The Efficacy of Pretreatment 18F-FDG PET-CT-Based Deep Learning Network Structure to Predict Survival in Nasopharyngeal Carcinoma.

Background: Previous studies have shown that the 5-year survival rates of patients with nasopharyngeal carcinoma (NPC) were still not ideal despite great improvement in NPC treatments. To achieve individualized treatment of NPC, we have been looking for novel models to predict the prognosis of patients with NPC. The objective of this study was to use a novel deep learning network structural model to predict the prognosis of patients with NPC and to compare it with the traditional PET-CT model combining metabolic parameters and clinical factors. Methods: A total of 173 patients were admitted to 2 institutions between July 2014 and April 2020 for the retrospective study; each received a PET-CT scan before treatment. The least absolute shrinkage and selection operator (LASSO) was employed to select some features, including SUVpeak-P, T3, age, stage II, MTV-P, N1, stage III and pathological type, which were associated with overall survival (OS) of patients. We constructed 2 survival prediction models: an improved optimized adaptive multimodal task (a 3D Coordinate Attention Convolutional Autoencoder and an uncertainty-based jointly Optimizing Cox Model, CACA-UOCM for short) and a clinical model. The predictive power of these models was assessed using the Harrell Consistency Index (C index). Overall survival of patients with NPC was compared by Kaplan-Meier and Log-rank tests. Results: The results showed that CACA-UOCM model could estimate OS (C index, 0.779 for training, 0.774 for validation, and 0.819 for testing) and divide patients into low and high mortality risk groups, which were significantly associated with OS (P < .001). However, the C-index of the model based only on clinical variables was only 0.42. Conclusions: The deep learning network model based on 18F-FDG PET/CT can serve as a reliable and powerful predictive tool for NPC and provide therapeutic strategies for individual treatment.

The relationship between expression of PD-L1 and HIF-1α in glioma cells under hypoxia.

Hypoxia inducible factor-1α (HIF-1α) up-regulates the expression of programmed death ligand-1 (PD-L1) in some extracranial malignancies. However, whether it could increase PD-L1 expression in intracranial tumor is still unknown. Here, we explored the relationship between HIF-1α and PD-L1 expression in glioma, and investigated their clinical significance. In glioma patients, HIF-1α and PD-L1 were overexpressed in high grade glioma tissues and were significantly associated with poor survival. In glioma cells, PD-L1 expression was induced under hypoxia condition, and the enhanced PD-L1 expression was abrogated by either HIF-1α knock-down or HIF-1α inhibitor treatment. Furthermore, ChIP-qPCR analysis showed the direct binding of HIF-1α to PD-L1 proximal promoter region, providing evidence that HIF-1α up-regulates PD-L1 in glioma. In glioma murine model, the combination treatment with HIF-1α inhibitor and anti-PD-L1 antibody caused a more pronounced suppressive effect on tumor growth compared to either monotherapy. Immunologically, the combination treatment improved both dendritic cell (DC) and CD8+ T cell activation. Overall, our results demonstrated that positive correlation between PD-L1 and HIF-1α in glioma, and provide an alternative strategy, inhibiting HIF-1α, as combination therapies with immunotherapies to advance glioma treatment.

The Change of Soluble Programmed Cell Death-Ligand 1 in Glioma Patients Receiving Radiotherapy and Its Impact on Clinical Outcomes.

Background: The programmed cell death ligand 1 (PD-L1) plays a key role in glioma development. However, due to the specificity of glioma's anatomical position, the role of its expression as a tumor biomarker is limited. It has been proven that the levels of soluble programmed death-ligand 1 (sPD-L1) are associated with prognosis in many malignancies including glioma. However, the expression of sPD-L1 in glioma patients receiving radiotherapy (RT) remains unclear. The purpose of this study was to evaluate the concentration of sPD-L1 in the plasma of glioma patients before and after RT and to explore its relationship with clinical outcomes. Methods: Between October 2017 and September 2018, glioma patients treated with RT (30 ± 10 Gy, 2 Gy/f) were enrolled, and blood samples were collected before and after RT. We quantified the sPD-L1 levels by enzyme-linked immunosorbent assay (ELISA). The isocitrate dehydrogenase-1 (IDH-1) mutational status and Ki-67 expression of tumors were evaluated by immunohistochemistry. Glioma murine model were used to address whether circulating sPD-L1 molecules are directly targeted by an anti-PD-L1 antibody. The associations between sPD-L1 and clinical features were assessed with Pearson's or Spearman's correlation analysis. The progression-free survival (PFS) and overall survival (OS) were determined by the Kaplan-Meier method. Results: Sixty glioma patients were included, with a median age of 52 years. The proportions of grade I, II, III, and IV gliomas were 6.7%, 23.3%, 28.4%, and 41.6%, respectively. The baseline sPD-L1 levels were significantly associated with tumor grade, IDH-1 mutation status and Ki-67 expression. Using 14.35 pg/ml as the cutoff, significantly worse PFS and OS were both observed in patients with higher baseline levels of sPD-L1 (P = 0.027 and 0.008, respectively). RT significantly increased the mean level of sPD-L1 (P < 0.001). Further analysis showed that the level of sPD-L1 in IDH-1 mutation patients was higher than that in wild-type patients. Furthermore, an analysis of glioma murine model indicated that anti-PD-L1 antibody combine with RT can be a potentially powerful cancer therapy. Conclusion: This study reported that sPD-L1 might be a potential biomarker to predict the outcome in glioma patients receiving RT. The elevated level of sPD-L1 after RT suggested that the strategy of a combination of immune checkpoint inhibitors and RT might be promising for glioma patients, especially for those with IDH-1 mutations.

