Insight of a Metabolic Prognostic Model to Identify Tumor Environment and Drug Vulnerability for Lung Adenocarcinoma.

Metabolic reprogramming is a novel method for the treatment of malignant tumors. The exploration of metabolism procedures between radiosensitive and radioresistant tumors may provide novel perspectives for lung adenocarcinoma (LUAD) patients after radiation therapy. In our study, metabolic reprogramming and immune response changes were found between radioresistant cell line (A549RR) and its parent cells (A549) using gene ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. Nucleotide/amino acid, lipid, and glucose metabolic process, including Alanine, aspartate and glutamate metabolism, Tryptophan/Tyrosine metabolism, Butanoate metabolism, Purine/Pyrimidine metabolism, were screened out. Then molecular signatures database and The Cancer Genome Atlas Program (TCGA) lung adenocarcinoma datasets were used to identify metabolism-related genes (MRGs) between radiosensitive and radioresistant lung adenocarcinoma (LUAD) cells. A metabolism-based prognostic model, receiver operating characteristic (ROC) curve and nomogram were constructed using Metabolism Score calculated by 14 metabolism-related genes (MRGs). Three independent public datasets, (GSE72094, GSE3141, GSE8894) and one immunotherapy cohort (IMvigor210) were used as external validation cohorts. Expression of 14 hub genes in cells, normal and LUAD specimens were explored by Human Protein Atlas, TIMER2.0 and RT-qPCR. Patients with low-Metabolism Scores were correlated with longer survival times, higher response rates to immune checkpoint inhibitors (ICIs), different immune cell infiltrations and drug vulnerability. Our study demonstrated a comprehensive landscape between radiosensitive and radioresistant LUAD, and provide novel targets for NSCLC, especially those patients received radiation therapy. Moreover, this metabolism-based prognostic model may help to investigate connections between radiosensitivity, immune response, metabolic reprogramming, and patients' prognosis.

Final Overall Survival Analysis of Gemcitabine and Cisplatin Induction Chemotherapy in Nasopharyngeal Carcinoma: A Multicenter, Randomized Phase III Trial.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically on the based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.We previously reported significantly improved failure-free survival using gemcitabine plus cisplatin induction chemotherapy in locoregionally advanced nasopharyngeal carcinoma. Here, we present the final overall survival (OS) analysis. In this multicenter, randomized trial, patients were assigned to be treated with concurrent chemoradiotherapy alone (standard therapy, n = 238) or gemcitabine and cisplatin induction chemotherapy before concurrent chemoradiotherapy (n = 242). With a median follow-up of 69.8 months, the induction chemotherapy group had a significantly higher 5-year OS (87.9% v 78.8%, hazard ratio, 0.51 [95% CI 0.34 to 0.78]; P = .001) and a comparable risk of late toxicities (≥ grade 3, 11.3% v 11.4%). Notably, the depth of the tumor response to induction chemotherapy correlated significantly and positively with survival (complete response v partial response v stable/progressive disease, 5-year OS, 100% v 88.4% v 61.5%, P = .005). Besides, patients with a low pretreatment cell-free Epstein-Barr virus DNA load (< 4,000 copies/mL) might not benefit from induction chemotherapy (5-year OS, 90.6% v 91.4%, P = .77). In conclusion, induction chemotherapy before concurrent chemoradiotherapy improved OS significantly in patients with locally advanced nasopharyngeal carcinoma, without increasing the risk of late toxicities. Tumor response to induction chemotherapy and pretreatment cell-free Epstein-Barr virus DNA might be useful to guide individualized treatment.

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.

Inhibition of leucine-rich repeats and calponin homology domain containing 1 accelerates microglia-mediated neuroinflammation in a rat traumatic spinal cord injury model.

BACKGROUND: Spinal cord injury (SCI) triggers the primary mechanical injury and secondary inflammation-mediated injury. Neuroinflammation-mediated insult causes secondary and extensive neurological damage after SCI. Microglia play a pivotal role in the initiation and progression of post-SCI neuroinflammation. METHODS: To elucidate the significance of LRCH1 to microglial functions, we applied lentivirus-induced LRCH1 knockdown in primary microglia culture and tested the role of LRCH1 in microglia-mediated inflammatory reaction both in vitro and in a rat SCI model. RESULTS: We found that LRCH1 was downregulated in microglia after traumatic SCI. LRCH1 knockdown increased the production of pro-inflammatory cytokines such as IL-1ß, TNF-α, and IL-6 after in vitro priming with lipopolysaccharide and adenosine triphosphate. Furthermore, LRCH1 knockdown promoted the priming-induced microglial polarization towards the pro-inflammatory inducible nitric oxide synthase (iNOS)-expressing microglia. LRCH1 knockdown also enhanced microglia-mediated N27 neuron death after priming. Further analysis revealed that LRCH1 knockdown increased priming-induced activation of p38 mitogen-activated protein kinase (MAPK) and Erk1/2 signaling, which are crucial to the inflammatory response of microglia. When LRCH1-knockdown microglia were adoptively injected into rat spinal cords, they enhanced post-SCI production of pro-inflammatory cytokines, increased SCI-induced recruitment of leukocytes, aggravated SCI-induced tissue damage and neuronal death, and worsened the locomotor function. CONCLUSION: Our study reveals for the first time that LRCH1 serves as a negative regulator of microglia-mediated neuroinflammation after SCI and provides clues for developing novel therapeutic approaches against SCI.

