The m6A reader HNRNPC promotes glioma progression by enhancing the stability of IRAK1 mRNA through the MAPK pathway.

Glioma is the most common and aggressive type of primary malignant brain tumor. The N6-methyladenosine (m6A) modification widely exists in eukaryotic cells and plays an important role in the occurrence and development of human tumors. However, the function and mechanism of heterogeneous nuclear ribonucleoprotein C (HNRNPC), an RNA-binding protein and m6A reader in gliomas remains to be comprehensively and extensively explored. Herein, we found that HNRNPC mRNA and protein overexpression were associated with a poor prognosis for patients with gliomas, based on the data from TCGA, the CGGA, and the TMAs. Biologically, HNRNPC knockdown markedly repressed malignant phenotypes of glioma in vitro and in vivo, whereas ectopic HNRNPC expression had the opposite effect. Integrative RNA sequencing and MeRIP sequencing analyses identified interleukin-1 receptor-associated kinase 1 (IRAK1) as a downstream target of HNRNPC. The glioma public datasets and tissue microarrays (TMAs) data indicated that IRAK1 overexpression was associated with poor prognosis, and IRAK1 knockdown significantly repressed malignant biological behavior in vitro. Mechanistically, HNRNPC maintains the mRNA stability of IRAK1 in an m6A-dependent manner, resulting in activation of the mitogen-activated protein kinase (MAPK) signaling pathway, which was necessary for the malignant behavior of glioma. Our findings demonstrate the HNRNPC-IRAK1-MAPK axis as a crucial carcinogenic factor for glioma and the novel underlying mechanism of IRAK1 upregulation, which provides a rationale for therapeutically targeting epitranscriptomic modulators in glioma.

Selectively sparing of the supraclavicular area during intensity-modulated radiotherapy in nasopharyngeal carcinoma: A double-center observation study.

BACKGROUND AND PURPOSE: This study was aimed at evaluating the feasibility of sparing the supraclavicular area, namely levels IVb and Vc, during intensity-modulated radiotherapy (IMRT) in nasopharyngeal carcinoma (NPC) patients with N1-2 disease[except N1 disease with purely restropharyngeal lymph nodes(RPN) involvement], and providing a basis for the revision of International Guideline for the delineation of the clinical target volume (CTV). PATIENTS AND MATERIALS: Patients with NPC (stage TanyN1-2M0) diagnosed pathologically in Fujian Cancer Hospital (Center 1, Only Lin SJ's attending group) from January 2014 to March 2018 and Jiangxi Cancer Hospital(Center 2) from January 2014 to December 2015 were included. According to our principle, the supraclavicular area (levels IVb and Vc) were excluded from the CTVnd. Survival outcomes focused on regional recurrence-free survival (RRFS) and recurrence rates of levels IVb and Vc were analysed. RESULTS: A total of 672 eligible patients were recruited (Center 1, n = 362; Center 2, n = 310). There was no significant difference in 5-year RRFS (97.33 % vs. 97.24 %, p = 0.980), overall survival (OS) (89.14 % vs. 88.56 %, p = 0.327), local recurrence-free survival (LRFS) (94.90 % vs. 95.30 %, p = 0.593) and distant metastasis-free survival (DMFS) (89.38 % vs. 86.60 %, p = 0.130) between Center 1 and Center 2. Twenty patients developed regional failure (median: 36 months), among them, only one case (0.15 %) was recorded as levels IVb and Vc recurrence. CONCLUSION: Omitting the supraclavicular area (levels IVb and Vc) during IMRT should be safe and feasible for N1-2 disease (except N1 disease with purely RPN involvement). Well-designed multicenter prospective trials should be conducted to confirm our findings.

Nutritional Status and Incidence of Radiation-Induced Oral Mucositis in Nasopharyngeal Carcinoma Patients Treated with Chemoradiotherapy.

