Function Injury in Patients with Stage N0 Nasopharyngeal Carcinoma from Physical and Dosimetric Aspects.

Objective: To study the feasibility of intensity modulated radiation therapy (IMRT) for stage N0 nasopharyngeal carcinoma (NPC) and its parotid gland (PG) function preservation from physical and dosimetric aspects. Methods: All the clinical data of 77 patients with pathologically confirmed T1-4N0M0 NPC who received radiotherapy between July 2017 and October 2019 in the Radiotherapy Center of Taizhou Hospital of Zhejiang Province affiliated to Wenzhou Medical University were analyzed retrospectively. Three-dimensional conformal radiotherapy (3D-CRT) and IMRT were used in 35 and 42 cases, respectively. The treatment efficiency and the dosimetry differences of the PG in the intensity modulation plan were compared between groups. Quantitative monitoring of 99mTc radionuclide imaging of PG was performed before, at the end of, and 3, 6, and 12 months after radiotherapy. The degree of PG function injury and xerostomia was compared between groups at the end of radiotherapy and 12 months later. Results: Higher minimal, maximal, and average irradiation doses of PG were determined in 3D-CRT-treated patients compared with IMRT-treated cases (P < 0.05). Compared with before radiotherapy, the PG uptake index (UI) and excretion index (EI) of both cohorts of patients decreased to varying degrees at the end of radiotherapy, with PG function injury and xerostomia symptoms observed in all cases but with no obvious difference between groups (P > 0.05). To a certain extent, the PG function recovered and the xerostomia symptoms relieved in both groups 12 months after radiotherapy, with better improvements in IMRT group versus 3D-CRT group. Conclusion: IMRT has similar short-term efficacy to 3D-CRT in treating patients with stage N0 NPC, but it can effectively reduce the dose of PG radiotherapy and protect the PG function on the premise of ensuring sufficient tumor coverage and dose, showing certain dosimetry advantages.

Parotid Gland Stem Cell Preservation during Intensity-Modulated Radiotherapy for Nasopharyngeal Carcinoma: Dosimetric Analysis and Feasibility.

Objective: Parotid gland (PG) is a radiosensitive organ, and xerostomia (XS) is a key factor affecting patients' life quality after conventional radiotherapy for head and neck tumors. In this study, dosimetry analysis was performed on PG stem cell preservation in intensity-modulated radiotherapy (IMRT) for nasopharyngeal carcinoma (NPC). Methods: All clinical data of 80 NPC patients diagnosed pathologically in the Radiotherapy Department of Taizhou Hospital of Zhejiang Province Affiliated with Wenzhou Medical University from August 2017 to September 2019 were retrospectively analyzed. Patients were assigned to a regular group and a restricted group according to different IMRT plans, in which a dose limitation for the parotid duct was added in the restricted group in addition to the conventional plan used in the regular group to minimize the parotid duct radiation dose. The differences in planning target volume (PTV) dose distribution, organ at risk (OAR) dose, and dose to the PG and its ducts were compared between the two groups. Results: Significantly higher mean irradiation doses of the brainstem, mandible, and oral cavity were determined in the restricted group compared with the regular group (P > 0.05), but there was no significant difference in the mean dose of other OARs irradiated (P > 0.05). As compared to the irradiation of bilateral PGs, no statistical differences were found in the mean irradiation dose and V30 between regular and restricted groups (P > 0.05), but lower V20 and higher V45 were determined in the restricted group (P < 0.05). The mean irradiation dose, V15, V20, and V26 of bilateral parotid ducts were lower in the restricted group as compared to the regular group (P < 0.05). Conclusion: IMRT for NPC can effectively reduce the mean irradiation dose and play a PG stem cell preservation role by giving specific dose limitation conditions to the parotid duct area without affecting PTV dose distribution and OAR irradiation dose, which has certain feasibility.

Effect of three-dimensional conformal radiotherapy and intensity-modulated radiotherapy on parotid gland function and quality of life in patients with nasopharyngeal carcinoma.

