Plasma Metabolic Profiles-Based Prediction of Induction Chemotherapy Efficacy in Nasopharyngeal Carcinoma: Results of a Bidirectional Clinical Trial.

PURPOSE: The efficacy of induction chemotherapy (IC) as a primary treatment for advanced nasopharyngeal carcinoma (NPC) remains a topic of debate, with a lack of dependable biomarkers for predicting its efficacy. This study seeks to establish a predictive classifier utilizing plasma metabolomics profiling. EXPERIMENTAL DESIGN: A total of 166 NPC patients enrolled in the clinical trial NCT05682703 and undergoing IC were included in the study. Plasma lipoprotein profiles were obtained using 1H-NMR before and after IC treatment. An AI-assisted radiomics method was developed to effectively evaluate the efficacy. Metabolic biomarkers were identified through a machine learning approach based on a discovery cohort and subsequently validated in a validation cohort that mimicked the most unfavorable scenario in real-world. RESULTS: Our research findings indicate that the effectiveness of IC varies among individual patients, with a correlation observed between efficacy and changes in metabolite profiles. Utilizing machine learning techniques, it was determined that the XGB model exhibited notable efficacy, attaining an Area Under the Curve (AUC) value of 0.792 (95% CI, 0.668-0.913). In the validation cohort, the model exhibited strong stability and generalizability with an AUC of 0.786 (95%CI, 0.533-0.922). CONCLUSION: In this study, we found that dysregulation of plasma lipoprotein may result in resistance to IC in NPC patients. The prediction model constructed based on the plasma metabolites' profile as good predictive capabilities and potential for real-world generalization. This discovery has implications for the development of treatment strategies and may offer insight into potential targets for enhancing the effectiveness of IC.

VLDL and LDL Subfractions Enhance the Risk Stratification of Individuals Who Underwent Epstein-Barr Virus-Based Screening for Nasopharyngeal Carcinoma: A Multicenter Cohort Study.

Serological tests for Epstein-Barr virus (EBV) antibodies have been widely conducted for the screening of nasopharyngeal carcinoma (NPC) in endemic areas. Further risk stratification of NPC can be achieved through plasma lipoprotein and metabolic profiles. A total of 297 NPC patients and 149 EBV-positive participants are enrolled from the NCT03919552 and NCT05682703 cohorts for plasma nuclear magnetic resonance (NMR) metabolomic analysis. Small, dense very low density lipoprotein particles (VLDL-5) and large, buoyant low density lipoprotein particles (LDL-1) are found to be closely associated with nasopharyngeal carcinogenesis. Herein, an NMR-based risk score (NRS), which combines lipoprotein subfractions and metabolic biomarkers relevant to NPC, is developed and well validated within a multicenter cohort. Combining the median cutoff value of the NRS (N50) with that of the serological test for EBV antibodies, the risk stratification model achieves a satisfactory performance in which the area under the curve (AUC) is 0.841 (95% confidence interval: 0.811-0.871), and the positive predictive value (PPV) reaches 70.08% in the combined cohort. These findings not only suggest that VLDL-5 and LDL-1 particles can serve as novel risk factors for NPC but also indicate that the NRS has significant potential in personalized risk prediction for NPC.

Construction and application of nasopharyngeal carcinoma-specific big data platform based on electronic health records.

