Homeobox B2 promotes malignant behavior and contributes to the radioresistance of nasopharyngeal carcinoma by regulating forkhead box protein O1.

Background: Nasopharyngeal carcinoma (NPC) is an epithelial tumor of the head and neck with heterogeneous racial and geographical distributions. Homeobox B2 (HOXB2) is a tumor promoter in many cancers. However, the biological role of HOXB2 in NPC has not been elucidated. Methods: Bioinformatics analysis was performed to identify the differentially expressed genes (DEGs) between samples of patients with radiosensitive and radioresistant NPC. qRT-PCR, western blotting and immunohistochemistry were used to detect the expression levels of the corresponding mRNA and proteins. Cell viability was detected by CCK-8 assay and colony-forming capability was evaluated using colony formation assays. Further, migration and invasion abilities were examined using wound-healing and transwell chamber assays, respectively. Cellular apoptosis after irradiation was assessed using flow cytometry and terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) staining. Results: HOXB2 was identified as a potential regulator of radioresistance in NPC. Our in vitro results indicate that HOXB2 overexpression (HOXB2-OE) promoted malignant behaviors including invasion, migration, proliferation, and inhibited the irradiation-induced apoptosis of NPC cells. Consistent with these results, HOXB2 knockdown (HOXB2-sh) exhibited the opposite trends in these biological activities. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed that the DEGs were enriched in the FOXO signaling pathway. Mechanistically, western blotting showed that HOXB2-OE inhibited forkhead box protein O1 (FOXO1) expression in NPC cells. Thereafter, we transferred the FOXO1-OE plasmid to HOXB2-OE NPC cells and found that overexpression of FOXO1 reversed cell proliferation, migration, invasion, and radioresistance profiles promoted by HOXB2 overexpression. Conclusion: Our findings showed that HOXB2 acts as a tumor promoter in NPC, activating malignant behaviors and radioresistance of tumors via FOXO1 regulation. Moreover, the inactivation of HOXB2 or activation of FOXO1 are potential strategies to inhibit tumor progression and overcome radioresistance in NPC.

A machine learning approach for predicting radiation-induced hypothyroidism in patients with nasopharyngeal carcinoma undergoing tomotherapy.

The purpose of this study was to establish an integrated predictive model that combines clinical features, DVH, radiomics, and dosiomics features to predict RIHT in patients receiving tomotherapy for nasopharyngeal carcinoma. Data from 219 patients with nasopharyngeal carcinoma were randomly divided into a training cohort (n = 175) and a test cohort (n = 44) in an 8:2 ratio. RIHT is defined as serum thyroid-stimulating hormone (TSH) greater than 5.6 µU/mL, with or without a decrease in free thyroxine (FT4). Clinical features, 27 DVH features, 107 radiomics features and 107 dosiomics features were extracted for each case and included in the model construction. The least absolute shrinkage and selection operator (LASSO) regression method was used to select the most relevant features. The eXtreme Gradient Boosting (XGBoost) was then employed to train separate models using the selected features from clinical, DVH, radiomics and dosiomics data. Finally, a combined model incorporating all features was developed. The models were evaluated using receiver operating characteristic (ROC) curves and decision curve analysis. In the test cohort, the area under the receiver operating characteristic curve (AUC) for the clinical, DVH, radiomics, dosiomics and combined models were 0.798 (95% confidence interval [CI], 0.656-0.941), 0.673 (0.512-0.834), 0.714 (0.555-0.873), 0.698 (0.530-0.848) and 0.842 (0.724-0.960), respectively. The combined model exhibited higher AUC values compared to other models. The decision curve analysis demonstrated that the combined model had superior clinical utility within the threshold probability range of 1% to 79% when compared to the other models. This study has successfully developed a predictive model that combines multiple features. The performance of the combined model is superior to that of single-feature models, allowing for early prediction of RIHT in patients with nasopharyngeal carcinoma after tomotherapy.

Impact of chrono-radiotherapy on the prognosis and treatment-related toxicity in patients with locally advanced nasopharyngeal carcinoma: A multicenter propensity-matched study.

