Genetic Associations of Primary Angle-Closure Disease: A Systematic Review and Meta-Analysis.

Importance: Effects of genetic variants on primary angle-closure disease remained uncertain. Objective: To systematically review the associations of common single-nucleotide variants (SNVs) and rare coding variants with primary angle-closure disease, its subtypes (including primary angle-closure glaucoma, primary angle-closure suspect, and primary angle-closure) and progression. Data Sources: Eligible studies from PubMed, Embase, and Web of Science were retrieved up to April 3, 2023. SNV information was extracted from eligible reports and 2 genome-wide association studies summary statistics, UK BioBank and FinnGen. Study Selection: Studies providing analyzable genotype or allele data in a case-control design for primary angle-closure disease association and longitudinal case-only design for primary angle-closure disease progression. Data Extraction and Synthesis: PRISMA guidelines were used for literature screening and the Newcastle Ottawa Scale for data quality assessment. Pooled effect size with 95% CIs of SNV associations were calculated using fixed- or random-effect models according to I2 statistics. Main Outcomes and Measures: SNVs reported in 2 or more studies were meta-analyzed to generate pooled odds ratios and P values. Common and rare coding variants from single reports were summarized. Results: Sixty-nine citations were eligible for meta-analysis on overall primary angle-closure disease, involving 206 SNVs in 64 genes or loci. Seventeen SNVs in 15 genes or loci showed associations with primary angle-closure disease, and 15 SNVs in 13 genes or loci showed associations with primary angle-closure glaucoma. Two SNVs, ABCA1 rs2422493 and ZNRF3 rs3178915, were associated only with primary angle-closure disease. Two SNVs, PCMTD1-ST18 rs1015213 and COL11A1 rs3753841, were associated with primary angle-closure suspect, and 1 SNV, MMP9 rs3918249, was associated with primary angle-closure. This systematic review and meta-analysis newly confirmed 7 genes or loci associated with primary angle-closure glaucoma: ATOH7, CALCRL, FBN1, IL6, LOXL1, MMP19, and VAV3. Common and rare coding variants in 16 genes or loci that have been associated with primary angle-closure disease were cataloged. Stratification analysis revealed different primary angle-closure disease-associated genes in different ethnic populations. Only 1 study regarding the genetic association of primary angle-closure glaucoma progression was identified. Conclusions and Relevance: This study revealed the genetic complexity of primary angle-closure disease, involving common SNVs and rare coding variants in more than 30 genes or loci, with ethnic and phenotypic diversities. Further replication, genotype-phenotype correlation, and pathway analyses are warranted.

Reduced-dose radiotherapy for Epstein-Barr virus DNA selected staged III nasopharyngeal carcinoma: A single-arm, phase 2 trial.

BACKGROUND: Radiotherapy-related toxicities of nasopharyngeal carcinoma (NPC) caused by a standard dose of 70 Gy remain a critical issue. Therefore, we assessed whether a radiotherapy dose of 60 Gy was non-inferior to the standard dose in patients with low-risk stage III NPC with a favourable response to induction chemotherapy (IC). PATIENTS AND METHODS: We did a single-arm, single-centre, phase II clinical trial in China. Patients with low-risk (Epstein-Barr virus [EBV] DNA level <4000 copies/ml) stage III NPC were treated with two cycles IC. Patients with complete/partial response and undetectable EBV DNA level were assigned 60 Gy intensity-modulated radiotherapy concurrently with three cycles of cisplatin. The primary end-point was 2-year progression-free survival (PFS). This trial is registered with ClinicalTrials.gov, number NCT03668730. RESULTS: One patient quit because of withdrawal of informed consent after IC. In total, 215 patients completed two cycles of IC, after which 116 (54.0%) and 99 (46.0%) patients were assigned 60 and 70 Gy radiotherapy, respectively. For 215 patients, the 2-year PFS was 90.7% (95% CI, 86.8%-94.6%) with a median follow-up of 43.9 months (interquartile range [IQR], 39.8-46.2). For patients treated with 60 Gy radiotherapy, the 2-year PFS rate was 94.8% (95%CI 90.7%-98.9%) with a median follow-up of 43.9 months (IQR 40.2-46.2). The most common late toxicity was grade 1-2 dry mouth (incidence rate: 54.3%). No grade 3+ long-term adverse event was observed, and most quality-of-life items, domains, and symptom scores returned to baseline by 6 months. CONCLUSION: Reduced-dose radiation (60 Gy) is associated with favourable survival outcomes and limited treatment-related toxicities in patients with low-risk stage III NPC sensitive to IC.

A phase II randomised controlled trial of adjuvant tumour-infiltrating lymphocytes for pretreatment Epstein-Barr virus DNA-selected high-risk nasopharyngeal carcinoma patients.

