PYCR1 regulates TRAIL­resistance in non­small cell lung cancer cells by regulating the redistribution of death receptors.

Although recombinant human TNF-related apoptosis-inducing ligand (TRAIL) protein exhibits antitumor activity in a number of lung and liver cancer cells and tumor-bearing animals, TRAIL resistance has substantially restricted its clinical application. Pyrroline-5-carboxylate reductase 1 (PYCR1) is a key enzyme in the regulation of proline synthesis. PYCR1 is highly expressed in various types of malignant tumor, in which it has been implicated in 5-fluorouracil resistance. However, the possible relationship between PYCR1 and TRAIL resistance remains unclear. In the present study, both reverse transcription-quantitative PCR and western blotting were performed. The results indicated that H1299 cells had higher PYCR1 expression levels and were less sensitive to TRAIL compared with the TRAIL-sensitive cell line, H460. PYCR1 knockdown in H1299 cells increased TRAIL sensitivity, increased the localization of death receptors (DRs) on the cell surface and activated Caspase-3/8. By contrast, overexpression of PYCR1 in H1299 cells decreased TRAIL sensitivity, reduced the distribution of DRs on the cell surface and suppressed the activation of Caspase-3/8. Taken together, these results suggested that PYCR1 promoted TRAIL resistance in the non-small cell lung cancer cell line, H1299, by preventing redistribution of DRs to the plasma membrane. This in turn inhibited TRAIL-mediated cell apoptosis by reducing the activation of Caspase-3/8.

Ultrasound Microbubble-Stimulated miR-145-5p Inhibits Malignant Behaviors of Breast Cancer Cells by Targeting ACTG1.

ABSTRACT: Ultrasound-targeted microbubble destruction (UTMD) technology combines ultrasound with a variety of functional microbubble vectors to enhance the transfection and expression of target genes, and has become a promising noninvasive method for localized gene transfer, which is widely used in gene therapy for cancer. This research aimed to explore the role of UTMD-mediated miR-145-5p on breast cancer (BC) tumorigenesis and the underlying mechanisms. To achieve UTMD-mediated miR-145-5p overexpression, BC cells were cotransfected with microbubbles (MBs) and miR-145-5p mimics. The BC cell malignant phenotypes were assessed through CCK-8, wound healing, and transwell assays. MiR-145-5p and actin gamma 1 (ACTG1) binding relationship was verified through luciferase reporter and RNA pull-down assays. MiR-145-5p and ACTG1 levels in BC cells and tissues were detected through RT-qPCR and Western blotting. ACTG1 was upregulated, whereas miR-145-5p was downregulated in BC cells and tissues. MiR-145-5p targeted ACTG1 and negatively regulated its level in BC cells. Overexpressing miR-145-5p restrained BC cell growth, migration, and invasion. Ultrasound-targeted microbubble destruction improved the overexpression efficiency of miR-145-5p and enhanced the suppressive influence on BC cell malignant phenotypes. In addition, ACTG1 overexpression compromises the repression of UTMD-mediated miR-145-5p on cellular behaviors in BC. Ultrasound-targeted microbubble destruction-delivered miR-145-5p hindered malignant behaviors of BC cells through downregulating ACTG1.

LUM as a novel prognostic marker and its correlation with immune infiltration in gastric cancer: a study based on immunohistochemical analysis and bioinformatics.

BACKGROUND: Gastric cancer (GC) is considered the sixth highly prevailing malignant neoplasm and is ranked third in terms of cancer mortality rates. To enable an early and efficient diagnosis of GC, it is important to detect the fundamental processes involved in the oncogenesis and progression of gastric malignancy. The understanding of molecular signaling pathways can facilitate the development of more effective therapeutic strategies for GC patients. METHODS: The screening of genes that exhibited differential expression in early and advanced GC was performed utilizing the Gene Expression Omnibus databases (GSE3438). Based on this, the protein and protein interaction network was constructed to screen for hub genes. The resulting list of hub genes was evaluated with bioinformatic analysis and selected genes were validated the protein expression by immunohistochemistry (IHC). Finally, a competing endogenous RNA network of GC was constructed. RESULTS: The three genes (ITGB1, LUM, and COL5A2) overexpressed in both early and advanced GC were identified for the first time. Their upregulation has been linked with worse overall survival (OS) time in patients with GC. Only LUM was identified as an independent risk factor for OS among GC patients by means of additional analysis. IHC results demonstrated that the expression of LUM protein was increased in GC tissue, and was positively associated with the pathological T stage. LUM expression can effectively differentiate tumorous tissue from normal tissue (area under the curve = 0.743). The area under 1-, 3-, and 5-year survival relative operating characteristics were greater than 0.6. Biological function enrichment analyses suggested that the genes related to LUM expression were involved in extracellular matrix development-related pathways and enriched in several cancer-related pathways. LUM affects the infiltration degree of cells linked to the immune system in the tumor microenvironment. In GC progression, the AC117386.2/hsa-miR-378c/LUM regulatory axis was also identified. CONCLUSION: Collectively, a thorough bioinformatics analysis was carried out and an AC117386.2/hsa-miR-378c/LUM regulatory axis in the stomach adenocarcinoma dataset was detected. These findings should serve as a guide for future experimental investigations and warrant confirmation from larger studies.

