Radiomic signatures reveal multiscale intratumor heterogeneity associated with tissue tolerance and survival in re-irradiated nasopharyngeal carcinoma: a multicenter study.

BACKGROUND: Post-radiation nasopharyngeal necrosis (PRNN) is a severe adverse event following re-radiotherapy for patients with locally recurrent nasopharyngeal carcinoma (LRNPC) and associated with decreased survival. Biological heterogeneity in recurrent tumors contributes to the different risks of PRNN. Radiomics can be used to mine high-throughput non-invasive image features to predict clinical outcomes and capture underlying biological functions. We aimed to develop a radiogenomic signature for the pre-treatment prediction of PRNN to guide re-radiotherapy in patients with LRNPC. METHODS: This multicenter study included 761 re-irradiated patients with LRNPC at four centers in NPC endemic area and divided them into training, internal validation, and external validation cohorts. We built a machine learning (random forest) radiomic signature based on the pre-treatment multiparametric magnetic resonance images for predicting PRNN following re-radiotherapy. We comprehensively assessed the performance of the radiomic signature. Transcriptomic sequencing and gene set enrichment analyses were conducted to identify the associated biological processes. RESULTS: The radiomic signature showed discrimination of 1-year PRNN in the training, internal validation, and external validation cohorts (area under the curve (AUC) 0.713-0.756). Stratified by a cutoff score of 0.735, patients with high-risk signature had higher incidences of PRNN than patients with low-risk signature (1-year PRNN rates 42.2-62.5% vs. 16.3-18.8%, P < 0.001). The signature significantly outperformed the clinical model (P < 0.05) and was generalizable across different centers, imaging parameters, and patient subgroups. The radiomic signature had prognostic value concerning its correlation with PRNN-related deaths (hazard ratio (HR) 3.07-6.75, P < 0.001) and all causes of deaths (HR 1.53-2.30, P < 0.01). Radiogenomics analyses revealed associations between the radiomic signature and signaling pathways involved in tissue fibrosis and vascularity. CONCLUSIONS: We present a radiomic signature for the individualized risk assessment of PRNN following re-radiotherapy, which may serve as a noninvasive radio-biomarker of radiation injury-associated processes and a useful clinical tool to personalize treatment recommendations for patients with LANPC.

First-Line Immunochemotherapy Versus Palliative Chemotherapy Plus Definitive Radiation Therapy for de novo Metastatic Nasopharyngeal Carcinoma: A Matched Cohort Study.

BACKGROUND: The combined use of immune checkpoint inhibitors (ICIs) with palliative chemotherapy (PCT) is a promising first-line treatment for de novo metastatic nasopharyngeal carcinoma (mNPC). However, the efficacy of ICIs with PCT vs PCT with definitive radiation therapy (DRT) remain unclear. METHODS: Patients with mNPC who received first-line immunochemotherapy (ICI + PCT) or PCT + DRT were included. Propensity score matching (PSM) was applied to balance potential confounders between patients who did and did not undergo DRT (at a ratio of 1:1). Progression free survival (PFS) and overall survival (OS) were compared between the 2 groups using a log-rank test and Cox proportional hazard model. RESULTS: Among all participants, 149 received ICI + PCT. After PSM, 149 patients were included in the PCT + DRT group. First-line immunochemotherapy was associated with significantly improved PFS (median 9.0 months vs 12.0 months, P < .001) and OS (median 12.5 months vs 19.9 months, P < .001). Subgroup analysis revealed that tumor response to immunochemotherapy, metastatic organs, and number of metastatic sites potentially affected the efficacy of DRT after first-line immunochemotherapy. CONCLUSION: Compared with PCT + DRT, first-line immunochemotherapy was associated with improved PFS and OS in patients with mNPC but not in patients with unfavorable tumor response and metastasis involving the liver, distant nodes, or multiple sites.

Prognostic significance of AKR1C4 and the advantage of combining EBV DNA to stratify patients at high risk of locoregional recurrence of nasopharyngeal carcinoma.

BACKGROUND: Distinguishing patients at a greater risk of recurrence is essential for treating locoregional advanced nasopharyngeal carcinoma (NPC). This study aimed to explore the potential of aldo-keto reductase 1C4 (AKR1C4) in stratifying patients at high risk of locoregional relapse. METHODS: A total of 179 patients with locoregionally advanced NPC were grouped by different strategies; they were: (a) divided into two groups according to AKR1C4 expression level, and (b) classified into three clusters by integrating AKR1C4 and Epstein-Barr virus (EBV) DNA. The Kaplan-Meier method was used to calculate locoregional relapse-free survival (LRFS), overall survival (OS), progression-free survival (PFS), and distant metastasis-free survival (DMFS). The Cox proportional hazards model was used to determine potential prognostic factors, and a nomogram was generated to predict 3-year and 5-year LRFS. RESULTS: A significant difference in the 5-year LRFS was observed between the high and low AKR1C4 expression groups (83.3% vs. 92.7%, respectively; p = 0.009). After integrating AKR1C4 expression and EBV DNA, the LRFS (84.7%, 84.5%, 96.9%, p = 0.014) of high-, intermediate-, and low- AKR1C4 and EBV DNA was also significant. Multivariate analysis indicated that AKR1C4 expression (p = 0.006) was an independent prognostic factor for LRFS. The prognostic factors incorporated into the nomogram were AKR1C4 expression, T stage, and EBV DNA, and the concordance index of the nomogram for locoregional relapse was 0.718. CONCLUSIONS: In conclusion, high AKR1C4 expression was associated with a high possibility of relapse in NPC patients, and integrating EBV DNA and AKR1C4 can stratify high-risk patients with locoregional recurrence.

