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Green synthesis of gold nanoparticles (AuNPs) using Ginkgo biloba leaf aqueous extract was optimized by response surface methodology to yield monodispersed, crystalline nanoparticles of 18 ± 4 nm diameter. Fourier transform infrared spectroscopy confirmed capping by flavonoids, terpenoids and polyphenols providing stability for over 6 months. The biosynthesized AuNPs exhibited promising in vitro dose and time-dependent antiproliferative effects against human nasopharyngeal carcinoma CNE1 cells with IC50 reducing from 65.7 to 39.2 μg/mL over 24–72 hrs. Distinct cytoplasmic damage was observed under microscope. Treatment with 50 μg/mL AuNPs for 48 hrs dramatically upregulated pro-apoptotic Bax, Caspase-3 and p53 by 8.7, 6.5 and 4.3 fold respectively while downregulating anti-apoptotic Bcl-2 by 11.2 fold, indicating apoptosis induction via mitochondrial intrinsic pathway. The green fabricated G. biloba AuNPs displayed preferential toxicity towards carcinoma cells compared to normal fibroblasts, indicating potential for targeted nasopharyngeal cancer therapy. [ABSTRACT FROM AUTHOR]

This study aimed to investigate whether the RapidPlan (RP) model configured by volumetric modulated arc therapy (VMAT) plans of nasopharyngeal carcinoma (NPC) could be used to assist in the optimization of HT plans and improve their quality. An RP model was trained using 100 clinically accepted VMAT plans of NPC patients. The predicted dose constraints of the VMAT trained RP model were used to reoptimize 25 consecutive clinically accepted HT plans (HT_clinical) and perform new VMAT plans based on the same computed topography (CT). The dosimetric quality of the reoptimized HT plans (HT_reoptimized), HT_clinical, and VMAT group were compared. The minimum dose encompassing 2% target (D 2%), the minimum dose encompassing 98% target (D 98%), homogeneity index (HI) and conformity index (CI) were similar for most targets between the HT_clinical and HT_reoptimized plans, although certain targets in the HT_reoptimized plans had higher D 2% and HI and lower D 98%. The HT_reoptimized plans outperformed the HT_clinical plans in the Dmax and D1cc of the spinal cord, V 40Gy of the left temporal lobe, Dmean and V 30Gy of the oral cavity, Dmean of the larynx and thyroid, and the differences were statistically significant. HT plans had higher CI and HI than VMAT plans. HT plans outperformed VMAT plans in the Dmax of the spinal cord and lenses, V 30Gy of the oral cavity and parotids, and V 40Gy of the temporal lobes, but underperformed in the Dmax and D1cc of the brainstem, D1cc of the spinal cord and Dmean of the oral cavity. The VMAT-based RP model can be used to assist in the planning of HT plans and improve the dosimetry quality of HT plans. [ABSTRACT FROM AUTHOR]

This study aims to establish a delineation guideline for the contouring of the hypoglossal nerve by dividing the nerve into different segments, and to test the possibility of a radiation dose reduction to the hypoglossal nerve in NPC patients receiving radiotherapy. Twenty NPC patients were selected arbitrarily. The hypoglossal nerves were delineated using anatomic landmarks and divided into the cisternal, intracanalicular, carotid, and transverse segments. The tumor coverage by radiation and dose-volume parameters of the nerve with and without various dose constraints to the hypoglossal nerve were compared. The hypoglossal nerve, which is invisible on CT images, can be delineated accurately with the assistance of several anatomic landmarks. Without a dose constraint to the hypoglossal nerve, the carotid space, intracanalicular, and transverse segments had high radiation dose-volumes. The dose-volume to the nerve, however, can be reduced when the nerve was defined and a dose constraint was given. The delineation of the hypoglossal nerve with its different segments is feasible. The carotid space, intracanalicular, and transverse segments received the highest dose, where the nerve damage was most likely located. The dose to the nerve can be reduced to less than 70 Gy using the intensity-modulated radiotherapy technique. [ABSTRACT FROM AUTHOR]

To evaluate whole-node histogram parameters of blood flow (BF) maps derived from three-dimensional pseudo-continuous arterial spin-labelled (3D pCASL) imaging in discriminating metastatic from benign upper cervical lymph nodes (UCLNs) for nasopharyngeal carcinoma (NPC) patients. Eighty NPC patients with a total of 170 histologically confirmed UCLNs (67 benign and 103 metastatic) were included retrospectively. Pre-treatment 3D pCASL imaging was performed and whole-node histogram analysis was then applied. Histogram parameters and morphological features, such as minimum axis diameter (M in AD), maximum axis diameter (M ax AD), and location of UCLNs, were assessed and compared between benign and metastatic lesions. Predictors were identified and further applied to establish a combined model by multivariate logistic regression in predicting the probability of metastatic UCLNs. Receiver operating characteristic (ROC) curves were used to analyse the diagnostic performance. Metastatic UCLNs had larger M in AD and M in AD/M ax AD ratio, greater energy and entropy values, and higher incidence of level II (upper jugular group), but lower BF 10th value than benign nodes (all p <0.05). M in AD, BF 10th , energy, and entropy were validated as independent predictors in diagnosing metastatic UCLNs. The combined model yielded an area under the curve (AUC) of 0.932, accuracy of 84.42 %, sensitivity of 80.6 %, and specificity of 90.29 %. Whole-node histogram analysis on BF maps is a feasible tool to differentiate metastatic from benign UCLNs in NPC patients, and the combined model can further improve the diagnostic efficacy. • Whole-node histogram parameters could act as a noninvasive effective biomarker. • A nomogram combining histogram parameters and M in AD of UCLNs was constructed. • The nomogram could serve as a novel diagnostic tool for the status of UCLNs. [ABSTRACT FROM AUTHOR]

A 63-year-old man with diabetes presented with unilateral ptosis and an exotropia. A diagnosis of isolated diabetic III nerve palsy was made. Subsequent neuro-ophthalmologic evaluation showed multiple cranial nerves involvement consistent with a diagnosis of orbital apex syndrome. Review of past medical history was significant for a previous nasopharyngeal carcinoma, and biopsy of the involved site was consistent with tumor recurrence. This case highlights the importance of correct medical history taking and anatomo-clinical correlation in neuro-ophthalmology. [ABSTRACT FROM AUTHOR]

Head and neck cancer (HNC) is the sixth most common cancer worldwide. The condition and its treatment often lead to marked morbidities and, for some patients, premature death. Inferentially, HNC imposes a significant economic burden on society. This study aims to provide a comprehensive and detailed estimation of the cost of illness of HNC for Sweden in 2019. This is a prevalence-based cost of illness study. Resource utilization and related costs are quantified using national registry data. A societal perspective is applied, including (1) direct costs for healthcare utilization, (2) costs for informal care from family and friends, and (3) costs for productivity loss due to morbidity and premature death. The human capital approach is used when estimating productivity losses. The societal cost of HNC for Sweden in 2019 was estimated at €92 million, of which the direct costs, costs for informal care, and costs for productivity loss represented 34%, 2%, and 64%, respectively. Oral cavity cancer was the costliest HNC, followed by oropharyngeal cancer, whereas nasopharyngeal cancer was the costliest per person. The cost of premature mortality comprised 60% of the total cost of productivity loss. Males accounted for 65% of direct costs and 67% of costs for productivity loss. The societal cost of HNC is substantial and constitutes a considerable burden to Swedish society. The results of the present study may be used by policymakers for planning and allocation of resources. Furthermore, the information may be used for future cost-effectiveness analyses. • Available cost-of-illness studies of head and neck cancer often lack in comprehensiveness, are not tumor site-specific, and do not have a societal perspective. • The cost for head and neck in Sweden for 2019 was estimated to €92 386 801: 64% was generated by productivity loss due to morbidity (sick leave) and premature death (early retirement). The data are tumor-site-specific and include costs for healthcare utilization, informal care, and productivity loss. • The results highlight the marked impact of costs for productivity loss on the total societal costs for head and neck cancer, which may have implications for decisions such as whether or not to implement standardized programs for early rehabilitation. The data provide a basis for future cost-effectiveness analyses. [ABSTRACT FROM AUTHOR]

Nasopharyngeal carcinomas (NPC) are endemic in southeast Asia and rare in Europe with an incidence of 0.07/100.000 persons. Five-year survival is about 50%. Diagnosis is provided by histological findings and staging classification is done according to AJCC. EBV DNA serum levels should be determined before and after local treatment, carry prognostic significance and can be used in the active surveillance of cancer survivors. The best method for serum determination of EBV DNA is still under discussion. Advanced locoregional disease carries a greater risk of distant spread, highlighting the need of treatment intensification in higher risk patients. The best treatment plan is still under discussion: concurrent chemoradiation followed by adjuvant chemotherapy (ACT) or induction chemotherapy (ICT) followed by chemoradiation. ACT/ICT regimens should consist of two-/three-drug regimens, including a platinum agent and the best drug regimen is still under investigation. ACT carries great toxicity (50% require dose reductions, 60% complete treatment) and has a relatively low PFS and OS benefit. ICT is better tolerated, but may compromise cisplatin cumulative dose in concomitant chemoradiation and delay radiation start, possibly compromising the effectiveness of local treatment. Nonetheless, ICT improves PFS and OS when compared to chemoradiation alone, mostly because of better metastasis free survival (MFS), making this a promising strategy in properly selected high risk patients. Most NPC trials were conducted in countries where NPC is endemic, primarily non-queratinizing and EBV-related. Data in non-endemic countries are lacking. Our study aims to compare ACT and ICT in locally advanced and oligometastatic NPC patients treated in a European reference centre. Retrospective, observational study of patients with NPC diagnosis between January 2017 and September 2023 and disease stage III-IVb. Data were collected from patient records and included patient characteristics (gender, age, smoking history, ECOG performance status), tumor characteristics (T, N, staging, histology, EBV-status) and treatment characteristics (ACT, ICT, toxicities). PFS and OS were analyzed. Toxicity grading is according to CTCAE 5.0 and statistical analysis is descriptive. A total of 69 patients were included. Most patients were male (56.5%, n=39) with a median age of 53.0 years (18-75). Most patients had a good performance status (0 or 1 in 98.5%, n=68). Stage IVa was the most frequent initial staging (50.7%, n=35), with a majority of patients having T4 (33.3%, n=23) and N3 (39.1%, n=27) tumours. All tumours were undifferentiated queratinizing carcinomas and 86.9% (n=60) were EBV-positive. EBV DNA was rarely determined. [Display omitted] Until 2019 the most frequent treatment strategy was ACT with cisplatin-5FU (57.9%, n=40), after which ICT became more frequently used (15.9%, n=11), mostly with cisplatin-gemcitabin (45.4%, n=5). ICT had less acute toxicities that lead to treatment discontinuation (0.9% (n=1) versus 39.7% (n=23)). All patients completed radiotherapy after ICT, but in 4 patients optimal concomitant cisplatin dose (≥200mg/m2) was compromised. Both ICT and ACT showed good response rates, with a complete response in 63.6% versus 79.3%, respectively. Median follow up was 45 months in the ACT group (4-125) and 27 months (1-55) in the ICT group. PFS with ACT was 45.0 months (95%CI 34.8-55.2) and OS was 46.0 months (95%CI 38.5-53.4). The ICT group is small and has a short follow-up time; PFS and OS data will be determined in the future. [Display omitted] The best course of treatment of advanced NPC is still unclear - which patients and histologies benefit most from treatment intensification? What is the role of EBV DNA and what is the best method for its determination? Should ACT or ICT be preferred? Which chemotherapy regimen is better? Treatment center expertise and the ability to provide timely treatment may also play a role in treatment decisions. Our study presents the experience of a European reference centre where ACT was the preferred treatment for a longer period of time and therefore has a significantly larger patient population with longer follow-up time. ACT seems to provide good patient outcomes, despite a worse toxicity profile and more related treatment discontinuations, but group comparison is not yet possible since our centre only recently changed strategies in managing advanced NPC patients, preferring ICT over ACT. ICT patients are still underrepresented in this analysis, with fewer patients and shorter follow-up time. Moreover, the ICT patient group has more advanced disease, including IVb oligometastatic disease (that was not included in the intensification ACT and ICT studies), making head-to-head comparisons difficult. The management of advanced NPC is a clinical challenge and more data are needed to better select both patients and treatment strategies for treatment intensification, while taking into consideration the differences between endemic and non-endemic NPC. [ABSTRACT FROM AUTHOR]

