Development and validation of a 18F-FDG PET/CT radiomics nomogram for predicting progression free survival in locally advanced cervical cancer: a retrospective multicenter study.

BACKGROUND: The existing staging system cannot meet the needs of accurate survival prediction. Accurate survival prediction for locally advanced cervical cancer (LACC) patients who have undergone concurrent radiochemotherapy (CCRT) can improve their treatment management. Thus, this present study aimed to develop and validate radiomics models based on pretreatment 18Fluorine-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET)-computed tomography (CT) images to accurately predict the prognosis in patients. METHODS: The data from 190 consecutive patients with LACC who underwent pretreatment 18F-FDG PET-CT and CCRT at two cancer hospitals were retrospectively analyzed; 176 patients from the same hospital were randomly divided into training (n = 117) and internal validation (n = 50) cohorts. Clinical features were selected from the training cohort using univariate and multivariate Cox proportional hazards models; radiomic features were extracted from PET and CT images and filtered using least absolute shrinkage and selection operator and Cox proportional hazard regression. Three prediction models and a nomogram were then constructed using the previously selected clinical, CT and PET radiomics features. The external validation cohort that was used to validate the models included 23 patients with LACC from another cancer hospital. The predictive performance of the constructed models was evaluated using receiver operator characteristic curves, Kaplan Meier curves, and a nomogram. RESULTS: In total, one clinical, one PET radiomics, and three CT radiomics features were significantly associated with progression-free survival in the training cohort. Across all three cohorts, the combined model displayed better efficacy and clinical utility than any of these parameters alone in predicting 3-year progression-free survival (area under curve: 0.661, 0.718, and 0.775; C-index: 0.698, 0.724, and 0.705, respectively) and 5-year progression-free survival (area under curve: 0.661, 0.711, and 0.767; C-index, 0.698, 0.722, and 0.676, respectively). On subsequent construction of a nomogram, the calibration curve demonstrated good agreement between actually observed and nomogram-predicted values. CONCLUSIONS: In this study, a clinico-radiomics prediction model was developed and successfully validated using an independent external validation cohort. The nomogram incorporating radiomics and clinical features could be a useful clinical tool for the early and accurate assessment of long-term prognosis in patients with LACC patients who undergo concurrent chemoradiotherapy.

Expression and Clinical Significance of KLRG1 and 2B4 on T Cells in the Peripheral Blood and Tumour of Patients with Cervical Cancer.

BACKGROUND: Killer cell lectin-like receptor G1 (KLRG1) and 2B4 play important roles in the immune regulation and immune tolerance to tumor cells by inhibiting T cell function. However, the clinical relevance of KLRG1 and 2B4 to cervical cancer remains to be understood. METHODS: We measured the frequency of KLRG1+ or 2B4+ cells in CD4+ or CD8 + T cells derived from peripheral blood or tumour biopsies in cervical cancer patients by flow cytometry. RESULTS: Compared with healthy controls, the level of KLRG1 and 2B4 on CD8 + T cells in the blood of the patients increased significantly (P = .0056 and .0441). KLRG1 level on CD8 + T cells and 2B4 level on CD4 + T cells in peripheral blood were significantly higher than in tumor tissues (P < .0001 and P = .0003). Higher KLRG1 level on blood-derived CD8 + T cells was observed in patients older than 54 years (P = .001) or tested to be HPV-negative (P = .026). Tumor-infiltrated CD8 + T cells demonstrated elevated KLRG1 level in patients having pelvic lymph node metastasis (P = .016). Increased 2B4 level on blood-derived CD8 + T cells was also observed in patients older than 54 years (P < .001). KLRG1 expression on both CD4 + T (P = .0158) and CD8 + T (P = .0187) cells in the peripheral blood increased after radiotherapy. CONCLUSION: KLRG1 level on T cells was related to age and HPV in patients with cervical cancer, while 2B4 level on T cells was related to age, underlying their roles in the host immune response to cervical cancer. Radiotherapy can improve the immune function of patients.

Detection of methylation status of Epstein-Barr virus DNA C promoter in the diagnosis of nasopharyngeal carcinoma.