Long-term outcomes of metastasis-directed stereotactic body radiation therapy in metastatic nasopharyngeal carcinoma.

BACKGROUND: The study aims to evaluate the outcomes of metastasis-directed stereotactic body radiation therapy (SBRT) in metastatic nasopharyngeal carcinoma (mNPC). METHODS: We reviewed all SBRT conducted in patients with mNPC in our institution between 2013 and 2022. Systemic therapy was performed with chemotherapy with or without anti-programmed death-1 (PD-1) therapy. Local treatment delivered with ablative purpose in stereotactic setting with dose/fraction ≥5 Gy was evaluated. Kaplan-Meier analyses were used to determine the rates of local control (LC), progression-free survival (PFS), and overall survival (OS). Univariate and multivariate analyses were performed by Cox regression. RESULTS: A total of 54 patients with 76 metastatic sites receiving SBRT were analyzed. Median follow-up was 49 months. The 3-year LC, PFS, and OS rates were 89.1%, 29.4%, and 57.9%, respectively. Adding a PD-1 inhibitor to SBRT tended to prolong median OS (50.1 vs. 32.2 months, p = 0.068). Patients receiving a biological effective dose (BED, α/ß = 10) ≥ 80 Gy had a significantly longer median OS compared to those who received a lower dose (not reached vs. 29.5 months, p = 0.004). Patients with oligometastases (1-5 metastases) had a better median OS (not reached vs. 29.5 months, p < 0.001) and PFS (34.3 vs. 4.6 months, p < 0.001). Pretreatment EBV-DNA and maintenance therapy were also significant predictors for OS. CONCLUSIONS: Metastatic NPC patients could benefit from metastases-directed SBRT in combination with systemic therapy.

Advancements of radiotherapy for recurrent head and neck cancer in modern era.

Head and neck cancer is a kind of cancer which can be eradicated from radical radiation therapy. However, with best efforts, nearly 40% patients will experience locoregional recurrence. Locoregional recurrence is the main cause of cancer-related death in head and neck cancers, so local treatments play a key role in improving progression free survival. In the last decades, radiation techniques have been tremendously developed, highly conformal radiation techniques such as intensity-modulated radiotherapy, stereotactic body radiation therapy, brachytherapy and proton or heavy ion radiation therapy have their unique radiobiological advances. Although reirradiation is widely used in clinical practice, but little is known when comparing the different techniques. In this review, we will provide a comprehensive overview of the role of reirradiation in recurrent head and neck cancers including radiation techniques, patient selection, overall clinical benefits, and toxicities.

First-line immunotherapy combinations for recurrent or metastatic nasopharyngeal carcinoma: An updated network meta-analysis and cost-effectiveness analysis.

