Radiomics signature for dynamic changes of tumor-infiltrating CD8+ T cells and macrophages in cervical cancer during chemoradiotherapy.

BACKGROUND: Our previous study suggests that tumor CD8+ T cells and macrophages (defined as CD68+ cells) infiltration underwent dynamic and heterogeneous changes during concurrent chemoradiotherapy (CCRT) in cervical cancer patients, which correlated with their short-term tumor response. This study aims to develop a CT image-based radiomics signature for such dynamic changes. METHODS: Thirty cervical squamous cell carcinoma patients, who were treated with CCRT followed by brachytherapy, were included in this study. Pre-therapeutic CT images were acquired. And tumor biopsies with immunohistochemistry at primary sites were performed at baseline (0 fraction (F)) and immediately after 10F. Radiomics features were extracted from the region of interest (ROI) of CT images using Matlab. The LASSO regression model with ten-fold cross-validation was utilized to select features and construct an immunomarker classifier and a radiomics signature. Their performance was evaluated by the area under the curve (AUC). RESULTS: The changes of tumor-infiltrating CD8+T cells and macrophages after 10F radiotherapy as compared to those at baseline were used to generate the immunomarker classifier (AUC= 0.842, 95% CI:0.680-1.000). Additionally, a radiomics signature was developed using 4 key radiomics features to predict the immunomarker classifier (AUC=0.875, 95% CI:0.753-0.997). The patients stratified based on this signature exhibited significant differences in treatment response (p = 0.004). CONCLUSION: The radiomics signature could be used as a potential predictor for the CCRT-induced dynamic alterations of CD8+ T cells and macrophages, which may provide a less invasive approach to appraise tumor immune status during CCRT in cervical cancer compared to tissue biopsy.

Current and future on definitive concurrent chemoradiotherapy for inoperable locally advanced esophageal squamous cell carcinoma.

Esophageal squamous cell carcinoma (ESCC) is an aggressive and fatal disease that is usually diagnosed when the chances for surgical intervention has been missed. Definitive concurrent chemoradiotherapy (dCRT) is the first choice of treatment for inoperable locally advanced esophageal squamous cell carcinoma (LA-ESCC). Nevertheless, the local recurrence rate for esophageal cancer patients undergoing dCRT remains high at 40-60%, with a 5-year overall survival rate of solely 10-30%. Immunotherapy in combination with dCRT is a promising treatment for inoperable LA-ESCC, for that improved long-term survival is expected. The present review provides a comprehensive overview of the evolutionary trajectory of dCRT for LA-ESCC, delineates notable relevant clinical studies, addresses unresolved concerns regarding the combination of dCRT with immunotherapy, and highlights promising directions for future research. When dCRT is combined with immunotherapy, the following aspects should be carefully explored in the future studies, including the optimal irradiation dose, segmentation scheme, radiotherapy technique, timing, sequence and duration of radiotherapy, and the selection of chemotherapeutic and immunologic drugs. In addition, further investigations on the mechanisms of how dCRT combined with immunotherapy exerts synergistic anti-tumor effects and molecular biomarkers ensuring precise screening of ESCC patients are needed.

Efficacy of fosaprepitant combined with tropisetron plus dexamethasone in preventing nausea and emesis during fractionated radiotherapy with weekly cisplatin chemotherapy: interim analysis of a randomized, prospective, clinical trial using competing risk analysis.

PURPOSE: There are no well-recognized guidelines for antiemesis during concurrent chemoradiotherapy (CCRT) for cervical cancer (CC) and nasopharyngeal cancer (NPC) until now. The study was designed to assess the efficacy and safety of fosaprepitant combined with tropisetron and dexamethasone in preventing nausea and vomiting during 5 weeks of fractionated radiotherapy and concomitant weekly low-dose cisplatin chemotherapy in patients with CC or NPC. METHODS: Patients with CC or NPC were scheduled to receive fractionated radiotherapy and weekly cisplatin (25-40 mg/m2) chemotherapy for at least 5 weeks. Patients stratified by tumor type and induction chemotherapy were 1:1 randomly assigned to receive fosaprepitant, tropisetron, and dexamethasone or tropisetron plus dexamethasone as an antiemetic regimen. Efficacy was assessed primarily by the cumulative incidence of emesis after 5 weeks of treatment, and safety by adverse events (AEs). RESULTS: Between July 2020 and July 2022, 116 patients consented to the study of whom 103 were included in this interim analysis (fosaprepitant group [N = 52] vs control group [N = 51]). The cumulative incidence of emesis at 5 weeks (competing risk analysis) was 25% (95% CI 14.2-37.4) for the fosaprepitant group compared with 59% (95% CI 43.9-71.0) for the control group. There was a significantly lower cumulative risk of emesis in the fosaprepitant group (HR 0.35 [95% CI 0.19-0.64]; p < 0.001). Fosaprepitant was well tolerated as the incidences of adverse events in the two groups were comparable. CONCLUSION: The addition of fosaprepitant to tropisetron plus dexamethasone significantly reduced the risk of nausea and vomiting during 5 weeks of CCRT in patients with CC or NPC, and fosaprepitant was well tolerated. TRIAL REGISTRATION: The trial was registered with ClinicalTrials.gov on October 3, 2022, number NCT05564286.