Postoperative intensity-modulated radiation therapy reduces local recurrence and improves overall survival in III-N2 non-small-cell lung cancer: A single-center, retrospective study.

PURPOSE: To determine the postoperative effects of radiotherapy (PORT) on the local recurrence-free survival (LRFS) and overall survival (OS) of stage III-N2 non-small-cell lung cancer (NSCLC). MATERIALS AND METHODS: 183 patients with resected stage III-pN2 NSCLC from Hunan Cancer Hospital between 2013 and 2016 were divided into two groups for postoperative chemotherapy (POCT) (n = 105) or combination chemotherapy and radiotherapy (POCRT) (n = 78). The LRFS and OS were compared and the factors affecting local recurrence were illustrated in these two groups. The sites of failure based on the lobe of the primary tumor in two groups were described. RESULTS: PORT leads to a strikingly lower risk for local recurrence and brought superior OS benefit. For different pN2 Subclassification, Patients with multiple-station pN2 ± pN1 disease had the worst LRFS (11 months) and single-station pN2 + multiple station pN1 disease had a relatively short LRFS (24 months) in group POCT. Short LRFS is correlated with multiple-station pN2, older age (Y > 55), patients with a high positive LN ratio > 1/3 and a poor tumor histological differentiation degree. In group POCT, the most frequent failure site occurs at the ipsilateral hilum (21.0%), the bronchial stump (20.0%), followed by LNs4R (19.0%), LNs4L (18.1%), LNs7 (15.2%), most of left-sided tumors more frequently involved the contralateral mediastinum, whereas the ipsilateral recurrences dominated for right-sided tumors, especially for LNs4R. In group POCRT, the highest failure site was the bronchial stump (11.5%), followed by LNs4L (8.97%), LNs1 (7.69%), the ipsilateral hilum (6.41%) and LNs4R (6.41%). CONCLUSION: PORT remarkably reduced local recurrence and improved OS in stage III-pN2 NSCLC, especially in the multiple-station pN2 group.

The prognostic value of major facilitator superfamily domain-containing protein 2A in patients with hepatocellular carcinoma.

INTRODUCTION: We aimed to characterize the expression of major facilitator superfamily domain-containing protein 2A (MFSD2A) in hepatocellular carcinoma (HCC) patients and analyze its prognostic value. RESULTS: Immunohistochemistry revealed that low expression of MFSD2A was present in 37 of 79 cases (46.84%), which was significantly correlated with poor histological differentiation (P = 0.012). The plasma MFSD2A level in HCC patients was significantly lower than in healthy controls (P = 0.0079) and controls with chronic hepatitis B virus (HBV) infection (P = 0.0430). Moreover, patients with lower MFSD2A expression had shorter survival than higher expression (P = 0.021). Multivariate analysis revealed that MFSD2A was an independent prognostic predictor for HCC patients (P = 0.027). CONCLUSION: The current study indicate MFSD2A may be an optimal diagnostic and prognostic biomarker for HCC. METHODS: First, we examined MFSD2A expression in 24 paired HCC and nontumorous tissues by real-time quantitative PCR (RT-qPCR). Second, the protein levels of MFSD2A in 11 paired HCC and nontumorous tissues were investigated by western blotting (WB). Moreover, MFSD2A protein expression was evaluated by immunohistochemistry in 79 HCC patients. In addition, we detected the plasma level of MFSD2A in HCC patients and healthy individuals and investigated the relationship between MFSD2A expression and clinicopathological parameters or prognosis of HCC patients.

Gemcitabine and Cisplatin Induction Chemotherapy in Nasopharyngeal Carcinoma.