Malnutrition is prevalent among patients with nasopharyngeal carcinoma undergoing radiotherapy. This study examined the nutritional status and incidence of radiation-induced oral mucositis (RIOM) in patients with nasopharyngeal carcinoma. A retrospective analysis was conducted to compare the incidence of RIOM, Nutritional Risk Screening (NRS) 2002 score, weight, body mass index (BMI), and hemoglobin levels in 338 patients treated with induction chemotherapy (IC) plus concurrent chemoradiotherapy (CCRT) or treated with CCRT alone. The IC + CCRT group exhibited an increase in weight and BMI but a decrease in hemoglobin levels after IC compared with baseline (p < 0.001). Both groups showed differences in weight at Week 0 and BMI at Weeks 0-2 of radiotherapy (p < 0.05). The IC + CCRT group experienced an increase in NRS 2002 scores from Week 2 to Week 6 (p < 0.05). The hemoglobin levels of the IC + CCRT group were consistently lower throughout radiotherapy (p < 0.001). However, no significant difference was observed in the incidence of RIOM between the two groups (p = 0.246). Patients treated with IC + CCRT exhibited a higher nutritional risk during radiotherapy. Although the incidence of Grade III RIOM was high, no significant difference was found between the groups.

Anatomic prognostic factors and their potential roles in refining M1 classification for de novo metastatic nasopharyngeal carcinoma.

BACKGROUND AND PURPOSE: To identify anatomic prognostic factors and their potential roles in refining M1 classification for de novo metastatic nasopharyngeal carcinoma (M1-NPC). MATERIALS AND METHODS: All M1-NPC treated with chemotherapy and/or radiotherapy between 2010 and 2019 from two centers (training and validation cohort) were included. The prognostic value of metastatic disease extent and involved organs for overall survival (OS) were assessed by several multivariable analyses (MVA) models. A new M1 classification was proposed and validated in a separate cohort who received immuno-chemotherapy. RESULTS: A total of 197 M1-NPC in the training and 307 in the validation cohorts were included for M1 subdivision study with median follow-up of 46 and 57 months. MVA model with "≤2 organs/≤5 lesions" as the definition of oligometastasis had the highest C-index (0.623) versus others (0.606-0.621). Patients with oligometastasis had better OS versus polymetastasis (hazard ratio [HR] 0.47/0.63) while liver metastases carried worse OS (HR 1.57/1.45) in MVA in the training/validation cohorts, respectively. We proposed to divide M1-NPC into M1a (oligometastasis without liver metastases) and M1b (liver metastases or polymetastasis) with 3-year OS of 66.5%/31.7% and 64.9%/35.0% in the training/validation cohorts, respectively. M1a subset had a better median progress-free survival (not reach vs. 17 months, p < 0.001) in the immuno-chemotherapy cohort (n = 163). CONCLUSION: Oligometastasis (≤2 organs/≤5 lesions) and liver metastasis are prognostic for M1-NPC. Subdivision of M1-NPC into M1a (oligometastasis without liver metastasis) and M1b (liver metastasis or polymetastasis) depicts the prognosis well in M1-NPC patients who received immuno-chemotherapy.

Lack of association between XRCC1 SNPs and acute radiation­induced injury or prognosis in patients with nasopharyngeal carcinoma.

The response to radiation therapy (RT) is closely associated with DNA damage repair. X-ray repair cross-complementing group-1 (XRCC1) is a key gene in the DNA damage repair pathway, and SNPs in this gene alter the expression and activity of its effector protein, which may in turn affect sensitivity to RT. Therefore, the course of tumor treatment and local control rate can be influenced. In the present study, a group of 158 patients with nasopharyngeal carcinoma (NPC) who received intensity-modulated RT at Fujian Cancer Hospital (Fuzhou, China) between July 2012 and October 2013 were included in retrospective chart review and followed up. Plasma was collected before treatment for genotype analysis of the three SNPs of XRCC1, namely Arg194Trp, Arg280His and Arg399Gln. Acute radiation-induced injuries sustained during treatment was graded according to the Radiation Therapy Oncology Group scoring criteria. Post-treatment follow-up was performed until August 2020. In the 158 cases of NPC, no statistically significant association was observed between the three SNPs of the XRCC1 gene and the severity of acute radiation-induced injury or prognosis. However, the AA genotype of XRCC1-Arg399Gln tended to be associated with worse progression-free survival (PFS) compared with the GA + GG genotype, although this was not significant (P=0.069). In addition, multivariate logistic analysis showed that nodal stage was significantly associated with the occurrence of acute severe radiation-induced oral mucositis (P=0.018), and there was also a trend towards an association between nodal stage and the incidence of acute severe radiation-induced pharyngitis; however, this was not statistically significant (P=0.061). Furthermore, multivariate Cox regression analysis showed that older age, distant metastasis and higher clinical stage were independent risk factors for PFS in patients with NPC. In conclusion, relying solely on the aforementioned SNPs of the XRCC1 gene may not provide a robust enough basis to predict the response to RT or prognosis in patients with NPC.

