BACKGROUND: Cervical squamous cell carcinoma (CESC), the most common subtype of cervical cancer, is primarily caused by the high-risk human papillomavirus (HPV) infection and genetic susceptibility. Single-cell RNA sequencing (scRNA-seq) has been widely used in CESC research to uncover the diversity of cell types and states within tumor tissues, enabling a detailed study of the tumor microenvironment (TME). This technology allows precise mapping of HPV infection in cervical tissues, providing valuable insights into the initiation and progression of HPV-mediated malignant transformation. METHODS: We performed the scRNA-seq to characterize gene expression in tumor tissues and paired adjacent para-cancerous tissues from four patients with early-stage CESC using the 10× Genomics platform. The HPV infection and its subtypes were identified using the scRNA data and viral sequence mapping, and trajectory analyses were performed using HPV+ or HPV- cells. Interactions between different types of keratinized cells and their interactions with other cell types were identified, and pathways and specificity markers were screened for proliferating keratinized cells. The Cancer Genome Atlas (TCGA) dataset was used to verify the prognostic correlation between tumor-specific PI3+S100A7+ keratinocyte infiltration and CESC, and the localization relationship between PI3+S100A7+ keratinocytes and macrophages was verified by immunofluorescence staining. RESULTS: Various types of keratinocytes and fibroblasts were the two cell types with the most significant differences in percentage between the tumor tissue samples and paired adjacent non-cancerous tissue samples in the early stages of CESC. We found that PI3+S100A7+ keratinocytes were associated with early HPV-positive CESC, and PI3+S100A7+ keratinocytes were more abundant in tumors than in adjacent normal tissues in the TCGA-CESC dataset. Analysis of clinical information revealed that the infiltration of PI3+S100A7+ keratinocytes was notably higher in tumors with poor prognosis than in those with good prognosis. Additionally, multiplex immunofluorescence analysis showed a specific increase in PI3+S100A7+ expression within tumor tissues, with PI3+S100A7+ keratinocytes and CD163+ macrophages being spatially very close to each other. In the analysis of cell-cell interactions, macrophages exhibited strong crosstalk with PI3+S100A7+ proliferating keratinocytes in HPV-positive CESC tumors, mediated by tumor necrosis factor (TNF), CCL2, CXCL8, and IL10, highlighting the dynamic and tumor-specific enhancement of macrophage-keratinocyte interactions, which are associated with poor prognosis and immune modulation. Using CIBERSORTx, we discovered that patients with high infiltration of both PI3+S100A7+ proliferating keratinocytes and macrophages had the shortest overall survival. In the analysis of cell-cell interactions, PI3+S100A7+ proliferating keratinocytes and macrophages were found to be involved in highly active pathways that promote differentiation and structure formation, including cytokine receptor interactions, the Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathway, and TNF signaling pathway regulation. Further subtyping of fibroblast populations identified four subtypes. The C1 group, characterized by its predominance in tumor tissues, is a subtype enriched with cancer-associated fibroblasts (CAFs), whereas the C3 group is primarily enriched in adjacent non-cancerous tissues and consists of undifferentiated cells. Moreover, the distinct molecular and cellular differences between HPV16- and HPV66-associated tumors were demonstrated, emphasizing the unique tumor-promoting mechanisms and microenvironmental influences driven by each HPV subtype. CONCLUSIONS We discovered a heterogeneous population of keratinocytes between tumor and adjacent non-cancerous tissues caused by HPV infection and identified macrophages and specific CAFs that play a crucial role during the early stage in promoting the inflammatory response and remodeling the cancer-promoting TME. Our findings provide new insights into the transcriptional landscape of early-stage CESC to understand the mechanism of HPV-mediated malignant transformation in cervical cancer.
Humans ; Female ; Papillomavirus Infections/genetics* ; Uterine Cervical Neoplasms/genetics* ; Carcinoma, Squamous Cell/pathology* ; Keratinocytes/metabolism* ; Single-Cell Analysis/methods* ; Tumor Microenvironment/genetics*

The incidence and mortality of lung cancer rank first among malignant tumors in the world worldwide. Non-small cell lung cancer (NSCLC) is the main pathological type, with a significant proportion being driver gene-negative NSCLC. When accompanied by brain metastasis, radiotherapy is the optimal local therapy, apart from surgery, and which is widely used applied in clinical practice. With the continuous development of technology and drugs, the survival of patients with brain metastases has been generally improvedprolonged. In the era of precision medicine, the concept and technology of radiotherapy are evolving towards precision and diversification. In this article, the evolution of radiotherapy techniques and its combined application with other treatment methods were reviewed, aiming to provide references for the selection of radiotherapy protocol for driver gene-negative NSCLC patients with brain metastases in clinical practice.

