Prognostic significance of carboxypeptidase Q and its methylation in glioblastoma.

Background: Glioblastoma (GBM) is a highly aggressive intracranial malignant tumor. The role of carboxypeptidase Q (CPQ) in GBM remains unknown. This study was to investigate the prognostic significance of CPQ and its methylation in GBM. Methods: We collected data from The Cancer Genome Atlas (TCGA)-GBM database and analyzed the different expression of CPQ in GBM tissues and normal tissues. Then we explored the correlation of CPQ mRNA expression and DNA methylation, and confirmed the prognostic significance of them based on six additional datasets from TCGA, The Chinese Glioma Genome Atlas (CGGA) and Gene Expression Omnibus (GEO) databases. Gene Ontology analysis and Kyoto Encyclopedia of Genes and Genomes analysis were utilized to investigate the biological function of CPQ in GBM. Furthermore, we determined the association of CPQ expression and immune cell infiltration, immune markers and tumor microenvironment using different bioinformatic algorithms. R (version 4.1) and GraphPad Prism (version 8.0) were used to analyze the data. Results: CPQ mRNA expression in GBM tissues was significantly higher than that in normal brain tissues. DNA methylation of CPQ was negatively correlated with its expression. Patients with low CPQ expression or higher CPQ methylation level had remarkably better overall survival (OS). The TOP20 biological processes relevant to the differentially expressed genes between high and low CPQ patients were almost all related to immunity. And the differentially expressed genes were involved in several immune-related signaling pathways. CPQ mRNA expression was outstandingly correlated with CD8+ T cells, neutrophils, macrophages and dendritic cell (DC) infiltration. Moreover, CPQ expression was meaningfully associated with the ESTIMATE score and almost all immunomodulatory genes. Conclusions: Low CPQ expression and high methylation are associated with longer OS. CPQ is a promising biomarker for predicting prognosis in patients with GBM.

The valuable role of dynamic 18F FDG PET/CT-derived kinetic parameter Ki in patients with nasopharyngeal carcinoma prior to radiotherapy: A prospective study.

BACKGROUND AND PURPOSE: Dynamic positron emission tomography/computed tomography (PET/CT) served the potential role of characterizing malignant foci. The main objective of this prospective study was to explore the advantage of dynamic PET/CT imaging in characterizing nasopharyngeal carcinoma (NPC). METHODS AND MATERIALS: Patients with probable head and neck disease underwent a local dynamic PET/CT scan followed by a whole-body static scan. Patlak analysis was used to generate parametric influx rate constant (Ki) images from 48 frames obtained from a dynamic PET/CT scan. By delineating the volumes-of-interest (VOIs) of: primary tumor (PT), lymph node (LN), and normal nasopharyngeal tissues (N), we acquired the corresponding Ki mean and SUVmean of each site respectively to perform the quantitative statistical analysis. RESULTS: Qualified images of 71 patients with newly diagnosed NPC and 8 without nasopharyngeal malignant lesions were finally included. We found the correlations between Ki mean-PT and critical clinical features, including clinical stage (r = 0.368), T category (r = 0.643) and EBV-DNA copy status (r = 0.351), and Ki mean-PT differed within the group. SUVmean-PT showed correlations with clinical stage (r = 0.280) and T category (r = 0.472), but could hardly differ systematically within group of clinical features except T category. Ki mean-LN offered the positive correlations with N category (r = 0.294), M category (r = 0.238) and EBV-DNA copy status (r = 0.446), and differed within the group. In addition, Ki mean represented a sensitivity of 94.4 % and a specificity of 100 %, in distinguishing NPC from the non-NPC, when the cut-off was defined as 0.0106. When the cut-off of SUV being defined as 2.03, the sensitivity and specificity were both 100 %. CONCLUSION: Our research confirmed Ki compared favorably to SUV in characterizing NPC and found that Ki can serve as an effective imaging marker of NPC.

Neoadjuvant toripalimab combined with gemcitabine and cisplatin in resectable locally advanced head and neck squamous cell carcinoma (NeoTGP01): An open label, single-arm, phase Ib clinical trial.