The timing of radiotherapy (RT) delivery has been reported to affect both cancer survival and treatment toxicity. However, the association among the timing of RT delivery, survival, and toxicity in locally advanced nasopharyngeal carcinoma (LA-NPC) has not been investigated. We retrospectively reviewed patients diagnosed with LA-NPC who received definitive RT at multiple institutions. The median RT delivery daytime was categorized as morning (DAY) and night (NIGHT). Seasonal variations were classified into the darker half of the year (WINTER) and brighter half (SUMMER) according to the sunshine duration. Cohorts were balanced according to baseline characteristics using propensity score matching (PSM). Survival and toxicity outcomes were evaluated using Cox regression models. A total of 355 patients were included, with 194/161 in DAY/NIGHT and 187/168 in WINTER/SUMMER groups. RT delivered during the daytime prolonged the 5-year overall survival (OS) (90.6% vs. 80.0%, p = 0.009). However, the significance of the trend was lost after PSM (p = 0.068). After PSM analysis, the DAY cohort derived a greater benefit in 5-year progression-free survival (PFS) (85.6% vs. 73.4%, p = 0.021) and distant metastasis-free survival (DMFS) (89.2% vs. 80.8%, p = 0.051) in comparison with the NIGHT subgroup. Moreover, multivariate analysis showed that daytime RT was an independent prognostic factor for OS, PFS, and DMFS. Furthermore, daytime RT delivery was associated with an increase in the incidence of leukopenia and radiation dermatitis. RT delivery in SUMMER influenced only the OS significantly (before PSM: p = 0.051; after PSM: p = 0.034). There was no association between toxicity and the timing of RT delivery by season. In LA-NPC, the daytime of radical RT served as an independent prognostic factor. Furthermore, RT administered in the morning resulted in more severe toxic side effects than that at night, which needs to be confirmed in a future study.

Efficacy of salvage surgery versus re-irradiation for isolated regional lymph node recurrence in patients with nasopharyngeal carcinoma.

BACKGROUND: To compare the clinical characteristics and prognoses of patients with isolated regional lymph node recurrent nasopharyngeal carcinoma (irrNPC) who underwent surgery or re-irradiation treatment. METHODS: We retrospectively reviewed 124 irrNPC patients who underwent initial radiotherapy between January 2010 and December 2020. The staging of regional lymph node recurrence was as follows: 75.8% for rN1, 14.5% for rN2, and 9.7% for rN3. Fifty-five patients underwent regional lymph node surgery (Surgery group), and sixty-nine patients received salvage radiotherapy with or without chemotherapy (Re-irradiation group). The survival rate was compared using Kaplan‒Meier analysis and evaluated by the log-rank test. Cox proportional hazard models were used to analyze prognostic factors. RESULTS: The median follow-up time was 70 months, the 5-year overall survival (OS) was 74%, and the median survival time was 60.8 months. There were no significant differences in 5-year OS (75.6% vs. 72.4%, P = 0.973), regional recurrence-free survival (RRFS, 62.7% vs. 71.1%, P = 0.330) or distant metastasis-free survival (DMFS, 4.2% vs.78.7%, P = 0.677) between the Surgery group and Re-irradiation group. Multivariate analysis revealed age at recurrence, radiologic extra-nodal extension (rENE) status, and recurrent lymph node (rN) classification as independent prognostic factors for OS. The rENE status was an independent prognostic factor for DMFS. Subgroup analysis of the Surgery group revealed that the rN3 classification was an adverse prognostic factor for OS. Age at recurrence ≥ 50 years, GTV-N dose, and induction chemotherapy were found to be independent prognostic factors for OS, RRFS, and DMFS, respectively, in the Re-irradiation group. CONCLUSIONS: For NPC patients with isolated regional lymph node recurrence after initial radiotherapy, those who underwent surgery had survival prognosis similar to those who underwent re-radiotherapy with or without chemotherapy. A prospective study is needed to validate these findings.

Could nutrition status predict fatigue one week before in patients with nasopharynx cancer undergoing radiotherapy?