OBJECTIVE: To investigate the effects of three-dimensional conformal radiotherapy (3DCRT) and intensity-modulated radiotherapy (IMRT) on parotid gland function and quality of life in patients with nasopharyngeal carcinoma (NPC). METHODS: Ninety-six patients with NPC diagnosed and treated in our hospital were divided into two groups using a random number table. The control group was treated with three-dimensional conformal radiotherapy and the research group was treated with intensity-modulated radiotherapy. Observation and comparison were conducted for differences of baseline indicators between the two groups including; short-term response rate, relevant indicators regarding parotid gland function before and after treatment, uptake index (UI) and excretion index (EI), dry mouth (xerostomia) grading and quality of life indicators after treatment, and the prognosis of patients. RESULTS: There was no significant difference in baseline data between the two groups (all P>0.05). The short-term response rate in the research group was significantly higher than that in the control group (P<0.05). After treatment, UI and EI in both groups were significantly decreased compared to those before treatment (all P<0.05); UI and EI in the research group were significantly higher than those in control group (all P<0.05). Dry mouth grading in the research group was significantly lower than that in the control group (all P<0.05). After treatment, the levels of related indicators regarding quality of life, local recurrence-free rate, and distant metastasis-free rate in the research group were higher than those in the control group (all P<0.05). CONCLUSION: IMRT for patients with NPC can significantly improve short-term response rate, reduce mouth dryness and parotid gland injury after radiotherapy, enhance quality of life, and facilitate the prognosis of patients.

A conserved PLPLRT/SD motif of STING mediates the recruitment and activation of TBK1.

Nucleic acids from bacteria or viruses induce potent immune responses in infected cells1-4. The detection of pathogen-derived nucleic acids is a central strategy by which the host senses infection and initiates protective immune responses5,6. Cyclic GMP-AMP synthase (cGAS) is a double-stranded DNA sensor7,8. It catalyses the synthesis of cyclic GMP-AMP (cGAMP)9-12, which stimulates the induction of type I interferons through the STING-TBK1-IRF-3 signalling axis13-15. STING oligomerizes after binding of cGAMP, leading to the recruitment and activation of the TBK1 kinase8,16. The IRF-3 transcription factor is then recruited to the signalling complex and activated by TBK18,17-20. Phosphorylated IRF-3 translocates to the nucleus and initiates the expression of type I interferons21. However, the precise mechanisms that govern activation of STING by cGAMP and subsequent activation of TBK1 by STING remain unclear. Here we show that a conserved PLPLRT/SD motif within the C-terminal tail of STING mediates the recruitment and activation of TBK1. Crystal structures of TBK1 bound to STING reveal that the PLPLRT/SD motif binds to the dimer interface of TBK1. Cell-based studies confirm that the direct interaction between TBK1 and STING is essential for induction of IFNß after cGAMP stimulation. Moreover, we show that full-length STING oligomerizes after it binds cGAMP, and highlight this as an essential step in the activation of STING-mediated signalling. These findings provide a structural basis for the development of STING agonists and antagonists for the treatment of cancer and autoimmune disorders.

Radiation-induced gray matter atrophy in patients with nasopharyngeal carcinoma after intensity modulated radiotherapy: a MRI magnetic resonance imaging voxel-based morphometry study.

BACKGROUND: Gray matter (GM) damage after radiotherapy (RT) in nasopharyngeal carcinoma (NPC) patients can result in cognitive impairment, while there may be no visible brain tissue change according to the conventional magnetic resonance imaging (MRI). This study investigated radiation-induced GM volume differences between NPC patients who received RT and those who did not. METHODS: High-resolution brain structural MRI data from two groups of patients were acquired. The pre-RT group was composed of 56 newly diagnosed but not yet medically treated NPC patients, while the after-RT group consisted of 40 NPC patients who had completed RT more than 1 year ago. Voxel-based morphometry (VBM) was applied to assess GM volumes. Two sample t-test was used to analyze GM volumes voxel-by-voxel using the VBM8 toolbox built in the SPM software. Radiation-induced cortical volume alteration in all NPC patients after RT and dosimetry of 36 patients were analyzed. RESULTS: Compared to pre-treatment group, cortical volumes of GM were significantly smaller in the left hippocampus, the right pulvinar and the right middle temporal gyrus (MTG, P<0.001, AlphaSim correction, cluster size ≥157). The mean dose (Dmean) for bilateral hippocampal heads were significantly higher than other different parts of the brain (P<0.001). No significant correlations between the GM volume in any brain regions and the mean dose of corresponding position of these brain regions were observed (P>0.05). CONCLUSIONS: Radiation to the NPC patients can not only induce damage of the hippocampus, but also other secondary damages of GM.

NONO Detects the Nuclear HIV Capsid to Promote cGAS-Mediated Innate Immune Activation.