BACKGROUND: Neoadjuvant programmed death receptor-1 (PD-1) inhibitors have drawn increasing attention in locally advanced head and neck squamous cell carcinoma (HNSCC). In this study, we investigated the safety and efficacy of gemcitabine and cisplatin (GP), combined with a PD-1 inhibitor, in patients with locally advanced HNSCC. MATERIALS AND METHODS: A total of 23 eligible patients were administered two cycles of toripalimab and GP followed by surgical resection. The primary endpoints were safety, treatment-related adverse events (TRAEs), and non-operation delay rates. The secondary endpoints consisted of pathological complete response (pCR) rate, major pathological response (MPR) rate, objective response rate (ORR), and R0 resection rate. RESULTS: The incidence of TRAEs from grades 1 to 4 was 43.5%, 34.8%, 13.0%, and 8.7%, respectively. Grade 3/4 TRAEs included neutropenia, fatigue, hyperglycemia, nausea and vomiting, decreased appetite, rash, and diarrhea. No treatment-related surgical delay was observed. The radiographic response rates were 5.0% (CR), 40.0% (PR), and 55.0% (SD). The ORR reached 45.0%. Eighteen patients underwent successful surgical resection. The R0 resection rate was 100%. The pathological response rates were 16.7% (pCR), 27.8% (MPR, two of five near-pCR), 16.7% (PPR), and 38.8% (NPR). CD4, CD8, CD20, and CD38 expression in the tumors significantly increased after neoadjuvant chemotherapy. The increase in CD20 levels after neoadjuvant treatment in patients with pCR/MPR was significantly higher than in patients with PPR/NPR. CONCLUSION: Triweekly neoadjuvant toripalimab-GP is feasible and achieves promising pCR and MPR rates in patients with resectable locally advanced HNSCC. TRIAL REGISTRATION: Chinese clinical trial registry, ChiCTR2100043743, Registered 27 Febrary 2021- Retrospectively registered, http://www.chictr.org.cn/showproj.aspx?proj=120570.

Tumor Microbiome in Nasopharyngeal Carcinoma and Its Association With Prognosis.

Introduction: Previous studies have reported a close relationship between cancer and microbes, particularly gut and tumor microbiota; however, the presence of tumor microbiome in nasopharyngeal carcinoma (NPC) and its role in the prognosis of NPC remain unclear. Methods: We collected 64 samples including tissues from 50 patients with NPC (NPC group) and 14 patients with chronic nasopharyngitis (control group) receiver operating characteristics and we applied 16S ribosome RNA gene sequencing of all samples to assess microbiome profiles and immunohistochemistry to detect tumor microbiome in NPC. Results: Patients in the control group harbored higher species diversity than those in the NPC group; however, the beta diversity was more distinct in the NPC group. In total, three genera with statistically significant differences between the two groups were identified. The area under the receiver operating characteristics (ROC) curve (AUC) was calculated using the relative abundance of these three significant genera, and a value of 0.842 was achieved. Furthermore, Turicibacter was confirmed as a potentially independent prognostic factor for NPC patients, and the progression-free survival (PFS) was markedly prolonged in patients with a low relative abundance of Turicibacter compared to patients with a high relative abundance of this genus (cutoff: 0.0046, hazard ratio: 5.10, 95% confidence interval: 2.04-12.77, p = 0.004). Conclusions: The present study provided strong evidence of a correlation between tumor microbiome and NPC; the tumor microbiome may be considered a biomarker for early NPC diagnosis. Turicibacter potentially served as a independently prognostic indicator for NPC patients.

Targeting Myc-driven stress vulnerability in mutant KRAS colorectal cancer.

Mutant KRAS is a key driver in colorectal cancer (CRC) and promotes Myc translation and Myc-dependent stress adaptation and proliferation. Here, we report that the combination of two FDA-approved drugs Bortezomib and Everolimus (RAD001) (BR) is highly efficacious against mutant KRAS CRC cells. Mechanistically, the combination, not single agent, rapidly depletes Myc protein, not mRNA, and leads to GCN2- and p-eIF2α-dependent cell death through the activation of extrinsic and intrinsic apoptotic pathways. Cell death is selectively induced in mutant KRAS CRC cells with elevated basal Myc and p-eIF2α and is characterized by CHOP induction and transcriptional signatures in proteotoxicity, oxidative stress, metabolic inhibition, and immune activation. BR-induced p-GCN2/p-eIF2α elevation and cell death are strongly attenuated by MYC knockdown and enhanced by MYC overexpression. The BR combination is efficacious against mutant KRAS patient derived organoids (PDO) and xenografts (PDX) by inducing p-eIF2α/CHOP and cell death. Interestingly, an elevated four-gene (DDIT3, GADD45B, CRYBA4 and HSPA1L) stress signature is linked to shortened overall survival in CRC patients. These data support that Myc-dependent stress adaptation drives the progression of mutant KRAS CRC and serves as a therapeutic vulnerability, which can be targeted using dual translational inhibitors.