PURPOSE: The safety and objective clinical responses were observed in the phase I study using adjuvant autologous tumour-infiltrating lymphocytes (TILs) following concurrent chemoradiotherapy (CCRT) in nasopharyngeal carcinoma (NPC) patients. METHODS AND MATERIALS: One hundred fifty-six patients with stage III-IVb and pretreatment Epstein-Barr virus DNA levels of ≥4000 copies/ml were randomly assigned to receive CCRT combined with TIL infusion (n = 78) or CCRT alone (n = 78). All patients received CCRT and patients assigned to the TIL group received TIL infusion within 1 week after CCRT. The primary endpoint was investigator-assessed progression-free survival (PFS) at 3 years. RESULTS: After a median follow-up of 62.3 months, no significant difference was observed in the 3-year PFS rate between the CCRT plus TIL infusion group and CCRT alone group (75.6% versus 74.4%, hazard ratios, 1.08; 95% confidence intervals, 0.62-1.89). TIL infusion was safe without grade 3 or 4 adverse events and all the high-grade adverse effects were associated with myelosuppression caused by CCRT. Exploratory analysis showed that a potential survival benefit was observed with TILs in patients with lower levels of circulating CD8+TIM3+ cells, serum IL-8 or PD-L1. The infused TIL products in patients with favourable outcomes were associated with increased transcription of interferon-γ and a series of inflammatory related genes and a lower exhausted score. CONCLUSION: The primary objective of prolonging PFS with CCRT plus TILs in high-risk NPC patients was not met. These findings may provide evidence for the design of future trials investigating the combination of TILs plus immune checkpoint inhibitors based on CCRT in high-risk NPC patients. TRIAL REGISTRATION NUMBER: NCT02421640.

Concurrent chemoradiotherapy followed by adjuvant cisplatin-gemcitabine versus cisplatin-fluorouracil chemotherapy for N2-3 nasopharyngeal carcinoma: a multicentre, open-label, randomised, controlled, phase 3 trial.

BACKGROUND: Patients with N2-3 nasopharyngeal carcinoma have a high risk of treatment being unsuccessful despite the current practice of using a concurrent adjuvant cisplatin-fluorouracil regimen. We aimed to compare the efficacy and safety of concurrent adjuvant cisplatin-gemcitabine with cisplatin-fluorouracil in N2-3 nasopharyngeal carcinoma. METHODS: We conducted an open-label, randomised, controlled, phase 3 trial at four cancer centres in China. Eligible patients were aged 18-65 years with untreated, non-keratinising, stage T1-4 N2-3 M0 nasopharyngeal carcinoma, an Eastern Cooperative Oncology Group performance status score of 0-1, and adequate bone marrow, liver, and renal function. Eligible patients were randomly assigned (1:1) to receive concurrent cisplatin (100 mg/m2 intravenously) on days 1, 22, and 43 of intensity-modulated radiotherapy followed by either gemcitabine (1 g/m2 intravenously on days 1 and 8) and cisplatin (80 mg/m2 intravenously for 4 h on day 1) once every 3 weeks or fluorouracil (4 g/m2 in continuous intravenous infusion for 96 h) and cisplatin (80 mg/m2 intravenously for 4 h on day 1) once every 4 weeks, for three cycles. Randomisation was done using a computer-generated random number code with a block size of six, stratified by treatment centre and nodal category. The primary endpoint was 3-year progression-free survival in the intention-to-treat population (ie, all patients randomly assigned to treatment). Safety was assessed in all participants who received at least one dose of chemoradiotherapy. This study was registered at ClinicalTrials.gov, NCT03321539, and patients are currently under follow-up. FINDINGS: From Oct 30, 2017, to July 9, 2020, 240 patients (median age 44 years [IQR 36-52]; 175 [73%] male and 65 [27%] female) were randomly assigned to the cisplatin-fluorouracil group (n=120) or cisplatin-gemcitabine group (n=120). As of data cutoff (Dec 25, 2022), median follow-up was 40 months (IQR 32-48). 3-year progression-free survival was 83·9% (95% CI 75·9-89·4; 19 disease progressions and 11 deaths) in the cisplatin-gemcitabine group and 71·5% (62·5-78·7; 34 disease progressions and seven deaths) in the cisplatin-fluorouracil group (stratified hazard ratio 0·54 [95% CI 0·32-0·93]; log rank p=0·023). The most common grade 3 or worse adverse events that occurred during treatment were leukopenia (61 [52%] of 117 in the cisplatin-gemcitabine group vs 34 [29%] of 116 in the cisplatin-fluorouracil group; p=0·00039), neutropenia (37 [32%] vs 19 [16%]; p=0·010), and mucositis (27 [23%] vs 32 [28%]; p=0·43). The most common grade 3 or worse late adverse event (occurring from 3 months after completion of radiotherapy) was auditory or hearing loss (six [5%] vs ten [9%]). One (1%) patient in the cisplatin-gemcitabine group died due to treatment-related complications (septic shock caused by neutropenic infection). No patients in the cisplatin-fluorouracil group had treatment-related deaths. INTERPRETATION: Our findings suggest that concurrent adjuvant cisplatin-gemcitabine could be used as an adjuvant therapy in the treatment of patients with N2-3 nasopharyngeal carcinoma, although long-term follow-up is required to confirm the optimal therapeutic ratio. FUNDING: National Key Research and Development Program of China, National Natural Science Foundation of China, Guangdong Major Project of Basic and Applied Basic Research, Sci-Tech Project Foundation of Guangzhou City, Sun Yat-sen University Clinical Research 5010 Program, Innovative Research Team of High-level Local Universities in Shanghai, Natural Science Foundation of Guangdong Province for Distinguished Young Scholar, Natural Science Foundation of Guangdong Province, Postdoctoral Innovative Talent Support Program, Pearl River S&T Nova Program of Guangzhou, Planned Science and Technology Project of Guangdong Province, Key Youth Teacher Cultivating Program of Sun Yat-sen University, the Rural Science and Technology Commissioner Program of Guangdong Province, and Fundamental Research Funds for the Central Universities.