The detection of Epstein-Barr virus (EBV) DNA load in nasopharyngeal (NP) brushing samples for diagnosis of nasopharyngeal carcinoma (NPC) has attracted great attention. Further improvements that eliminate the need for clinical settings will greatly extend its application. A total of 250 participants were recruited to obtain NP brushing samples. Brush sampling both with and without the guide of endoscopy was conducted in 38 NPC patients. EBV DNA load, EBV RNA transcript and EBV DNA C promoter methylation status were, respectively, evaluated. Typical latency II transcripts were observed in brushing samples from NPC patients but not controls. Unlike in tissues, multiple lytic gene transcripts were observed not only in NPC patients but also in controls. Apart from EBV RNA transcript, samples from NPC patients also showed higher levels of EBV DNA load and C promoter methylation degree than their controls. Qualitative analysis further showed that EBV DNA C promoter was methylated in all NPC patients but in only 18.4% of the control group. Combined analysis of EBV DNA methylated degree and EBV DNA load increased the sensitivity to 100% in the detection of NPC. Using qualitative methylated type as the criteria, up to 89.5% of samples collected via blind brushing showed consistent results with samples collected via endoscopy-guided brushing from NPC patients. Detection of the methylation status of EBV DNA C promoter in NP brushing samples shows great potential in diagnosing NPC and may provide an appealing alternative for the non-invasive detection and screening of NPC without the need for clinical settings.

Tumor Cell Content and RNA Integrity of Surgical Tissues from Different Types of Tumors and Its Correlation with Ex Vivo and In Vivo Ischemia.

BACKGROUND: Tissues from tumor patients are important resources for promoting cancer research, and therefore many biobanks have been established to collect tumor tissues; however, the quality of tumor tissues after surgical resection has not been well documented. METHODS: A total of 896 cases of tissues from 12 types of tumors were chosen for this study. First, histopathological examination was conducted to evaluate the tumor cell content; second, microchip electrophoresis was used to determine the RNA integrity number (RIN) in 466 cases of tissues with a tumor cell content ≥ 75%; and, finally, a correlation test was used to analyze the effect of ischemia on RNA integrity in 384 cases of tissues with a recorded ischemia time. RESULTS: Tumor tissues from 12 different organs had different tumor cell contents and RNA integrity. The liver had the highest percentage (69.7%) of tissue samples with a tumor cell content ≥ 75%, and the highest percentage (96%) of samples with an RIN ≥ 7. RNA integrity was not correlated with limited ex vivo ischemia time (5-60 min) in any of the 12 types of tumors. In contrast, a significant correlation with in vivo ischemia time was observed in several types of tumors. CONCLUSIONS: Not every sample of excised tumor tissue has a sufficient amount of tumor cells and enough RNA integrity. In vivo ischemia has a more significant influence on RNA integrity, and tumor tissues have different tolerances to pre-analytical variables. Those conducting translational research should pay attention to pre-analytical variables when collecting and utilizing tumor tissues.

Activated innate lymphoid cell populations accumulate in human tumour tissues.

BACKGROUND: Innate lymphoid cells (ILC) are part of a heterogeneous family of haematopoietic effector cells which lack re-arranged antigen-specific receptors. They promote host defense and contribute to tissue and metabolic homeostasis, wound healing and immune surveillance. Their role in human cancer immunity is less defined, and therefore we aimed to identify the frequency and phenotype of distinct ILC groups in various types of cancer. METHODS: Tissue samples and peripheral blood were collected from patients undergoing surgical resection of gastrointestinal and breast tumours. Single cell suspension of tumour tissue was immediately obtained following surgery using tumour dissociation. RESULTS: We observed significantly higher frequencies of ILC2 (p value: 0.04) in malignant breast cancer tissue and significantly higher frequencies of group 1 ILC (p value: 0.001) in malignant gastrointestinal tumours. Tumour infiltrating ILC were found to show an activated phenotype with higher expression of MHC-II, KLRG1, early activation marker CD69 and CD44. CONCLUSIONS: Activated innate lymphoid cells infiltrate tumours dependent on tumour type and location.

Frequency distribution of HLA alleles and haplotypes in Uyghur women with advanced squamous cell cervical cancer and relation to HPV status and clinical outcome.