A Novel Prognostic Model Predicts Outcomes in Non-Metastatic Nasopharyngeal Carcinoma Based on Inflammation, Nutrition, and Coagulation Signature.

Purpose: This study aimed to assess the prognostic and predictive value of a circulating hematological signature (CHS) and to develop a CHS-based nomogram for predicting prognosis and guiding individualized chemotherapy in non-metastatic nasopharyngeal carcinoma (NPC) patients. Patients and Methods: NPC patients were recruited between January 2014 and December 2017 at the Jiangxi Cancer Hospital. The CHS was constructed based on a series of hematological indicators. The nomogram was developed by CHS and clinical factors. Results: A total of 779 patients were included. Three biomarkers were selected by least absolute shrinkage and selection operator regression, including prognostic nutritional index, albumin-to-fibrinogen ratio, and prealbumin-to-fibrinogen ratio, were used to construct the CHS. The patients in the low-CHS group had better 5-year DMFS and OS than those in the high-CHS group in the training (DMFS: 85.0% vs 56.6%, p<0.001; OS: 90.3% vs 65.4%, p<0.001) and validation cohorts (DMFS: 92.3% vs 43.6%, p<0.001; OS: 92.1% vs 65.5%, p<0.001). The nomogram_CHS showed better performance than clinical stage in predicting distant metastasis (concordance index: 0.728 vs 0.646). In the low-TRS (total risk scores) group, the patients received RT alone, CCRT and IC plus CCRT had similar 5-year DMFS and OS (p>0.05). In the middle-TRS group, the patients received RT alone had worse 5-year DMFS (58.7% vs 80.8% vs 90.8%, p=0.002) and OS (75.0% vs 94.1% vs 95.0%, p=0.001) than those received CCRT or IC plus CCRT. In the high-TRS group, the patients received RT alone and CCRT had worse 5-year DMFS (18.6% vs 31.3% vs 81.5%, p<0.001) and OS (26.9% vs 53.2% vs 88.8%, p<0.001) than those received IC plus CCRT. Conclusion: The developed nomogram_CHS had satisfactory prognostic accuracy in NPC patients and may individualize risk estimation to facilitate the identification of suitable IC candidates.

MRI-based deep learning model predicts distant metastasis and chemotherapy benefit in stage II nasopharyngeal carcinoma.

Chemotherapy remains controversial for stage II nasopharyngeal carcinoma because of its considerable prognostic heterogeneity. We aimed to develop an MRI-based deep learning model for predicting distant metastasis and assessing chemotherapy efficacy in stage II nasopharyngeal carcinoma. This multicenter retrospective study enrolled 1072 patients from three Chinese centers for training (Center 1, n = 575) and external validation (Centers 2 and 3, n = 497). The deep learning model significantly predicted the risk of distant metastases for stage II nasopharyngeal carcinoma and was validated in the external validation cohort. In addition, the deep learning model outperformed the clinical and radiomics models in terms of predictive performance. Furthermore, the deep learning model facilitates the identification of high-risk patients who could benefit from chemotherapy, providing useful additional information for individualized treatment decisions.

Constructing an individualized surveillance framework for nasopharyngeal carcinoma based on a dynamic risk-adapted approach.

BACKGROUND AND PURPOSE: This study aims to evaluate the dynamic survival and recurrence hazard of nasopharyngeal carcinoma(NPC) patients after definitive chemoradiotherapy utilizing conditional survival(CS) analysis, and to propose a personalized surveillance strategy at different clinical stages. MATERIALS AND METHODS: Non-metastatic NPC patients who received curative chemotherapy between June 2005 and December 2011 were included. The Kaplan-Meier method was used to calculate the CS rate. RESULTS: A total of 1616 patients were analyzed. With the prolongation of survival time, both conditional locoregional recurrence free survival and distant metastatic free survival increased gradually. Changing pattern of annual recurrence risk over time varied among different clinical stages. The annual locoregional recurrence(LRR) risk in stage I-II was always less than 2%, while in stage III-IVa, it was greater than 2% for the first three years and decreased to below 2% only after the third year. The annual distant metastases (DM) risk was always less than 2% in stage I, but higher than 2% in stage II for the first 3 years (2.5-3.8%). For those with stage III-IVa, the annual DM risk retained at a high level(>5%), and only decreased to < 5% after the third year. Based on the dynamic changes in survival probability over time, we established a surveillance plan with different follow-up intensities and frequencies for different clinical stages. CONCLUSION: The annual risk of LRR and DM decrease over time. Our individual surveillance model will provide critical prognostic information to optimize clinical decision-making, and promote to formulate surveillance counseling and help with resources allocation.