Equivalent current dipole sources of neurofeedback training-induced alpha activity through temporal/spectral analytic techniques.

Much of the work in alpha NFT has focused on evaluating changes in alpha amplitude. However, the generation mechanism of training-induced alpha activity has not yet been clarified. The present study aimed to identify sources of training-induced alpha activity through four temporal/spectral analytic techniques, i.e., the max peak average (MPA), positive average (PA), negative average (NA) and event-related spectral perturbation average (ERSPA) methods. Thirty-five healthy participants were recruited into an alpha group receiving feedback of 8-12-Hz amplitudes, and twenty-eight healthy participants were recruited into a control group receiving feedback of random 4-Hz amplitudes from the range of 7 to 20 Hz. Twelve sessions were performed within 4 weeks (3 sessions per week). The control group had no change in the amplitude spectrum. In contrast, twenty-nine participants in the alpha group showed significant alpha amplitude increases exclusively and were identified as "responders". A whole-head EEG was recorded for the "responders" after NFT. The epochs of training-induced alpha activity from whole-head EEG were averaged by four different methods for equivalent current dipole source analysis. High agreement and Cohen's kappa coefficients on dipole source localization between each method were observed, showing that the dipole clusters of training-induced alpha activity were consistently located in the precuneus, posterior cingulate cortex (PCC) and middle temporal gyrus. The residual variance (goodness of fit) for dipole estimation of the MPA was significantly smaller than that of the others. Our findings indicate that the precuneus, PCC and middle temporal gyrus play important roles in enhancing training-induced alpha activity. The four averaging methods (especially the MPA method) were suitable for investigating sources of brainwaves. Additionally, three dipoles can be used for dipole source analysis of training-induced alpha activity in future research, especially the training sites are around the central regions.

Neurochemical properties of the synapses between the parabrachial nucleus-derived CGRP-positive axonal terminals and the GABAergic neurons in the lateral capsular division of central nucleus of amygdala.

The lateral capsular division of central nucleus of amygdala (CeC) contains neurons using γ-amino butyric acid (GABA) as the predominant neurotransmitter and expresses abundant calcitonin gene-related peptide (CGRP)-positive terminals. However, the relationship between them has not been revealed yet. Using GAD67-green fluorescent protein (GFP) knock-in mouse, we investigated the neurochemical features of synapses between CGRP-positive terminals and GABAergic neurons within CeC and the potential involvement of CGRP1 receptor by combining fluorescent in situ hybridization for CGRP1 receptor mRNA with immunofluorescent histochemistry for GFP and CGRP. The ultrastructures of these synapses were investigated with pre-embedding electron microscopy for GFP and CGRP. We found that some GABAergic neurons in the CeC received parabrachial nucleus (PBN) derived CGRP innervations and some of these GABAergic neurons can be activated by subcutaneous injection of formalin. Moreover, more than 90 % GABAergic neurons innervated by CGRP-positive terminal also express CGRP1 receptor mRNA. The CGRP-positive fibers made symmetric synapses onto the GABAergic somata, and asymmetric synapses onto the GABA-LI dendritic shafts and spines. This study provides direct ultrastructural evidences for the synaptic contacts between CGRP-positive terminals and GABAergic neurons within the CeC, which may underlie the pain-related neural pathway from PBN to CeC and be involved in the chronic pain modulation.

Activation of extracellular signal-regulated kinase1/2 in the medial prefrontal cortex contributes to stress-induced hyperalgesia.

Stressful stimuli can exacerbate persistent pain disorder. However, the underlying mechanism is still unknown. Here, to reveal the underlying mechanism for stressful stimuli-induced hyperalgesia in chronic pain, we investigated the effect of extracellular signal-regulated kinase1/2 (ERK1/2) activation on pain hypersensitivity using single-prolonged stress (SPS) model, complete Freund's adjuvant (CFA) model and SPS + CFA model. The experimental results revealed significantly reduced paw withdrawal threshold in the SPS, CFA, and SPS + CFA group compared with the control group. However, the increased phosphorylation of ERK1/2 in the medial prefrontal cortex (mPFC) was observed in the SPS- or SPS + CFA-exposed group but not the CFA group compared with control group. There was also a significant increase in mPFC ERK1/2 phosphorylation and mechanical allodynia after SPS + CFA treatment compared to SPS or CFA treatment alone. Furthermore, inhibiting ERK1/2 phosphorylation by microinjection of U0126, a MAPK kinase (MEK) inhibitor, into the mPFC attenuated SPS + CFA- and SPS- but not CFA-induced mechanical allodynia, anxiety-like behavior, and cognitive impairments. These results suggest that the activation of ERK1/2 in the mPFC may contribute to the process of stress-induced cognitive and emotional disorders, leading to an increase in pain sensitivity.