PURPOSE: This study aims to investigate the association of human leukocyte antigen (HLA) alleles and haplotypes in Uyghur women with advanced squamous cell cervical cancer (SCC). METHODS: A total of 131 Uyghur patients with advanced SCC (IIb-IVa) and 91 healthy subjects from Xinjiang province were genotyped for HLA-I and II genes using Polymerase Chain Reaction Sequence Based Typing. The different frequencies of HLA alleles and haplotypes between patients and controls were compared and the correlations were analyzed between HLA distribution and HPV status and prognosis. RESULTS: (1) The frequencies of B*51:01, DRB1*07:01, DQB1*02:01, A*01:01-C*06:02, A*01:01-DRB1*07:01, C*06:02-DQB1*02:01, DRB1*07:01-DQB1*02:01 and C*06:02-DRB1*07:01-DQB1*02:01 in cancer group were higher than control group whereas the frequencies of B*44:02, B*58:01, C*05:01, DRB1*04:01, DRB1*12:01, DRB1*13:01, DQB1*02:02, DQB1*05:02, DRB1*03:01-DQB1*02:02 and DRB1*04:01-DQB1*03:02 in cancer group were lower than control group (P < 0.05). (2) The frequencies of A*01:01-C*06:02, A*01:01-DRB1*07:01, C*06:02-DQB1*02:01, DRB1*07:01-DQB1*02:01 and C*06:02-DRB1*07:01-DQB1*02:01 in HPV positive group were lower than HPV negative group, differences of which were statistically significant (P < 0.05). (3) B*44:02 and B*58:01 were associated with reduced disease-specific survival (DSS) (P = 0.010 and 0.007). (4) Multivariate Cox proportional hazard models revealed that age, International Federation of Gynaecology and Obstetrics (FIGO) stage, tumor differentiation and allele B*58:01 as independent predictors for DSS while FIGO stage and tumor differentiation as independent factors for DFS. CONCLUSIONS: In the development and progression of advanced SCC among Uyghur population, the HLA alleles and its haplotypes play an important role. B*58:01 allele may act as an independent predictor for DSS.

Differential Expression and Clinical Significance of DNA Methyltransferase 3B (DNMT3B), Phosphatase and Tensin Homolog (PTEN) and Human MutL Homologs 1 (hMLH1) in Endometrial Carcinomas.

BACKGROUND The aim of this study was to investigate the expression and the clinicopathologic significance of DNA methyltransferase 3B (DNMT3B), phosphatase and tensin homolog (PTEN) and human MutL homologs 1 (hMLH1) in endometrial carcinomas between Han and Uygur women in Xinjiang. MATERIAL AND METHODS The expression of DNMT3B, PTEN, and hMLH1 in endometrial carcinomas were assessed by immunohistochemistry, followed by an analysis of their relationship to clinical-pathological features and prognosis. RESULTS There were a 61.7% (95/154) overexpression of DNMT3B, 50.0% (77/154) loss of PTEN expression and 18.2% (28/154) loss of hMLH1 expression. The expression of DNMT3B and PTEN in endometrial carcinomas was statistically significantly different between Uygur women and Han women (p=0.001, p=0.010, respectively). DNMT3B expression was statistically significant based on the grade of endometrial carcinomas (p=0.031). PTEN loss was statistically significant between endometrioid carcinomas (ECs) and non endometrioid carcinomas (NECs) (p=0.040). DNMT3B expression was statistically significant in different myometrial invasion groups in Uygur women (p=0.010). Furthermore, the correlation of DNMT3B and PTEN expression was significant in endometrial carcinomas (p=0.021). PTEN expression was statistically significant in the overall survival (OS) rate of women with endometrial cancers (p=0.041). CONCLUSIONS Our findings suggest that PTEN and DNMT3B possess common regulation features as well as certain ethnic differences in expression between Han women and Uygur women. An interaction may exist in the pathogenesis of endometrial carcinoma. DNMT3B was expressed differently in cases of myometrial invasion and PTEN was associated with OS, which suggested that these molecular markers may be useful in the evaluation of the biological behavior of endometrial carcinomas and may be useful indicators of prognosis in women with endometrial carcinomas.

[Relationship between human papilloma virus infection and expression of p16 and EGFR in head and neck squamous cell carcinoma and their prognostic significance].

