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Radiation is one of the standard therapies for pediatric high-grade glioma (pHGG), of which the prognosis remains poor. To gain an in-depth understanding of biological consequences beyond the classic DNA damage, we treated 9 patient-derived orthotopic xenograft (PDOX) models, including one with DNA mismatch repair (MMR) deficiency, with fractionated radiations (2 Gy/day x 5 days). Extension of survival time was noted in 5 PDOX models (P < 0.05) accompanied by γH2AX positivity in >95 % tumor cells in tumor core and >85 % in the invasive foci as well as ∼30 % apoptotic and mitotic catastrophic cell death. The model with DNA MMR (IC-1406HGG) was the most responsive to radiation with a reduction of Ki-67(+) cells. Altered metabolism, including mitochondria number elevation, COX IV activation and reactive oxygen species accumulation, were detected together with the enrichment of CD133+ tumor cells. The latter was caused by the entry of quiescent G0 cells into cell cycle and the activation of self-renewal (SOX2 and BMI1) and epithelial mesenchymal transition (fibronectin) genes. These novel insights about the cellular and molecular mechanisms of fractionated radiation in vivo should support the development of new radio-sensitizing therapies.

Accurate delineation of Gross Tumor Volume (GTV) is crucial for radiotherapy. Deep learning-driven GTV segmentation technologies excel in rapidly and accurately delineating GTV, providing a basis for radiologists in formulating radiation plans. The existing 2D and 3D segmentation models of GTV based on deep learning are limited by the loss of spatial features and anisotropy respectively, and are both affected by the variability of tumor characteristics, blurred boundaries, and background interference. All these factors seriously affect the segmentation performance. To address the above issues, a Layer-Volume Parallel Attention (LVPA)-UNet model based on 2D-3D architecture has been proposed in this study, in which three strategies are introduced. Firstly, 2D and 3D workflows are introduced in the LVPA-UNet. They work in parallel and can guide each other. Both the fine features of each slice of 2D MRI and the 3D anatomical structure and spatial features of the tumor can be extracted by them. Secondly, parallel multi-branch depth-wise strip convolutions adapt the model to tumors of varying shapes and sizes within slices and volumetric spaces, and achieve refined processing of blurred boundaries. Lastly, a Layer-Channel Attention mechanism is proposed to adaptively adjust the weights of slices and channels according to their different tumor information, and then to highlight slices and channels with tumor. The experiments by LVPA-UNet on 1010 nasopharyngeal carcinoma (NPC) MRI datasets from three centers show a DSC of 0.7907, precision of 0.7929, recall of 0.8025, and HD95 of 1.8702 mm, outperforming eight typical models. Compared to the baseline model, it improves DSC by 2.14 %, precision by 2.96 %, and recall by 1.01 %, while reducing HD95 by 0.5434 mm. Consequently, while ensuring the efficiency of segmentation through deep learning, LVPA-UNet is able to provide superior GTV delineation results for radiotherapy and offer technical support for precision medicine.

Male infertility is a global concern, with a noticeable increase in the decline of spermatogenesis and sperm quality. However, there are limited clinically effective treatments available. This study aimed to investigate the potential effectiveness of puerarin in treating male infertility, which leads to gonadal changes. The results obtained from various analyses such as CASA, immunofluorescence, DIFF-Quick, hematoxylin and eosin (H&E), and periodic acid-Schiff (PAS) staining demonstrated that puerarin supplementation significantly alleviated the busulfan-induced reduction in spermatogenesis and sperm quality in both young and adult mice. Furthermore, puerarin exhibited a marked improvement in the damage caused by busulfan to the architecture of seminiferous tubules, causal epididymis, blood-testicular barrier (BTB), as well as spermatogonia and Sertoli cells. Similarly, puerarin significantly reduced the levels of total antioxidant capacity (T-AOC), malondialdehyde (MDA), and caspase-3 in the testes of busulfan-induced mice, as determined by microplate reader analysis. Additionally, RNA-seq data, RT-qPCR, and western blotting revealed that puerarin restored the abnormal gene expressions induced by busulfan to nearly healthy levels. Notably, puerarin significantly reversed the impact of busulfan on the expression of marker genes involved in spermatogenesis and oxidative stress. Moreover, puerarin suppressed the phosphorylation of p38, ERK1/2, and JNK in the testes, as observed through testicular analysis. Consequently, this study concludes that puerarin may serve as a potential alternative for treating busulfan-induced damage to male fertility by inactivating the testicular MAPK pathways. These findings may pave the way for the use of puerarin in addressing chemotherapy- or other factors-induced male infertility in humans.