Epstein-Barr virus (EBV)-related nasopharyngeal carcinoma (NPC) is an epithelial malignancy arising from the nasopharyngeal mucosal lining. A high incidence was recorded in EBV-endemic areas (EA) such as East and Southeast Asia [1] while in Europe, a non-endemic area (NEA), is low (1/105/year); however, the estimated survival rate is much lower than that recorded in Asian EA (5-year age-standardized relative survival = 54–57% vs. 74%) [2]. Risk factors of NPC include genetic, ethnic and environmental factors [3]. Differences in incidence and survival rates between EA and NEA NPCs could involve several factors, including EBV-related factors, genetic susceptibility of the population to EBV infections, and environmental factors such as diet and pollution [4-7]. Nevertheless, all proposed models of NPC pathogenesis are based on data derived from EA in Asia. Furthermore, clinical, pathogenic, and microenvironmental characteristics may play additional roles. EBV-related NPC in EA has already been characterized using genomic and transcriptomic data analysis [8-9]. However, gene expression analysis data [10] of NEA NPC is limited. Comparing gene expression data from EA and NEA diseases allows the recognition of similarities and differences in incidence and outcome among diseases arising in different geographical areas. We investigated the transcriptomic patterns of genes involved in EA NPC to interpret these differences and verifying them to an Italian cohort with available tumor tissue and clinical data. The immune and biological/functional characterization of EA and NEA NPC could improve the identification of new therapeutic strategies. Currently, the treatment for localized NPC includes radiotherapy, which is often combined with platinum-based chemotherapy, especially for locally advanced cancer. Neoadjuvant chemotherapy with cisplatin and gemcitabine was administered in the case of high-risk disease [11 -12]. Immunotherapy with checkpoint inhibitors has shown clinical efficacy in recurrent/metastatic advanced NPC and is currently under evaluation to define its mechanism of action [13]. Our study aimed to dissect the gene expression (GE) and microenvironment of NPC, leading to the identification of the molecular subtypes of EA and NEA NPC. We also aimed to elucidate the biological and functional differences within EA NPC and between EA NPC and NEA NPC to eventually provide new insights into novel treatment strategies. Six GE datasets of NPC-EA transcriptomic repositories, including tumor and normal samples (GSE12452, GSE34573, GSE132112, GSE53819, GSE68799, GSE102349) and one validation dataset including both EA and NEA (https://doi.org/10.5281/zenodo.5347891) were retrieved. Four GE signatures associated to EBV related NPC prognosis (PMID: 24297049, 35262435, 32596151, 33096113), genes/pathways and gene sets (PMID: 35846746, 35394843, 35105963) were applied on EA and NEA NPC cohorts (Liu_NPC, Wood EBV EBNA1 Targets Down, Sengupta NPC_with LMP1 UP, REACTOME DNA Repair; Hallmarks). A bioinformatic meta-analysis approach was used to integrate the six EA datasets, and the classifier method was applied to the validation dataset in order to identify the subtype with worst prognosis. Moreover, RNA sequencing was performed on 50 Italian NEA NPC samples (study number: INT188/19; GSE208281). Biological and functional profiling of EA and NEA were performed using xCell, Gene set enrichment analyses, and treatment prediction methods (radiosensitivity index PMID: 16103067, pRRophetic R package, Immunophenoscore PMID: 28052254). Through the meta-analysis of EA-NPC datasets, four clusters (Cl) were identified. Prognostic analyses revealed that Cl3 had the worst prognosis (P=0.0476), confirmed by three of the four prognostic signatures and in the validation dataset (P=0.0368). The biological and functional characterization of these clusters disclosed the relative GE subtypes: Cl1, Immune-active; Cl2, Defense-response; Cl3, Proliferation;Cl4, Perineural-interaction/EBV-exhaustion. According to the treatment prediction methods, the sensitivity of each cluster was radiotherapy and immunotherapy for immune-active, radiochemotherapy and immunotherapy for defense-response, chemotherapy for proliferation, and cisplatin treatment for perineural-interaction/EBV-exhaustion. Only three clusters, excluding perineural-interaction/EBV-exhaustion, were expressed in our NEA cohort. Immune/biological characterization and treatment prediction analyses of NEA partially replicated the EA results. Our study provides a relevant biological overview of EBV-related NPC in both EA and NEA. The immune microenvironment plays a critical role in NPC owing to the viral etiology of this malignancy. The presence of a perineural-interaction/EBV-exhaustion cluster in EA suggests an inactive EBV infection according to the viral related "hit and run theory". Evaluation of miRNAs is ongoing along with miRNA/gene expression integration. Well characterized EA- and NEA-NPC retrospective and prospective cohorts are needed to validate the obtained results and can help designing future clinical studies. [ABSTRACT FROM AUTHOR]

Patients with nasopharyngeal carcinoma (NPC) benefit from antibiotics when there are infective complications during and around chemoradiotherapy, but there is some indication that antibiotics used peri treatment may affect patients' outcomes. Here we sought to elucidate the exact impacts of antibiotics on NPC patients' outcomes around primary treatment. This was a retrospective cohort study in a tertiary academic center in Hong Kong SAR. NPC patients treated for primary disease between 2010 and 2014 were evaluated for the impact of antibiotics prescribed around primary treatments on recurrence-free survival (RFS), disease-specific survival (DSS), and overall survival (OS), which was analyzed by multivariate Kaplan–Meier and Cox Proportional Hazard Regression analysis. The data were analyzed and performed with SPSS, V27.0 and GraphPad, V8.0 A total of 455 patients with primary NPC were included in the study. The cohort consisted of predominantly males (75.6%). Patients who had advanced tumor stage (p=0.019), received NC (p=0.008) or CCRT (p=0.002), were more likely to be prescribed antibiotics. On univariate analysis smoking (p=0.02), advanced stage of disease (p=0.007), lymph node metastasis (p= 0.004), NC administration (P<0.001) and antibiotic use was associated with a poorer year DSS in NPC patients. Antibiotic use around primary NPC treatment (5-year: HR 1.644 95%CI [1.015, 2.665], 10-year: 1.640 [1.085, 2.480]), within 2 weeks (5-year: 1.685 [1.015, 2.799], 10-year: 1.600 [1.030, 2.486]) or 1 week (5-year: 1.811 [1.073, 3.055]), were associated with significantly worse DSS in NPC patients, Figure 1 shows the Kaplan Meir curves. The negative elements included using specific antibiotics (5-year: 2.53 [1.331, 4.807], 10-year: 2.215 [1.236, 3.969]) and oral administration as well (5-year: 1.731 [1.069, 2.805], 10-year: 1.647 [1.087, 2.497]). Multivariate analysis showed a trend towards worse DSS at 5 years with antibiotic use at 1 week around therapy (P=0.054). [Display omitted] In NPC, antibiotics use around primary treatment, regardless of stage, had a poorer prognosis, especially disease-specific survival. In clinical practice, events leading to the prescription of antibiotics or the administration of antibiotics should be carefully considered in NPC patients treated for primary NPC. [ABSTRACT FROM AUTHOR]