BACKGROUND: Patients with nasopharyngeal carcinoma (NPC) undergoing radiotherapy experience significant fatigue, which is frequently underestimated due to the lack of objective indicators for its evaluation. This study aimed to explore the longitudinal association between fatigue and nutrition status 1 week in advance. METHODS: From January 2021 to June 2022, a total of 105 NPC patients who received intensity-modulated radiation therapy were enrolled in the observational longitudinal study. The significant outcomes, including the Piper Fatigue Scale-12 (PFS-12), the Scored Patient-Generated Subjective Global Assessment (PG-SGA), four body composition indices, and the Hospital Anxiety and Depression Scale (HADS), were assessed weekly from pre-treatment until the completion of radiotherapy (T0-T7) to explore their relationship. RESULTS: The trajectories of PFS-12 and all dimensions for 105 participants reached a peak during the fifth week. Sensory fatigue consistently received the highest scores (T0 = 1.60 ± 2.20, T5 = 6.15 ± 1.57), whereas behavior fatigue exhibited the fastest increase over time (T0 = 1.11 ± 1.86, T5 = 5.47 ± 1.70). Higher PG-SGA scores were found to be weakly explainable for aggravating fatigue (ß = 0.02 ~ 0.04). Unlike generalized additive mixed models, marginal structural models (MSM) produced larger effect values (ß = 0.12 ~ 0.21). Additionally, body composition indices showed weakly negative relationships with fatigue in MSMs one week in advance. CONCLUSIONS: The PG-SGA may be a more accurate predictor of future-week fatigue than individual body composition indicators, particularly when HADS is controlled for as a time-dependent confounder.

CircCDYL2 bolsters radiotherapy resistance in nasopharyngeal carcinoma by promoting RAD51 translation initiation for enhanced homologous recombination repair.

BACKGROUND: Radiation therapy stands to be one of the primary approaches in the clinical treatment of malignant tumors. Nasopharyngeal Carcinoma, a malignancy predominantly treated with radiation therapy, provides an invaluable model for investigating the mechanisms underlying radiation therapy resistance in cancer. While some reports have suggested the involvement of circRNAs in modulating resistance to radiation therapy, the underpinning mechanisms remain unclear. METHODS: RT-qPCR and in situ hybridization were used to detect the expression level of circCDYL2 in nasopharyngeal carcinoma tissue samples. The effect of circCDYL2 on radiotherapy resistance in nasopharyngeal carcinoma was demonstrated by in vitro and in vivo functional experiments. The HR-GFP reporter assay determined that circCDYL2 affected homologous recombination repair. RNA pull down, RIP, western blotting, IF, and polysome profiling assays were used to verify that circCDYL2 promoted the translation of RAD51 by binding to EIF3D protein. RESULTS: We have identified circCDYL2 as highly expressed in nasopharyngeal carcinoma tissues, and it was closely associated with poor prognosis. In vitro and in vivo experiments demonstrate that circCDYL2 plays a pivotal role in promoting radiotherapy resistance in nasopharyngeal carcinoma. Our investigation unveils a specific mechanism by which circCDYL2, acting as a scaffold molecule, recruits eukaryotic translation initiation factor 3 subunit D protein (EIF3D) to the 5'-UTR of RAD51 mRNA, a crucial component of the DNA damage repair pathway to facilitate the initiation of RAD51 translation and enhance homologous recombination repair capability, and ultimately leads to radiotherapy resistance in nasopharyngeal carcinoma. CONCLUSIONS: These findings establish a novel role of the circCDYL2/EIF3D/RAD51 axis in nasopharyngeal carcinoma radiotherapy resistance. Our work not only sheds light on the underlying molecular mechanism but also highlights the potential of circCDYL2 as a therapeutic sensitization target and a promising prognostic molecular marker for nasopharyngeal carcinoma.

Automatic IMRT treatment planning through fluence prediction and plan fine-tuning for nasopharyngeal carcinoma.

BACKGROUND: At present, the implementation of intensity-modulated radiation therapy (IMRT) treatment planning for geometrically complex nasopharyngeal carcinoma (NPC) through manual trial-and-error fashion presents challenges to the improvement of planning efficiency and the obtaining of high-consistency plan quality. This paper aims to propose an automatic IMRT plan generation method through fluence prediction and further plan fine-tuning for patients with NPC and evaluates the planning efficiency and plan quality. METHODS: A total of 38 patients with NPC treated with nine-beam IMRT were enrolled in this study and automatically re-planned with the proposed method. A trained deep learning model was employed to generate static field fluence maps for each patient with 3D computed tomography images and structure contours as input. Automatic IMRT treatment planning was achieved by using its generated dose with slight tightening for further plan fine-tuning. Lastly, the plan quality was compared between automatic plans and clinical plans. RESULTS: The average time for automatic plan generation was less than 4 min, including fluence maps prediction with a python script and automated plan tuning with a C# script. Compared with clinical plans, automatic plans showed better conformity and homogeneity for planning target volumes (PTVs) except for the conformity of PTV-1. Meanwhile, the dosimetric metrics for most organs at risk (OARs) were ameliorated in the automatic plan, especially Dmax of the brainstem and spinal cord, and Dmean of the left and right parotid glands significantly decreased (P < 0.05). CONCLUSION: We have successfully implemented an automatic IMRT plan generation method for patients with NPC. This method shows high planning efficiency and comparable or superior plan quality than clinical plans. The qualitative results before and after the plan fine-tuning indicates that further optimization using dose objectives generated by predicted fluence maps is crucial to obtain high-quality automatic plans.