BACKGROUND: Platinum-based concurrent chemoradiotherapy is the standard of care for patients with locoregionally advanced nasopharyngeal carcinoma. Additional gemcitabine and cisplatin induction chemotherapy has shown promising efficacy in phase 2 trials. METHODS: In a parallel-group, multicenter, randomized, controlled, phase 3 trial, we compared gemcitabine and cisplatin as induction chemotherapy plus concurrent chemoradiotherapy with concurrent chemoradiotherapy alone. Patients with locoregionally advanced nasopharyngeal carcinoma were randomly assigned in a 1:1 ratio to receive gemcitabine (at a dose of 1 g per square meter of body-surface area on days 1 and 8) plus cisplatin (80 mg per square meter on day 1), administered every 3 weeks for three cycles, plus chemoradiotherapy (concurrent cisplatin at a dose of 100 mg per square meter every 3 weeks for three cycles plus intensity-modulated radiotherapy) or chemoradiotherapy alone. The primary end point was recurrence-free survival (i.e., freedom from disease recurrence [distant metastasis or locoregional recurrence] or death from any cause) in the intention-to-treat population. Secondary end points included overall survival, treatment adherence, and safety. RESULTS: A total of 480 patients were included in the trial (242 patients in the induction chemotherapy group and 238 in the standard-therapy group). At a median follow-up of 42.7 months, the 3-year recurrence-free survival was 85.3% in the induction chemotherapy group and 76.5% in the standard-therapy group (stratified hazard ratio for recurrence or death, 0.51; 95% confidence interval [CI], 0.34 to 0.77; P = 0.001). Overall survival at 3 years was 94.6% and 90.3%, respectively (stratified hazard ratio for death, 0.43; 95% CI, 0.24 to 0.77). A total of 96.7% of the patients completed three cycles of induction chemotherapy. The incidence of acute adverse events of grade 3 or 4 was 75.7% in the induction chemotherapy group and 55.7% in the standard-therapy group, with a higher incidence of neutropenia, thrombocytopenia, anemia, nausea, and vomiting in the induction chemotherapy group. The incidence of grade 3 or 4 late toxic effects was 9.2% in the induction chemotherapy group and 11.4% in the standard-therapy group. CONCLUSIONS: Induction chemotherapy added to chemoradiotherapy significantly improved recurrence-free survival and overall survival, as compared with chemoradiotherapy alone, among patients with locoregionally advanced nasopharyngeal carcinoma. (Funded by the Innovation Team Development Plan of the Ministry of Education and others; ClinicalTrials.gov number, NCT01872962.).

Do all patients with advanced N-stage nasopharyngeal carcinoma benefit from the addition of induction chemotherapy to concurrent chemoradiotherapy?

BACKGROUND: The aim of this study was to evaluate the benefits from the addition of induction chemotherapy (IC) to concurrent chemoradiotherapy (CCRT) in N2-3 nasopharyngeal carcinoma (NPC). METHODS: A total of 3089 patients with nonmetastatic NPC, staged as N2-3 were retrospectively reviewed. IC contained cisplatin (80 mg/m2) with 5-fluorouracil (800 mg/m2/day over 120 h), or cisplatin (80 mg/m2) with docetaxel (80 mg/m2), or cisplatin (60 mg/m2) with 5-fluorouracil (600 mg/m2 over 120 h), and docetaxel (60 mg/m2) administered at 3-week intervals for two or three cycles. Concurrent chemotherapy consisted of cisplatin (80 or 100 mg/m2) given in weeks 1, 4, and 7 of radiotherapy, or cisplatin (40 mg/m2) given weekly during radiotherapy. Overall, three well-matched risk groups (low, intermediate, and high risk) were created using propensity score matching, and IC plus CCRT was compared with CCRT in each risk group. Our primary endpoint was distant metastasis-free survival (DMFS). RESULTS: A nomogram for DMFS was established with good prognostic accuracy (C-index, 0.69; 95% confidence interval, 0.64-0.73). The survival curves for low, intermediate, and high-risk groups stratified by the nomogram were significantly different between all three risk groups, with corresponding 5-year DMFS rates of 90.7%, 79.4%, and 64.9%, respectively (p < 0.001). IC plus CCRT was significantly associated with superior DMFS as compared with CCRT alone (69.5% versus 56.7%, p = 0.004) in the high-risk group. However, no significant difference between IC plus CCRT and CCRT was observed (p = 0.831 and 0.608, respectively) in the intermediate and low-risk groups. CONCLUSIONS: Our findings can help accurately guide the treatment of individual patients with advanced N-stage NPC.

Dose Escalation of Lobaplatin Concurrent with IMRT for the Treatment of Stage III-IVb NPC: A Phase I Clinical Trial.