Prognostic significance of AKR1C4 and the advantage of combining EBV DNA to stratify patients at high risk of locoregional recurrence of nasopharyngeal carcinoma.

BACKGROUND: Distinguishing patients at a greater risk of recurrence is essential for treating locoregional advanced nasopharyngeal carcinoma (NPC). This study aimed to explore the potential of aldo-keto reductase 1C4 (AKR1C4) in stratifying patients at high risk of locoregional relapse. METHODS: A total of 179 patients with locoregionally advanced NPC were grouped by different strategies; they were: (a) divided into two groups according to AKR1C4 expression level, and (b) classified into three clusters by integrating AKR1C4 and Epstein-Barr virus (EBV) DNA. The Kaplan-Meier method was used to calculate locoregional relapse-free survival (LRFS), overall survival (OS), progression-free survival (PFS), and distant metastasis-free survival (DMFS). The Cox proportional hazards model was used to determine potential prognostic factors, and a nomogram was generated to predict 3-year and 5-year LRFS. RESULTS: A significant difference in the 5-year LRFS was observed between the high and low AKR1C4 expression groups (83.3% vs. 92.7%, respectively; p = 0.009). After integrating AKR1C4 expression and EBV DNA, the LRFS (84.7%, 84.5%, 96.9%, p = 0.014) of high-, intermediate-, and low- AKR1C4 and EBV DNA was also significant. Multivariate analysis indicated that AKR1C4 expression (p = 0.006) was an independent prognostic factor for LRFS. The prognostic factors incorporated into the nomogram were AKR1C4 expression, T stage, and EBV DNA, and the concordance index of the nomogram for locoregional relapse was 0.718. CONCLUSIONS: In conclusion, high AKR1C4 expression was associated with a high possibility of relapse in NPC patients, and integrating EBV DNA and AKR1C4 can stratify high-risk patients with locoregional recurrence.

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.

Deep learning signatures reveal multiscale intratumor heterogeneity associated with biological functions and survival in recurrent nasopharyngeal carcinoma.

PURPOSE: How to discriminate different risks of recurrent nasopharyngeal carcinoma (rNPC) patients and guide individual treatment has become of great importance. This study aimed to explore the associations between deep learning signatures and biological functions as well as survival in (rNPC) patients. METHODS: A total of 420 rNPC patients with PET/CT imaging and follow-up of overall survival (OS) were retrospectively enrolled. All patients were randomly divided into a training set (n = 269) and test set (n = 151) with a 6:4 ratio. We constructed multi-modality deep learning signatures from PET and CT images with a light-weighted deep convolutional neural network EfficienetNet-lite0 and survival loss DeepSurvLoss. An integrated nomogram was constructed incorporating clinical factors and deep learning signatures from PET/CT. Clinical nomogram and single-modality deep learning nomograms were also built for comparison. Furthermore, the association between biological functions and survival risks generated from an integrated nomogram was analyzed by RNA sequencing (RNA-seq). RESULTS: The C-index of the integrated nomogram incorporating age, rT-stage, and deep learning PET/CT signature was 0.741 (95% CI: 0.688-0.794) in the training set and 0.732 (95% CI: 0.679-0.785) in the test set. The nomogram stratified patients into two groups with high risk and low risk in both the training set and test set with hazard ratios (HR) of 4.56 (95% CI: 2.80-7.42, p < 0.001) and 4.05 (95% CI: 2.21-7.43, p < 0.001), respectively. The C-index of the integrated nomogram was significantly higher than the clinical nomogram and single-modality nomograms. When stratified by sex, N-stage, or EBV DNA, risk prediction of our integrated nomogram was valid in all patient subgroups. Further subgroup analysis showed that patients with a low-risk could benefit from surgery and re-irradiation, while there was no difference in survival rates between patients treated by chemotherapy in the high-risk and low-risk groups. RNA sequencing (RNA-seq) of data further explored the mechanism of high- and low-risk patients from the genetic and molecular level. CONCLUSION: Our study demonstrated that PET/CT-based deep learning signatures showed satisfactory prognostic predictive performance in rNPC patients. The nomogram incorporating deep learning signatures successfully divided patients into different risks and had great potential to guide individual treatment: patients with a low-risk were supposed to be treated with surgery and re-irradiation, while for high-risk patients, the application of palliative chemotherapy may be sufficient.