OBJECTIVES: Recently updated results of randomized clinical trials (RCTs) have confirmed that toripalimab, camrelizumab, and tislelizumab plus chemotherapy (TOGP, CAGP, and TIGP) significantly prolonged survival compared to placebo plus chemotherapy (PLGP) in the first-line treatment for recurrent or metastatic nasopharyngeal carcinoma (R/M-NPC). However, the high cost of immunotherapies imposes a huge financial burden on patients and health care systems. MATERIALS AND METHODS: RCTs estimating immunotherapies for R/M-NPC were searched. A Bayesian network meta-analysis (NMA) was carried out; the main outcomes were hazard ratios (HRs) of overall survival (OS) and progression-free survival (PFS). The cost and efficacy of four first-line therapies were evaluated using the Markov model. The main outcome in the cost-effectiveness analysis (CEA) was incremental cost-utility ratios (ICURs). The model robustness was assessed by one-way, three-way, and probabilistic sensitivity analyses. RESULTS: Three RCTs (JUPITER-02, CAPTAIN-1st, and RATIONALE-309) involving 815 patients were included in the NMA. Compared with PLGP, chemo-immunotherapies have significantly longer PFS and OS. Compared to the PLGP group, TOGP, CAGP, and TIGP groups resulted in additional costs of $48 339, $22 900, and $23 162, with additional 1.89, 0.73, and 0.960 QALYs, respectively, leading to the ICURs of $25 576/QALY, $31 370/QALY, and $31 729/QALY. Pairwise comparisons showed TOGP was the most cost-effective option among chemo-immunotherapy groups. CONCLUSION: From the Chinese payers' perspective, first-line immunotherapy combination therapies provided significant survival and cost-effectiveness superiority over chemotherapy alone for patients with R/M-NPC at the WTP of $38 029/QALY. Among the three chemo-immunotherapy groups, TOGP was the most cost-effective option.

CDK4/6 Inhibitors in the First-Line Treatment of Postmenopausal Women with HR+/HER2- Advanced or Metastatic Breast Cancer: An Updated Network Meta-Analysis and Cost-Effectiveness Analysis.

(1) Background: This study aimed to conduct a NMA and CEA combined study to compare the effectiveness and cost-effectiveness of different CDK4/6 inhibitors (Abem, Palbo, and Ribo) plus NSAI with placebo plus NSAI in the first-line treatment of postmenopausal women with HR+/HER2- ABC from the perspective of payers in China. (2) Methods: Studies which evaluated CDK4/6 inhibitors plus NSAI for HR+/HER2- ABC were searched. A Bayesian NMA was carried out and the main outcomes were the hazard ratios (HRs) of overall survival (OS) and progression-free survival (PFS). The costs and efficacy of first-line therapies for HR+/HER2- ABC were evaluated using the Markov model. The main outcomes in the CEA were incremental cost-utility ratios (ICURs), incremental monetary benefit (INMB), and incremental net-health benefit (INHB). The robustness of the model was assessed by one-way, three-way, and probabilistic sensitivity analyses. Then, we further simulated the impact of different prices of CDK4/6 inhibitors on the results. (3) Results: Seven studies involving 5347 patients were included in the NMA. The three first-line CDK4/6 inhibitors plus NSAI groups provided significant PFS and OS superiority to NSAI alone. Abem + NSAI represented a significant statistical advantage onPFS (HR 0.74, 95% CI 0.61-0.90, p = 0.009) and indicated a trend of being the best OS benefit compared to the placebo + NSAI group (HR 0.89, 95% CI 0.72-1.08). The Abem + NSAI, Palbo + NSAI, and Ribo + NSAI groups resulted in additional costs of $12,602, $20,391, and $81,258, with additional effects of 0.38, 0.31, and 0.30 QALYs, respectively, leading to an ICUR of $33,163/QALY, $65,777/QALY, and $270,860/QALY. Additional pairwise comparisons showed that Abem + NSAI was the only cost-effective option in three CDK4/6 inhibitors plus NSAI groups at a willingness-to-pay (WTP) of $38,029/QALY. The sensitivity analyses showed that the proportion of receiving subsequent CDK4/6 inhibitors and the cost of Abem significantly influenced the results of Abem + NSAI compared with placebo + NSAI. (4) Conclusion: From the perspective of Chinese payers, Abem + NSAI was a cost-effective treatment option compared with placebo + NSAI at the WTP of $38,029/QALY, since only the ICUR of $33,163/QALY of Abem + NSAI was lower than the WTP of $38,029/QALY in China (2022). The Palbo + NSAI and Ribo + NSAI groups were not cost-effective unless drug prices were adjusted to 50% or 10% of current prices ($320.67 per cycle or $264.60 per cycle). (5) Others: We have prospectively registered the study with the PROSPERO, and the PROSPERO registration number is CRD42023399342.

A Local Strategy Toward Concurrent Chemoradiotherapy Based on Fibrin Gel for Postsurgical Cancer Treatment.