Clinical Characteristics and Prognosis of Small Cell Carcinoma in the Nasopharynx: A Population-Based Study.

BACKGROUND: Nasopharyngeal small cell carcinoma (SmCC) is a rare histological type of nasopharyngeal cancer, and its prognosis remains poor. This study aimed to determine the clinical characteristics and survival prognostic factors of nasopharyngeal SmCC. METHODS: Detailed clinicopathologic and therapeutic characteristics of a patient diagnosed with nasopharyngeal SmCC were determined. Nasopharyngeal SmCC cases reported previously were reviewed and summarized. Furthermore, a retrospective analysis was performed on data from the Surveillance, Epidemiology, and End Results (SEER) Program database. Kaplan-Meier analysis was conducted to compare survival within groups. Univariate and multivariate analyses were performed to investigate prognostic factors. RESULTS: A nasopharyngeal SmCC patient treated with chemoradiotherapy who achieved 46 months long-term survival was reported. In reviewing 16 reported cases with epidemiologic and therapeutic details, we found most of nasopharyngeal SmCC patients were diagnosed with advanced grades and received chemoradiotherapy. In total, 13,993 cases of nasopharyngeal cancer were extracted from the SEER database, from which 57 nasopharyngeal SmCC cases were eventually screened out. The mean age of the patients was 55.70 years, and 64.9% of these cases were either grade III or IV; the median overall survival (OS) was 18 months. Statistically significant differences were observed in the OS values of groups categorized by age (P = .025) or radiotherapy (P = .037). Age (<70 years) and radiotherapy were identified as independent survival and prognostic factors. CONCLUSION: Patients with nasopharyngeal SmCC are usually diagnosed with advanced grades and have poor prognoses; nevertheless, they can benefit from radiotherapy with prolonged overall survival.

Combination of Tumor Mutational Burden and Specific Gene Mutations Stratifies Outcome to Immunotherapy Across Recurrent and Metastatic Head and Neck Squamous Cell Carcinoma.

Purpose: To investigate the prognostic significance of tumor mutational burden (TMB) combined with specific prognosis-related gene mutations in immunotherapy for recurrent and metastatic head and neck squamous cell carcinoma (r/m HNSCC). Methods: One hundred thirty-two r/m HNSCC patients from the Morris and Allen cohorts had undergone immunotherapy. We constructed the immunotherapy-related gene prognostic index TP-PR combining TMB and PIK3CA, TP53, or ROS1 mutation. And we analyzed the differences in overall survival (OS) and immune cell infiltration between samples in different groups. The association of each signature's single-sample gene set enrichment analysis scores with TP-PR was tested using Spearman's correlation test. Results: The median OS of the patients with high TMB (TMB ≥10 mut/Mb) who received immunotherapy for r/m HNSCC was 2.5 times as long as that of the patients with low TMB (25 vs. 10 months). More importantly, the high TP-PR (TP-PR >0) group had better median OS (25 vs. 8 months) than the low TP-PR (TP-PR ≤0) group. CD8+ T cells and activated memory CD4+ T cells in the tissues of the patients with high TP-PR were higher than those in the patients with low TP-PR. Results showed that TP-PR stratification had a higher area under the curve (AUC) value (0.77, 95% CI 0.86-0.68) compared with TMB stratification (0.56, 95% CI 0.68-0.44). The differential gene expression in the high and low TP-PR groups mainly influenced metabolism-related signaling pathways. Conclusion: TP-PR was an effective predictor of immunotherapy outcome for r/m HNSCC, which might be better than TMB alone. Patients with high TP-PR had a better survival benefit than had the patients with low TP-PR.

Pathological and genomic phenotype of second neuroendocrine carcinoma during long-term follow-up after radical radiotherapy for nasopharyngeal carcinoma.