Association of Treatment Advances With Survival Rates in Pediatric Patients With Nasopharyngeal Carcinoma in China, 1989-2020.

IMPORTANCE: Advanced techniques and treatment methods have been found to be associated with improved survival rates in adults with nasopharyngeal carcinoma (NPC); however, not much is known about associations in pediatric patients. OBJECTIVE: To investigate whether advanced imaging diagnosis, radiotherapy (RT) technology, and treatment modality are associated with survival in pediatric patients with NPC. DESIGN, SETTING, AND PARTICIPANTS: In this retrospective cohort study, 810 pediatric patients ages 21 years and younger with nonmetastatic NPC diagnosed from 1989 to 2020 at a single cancer center in China were included. Data were analyzed from April through December 2021. EXPOSURES: Patients were divided into 3 groups by initial treatment date (ie, 1989-2002, 2003-2011, and 2012-2020). Associations between advances in technology and treatment and survival were investigated. Comparisons of advances vs older technology and treatments included those in imaging diagnosis (magnetic resonance imaging [MRI] vs computed tomography [CT] and positron emission tomography [PET]-CT with MRI vs CT), radiotherapy (RT) techniques (intensity-modulated RT [IMRT] or TomoTherapy [TOMO] vs 2-dimensional conventional radiotherapy [2D-CRT] or 3-dimensional conventional radiotherapy [3D-CRT]), and treatment methods (concurrent chemoradiotherapy [CCRT] vs RT alone, induction chemotherapy [IC] with CCRT vs RT alone, and CCRT or RT with adjuvant chemotherapy [AC] vs RT alone). MAIN OUTCOMES AND MEASURES: The primary end point was progression-free survival (PFS). Secondary end points were overall survival (OS), distant metastasis-free survival, and locoregional recurrence-free survival. Cox and competing-risks regression were used to estimate hazard ratios (HRs) and 95% CIs for associations between variables and survival. RESULTS: Among 810 pediatric patients with NPC, the median (IQR) age was 18 (15-20) years, and there were 577 [71.2%] male patients. This included 122 patients in the 1989 to 2002 period, 212 patients in the 2003 to 2011 period, and 476 patients in the 2012 to 2020 period. The 5-year PFS and OS rates increased, respectively, from 65.9% (95% CI, 56.6%-73.7%) and 69.9% (95% CI, 60.7%-77.4%) in 1989 to 2002 to 79.8% (95% CI, 73.7%-84.7%) and 86.2% (95% CI, 80.6%-90.3%) in 2003 to 2011, then 88.1% (95% CI, 84.2%-91.1%) and 95.0% (95% CI, 91.5%-97.0%) in 2012 to 2020. The 5- year cumulative incidence of distant metastasis rate was similar in the 3 periods (1989-2002: 11.7% [95% CI, 7.0%- 19.4%]; 2003-2011: 18.0% [95% CI, 13.4%-24.0%]; 2012-2020: 10.4% [95% CI, 7.6%-14.1%], while the 5-year cumulative incidence of locoregional recurrence rate decreased from 22.5% (95% CI, 15.9%-31.3%) in the first period to 2.9% (95% CI, 1.3%-6.3%) in the second period, remaining stable in the third period, at 4.3% (95% CI, 2.4%-7.6%). Advances in imaging diagnosis (MRI vs CT: hazard ratio [HR], 0.25 [95% CI, 0.17-0.38]; PET-CT with MRI vs CT: HR, 0.41 [95% CI, 0.27-0.62]), radiotherapy techniques (IMRT or TOMO vs 2D-CRT or 3D-CRT: HR, 0.42 [95% CI, 0.30-0.59]), and treatment methods (CCRT vs RT alone: HR, 0.55 [95% CI, 0.32-0.96]; IC with CCRT vs RT alone: HR, 0.59 [95% CI, 0.38-0.91]; CCRT or RT with AC vs RT alone: HR, 0.48 [95% CI, 0.25-0.91]) were associated with improved PFS. CONCLUSIONS AND RELEVANCE: This study found that advanced techniques and treatment methods were associated with improved survival rates in pediatric patients with NPC, but distant failure remained a key challenge.

Deintensified Chemoradiotherapy for Pretreatment Epstein-Barr Virus DNA-Selected Low-Risk Locoregionally Advanced Nasopharyngeal Carcinoma: A Phase II Randomized Noninferiority Trial.