PURPOSE: Postoperative cancer recurrence and metastasis have always been huge challenges in cancer therapy. The concurrent cisplatin (CDDP)-based chemoradiotherapy regimen is a standard therapeutic strategy in some cancer treatments after surgical resection. However, severe side effects and unsatisfactory local tumor concentrations of CDDP have hampered the application of this concurrent chemoradiotherapy. Therefore, a superior option that can enhance CDDP-based chemoradiotherapy efficacy with milder concurrent therapy-related toxicity is highly desirable. METHODS AND MATERIALS: We developed a platform based on fibrin gel (Fgel) loaded with CDDP to be implanted into the tumor bed after surgery combined with concurrent radiation therapy for the prevention of postoperative local cancer recurrence and distant metastasis. The postoperative subcutaneous tumor mouse models established by incomplete resection of primary tumors were used to evaluate the therapeutic advantages of this chemoradiotherapy regimen for postsurgical treatment. RESULTS: The local and sustained release of CDDP from Fgel could enhance the antitumor efficacy of radiation therapy in the residual tumor with lower systemic toxicity. The therapeutic benefits of this approach are demonstrated in breast cancer, anaplastic thyroid carcinoma, and osteosarcoma mouse models. CONCLUSIONS: Our work offers a general platform for concurrent chemoradiotherapy to prevent postoperative cancer recurrence and metastasis.

Network and pathway-based analysis of genes associated with esophageal squamous cell carcinoma.

Background: Although diagnostic methods and treatments have improved over the last few years, the 5-year survival rate of esophageal squamous cell carcinoma (ESCC) patients remains generally poor. The development of high-throughput technology has facilitated great achievements in localization of ESCC-related genes. To take a further step toward a thorough understanding of ESCC at a molecular level, the potential pathogenesis of ESCC needs to be deciphered. Methods: The interaction of ESCC-related genes was explored by collecting genes associated with ESCC and then performing gene enrichment assays, pathway enrichment assays, pathway crosstalk analysis, and extraction of ESCC-specific subnetwork to describe the relevant biochemical processes. Results: Through Gene Ontology (GO) enrichment analysis, many molecular functions related to response to chemical, cellular response to stimulus, and cell proliferation were found to be significantly enriched in ESCC-related genes. The results of pathway and pathway crosstalk analysis showed that pathways associated with multiple malignant tumors, the immune system, and metabolic processes were significantly enriched in ESCC-related genes. Through the analysis of specific subnetworks, we obtained some novel ESCC-related potential genes, such as MUC13, GSTO1, FIN, GRB2, CDC25C, and others. Conclusions: The molecular mechanism of ESCC is extremely complex. Some inducing factors change the expression status of many genes. The abnormal expression of genes mediates the biological processes involved in immunity and metabolism, apoptosis, and cell proliferation, leading to the occurrence of tumors. The genes MUC13, RYK, and FIN may be potential prognostic indicators of ESCC; GRB2 and CDC25C may be potential targets of ESCC in proliferation. Our work may provide valuable information for further understanding the molecular mechanisms for the development of ESCC.

Identification of m6A modification patterns and development of m6A-hypoxia prognostic signature to characterize tumor microenvironment in triple-negative breast cancer.

Background: N6-methylation (m6A) modification of RNA has been found to have essential effects on aspects of the tumor microenvironment (TME) including hypoxia status and mobilization of immune cells. However, there are no studies to explore the combined effect of m6A modification and hypoxia on molecular heterogeneity and TME of triple-negative breast cancer (TNBC). Methods: We collected The Cancer Genome Atlas (TCGA-TNBC, N=139), the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC-TNBC, N=297), the GSE103091, GSE21653, and GSE135565 series from the Gene Expression Omnibus (GEO-TNBC, N=247), and FUSCCTNBC (N=245) for our study. The non-negative matrix factorization algorithm was used to cluster TNBC samples. Immune cell infiltration was analyzed by the CIBERSORT algorithm. The enrichment scores were calculated by single-sample gene set enrichment analysis(ssGSEA) to characterize TME in TNBC samples. Immunohistochemistry (IHC) and qRT-PCR were performed to detect the gene expression. Results: Based on the expression of m6A-related genes, we identified three distinct m6A clusters (denoted A, B, and C) in TNBC samples. Comparing the TME characteristics among the three clusters, we observed that cluster C was strongly related to hypoxia status and immune suppression, whereas clusters A and B displayed more immune cell infiltration. Therefore, we combine m6A and hypoxia related genes to classify two m6A-hypoxia clusters of TNBC and screened six prognostic genes by LASSO-Cox regression to construct a m6A-hypoxia signature(MHPS), which divided TNBC samples into high- and low-risk groups. We identified different TME features, immune cell infiltration between the two groups, and a better immunotherapy response was observed in the low-risk group. A nomogram was constructed with tumor size, lymph node, and risk score to improve clinical application of MHPS. Conclusion: We identified distinct TME characteristics of TNBC based on three different m6A modification patterns. Then, we constructed a specific m6A-hypoxia signature for TNBC to evaluate risk and predict immunotherapy response of patients, to enable more accurate treatment in the future.