Identification of immune-related genes contributing to head and neck squamous cell carcinoma development using weighted gene co-expression network analysis.

BACKGROUND: This study aimed to identify genes related to the degree of immune cell infiltration in head and neck squamous cell carcinoma (HNSCC), explore their new biological functions, and evaluate their diagnostic and prognostic value in HNSCC. METHODS: Transcriptomic data from The Cancer Genome Atlas (TCGA) HNSCC dataset was used to screen differentially expressed genes between tumors and normal tissues, followed by weighted correlation network analysis (WGCNA) to identify immune-related modules. Differential gene expression, immune cell infiltration, and survival analyses were performed to screen key genes. The expression of these key genes was validated in Oncomine and gene expression omnibus (GEO) datasets and by immunohistochemistry (IHC). RESULTS: 1869 and 1578 genes were significantly upregulated and downregulated in HNSCC. WGCNA showed that the brown module was associated with the most significant number of immune-related genes. PPI network analysis demonstrated that PPL, SCEL, KRT4, KRT24, KRT78, KRT13, SPRR3, TGM3, CRCT1, and CRNN were key components in the brown module. Furthermore, the expression levels of KRT4, KRT78, KRT13, and SPRR3 in HNSCC correlated with infiltration levels of CD8+ T cells and macrophages. Survival analyses revealed that the expression of KRT78, KRT13, and SPRR3 in HNSCC correlated with overall survival (OS). The IHC assay indicated that KRT13 (p = .042), KRT78 (p < .001), and SPRR3 (p = .022) protein expression levels in HNSCC were significantly lower than in normal tissues. Analysis of GSE65858 and GSE41613 datasets showed that a worse OS was associated with low expression of KRT78 (p = .0086, and p = .005) and SPRR3 (p = .017, and p = .02). CONCLUSIONS: Our findings suggest that KRT4, KRT78, KRT13, and SPRR3 are related to the occurrence and development of HNSCC. Importantly, KRT78 and SPRR3 might serve as diagnostic and prognostic biomarkers of HNSCC.

Prioritizing sufficient dose to gross tumor volume over normal tissue sparing in intensity-modulated radiotherapy treatment of T4 nasopharyngeal carcinoma.

BACKGROUND: In intensity-modulated radiation therapy (IMRT) for nasopharyngeal carcinoma (NPC), priority is often given minimize dose to the critical organs at risk (OARs) to avoid potential morbid sequelae. However, in T4 NPC, dosimetric inadequacy enforced by dose constraints on OARs may significantly impact tumor control. METHODS: This was a single-institute cohort that patients diagnosed between July 2005 and December 2010 with T4 NPC treated with IMRT. All patients were re-classification according to the 7th-AJCC stage. RESULTS: Overall, the average doses such as Dmax , D1% , D2% and D1cc for various Central nervous system (CNS) OARs including brainstem, optic nerve, chiasm, temporal lobes and spinal cord were found to exceed published guidelines as RTOG0225. However, no clinical toxicities were seen during the follow-up period except for 13% patients with temporal lobe necrosis. CONCLUSION: Our retrospective review showed that its feasible to maximize gross tumor volume dose coverage while exceeding most CNS OAR constraint standards, with ideal local control and no obvious increase of craniocerebral toxicity.

Impaired geriatric 8 score is associated with worse survival after radical intensity modulated radiation therapy in elderly patients with nasopharyngeal carcinoma.