OBJECTIVE: To detect the infection of human papillomavirus (HPV) 6/11, 16/18, 31/33 in patients with head and neck squamous cell carcinoma and explore the relationship between HPV infection and expression of p16 and EGFR in the tumor tissue and their clinical significance. METHODS: The infection of HPV6/11, 16/18, 31/33 was detected by in situ hybridization (ISH), and expression of p16 and EGFR was assessed by immunohistochemistry in biopsy or surgical specimens of 43 cases of head and neck squamous cell carcinoma, and analyzed its impact on the prognosis. Spearman rank correlation method was used for analysis of the relationship. Overall survival rate of the patients was estimated by Kaplan-Meier analysis. Cox regression model was used for multivariate analysis. RESULTS: HPV6/11, 16/18, 31/33 were detected in 25.6% (11/43) of this group of patients, among them, HPV16/18 accounted for 63.6%, HPV31/33 accounted for 27.3%, and HPV6/11 accounted for 0. EGFR was expressed in 69.8% and p16 was expressed in 53.5% of the patients. The difference was statistically significant between the HPV-positive and HPV-negative groups in ethnicity, smoking, alcohol consumption (P = 0.045, 0.040, 0.011, respectively). HPV infection was found to be positively correlated with p16 expression and inversely correlated with EGFR expression (P = 0.029, P = 0.009). The expression of p16 protein was negatively correlated with EGFR protein expression (r = -0.447, P = 0.003). The 3-year overall survival rate was 60.0% in the HPV-positive group and 59.7% in the negative group (P = 0.789); 72.2% in the p16-positive patients and 43.9% in the p16-negative patients (P = 0.012); 48.8% in the EGFR-positive patients and 81.8% in the EGFR-negative patients (P = 0.037). CONCLUSIONS: The results of our study suggest that the HPV infection rate, HPV subtypes and clinicopathological features of HPV-positive SCCHN are in accordance with those reported in Western literatures. There may be differences between the HPV infections in Uygur and Han nationalities. HPV infection is positively correlated with p16 and negatively correlated with EGFR expressions. The prognosis of p16-positive patients is significantly better than that of negative cases, and p16 is an independent prognostic factor for head and neck squamous cell carcinoma.

Impact of different respiratory gating methods on target delineation and a radiotherapy plan for solitary pulmonary tumors.

BACKGROUND AND PURPOSE: Respiratory movement has an important impact on the radiotherapy for lung tumor. Respiratory gating technology is helpful to improve the accuracy of target delineation. This study investigated the value of prospective and retrospective respiratory gating simulations in target delineation and radiotherapy plan design for solitary pulmonary tumors (SPTs) in radiotherapy. METHODS: The enrolled patients underwent CT simulation with three-dimensional (3D) CT non gating, prospective respiratory gating, and retrospective respiratory gating simulation. The target volumes were delineated on three sets of CT images, and radiotherapy plans were prepared accordingly. Tumor displacements and movement information obtained using the two respiratory gating approaches, as well as the target volumes and dosimetry parameters in the radiotherapy plan were compared. RESULTS: No significant difference was observed in tumor displacement measured using the two gating methods (p > 0.05). However, the internal gross tumor volumes (IGTVs), internal target volumes (ITVs), and planning target volumes (PTVs) based on the retrospective respiratory gating simulation were larger than those obtained using prospective gating (group A: pIGTV = 0.041, pITV = 0.003, pPTV = 0.008; group B: pIGTV = 0.025, pITV = 0.039, pPTV = 0.004). The two-gating PTVs were both smaller than those delineated on 3D non gating images (p < 0.001). V5Gy, V10Gy, V20Gy, V30Gy, and mean lung dose in the two gated radiotherapy plans were lower than those in the 3D non gating plan (p < 0.001); however, no significant difference was observed between the two gating plans (p > 0.05). CONCLUSIONS: The application of respiratory gating could reduce the target volume and the radiation dose that the normal lung tissue received. Compared to prospective respiratory gating, the retrospective gating provides more information about tumor movement in PTV.

Prognostic nomogram combining 18F-FDG PET/CT radiomics and clinical data for stage III NSCLC survival prediction.

The aim of this study was to establish and validate the precision of a novel radiomics approach that integrates 18Fluorine-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET)-computed tomography (CT) scan data with clinical information to improve the prognostication of survival rates in patients diagnosed with stage III Non-Small Cell Lung Cancer (NSCLC) who are not candidates for surgery. We evaluated pretreatment 18F-FDG PET-CT scans from 156 individuals diagnosed with stage III inoperable NSCLC at Shandong Cancer Hospital. These individuals were divided into two groups: a training set comprising 110 patients and an internal validation set consisting of 46 patients. By employing random forest classifier and cox proportional hazards model , we identified and utilized relevant features to create predictive models and a nomogram. The effectiveness of these models was assessed through the use of the receiver operating characteristics(ROC) curves, Kaplan-Meier (KM) curves, and the application of the nomogram. Our findings showed that the combined model, which integrates both clinical and radiomic data, outperformed those based solely on clinical or radiomic features in predicting 3-year overall survival(OS). Furthermore, calibration plots revealed a high level of agreement between predicted and actual survival times. The research successfully established a predictive radiomics model that integrates 18F-FDG PET/CT imaging with clinical indicators to enhance survival predictions for patients with stage III inoperable NSCLC.

