The Prognostic Role of Plasma Epstein-Barr Virus DNA Levels in the Middle of Intensity Modulated Radiation Therapy to Guide Cisplatin Dose Recommendation in Concurrent Chemoradiation Therapy in Patients With Locally Advanced Nasopharyngeal Carcinoma: A Large Cohort Study.

Purpose: Our purpose was to investigate the prognostic role of plasma Epstein-Barr virus (EBV) DNA levels in the middle of intensity modulated radiation therapy (IMRT). Methods and Materials: In total, 1881 patients with stage III-IVa tumors were included. The overall survival (OS) and progression-free survival (PFS) were calculated using the Kaplan-Meier method, and the differences were compared using the log-rank test. Receiver operating characteristic curve analysis was performed to analyze the diagnostic value of EBV DNA levels for tumor progression or death. Multivariate analyses using the Cox model were used to evaluate potential prognostic factors. Results: The positive predict value and negative predict value of plasma EBV DNA > 0 copies/mL in the middle of IMRT in predicting nasopharyngeal carcinoma progression was 37.4% and 85.5%, respectively. In patients with plasma EBV DNA level = 0 copies/mL, no significant differences in OS were observed between patients treated with 200 mg/m² cisplatin and those treated with >200 mg/m² cisplatin (5-year OS, 94.9% vs 94.4%; PFS, 81.5% vs 87.6%). However, those treated with >200 mg/m² cisplatin had higher PFS. In patients with plasma EBV DNA level > 0 copies/mL, patients treated with >200 mg/m² cisplatin displayed a favorable 5-year OS (84.6% vs 73.9%) and PFS (72.3% vs 54.8%) compared with those treated with 200 mg/m² cisplatin. Additionally, higher incidences of grade 3 and 4 adverse events were recorded in patients treated with >200 mg/m² cisplatin than in those treated with 200 mg/m² cisplatin. Conclusions: Plasma EBV DNA > 0 copies/mL in the middle of IMRT suggests that higher doses of chemotherapy should be used. For concurrent chemoradiation therapy, >200 mg/m² cisplatin is recommended for patients with plasma EBV DNA level > 0 copies/mL in the middle of IMRT but not for patients with plasma EBV DNA level = 0 copies/mL considering the similar OS rates.

Determining the suitability of definitive radiation therapy in patients with metastatic nasopharyngeal carcinoma based on PET/CT: a large cohort study.

OBJECTIVES: To determine patients with de novo metastatic nasopharyngeal carcinoma (mNPC) who would benefit from receiving definitive radiation therapy (DRT) along with their pre-existing palliative chemotherapy (PCT) by evaluating their post-PCT Deauville scores and EBV DNA. METHODS: A total of 570 mNPC patients, treated with PCT or PCT+DRT, were studied. EBV DNA levels, along with post-PCT Deauville scores, were used to stratify risk based on the recursive partitioning analysis (RPA). RESULTS: Significant differences were observed in the survival rates of patients with Deauville scores of 1-3 and 4-5 (2-year progression-free survival (PFS): 23.4% versus 8.5%, p < 0.001; 2-year overall survival (OS): 56.8% versus 18.8%, p < 0.001). RPA yielded three distinct groups in the increasing order of risk (Deauville scores of all RPA I-II were within the range of 1-3): (1) RPA I: EBV DNA levels at a pretreatment concentration ≤ 4000 copies/mL and undetectable post-PCT; (2) RPA II: EBV DNA levels either at a pretreatment concentration > 4000 copies/mL or at a pretreatment concentration ≤ 4000 copies/mL and detectable post-PCT; (3) RPA III: Deauville scores 4-5. While patients in RPA I and RPA II had significantly PFS rates when treated with PCT+DRT than when treated with PCT alone (RPA I: 72.7% versus 13.4%, RPA II: 37.8% versus 6.3%), those in RPA III did not experience such PFS benefits (6.5% versus 9.7%). CONCLUSION: PCT+DRT might improve the survival rates in mNPC patients in the low- and mid-risk strata but not those of patients in the high-risk strata. KEY POINTS: We use the Deauville scores and the concentrations of the Epstein-Barr virus (EBV) DNA to determine those patients with de novo metastatic NPC who would benefit from radiation therapy.

Cost-Effectiveness analysis of combining plasma Epstein-Barr virus DNA testing and different surveillance imaging modalities for nasopharyngeal carcinoma patients in first remission.

BACKGROUND: To evaluate the cost-effectiveness of stage-based post-radiotherapy (PRT) nasopharyngeal carcinoma (NPC) surveillance strategies. METHODS: Four post-radiotherapy surveillance strategies were established by a Markov model based on data from 1664 patients: 1) clinical follow-up (CFP) with biannual Epstein-Barr virus (EBV) DNA (EBV DNA strategy); 2) CFP with biannual EBV DNA, annual head and neck magnetic resonance imaging (HNMRI), chest X-ray, abdominal ultrasonography, bone scan (only for the first two years) for five years (MCWU strategy); 3) CFP with biannual EBV DNA, annual HNMRI, chest, abdomen, pelvic computerized tomography (CT) and bone scan for the first two years, followed by annual MCWU strategy (without bone scans) for the last three years (CT strategy); 4) CFP with biannual EBV DNA, annual whole-body positron emission/computerized tomography (PET/CT) for the first two years and biannual EBV DNA for the last three years (PET/CT strategy). RESULTS: Compared with the EBV DNA strategy, the MCWU, CT, and PET/CT strategies gained 0.017, 0.047, and 0.082 quality-adjusted life years (QALY) for stage I-II patients. For stage III and IVa patients, the PET/CT strategy had a favorable incremental effectiveness (ICERs) of 0.277 and 0.385 QALY, respectively. The ICERs for the MCWU, CT, and PET/CT strategies were $74,037, $34,882, and $34,696 for stage III and $62,364, $27,981, and $28,340 for stage IVa, respectively. CONCLUSION: EBV DNA strategy was cost-effective for the long-term surveillance of stage I-II NPC patients with CR. PET/CT strategy was recommeded for patients having IVa NPC. As for stage III NPC, PET/CT strategy was still acceptable with the development of economy in China.