PURPOSE: Cumulative doses of 200 mg/m2 for concurrent cisplatin (DDP) were indicated by retrospective studies as sufficient in conferring survival benefit for locoregionally advanced nasopharyngeal carcinoma (LA-NPC). We performed an open-label, phase II, randomized, controlled trial to test the noninferiority of a two-cycle 100 mg/m2 concurrent DDP regimen over three-cycle in patients with low-risk LA-NPC with pretreatment Epstein-Barr virus DNA levels < 4,000 copies/mL. PATIENTS AND METHODS: Eligible patients were randomly assigned 1:1 to receive two cycles or three cycles concurrent DDP-based chemoradiotherapy. The primary end point was 3-year progression-free survival (PFS). The secondary end points included overall survival, distant metastasis-free survival, locoregional relapse-free survival, etc. RESULTS: Between September 2016 and October 2018, 332 patients were enrolled, with 166 in each arm. After a median follow-up of 37.7 months, the estimated 3-year PFS rates were 88.0% in the two-cycle group and 90.4% in the three-cycle group, with a difference of 2.4% (95% CI, -4.3 to 9.1, Pnoninferiority = .014). No differences were observed between groups in terms of PFS, overall survival, and the cumulative incidences of locoregional relapse and distant metastasis. Patients in the three-cycle group developed significantly more grade 3-4 mucositis (41 [24.8%] v 25 [15.1%]), hyponatremia (26 [15.8%] v 14 [8.4%]), and dermatitis (9 [5.5%] v 2 [1.2%]). The overall all-grade and grade 3-4 toxicity burdens were heavier in three-cycle group (T-scores, 12.33 v 10.57, P < .001 for all grades; 1.76 v 1.44, P = .05 for grade 3-4). Patients in the three-cycle group also showed more all-grade hearing impairment, dry mouth and skin fibrosis, and impaired long-term quality of life. CONCLUSION: Intensity-modulated radiotherapy plus two cycles of concurrent 100 mg/m2 DDP could be an alternative treatment option for patients with low-risk LA-NPC.

Identifying distinct risks of treatment failure in nasopharyngeal carcinoma: Study based on the dynamic changes in peripheral blood lymphocytes, monocytes, N classification, and plasma Epstein-Barr virus DNA.

BACKGROUND: To evaluate the prognostic value of the dynamic change in absolute lymphocyte counts (ALCs) and absolute monocyte counts (AMCs) and identify patients with N stage and plasma Epstein-Barr virus (EBV) DNA levels in nasopharyngeal carcinoma (NPC) who are at risk of treatment failure. METHODS: A total of 1124 eligible patients with Stage II-IVb NPC treated with concurrent chemoradiotherapy (CCRT) were enrolled. Percentage changes in the ALC (ΔALC%) and AMC (ΔAMC%) were calculated. RESULTS: Patients with high ΔALC% were correlated with poorer 5-year overall survival (OS), progression-free survival (PFS), and distant metastasis-free survival (DMFS) rates than those with low ΔALC%. Likewise, high ΔAMC% was significantly associated with worse outcome than low ΔAMC% (OS, p = 0.001; PFS, p = 0.001; DMFS, p = 0.034). Multivariate analyses revealed that ΔALC% (p = 0.046), ΔAMC% (p = 0.019), and EBV DNA level (p < 0.001) were independent prognostic factors for OS. With respect to PFS, ΔALC% (p = 0.036), ΔAMC% (p = 0.011), N classification (p = 0.016), and EBV DNA level (p < 0.001) were also independent prognosticators. Based on the aforementioned independent risk factors (ΔALC% ≥ 83.33%, ΔAMC% ≥ 40.00%, Stage N2-3, EBV DNA ≥ 4000 copies/ml), patients were divided into three different risk groups (low-risk group [with <1 risk factor], intermediate risk group [with 1-3 risk factors], and high-risk group [with 4 risk factors]) that correlated with disparate risks of death (p < 0.001), disease progression (p < 0.001), and distant metastasis (p < 0.001). CONCLUSIONS: High ΔALC% and ΔAMC% were correlated with poor prognosis in patients with NPC. Risk stratification based on ΔALC%, ΔAMC%, N classification, and plasma EBV DNA levels could provide potential utility for risk-adapted therapeutic strategies for NPC.

Effect of Concurrent Chemoradiotherapy With Nedaplatin vs Cisplatin on the Long-term Outcomes of Survival and Toxic Effects Among Patients With Stage II to IVB Nasopharyngeal Carcinoma: A 5-Year Follow-up Secondary Analysis of a Randomized Clinical Trial.