Objective:To explore the prognostic value of baseline 18F-FDG PET/CT metabolic parameters in locally advanced cervical cancer (LACC) after concurrent chemoradiotherapy (CCRT). Methods:From September 2015 to October 2021, the clinical data of 180 LACC patients (age: 22-76 years) who underwent 18F-FDG PET/CT before CCRT at Affiliated Cancer Hospital of Shandong First Medical University were analyzed retrospectively. The metabolic tumor volume (MTV), total lesion glycolysis (TLG), SUV max, and SUV mean were computed by using the margin threshold of 42%SUV max. The optimal threshold for predicting progression-free survival (PFS) was obtained by ROC curve analysis. The Kaplan-Meier method was applied for survival analysis, and the log-rank test was applied to compare the survival rate between groups. Multivariate Cox proportional hazard regression was used to analyze progression for PFS. Results:The median follow-up was 19.1 months, and 54 patients (30.0%, 54/180) suffered from disease progression. ROC curve analysis showed that the optimal cut-off value of MTV was 31.145 ml, with the AUC of 0.641. Para-aortic lymph node (PALN) metastasis had the highest AUC value (0.589) among the clinical factors, followed by International Federation of Gynecology and Obstetrics (FIGO) stage (0.581). The 1-year PFS rates of patients with MTV<31.145 ml ( n=88) and MTV≥31.145 ml ( n=92) were 80.68% and 59.78%, respectively ( χ2=13.72, P<0.001). Multivariate Cox analysis demonstrated that pathological type (hazard ratio ( HR)=3.075, 95% CI: 1.370-6.901, P=0.006), FIGO stage ( HR=1.955, 95% CI: 1.031-3.707, P=0.040), PALN metastasis ( HR=2.136, 95% CI: 1.202-3.796, P=0.010) and MTV ( HR=2.449, 95% CI: 1.341-4.471, P=0.004) were the significant predictors for PFS. Conclusions:Pathological type, FIGO stage, PALN metastasis and MTV are independent prognostic risk factors for PFS. MTV as the baseline 18F-FDG PET/CT metabolic parameter, can realize prognostic stratification analysis.

Objective:To explore the Epstein-Barr virus (EBV) latent infection membrane protein (LMP) 1 or LMP2 specific T cell immune response and clinical significance in stage III-IVa nasopharyngeal carcinoma (NPC), aiming to provide ideas and evidence for immunotherapy in NPC.Methods:Fifty-nine NPC patients admitted to the Affiliated Tumor Hospital of Xinjiang Medical University from February 2018 to October 2020 for primary treatment were collected. Peripheral blood monocytes (PBMCs) were stimulated by LMP antigen. Intracellular cytokine staining and flow cytometry were applied to study the expression levels of IL-2, IL-13, interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α) from CD4 + T and CD8 + T cells, and then analyzed in conjunction with clinical factors. Results:The positive rates of total PBMCs to LMP1 and LMP2 in NPC patients were different. The positive rate of LMP1 specific CD4 + T cells was statistically higher in stage T 3-T 4 NPC than that in stage T 1-T 2 (51.0% vs. 10.0%, P=0.042). There were also differences in the expression of cytokines between LMP1 and LMP2, CD4 +T cells and CD8 +T cells. Survival analysis showed the 2-year and 3-year overall survival (OS) rates were 91.5% and 88.2%, and the 2-year and 3-year progression-free survival (PFS) rates were 83.3% and 75.3%. Univariate analysis suggested that smoking history, male and LMP1 stimulated IL-13 positive expression in CD4 + T cells affected the disease progression ( P=0.026, 0.045 and 0.006); multivariate analysis showed LMP1 stimulated IL-13 positive expression in CD4 + T cells and smoking history were the independent prognostic factors affecting PFS ( P=0.017, 0.019). Conclusions:LMP1 and LMP2 generate specific T-cell immune response in PBMCs of NPC patients, with differential expression in two T-cell subsets. LMP1 and LMP2 specific T cell immune response is associated with primary tumor size and metastatic lymph node volume. LMP1 stimulated IL-13 positive expression in CD4 + T cells and smoking history affects the disease progression.