Comprehensive Expression Profile Analysis of Neutrophil Extracellular Trap-Affected Genes in Gastric Cancer Cells and the Clinical Significance of lncRNA NEAT1-Related Signaling.

Background: Gastric cancer (GC) is the fifth most common malignant tumor and the third leading cause of cancer-related deaths worldwide. Neutrophil extracellular traps (NETs) can enhance the invasion of GC cells and are associated with poor prognosis in patients. However, its mechanism of action is not completely understood. Methods: The content of NETs in the peripheral blood of patients with GC was detected by enzyme-linked immunosorbent assay. GC AGS cells were treated with or without NETs for 24 h. High-throughput RNA sequencing was performed to screen differentially expressed long non-coding RNAs (lncRNAs), microRNAs (miRNAs), and messenger RNAs (mRNAs). Real-time polymerase chain reaction (PCR) was used to verify gene expression. A competing endogenous RNA (ceRNA) regulatory network was constructed. Modules were screened using the molecular complex detection (MCODE) plug-in. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses were performed using the genes in the network. The role and clinical significance of the lncRNA NEAT1-related signaling pathway were validated. Results: The content of NETs in the patients with GC was significantly higher than that in healthy controls and was also higher in patients with high-grade (stages III and IV) GC. NETs promoted the invasion of AGS cells. A total of 1,340 lncRNAs, 315 miRNAs, and 1,083 mRNAs were differentially expressed after NET treatment. The expression of five genes was validated using real-time PCR, which were in accordance with the RNA sequencing results. A ceRNA regulatory network was constructed with 1,239 lncRNAs, 310 miRNAs, and 1,009 mRNAs. Four genes (RAB3B, EPB41L4B, ABCB11, and CCDC88A) in the ceRNA network were associated with patient prognosis, with RAB3B being the most prominent and with signaling among the lncRNA NEAT1, the miRNA miR-3158-5p, and RAB3B. NEAT1 was upregulated in AGS cells after NET treatment. RNA interference of NEAT1 inhibited the invasion of AGS cells induced by NETs, inhibited miR-3158-5p expression, and promoted RAB3B expression. NEAT1 and RAB3B expression were positively correlated in patients with GC. Furthermore, RAB3B was upregulated and miR-3158-5p was downregulated in GC tissues compared with adjacent normal tissues, which was also associated with cancer stage. Conclusion: This study provides a comprehensive analysis of differentially expressed genes in NET-treated GC cells and validated the clinical significance of NEAT1-related signaling.

Sequential induction chemotherapy plus intensity-modulated radiotherapy versus concurrent chemoradiotherapy in locoregionally advanced nasopharyngeal carcinoma: the three-year report of a phase II, single center, randomized, non-inferiority trial.

To compare the efficacy and safety of induction chemotherapy (IC) followed by intensity-modulated radiotherapy (IMRT) alone versus concurrent CCRT in locoregionally advanced nasopharyngeal carcinoma (LA-NPC). Patients with newly diagnosed stage III to IVB nasopharyngeal carcinoma (NPC) were randomized to receive IC plus IMRT (IC+RT arm), or concurrent chemotherapy plus IMRT (CCRT arm), using a random number table. Both treatment arms received the same chemotherapy regimen. The primary endpoint was progression-free survival (PFS). Secondary end points included overall survival (OS), locoregional recurrence-free survival (LRRFS), distant metastasis-free survival (DMFS), treatment response, and acute treatment toxicities. From June 2013 to September 2018, a total of 204 patients histologically diagnosed with LA-NPC were enrolled in the study, with 102 patients randomly assigned to each arm. After a median follow-up duration of 45 months (range 4 to 84 months), the 3-year PFS, OS, LRRFS and DMFS were 72.2%, 87.8%, 92.3%, and 82.7% in the IC+RT arm, compared with 82.6%, 92.8%, 94.7%, and 88.2% in the CCRT arm. No statistical difference for PFS, OS, LRRFS, DMFS, or treatment response was observed between the two arms (p > 0.05). The incidences of leukopenia (p = 0.008) and anemia (p = 0.015) were significantly higher in patients in the CCRT arm than those in the IC+RT arm. Compared to CCRT, IC plus IMRT alone provided similarly favorable treatment outcomes in terms of PFS, OS, LRRFS, and DMFS for patients with LA-NPC, but resulted in fewer incidences of leukopenia and anemia.