Genomic profiles and their relationships with clinical characteristics and immune features in cervical cancer.

OBJECTIVE: This study aimed to investigate the genomic alteration profiles of cervical cancer patients, examine the correlation between mutation patterns and clinical and immune attributes, and discover novel targets for treatment of individuals with cervical cancer. METHODS: We performed targeted next-generation sequencing of tumor tissues and blood samples obtained from 45 cervical cancer patients to analyze somatic alterations, mutation patterns, and HLA alleles comprehensively. Additionally, we used flow cytometry to assess expression levels of immune checkpoint genes. RESULTS: Notably, genes such as AR (78%), KMT2D (76%), and NOTCH1 (62%) exhibited higher mutation frequencies. Moreover, the tumor mutation burden (TMB) was significantly greater in HPV-positive cervical cancer patients than in HPV-negative patients (P=0.029). BMI (P=0.047) and mutations in BARD1 (P=0.034), CEP290 (P=4E-04), and SLX4 (P=0.0128) were identified as predictors of shorter overall survival in cervical cancer patients. Furthermore, the present study revealed significant upregulation of PD-1 (P=0.027) and Tim-3 (P=0.048) in the high mutant-allele tumor heterogeneity (MATH) cohort. In the elderly cervical cancer patient population, HLA-A03:01 emerged as a high-risk allele (OR=3.2, P<0.0001); HLA-C07:02 (OR=0.073, P=0.02) and HLA-B*07:02 (OR=0.257, P=0.037) were associated with a reduced risk among patients with low TMB. CONCLUSIONS: This study offers insights into the mutation characteristics of cervical cancer patients and identifies potential therapeutic.

Radiomics-based machine learning models for differentiating pathological subtypes in cervical cancer: a multicenter study.

Purpose: This study was designed to determine the diagnostic performance of fluorine-18-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET)/computed tomography (CT) radiomics-based machine learning (ML) in the classification of cervical adenocarcinoma (AC) and squamous cell carcinoma (SCC). Methods: Pretreatment 18F-FDG PET/CT data were retrospectively collected from patients who were diagnosed with locally advanced cervical cancer at two centers. Radiomics features were extracted and selected by the Pearson correlation coefficient and least absolute shrinkage and selection operator regression analysis. Six ML algorithms were then applied to establish models, and the best-performing classifier was selected based on accuracy, sensitivity, specificity, and area under the curve (AUC). The performance of different model was assessed and compared using the DeLong test. Results: A total of 227 patients with locally advanced cervical cancer were enrolled in this study (N=136 for the training cohort, N=59 for the internal validation cohort, and N=32 for the external validation cohort). The PET radiomics model constructed based on the lightGBM algorithm had an accuracy of 0.915 and an AUC of 0.851 (95% confidence interval [CI], 0.715-0.986) in the internal validation cohort, which were higher than those of the CT radiomics model (accuracy: 0.661; AUC: 0.513 [95% CI, 0.339-0.688]). The DeLong test revealed no significant difference in AUC between the combined radiomics model and the PET radiomics model in either the training cohort (z=0.940, P=0.347) or the internal validation cohort (z=0.285, P=0.776). In the external validation cohort, the lightGBM-based PET radiomics model achieved good discrimination between SCC and AC (AUC = 0.730). Conclusions: The lightGBM-based PET radiomics model had great potential to predict the fine histological subtypes of locally advanced cervical cancer and might serve as a promising noninvasive approach for the diagnosis and management of locally advanced cervical cancer.

Machine learning for differentiating lung squamous cell cancer from adenocarcinoma using Clinical-Metabolic characteristics and 18F-FDG PET/CT radiomics.

Noninvasive differentiation between the squamous cell carcinoma (SCC) and adenocarcinoma (ADC) subtypes of non-small cell lung cancer (NSCLC) could benefit patients who are unsuitable for invasive diagnostic procedures. Therefore, this study evaluates the predictive performance of a PET/CT-based radiomics model. It aims to distinguish between the histological subtypes of lung adenocarcinoma and squamous cell carcinoma, employing four different machine learning techniques. A total of 255 Non-Small Cell Lung Cancer (NSCLC) patients were retrospectively analyzed and randomly divided into the training (n = 177) and validation (n = 78) sets, respectively. Radiomics features were extracted, and the Least Absolute Shrinkage and Selection Operator (LASSO) method was employed for feature selection. Subsequently, models were constructed using four distinct machine learning techniques, with the top-performing algorithm determined by evaluating metrics such as accuracy, sensitivity, specificity, and the area under the curve (AUC). The efficacy of the various models was appraised and compared using the DeLong test. A nomogram was developed based on the model with the best predictive efficiency and clinical utility, and it was validated using calibration curves. Results indicated that the logistic regression classifier had better predictive power in the validation cohort of the radiomic model. The combined model (AUC 0.870) exhibited superior predictive power compared to the clinical model (AUC 0.848) and the radiomics model (AUC 0.774). In this study, we discovered that the combined model, refined by the logistic regression classifier, exhibited the most effective performance in classifying the histological subtypes of NSCLC.