Objective:To construct machine learning models based on CT imaging and clinical parameters for predicting progression-free survival (PFS) of locally advanced cervical cancer (LACC) patients after concurrent chemoradiotherapy (CCRT).Methods:Clinical data of 167 LACC patients treated with CCRT at Shandong Cancer Hospital from September 2015 to October 2021 were retrospectively analyzed. All patients were randomly divided into the training and validation cohorts according to the ratio of 7 vs. 3. Clinical features were selected by univariate and multivariate Cox proportional hazards model ( P<0.1). Radiomics models and nomograms were constructed by radiomics features which were selected by least absolute shrinkage and selection operator (LASSO) Cox regression model to predict the 1-, 3- and 5-year PFS. Combined models and nomogram models were developed by selected clinical and radiomics features. The Kaplan Meier-curve, receiver operating characteristic (ROC) curve, C-index and calibration curve were used to evaluate the model performance. Results:A total of 1 409 radiomics features were extracted based on the region of interest (ROI) in CT images. CT radiomics models showed better performance for predicting 1-, 3-and 5-year PFS than the clinical model in the training and validation cohorts. The combined model displayed the optimal performance in predicting 1-, 3-and 5-year PFS in the training cohort [area under the curve (AUC): 0.760, 0.648, 0.661, C-index: 0.740, 0.667, 0.709] and verification cohort (AUC: 0.763, 0.677, 0.648, C-index: 0.748, 0.668, 0.678).Conclusions:Combined model constructed based on CT radiomics and clinical features yield better prediction performance than that based on radiomics or clinical features alone. As an objective image analysis approach, it possesses high prediction efficiency for PFS of LACC patients after CCRT, which can provide reference for clinical decision-making.

Primary lung cancer is the first malignant tumor in our country and in the world with an increasing mortality trend, which seriously endangers the human health. By digging the deep relationship between high-dimensional imaging features and pathophysiological features, radiomics can establish a predictive model to distinguish pathological types, tumor stages, distant metastases and survival, guide individualized diagnosis and treatment strategies, and improve prognosis. PET/CT has higher diagnostic accuracy and specificity by reflecting tumor tissue metabolism. This article reviews the application of PET/CT radiomics in the treatment of non-small-cell lung cancer (NSCLC).

Objective:To investigate the prognostic value of absolute lymphocyte count (ALC) and neutrophil-lymphocyte ratio (NLR), macrophage-lymphocyte ratio (MLR) and platelet-lymphocyte ratio (PLR) before treatment in patients with locally advanced cervical cancer (LACC).Methods:A total of 175 patients newly-diagnosed with LACC admitted to Cancer Hospital affiliated to Xinjiang Medical University from August 2016 to October 2019 were enrolled in this study. Complete clinical data and ALC before treatment were recorded and NLR, MLR and PLR were calculated. Multivariate Cox′s proportional hazard regression model was used to analyze the prognostic factors of patients with LACC.Results:The progress-free survival (PFS) of LACC patients in the NLR reduction group (<3.34) and MLR reduction group (<0.315) were significantly higher than those in the NLR and MLR elevation groups (both P<0.05). The overall survival (OS) of LACC patients in the ALC elevation group (≥1.375 × 10 9/L) and the PLR reduction group (<160.575) were significantly higher compared with those in the ALC reduction group and PLR elevation group (both P<0.05). Univariate analysis showed that EQD 2Gy, the equivalent dose of HR-CTV, was an important prognostic factor of PFS in patients with LACC ( P=0.030). Multivariate Cox′s regression analysis demonstrated that FIGO staging ( HR=2.339, 95% CI 1.22-4.48, P=0.010) and concurrent chemoradiotherapy ( HR=0.213, 95% CI 0.11-0.43, P<0.001) were the independent predicators of PFS in patients with LACC. However, concurrent chemoradiotherapy ( HR=0.229, 95% CI 0.07-0.81, P=0.023) and MLR ( HR=4.933, 95% CI 1.39-17.54, P=0.014) before treatment were the independent predictors of OS in patients with LACC. Conclusions:Patients with locally advanced cervical cancer can benefit from concurrent chemoradiotherapy. HR-CTV EQD 2Gy is a critical prognostic factor of PFS in patients with LACC. The increase of MLR before treatment is an independent prognostic factor of OS in LACC patients.