Nomograms based on the lymphocyte-albumin-neutrophil ratio (LANR) for predicting the prognosis of nasopharyngeal carcinoma patients after definitive radiotherapy.

Much evidence has accumulated to show that inflammation and nutritional status are associated with the prognosis of patients with various cancers. The present study was designed to explore the prognostic role of the LANR in NPC patients receiving definitive radiotherapy and to construct a nomogram for predicting patient survival. This study retrospectively reviewed 805 NPC patients (604 in the training cohort and 201 in the validation cohort) who received definitive radiotherapy between January 2013 and December 2019. The clinical data and pretreatment laboratory test data, including lymphocyte count, neutrophil count, and serum ALB concentration, were collected for all patients. The LANR was calculated as the albumin × lymphocyte/neutrophil ratio. Patients in the training cohort and validation cohort were categorized into high-LANR and low-LANR groups according to the corresponding cutoff values. The independent prognostic factors for overall survival (OS), progression-free survival (PFS), relapse-free survival (RFS), and metastasis-free survival (MFS) were evaluated by univariate and multivariate Cox regression analyses, and a nomogram was subsequently constructed. The performance of the nomogram was evaluated by the concordance index (C-index) and calibration curve. A low LANR (< 14.3) was independently associated with worse OS, PFS and MFS in NPC patients. A prognostic prediction nomogram was established based on T stage, N stage, Eastern Cooperative Oncology Group (ECOG) score, treatment modality, and LANR and was validated. The C-indices of the nomograms for OS and PFS in the training cohort were 0.729 and 0.72, respectively. The C-indices of the nomograms for OS and PFS in the validation cohort were 0.694 and 0.695, respectively. The calibration curve revealed good consistency between the actual survival and the nomogram prediction. Patients with NPC with low pretreatment LANR had a poor prognosis. The nomogram established on the basis of the LANR was efficient and clinically useful for predicting survival in NPC patients who underwent definitive radiotherapy.

Risk factors and the nomogram model for malnutrition in patients with nasopharyngeal carcinoma.

BACKGROUND: For patients with nasopharyngeal carcinoma (NPC), the incidence of malnutrition is quite high, and malnutrition has severe effects on NPC patients. However, there is currently no recognized gold standard or specific nutritional assessment tool available to assess malnutrition in NPC patients. Our objective was to develop and verify a new nomogram model for NPC patients. METHODS: Data were collected from NPC patients. To evaluate risk factors for malnutrition, univariate and multivariate logistic regression analyses were used. Based on the risk factors, a new nomogram model was developed. The efficacy of the model was evaluated and validated. RESULTS: Logistic regression analysis showed that age ≥ 65 years, the number of chemotherapy cycles completed ≥ 1, a high total radiation dose received, low body mass index (BMI), low albumin, and low chloride were the risk factors. The assessment effect of the new model was good by evaluation and validation; it can be used as an assessment tool for malnutrition in NPC patients. CONCLUSIONS: Age ≥ 65 years, completing ≥ 1 chemotherapy cycles, a high total radiation dose received, low BMI, low albumin, and low chloride levels are risk factors for malnutrition in NPC patients. The assessment effect of the new model, developed based on these risk factors, is good, and it can be used as an assessment tool for malnutrition in NPC patients.

Quality of life in patients with nasopharyngeal carcinoma receiving IMRT vs IMPT: a multicenter prospective longitudinal study.