Ferroptosis regulators related scoring system by Gaussian finite mixture model to predict prognosis and immunotherapy efficacy in nasopharyngeal carcinoma.

The role of ferroptosis in tumor progression and metastasis has been demonstrated. Nonetheless, potential biological function of ferroptosis regulatory pattern in nasopharyngeal carcinoma (NPC) remains unknown. Ferroptosis regulatory patterns of nasopharyngeal carcinoma samples were evaluated based on 113 ferroptosis regulators and three distinct ferroptosis subtypes were determined by unsupervised clustering. The ferroptosis score (FEP score) was identified to quantify ferroptosis patterns within individual tumors by Gaussian finite mixture model and systematically correlated with representative tumor characteristics. Subtype 1 and subtype 3 were consistent with immune activated phenotype, while subtype 2 was consistent with immune suppressed phenotype. High ferroptosis score, characterized by immune activation and suppression of mRNA based stemness index (mRNAsi) and Epstein-Barr virus (EBV) genes, indicated an immune activated tumor microenvironment (TME) phenotype, with better progression free survival (PFS) and lower risk of recurrence and metastasis. Low ferroptosis score, characterized by activation of Wnt and NF-κB signaling pathways and lack of effective immune infiltration, indicated an immune suppressed tumor microenvironment phenotype and poorer survival. High ferroptosis score was also correlated to enhanced response to immunotherapy, and was confirmed to correlate with therapeutic advantages and clinical benefits in an anti-programmed cell death 1 ligand 1 (PD-L1) immunotherapy cohort. As ferroptosis played a crucial role in the tumor microenvironment's diversity, assessing the ferroptosis pattern within individual tumor with ferroptosis score could enhance our understanding of tumor microenvironment infiltration characterization and help develop more effective immunotherapy.

Automatic Delineation of Gross Tumor Volume Based on Magnetic Resonance Imaging by Performing a Novel Semisupervised Learning Framework in Nasopharyngeal Carcinoma.

PURPOSE: We aimed to validate the accuracy and clinical value of a novel semisupervised learning framework for gross tumor volume (GTV) delineation in nasopharyngeal carcinoma. METHODS AND MATERIALS: Two hundred fifty-eight patients with magnetic resonance imaging data sets were divided into training (n = 180), validation (n = 20), and testing (n = 58) cohorts. Ground truth contours of nasopharynx GTV (GTVnx) and node GTV (GTVnd) were manually delineated by 2 experienced radiation oncologists. Twenty percent (n = 36) labeled and 80% (n = 144) unlabeled images were used to train the model, producing model-generated contours for patients from the testing cohort. Nine experienced experts were invited to revise model-generated GTV in 20 randomly selected patients from the testing cohort. Six junior oncologists were asked to delineate GTV in 12 randomly selected patients from the testing cohort without and with the assistance of the model, and revision degrees were compared under these 2 modes. The Dice similarity coefficient (DSC) was used to quantify the accuracy of the model. RESULTS: The model-generated contours showed a high accuracy compared with ground truth contours, with an average DSC score of 0.83 and 0.80 for GTVnx and GTVnd, respectively. There was no significant difference in DSC score between T1-2 and T3-4 patients (0.81 vs 0.83; P = .223), or between N1-2 and N3 patients (0.80 vs 0.79; P = .807). The mean revision degree was lower than 10% in 19 (95%) patients for GTVnx and in 16 (80%) patients for GTVnd. With assistance of the model, the mean revision degree for GTVnx and GTVnd by junior oncologists was reduced from 25.63% to 7.75% and from 21.38% to 14.44%, respectively. Meanwhile, the delineating efficiency was improved by over 60%. CONCLUSIONS: The proposed semisupervised learning-based model showed a high accuracy for delineating GTV of nasopharyngeal carcinoma. It was clinically applicable and could assist junior oncologists to improve GTV contouring accuracy and save contouring time.