Objective:To investigate the relationship between human papilloma virus (HPV)16 E6/7-specific T cell immune response in the periphral blood and clinical features and prognosis of patients with cervical squamous cell carcinoma (CSCC).Methods:Seventy-two patients pathologically diagnosed with CSCC admitted to Affiliated Tumor Hospital of Xinjiang Medical University from June 2013 to October 2015, and 75 healthy controls were enrolled in this study. The special responses of peripheral blood T cells to E6 and E7 overlapping peptides before treatment were detected by enzyme-linked immunosorbent assay (ELISA). The differences of frequency and intensity expression of specific immune responses between two groups were analyzed by chi-square χ2 test and nonparametric test. The correlation between antigen-specific immune response and T cell subsets was analyzed by Spearman test. Log-rank test and Cox’s regression model were employed for univariate and multivariate prognostic analyses. Results:The frequencies of HPV16 E6-ad E7-specific T cell responses in CSCC patients were significantly higher than those in healthy controls (51.39% vs. 29.33%, P=0.006 and 45.83% vs.25.33%, P=0.009), and the mean intensities were also considerably higher than those in healthy controls (20.00 SFC/10 6vs.10.76 SFC/10 6, P<0.001 and 16.17 SFC/10 6vs.10.72 SFC/10 6, P=0.017). The intensity of HPV16 E6-specific T cell immune response was positively correlated with the CD 4+/CD 8+ ratio in the peripheral blood of CSCC patients ( r=0.279, P=0.018). And a strong correlation was noted between E7-specific T cell immune response intensity and increasing proportion of NK+ cells ( r=0.274, P=0.020). Univariate and multivariate analyses showed that therapeutic mode (radiotherapy vs. concurrent chemoradiotherapy, HR=2.918, 95% CI 1.454-5.854, P=0.003) and E6-specific T cell response (response group vs. no response group, HR=0.491, 95% CI 0.243-0.99, P=0.047) were the independent prognostic factors influencing the clinical prognosis. The 5-year overall survival in patients with HPV16 E6-specific T cell responses was significantly higher than that in the no response group (64% vs.41%, P=0.041). Conclusions:The intensity of HPV16 E6-specific T cell immune response is positively correlated with the CD 4+/CD 8+ ratio. No HPV16 E6-specific T cell response and radiotherapy alone are more likely to cause poor prognosis of CSCC patients.

Objective:To analyze the prognostic factors of patients with locally advanced nasopharyngeal carcinoma after treatment, to develop and validate the prognostic Nomogram model.Methods:From July 2010 to June 2017, 317 patients with nasopharyngeal carcinoma who were treated with definitive intensity modulated radiation therapy were selected. The regression method of least absolute shrinkage and selection operator (LASSO) was used for univariate screening, and Cox multivariate regression analysis was performed. The prognostic Nomogram model was constructed for locally advanced nasopharyngeal carcinoma patients. C-index, calibration curve, Net Reclassification Index (NRI), integrated discrimination improvement (IDI) were used to validate and evaluate the model between Nomogram and TNM staging system. The risk evaluated through nomogram was stratified by decision tree algorithm, and the survival rate was calculated by Kaplan-Meier method and compared by Log-rank test.Results:T stage, N stage, LDH, GTVnd and pre-treated plasma EBV-DNA copy (EBV-DNA) were correlated with total survival (OS). All the above factors were included in prognostic Nomogram model, and C-index was 0.784 (95% CI: 0.736-0.831, P<0.01). The calibration curve showed that the OS probability predicted by Nomogram model was in good agreement with the actual OS, and the result were verified in the validation cohort. Furthermore, the accuracy of the Nomogram model for OS predicting was superior to AJCC 8 th version staging system judged by NRI and IDI. According to the Nomogram score, patients can be divided into four subgroups with different risk by decision tree algorithm. K-M survival curve showed that the difference of OS between different groups was statistically significant ( χ2=113.21, P<0.01), and patients in high-risk group can benefit from induction chemotherapy combined with concurrent chemoradiotherapy in survival. Conclusions:The Nomogram model established by our research group can provide information on diagnosis, treatment and prognosis evaluation for locally advanced nasopharyngeal carcinoma patients in this area.

Objective:To investigate the application of radiotherapy and the basic situation of teaching and scientific research in Xinjiang.Methods:A unified questionnaire was adopted, distributed and collected by mail, instant messaging software and telephone. The basic situation of all radiotherapy affiliations in the whole region was counted.Results:The questionnaire coverage rate was 100% with a recovery rate of 100%. In 2020, 17 affiliations operated radiotherapy in Xinjiang, including 23 linear accelerators, 1 cobalt-60 therapeutic machine, 3 gamma knives, 6 post-installed therapeutic machines, 13 special analogue positioning machines, 46 treatment planning systems, and 103 sets of radiotherapy quality control equipment. It was estimated that the number of radiotherapy equipment for one million people in the whole region was approximately 0.84. In Xinjiang, 359 radiotherapy personnel were registered, including 220 physicians, 49 physicists and 90 technicians. A total of 1 270 beds were available, with an average daily treatment volume of approximately 1 255 person-times. From 2016 to 2021, 17 affiliations have undertaken 9 National Natural Science Foundation of China and 49 provincial and ministerial projects. Nineteen doctoral degrees and 87 master′s degrees were accredited. These affiliations participated in the publication of 25 articles in Chinese Journal of Radiation Oncology, of which 18 were published as the first authors and/or corresponding authors.Conclusions:The radiotherapy work in Xinjiang has developed rapidly in recent years, but there is still a certain gap with the national average level. At the same time, several problems still exist in the whole region, such as regional differences, unbalanced allocation of radiotherapy resources and scientific research and teaching resources, which need further improvement.