PURPOSE: Nasopharyngeal carcinoma (NPC) patients may experience symptom distress and depression during and after radiation therapy, which negatively impacts quality of life (QOL). We sought to identify trajectories of symptom distress, depression, social support, and QOL in patients with NPC receiving intensity-modulated radiation therapy (IMRT) vs intensity-modulated proton therapy (IMPT). METHODS: A multicenter prospective longitudinal study recruited NPC patients from two leading medical centers in Taiwan. The 121 NPC patients were followed from before RT (T0), at 4 weeks after beginning RT (T1), at 6 weeks of RT or the end of treatment (T2), and at 4 weeks post-RT (T3). Generalized estimating equation analysis was used to identify the factors related to QOL. RESULTS: Patients' symptom distress and depression increased from T0, peaked at T2, and decreased at T3. Physical-QOL and psychosocial-QOL decreased from T0 to T2, then increased by T3. Patients who had early-stage cancer, received a lower RT dose, had less symptom distress, and had less depression were more likely to have better QOL. Greater physical-QOL was associated with IMPT receipt, higher education level, early cancer stage, lower radiation dose, less symptom distress, and less depression. Patients who had good physical performance, received a lower radiation dose, had less symptom distress, and had less depression were more likely to have better psychosocial-QOL. CONCLUSION: Radiation dose, symptom distress, and depression were the most important factors affecting QOL in patients with NPC. Understanding the factors associated with the trajectory of QOL can guide care during radiation treatment.

Clinical features and prognostic factors of nasopharyngeal carcinoma with brain metastases.

BACKGROUND: Brain metastasis in nasopharyngeal carcinoma is a rare occurrence, and the characteristics of patients in this subgroup remain poorly defined. This study aims to delineate the clinical features, treatment modalities, prognostic factors, and survival of nasopharyngeal carcinoma patients with brain metastasis. METHODOLOGY: A retrospective analysis was conducted on patients diagnosed with nasopharyngeal carcinoma who developed brain metastasis and were treated at the Sun Yat-sen University Cancer Center between July 2000 and July 2023. Clinical data from patients were collected and used to assess their survival after brain metastases and prognostic factors. RESULTS: Among 82,434 nasopharyngeal carcinoma patients, 40 (0.06 %) developed Brain metastasis with a median follow-up of 5.1 years. The predominant histological subtype was non-keratinizing squamous cell carcinoma (85 %). The median post-BM survival was 25 months. The age, the Eastern Cooperative Oncology Group (ECOG), and the procedural treatment of BM were prognostic factors. Notably, patients receiving local treatments had significantly prolonged post-BM survival compared to those receiving systemic therapy alone (median, 47.00 vs. 11.00 months; p = 0.011). CONCLUSIONS: This is the largest cohort of brain metastasis in nasopharyngeal carcinoma to date. Local therapeutic measures after brain metastasis can significantly enhance the prognosis of these patients, particularly when radiotherapy is applied.

Prediction of severe radiation-induced oral mucositis in locally advanced nasopharyngeal carcinoma using the combined systemic immune-inflammatory index and prognostic nutritional index.

OBJECTIVE: Severe radiation-induced oral mucositis (sRIOM) can seriously affect patients' quality of life and treatment compliance. This study was to investigate the utility of the systemic immune-inflammatory index (SII) and prognostic nutritional index (PNI) in predicting sRIOM in patients with locally advanced nasopharyngeal carcinoma (LANPC). METHODS: 295 patients with LANPC were retrospectively screened. The pre-radiotherapy SII and PNI were calculated based on peripheral blood samples. A receiver operating characteristic (ROC) curve was used to determine the cut-off value. Logistic regression was used for univariate and multivariate analyses. Patients were classified into three groups based on the SII-PNI score: score of 2, high SII (> cut-off value) and low PNI (≤ cut-off value); score of 1, either high SII or low PNI; score of 0, neither high SII nor low PNI. RESULTS: The SII-PNI demonstrated significant predictive ability for sRIOM occurrence, as evidenced by an area under the curve (AUC) of 0.738. The incidence rates of sRIOM with SII-PNI score of 2, 1, and 0 were 73.86%, 44.35%, and 18.07%, respectively. Multivariate analysis confirmed that the SII-PNI score was an independent risk factor for sRIOM. CONCLUSION: The SII-PNI score is a reliable and convenient indicator for predicting sRIOM in patients with LANPC.

CPNE1, A Potential Therapeutic Target in Nasopharyngeal Carcinoma, Affects Cell Growth and Radiation Resistance.