Cost-effectiveness analysis of capecitabine maintenance therapy plus best supportive care vs. best supportive care alone as first-line treatment of newly diagnosed metastatic nasopharyngeal carcinoma.

Objectives: Maintenance therapy with capecitabine after induction chemotherapy for patients with newly diagnosed metastatic nasopharyngeal carcinoma (mNPC) has been confirmed to be effective. This study aimed to evaluate the cost-effectiveness of capecitabine as maintenance therapy for patients with mNPC from the Chinese payers' perspective. Methods: Markov model was conducted to simulate the disease progress and evaluated the economic and health outcomes of capecitabine maintenance plus best-supported care (CBSC) or best-supported care (BSC) alone for patients with mNPC. Survival data were derived from the NCT02460419 clinical trial. Costs and utilities were obtained from the standard fee database and published literature. Measured outcomes were total costs, quality-adjusted life-years (QALYs), life-years (LYs), incremental cost-utility ratios (ICURs), incremental cost-effectiveness ratios (ICERs), incremental net monetary benefit (INMB), and incremental net-health benefit (INHB). Sensitivity analyses were performed to assess model robustness. Additional subgroup cost-effectiveness analyses were accomplished. Results: Throughout the course of the disease, the CBSC group provide an incremental cost of $9 734 and additional 1.16 QALYs (1.56 LYs) compared with the BSC group, resulting in an ICUR of $8 391/QALY and ICER of $6 240/LY. Moreover, the INHB was 0.89 QALYs, and the INMB was $32 034 at the willingness-to-pay threshold of $36 007/QALY. Subgroup analyses revealed that CBSC presented a positive trend of gaining an INHB in all subgroups compared with the BSC group. The results of sensitivity analyses supported the robustness of our model. Conclusion: Compared with BSC, after induction chemotherapy, CBSC as a first-line treatment was cost-effective for newly diagnosed mNPC. These results suggest capecitabine maintenance therapy after induction chemotherapy as a new option for patients with newly diagnosed mNPC.

A novel dosimetric metrics-based risk model to predict local recurrence in nasopharyngeal carcinoma patients treated with intensity-modulated radiation therapy.

BACKGROUND: To develop a risk model based on dosimetric metrics to predict local recurrence in nasopharyngeal carcinoma (NPC) patients treated with intensive modulated radiation therapy (IMRT). METHODS: 493 consecutive patients were included, among whom 44 were with local recurrence. One-to-two propensity score matching (PSM) was used to balance variables between recurrent and non-recurrent groups. Dosimetric metrics were extracted, and critical dosimetric predictors of local recurrence were identified by Cox regression model. Moreover, recurrent sites and patterns were examined by transferring the recurrent tumor to the pretreatment planning computed tomography. RESULTS: After PSM, 44 recurrent and 88 non-recurrent patients were used for dosimetric analysis. The univariate analysis showed that eight dosimetric metrics and homogeneity index were significantly associated with local recurrence. The risk model integrating D5 and D95 achieved a C-index of 0.706 for predicting 3-year local recurrence free survival (LRFS). By grouping patients using median value of risk score, patients with risk score ˃ 0.885 had significantly lower 3-year LRFS (66.2% vs. 86.4%, p = 0.023). As for recurrent features, the proportion of relapse in nasopharynx cavity, clivus, and pterygopalatine fossa was 61.4%, 52.3%, and 40.9%, respectively; and in field, marginal, and outside field recurrence constituted 68.2%, 20.5% and 11.3% of total recurrence, respectively. CONCLUSIONS: The current study developed a novel risk model that could effectively predict the LRFS in NPC patients. Additionally, nasopharynx cavity, clivus, and pterygopalatine fossa were common recurrent sites and in field recurrence remained the major failure pattern of NPC in the IMRT era.

Local treatment of metastases plus systemic chemotherapy on overall survival of patients with metastatic nasopharyngeal carcinoma.