Increased co-expression of 4-1BB with PD-1 on CD8+ tumor-infiltrating lymphocytes is associated with improved prognosis and immunotherapy response in cervical cancer.

Background: The combination of agonistic antibodies with immune checkpoint inhibitors presents a promising avenue for cancer immunotherapy. Our objective is to explore the co-expression of 4-1BB, ICOS, CD28, with PD-1 on CD8+ T cells in the peripheral blood and tumor tissue of cervical cancer(CC) patients, with a specific focus on the association between the co-expression levels of 4-1BB with PD-1 and clinical features, prognosis as well as immunotherapy response. The goal is to offer valuable insights into cervical cancer immunotherapy. Methods: In this study, 50 treatment-naive patients diagnosed with CC were enrolled. Flow cytometry was used to detect PD-1/4-1BB, PD-1/ICOS and PD-1/CD28 co-expression on CD8+ T cells. Subsequent analysis aimed to investigate the differential co-expression between peripheral blood and cancer tissue, and also the correlation between co-expression and clinical features in these patients. Gene Expression Omnibus (GEO) datasets, The Cancer Genome Atlas (TCGA) cohort, The IMvigor210 cohort, The BMS038cohort and Immunophenoscores were utilized to investigate the correlation between PD-1/4-1BB and the immune microenvironment, prognosis, immunotherapy, and drug sensitivity in cervical cancer. Results: The co-expression levels of PD-1/4-1BB, PD-1/ICOS, and PD-1/CD28 on CD8+ tumor-infiltrating lymphocytes (TILs) were significantly higher in cervical cancer patients compared to those in peripheral blood. Clinical feature analysis reveals that on CD8+ TILs, the co-expression of PD-1/4-1BB is more closely correlated with clinical characteristics compared to PD-1/ICOS, PD-1/CD28, PD-1, and 4-1BB. Pseudo-time analysis and cell communication profiling reveal close associations between the subgroups harboring 4-1BB and PD-1. The prognosis, tumor mutation burden, immune landscape, and immunotherapy response exhibit statistically significant variations between the high and low co-expression groups of PD-1/4-1BB. The high co-expression group of PD-1/4-1BB is more likely to benefit from immunotherapy. Conclusion: PD-1/4-1BB, PD-1/ICOS, and PD-1/CD28 exhibit elevated co-expression on CD8+TILs of cervical cancer, while demonstrating lower expression in circulating T cells. The co-expression patterns of PD-1/4-1BB significantly contributed to the prediction of immune cell infiltration characteristics, prognosis, and tailored immunotherapy tactics. PD-1/4-1BB exhibits potential as a target for combination immunotherapy in cervical cancer.

Accurate location describe and management of lymph node recurrence after esophagectomy for thoracic esophageal squamous cell carcinoma: a retrospective cohort study.

BACKGROUND: Describe the accurate locations of lymph node recurrence (LNR) of Chinese patients with postoperative thoracic esophageal squamous cell carcinoma (ESCC) is essential for determining the need for further surveillance protocols and treatments. The authors aimed to evaluate the patterns of postoperative ESCC and its current risk stratification with LNR. METHODS: This population-based cohort study included a retrospective review of the medical records and image material of patients with ESCC who underwent LNR after radical surgery between January 2013 and September 2022, with a median follow-up time of 5.71 years. Clinical features were extracted from these records, and survival analysis was performed. The primary endpoint was the accurate location and range of LNR according to the nomenclature of the Japanese Society for Esophageal Diseases. The second endpoints was to explore the related factors of recurrence range and overall survival. RESULTS: A total of 3268 lymph node regions were recurrence from 1129 patients, with a mean of 2.89 regions per patient. No.104, 106, and 107 was the most common recurrence of thoracic ESCC with an LNR rate higher than 15%. In upper thoracic ESCC, No.105 was a common recurrence site and abdominal LNR was rare. In lower thoracic ESCC, retroperitoneal lymph node was a unique regions (15.4%). Anastomotic recurrence is an important recurrence pattern in patients with postoperative esophageal cancer, with an incidence of 24.5%. Rates of LNR in range of lymph node dissection was low (13.9%). The median time of LRT was 20.0 (1.5-184.0) months. High range of recurrence was associated with significantly poorer OS in patients. Multiple linear regression analysis identified demonstrated N stage, tumor differentiation, adjuvant radiotherapy, and total lymph nodes removed were association with recurrence range for patients. CONCLUSIONS: Supraclavicular and upper mediastinums lymph nodes were common recurrence site for ESCC patients, and careful initial staging and surveillance are needed. Thorough lymph node dissection may reduce the range of regional recurrence.