While recurrence is frequent in ependymoma, the underlying molecular mechanisms remain to be explored. Here, the authors investigate epigenetic, genetic and tumorigenic changes in 30 patient-matched repeated relapses over 13 years and identify distinct patterns of DNA methylation.

Summary: Chemotherapy remains controversial for stage II nasopharyngeal carcinoma because of its considerable prognostic heterogeneity. We aimed to develop an MRI-based deep learning model for predicting distant metastasis and assessing chemotherapy efficacy in stage II nasopharyngeal carcinoma. This multicenter retrospective study enrolled 1072 patients from three Chinese centers for training (Center 1, n = 575) and external validation (Centers 2 and 3, n = 497). The deep learning model significantly predicted the risk of distant metastases for stage II nasopharyngeal carcinoma and was validated in the external validation cohort. In addition, the deep learning model outperformed the clinical and radiomics models in terms of predictive performance. Furthermore, the deep learning model facilitates the identification of high-risk patients who could benefit from chemotherapy, providing useful additional information for individualized treatment decisions.

Glioblastoma multiforme (GBM) is a highly aggressive malignancy and represents the most common brain tumor in adults. To better understand its biology for new and effective therapies, we examined the role of GDP-mannose pyrophosphorylase B (GMPPB), a key unit of the GDP-mannose pyrophosphorylase (GDP-MP) that catalyzes the formation of GDP-mannose. Impaired GMPPB function will reduce the amount of GDP-mannose available for O-mannosylation. Abnormal O-mannosylation of alpha dystroglycan (α-DG) has been reported to be involved in cancer metastasis and arenavirus entry. Here, we found that GMPPB is highly expressed in a panel of GBM cell lines and clinical samples and that expression of GMPPB is positively correlated with the WHO grade of gliomas. Additionally, expression of GMPPB was negatively correlated with the prognosis of GBM patients. We demonstrate that silencing GMPPB inhibits the proliferation, migration, and invasion of GBM cells both in vitro and in vivo and that overexpression of GMPPB exhibits the opposite effects. Consequently, targeting GMPPB in GBM cells results in impaired GBM tumor growth and invasion. Finally, we identify that the Hippo/MMP3 axis is essential for GMPPB-promoted GBM aggressiveness. These findings indicate that GMPPB represents a potential novel target for GBM treatment.

Abstract Background To determine whether concurrent chemotherapy is necessary during locoregional radiotherapy (RT) after palliative chemotherapy (PCT) in patients with de novo metastatic nasopharyngeal carcinoma (mNPC). Methods A total of 746 patients with mNPC from 2000 to 2017 at our hospital were retrospectively reviewed. Among them, 355 patients received PCT followed by RT. Overall survival (OS) and progression-free survival (PFS), including locoregional progression-free survival (LRPFS) and distant progression-free survival (DPFS) were estimated with the Kaplan–Meier method and log-rank test. Cox proportional-hazards models, landmark analyses, propensity score matching, and subgroup analyses were used to address confounding. Results Of the patients included in our study, 192 received radiotherapy alone after PCT (PCT + RT), and 163 received concurrent chemoradiotherapy after PCT (PCT + CCRT). The prognosis of PCT + CCRT was significantly better than that of PCT + RT (5 year OS, 53.0 vs 36.2%; P = 0.004). After matching, the 5 year OS rates of the two groups were 55.7 and 39.0%, respectively (P = 0.034) and the median DPFS were 29.4 and 18.7 months, respectively (P = 0.052). Multivariate Cox regression analysis indicated that PCT + CCRT was an independent favorable prognostic factor (P = 0.009). In addition, conducting concurrent chemoradiotherapy after 4–6 cycles of PCT or conducting concurrent chemotherapy with single-agent platinum was associated with significant survival benefit in the matched cohort (5 year OS rate, 60.4 or 57.4%, respectively). The survival difference between groups remained significant when evaluating patients who survived for ≥ 1 year (P = 0.028). Conclusions The optimal treatment strategy of mNPC is the combination of PCT followed by concurrent chemoradiotherapy. More specifically, concurrent chemoradiotherapy with single-agent platinum after 4–6 cycles of PCT is suggested.