OBJECTIVE: To establish a nasopharyngeal carcinoma-specific big data platform based on electronic health records (EHRs) to provide data support for real-world study of nasopharyngeal carcinoma. METHODS: A multidisciplinary expert team was established for this project. Based on industry standards and practical feasibility, the team designed the nasopharyngeal carcinoma data element standards including 14 modules and 640 fields. Data from patients diagnosed with nasopharyngeal carcinoma who visited Southern Hospital after 1999 were extracted from 15 EHRs systems and were cleaned, structured, and standardized using information technologies such as machine learning and natural language processing. In addition, a series of measures such as quality control and data encryption were taken to ensure data quality and patient privacy. At the platform application level, 10 functional modules were designed according to the needs of nasopharyngeal carcinoma research. RESULTS: As of 1 October 2022, the Big Data platform has included 11,617patients, of whom 8228 (70.83 %) were male and 3389 (29.17 %) were female, with a median age of 48 years (interquartile range, 40 years). The data in the platform were validated to have a high level of completeness and accuracy, especially for key variables such as social demographics, laboratory tests and vital signs. Currently, six projects involving risk factors, early diagnosis, treatment efficacy and prevention of treatment-related toxic reactions have been conducted on the platform. CONCLUSIONS: We have established a high-quality NPC-specific big data platform by integrating heterogeneous data from multiple sources in the EHR. The platform provides an effective tool and strong data support for real-world studies of nasopharyngeal carcinoma, which helps to improve research efficiency, reduce costs, and improve the quality of research results. We expect to promote multicenter nasopharyngeal carcinoma data sharing in the future to facilitate the generation of high-quality real-world evidence in nasopharyngeal carcinoma. This article may provide some reference value for other comprehensive hospitals to establish a big data platform for nasopharyngeal carcinoma.

Host-guest binding of tetracationic cyclophanes to photodynamic agents inhibits posttreatment phototoxicity and maintains antitumour efficacy.

In the past two decades, photodynamic therapy (PDT) has become an effective method for the treatment of cancer. However, the posttreatment residue of photodynamic agents (PDAs) causes long-term skin phototoxicity. Here, we apply naphthalene-derived, box-like tetracationic cyclophanes, named NpBoxes, to bind to clinically used porphyrin-based PDAs to alleviate their posttreatment phototoxicity by reducing their free content in skin tissues and 1O2 quantum yield. We show that one of the cyclophanes, 2,6-NpBox, could include the PDAs to efficiently suppress their photosensitivity for the generation of reactive oxygen species. A tumour-bearing mouse model study revealed that, when Photofrin, the most widely used PDA in clinic, was administrated at a dose corresponding to the clinical one, 2,6-NpBox of the same dose could significantly suppress its posttreatment phototoxicity on the skin induced by simulated sunlight irradiation, without imposing a negative influence on its PDT efficacy.

The prognostic value of the ratio of standard uptake value of lymph node to primary tumor before treatment of locally advanced nasopharyngeal carcinoma.

BACKGROUND: To evaluate the prognostic value of the ratio of the standard uptake value of the lymph node and primary tumor before the treatment of locally advanced nasopharyngeal carcinoma and examine the prognostic value of the tumor metabolic parameters (SUVmax, MTV, and TLG) of the lymph node and primary tumor of locally advanced nasopharyngeal carcinoma. METHODS: A total of 180 patients with locally advanced nasopharyngeal carcinoma diagnosed pathologically from January 1, 2016 to December 31, 2018 were selected, and the MEDEX system was used to automatically delineate the SUVmax, MTV, and TLG of the lymph node metastases and nasopharyngeal carcinoma primary tumor. In addition, the ratio of LN-SUVmax (SUVmax of the lymph node metastases) to T-SUVmax (SUVmax of the nasopharyngeal carcinoma primary tumor) was calculated, and a ROC curve was drawn to obtain the best cut-off value. Kaplan-Meier and Cox regression models were used for survival and multivariate analyses, respectively. RESULTS: The median follow-up period for participants was 32 (4-62) months. Univariate analysis showed that age (P = 0.013), LN-SUVmax (P = 0.001), LN-TLG (P = 0.007) and NTR (P = 0.001) were factors influencing the overall survival (OS). Factors affecting local progression-free survival (LPFS) were LN-SUVmax (P = 0.005), LN-TLG (P = 0.003) and NTR (P = 0.020), while clinical stage (P = 0.023), LN-SUVmax (P = 0.007), LN-TLG (P = 0.006), and NTR (P = 0.032) were factors affecting distant metastasis-free survival (DMFS). Multivariate analysis showed that NTR was an independent influencing factor of OS (HR 3.00, 95% CI 1.06-8.4, P = 0.038), LPFS (HR 3.08, 95% CI 1.27-7.50, P = 0.013), and DMFS (HR 1.84, 95% CI 0.99-3.42, P = 0.054). Taking OS as the main observation point, the best cut-off point of NTR was 0.95. Kaplan-Meier results showed that the 3-year OS (97.0% vs 85.4%, χ2 = 11.25, P = 0.001), 3-year LPFS (91.3% vs 82.1%, χ2 = 4.035, P = 0.045), and 3-year DMFS (92.3% vs 87.9%, χ2 = 4.576, P = 0.032) of patients with NTR < 0.95 were higher than those with NTR > 0.95. CONCLUSIONS: High NTR before treatment indicates a poor prognosis for patients with nasopharyngeal carcinoma. This can serve as a reference value for the reasonable treatment and prognosis monitoring of such patients.