BACKGROUND: Second head and neck neuroendocrine carcinoma (NEC) after radical radiotherapy for nasopharyngeal carcinoma (NPC) treatment is rarely reported. The prognosis of second cancer is poor, and our research focuses on finding a breakthrough in the treatment. In this study, we aimed to investigate clinicopathological characteristics and to identify the genomic landscape of second head and neck NECs. METHODS: We collected five second head and neck NEC cases in the recent three years from our patient database. Clinicopathological data and images were obtained. Genomic analysis was performed using high-throughput second generation sequencing. KEGG pathway enrichment analyses between high-frequency mutations were performed using the STRING database. RESULTS: All patients had been diagnosed with second NEC, according to the pathological observations. The interval between diagnosis of NPC and NEC ranged from 10 to 18 years. Two patients had brain or liver metastasis at three and nine months, respectively, after the diagnosis of NEC. Three patients died of the disease with the overall survival time ranging from three to nine months. Commonly altered genes (50%) in second head and neck NECs included TP53, RB1, NOTCH2, PTEN, POLG, KMT2C, U2AF1, EPPK1, ELAC2, DAXX, COL22A1, and ABL1. Those genetic lesions might affect p53 signaling, MAPK signaling, PI3K-Akt signaling, sphingolipid signaling, and neurotrophin signaling pathways. CONCLUSIONS: Second head and neck NECs had poor prognosis. We revealed, for the first time, the mutational landscape, high-frequency somatic mutations, and potential signaling pathways of second head and neck NECs. Its optimal treatment model needs to be further studied in future clinical trials.

Prognostic value of magnetic resonance imaging features in low-grade gliomas.

Introduction: The treatment strategy for low-grade gliomas (LGGs) is still controversial, and there are no standardized criteria to predict the prognosis of patients with LGGs. Magnetic resonance imaging (MRI) is a routine test for preoperative diagnosis for LGG and can reflect the destructive features for the tumor. In the present study, we aimed to explore the relationship between the MRI features and prognosis in patients with LGG.Methods: Clinical data of 80 patients with pathologically proved LGGs between January 2010 and December 2016 were analyzed retrospectively. MRI features were classified as contrast enhancement pattern (focal enhancement, diffuse enhancement and ring-like enhancement), necrosis and cysts based on the preoperative MR images. Kaplan-Meier method and multivariate analysis were performed on the data by SPSS software to explore the prognostic significance of MRI features.Results: Patients with cystic LGG had a significantly longer 5-year progression-free survival (PFS) than that with no cyst (90.9 ± 8.7 vs 65.7 ± 9.1%, P=0.045). Multivariate analysis further verified cyst as an independent prognosis factor for PFS (P=0.027, hazard ratio [HR] = 0.084). Additionally, patients with ring-like enhancement exhibited significantly longer 5-year PFS time in the Kaplan-Meier survival curves (100 vs 67.2 ± 7.7%, P=0.049). There was no significant difference in PFS and overall survival (OS) between patients with or without necrosis.Conclusion: Our study suggests that cyst formation and ring-like enhancement on preoperative MR images can be useful to predict a favorable prognosis in patients with LGGs.

Antiferroptotic activity of non-oxidative dopamine.

Dopamine is a neurotransmitter that has many functions in the nervous and immune systems. Ferroptosis is a non-apoptotic form of regulated cell death that is involved in cancer and neurodegenerative diseases. However, the role of dopamine in ferroptosis remains unidentified. Here, we show that the non-oxidative form of dopamine is a strong inhibitor of ferroptotic cell death. Dopamine dose-dependently blocked ferroptosis in cancer (PANC1 and HEY) and non-cancer (MEF and HEK293) cells following treatment with erastin, a small molecule ferroptosis inducer. Notably, dopamine reduced erastin-induced ferrous iron accumulation, glutathione depletion, and malondialdehyde production. Mechanically, dopamine increased the protein stability of glutathione peroxidase 4, a phospholipid hydroperoxidase that protects cells against membrane lipid peroxidation. Moreover, dopamine suppressed dopamine receptor D4 protein degradation and promoted dopamine receptor D5 gene expression. Thus, our findings uncover a novel function of dopamine in cell death and provide new insight into the regulation of iron metabolism and lipid peroxidation by neurotransmitters.