Late effects of cancer treatment, such as neurocognitive deficits and fatigue, can be debilitating. Yet other than head and neck cancer (HNC) specific functional deficits such as impairments in swallowing and speech, little is known about survivorship after oropharyngeal cancer(OPC). The National Comprehensive Cancer Network (NCCN) defines fatigue as "a distressing, persistent, subjective sense of physical, emotional, and/or cognitive tiredness or exhaustion related to cancer or cancer treatment that is not proportional to recent activity and interferes with usual functioning" [1]. It is one of the most prevalent and distressing late effects of cancer treatment [2,3]. Chronic fatigue is fatigue lasting for six months or more [4,5]. In a cross-sectional study of patients with HNC, a moderate-to-severe fatigue rate of 18% at least 1 year after radiotherapy was reported [6]. This is high in comparison to a prevalence rate in the general population of approximately 0.5-1% [7,8]. During head and neck radiotherapy normal brain tissues may receive a low radiation dose, and this could have a detrimental effect on neurocognitive function[9-11]. Several small retrospective HNC series report neurocognitive dysfunction within 2 years of treatment[12-14]. Observed cognitive decline appears to persist >5 years post-treatment[15-16] and memory problems, fatigue, anxiety and reduced QoL are reported in HNC survivors[17-22]. These studies are limited by small sample sizes, heterogeneity of HNC patients sampled or having a sole focus on nasopharyngeal cancer. In addition, neurocognition has often been assessed using screening tools which lack sensitivity and domain-specific information. In addition, previous studies have mostly had quantitative methodology[23], which although valuable, lacks contextual information on how late effects may impact on patients' everyday lives. In view of the typical profile of patients with HPV OPC the need to preserve QoL is highly relevant. Therefore, we undertook the ROC-oN study (Radiotherapy for Oropharyngeal Cancer and impact on Neurocognition reference 22/WM/0207), a mixed method cross sectional study evaluating fatigue and neurocognitive function in patients following RT +/- chemotherapy for OPC and impact on QoL. This work is part of the multicentre study ROC-oN which was approved by the West Midlands Research Ethics Committee in October 2022 (22/WM/0207), evaluating fatigue and neurocognitive function in adult patients following radiotherapy +/- chemotherapy) for oropharyngeal cancer >/=24 months post-treatment and impact of these issues on quality of life. The full study involved patients with OPC being invited to complete a quantitative survey as well as an online, unsupervised cognitive test battery, after which a subset of participants were invited for qualitative interviews to investigate the lived experience of fatigue and neurocognitive deficits in survivors and impact on their daily lives. Semi-structured interviews were conducted and reflexive thematic analysis was performed. The NCCN definition of fatigue was adopted [1]. As both fatigue and neurocognition are multidimensional constructs, there is some overlap between the emotional and cognitive aspects of fatigue and neurocognitive function, and fatigue will impact on neurocognitive performance. For the purpose of this study, emotional/cognitive fatigue was considered a psychobiological state caused by demanding neurocognitive tasks, presenting as a feeling of tiredness, lack of energy, decreased motivation and alertness[24,25], while physical fatigue referred to the physical sensation of tiredness and impact of fatigue on physical activity[1,26]. A total of 257 ROC-oN study participants expressed an interest in being interviewed, of whom 33 were approached and 21 were interviewed. 11 men and 10 women participated, median age was 58 years and median time post-treatment was 5 years (inter quartile range 4-8 years). Interviews took on average 52 minutes (range 41-70minutes) and produced six themes with sub-themes Participants described fatigue that persisted beyond the acute period as well as changes in neurocognitive abilities across several neurocognitive domains with memory and attention commonly affected. This negatively influenced paid and unpaid work, as well as emotions and mood. Participants described navigating the new normal by adopting self-management strategies and accepting external support. They felt there was a lack of recognition of these late effects and expressed being poorly informed and unprepared for these. Follow up services were thought to be inadequate. Fatigue and neurocognitive impairment were frequently experienced by survivors of oropharyngeal cancer, at least two years after treatment. Emotional and cognitive fatigue were most affected, along with cognitive complaints across several domains, with a likely strong correlation between these late effects. Patients felt ill-prepared for these late sequelae, highlighting opportunities for the improvement of patient information and support services. [ABSTRACT FROM AUTHOR]

[Display omitted] • High ENOX2 expression is associated with immune excluded/deserted phenotypes in NPC. • ENOX2 inhibitor, idronoxil enhances CD8+ memory T -cell immunity in response to chemotherapy. • Combined treatment with idronoxil and cisplatin enhances tumor response in humanized mice model. • Combined treatment increases CD8+ T -cell expansion with cytolytic effector memory (Tem) feature. • T -cell infiltrates and tumor-associated ENOX2 have predictive value for anti-tumor response. The immunosuppressive tumor microenvironment is a major barrier for chemotherapy. Different chemosensitization approaches to reinstate immunological surveillance for cancers that are immune quiescent at the outset, have thus been devised. Cancer-specific ENOX2 expression is correlated with abnormal cell growth and has been proposed as a cellular target for anti-cancer activity. However, the potential effects of ENOX2 on the interaction between immune system and tumor cells remain elusive. To understand the mechanisms by which tumor-intrinsic ENOX2-mediated alterations in anti-tumor activity of T -cells and response to chemotherapy. In situ multiplexed immunohistochemistry with single cell and bulk RNA sequencing data from nasopharyngeal carcinoma (NPC) human tissues were used to define tumor phenotypes. Two NPC cell lines, with distinct ENOX2 expression, were used in a co-culture platform to study tumor-immune interactions between cancer cells/spheroids and T -cells. The effect of cisplatin treatment with ENOX2 inhibition by idronoxil (IDX) were tested in vitro and in vivo. Multi-parametric flow cytometry was used to characterize T -cell infiltrates in an NPC tumor humanized mouse model treated with combined treatment. NPC predominantly displayed an immune-excluded profile. This "cold-phenotype" was shown to exhibit higher ENOX2 expression and was associate with poorer progression-free survival (PFS). The therapeutic combination of IDX with cisplatin was effective in promoting CD8+ effector memory T cell (Tem) differentiation and mobilization. This Tem signature was highly cytotoxic, with Tem-mediated preferential lysis of higher ENOX2-expressing NPC cells. A combination-treated humanized mouse model showing dramatic shrinkage in tumors, were intra-tumoral Tem-enriched. Tumor-intrinsic ENOX2 expression is associated with tumor phenotype and PFS in NPC. Targeting ENOX2 with IDX and cisplatin impose qualitative control of T -cell response by preferentially increasing immune cells infiltration, Tem differentiation and tumor suppression. We suggest that ENOX2 inhibition may be a promising therapeutic strategy to enhance the effects of chemotherapy. [ABSTRACT FROM AUTHOR]

A neural network method was used to establish a dose prediction model for organs at risk (OARs) during intensity-modulated radiotherapy (IMRT) for nasopharyngeal carcinoma (NPC). In total, 103 patients with NPC were randomly selected for IMRT. Suborgans were automatically generated for OARs using ring structures based on distance to the target using a MATLAB program and the corresponding volume of each suborgan was determined. The correlation between the volume of each suborgan and the dose to each OAR was analysed and neural network prediction models of the OAR dose were established using the MATLAB Neural Net Fitting application. The R-value and mean square error in the regression analysis were used to evaluate the prediction model. The OAR dose was related to the volume of the corresponding sub-OAR. The average R-values for the normalised mean dose (Dnmean) to parallel organs and serial organs and the normalised maximum dose (Dn0) to serial organs in the training set were 0.880, 0.927 and 0.905, respectively. The mean square error for each OAR in the prediction model was low (ranging from 1.72 × 10−4 to 7.06 × 10−3). The neural network-based model for predicting OAR dose during IMRT for NPC is simple, reliable and worth further investigation and application. • The suborgan for each OAR was automatically generated by MATLAB application program. • Analysis the correlation between volume of each suborgan and the dose to the OAR. • Neural network prediction models of the OAR dose were established. • The neural network-based model for predicting OAR dose in IMRT for NPC was reliable. [ABSTRACT FROM AUTHOR]

This study was performed to analyse the age-specific characteristics of head and neck second primary malignancies (SPMs) in patients treated for nasopharyngeal carcinoma (NPC). The medical records of 56 NPC patients diagnosed with head and neck SPMs were reviewed retrospectively. Patients < 45 years old at NPC diagnosis were assigned to the younger group and those ≥ 45 years of age were assigned to the older group. The treatment of the index NPC, latency period, pathological TNM stage, survival status, and SPM subsite were analysed. Patients in the older group were found to have a shorter median latency period than those in the younger group: 8.5 years (range 3–20 years) versus 11 years (range 1–30 years) (P = 0.015). The proportion of SPMs in the jaw was significantly higher in the younger group (P = 0.002). Patients in the younger group receiving radiotherapy with chemotherapy had a shorter latency period (P = 0.003) and higher risk of developing SPMs in the jaw (P = 0.036) than those receiving radiotherapy alone. A long-term and age-dependent regular customised follow-up strategy for NPC is necessary for the prevention and early detection of head and neck second primary malignancies. [ABSTRACT FROM AUTHOR]

Evidence of a volume–outcome association in cancer surgery has shaped the centralization of cancer services; however, it is unknown whether a similar association exists for radiation therapy. The objective of this study was to determine the association between radiation therapy treatment volume and patient outcomes. This systematic review and meta-analysis included studies that compared outcomes of patients who underwent definitive radiation therapy at high-volume radiation therapy facilities (HVRFs) versus low-volume facilities (LVRFs). The systematic review used Ovid MEDLINE and Embase. For the meta-analysis, a random effects model was used. Absolute effects and hazard ratios (HRs) were used to compare patient outcomes. The search identified 20 studies assessing the association between radiation therapy volume and patient outcomes. Seven of the studies looked at head and neck cancers (HNCs). The remaining studies covered cervical (4), prostate (4), bladder (3), lung (2), anal (2), esophageal (1), brain (2), liver (1), and pancreatic cancer (1). The meta-analysis demonstrated that HVRFs were associated with a lower chance of death compared with LVRFs (pooled HR, 0.90; 95% CI, 0.87- 0.94). HNCs had the strongest evidence of a volume–outcome association for both nasopharyngeal cancer (pooled HR, 0.74; 95% CI, 0.62-0.89) and nonnasopharyngeal HNC subsites (pooled HR, 0.80; 95% CI, 0.75-0.84), followed by prostate cancer (pooled HR, 0.92; 95% CI, 0.86-0.98). The remaining cancer types showed weak evidence of an association. The results also demonstrate that some centers defined as HVRFs are undertaking very few procedures per annum (<5 radiation therapy cases per year). An association between radiation therapy treatment volume and patient outcomes exists for most cancer types. Centralization of radiation therapy services should be considered for cancer types with the strongest volume–outcome association, but the effect on equitable access to services needs to be explicitly considered. [ABSTRACT FROM AUTHOR]

Patients with nasopharyngeal carcinoma (NPC) who undergo longitudinal follow-up contrast-enhanced MRI are at risk of developing gadolinium deposition in their neural tissue, which may potentially harm them. Therefore, for these patients, a non-contrast-enhanced method is potentially beneficial as an alternative approach to predict enhancement in T1-weighted imaging (CE-T1WI). The traditional intravoxel incoherent motion (IVIM) is one of the non-contrast-enhanced methods; however, the severe distortion and signal loss limit its application in patients with NPC. The present study aimed to investigate whether non-distortion IVIM could reduce the need of CE-T1WI in the follow-up of patients with NPC. The patients with NPC underwent Turbo Spin-echo MVXD diffusion-weighted imaging-based IVIM (non-distortion IVIM) from November 2021 to May 2022. Firstly, thirty patients with NPC were underwent both non-distortion IVIM and traditional IVIM. The distortion rate (DR) of the non-distortion IVIM was compared with the traditional IVIM. Then, twenty-one NPC patients with tumors (areas >50mm2) were included and correlation coefficient analysis was used to assess the relationship between their non-distortion IVIM and CE-T1WI. Linear regression analysis was performed to determine whether non-distortion IVIM predictors could predict CE-T1WI. The correlation was observed between the parameter f of the non-distortion IVIM and the enhancement ratio of CE-T1WI (r = 0.543, P = 0.011). Moreover, the linear regression analysis revealed that f was an independent IVIM predictor of CE-T1WI in patients with NPC (P = 0.011). The DR of the non-distortion IVIM was significantly smaller than that of the traditional IVIM (0.12 ± 0.05 vs 0.48 ± 0.16, P < 0.001). In patients with NPC, non-distortion IVIM showed potential clinical benefits to reduce the need for contrast agents, and it can independently predict the enhancement ratio. [ABSTRACT FROM AUTHOR]