Heterogeneity of IFN-Mediated Responses and Tumor Immunogenicity in Patients with Cervical Cancer Receiving Concurrent Chemoradiotherapy.

PURPOSE: To ask whether the expression of immune markers and IFN signaling in tumor biopsies changes during concurrent chemoradiotherapy (CCRT). EXPERIMENTAL DESIGN: Tumor biopsies and peripheral mononuclear blood cells (PMBC) before and immediately after 20 Gy/10 fractions (F) of radiation treatment (RT) from 30 patients with cervical cancer receiving CCRT were evaluated by IHC and qRT-PCR for immune markers and correlated with the short-term response. RESULTS: Tumor immune response to radiation before and after 10F RT as reflected by CD8+ T-cell infiltration had substantial heterogeneity with increases, decreases, and no change all evident. Increases in CD8+ T cells during CCRT correlated with the presence of nuclear IRF1 in tumor cells (r = 0.68, P < 0.0001) and the patient short-term response (P < 0.01). Similarly, in a subset of patients (∼40%) PD-L1 positivity in tumor cells increased, which also correlated with nuclear IRF1 staining (r = 0.48, P < 0.01). Patients with augmented PMBC IFN signature expression after 10F had a significantly higher probability of PD-L1 induction (83% vs. 7%, P < 0.0001). Most patients exhibited abundant expression of SERPINB9 and CD47 in tumor cells, and tumor infiltration by CD68+ cells. SERPINB9 expression correlated with STAT1 signaling in tumor cells. CONCLUSIONS: CCRT leads to differential tumor immunogenicity and IFN signaling in patients with cervical cancer, suggesting radiation induction of immunity is limited to a subset of patients and may reflect the heterogeneity of intratumoral induction of IFNs.See related commentary by Mondini and Deutsch, p. 3815.

[Progress in the treatment of diabetic wound healing via stem cells transplant].

The morbidity of diabetes has been increasing rapidly in recent years. Delayed wound healing has become a common complication in diabetes, which seriously affects the orthobiosis of patients. Exploring and finding the molecular mechanisms of diabetic wound healing and the effective therapies to promote wound healing have important clinical significances. Stem cells transplant has become a research hotspot in accelerating diabetic wound healing. This article reviewed the present approaches concerning stem cells transplant in diabetic wound healing both at domestic and abroad, and looked forward the clinical therapy of stem cells on diabetic wound healing.

MicroRNA-1 aggravates cardiac oxidative stress by post-transcriptional modification of the antioxidant network.

Oxidative stress plays an important role in cardiovascular diseases. Studies have shown that miR-1 plays an important role in the regulation of cardiomyocyte apoptosis, which can be the result of oxidative stress. This study was designed to determine whether increased miR-1 levels lead to alterations in the expression of proteins related to oxidative stress, which could contribute to heart dysfunction. We compared cardiac function in wild-type (WT) and miR-1 transgene (miR-1/Tg) C57BL/6 mice (n ≥ 10/group). Echocardiography showed that stroke volume (SV), ejection fraction (EF), and fractional shortening (FS) were significantly decreased in miR-1/Tg mice. Concomitantly, the level of reactive oxygen species (ROS) was elevated in the cardiomyocytes from the miR-1/Tg mice, and activities of lactate dehydrogenase (LDH) and creatinine kinase (CK) in plasma were also increased in the miR-1/Tg mice. All of these changes could be reversed by LNA-anti-miR-1. In the cardiomyocytes of neonatal Wistar rats, overexpression of miR-1 exhibits higher ROS levels and lower resistance to H2O2-induced oxidative stress. We demonstrated that SOD1, Gclc, and G6PD are novel targets of miR-1 for post-transcriptional repression. MicroRNA-1 post-transcriptionally represses the expression of SOD1, Gclc, and G6PD, which is likely to contribute to the increased ROS level and the susceptibility to oxidative stress of the hearts of miR-1 transgenic mice.