In vitro and in vivo evaluation of the safety and efficacy of a novel liquid fiducial marker for image-guided radiotherapy.

The true extent of a tumor is difficult to visualize, during radiotherapy, using current modalities. In the present study, the safety and feasibility of a mixture of N-butyl cyanoacrylate and lipiodol (NBCA/Lip) was evaluated in order to investigate the optimal combination for application as a fiducial marker for radiotherapy. Four combinations of NBCA/Lip injection (1:1-0.1, 1:1-0.15, 1:3-0.1 and 1:3-0.15 ml) were injected into the subcutaneous tissue of BALB/c mice. The changes in gross histopathology, body weight, skin score, marker volume, neutrophil and macrophage counts were observed to analyze the effects of the different mixing ratios and injection volumes, in order to identify the best combination. Evaluation according to the International Organization for Standardization criteria was further conducted in order to test the biocompatibility of the mixture, including an acute systematic assay with mice, cytotoxicity with L929 fibroblasts and delayed-type hypersensitivity tests with guinea pigs and an intradermal test with rabbits. The results revealed that at the seventh week, 42 markers (42/48; 87.5%) were still visible using computed tomography (CT) imaging. No serious adverse effects were observed throughout the study period; however, the combination of 1:1-0.1 ml had the lowest body weight and worst skin score. A review of the histopathological reaction to NBCA/Lip revealed a combination of acute inflammation, chronic inflammation, granulation tissue, foreign-body reaction and fibrous capsule formation. The 1:1 NBCA combination ratio resulted in the most intense tissue repair reaction and a slower degradation rate of markers. In general, the combination of 1:3-0.15 ml had a better fusion with local tissue, maintained a stable imaging nodule on CT images for 7 weeks and the final biocompatibility test demonstrated its safety. Overall, the findings of the present study demonstrated NBCA/Lip as a safe and feasible fiducial marker, when using the 1:3-0.15 ml combination.

Ten-Year Outcomes Of Intensity-Modulated Radiotherapy (IMRT) Combine With Chemotherapy Versus IMRT Alone For Stage II Nasopharyngeal Carcinoma In The Real-World Study (RWD).

OBJECTIVES: The aim was to define the role of chemotherapy in stage II nasopharyngeal carcinoma (NPC) and to identify the toxicity of chemotherapy for these patients in the era of intensity-modulated radiotherapy (IMRT). METHODS: Between January 2002 and December 2013, 169 patients with stage II NPC were analyzed. Of these patients, 149 patients treated with chemotherapy were divided into three groups as follows: neoadjuvant chemotherapy followed by IMRT (NCT) group, concurrent chemotherapy with IMRT (CCRT) group, and neoadjuvant chemotherapy followed by CCRT (NC+CCRT) group. In addition, 20 patients received IMRT alone. We retrospectively assessed the 10-year survival and acute adverse effects in the patients using SPSS software. RESULTS: The median follow-up time was 93 months (2-160 months). The 10-year OS of the NCT, CCRT, NC+CCRT groups vs the IMRT alone group was 69.8%, 63.4%, 69.7% vs 72.4%, respectively (P=0.664, 0.940, and 0.998, respectively). Both univariable and multivariable analyses showed that the addition of chemotherapy to IMRT did not significantly improve the 10-year survival outcomes. The hematotoxicity and mucous reaction of patients with chemotherapy were more serious than those with IMRT alone (P=0.007 and 0.049). Distant metastasis for stage II NPC patients mostly occurred within 3 years, which is very different from patients with advanced NPC. CONCLUSION: Patients with stage II NPC who are treated with IMRT may obtain satisfactory long-term survival outcomes. The additional chemotherapy cannot significantly increase survival; however, it may remarkably increase treatment-associated acute toxic reactions.