Vascular stenosis is a late radiation complication that develops in long-term survivors of nasopharyngeal carcinoma. Vertebral arteries (VAs) are major vessels responsible for posterior circulation. In this study, we evaluated the feasibility of VA-sparing volumetric modulated arc therapy (VMAT) techniques. A total of 20 patients with nasopharyngeal carcinoma treated by a TrueBeam linear accelerator were enrolled in this study. The original VMAT plan was designed without the contouring of VAs as organs at risk (OARs). The same image set of the original VMAT plan was used to contour the VAs for each patient. A new VA-sparing VMAT plan was developed by avoiding VAs as OARs. Finally, a paired t-test was used to compare the dosimetric differences. The VA-sparing VMAT plan had similar target coverage and dose to those of other OARs. The VA-sparing plan yielded a significantly low VA dose from 53 to 40 Gy, with V35Gy changing from 97% to 56%, V50Gy changing from 67% to 35%, and V63Gy changing from 15% to approximately 7%–10% (p < 0.001 for all comparisons). VAs should be correctly identified as OARs. Photon VMAT with VA sparing can help substantially decrease the VA dose. [ABSTRACT FROM AUTHOR]

Treatment of nasopharyngeal cancer is based on radiotherapy associated to chemotherapy. The standard for patients with locoregionally advanced carcinoma is induction chemotherapy associated to concurrent chemoradiotherapy. The aim of our study is to determine the recurrence free survival and overall survival. Our study focused on non metastatic patients with locoregionally advanced nasopharyngeal carcinoma: T3-T4 with positive nodes. Treated by induction chemotherapy and concurrent chemoradiotherapy between 2018 and 2021. For the induction chemotherapy, patients received cisplatin associated to gemcitabine for three cycles. In concurrent chemoradiotherapy, total dose was 69,96-70 Gray in 33-35 fractions 5 days a week using Volumetric Modulated Arc Therapy (VMAT) plus cisplatin weekly at a dose of 40 mg per square meter of body surface. Treatment, side effects, loco-regional and distant control and overall survival were collected. A total of 153 patients were included in the study, patients with metastatic disease were excluded. We had 61,4% of men vs 38,6% of women with a median age of 49 years old. 13,7% of patients had arterial hypertension or diabetes. A total of 83,1% of the patients received three cycles of induction chemotherapy. 81,6% received the full dose of radiotherapy, the others interrupted the treatment for side effects. 52,3% of the patients received seven cycles of concurrent chemotherapy. Side effects were reported in 41,8% of the patients with a higher incidence of neutropenia, anemia, nausea-vomiting, renal toxicity and mucositis. Grade 3 or 4 toxic side effects were reported in 19,6% of the patients. At a median follow-up of 44 months, the 2-year recurrence-free survival was 73,2%. Overall survival at 2 years was 89.4%. The results of our study are similar to literature's results; the induction chemotherapy followed by concurrent chemoradiotherapy in the locoregionally advanced nasopharyngeal carcinoma promotes distant control and increases overall survival. Sides effects are unavoidable so they must be recognized and treated early to avoid grade 3 and 4. [ABSTRACT FROM AUTHOR]

To evaluate the prognostic and Survival of patients with locally advanced nasopharyngeal carcinoma with opticpathways involvement, treated by intensity-modulated radiotherapy (IMRT) and concomitant Cisplatin, with or without induction chemotherapy. We retrospectively reviewed data for 40 consecutive patients treated by IMRT in the radiotherapy departement of Salah azeiez hospital in Tunisia, between 2014 and 2018. The mean patient age at diagnosis was 42,65 years (19-81) and the sex ratio was 1,85. All patients had undifferentiated carcinoma of the nasopharynx (UCNT) and were staged T4 according to the seventh edition of the American Joint Committee on Cancer (AJCC) staging system. Patients presented a variety of ocular symptoms, along with other signs such as; diplopia (28,2%), proptosis (10,3%), exophtalmie (5,1%) and oculomotor nerve pulsy (5,1%).Symptomatic orbital invasion by tumor occurred in 19 of the 40 patients (48,7%). Ocular signs, but no orbital invasion, was present in 13 patients (32,5%). The CT scan showed orbital involvement in 21 cases (52,5%), sphenoidal involvement in 32 cases (80%), ethmoidal involvement in 22 cases (55%) and skull base invasion in 38 cases (95%). Neoadjuvant chemotherapy was adminisered to 22 patients (55%). All patients underwent concomitant cisplatin based chemoradiotherapy. The median follow-up was 48,5 months (24 to 83 months), 20 patients (50%) died and 20 (50%) were still alive. A total of 18 (45%) patients experienced failures (30%) and distant metastases (25%). Locoregional failures were seen in 12 (30%) patients. 10 patients (25%) experienced local failure and 2 (5%) patients experienced a nodal failure. Three patients (7,5%) presented unilateral blindness which might be resulted from radiation-induced optic neuropathy. At last follow-up, 19 out of 40 patients (47,5%) were alive without any disease The mean overall survival (OS) was 40,22 months (HR=4,161, 95%CI 32,070-48,382). The 5-year rate of OS was 47,4%. The mean disease free survival (DFS) was 37,740 months (HR=4,754, 95%CI 28,421-47,058). The 5-year rate of DFS was 49 %. The univariate analysis revealed that orbital involvement did significantly affect overall survival (P=0,000). Orbital involvement was also identified as an independent prognostic factor for OS (hazard ratio 0,159; 95 % CI 0.043-0.588; P = 0.006). However, Tumor volume higher than 100 cm3 (hazard ratio=0,130; 95 % CI 0,022 - 0,771; P = 0,025) and dose at CTVp1 lower than 66 Gy (hazard ratio=0,137; 95 % CI 0,028-0,665; P = 0,014) were identified as an independent prognostic factors for DFS. T4 non metastatic locally advanced NPC with optic pathways involvement is uncommon and it confers a particular bad prognosis. Indeed, the IMRT modality provides adequate local-regional control for T4 NPC. However, even with the most sophisticated treatment techniques, the clinical outcome remains low for this subgroup. [ABSTRACT FROM AUTHOR]

Intensity modulated radiation (IMRT) technique, associated with induction chemotherapy (IC) and/or concomitant chemotherapy (CC) is actually the recommended treatment modality for nasopharyngeal carcinomas (NPC). The aim of this study was to evaluate the therapeutic results and the patterns of relapse with this treatment protocol. A retrospective monocentric study of 145 patients with NPC treated between June 2016 and July 2021. All patients received IMRT with integrated simultaneous boost (SIB) of 33 daily fractions at a dose of 69.96 Gy for high-risk volume, 60 Gy for intermediate risk volume and 54 Gy for low-risk volume. High risk volume dose was 66.5 Gy in children. Survival analysis was performed according to Kaplan-Meier method and Log-rank test was used to compare factors that may influence survivals. Median age was 48 years (11-80) with a sex ratio of 2.9. One hundred-twenty tumors (82.7%) were classified as stages III-IV according to the 2017 UICC TNM classification. Ten patients (6.9%) were metastatic at diagnosis. One hundred-thirty-five patients (93.1%) received IC, 104 of which (77%) were TPF-based (taxanes, cisplatin and 5 fluoro-uracil). One hundred-thirty-eight patients (95.2%) received CC, mostly cisplatin in 134 cases (97%). After a median follow up of 56 months [28-86], 46 patients (31.7%) had a relapse: 12 (8.2%) experienced local and/or regional relapse after a median of 18 months [6-43], 29 (20%) experienced distant relapse after a median of 9 months [2-24] and 5 patients (3.4%) had both. Thirty-five patients (24.1%) died including 5 (3.4%) from a cause other than their cancer. Three-year overall survival (OS), cancer specific survival, disease free survival, metastasis free survival and loco-regional free survival were respectively 78.1%, 81.3%, 67.8%, 74.5% and 88.1%. Anatomo-clinic factors predicting OS were an age > 50 years (88.7 vs 70.5%; p=0.004), diabetes history (81.2 vs 66.7%; p=0.027), UICC N classification (100 vs 95 vs 77.5 vs 68.8% respectively for N0, N1, N2 and N3; p=0.008), the practice of a lymph node biopsy (84.2 vs 57%; p=0.05), and UICC TNM stages III-IV (93.8 vs 73.6% respectively for stage I-II vs III-IV; p=0.044). Therapeutic factors predicting OS were number of CC courses (less than 4 courses: 65.8 vs 86%; p=0.03, less than 5 courses: 71.5 vs 89%; p=0.041), a weight loss > 10% during treatment (84.1 vs 60.9%; p=0.021) and a total cumulative cisplatin dose, including IC and CC, < 380 mg/m2 (64.4 vs 87.6%; p=0.003). Radiotherapy delay and total duration did not significantly affect OS. No grade 3-4 late side effects were noted in the evaluable 127 patients (87.6%). The most common toxicity was dry mouth that was grade 2 in 47 cases (37%) and grade 1 in 55 cases (43.3%). IMRT for nasopharyngeal carcinoma granted a high loco-regional control rate for patients during the last five years. However, distant relapses remain frequent and conditionate the prognosis. We identified many anatomo-clinic and therapeutic prognosis factors. Therefore, high risk patients require a more aggressive therapeutic approach such as radiotherapy dose escalation or adding adjuvant chemotherapy. [ABSTRACT FROM AUTHOR]