The maximum tolerated dose (MTD) of lobaplatin as a single agent chemotherapy concurrent with intensity-modulated radiotherapy (IMRT) in Asian population with nasopharyngeal carcinoma (NPC) remains unclear. From June 2016 to December 2017, 17 patients diagnosed with stage III-IVb NPC from an Asian population were prospectively enrolled. Patients were administered lobaplatin with 25-50 mg/m2 escalation of dosage on day 1. Every 21 days (days 1, 22, and 43) during radiotherapy, cycles were repeated. We administered radiotherapy as 2.12-2.27 Gy per fraction with five daily fractions each week for 6 to 7 weeks. The evaluation of lobaplatin-related toxic effects was based on the Common Terminology Criteria for Adverse Events version 4.0. During the weekly treatment period, complete blood counts and biochemistry were performed. Dose-limiting toxicities (DLTs) were determined by the following events during any cycle in which lobaplatin was administered. Each dose group consisted of at least three cases. We proceeded to the subsequent dose group in the absence of DLT with a dose increment of 5 mg/m2 until DLT occurred. Periods from 1 week prior to the chemotherapy initiation to 3 weeks after the last chemotherapy were defined as DLT observation periods. MTD was determined by the dose that was immediately below the dose that produced DLT. After analysis, DLT occurred in three patients, including a group with two of three patients in 45 mg/m2 lobaplatin and another group with one of five patients in 40 mg/m2 lobaplatin. No grade 3-4 toxicity was observed in patients treated with lobaplatin <40 mg/m2. The tumor response rate at 12 weeks after treatment was 100%. In summary, lobaplatin concurrent with IMRT was active in stage III-IVb NPC, and the MTD for the lobaplatin as single-agent chemotherapy was 40 mg/m2 when combined with IMRT in an Asian population. This trial is registered with ClinicalTrials.gov, number NCT03188497.

[Prognosis and Survival Analysis of Patients with Essential Thrombocythemia].

OBJECTIVE: To investigate the survival status and prognosis of patients with essential thrombocythemia(ET) and analyze the prognostic factors for the patients' survival, so as to provide a evidence for clinical treatment and prognosis evaluation. METHODS: A retrospective analysis of 118 patients with ET was conducted in the Fifth Affiliated Hospital of Sun Yat-Sen University and Zhongshan Municipale People's Hospital from December 2002 to December 2013. The clinical characteristics were summarized, such as the survival curve and multi-factor analysis, therefore looking for the disease characteristics and risk factors affecting the survival and prognosis. RESULTS: Among 118 ET patients enrolled in this study, the survival rate of ET patients for 1, 3, 5 and 10 years were 95.5%,92.6%,89% and 81.6%, respectively. Kaplan-Meier survival curve showed that the age ≥60 years old at diagnosis, cardiovascular risk factors, anamnesis of thrombosis or hemorrhage, anemia(hemoglobin<120 g/L), thrombocythemia (≥1 000×109/L), risk stratification and hydroxyurea or HHT(hemoharringtonine) use in high-risk group were factors affecting the suvival rate, 7 out of those factors influencing survival rate were statistically significant (P<0.05). COX regression analysis showed that independent risk factors affecting survival have not yet been found. CONCLUSION: ET patients display a high survival rate and long survival time, and their conversion risk into the marrow fibrosis or leukemia has been found to be low. The age≥60 years old at diagnosis, cardiovascular risk factors, anamnesis of thrombosis or hemorrhage, anemia and therombocythemia are the risk factors affecting prognosis. The use of hydroxyurea or HHT in high-risk group can improve the prognosis.

Identifying FGA peptides as nasopharyngeal carcinoma-associated biomarkers by magnetic beads.

Early diagnosis and treatment is known to improve prognosis for nasopharyngeal carcinoma (NPC). The study determined the specific peptide profiles by comparing the serum differences between NPC patients and healthy controls, and provided the basis for the diagnostic model and identification of specific biomarkers of NPC. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) can be used to detect the molecular mass of peptides. Mass spectra of peptides were generated after extracting and purification of 40 NPC samples in the training set, 21 in the single center validation set and 99 in the multicenter validation set using weak cationic-exchanger magnetic beads. The spectra were analyzed statistically using FlexAnalysis™ and ClinProt™ bioinformatics software. The four most significant peaks were selected out to train a genetic algorithm model to diagnose NPC. The diagnostic sensitivity and specificity were 100% and 100% in the training set, 90.5% and 88.9% in the single center validation set, 91.9% and 83.3% in the multicenter validation set, and the false positive rate (FPR) and false negative rate (FNR) were obviously lower in the NPC group (FPR, 16.7%; FNR, 8.1%) than in the other cancer group (FPR, 39%; FNR, 61%), respectively. So, the diagnostic model including four peptides can be suitable for NPC but not for other cancers. FGA peptide fragments identified may serve as tumor-associated biomarkers for NPC.