BACKGROUND: To investigate the effect of local treatment of metastases on overall survival (OS) of patients with metastatic nasopharyngeal carcinoma (NPC). METHODS: One hundred and forty-seven patients were included. The association between local treatment and OS was examined with propensity score matching (PSM) method. RESULTS: In entire cohort, the median OS was significantly longer in patients with local treatment of metastases plus chemotherapy compared to those with chemotherapy alone (71.7 vs. 16.2 months; p < 0.001). In PSM cohort, similar OS benefit of patients with local treatment was observed (55.6 vs. 17.6 months; p = 0.011). The survival benefit of local treatment remained regardless of the number of metastatic lesions and metastatic sites. Patients received radiation doses of >60 Gy had longer OS than those who received less. CONCLUSIONS: Local treatment of metastases could improve OS of patients with metastatic NPC and could be considered in their treatment in addition to chemotherapy.

Characteristics and forecasting of respiratory viral epidemics among children in west China.

ABSTRACT: We aimed to assess the respiratory virus characteristics and forecasts among young children with acute respiratory tract infection (ARTI) in west China.This retrospective study investigated the epidemic characteristics of respiratory viruses among 11,813 paediatric ARTI patient samples (mean age, 2.25 years) between March 2018 and March 2020.The ratio of boys to girls was 1.36. The 2 predominant viruses were influenza (Flu) A and respiratory syncytial virus (RSV) in both years, with Flu A accounting for 47.3% and 47.5% in the first and second years and RSV accounting for 32.7% and 24.7% of the positive samples in the first and second years, respectively. The Flu B positive rates were 10.9% and 13.1%, and those of the other 4 viruses were <7%. The most common virus was RSV in children below 5 years and Flu A in those between 5 and 10 years. Flu A and RSV demonstrated pronounced seasonality, and their infection rates increased from October. During the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic, isolation measures led to a decline in the number of ARTI cases.This study provides surveillance data of the respiratory viruses in west China. It could guide medical staff in implementing necessary prevention and management strategies before future viral outbreaks.

m6A Regulators Mediated Methylation Modification Patterns and Tumor Microenvironment Infiltration Characterization In Nasopharyngeal Carcinoma.

Background: The role of RNA N6-methyladenosine (m6A) modification in tumor progression and metastasis has been demonstrated. Nonetheless, potential biological function of m6A modification patterns in nasopharyngeal carcinoma (NPC) remains unknown. Methods: The m6A modification patterns were comprehensively evaluated based on 26 m6A regulators in NPC, and m6A subtype and also m6A score were identified and systematically correlated with representative tumor characteristics. Results: Two distinct m6A subtypes were determined and were highly consistent with immune activated and immune suppressed phenotypes, respectively. More representative m6A scores of individual tumors could predict tumor microenvironment (TME) infiltration, mRNA based stemness index (mRNAsi), EBV gene expression, genetic variation, and prognosis of NPC patients. Low m6A score, characterized by activation of immunity and suppression of mRNAsi and EBV gene, indicated an activated TME phenotype and better PFS and also lower risk of recurrence and metastasis. High m6A score, characterized by activation of Wnt and NF-κB signaling pathway and lack of effective immune infiltration, indicated an immune suppressed TME phenotype and poorer survival. Low m6A score was also correlated with increased tumor mutation burden (TMB) and better response to immunotherapy, and vice versa. A significant therapeutic advantage in patients with low m6A score was confirmed with an anti-PDL1 immunotherapy cohort. Conclusions: m6A patterns played an important role in the diversity and complexity of TME. m6A score could be used to evaluate the m6A pattern of individual tumor to enhance our understanding of TME infiltration and guide more effective immunotherapy strategies.

Synchronous Metastatic Nasopharyngeal Carcinoma: Characteristics and Survival of Patients Adding Definitive Nasopharyngeal-Neck Radiotherapy to Systematic Chemotherapy.