Porous organic polymer overcomes the post-treatment phototoxicity of photodynamic agents and maintains their antitumor efficiency.

Since 1995, photodynamic therapy (PDT) has been utilized as an effective method for cancer treatment. However, the residues of photosensitizers in the normal tissues after PDT can be activated by sunlight to cause severe skin phototoxicity, for which currently there are no clinical solutions. As a result, post-PDT patients need to remain out of sunlight for up to five weeks, which produces great living and mental burdens for patients. Herein, we report that a biocompatible porous organic polymer (POP) with average 3.1 nm porosity is able to suppress the skin phototoxicity of clinically used porphyrin-based photodynamic agents (PDAs), including Photofrin, Talaporfin and Hiporfin, through an adsorption-elimination mechanism. Fluorescence titration and dialysis experiments show that POP can adsorb and retain the PDAs at a micromolar concentration. In vivo experiments demonstrate that POP can significantly suppress the skin phototoxicity caused by all the three PDAs without reducing their PDT efficacy. STATEMENT OF SIGNIFICANCE: Up to now, no efficient clinical treatment for the inhibition of post-PDT phototoxicity of clinically used porphyrin-based PDAs is available. In the manuscript, a water-soluble cationic porous organic polymer has been revealed to include three clinically used PDAs. In vivo experiments show that this inclusion remarkably reduces the content of PDAs in mouse skins, leading to significant alleviation of their post-PDT phototoxicity without no negative effect on their PDT efficacy. Thus, this work provides a strategy for overcoming the drawback of clinically used photodynamic agents.

Adsorption-Based Detoxification of Endotoxins by Porous Flexible Organic Frameworks.

Bacterial lipopolysaccharides (LPS, endotoxins) cause sepsis that is responsible for a huge amount of mortality globally. However, their neutralization or detoxification remains an unmet medical need. We envisaged that cationic organic frameworks with persistent hydrophobic porosity may adsorb and thus neutralize LPS through a combination of cooperative ion-pairing electrostatic attraction and hydrophobicity. We here report the preparation of two water-soluble flexible organic frameworks (FOF-1 and FOF-2) from tetratopic and ditopic precursors through quantitative formation of hydrazone bonds at room temperature. The two FOFs are revealed to possess hydrodynamic diameters, which range from 20 to 120 nm, depending on the concentrations. Dynamic light scattering and isothermal titration calorimetric and chromogenic limulus amebocyte lysate experiments indicate that both frameworks are able to adsorb and thus reduce the concentration of free LPS molecules in aqueous solution, whereas cytokine inhibition experiments with RAW264.7 support that this adsorption can significantly decrease the toxicity of LPS. In vivo experiments with mice (five males per group) show that the injection of FOF-1 at a dose of 0.6 mg/kg realizes the survival of all of the mice administrated with LPS of the d-galactosamine (d-Gal)-sensitized absolute lethal dose (LD100, 0.05 mg/kg), whereas its maximum tolerated dose for mice is determined to be 10 mg/kg. These findings provide a new promising sequestration strategy for the development of porous agents for the neutralization of LPS.