Importance: Nedaplatin-based concurrent chemoradiotherapy (CCRT) regimen at 2 years was noninferior to cisplatin-based regimen in patients with locoregional, stage II to IVB nasopharyngeal carcinoma (NPC) and was associated with fewer late adverse events, but longer-term outcomes and toxicity are unclear. Objective: To evaluate the 5-year outcomes and late toxicity profile of nedaplatin-based CCRT in patients with locoregional, stage II to IVB NPC. Design, Settings, and Participants: This 5-year follow-up secondary analysis of an open-label, noninferiority, multicenter randomized clinical trial enrolled patients with nonkeratinizing stage II to IVB NPC between January 16, 2012, and July 16, 2014, with a median follow-up duration of 78 months (IQR, 3-99 months). Data analysis was conducted from November 10, 2020, to July 8, 2021. Interventions: Patients were randomly assigned (1:1) to receive nedaplatin (100 mg/m2)- or cisplatin (100 mg/m2)-based chemotherapy every 3 weeks for 3 cycles concurrently with intensity-modulated radiotherapy. Main Outcomes and Measures: The primary end point was progression-free survival (PFS). Secondary end points were overall survival, distant metastasis-free survival, and locoregional relapse-free survival. Results: A total of 402 eligible participants were enrolled (median [IQR] age, 45 [18-65] years; 302 [75.1%] male). Patients were randomly assigned to receive nedaplatin- or cisplatin-based CCRT (n = 201 for each): 196 patients (97.5%) started nedaplatin-based CCRT and 197 patients (98.0%) started cisplatin-based CCRT. Intention-to-treat analysis demonstrated a 5-year progression-free survival rate of 81.4% (95% CI, 75.9%-86.9%) for the cisplatin group and 79.8% (95% CI, 74.1%-85.5%) for nedaplatin group, with a difference of 1.6% (95% CI, -6.3% to 9.5%; P = .002 for noninferiority). No significant survival differences were observed between the cisplatin and nedaplatin groups for 5-year overall survival (89.4% vs 88.8%, P = .63), distant metastasis-free survival (85.9% vs 90.4%, P = .17), and locoregional relapse-free survival (92.6% vs 89.6%, P = .17) rates. The cisplatin group had a higher incidence of grade 3 and 4 auditory toxic effects than the nedaplatin group (35 [17.7%] vs 21 [10.5%], P = .04). Conclusions and Relevance: In this secondary analysis of a randomized clinical trial, long-term analysis confirmed that nedaplatin-based CCRT could be regarded as an alternative doublet treatment strategy to cisplatin-based CCRT in stage II to IVB NPC. Trial Registration: ClinicalTrials.gov Identifier: NCT01540136.

Percent change in apparent diffusion coefficient and plasma EBV DNA after induction chemotherapy identifies distinct prognostic response phenotypes in advanced nasopharyngeal carcinoma.

BACKGROUND: To evaluate the prognostic value of the apparent diffusion coefficient (ADC) derived from diffusion-weighted magnetic resonance imaging (MRI) and monitor the early treatment response to induction chemotherapy (IC) with plasma EBV DNA in locoregionally advanced nasopharyngeal carcinoma (LA-NPC). RESULTS: A total of 307 stage III-IVb NPC patients were prospectively enrolled. All patients underwent MRI examinations to calculate ADC and plasma EBV DNA measurements pretreatment and post-IC. The participants' ADC value of 92.5% (284/307) increased post-IC. A higher percent change in ADC value (ΔADC%high group) post-IC was associated with a higher 5-year OS rate (90.7% vs 74.9%, p < 0.001) than those in the ΔADC%low group. Interestingly, ΔADC% was closely related to the response measured by RECIST 1.1 (p < 0.001) and plasma EBV DNA level (p = 0.037). The AUC significantly increased when post-IC plasma EBV DNA was added to ΔADC% to predict treatment failure. Thus, based on ΔADC% and plasma EBV DNA, we further divided the participants into three new prognostic response phenotypes (early response, intermediate response, and no response) that correlated with disparate risks of death (p = 0.001), disease progression (p < 0.001), distant metastasis (p < 0.001), and locoregional relapse (p < 0.001). CONCLUSION: The percentage change in ADC post-IC is indicative of treatment response and clinical outcome. ΔADC% and plasma EBV DNA-based response phenotypes may provide potential utility for early termination of treatment and allow guiding risk-adapted therapeutic strategies for LA-NPC.

Alpha-fetoprotein-producing recurrent nasopharyngeal carcinoma: A case report.

Alpha-fetoprotein hardly increased due to nasopharyngeal cancer. In this article, we reported a 57-year-old male nasopharyngeal carcinoma patient who had posttreatment subscapular metastasis with high serum alpha-fetoprotein but negative plasma Epstein-Barr virus DNA. Pathology results indicated that the scapular mass was undifferentiated non-keratinizing carcinoma originated in the nasopharynx. Moreover, no liver lesion was detected by imaging examination. In view of the positive alpha-fetoprotein and alpha-fetoprotein messenger RNA staining result in the right scapular mass fine needle aspiration biopsy sample, we considered the diagnosis of alpha-fetoprotein-producing nasopharyngeal carcinoma that had never been reported before.

Induction or adjuvant chemotherapy plus concurrent chemoradiotherapy versus concurrent chemoradiotherapy alone in paediatric nasopharyngeal carcinoma in the IMRT era: A recursive partitioning risk stratification analysis based on EBV DNA.