The increased expression of Copine 1 (CPNE1) has been observed in various cancers, which promotes cell proliferation, apoptosis, and radio resistance. However, the potential mechanism of CPNE1 in nasopharyngeal carcinoma (NPC) remains elusive. Consequently, our objective was to investigate the role of CPNE1 in regulating proliferation and radio resistance of NPC. CPNE1 expression in NPC and normal patients were obtained from Cancer Genome Atlas (TCGA) database. An elevated CPNE1 was observed in NPC patients and cells (C666-1, SUNE-1, and HNE-1). Then, C666-1 and SUNE-1 cells were subjected to si-CPNE1 under different radiations (0-8 Gy). Cell growth and proliferation were measured by CCK8 and EDU assays, which demonstrated si-CPNE1 suppressed proliferation. Colony formation was performed to detect cell viability under different radiation therapy and survival curve of cell was plotted, which indicated that CPNE1 knockdown improved cell radiosensitivity. Additionally, flow cytometry showed silence of CPNE1 enhanced apoptosis rate in radiated cells. To further investigate the mechanisms of CPNE1 regulating NPC, the expression of activated phosphate Akt (p-Akt) was assessed through western blotting. We observed elevated p-Akt in si-CPNE1 transfected C666-1 and SUNE-1 cells. In conclusion, these results demonstrated that CPNE1 expression is elevated in nasopharyngeal carcinoma cells, and its silencing could attenuate nasopharyngeal carcinoma advancement and improve radiosensitivity to radiation therapy by controlling Akt activation.

Tumor volume instead of recurrent T category predicts clinical outcome of patients with locally recurrent nasopharyngeal carcinoma salvaged by carbon ion radiation therapy.

BACKGROUND: Although carbon ion radiation therapy (CIRT) substantially improves the overall survival (OS) of patients with LR-NPC, approximately 40% of the patients may develop local recurrence. The purpose of study is to assess the value of tumor volume (TV) as a predictive tool to guide individualized CIRT. METHODS: Consecutive patients with LR-NPC treated using CIRT at Shanghai Proton and Heavy Ion Center between April 2015 and May 2019 were included. TV before CIRT was delineated and calculated. The generalized additive Cox model was used to examine the relationship between TV and OS and local progression-free survival (LPFS). A cutoff value of tumor volume was identified to best discriminate patients with different 2-year OS rates, using receiver operating characteristic (ROC) analysis. RESULTS: A total of 157 patients were enrolled. The median tumor volume was 22.49 (2.52-90.13) ml. In the univariable analyses, tumor volume was significantly associated with OS (p < 0.001) and LPFS (p = 0.01). The relationships with OS (p = 0.009) and LPFS (p = 0.020) remained significant in multivariable analyses. Using ROC analysis, a TV of 26.69 ml was identified to predict the 2-year OS rate. To facilitate potential clinical use, 25 ml was designated as the final cutoff value. The 2-year OS and LPFS rates were 88.6 % vs 62.3 %, and 54.7 % vs 35.5 %, for patients with a TV ≤ 25 ml and > 25 ml, respectively. CONCLUSION: Tumor volume could predict the OS and LPFS of patients. We propose that tumor volume should be considered in the risk stratification and CIRT-based treatment for patients with LR-NPC.

Multi-domain neurocognitive impairment following definitive intensity-modulated radiotherapy for nasopharyngeal cancer: A cross-sectional study.

INTRODUCTION: Neurocognitive impairment from inadvertent brain irradiation is common following intensity-modulated radiotherapy (IMRT) for nasopharyngeal carcinoma (NPC). This study aimed to determine the prevalence, pattern, and radiation dose-toxicity relationship of this late complication. MATERIALS AND METHODS: We undertook a cross-sectional study of 190 post-IMRT NPC survivors. Neurocognitive function was screened using the Montreal Cognitive Assessment-Hong Kong (HK-MoCA). Detailed assessments of eight distinct neurocognitive domains were conducted: intellectual capacity (WAIS-IV), attention span (Digit Span and Visual Spatial Span), visual memory (Visual Reproduction Span), verbal memory (Auditory Verbal Learning Test), processing speed (Color Trail Test), executive function (Stroop Test), motor dexterity (Grooved Pegboard Test) and language ability (Verbal Fluency Test). The mean percentiles and Z-scores were compared with normative population data. Associations between radiation dose and brain substructures were explored using multivariable logistic regression. RESULTS: The median post-IMRT interval was 7.0 years. The prevalence of impaired HK-MoCA was 25.3 % (48/190). Among the participants, 151 (79.4 %) exhibited impairments in at least one neurocognitive domain. The predominantly impaired domains included verbal memory (short-term: mean Z-score, -0.56, p < 0.001; long-term: mean Z-score, -0.70, p < 0.001), processing speed (basic: mean Z-score, -1.04, p < 0.001; advanced: mean Z-score, -0.38, p < 0.001), executive function (mean Z-score, -1.90, p < 0.001), and motor dexterity (dominant hand: mean Z-score, -0.97, p < 0.001). Radiation dose to the whole brain, hippocampus, and temporal lobe was associated with impairments in executive function, verbal memory, processing speed, and motor dexterity. CONCLUSIONS: Neurocognitive impairment is prevalent and profound in post-IMRT NPC survivors. Cognitive assessment and rehabilitation should be considered part of survivorship care.