Detection of viruses by innate immune sensors induces protective antiviral immunity. The viral DNA sensor cyclic GMP-AMP synthase (cGAS) is necessary for detection of HIV by human dendritic cells and macrophages. However, synthesis of HIV DNA during infection is not sufficient for immune activation. The capsid protein, which associates with viral DNA, has a pivotal role in enabling cGAS-mediated immune activation. We now find that NONO is an essential sensor of the HIV capsid in the nucleus. NONO protein directly binds capsid with higher affinity for weakly pathogenic HIV-2 than highly pathogenic HIV-1. Upon infection, NONO is essential for cGAS activation by HIV and cGAS association with HIV DNA in the nucleus. NONO recognizes a conserved region in HIV capsid with limited tolerance for escape mutations. Detection of nuclear viral capsid by NONO to promote DNA sensing by cGAS reveals an innate strategy to achieve distinction of viruses from self in the nucleus.

Efficacy and Safety of Chemotherapy Combined with Stereotactic Radiotherapy in the Treatment of Nasopharyngeal Carcinoma.

BACKGROUND The aim of this study was to investigate the efficacy and safety of chemotherapy (CT) combined with stereotactic radiotherapy (SRT) in the treatment of nasopharyngeal carcinoma (NPC). MATERIAL AND METHODS A total of 329 NPC patients without any previous treatment were included in this study between January 2009 and November 2013. These patients were divided into three groups: CT group (n=114), SRT group (n=109), and CT + SRT group (n=106). Contrast-enhanced nasopharyngeal computed tomography (CT)/magnetic resonance (MR) scan was performed on the third month after treatment. Short-term efficacy was evaluated according to the Response Evaluation Criteria in Solid Tumors (RECIST). Toxicity was graded according to the Acute Radiation Morbidity Scoring Criteria (RTOG) and the World Health Organization (WHO) toxicity grading scale. Overall survival (OS), progression free survival (PFS), and incidence rate of acute toxicity (grade ≥3) were calculated after a 24 month follow-up. RESULTS Total response rate of all patients was 85.41%. Compared with the CT group and the SRT group, the CT + SRT group showed a substantially improved efficacy in NPC treatment. The incidence rate of the acute toxicity in the CT + SRT group was slightly higher than in the CT group and the SRT group, but the difference was not statistically significant. No treatment-related deaths were observed. The CT + SRT group had the highest two-year OS and PFS, followed by the CT group and the SRT group. CONCLUSIONS It was shown that NPC patients treated with CT + SRT had better short- and long-term efficacy than those treated with CT or SRT alone.

Numb Gene Enhances Radiation Sensitivity of Nonsmall Cell Lung Cancer Stem Cells.

OBJECTIVE: To study the effects of Numb gene expression on radiation sensitivity of nonsmall cell lung cancer (NSCLC) stem cells. MATERIALS AND METHODS: The side population (SP) cells A549-SP were transfected with pcDNA3.1 (pcDNA3.1 group), pcDNA-Numb (pcDNA-Numb group) and shRNA-Numb (shRNA-Numb group). Real-time quantitative polymerase chain reaction and Western blot were performed to determine Numb expression; MTT method was used to measure the proliferation activity change of the NSCLC stem cells both before and after irradiation with different doses of 60Coγ ray; Hoechst staining and Annexin V-FITC/PI were used to detect the apoptosis of the NSCLC stem cells; and colony-forming assay was used to determine the effect of Numb expression on radiation sensitivity of the NSCLC stem cells. RESULTS: Increased mRNA and protein expressions of the A549-SP cells were found in the pcDNA-Numb group, and decreased mRNA and protein expressions were found in the shRNA-Numb group. The optical density value of the cells decreased in the pcDNA-Numb group but increased in the shRNA-Numb group. The cells with over-expressed Numb showed obvious nuclear condensation and fragmentation; the apoptosis rate increased significantly. The cells with knockdown Numb showed less nuclear damage; the apoptosis rate significantly decreased. After irradiation, the cells in the pcDNA-Numb group showed decreased survival rate, clonality, and the values of D0, Dq, N, and SF2; whereas the cells in the shRNA-Numb group showed the opposite trend. CONCLUSIONS: Radiation sensitivity of NSCLC stem cells was enhanced with the increase of Numb expression. Determination of Numb expression helped to evaluate the response of lung cancer to radiotherapy, which was important for guiding tumor treatment clinically.