PURPOSE: To compare the prognosis and adverse effects of induction or adjuvant chemotherapy (IC or AC) plus concurrent chemoradiotherapy (CCRT) versus CCRT alone in paediatric nasopharyngeal carcinoma (NPC) patients in the intensity-modulated radiotherapy (IMRT) era. METHODS AND MATERIALS: 549 patients diagnosed from 2005 to 2021 were enrolled. Our primary endpoint was progression-free survival (PFS). The recursive partitioning analysis (RPA) was applied to derive a risk stratification system. Kaplan-Meier survival curves were used to assess the cumulative survival rates, and cox analysis was applied to evaluate the relationship between variables and endpoints. RESULTS: The RPA-based risk stratification identified three different risk groups. In the intermediate-risk (stage IVa and EBV<4000 copies/ml) group, patients who received IC followed by CCRT achieved a significantly better 3-year PFS rate than those treated with CCRT alone (87.35% versus 75.89%; P = 0.04). But survival benefit was not obtained from the additional IC or AC in the low-risk (stage II-III and EBV<4000 copies/ml) or high-risk (stage II-IVa and EBV≥4000 copies/ml) group. The most common grade 3 or 4 adverse events in patients treated with CCRT, IC + CCRT, and CCRT + AC were neutropenia (8.1%, 33.0% versus 36.9%, respectively) and leukopenia (14.1%, 26.8% versus 32.3%, respectively) with statistically significant difference. CONCLUSIONS: Paediatric NPC patients in the intermediate-risk group treated with IC followed by CCRT had significantly better PFS compared with patients treated with CCRT alone. And the overall incidence of acute adverse events in patients treated with IC or AC plus CCRT was higher than in patients treated with CCRT alone.

Increased Angiogenin Expression Correlates With Radiation Resistance and Predicts Poor Survival for Patients With Nasopharyngeal Carcinoma.

Background: Despite the development of such multiple therapeutic approaches, approximately 20% patients experience recurrence. Identification of molecular markers for stratifying the different risks of tumour recurrence and progression is considered imperative. Methods: We used a RayBio Human Cytokine Antibody Array that simultaneously detected the levels of 297 proteins and profiled the conditioned medium of HONE1 cells and the radioresistant NPC cells HONE1-IR. We found Angiogenin(ANG) expression to be significantly increased in HONE1-IR and HONE1-IR cells exposed to 4-Gy X-ray radiation. Results: We investigated the expression of ANG in NPC tissues and explored its prognostic significance in patients with NPC. We found that ANG expression was increased in recurrent NPC tissues. Elevated expression of ANG induced radio-resistance in NPC cells, in addition to being significantly associated with shorter PFS, OS, and LRFS in patients with NPC. Multivariate analysis results revealed that ANG was an independent prognostic factor that predicted PFS, OS, and LRFS. Furthermore, a nomogram model was generated to predict OS in terms of ANG expression. Conclusion: Our results found the radioresistant function of ANG and proved the clinical prognostic significance of ANG, and the results could help predict radio-sensitivity and stratify high-risk patients or tumour recurrence.

Management of suboptimal response to induction chemotherapy in locoregionally advanced nasopharyngeal carcinoma: Re-induction therapy or direct to Radiotherapy?

BACKGROUND: Unsatisfactory tumor response to induction chemotherapy (IC) is an adverse prognostic factor of locoregionally advanced nasopharyngeal carcinoma (LANPC). A re-induction strategy which applies additional cycles of an alternative IC regimen prior to radiotherapy (RT) has been adopted. METHODS: A total of 419 LANPC patients who attained suboptimal response (stable disease or disease progression) according to the Response Evaluation in Solid Tumors (RECIST) guideline after initial IC were retrospectively included. They were divided into those who received additional cycles of re-induction regimen prior to RT (re-induction group, n = 87) and those who had no additional chemotherapy (direct to RT group, n = 332). Propensity score matching (PSM) was used to adjust for potential confounders. Tumor response and long-term survival were compared between two groups. RESULTS: After receiving a second IC regimen, 39.1% of the patients in re-induction group attained partial response; however, the tumor control of subsequent RT was not significantly improved when compared with direct to RT group (patients attaining complete response after RT 55.2% vs. 52.5%, P = 0.757). Patients who received re-induction therapy showed worse locoregional relapse-free survival (LRFS) and progression-free survival (PFS) than those proceeded directly to RT (3-year LRFS 75.7% vs. 83.1%, P = 0.005; 3-year PFS 62.4% vs. 68.3%, P = 0.037). The increased hematological toxicities were observed in re-induction group that included grade 3-4 anemia, thrombocytopenia and liver enzyme increase. CONCLUSION: Re-induction therapy decreased LRFS and PFS and increased toxicities among patients who attain suboptimal response to initial IC regimen, as compared with direct to RT strategy.

Geriatric nutritional risk index as an independent prognostic factor in locally advanced nasopharyngeal carcinoma treated using radical concurrent chemoradiotherapy: a retrospective cohort study.