BACKGROUND: Geriatric 8 score (G8) was an independent prognostic factor for survival and toxicities in various malignancies, but it has never been tested in nasopharyngeal carcinoma (NPC). OBJECTIVES: To evaluate the value of G8 in predicting survival in elderly patients with NPC. MATERIAL AND METHODS: Patients with NPC aged ≥70 who received intensity-modulated radiation therapy were recruited into this study. The overall survival (OS), progression-free survival (PFS), locoregional recurrence rate (LRR), and distant metastasis rate (DMR) between the patients with G8 > 14 and G8 ≤ 14 were calculated using the Kaplan-Meier method and compared with the Log-rank test. Cox proportional hazards model was applied to perform univariate and multivariate analysis. RESULTS: G8 ≤ 14 had significantly reduced OS (p = .001) and PFS (p = .032) than those with G8 > 14 by log-rank test. G8 score remained an independent prognosticator for OS (HR = 0.490, 95% CI = 0.267-0.900, p = .021) and was a borderline significance towards PFS (HR = 0.639, 95% CI = 0.386-1.058, p = .082) in multivariate analysis. Grade 3-4 acute toxicities were significantly more common in patients with G8 ≤ 14 than in those with G8 > 14. CONCLUSIONS AND SIGNIFICANCE: G8 is useful in predicting the OS in elderly patients with NPC. Further prospective study stratified by G8 is needed to explore the value of CT in elderly patients with NPC.

Budding uninhibited by benzimidazoles 1 overexpression is associated with poor prognosis and malignant phenotype: A promising therapeutic target for lung adenocarcinoma.

BACKGROUND: The budding uninhibited by benzimidazoles (BUB) family is involved in the cell cycle process as mitotic checkpoint components. Abnormal proliferation is a vital process in the development of lung adenocarcinoma (LUAD). Nevertheless, the roles of BUB1 in LUAD remain unclear. In this study, we evaluated the prognostic value and biological functions of BUB1 in LUAD using data from The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), clinical LUAD samples, and in vitro experiments. METHODS: The expression, prognostic significance, functions, immune infiltration, and methylation of BUB1 in LUAD were comprehensively analyzed using TCGA, GEO, Gene Expression Profiling Interactive Analysis, Metascape, cBioPortal, MethSurv, and cancerSEA databases. Furthermore, we performed a battery of in vitro experiments and immunohistochemistry (IHC) to verify the bioinformatics results. RESULTS: Multivariate analysis revealed that BUB1 overexpression was an independent prognostic factor (hazard ratio = 1.499, p = 0.013). Functional enrichment analysis showed that BUB1 was correlated with cell cycle, proliferation, DNA repair, DNA damage, and invasion (p < 0.05). Finally, in vitro experiments showed that downregulation of BUB1 inhibited the proliferation, migration, and invasion of LUAD cells and promoted LUAD cell apoptosis. IHC also showed that BUB1 was overexpressed in LUAD (p < 0.001) and was significantly associated with poor prognosis (p < 0.001). CONCLUSIONS: Our bioinformatics and IHC analyses revealed that BUB1 overexpression was an adverse prognostic factor in LUAD. In vitro experiments demonstrated that BUB1 promoted tumor cell proliferation, migration, and invasion in LUAD. These results indicated that BUB1 was a promising biomarker and potential therapeutic target in LUAD.

Serum and urine metabolomics analyses reveal metabolic pathways and biomarkers in relation to nasopharyngeal carcinoma.

RATIONALE: Nasopharyngeal carcinoma (NPC) is a malignant tumor that is endemic in Southeast Asia, North Africa, and southern China. There is an urgent need for effective early diagnosis and treatment of this disease since NPC is currently often detected at advanced stages. METHODS: To reveal the underlying metabolic mechanisms and discover potential diagnostic biomarkers of NPC, we employed ultrahigh-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF-MS) and UHPLC-Q-Exactive Orbitrap MS, respectively, to analyze 54 serum samples and 54 urine samples from 27 patients with NPC and 27 healthy control individuals. RESULTS: A total of 1230 metabolites were determined in serum samples, and 181 of the 1230 metabolites were significantly changed in NPC patients. The 181 metabolites were enriched in 16 pathways, including biosynthesis of unsaturated fatty acids, cholesterol metabolism, and ferroptosis. A total of 2509 metabolites were detected in the urine samples. Among them, 179 metabolites were significantly altered in NPC patients, and these metabolites were enriched in eight pathways, including the tricarboxylic acid (TCA) cycle and caffeine metabolism. Seven metabolites, including creatinine and paraxanthine, were found to be significantly changed in both NPC serum and urine samples. Based on them, further biomarker analysis revealed that the panel of three serum metabolites, octanoylcarnitine, creatinine, and decanoyl-l-carnitine, displayed a perfect diagnostic performance (area under the curve [AUC] = 0.973) to distinguish NPC patients from controls, while the other three-metabolite biomarker panel, consisting of stachydrine, decanoyl-l-carnitine, and paraxanthine, had an AUC = 0.809 to distinguish NPC and control in urine samples. CONCLUSION: This work highlights the key metabolites and metabolic pathways disturbed in NPC and presents potential biomarkers for effective diagnosis of this disease.