Reirradiation has been identified as a viable treatment modality for patients with recurrent head and neck cancer (rHNC). Retrospective series demonstrate the superiority of intensity-modulated radiation therapy (IMRT) over stereotactic ablative radiotherapy (SABR) for patients in the Multi-Institution Reirradiation Collaborative (MIRI) class 2 risk group (treatment interval > 2 years without resection or treatment interval ≤ 2 years without organ dysfunction). he objective of this study was to investigate the efficacy and toxicity of SABR in patients classified as "RPA Class 2" rHNC. The data of 85 cases diagnosed with rHNC who underwent reirradiation with the SABR technique between 2007 and 2022 in our department were evaluated retrospectively. We did not incorporate cases of primary nasopharynx cancer due to its comparatively more favorable prognosis in relation to other types of head and neck cancers. The Kaplan-Meier method was used for survival analyzes (IBM SPSS v23). Patient, tumor and treatment characteristics are presented in Table 1. The median age was 59 (range, 19-87). The median follow-up period was 12 months (range,1-178 months). The first assessment following SABR revealed that 30% of the patients achieved a full response, 35% achieved a partial response, 11% had stable disease, and 4% experienced disease progression. During follow-up, local recurrence (LR) developed in 31 patients (36%) and distant metastasis (DM) developed in 24 patients (28%). The local control (LC) rate with SBRT was 64%. The most common sites of DM are the lung, bone, and liver. In 31 patients who developed LR after SABR, the median time to LR development was 8 months (range, 2-55 months). Subsequently, a third course of radiation therapy (RT) was administered to 16 of them (52%). The 1- and 2-year overall survival (OS), local recurrence-free survival (LRFS) and distant metastasis-free survival (DMFS) rates were 50% and 30%, 39% and 21%, 46% and 27%, respectively. In univariate analysis, age (≤59 vs. >59 years), gender (male vs. female), interval between treatments (≤2 vs. >2 years), organ dysfunction before SABR (present vs. absent) or surgery (present vs. absent), SABR dose (≤30 vs. >30 Gy), technique (robotic vs. linear accelerator-based), recurrent tumor volume (≤43 vs. >43 cc), and recurrence location (primary vs. neck) parameters did not have prognostic effect on OS, LRFS and DMFS. The rate of grade 3 or 4 late toxicity was 11%, and the rate of grade 5 toxicity was 9%. Eight patients (9%) developed massive hemorrhage secondary to carotid blow out syndrome (CBOS), 6 patients (7%) developed brain parenchymal necrosis, 2 patients (2.5%) required permanent gastrostomy, and 1 patient (1.5%) developed optic neuropathy and vision loss. The administration of SABR in consecutive or alternate day fractions shown comparable effects on toxicity. [Display omitted] The utilization of the SABR as a method of reirradiation in rHNC patients has demonstrated favorable outcomes in terms of achieving effective LC while maintaining acceptable levels of treatment-related toxicity. We provide a study that demonstrates highly favorable survival outcomes with SABR for patients classified as RPA class 2 rHNC. There is a need for prospective randomized studies to be conducted in order to ascertain the ideal approach for reirradiation, specifically comparing SABR and IMRT. These studies would also help identify the patient population that would benefit the most from such reirradiation techniques. [ABSTRACT FROM AUTHOR]

Local recurrence (LR) rates in nasopharyngeal carcinoma (NPC) following definitive radiation (RT) ± chemotherapy (CT) range from 7–15%. A prospective trial comparing endoscopic surgery and reirradiation in recurrent cases found that surgery improved survival in a carefully chosen group of patients with low-volume mucosal recurrence. However, the fact that the recurrent disease is mostly multifocal and infiltrative in nature makes a limited group of patients suitable for surgery. In this study, we aimed to report our stereotactic ablative radiotherapy (SABR) outcomes in cases diagnosed with recurrent NPC. The data of 83 patients who underwent SABR in our department between 2007 and 2022 with the diagnosis of local-regional recurrent NPC, which was unresectable or had surgical margin positivity after resection were evaluated retrospectively. The Kaplan-Meier method was used for survival analyses (IBM SPSS v.23). Patient, tumor, and treatment characteristics are presented in Table 1. The median age was 53 (range, 19-78). The median follow-up was 24 months (range, 3–151 months). The median interval between patients' first and second RT's was 39 months (range, 4–238 months). The initial response evaluation following reirradiation found a complete response in 38%, a partial response in 40%, stable disease in 8%, and progression in 1%. In follow-up, LR developed in 20 patients (24%) and distant metastasis (DM) developed in 14 patients (17%). The most common sites of DM were the lung, bone, and liver. SABR provided 76% local control (LC). The 1- and 2-year overall survival (OS), local recurrence-free survival (LRFS), and distant metastasis-free survival (DMFS) rates were 67% and 53%, 65% and 46%, and 62% and 49%, respectively. In univariate analysis, LRFS (60% vs. 34%, p=0.002) and DMFS (63% vs. 31%, p=0.007) rates were higher in patients with recurrent tumor volume ≤36 cc compared to patients with tumor volume >36 cc. Age (≤53 vs. >53 years), gender (male vs. female), interval between RTs (≤2 vs. >2 years), surgery before SBRT (yes vs. no), SBRT dose (≤30 vs. >30 Gy) and device (robotic- vs. linear accelerator-based), and site of recurrence (primary vs. neck recurrence) could not be identified for prognostic significance for OS, LRFS, and DMFS parameters. A notable proportion of patients experienced late toxicity, with 20% exhibiting grade 3 or 4 toxicity and 12% experiencing grade 5 toxicity. Fourteen patients (17%) experienced massive hemorrhage as a result of carotid blow-out syndrome (CBOS); two patients (2%) suffered from cerebrovascular disease as a result of carotid artery stenosis; five patients (6%) experienced brain parenchymal necrosis; three patients (3.5%) had permanent gastrostomies; and three patients (3.5%) had hearing loss. There was no observed disparity in toxicity levels between doses administered consecutively or every other day. [Display omitted] Using SABR as a reirradiation method for people with recurrent NPC has shown to be very effective at achieving LC while keeping treatment-related side effects at a level that can be tolerated. There is a positive correlation between a smaller recurring tumor volume and higher levels of local recurrence-free survival (LRFS) and distant metastasis-free survival (DMFS). [ABSTRACT FROM AUTHOR]

The aim of the study was to test the hypothesis that Intensity Modulated Proton Therapy (IMPT) reduces acute and late radiation toxicity in nasopharyngeal cancer (NPC) patients compared to photon-based radiation techniques including IMRT and VMAT. The study population of this prospective cohort study was composed of 131 NPC patients treated with curative radiotherapy (RT) or chemoradiotherapy. Between July 2007 and December 2017, all patients were treated with IMRT or VMAT. Since January 2018, 97 out of 99 patients (98%) qualified for IMPT according to model-based selection. All patients were included in a prospective data registration program in which acute and late toxicity was prospectively scored weekly during RT and at fixed time points after RT (6 weeks, 6, 12, 18 and 24 months). To determine the overall effect on acute and late toxicity, the Weighted Overall Toxicity Burden (WOTB) was calculated, defined as the sum of all toxicities weighted by toxicity grading. In addition, the WOTB Area Under the Curve (WOTB-AUC) was calculated representing the WOTB from the start of treatment until 24 months after completion of treatment. The two groups were well balanced regarding gender, age, race, T-stage, N-stage, AJCC-stage, and EBV-status. However, there was a significant difference regarding the chemotherapy regimens used between the two groups. In the photon cohort, 33% of patients were treated with conventional RT, 7% with concurrent chemoradiation, 2% with induction chemotherapy + concurrent chemoradiation and 57% with concurrent chemoradiation + adjuvant chemotherapy, while this was 25%, 37%, 36% and 2% in the proton cohort, respectively. The mean dose to all relevant organs at risk (i.e., oral cavity, pharyngeal constrictor muscles, parotid, and submandibular glands) were significantly lower with IMPT compared to photons. This was particularly true for the mean dose to the oral cavity which decreased from 27.2 Gy with IMRT/ VMAT to 10.7 Gy with IMPT (p<0.001). From January 2018, a plan comparison was made in all NPC patients referred for radiotherapy to our centre between IMPT and VMAT. In total, 97 out of 99 patients qualified for protons based on the estimated risk difference on dysphagia and xerostomia resulting from the dose reductions obtained with IMPT. IMPT resulted in significant reductions of various acute and late toxicities (Figure 1), including xerostomia, loss of taste, dysphagia, tube feeding dependence, sore mouth, and mucosal reactions. Only acute dermatitis was significantly worse at the end of IMPT, but completely recovered at 5 weeks after treatment in all patients. [Display omitted] The WOTB was significantly lower after IMPT (Figure 2) at all time points. In the IMPT group, the WOTB-AUC as measure for overall toxicity was 68% lower. The WOTB-AUC reduction was 60% in the acute phase (week 1 to 7), 69% in the recovery phase (from end of treatment to 6 months after RT) and 70% in the late phase (from 6 to 24 months after RT). In this prospective cohort study, patients treated with IMPT had statistically significant and clinically relevant reductions of various acute and late toxicities as compared to modern photon techniques like IMRT and VMAT as a historical control group. [ABSTRACT FROM AUTHOR]

The objective of this study was to estimate the long-term survival, late toxicity profile, and quality of life of patients with locoregionally advanced nasopharyngeal carcinoma (NPC) treated with combined induction chemotherapy (IC) and concurrent chemoradiotherapy from a clinical trial focused on reducing the target volume of intensity modulated radiation therapy (IMRT). This prospective, randomized clinical trial was conducted across 6 Chinese hospitals and included 212 patients with stage III-IVB NPC who were randomly allocated to a pre-IC or post-IC group. Eligible patients were treated with 2 cycles of IC + CCRT. All patients underwent radical IMRT. Gross tumor volumes of the nasopharynx were delineated according to pre-IC and post-IC tumor extent in the pre-IC and post-IC groups, respectively. After a median follow-up of 98.4 months, 32 of 97 (32.9%) and 33 of 115 (28.7%) patients experienced treatment failure or died in the pre-IC and post-IC groups, respectively. None of the patients developed grade 4 late toxicity. Late radiation-induced toxicity predominantly manifested as grade 1 to 2 subcutaneous fibrosis, hearing loss, tinnitus, and xerostomia, whereas grade 3 late toxicity included xerostomia and hearing loss. The 5-year estimated overall, progression-free, locoregional recurrence-free, and distant metastasis-free survival rates in the pre-IC and post-IC groups were 78.2% versus 83.3%, 72.0% versus 78.1%, 90.2% versus 93.5%, and 78.1% versus 82.1%, respectively. The pre-IC group had a significantly higher incidence of xerostomia and hearing damage than the post-IC group. In terms of quality of life, compared with the pre-IC group, the post-IC group showed significant improvement in cognitive function (P =.045) and symptoms including dry mouth (P =.004), sticky saliva (P =.047), and feeling ill (P =.041). After long-term follow-up, we confirmed that reducing the target volumes of IMRT after IC in locoregionally advanced NPC showed no inferiority in terms of the risk of locoregional relapse and potentially improved quality of life and alleviated late toxicity. [ABSTRACT FROM AUTHOR]