BACKGROUND: Nutritional status is a key factor influencing the prognosis of patients with cancer. The Geriatric Nutritional Risk Index (GNRI) has been used to predict mortality risk and long-term outcomes. In this study, we aimed to evaluate the predictive value of pretreatment GNRI in patients with nasopharyngeal carcinoma (NPC). METHODS: A total of 1,065 patients with biopsy-proven non-disseminated nasopharyngeal carcinoma were included. Based on a cutoff value of pretreatment GNRI, patients were divided into two groups (low ≤107.7 and high >107.7). Combining GNRI and baseline Epstein-Barr virus (EBV) DNA, all patients were further stratified into three risk groups, namely, high-risk (high EBV DNA and low GNRI), low-risk (low EBV DNA and high GNRI), and medium-risk (except the above) groups. Multivariate analyses were performed using the Cox proportional hazards model to assess the predictive value of the GNRI. RESULTS: Among the 1,065 patients, 527 (49.5%) and 538 (50.5%) were divided into low and high GNRI groups, respectively. Within a median follow-up of 83 months, patients with a high GNRI score exhibited significantly higher overall survival (OS), progression-free survival (PFS), and distant metastasis-free survival (DMFS) compared to those with low GNRI scores (P<0.05). Multivariate analyses revealed that high GNRI is an independent prognostic factor for OS and PFS (hazard ratio, HR, 0.471, 95% CI, 0.270-0.822, P=0.008; HR 0.638, 95% CI, 0.433-0.941, P=0.023, respectively). Using a combination of baseline GNRI and EBV DNA, a satisfying separation of survival curves between different risk groups for OS, PFS, DMFS was observed. The survival rates of patients in the high-risk group were significantly lower than those in the low- and medium-risk groups (all P<0.001). The combined classification was demonstrated to be an independent prognostic factor for OS and PFS after adjustment using multivariate analysis. CONCLUSIONS: Pretreatment GNRI is an independent prognostic factor for NPC patients. The combination of baseline GNRI score and EBV DNA level improved the prognostic stratification of NPC patients.

Development and validation of a normal tissue complication probability model for acquired nasal cavity stenosis and atresia after radical radiotherapy for nasopharyngeal carcinoma.

PURPOSE: Curative radiotherapy for nasopharyngeal carcinoma (NPC) can lead to acquired nasal cavity stenosis and atresia (ANCSA). As the first study to investigate risk factors of ANCSA in a large cohort of NPC patients, this article aims to develop and validate a multivariate normal tissue complication probability (NTCP) model to predict the development of ANCSA and to establish a nomogram for clinical use. METHODS AND MATERIALS: The retrospective cohort was comprised of 548 NPC patients treated with radical radiotherapy. The cohort was randomly divided into training and validation groups. Least absolute shrinkage and selection operator regression was performed for variable selection from the clinical and dosimetric characteristics in the training group. A multivariate NTCP model and a nomogram were established for the prediction of ANCSA development. Discrimination and calibration were tested using receiver operating characteristic (ROC) curves and calibration tests, respectively, for both groups. RESULTS: ANCSA was observed in 132 (24.1%) of 548 patients with NPC who underwent radical radiotherapy. The median time to ANCSA detection after treatment was 2.8 months (range, 0.0-57.7 months). Five potential predictors, including choanal invasion, low white blood cell count, high C-reactive protein level, high serum amyloid A level, and high V70Gy of the nasal cavity, were selected to develop the NTCP model based on 365 patients in the training group. The model had a fairly good discriminative power according to the ROC analysis in both the training (area under ROC curve = 0.79, 95%CI: 0.73-0.84) and validation (0.73, 0.64-0.82) groups. The calibration power was tested using the calibration test in the training (E-max = 0.069, E-avg = 0.015, p = 0.977) and validation (E-max = 0.057, E-avg = 0.032, p = 0.747) groups. CONCLUSIONS: We developed and successfully validated an NTCP model for early prediction of ANCSA in patients with NPC after radical radiotherapy. This could help clinicians assess the risk of ANCSA before the initiation of follow-ups and ensure appropriate and timely management of this complication.

Nomogram for the prediction of primary distant metastasis of nasopharyngeal carcinoma to guide individualized application of FDG PET/CT.

PURPOSE: This study aimed to establish an effective nomogram to predict primary distant metastasis (DM) in patients with nasopharyngeal carcinoma (NPC) to guide the application of PET/CT. METHODS: In total, 3591 patients with pathologically confirmed NPC were consecutively enrolled. The nomogram was constructed based on 1922 patients treated between 2007 and 2014. Multivariate logistical regression was applied to identify the independent risk factors of DM. The predictive value of the nomogram was evaluated using the concordance index (C-index), calibration curve, probability density functions (PDFs), and clinical utility curve (CUC). The results were validated in 1669 patients enrolled from 2015 to 2016. Net reclassification improvement (NRI) was applied to compare performances of the nomogram with other clinical factors. The best cut-off value of the nomogram chosen for clinical application was analyzed. RESULTS: A total of 355 patients showed primary DM among 3591 patients, yielding an incidence rate of 9.9%. Sex, N stage, EBV DNA level, lactate dehydrogenase level, and hemoglobin level were independent predictive factors for primary DM. C-indices in the training and validation cohort were 0.796 (95% CI, 0.76-0.83) and 0.779 (95% CI, 0.74-0.81), respectively. The NRI indices demonstrated that this model had better predictive performance than plasma EBV DNA level and N stage. We advocate for a threshold probability of 3.5% for guiding the application of PET/CT depending on the clinical utility analyses. CONCLUSION: This nomogram is a useful tool to predict primary DM of NPC and guide the clinical application of PET/CT individually at the initial staging.