The role of radiologic extranodal extension in predicting prognosis and chemotherapy benefit for T1-2 N1 nasopharyngeal carcinoma: A multicenter retrospective study.

BACKGROUND AND PURPOSE: This multicenter retrospective study aimed to investigated the prognostic value of unequivocal radiologic extranodal extension (rENE) and the efficacy of chemotherapy for stage T1-2 N1 nasopharyngeal carcinoma (NPC) in the IMRT era. MATERIALS AND METHODS: We included 1,082 patients treated in 2005-2017 from three centers. rENE was recorded as G1 (coalescent nodal mass comprising ≥ 2 inseparable nodes) or G2 (invading beyond perinodal fat to frankly infiltrate adjacent structures). Multivariable analysis (MVA) evaluated the prognostic value of rENE. The value of chemotherapy was assessed in rENE-positive (rENE + ) and rENE-negative (rENE - ) subset separately. RESULTS: Centers 1, 2, and 3 had 139/515 (27.0 %), 100/365 (27.4 %), and 43/202 (21.3 %) cN + patients with rENE, respectively. Compared to rENE-, rENE + patients had a worse distant metastasis-free survival (DMFS) and overall survival (OS) (all p < 0.001). MVA confirmed the prognostic of both G1-rENE and G2-rENE for distant metastasis [G1: hazard ratio (HR): 2.933, G2: HR: 6.942, all p < 0.001] and death (G1: HR: 1.587, p = 0.040; G2: HR: 6.162, p < 0.001). There was no significant difference for DMFS and OS between chemo-radiotherapy and radiotherapy alone in rENE + and rENE - groups (all p > 0.1). However, rENE + patients with a cumulative cisplatin/nedaplatin dose (CCND) of > 160 mg/m2 had an improved DMFS (p = 0.033) but no OS (p = 0.197). CONCLUSION: Unequivocal rENE is prognostic in patients with T1-2 N1 NPC. Addition of chemotherapy to radiotherapy did not affect DMFS and OS in rENE - patients. Chemotherapy with a CCND of > 160 mg/m2 improved DMFS in rENE + patients.

Integrin subunit alpha V is a potent prognostic biomarker associated with immune infiltration in lower-grade glioma.

As a member of integrin receptor family, ITGAV (integrin subunit α V) is involved in a variety of cell biological processes and overexpressed in various cancers, which may be a potential prognostic factor. However, its prognostic value and potential function in lower-grade glioma (LGG) are still unclear, and in terms of immune infiltration, it has not been fully elucidated. Here, the expression preference, prognostic value, and clinical traits of ITGAV were investigated using The Cancer Genome Atlas database (n = 528) and the Chinese Glioma Genome Atlas dataset (n = 458). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses and gene set enrichment analysis (GSEA) were used to explore the biological function of ITGAV. Using R package "ssGSEA" analysis, it was found thatthe ITGAV mRNA expression level showed intense correlation with tumor immunity, such as tumor-infiltrating immune cells and multiple immune-related genes. In addition, ITGAV is associated with some immune checkpoints and immune checkpoint blockade (ICB) and response to chemotherapy. and the expression of ITGAV protein in LGG patients was verified via immunohistochemistry (IHC). ITGAV expression was higher in LGG tissues than in normal tissues (P < 0.001) and multifactor analysis showed that ITGAV mRNA expression was an independent prognostic factor for LGG overall survival (OS; hazard ratio = 2.113, 95% confidence interval = 1.393-3.204, P < 0.001). GSEA showed that ITGAV expression was correlated with Inflammatory response, complement response, KRAS signal, and interferon response. ssGSEA results showed a positive correlation between ITGAV expression and Th2 cell infiltration level. ITGAV mRNA was overexpressed in LGG, and high ITGAV mRNA levels were found to be associated with poor protein expression and poor OS. ITGAV is therefore a potential biomarker for the diagnosis and prognosis of LGG and may be a potential immunotherapy target.