To explore the clinical utility of the systemic inflammation response index (SIRI) in the prediction of patients with poor treatment response to concurrent chemoradiotherapy (CCRT) in locally advanced nasopharyngeal cancer (NPC). A total of 167 stage III-IVB (AJCC 7th edition) nasopharyngeal cancer patients who received CCRT were retrospectively collected. The SIRI was calculated using the following formula: SIRI = neutrophil count × monocyte count/lymphocyte count (109/L). The optimal cutoff values of the SIRI for noncomplete response were determined by receiver operating characteristic curve analysis. Logistic regression analyses were performed to identify factors predictive of treatment response. We used Cox proportional hazards models to identify predictors of survival. Multivariate logistic regression showed that only the posttreatment SIRI was independently associated with treatment response in locally advanced NPC. A posttreatment SIRI≥1.15 was a risk factor for developing an incomplete response after CCRT (odds ratio 3.10, 95% confidence interval (CI): 1.22–9.08, p = 0.025). A posttreatment SIRI≥1.15 was also an independent negative predictor of progression-free survival (hazard ratio 2.38, 95% CI: 1.35–4.20, p = 0.003) and overall survival (hazard ratio 2.13, 95% CI: 1.15–3.96, p = 0.017). The posttreatment SIRI could be used to predict the treatment response and prognosis of locally advanced NPC. [ABSTRACT FROM AUTHOR]

Radiation therapy is the standard treatment for patients with nasopharyngeal carcinoma (NPC), but relapse occurs in 10% to 20% of patients. The treatment of recurrent nasopharyngeal carcinoma (rNPC) remains challenging. Chimeric antigen receptors (CAR)-T-cell therapy has achieved good outcomes in the treatment of leukemia and seems to be a promising therapeutic strategy for solid tumors. c-Met has been found to be highly expressed in multiple cancer types, and the activation of c-Met leads to the proliferation and metastasis of cancer cells. However, the expression of c-Met in rNPC tissues and whether it can be used as a target for CAR-T therapy in rNPC remain to be investigated. We detected the expression of c-Met in 24 primary human rNPC tissues and three NPC cell lines and constructed two different antibody-derived anti-c-Met CARs, namely, Ab928z and Ab1028z. To estimate the function of these two different c-Met-targeted CAR-T cells, CD69 expression, cytotoxicity and cytokine secretion of CAR-T cells were assessed after coculture with target cells. A cell line-derived xenograft mouse model also was used to evaluate these two anti-c-Met CAR-T cells. Furthermore, we determined whether combination with an anti-EGFR antibody could promote the antitumor effect of CAR-T cells in a patient-derived xenograft mouse model. High c-Met expression was detected in 23 of 24 primary human rNPC tissues by immunohistochemistry staining and in three NPC cell lines by flow cytometry. Ab928z-T cells and Ab1028z-T cells showed significantly upregulated expression of CD69 after coculture with targeted cells. However, Ab1028z-T cells showed superior cytokine secretion and antitumor activity. Furthermore, Ab1028z-T cells effectively suppressed tumor growth compared with control CAR-T cells, and the combination with nimotuzumab further enhanced the tumor-clearing ability of Ab1028z-T cells. We found that c-Met is highly expressed in rNPC tissues and confirmed its potential as a CAR-T target for rNPC. Our study provides a new idea for the clinical treatment of rNPC. [ABSTRACT FROM AUTHOR]

To establish and validate radiomic models for response prediction to induction chemotherapy (IC) in nasopharyngeal carcinoma (NPC) using the radiomic features from pretreatment MRI. This retrospective analysis included 184 consecutive NPC patients, 132 in the primary cohort and 52 in the validation cohort. Radiomic features were derived from contrast-enhanced T1-weighted imaging (CE-T1) and T2-weighted imaging (T2-WI) for each subject. The radiomic features were then selected and combined with clinical characteristics to build radiomic models. The potential of the radiomic models was evaluated based on its discrimination and calibration. To measure the performance of these radiomic models in predicting the treatment response to IC in NPC, the area under the receiver operating characteristic curve (AUC), and sensitivity, specificity, and accuracy were used. Four radiomic models were constructed in the present study including the radiomic signature of CE-T1, T2-WI, CE-T1 + T2-WI, and the radiomic nomogram of CE-T1. The radiomic signature of CE-T1 + T2-WI performed well in distinguishing response and non-response to IC in patients with NPC, which yielded an AUC of 0.940 (95% CI, 0.885–0.974), sensitivity of 83.1%, specificity of 91.8%, and accuracy of 87.1% in the primary cohort, and AUC of 0.952 (95% CI, 0.855–0.992), sensitivity of 74.2%, specificity of 95.2%, and accuracy of 82.7% in the validation cohort. MRI-based radiomic models could be helpful for personalised risk stratification and treatment in NPC patients receiving IC. • Pretreatment response to IC prediction in NPC is crucial. • Predictive performance of proposed radiomics model showed excellent. • Radiomics is a promising non-invasive method to aid clinical decision-making. [ABSTRACT FROM AUTHOR]

The development and progression of nasopharyngeal carcinoma (NPC) is closely associated with Epstein-Barr virus (EBV) infection. NPC is usually asymptomatic until it spreads to other sites, and more than 70% of cases are classified as locally advanced disease at diagnosis. EBV-positive nasopharyngeal cancer tissues express only limited viral latent proteins, but express high levels of the EBV-encoded BamHI-A rightward transcript (BART) miRNA molecules. Here, we report that EBV-miRNA-BART2-5p (BART2-5p) promotes NPC cell invasion and metastasis in vivo and in vitro but has no effect on NPC cell proliferation and apoptosis. In addition, BART2-5p altered the mRNA and miRNA expression profiles of NPC cells. The development of human tumors has been reported to be associated with altered miRNAs expression, and overall miRNAs expression is reduced in many types of tumors. We found that BART2-5p downregulated the expression of several miRNAs that could exert oncogenic functions. Mechanistically, BART2-5p directly targets the RNase III endonuclease DICER1, inhibiting its function of cleaving double-stranded stem-loop RNA into short double-stranded RNA, which in turn causes altered expression of a series of key epithelialmesenchymal transition molecules, and reverting DICER1 expression can rescue this phenotype. Furthermore, analysis from clinical samples showed a negative correlation between BART2-5p and DICER1 expression. According to our study, high expression of BART2-5p in tissues and plasma of patients with NPC is associated with poor prognosis. Our results suggest that, BART2-5p can accelerate NPC metastasis through modulating miRNA profiles which are mediated by DICER1, implying a novel role of EBV miRNAs in the pathogenesis of NPC. [ABSTRACT FROM AUTHOR]

To assess daily targets variations using fan beam computed tomography (FBCT) and determine optimal target-specific planning target volume (PTV) margins for intensity-modulated radiation therapy (IMRT) of nasopharyngeal carcinoma (NPC). From March 2022 to July 2023, 13 NPC patients (II:1, III:9, IVA:3) received radical IMRT (6996cGy/33Fr) with daily FBCT guidance. Excluding missing FBCTs due to machine maintenance and those with insufficient scan coverage, 352 FBCTs were retrospectively collected. Organs at risk (OARs) and targets on FBCTs, including gross tumor volumes (GTVp), involved cervical lymph nodes (GTVnd), clinical target volumes (CTV1 and CTV2) were auto-contoured and reviewed by two radiation oncologists. CTV2 was segmented into upper (CTV2_U), middle (CTV2_M), and lower (CTV2_L) parts at the inferior border of mastoid and hyoid. Targets on daily FBCTs were copied onto the planning CT (pCT) based on treatment registration. Volume coverage of daily FBCT targets by 1-3 mm PTV margins was calculated as (Target_FBCT ∩ PTV_pCT) / Target_FBCT. Auto-planning was performed on the pCT with proposed target-specific and 3mm PTV margins, and then the two plans were copied to FBCTs. Dose to 95% of volume (D95) of PGTVp, PGTVn, PCTVs, and OARs doses were calculated based on weekly FBCTs. Dose coverage of targets and sparing of OARs between two plans were compared. The average volume coverage of targets by 3 mm PTV margins ranged from 98.18% to 100.00% (Table 1). The minimum coverage, 98.18%, was used as the threshold to determine optimized target-specific margins for these six targets. Optimized margins for GTVp, GTVn, CTV1, CTV2_U, CTV2_M, and CTV2_L were 1 mm, 3 mm, 1 mm, 1 mm, 1 mm, and 3 mm, respectively, achieving volume coverage between 98.18% and 99.94% (Table 1). No significant differences were observed in the percentage of fractions where D95 ≥ 100% of prescription dose for all targets between plans with target-specific and 3 mm PTV margins, with the percentages of 100% and 100% for PGTVp, 83% and 84% for PGTVn, 100% and 100% for PCTV1, and 70% and 75% for PCTV2, respectively. OARs received reduced doses with target-specific margins compared to 3 mm margins. Top three OARs with greatest dose sparing were optic nerves, chiasm, and parotids, with average dose reduction of 1275 cGy, 1218 cGy and 518 cGy. Optimal PTV margins for radiotherapy should be tailored to specific targets. Compared to 3mm PTV margins, target-specific margins ensure dose coverage of targets while reducing OAR doses in NPC patients. [ABSTRACT FROM AUTHOR]

Due to the diversity of symptoms and insidious location of Nasopharyngeal carcinoma (NPC), up to 85% of patients have regional lymph node metastasis at the time of diagnosis. The presence of cervical lymph node metastases is an important prognostic factor for patients with NPC; however, the management of patients with cN0 remains controversial. Currently, the clinical consensus is that cervical lymph nodes with a short diameter of >1 cm, necrosis, incomplete peritoneum, and extra-nodal infiltration are metastatic lymph nodes. Suspicious lymph nodes without obvious signs of the above-mentioned characteristics still need to be confirmed using histological or cytological puncture. Consequently, we aim to develop a clinical radiomics model using multimodal magnetic resonance to predict the presence of suspicious lymph node metastasis in NPC and validate its accuracy. Retrospectively, a total of 382 lymph nodes from 275 patients with NPC were included in the study (260 in the training set and 122 in the validation set). All lymph nodes, underwent puncture biopsy for pathological evaluation and had complete clinical imaging data. The lymph nodes were grouped based on the patients, and feature selection was performed using the Least Absolute Shrinkage and Selection Operator (LASSO) method. The optimal model performance was then constructed using Logistic, Random Forest (RF), XGBoost, and Native Bayes (NB), respectively. Clinical features were further screened using multivariate logistic analysis to build the clinical radiomics model. The results were visualized through column-line diagrams. The model efficacy was assessed using the Area Under the Curve (AUC) and calibration curves of the subjects' work characteristics. In the training set, the stacked sequence-based logistic, RF, XGBoost, and NB imaging genomics models achieved AUCs of 0.810, 0.776, 0.722, and 0.705, respectively. However, the clinical radiomics model incorporating clinical features (short-axis diameter, N stage, lymph node location) showed better calibration and differentiation ability in both the training and validation sets, with an AUC of 0.867 in the training set and 0.840 in the validation set, and clinical decision curves confirmed the higher clinical applicability of the clinical radiomics model. Clinical radiomics models based on multiple sequences have the potential to more accurately identify metastatic lymph nodes of NPC, even when they do not meet the diagnostic criteria for image-positive lymph nodes. This can significantly impact clinical practice by guiding treatment decisions and improving the precision and cost-effectiveness of treatment protocols. [ABSTRACT FROM AUTHOR]