Management of first-line palliative chemotherapy for post-treatment metastasis after gemcitabine plus cisplatin induction chemotherapy: Gemcitabine plus cisplatin and non-gemcitabine plus cisplatin chemotherapy.

BACKGROUND: To evaluate whether patients with post-treatment metastasis are suitable for GP first-line palliative chemotherapy (PCT) after undergoing GP IC. METHODS: Seven hundred and forty-six patients with post-treatment metastasis after undergoing GP IC were eligible. Survival outcomes were compared. RESULTS: Significant differences in survival rates were observed between patients treated with GP and non-GP chemotherapy (2-year progression-free survival [PFS]: 0.7% vs. 9.7%). We investigated survival outcomes of patients treated with GP PCT within 2 years after undergoing GP IC, treated with GP PCT 2 years after undergoing GP IC, and those of non-GP PCT patients (2-year PFS: 0.0%, 2.3%, 9.7%). However, there was no difference in the 2-year PFS between the patients that received GP PCT 2 years after undergoing GP IC and the non-GP PCT treated patients. CONCLUSIONS: GP is not recommended for patients that have received GP IC within 2 years. Two years after undergoing GP IC, GP can be considered.

Pyruvate cycle increases aminoglycoside efficacy and provides respiratory energy in bacteria.

The emergence and ongoing spread of multidrug-resistant bacteria puts humans and other species at risk for potentially lethal infections. Thus, novel antibiotics or alternative approaches are needed to target drug-resistant bacteria, and metabolic modulation has been documented to improve antibiotic efficacy, but the relevant metabolic mechanisms require more studies. Here, we show that glutamate potentiates aminoglycoside antibiotics, resulting in improved elimination of antibiotic-resistant pathogens. When exploring the metabolic flux of glutamate, it was found that the enzymes that link the phosphoenolpyruvate (PEP)-pyruvate-AcCoA pathway to the TCA cycle were key players in this increased efficacy. Together, the PEP-pyruvate-AcCoA pathway and TCA cycle can be considered the pyruvate cycle (P cycle). Our results show that inhibition or gene depletion of the enzymes in the P cycle shut down the TCA cycle even in the presence of excess carbon sources, and that the P cycle operates routinely as a general mechanism for energy production and regulation in Escherichia coli and Edwardsiella tarda These findings address metabolic mechanisms of metabolite-induced potentiation and fundamental questions about bacterial biochemistry and energy metabolism.

Metabolic Mechanism for l-Leucine-Induced Metabolome To Eliminate Streptococcus iniae.

Crucial metabolites that modulate hosts' metabolome to eliminate bacterial pathogens have been documented, but the metabolic mechanisms are largely unknown. The present study explores the metabolic mechanism for l-leucine-induced metabolome to eliminate Streptococcus iniae in tilapia. GC-MS-based metabolomics was used to investigate the tilapia liver metabolic profile in the presence of exogenous l-leucine. Thirty-seven metabolites of differential abundance were determined, and 11 metabolic pathways were enriched. Pattern recognition analysis identified serine and proline as crucial metabolites, which are the two metabolites identified in survived tilapias during S. iniae infection, suggesting that the two metabolites play crucial roles in l-leucine-induced elimination of the pathogen by the host. Exogenous l-serine reduces the mortality of tilapias infected by S. iniae, providing a robust proof supporting the conclusion. Furthermore, exogenous l-serine elevates expression of genes IL-1ß and IL-8 in tilapia spleen, but not TNFα, CXCR4 and Mx, suggesting that the metabolite promotes a phagocytosis role of macrophages, which is consistent with the finding that l-leucine promotes macrophages to kill both Gram-positive and Gram-negative bacterial pathogens. Therefore, the ability of phagocytosis enhanced by exogenous l-leucine is partly attributed to elevation of l-serine. These results demonstrate a metabolic mechanism by which exogenous l-leucine modulates tilapias' metabolome to enhance innate immunity and eliminate pathogens.

Glucose enhances tilapia against Edwardsiella tarda infection through metabolome reprogramming.

We have recently reported that the survival of tilapia, Oreochromis niloticus, during Edwardsiella tarda infection is tightly associated with their metabolome, where the survived O. niloticus has distinct metabolomic profile to dying O. niloticus. Glucose is the key metabolite to distinguish the survival- and dying-metabolome. More importantly, exogenous administration of glucose to the fish greatly enhances their survival for the infection, indicating the functional roles of glucose in metabolome repurposing, known as reprogramming metabolomics. However, the underlying information for the reprogramming is not yet available. Here, GC/MS based metabolomics is used to understand the mechanisms by which how exogenous glucose elevates O. niloticus, anti-infectious ability to E. tarda. Results showed that exogenous glucose promotes stearic acid and palmitic acid biosynthesis but attenuates TCA cycle to potentiate O. niloticus against bacterial infection, which is confirmed by the fact that exogenous stearic acid increases immune protection in O. niloticus against E. tarda infection in a manner of Mx protein. These results indicate that exogenous glucose reprograms O. niloticus anti-infective metabolome that characterizes elevation of stearic acid and palmitic acid and attenuation of the TCA cycle. Therefore, our results proposed a novel mechanism that glucose promotes unsaturated fatty acid biosynthesis to cope with infection, thereby highlighting a potential way of enhancing fish immunity in aquaculture.