Is a high-risk clinical target volume required? Evaluation of the dosimetric feasibility based on T staging.

Background: Clinical target delineation is a primary focus in the field of radiotherapy. This study aimed to investigate whether high-risk clinical target volume can be removed in nasopharyngeal carcinoma patients with different T stages. Materials and methods: We designed a test plan without the high-risk clinical target volume for 111 nasopharyngeal carcinoma patients and further compared the test plans with the treatment plans in the parameters of planning target volumes and the radiation dose to normal organs. Results: Our data showed that when high-risk clinical target volume was abnegated, target coverage, conformity indices, and homogeneity indices of planning target volumes and doses of normal organs were not influenced in the T4 nasopharyngeal carcinoma patients, and more than 95% of the high-risk planning target volume area could still be covered by the 60 Gy dose line. However, only some T1-3 patients achieved the ideal dose coverage, and even fewer after induction chemotherapy (62.8% vs. 41.2%, p = 0.018). Gross tumor volume was positively correlated with the target coverage of the original high-risk planning target volume in the test-plan (p = 0.0001). Gross tumor volume can be used to predict whether the target coverage of high-risk planning target volume is more than 95% (area under the curve = 0.868). Conclusion: Omitting high risk clinical target volume can be considered in patients with T4 nasopharyngeal carcinoma according to physical evaluations. However, this approach is only suitable for a specific subset of T1-3 patients.

Stereotactic body radiotherapy extends the clinical benefit of PD-1 inhibitors in refractory recurrent/metastatic nasopharyngeal carcinoma.

PURPOSE: Emerging evidence shows that immune checkpoint inhibitors lead to durable responses in a variety of cancers, including nasopharyngeal carcinoma (NPC), however, combination approaches (i.e., stereotactic body radiation therapy, SBRT) are required to extend this benefit beyond a subset of patients. This study retrospectively evaluated eight recurrent/metastatic NPC patients, to investigate how radiation could potentiate PD-1 checkpoint inhibition therapy. METHODS: Between September 2016 and July 2017, eight consecutive cases with histologically confirmed PDL1-positive status, for which prior standard therapy had been ineffective (five patients), were treated at our institution and Macao Clinics and two patients had disease progression within 6 months of completion of definitive chemoradiation, or one patient refused to receive chemoradiotherapy. All received PD-1 inhibitors first, seven of them accepted SBRT with an unmodified PD-1 inhibitors regimen after first evaluation as they were unresponsive to PD-1 inhibitors alone. Treatment was discontinued as long as patients were experiencing a clinical benefit in the opinion of the physicians and at least five cycles were given before stoppage. RESULTS: Median follow-up time was 56.7 months. The confirmed objective response rate based on RECIST-v1.1 at first evaluation was 12.5% (1/8). For the seven cases who received SBRT, six of them experience an objective response (6/7, 85.7%) after SBRT. Only one patient showed rapid progress and die within 95 days after the initiation of SBRT intervention. Three patients who did not have all lesions exposed to irradiation were available to evaluate the incidence of an abscopal effect, however, it did not occur as expected. Median PFS and OS for the seven patients were 8.0 and 30.8 months after SBRT intervention, respectively. Two-year OS as indicated was 71.0%. CONCLUSIONS: PD-1 inhibitors combined with SBRT demonstrated promising antitumor activity in patients with PD-L1 positive RM-NPC. Patients may benefit from continue immunotherapy beyond disease progression when SBRT was introduced.

Clinical Efficacy of Osimertinib in Patients with Advanced Non-Small Cell Lung Cancer and Its Effect on Serum CEA and VEGF Expression.

Objective: To assess the clinical efficacy of osimertinib in patients with advanced non-small cell lung cancer and its effect on serum carcinoembryonic antigen (CEA) and vascular endothelial growth factor (VEGF) expression. Methods: Between July 2018 and January 2020, 80 patients with advanced non-small cell lung cancer were assessed for eligibility and recruited. The patients were assigned at a ratio of 1 : 1 to receive either the PC regimen (pemetrexed + cisplatin) (conventional group) or osimertinib (experimental group). The primary endpoint was the clinical efficacy, and the secondary endpoints were the adverse events, expression of serum CEA and VEGF, and 2-year survival. Results: Osimertinib was associated with a significantly higher response rate and disease control rate versus pemetrexed plus cisplatin (P < 0.05). Osimertinib resulted in a significantly lower incidence of adverse events versus the PC regimen (P < 0.05). Patients given osimertinib had significantly lower levels of CEA and VEGF versus those given pemetrexed plus cisplatin (P < 0.05). Osimertinib was associated with a significantly higher 1-year and 2-year survival rate versus pemetrexed plus cisplatin. Conclusion: Osimertinib could inhibit the expression of serum CEA and VEGF in patients with advanced non-small cell lung cancer and reduce the adverse events with significant efficacy, so it is worthy of clinical promotion and application.