Unraveling the mechanisms of RECQL4-mediated cervical cancer progression through the PI3K/AKT pathway.

BACKGROUND: RECQL4 is a member of the DNA helicase family and is critical for DNA replication, DNA damage repair, and tumor progression. However, its specific role in cervical cancer remains uncertain. METHODS: In this study, we aimed to investigate the impact of RECQL4 on cervical cancer prognosis using clinical specimens from The Cancer Genome Atlas. We evaluated the malignant effects of RECQL4 through various experimental assays including cell Cell Counting Kit-8, EdU, colony formation, cell cycle analysis, cell apoptosis, scratch, and Transwell assays. We explored the mechanisms of RECQL4-regulated malignancy using analyses of bioinformatics, RNA sequencing data, polymerase chain reaction (PCR), western blotting, and cell immunofluorescence experiments. Furthermore, we validated the effects of RECQL4 knockdown on tumor growth using subcutaneous tumor models in nude mice. RESULTS: RECQL4 was upregulated in cervical cancer and correlated with prognosis, demonstrating a positive relationship with tumor mutational burden. Knockdown of RECQL4 inhibits cervical cancer cell proliferation, migration, and invasion, suppresses epithelial-mesenchymal transition status, induces cell cycle arrest, and promotes apoptosis. Mechanistically, RECQL4 mediated malignancy through the PI3K/AKT pathway and reduced nuclear ß-catenin expression. In vivo studies further confirmed that RECQL4 knockout significantly inhibited tumor growth. CONCLUSIONS: Our findings provide novel insights into the mechanism behind RECQL4-mediated cervical cancer progression through the PI3K/AKT pathway. Furthermore, our study suggests potential therapeutic strategies for targeting RECQL4 in cervical cancer treatment.

Increased co-expression of TIM-3 with TIGIT or 2B4 on CD8+ T cells is associated with poor prognosis in locally advanced nasopharyngeal carcinoma.

The use of immune checkpoint inhibitors in malignant tumors improves patient outcomes. Because single-agent immune checkpoint blockade has a low objective response rate, it is meaningful to explore combined blockade of immune checkpoint receptors. We aimed to investigate the co-expression of TIM-3 with TIGIT or 2B4 on peripheral blood CD8+ T cells from patients with locally advanced nasopharyngeal carcinoma. The correlation between co-expression level and clinical characteristics and prognosis was studied to provide a basis for immunotherapy for nasopharyngeal carcinoma. Flow cytometry was used to detect TIM-3/TIGIT and TIM-3/2B4 co-expression on CD8+ T cells. The differences in co-expression between patients and healthy controls were analyzed. The correlation between co-expression of TIM-3/TIGIT or TIM-3/2B4 and the patient clinical characteristics and prognosis was examined. Also, the correlation between the TIM-3/TIGIT or 2B4 co-expression and other common inhibitory receptors was analyzed. We further validated our results using mRNA data from the Gene Expression Omnibus (GEO) database. TIM-3/TIGIT and TIM-3/2B4 co-expression was upregulated on peripheral blood CD8+ T cells from patients with nasopharyngeal carcinoma. They were both correlated with poor prognosis. There was a correlation between TIM-3/TIGIT co-expression and patient age and pathological stage, whereas TIM-3/2B4 co-expression correlated with age and sex. CD8+ T cells with elevated mRNA levels of TIM3/TIGIT and TIM3/2B4 also showed increased expression of multiple inhibitory receptors, indicating T cell exhaustion in locally advanced nasopharyngeal carcinoma. TIM-3/TIGIT or TIM-3/2B4 can be used as potential targets for combination immunotherapy in locally advanced nasopharyngeal carcinoma.

Thickness Impact on the Morphology, Strain Relaxation and Defects of Diamond Heteroepitaxially Grown on Ir/Al2O3 Substrates.