The individualized delineation of clinical target volume for primary nasopharyngeal carcinoma based on invasion risk of substructures: A prospective, real-world study with a large population.

BACKGROUND AND PURPOSE: The delineation of clinical target volume (CTV) for primary nasopharyngeal carcinoma (NPC) is currently controversial and the international guideline still recommend a uniform border for CTV regardless of the tumor extent. We conducted this prospective, real-world study to evaluate the clinical outcomes of our individualized CTV delineation method based on distance plus substructures. MATERIALS AND METHODS: We preliminarily investigated the local extension patterns of NPC on 354 newly diagnosed patients and defined the structures surrounding the nasopharynx as Level-1 to Level-4 substructures stratified by the risk of invasion. We then enrolled patients with newly diagnosed NPC without distant metastasis to investigate our individualized CTV delineation protocol. All patients received intensity modulated radiotherapy. CTV1 and CTV2 were prescribed doses of 60 Gy and 54 Gy in 30 âˆ¼ 33 fractions. The primary endpoint was local recurrence-free survival (LRFS); secondary endpoints included regional control and survival, estimated using the Kaplan-Meier method. The local failure patterns were also analyzed. RESULTS: From January 2008 to December 2012 and from January 2013 to September 2019, 356 and 648 patients were enrolled, named as training set and validation set, respectively. With a median follow-up of 104.6 (interquartile, 73.1-126.9) and 51.4 (39.5-78.5) months, 31 (8.7 %) and 38 (5.9 %) patients in training and validation sets experienced local recurrence, and the 5-year LRFS was 93.0 % and 93.2 %, respectively; 63 (17.7 %) and 39 (6 %) patients died in training and validation sets, and the 5-year overall survival (OS) was 88.5 % and 93.4 %, respectively. For the whole study cohort (N = 1004) with a median follow-up of 66.6 (41.5-98.0) months, the 5-year LRFS and OS was 93.2 % and 91.5 %. The grade 3 late toxicities included xerostomia, subcutaneous fibrosis, hearing impairment, trismus, visuality impairment and skin atrophy, with a total incidence of 1.5 %. Sixty-seven of 69 (97.1 %) local recurrence was in high-dose area. CONCLUSION: Our individualized CTV delineation method can achieve favorable local tumor control and long-term survival outcomes with acceptable late toxicities.

Evolution of radiation-induced temporal lobe injury after intensity-modulated radiation therapy in nasopharyngeal carcinoma: a large cohort retrospective study.

BACKGROUND: Previous studies have demonstrated conflicting findings regarding the initial MRI patterns of radiotherapy-induced temporal lobe injury (RTLI) and the evolution of different RTLI patterns. The aim of this study was to evaluate the initial MRI pattern and evolution of RTLI in patients with nasopharyngeal carcinoma (NPC) by means of a large cohort study. METHODS: Data of patients with RTLI were retrospectively collected from two hospitals between January 2011 and December 2021. The injured lobes were categorized into three patterns based on initial MRI patterns: isolated white matter lesions (WMLs), isolated contrast-enhanced lesions (CELs), and combined WMLs and CELs. The latency period, MRI appearances, and temporal changes in WMLs and CELs were evaluated. RESULTS: A total of 913 RTLI patients with 1092 injured lobes were included in this study. The numbers of isolated WMLs, isolated CELs, and combined WMLs and CELs identified at the first MRI detection were 7 (0.6%), 172 (15.8%), and 913 (83.6%), respectively. The evolution of bilateral RTLI was different in the same patient, and that of unilateral RTLI combined with WMLs and CELs also may occur asynchronously. The time intervals from the initial MRI detection of isolated WMLs, isolated CELs, combined WMLs and CELs to the last negative MRI scan were 8.6, 8.9 and 11.0 months, respectively. A significant difference was observed in the time intervals between the three patterns (H = 14.287, P = 0.001). And the time interval was identified as an independent factor influencing the initial MRI pattern of RTLI after Poisson regression (P = 0.002). CONCLUSION: Both WMLs and CELs could be the initial and only MRI abnormalities in patients with RTLI. This study is of great significance in accurately diagnosing RTLI early and providing timely treatment options. Additionally, it provides clinical evidence for guidelines on NPC, emphasizing the importance of regular follow-up of NPC patients.