To make a comparison between childhood nasopharyngeal carcinoma (NPC) and adult NPC patients regarding treatment outcomes and late toxicities in the era of IMRT. A total of 140 childhood and adolescent NPC patients aged ≤21 years treated at our institution between January 2004 and November 2019 were reviewed. A propensity score matching method was used to screen 280 matched adult NPC patients at a ratio of 1:2. Treatment outcomes and late sequelae between child and adult groups were compared. Compared with adult NPC, childhood and adolescent NPC exhibited distinct differences in clinical features with more advanced stages, more sensitive to radiotherapy and more favorable prognosis. The 5-year overall survival (OS), progression-free survival (PFS), locoregional relapse rate (LRR) and distant metastasis (DM) rates for the child group versus the adult group were 83.1% versus 71.9% (P = 0.001), 71.6% versus 60.9% (P = 0.023), 3.1% versus 12.6% (P = 0.002), and 25.8% versus 29.3% (P = 0.498), respectively. After neoadjuvant chemotherapy (NACT), 63.9% of childhood and adolescent NPC patients achieved complete response (CR) or partial response (PR), while in adult group, a CR/PR was observed in 51.4% patients. It is interesting to note that, in childhood and adolescent patients who receive NACT, there were no differences according to OS, PFS, LRR and DM when comparing CR/PR patients with those individuals with SD/PD. However, the response to NACT was a significant prognostic factor in adult group regarding OS (P = 0.017), PFS (P <0.001) and DM (P <0.001). More patients in child group were successfully salvaged compared with patients in adult group (42.1% versus 21.7%, P = 0.015). The 2-year and 5-year PFS-2 (PFS-2 was defined as the duration from the date of first progression until further progression) were 56.7% and 36.4% in child group versus 35.9% and 19.5% in adult group (P = 0.012). Late toxicities showed higher incidence in adult group regarding xerostomia (P = 0.015), neck fibrosis (P = 0.014) and temporal lobe necrosis (P = 0.060), but lower incidence in hypothyroidism (P = 0.030) when compared with child group. Childhood and adolescent NPC patients have better survival outcomes than adult patients, regardless of the higher proportion of locoregionally advanced disease. The low locoregional relapse rate indicated young patients are more sensitive to radiotherapy. Compared with adult patients, there is a higher rate of successful salvage treatment in children and adolescents. Late toxicity profiles were differed between child patients and adult patients. [ABSTRACT FROM AUTHOR]

Nasopharyngeal carcinoma (NPC) is characterized by a distinct geographic distribution with >90% of worldwide incidence and mortality occurring in East and Southeast Asia and Northern Africa. Current clinical trials are seeking to optimize treatment strategies to improve NPC outcomes; however, little is known about their geographic distribution in relation to the well-known disease endemicity. Using ClinicalTrials.gov, we identified phase II and III clinical trials on adult patients with NPC from 2013-2023. Trial characteristics were extracted and analyzed. Endemic countries were defined as having an age-standardized incidence rate (ASIR) higher than the world ASIR of 1.3 per 100,000 person-years using the GLOBOCAN 2022 database. There were 253 clinical trials eligible for analysis. Eighty-five trials (34%) were recruiting, 38 (15%) not yet recruiting, 31 (12%) active but not recruiting, 21 (10%) completed, and 5 (2%) terminated. Trials most commonly originated from China (199 [79%]) followed by the United States (12 [5%]) and Singapore (4 [2%]). One hundred one (40%) were single-institution trials, 126 (50%) were single-country multi-institution, and only 11 (4%) were international. Of the 29 NPC-endemic countries, only five (17%) are represented in international trials, namely, China (including Taiwan), Malaysia, Singapore, Thailand, and Tunisia, 4 (80%) of which are high and upper-middle income countries. In contrast, 18 (75%) out of the 24 underrepresented NPC-endemic countries are classified as low and lower-middle income countries. Study population consists of initial diagnosis, both early and locally advanced, in 133 (53%) trials and recurrent/metastatic in 120 (47%). Trial intervention includes chemotherapy in 155 (61%), immunotherapy/targeted therapy in 134 (53%), and radiotherapy in 116 (46%), with 2 (4%) trials involving biomarkers. A significant imbalance exists in the geographic distribution of current NPC clinical trials in terms of trial origin and country locations that do not match the global disease endemicity of NPC. Lower income NPC-endemic countries are severely underrepresented. Efforts are needed to diversify trial inclusion and improve representation of NPC-endemic countries. [ABSTRACT FROM AUTHOR]

To explore a multi-sequence MRI based prediction of metachronous oligometastases (MO) in nasopharyngeal carcinoma (NPC) patients. The MRI, clinical variable (CV) and follow-up data of the186 patients with NPC were collected. Gross tumor volume (GTV) and lymph node gross tumor volume (GTVln) prior to treatment were defined on T1WI, T2WI and CE-T1WI. After image normalization, the deep learning platform Python (version 3.9.12) was used in Ubuntu 20.04.1 LTS to construct automatic tumor detection and MO prediction model. We found that the overall performance of automatic tumor detection model was the model based on CE-T1WI. Automatic segmentation algorithm based on Mask Scoring R-CNN had the best overall performance for automatic identification of tumor and metastatic lymph nodes on CE-T1WI images (mAP@0.5 = 57.8%). When the Mask R-CNN instance segmentation algorithm was used for automatic detection, the AUCs of the MO prediction model based on T1WI, T2WI and CE-T1WI were 0.722, 0.695 and 0.733, respectively. When Cascade Mask R-CNN and Mask Scoring R-CNN instance segmentation algorithm were used for automatic detection, similar prediction model could be acquired. After adding CV, the prediction ability of the prediction model based on T1WI, T2WI and CE-T1WI was further improved under the three automatic segmentation algorithms. The largest AUC (0.775, 95% CI = 0.606-0.945, p = 0.001) was acquired in the prediction model based on the CE-T1WI and CV when Mask R-CNN automatic segmentation algorithm was used. By comparing the 3-year survival of high-risk and low-risk patients based on the combined model, we found that the 3-year DMFS and OS of high and low MO risk patients were 11.4% vs 95% and 85.3% vs 97% respectively (p <0.05). Deep learning based on multimodal MRI is expected to accurately predict MO of NPC. The intelligent prediction model based on magnetic resonance imaging alone or in combination with clinical data has excellent performance in automatic tumor detection and MO prediction for NPC patients, and is worthy of clinical application. [ABSTRACT FROM AUTHOR]

Growing evidence reported that parotid nodes groups (PNG, nominated as level VIII) was the major out-field site of regional failure after curative intensity modulated radiotherapy (IMRT) in nasopharyngeal carcinoma (NPC) patients, and a majority of them presented with sub-centimeter lymph nodes (<10 mm) in level VIII at their baseline magnetic resonance imaging (MRI). This situation raised the concern for reconsidering the diagnostic criteria of level VIII lymph nodes (LNs) metastasis. This study was conducted to evaluate the rationality of current radiologic criteria of metastatic PNG, and provide evidence for possible refinement. Patients with histologically-proven NPC who received curative IMRT with or without chemotherapy at our attending group between January 2014 and March 2018 were candidates for this study. Other eligible criteria were listed as following: (1) has no history of previous treatment or prior malignancy; (2) has available imaging data for re-staging according to the TNM-8 and evaluating the status of PNG. Of note, PNGs with the minimal axial diameter (MAD) ≥ 5 mm of the largest lymph node at baseline MRI were all recorded. Survival outcome focus on regional relapse free survival (RRFS) and the incidence of PNG were analyzed. A total of 627 patients were finally included for this analysis. With a median following up time of 69 months, 5-year OS and RRFS, LRFS and DMFS were reported to be 89.5%, 95.6%, 97.2%, and 88.4%, respectively. At time of censorship, 20 cases developed regional recurrence, of which 9 were located at level VIII. Notably, 8 out of the 9 patients with level VIII failure had sub-centimeter lymph nodes (<10 mm) in situ at baseline MRI. After re-evaluation the baseline imaging data for the whole cohort of patients, a total of 72 patients presented to have sub-centimeter lymph nodes at baseline, among them, 4 cases received PLNs-covering IMRT and did not experience level VIII recurrence. Of the remaining 68 patients who underwent PLNs-sparing IMRT, 53 cases were recorded as ≥ 5 mm but <6mm, 1(1.9%) out of these 53 patients developed level VIII relapse. For the 15 patients who had sub-centimeter lymph nodes of ≥6mm at baseline, 5(33.3%, 5/15) of them occurred regional relapse at level VIII. Five out of the 68 patients had baseline sub-centimeter lymph nodes of 7mm or larger, two of them experience in situ recurrence in level VIII. All the three patients with sub-centimeter lymph nodes of ≥8mm at diagnosis experienced in situ recurrence (100%). Current radiologic criteria (≥10 mm) for assessing PNGs should be implemented with caution, as a substantial proportion of patients with sub-centimeter lymph nodes of >6mm at baseline occurred in situ regional failure at level VIII. Pathological puncture was recommended for patients with sub-centimeter lymph nodes of ≥6mm at baseline. Well-designed prospective multi-center study is warranted to confirm our findings. [ABSTRACT FROM AUTHOR]