Predictive Value of Pretreatment Lymphocyte-to-Monocyte Ratio and Platelet-to-Lymphocyte Ratio in the Survival of Nasopharyngeal Carcinoma Patients.

OBJECTIVE: The present study aimed to investigate the predictive value of some indexes, such as neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), systemic inflammatory response index (SIRI), and systemic immune-inflammatory index (SII) in the survival of nasopharyngeal carcinoma (NPC) and provide reference for the treatment. METHODS: A retrospective analysis was performed on 216 patients from 2016 to 2018. The cutoff values of these indexes were determined by the receiver operating characteristic (ROC) curve. The prognostic value of the indexes was evaluated according to the rate of overall survival (OS), regional recurrence-free survival (RRFS), locoregional recurrence-free survival (LRRFS), and distant metastasis-free survival (DMFS). RESULTS: The survival analysis showed that NLR ≤2.695 (P = 0.017) and PLR ≤140.065 (P = 0.041) were associated with poor OS; however, the LMR and SIRI showed no significant statistical significance. NLR ≤2.045 (P = 0.018) and PLR ≤125.605 (P = 0.003) were associated with poor RRFS, LMR ≤2.535 (P = 0.027) and PLR ≤140.065 (P = 0.009) were associated with poor DMFS, NLR ≤2.125 (P = 0.018) and PLR ≤132.645 (P = 0.026) were associated with poor LRRFS, respectively. Logistic regression analysis showed that low LMR (≤2.535) was significantly inferior in OS (HR 23.085, 95% CI 3.425-155.622, P = 0.001) and DMFS (HR 22.839, 95% CI 4.096-127.343, P < 0.001). Moreover, low PLR (≤140.065) remained significantly related to worse OS (HR 11.908, 95% CI 1.295-109.517, P = 0.029) and DMFS (HR 9.556, 95% CI 1.448-63.088, P = 0.019). CONCLUSION: The index LMR and PLR can be used for predicting survival in NPC patients.

Long term outcomes and prognostic factors of n0 stage nasopharyngeal carcinoma: a single institutional experience with 610 patients.

Treatment responses of N0 stage nasopharyngeal carcinoma were firstly analyzed comprehensively to evaluate long term outcomes of patients and identify prognostic factors. A total of 610 patients with N0 NPC, undergoing definitive radiotherapy to their primary lesion and prophylactic radiation to upper neck, were reviewed retrospectively. Concomitant chemotherapy was administrated to 65 out of the 610. Survival rates of the patients were calculated using the Kaplan-Meier method and compared by log-rank test. Prognostic factors were identified by the Cox regression model. The study revealed the 5-year and 10-year overall, disease-free, disease-specific, local failure-free, regional failure-free, locoregional failure-free and distant metastasis-free survival rates to be 78.7% and 66.8%, 68.8% and 55.8%, 79.9% and 70.4%, 81.2% and 72.5%, 95.8% and 91.8%, 78.3% and 68.5%, 88.5% and 85.5%, respectively. There were 192 patients experiencing failure (31.5%) after radiotherapy or chemoradiotherapy. Of these, local recurrence, regional relapse and distant metastases as the first event of failure occurred in 100 (100/610, 16.4%), 15(15/610, 2.5%) and 52 (52/610, 8.5%), respectively. Multivariate analysis showed that T stage was the only independent prognostic factor for patients with N0 NPC (P=0.000). Late T stage (P=0.000), male (P=0.039) and anemia (P=0.007) were independently unfavorable factors predicting disease-free survival. After treatment, satisfactory outcome wasgenerally achieved in patients with N0 NPC. Local recurrence represented the predominant mode of treatment failure, while T stage was the only independent prognostic factor for overall survival. Late T stage, male gender, and anemia independently predicted lower possibility of the disease-free survival.