High Expression of CKS2 Predicts Adverse Outcomes: A Potential Therapeutic Target for Glioma.

Cyclin-dependent kinase regulatory subunit 2 (CKS2) is a potential prognostic marker and is overexpressed in various cancers. This study analyzed sequencing and clinical data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus, with external validation using the Chinese Glioma Genome Atlas (CGGA) data. CKS2 expression in the normal brain and tumor tissue was compared. cBioPortal and MethSurv were utilized to scrutinize the prognostic value of CKS2 methylation. Gene set enrichment examination and single-sample gene set enrichment analysis were employed to explore the potential biological functions of CKS2. Cell viability, colony formation, and transwell assays were conducted to evaluate the influence of CKS2 on glioma cell proliferation and invasion. Compared with normal brain tissue, the expression of CKS2 was upregulated in glioma samples (p < 0.001). Multivariate data analysis from TCGA and CGGA indicated that increased expression of CKS2 was an independent risk factor for the prognosis of overall survival in glioma patients. CKS2 methylation was negatively associated with CKS2 expression. Patients with CKS2 hypomethylation had worse overall survival compared with patients with CKS2 methylation, as suggested by the analysis of both TCGA and CGGA datasets. The expression level of CKS2 is closely related to tumor immunity, including the correlation of tumor immune cell infiltration, immune score, and co-expression of multiple immune-related genes. In addition, CKS2 is associated with several immune checkpoints and responses to the chemotherapy drug cisplatin. CKS2 knockdown impeded the expansion and aggression of glioma cell lines. The changes in CKS2 expression may provide a novel prognostic biomarker that can be used to improve patient overall survival rates.

Plasma Epstein-Barr Virus MicroRNA BART8-3p as a Diagnostic and Prognostic Biomarker in Nasopharyngeal Carcinoma.

BACKGROUND: Nasopharyngeal carcinoma is an Epstein-Barr virus (EBV)-associated tumor that is highly common in southern China. Our previous sequencing data demonstrated that the EBV-encoded microRNA BART8-3p was most upregulated in nasopharyngeal carcinoma (NPC) and was closely associated with the metastasis of NPC. However, the values of plasma BART8-3p in NPC patients have not yet been well characterized. MATERIAL AND METHODS: We quantified plasma BART8-3p expression by quantitative real-time PCR in 205 newly diagnosed NPC patients. Kaplan-Meier analysis was used to compare overall survival (OS), distant metastasis-free survival (DMFS), and locoregional relapse-free survival (LRRFS) between the groups. RESULTS: Plasma pretreatment BART8-3p was highly expressed in NPC patients compared with healthy controls. Pretreatment BART8-3p yielded a 92% predictive value for detecting NPC. Importantly, BART8-3p decreased dramatically after therapy relative to pretreatment levels. High levels of pretreatment or post-treatment BART8-3p were associated with worse OS, DMFS, and LRRFS. Multivariate analysis showed that high pretreatment or post-treatment BART8-3p was an independent unfavorable prognostic marker for OS (HR 3.82, 95% CI 1.77-8.24, P = .001 or HR 2.74, 95% CI 1.27-5.91, P = .010), DMFS (HR 2.82, 95% CI 1.36-5.85, P = .005 or HR 3.27, 95% CI 1.57-6.81, P = .002), and LRRFS (HR 1.94, 95% CI 1.12-3.35, P = .018 or HR 2.03, 95% CI 1.14-3.62, P = .016) in NPC. Subgroup analysis revealed that for patients with locally advanced NPC with high levels of pretreatment BART8-3p (n = 58), more cycles of chemotherapy (≥6 cycles) tended to prolong OS (P = .070). Over 50% (6/11) patients with high levels of post-treatment BART8-3p presented distant metastasis. CONCLUSION: Plasma BART8-3p is a promising biomarker for the detection and prognosis of NPC.