This paper investigates the formation and propagation of defects in the heteroepitaxial growth of single-crystal diamond with a thick film achieving 500 µm on Ir (001)/Al2O3 substrate. The growth of diamond follows the Volmer-Weber mode, i.e., initially shows the islands and subsequently coalesces to closed films. The films' strain imposed by the substrate gradually relaxed as the film thickness increased. It was found that defects are mainly located at the diamond/Ir interface and are then mainly propagated along the [001] direction from the nucleation region. Etching pits along the [001] direction formed by H2/O2 plasma treatment were used to show defect distribution at the diamond/Ir/Al2O3 interface and in the diamond bulk, which revealed the reduction of etching pit density in diamond thick-film surface. These results show the evident impact of the thickness on the heteroepitaxially grown diamond films, which is of importance for various device applications.

Construction of a B cell-related gene pairs signature for predicting prognosis and immunotherapeutic response in non-small cell lung cancer.

Background: Accumulating evidence indicates that the B cells play important roles in anti-tumor immunity and shaping tumor development. This study aimed to explore the expression profiles of B cell marker genes and construct a B cell-related gene pairs (BRGPs) signature associated with the prognosis and immunotherapeutic efficiency in non-small cell lung cancer (NSCLC) patients. Methods: B cell-related marker genes in NSCLC were identified using single-cell RNA sequencing data. TCGA and GEO datasets were utilized to identify the prognostic BRGPs based on a novel algorithm of cyclically single pairing along with a 0-or-1 matrix. BRGPs signature was then constructed using Lasso-Cox regression model. Its prognostic value, associated immunogenomic features, putative molecular mechanism and predictive ability to immunotherapy were investigated in NSCLC patients. Results: The BRGPs signature was composed of 23 BRGPs including 28 distinct B cell-related genes. This predictive signature demonstrated remarkable power in distinguishing good or poor prognosis and can serve as an independent prognostic factor for NSCLC patients in both training and validation cohorts. Furthermore, BRGPs signature was significantly associated with immune scores, tumor purity, clinicopathological characteristics and various tumor-infiltrating immune cells. Besides, we demonstrated that the tumor mutational burden scores and TIDE scores were positively correlated with the risk score of the model implying immune checkpoint blockade therapy may be more effective in NSCLC patients with high-risk scores. Conclusions: This novel BRGPs signature can be used to assess the prognosis of NSCLC patients and may be useful in guiding immune checkpoint inhibitor treatment in our clinical practice.

Radiomics Nomogram Based on Multiple-Sequence Magnetic Resonance Imaging Predicts Long-Term Survival in Patients Diagnosed With Nasopharyngeal Carcinoma.

Purpose: Although the tumor-node-metastasis staging system is widely used for survival analysis of nasopharyngeal carcinoma (NPC), tumor heterogeneity limits its utility. In this study, we aimed to develop and validate a radiomics model, based on multiple-sequence magnetic resonance imaging (MRI), to estimate the probability of overall survival in patients diagnosed with NPC. Methods: Multiple-sequence MRIs, including T1-weighted, T1 contrast, and T2-weighted imaging, were collected from patients diagnosed with NPC. Radiomics features were extracted from the contoured gross tumor volume of three sequences from each patient using the least absolute shrinkage and selection operator with the Cox regression model. The optimal Rad score was determined using 12 of the 851 radiomics features derived from the multiple-sequence MRI and its discrimination power was compared in the training and validation cohorts. For better prediction performance, an optimal nomogram (radiomics nomogram-MS) that incorporated the optimal Rad score and clinical risk factors was developed, and a calibration curve and a decision curve were used to further evaluate the optimized discrimination power. Results: A total of 504 patients diagnosed with NPC were included in this study. The optimal Rad score was significantly correlated with overall survival in both the training [C-index: 0.731, 95% confidence interval (CI): 0.709-0.753] and validation cohorts (C-index: 0.807, 95% CI: 0.782-0.832). Compared with the nomogram developed with only single-sequence MRI, the radiomics nomogram-MS had a higher discrimination power in both the training (C-index: 0.827, 95% CI: 0.809-0.845) and validation cohorts (C-index: 0.836, 95% CI: 0.815-0.857). Analysis of the calibration and decision curves confirmed the effectiveness and utility of the optimal radiomics nomogram-MS. Conclusions: The radiomics nomogram model that incorporates multiple-sequence MRI and clinical factors may be a useful tool for the early assessment of the long-term prognosis of patients diagnosed with NPC.