A protocol for a randomized trial evaluating the role of carbon-ion radiation therapy plus camrelizumab for patients with locoregionally recurrent nasopharyngeal carcinoma.

PURPOSE: Management of locoregionally recurrent nasopharyngeal carcinoma (LR NPC) is difficult. Although carbon-ion radiation therapy (CIRT) could substantially improve the overall survival (OS) of those patients, around 40% of the patients may still develop local failure. Further improvement of the disease control is necessary. Immunotherapy, such as immune checkpoint inhibitors (ICIs) becomes a promising antitumor treatment. The role of ICIs was proved in head and neck cancers including recurrent/metastatic NPC. Preclinical studies indicated potential synergistic effects between radiation therapy and ICIs. Therefore, we conduct a randomized phase 2 trial to evaluate the efficacy and safety of camrelizumab, an anti-PD-1 monoclonal antibody, along with CIRT in patients with LR NPC. METHODS: Patients will be randomly assigned at 1:1 to receive either standard CIRT with 63 Gy (relatively biological effectiveness, [RBE]) in 21 fractions, or standard CIRT plus concurrent camrelizumab. Camrelizumab will be administered intravenously with a dose of 200 mg, every 2 week, for a maximum of 1 year. We estimate addition of camrelizumab will improve the 2-year progression-free survival (PFS) from 45% to 60%. A total of 146 patients (with a 5% lost to follow-up rate) is required to yield a type I error of 0.2, and a power of 0.8. RESULTS AND CONCLUSION: The results of the trial may shed insights on the combined therapy with ICIs and CIRT.

Worth of pan-immune-inflammation value in trismus prediction after concurrent chemoradiotherapy for nasopharyngeal carcinomas.

OBJECTIVE: Radiation-induced trismus (RIT), one of the rare but serious side effects of concurrent chemoradiotherapy (C-CRT), is difficult to predict with high accuracy. We aimed to examine whether the pretreatment pan-immune-inflammation value (PIV) measures predict RIT in patients with locally advanced nasopharyngeal carcinoma (LA-NPC) receiving C-CRT. METHODS: Data of patients with LA-NPC who underwent C-CRT and had maximum mouth openings (MMO) > 35 mm were reviewed. Any MMO of 35 mm or less after C-CRT was considered RIT. All PIV values were computed using the complete blood count test results: PIV = (Platelets × Monocytes × Neutrophils) ÷ Lymphocytes. The receiver operating characteristic analysis was employed to dissect a possible association between pre-treatment PIV readings and RIT status. Confounding variables were tested for their independent relationship with the RIT rates using logistic regression analysis. RESULTS: The research comprised 223 participants, and RIT was diagnosed in 46 (20.6%) at a median time from C-CRT to RIT of 10 months (range: 5-18 months). Pre-C-CRT PIV levels and RIT rates were analyzed using receiver operating characteristic curve analysis, with 830 being the optimal cutoff (area under the curve: 92.1%; sensitivity: 87.5%; specificity: 85.5%; Youden index: 0.730). RIT was significantly more prevalent in the PIV > 830 cohort than its PIV ≤ 830 counterpart (60.3% vs. 5%; hazard ratio 5.79; P < 0.001). Multivariate logistic regression analysis revealed that advanced T-stage (P = 0.004), masticatory apparatus dose V58Gy≥%32 (P = 0.003), and PIV > 830 (P < 0.001) were independently linked with significantly elevated rates of RIT. CONCLUSION: The presence of elevated pre-C-CRT PIV is a unique biological marker that independently predicts increased RIT rates in LA-NPC undergoing C-CRT.