Southeast Asia (SEA) is home to 685 million people, that is, almost 9% of the global population. Although the epidemiology of nasopharynx cancer (NPC) is well known in countries like the US and China, less is known about NPC in this large and diverse region. The number of new NPC (C11) cases and deaths were collected from the International Agency for Research on Cancer GLOBOCAN 2022 database for 10 SEA countries by sex and age groups. We report age-standardized incidence and mortality rates (ASIR and ASMR) per 100,000 person-years, and mortality-to-incidence ratio (MIR), a crude measure of survival outcomes. In 2022 and for men and women combined, NPC was most common in Brunei (ASIR 6.4 per 100,000), Indonesia (ASIR 6.1), and Malaysia (ASIR 5.9), and least common in Cambodia (ASIR 2.1) and Thailand (ASIR 2.2). Of note, ASIR in China was 2.4 per 100,000, and in the US, ASIR was 0.41. With regard to mortality, ASMR was greatest in Indonesia (4.3), Malaysia (4.2), and Brunei (4.1), triple the rates in China (ASMR 1.2) and ∼30x the ASMR in the US (0.14 per 100,000). In SEA, ASMR was lowest in Thailand (1.3) and Cambodia (1.5). MIR was greatest in Lao PDR, Cambodia, Malaysia, and Indonesia, and was lowest in Singapore and Thailand. In all SEA countries, ASIR was greater among men than among women. ASMR was also greater among men than among women. ASIR and ASMR are reported per 100,000 population in the table. In 2022, the incidence of NPC varied greatly within SEA, with ASIR almost three times that of China and over 10x that of the US in countries such as Brunei and Indonesia, highlighting both global and regional heterogeneity. Mortality varied widely as well, with ASMR in Indonesia, Malaysia, and Brunei up to 30x that of the US. Mortality-to-incidence ratio was greatest in lower resourced settings and lowest in Singapore and Thailand, underscoring socioeconomic drivers of survival. [ABSTRACT FROM AUTHOR]

Researches into normal tissue complication probability (NTCP) models for Radiation-Induced Hypothyroidism (RIHT) have almost harnessed intricate algorithms that, while precise, are challenging to apply in clinical practice. We developed a new model that proposes a unique thyroid tolerance dose prescription to accurately forecast RIHT and simplifies clinical protocols for safeguarding thyroid tissue in nasopharyngeal carcinoma. Our study collected clinical data and dose distribution imaging from 336 nasopharyngeal carcinoma patients. The radiation doses were converted into the Equivalent Dose in 2 Gray fractions (EQD2) and the Dose-Volume Histogram (DVH), Dose-Remaining Volume Histogram (DRVH), and Dose-Remaining Absolute Volume Histogram (DRAVH) were calculated. Generated the DRVH and DRAVH for dose d ranging from 1 to 80 Gy, in 1 Gy increments, resulting in 79 sets of DRVH(d) and DRAVH(d). Patients were stratified into two groups based on individualized clinical features using a threshold value X, and univariate analyses were performed using DRVH and DRAVH as variables within each group. The doses d were ranked according to univariate analysis indicators, with the top 15 doses designated as the tolerance dose distribution. The average of these tolerance dose distributions was selected for each group's tolerance dose. These individualized clinical features and their corresponding tolerance doses were fitted using least squares regression, leading to a tolerance dose model. This model was then compared with classical NTCP and machine learning models based on clinical and dosimetric factors. A recommending customized prescription for thyroid irradiation was proposed. Among the 336 patients enrolled in our study, 36.9% developed RIHT. We noted significant differences in the distribution of variables such as gender, Thyroid Volume (TV), Equivalent Uniform Dose (EUD), Thyroid Stimulating Hormone (TSH), and TVI (TVI = TSH/TV) between RIHT and non-RIHT patients. Due to solid multicollinearity, gender was excluded from further study after correlation analysis. TV and TVI had stronger linear trends with tolerance doses than TSH, thus we included them as distinct variables in our tolerance dosage model. This model demonstrated superior predictive performance (TVI: AUC 0.814, C-index 0.738; TV: AUC 0.712, C-index 0.639) compared to classical NTCP models (Lyman: AUC 0.667, C-index 0.401; Ronjom: AUC 0.718, C-index 0.347; Boomsma: AUC 0.708, C-index 0.347; Cella: AUC 0.668, C-index 0.399) and machine learning algorithms (highest AUC 0.812, C-index 0.738). Our model yielded equal or superior predictive accuracy with more straightforward calculations. We also developed recommending thyroid dose prescription tables based on TV and TVI, respectively. We established a high-accuracy thyroid tolerance dose model and provided clinically applicable tables offering customized dosing prescriptions for thyroid irradiation. [ABSTRACT FROM AUTHOR]

To analyze the alterations in saliva metabolites among patients with nasopharyngeal carcinoma both pre-radiotherapy and post-radiotherapy by metabolomics. To analyze the change in saliva metabolites in patients with nasopharyngeal carcinoma before and after radiotherapy by applying MR radiomics features. To establish a foundation for early prediction of radiation-induced parotid gland injury. 21 patients with nasopharyngeal carcinoma who have undergone radiotherapy in the First Affiliated Hospital of Soochow University between 2022-1-1 and 2022-12-31 were selected in this study. Saliva specimens and MR Images were obtained before the first radiotherapy and after the last radiotherapy. Metabolites in saliva samples were detected using metabolomics, and the alterations in metabolite levels before and after radiotherapy were analyzed. The parotid gland was delineated on T1WI and T2WI sequences as regions of interest, from which the imaging features were extracted and screened to obtain stable characteristics. Subsequently, the changes in imaging features before and after radiotherapy were analyzed. The metabolic-imaging damage profile of parotid radiotherapy was derived by conducting correlation analysis on the omics data from both modalities. During parotid gland irradiation, changes in saliva metabolites and pathways more accurately reflect the combined effects of inflammation and tumor. The study identified six target metabolites. A total of 668 metabolites were detected in the saliva samples of the radiotherapy group. The T1WI and T2WI yielded a total of 1130 image omics features, and after screening using the lasso regression 5-fold cross-validation method, six of T1WI and four of T2WI non-zero coefficient image omics features were obtained. The Metascores, Radscore-T1 and Radscore-T2 scores were computed for each patient through the linear fusion of selected features. Through the correlation analysis of them, it is evident that there exists a strong and statistically significant correlation between Metascores and both Radscore-T1 and Radscore-T2 scores. Additionally, the readily obtainable imaging data can effectively reflect changes in saliva metabolomics. The integration of these two modalities enables a more comprehensive analysis model for assessing parotid gland injury. Radiation-induced injury of the parotid gland is a prevalent occurrence during and after radical radiotherapy for nasopharyngeal carcinoma, significantly impacting treatment compliance and patients' quality of life. This study presents an initial description of a comprehensive radiation damage map based on the parotid gland, identifying specific molecular markers and imaging characteristics that can effectively reflect the progression of this damage. By constructing dual-modal omics data, we aim to establish a metabolic-imaging damage map for parotid gland radiotherapy. [ABSTRACT FROM AUTHOR]

Upper-neck irradiation (UNI) at the uninvolved neck has shown similar regional relapse–free survival as standard whole-neck irradiation (WNI) in patients with N0-1 nasopharyngeal carcinoma. However, whether UNI at the contralateral uninvolved neck is feasible in unilateral N3 disease, defined as >6 cm and/or below the caudal border of the cricoid cartilage, remains unclear. Data for 291 patients with nasopharyngeal carcinoma with unilateral N3 disease who were treated with intensity modulated radiation therapy from 2009 to 2015 were retrospectively analyzed. Among them, 190 received bilateral WNI (WNI group); the remaining 101 received WNI at the involved neck and UNI at the contralateral uninvolved neck (UNI group). Survival rates were estimated using the Kaplan-Meier method, and differences between groups were compared using the log rank tests. The median follow-up was 79.4 months (interquartile range, 56.0-89.3). Twenty-five patients had regional lymph node relapses (UNI: 10.9%, 11/101 vs WNI: 7.4%, 14/190; P =.31). Of these, 23 patients relapsed within the previously involved neck regions, while only 2 patients had relapses in the contralateral uninvolved neck (1 each in the UNI and WNI groups). Five-year regional relapse–free survival rates were similar between groups (89.7% vs 92.7%, P =.29). Similar between-group findings were also observed for 5-year overall survival (76.1% vs 80.4%, P =.40), distant metastasis–free survival (74.9% vs 79.2%, P =.44), and local relapse–free survival (95.6% vs 94.7%, P =.64). Furthermore, oncologic outcomes in subgroup and multivariable analyses were similar between groups. Regional control and survival outcomes were comparable in UNI at the contralateral uninvolved neck and standard WNI in patients with nasopharyngeal carcinoma with unilateral N3 disease. Our findings provide evidence for future radiation therapy guidelines of nasopharyngeal carcinoma. [ABSTRACT FROM AUTHOR]

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. 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. 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. 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. 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. [ABSTRACT FROM AUTHOR]

Dysregulation of long noncoding RNAs (lncRNAs) contributes to tumorigenesis by modulating specific cancerrelated pathways, but the roles of N6-methyladenosine (m6A)-enriched lncRNAs and underlying mechanisms remain elusive in nasopharyngeal carcinoma (NPC). Here, we reanalyzed the previous genome-wide analysis of lncRNA profiles in 18 pairs of NPC and normal tissues as well as in ten paired samples from NPC with or without post-treatment metastases. We discerned that an oncogenic m6A-enriched lncRNA, LINC00839, which was substantially upregulated in NPC and correlated with poor clinical prognosis, promoted NPC growth and metastasis both in vitro and in vivo. Mechanistically, by using RNA pull-down assay combined with mass spectrometry, we found that LINC00839 interacted directly with the transcription factor, TATA-box binding protein associated factor (TAF15). Besides, chromatin immunoprecipitation and dual-luciferase report assays demonstrated that LINC00839 coordinated the recruitment of TAF15 to the promoter region of amine oxidase coppercontaining 1 (AOC1), which encodes a secreted glycoprotein playing vital roles in various cancers, thereby activating AOC1 transcription in trans. In this study, potential effects of AOC1 in NPC progression were first proposed. Moreover, ectopic expression of AOC1 partially rescued the inhibitory effect of downregulation of LINC00839 in NPC. Furthermore, we showed that silencing vir-like m6A methyltransferaseassociated (VIRMA) and insulin-like growth factor 2 mRNAbinding proteins 1 (IGF2BP1) attenuated the expression level and RNA stability of LINC00839 in an m6A-dependent manner. Taken together, our study unveils a novel oncogenic VIRMA/IGF2BP1-LINC00839-TAF15-AOC1 axis and highlights the significance and prognostic value of LINC00839 expression in NPC carcinogenesis. [ABSTRACT FROM AUTHOR]