PURPOSE: To determine the M1 sub-staging in synchronous metastatic nasopharyngeal carcinoma (smNPC) and to examine the effect of nasopharyngeal-neck radiotherapy (RT) and local treatment of metastases on overall survival (OS) of smNPC patients. PATIENTS AND METHODS: A total of 150 patients with smNPC were included. Metastatic characteristics associated with their potential prognostic significance were analyzed. Then, a stratification system of the M1 sub-staging in smNPC was provided according to metastatic features. Moreover, the OS of patients with or without nasopharyngeal-neck RT was compared by Log rank test. The OS of patients who received or did not receive local treatment of metastases was also analyzed. RESULTS: We successfully divided the M1 stage into three sub-staging: M1a (a single site with a single lesion), M1b (a single site with multiple lesions), and M1c (multiple sites with multiple lesions). The median OS was 53.2, 25.8, and 18.9 months for M1a, M1b, and M1c, respectively (p < 0.001). Nasopharyngeal-neck RT plus systematic chemotherapy (CT) significantly improved OS compared to systematic CT (median OS, 34.0 vs 15.2 months, p = 0.002). However, incorporation of local treatment of metastases did not bring survival benefit to smNPC patients who received nasopharyngeal-neck RT plus systematic CT (median OS, 25.8 vs 35.1 months, p = 0.374). CONCLUSION: The sub-staging of the M1 stage in smNPC had promising prognostic value. Adding nasopharyngeal-neck RT on the basis of systematic CT markedly improved the survival of smNPC patients, while addition of local treatment of metastases to nasopharyngeal-neck RT plus systematic CT for smNPC needed further exploration.

A novel immune checkpoint-related seven-gene signature for predicting prognosis and immunotherapy response in melanoma.

BACKGROUND: New emergence of immunotherapy has significantly improved clinical outcome of melanoma patients with advanced and metastatic diseases. We aimed to develop a gene signature based on the expression of PD-1/PD-L1 signaling pathway genes to predict prognosis and immunotherapy response in melanoma patients. METHODS: Melanoma samples from The Cancer Genome Atlas (TCGA) database and Gene Expression Omnibus (GEO) were used as the training set and external validation sets respectively. Prognostic genes for overall survival (OS) were identified by univariate Cox regression analysis. Then a multi-gene risk signature was established with the Least Absolute Shrinkage and Selector Operation (LASSO) regression and multivariate Cox regression. The predictive and prognostic value of gene signature was evaluated by Kaplan Meier curve, Time-dependent receiver operating characteristic (ROC) curve, and area under curve (AUC). Gene set enrichment analysis (GSEA) was performed to investigate the discrepantly enriched biological processes between low-risk and high-risk group of melanoma patients. RESULTS: A seven-gene risk signature (BATF2, CTLA4, EGFR, HLA-DQB1, IKBKG, PIK3R2, PPP3CA) was constructed. The signature was an independent risk factor for OS (hazard ratio = 1.544, p < 0.001) and it could robustly predict OS in both training and validation sets. Besides, high risk scores indicated advanced clinical stage and no response to immunotherapy for melanoma patients. GSEA demonstrated that high risk score was intimately associated with immune response and immune regulation. In conclusion, the novel seven-gene signature could serve as a robust biomarker for prognosis and a potential indicator of immunotherapy response in melanoma.

Extracellular vesicles transmitted miR-31-5p promotes sorafenib resistance by targeting MLH1 in renal cell carcinoma.

Sorafenib provides survival benefits in patients with advanced renal cell carcinoma (RCC), but its use is hampered by acquired drug resistance. It is important to fully clarify the molecular mechanisms of sorafenib resistance, which can help to avoid, delay or reverse drug resistance. Extracellular vesicles (EVs) can mediate intercellular communication by delivering effector molecules between cells. Here, we studied whether EVs are involved in sorafenib resistance of RCC and its possible molecular mechanisms. Using differential centrifugation, EVs were isolated from established sorafenib-resistant RCC cells (786-0 and ACHN), and EVs derived from sorafenib-resistant cells were uptaken by sensitive parental RCC cells and thus promoted drug resistance. Elevated exogenous miR-31-5p within EVs effectively downregulated MutL homolog 1 (MLH1) expression and thus promoted sorafenib resistance in vitro. Mice experiments also confirmed that miR-31-5p could mediate drug sensitivity in vivo. In addition, low expression of MLH1 was observed in sorafenib-resistant RCC cells and upregulation of MLH1 expression restored the sensitivity of resistant cell lines to sorafenib. Finally, miR-31-5p level in circulating EVs of RCC patients with progressive disease (PD) during sorafenib therapy was higher when compared to that in the pretherapy status. In conclusion, EVs shuttled miR-31-5p can transfer resistance information from sorafenib-resistant cells to sensitive cells by directly targeting MLH1, and thus magnify the drug resistance information to the whole tumor. Furthermore, miR-31-5p and MLH1 could be promising predictive biomarkers and therapeutic targets to prevent sorafenib resistance.