Abstract Nasopharyngeal carcinoma (NPC) is a malignant epithelial tumor originating in the nasopharynx and has a high incidence in Southeast Asia and North Africa. To develop these comprehensive guidelines for the diagnosis and management of NPC, the Chinese Society of Clinical Oncology (CSCO) arranged a multi‐disciplinary team comprising of experts from all sub‐specialties of NPC to write, discuss, and revise the guidelines. Based on the findings of evidence‐based medicine in China and abroad, domestic experts have iteratively developed these guidelines to provide proper management of NPC. Overall, the guidelines describe the screening, clinical and pathological diagnosis, staging and risk assessment, therapies, and follow‐up of NPC, which aim to improve the management of NPC.

Abstract Background Proton beam therapy (PBT) is a new-emerging cancer treatment in China but its treatment costs are high and not yet covered by Chinese public medical insurance. The advanced form of PBT, intensity-modulated proton radiation therapy (IMPT), has been confirmed to reduce normal tissue complication probability (NTCP) as compared to conventional intensity-modulated photon-radiation therapy (IMRT) in patients with oropharyngeal cancer (OPC). Herein, we evaluated the cost-effectiveness and applicability of IMPT versus IMRT for OPC patients in China, aiming at guiding the proper use of PBT. Methods A 7-state Markov model was designed for analysis. Base-case evaluation was performed on a 56-year-old (median age of OPC in China) patient under the assumption that IMPT could provide a 25% NTCP-reduction in long-term symptomatic dysphagia and xerostomia. Model robustness was examined using probabilistic sensitivity analysis, cohort analysis, and tornado diagram. One-way sensitivity analyses were conducted to identify the cost-effective scenarios. IMPT was considered as cost-effective if the incremental cost-effectiveness ratio (ICER) was below the societal willingness-to-pay (WTP) threshold. Results Compared with IMRT, IMPT provided an extra 0.205 quality-adjusted life-year (QALY) at an additional cost of 34,926.6 US dollars ($), and had an ICER of $170,082.4/ QALY for the base case. At the current WTP of China ($33,558 / QALY) and a current IMPT treatment costs of $50,000, IMPT should provide a minimum NTCP-reduction of 47.5, 50.8, 55.6, 63.3 and 77.2% to be considered cost-effective for patient age levels of 10, 20, 30, 40 and 50-year-old, respectively. For patients at the median age level, reducing the current IMPT costs ($50,000) to a $30,000 level would make the minimum NTCP-reduction threshold for “cost-effective” decrease from 91.4 to 44.6%, at the current WTP of China (from 69.0 to 33.5%, at a WTP of $50,000 / QALY; and from 39.7 to 19.1%, at a WTP of $100,000 / QALY). Conclusions Cost-effective scenarios of PBT exist in Chinese OPC patients at the current WTP of China. Considering a potential upcoming increase in PBT use in China, such cost-effective scenarios may further expand if a decrease of proton treatment costs occurs or an increase of WTP level.

Summary: Background: Nasopharyngeal carcinoma (NPC) exhibits significant familial aggregation; however, its susceptibility genes are largely unknown. Thus, this study aimed to identify germline mutations that might contribute to the risk of familial NPC, and explore their biological functions. Methods: Whole-exome sequencing was performed in 13 NPC pedigrees with multiple cases. Mutations co-segregated with disease status were further validated in a cohort composed of 563 probands from independent families, 2,953 sporadic cases, and 3,175 healthy controls. Experimental studies were used to explore the functions of susceptibility genes and their disease-related mutations. Findings: The three rare missense mutations in POLN (DNA polymerase nu) gene, P577L, R303Q, and F545C, were associated with familial NPC risk (5/576 [0·87%] in cases vs. 2/3374 [0·059%] in healthy controls with an adjusted OR of 44·84 [95% CI:3·91-514·34, p = 2·25 × 10−3]). POLN was involved in Epstein-Barr virus (EBV) lytic replication in NPC cells in vitro. POLN promoted viral DNA replication, immediate-early and late lytic gene expression, and progeny viral particle production, ultimately affecting the proliferation of host cells. The three mutations were located in two pivotal functional domains and were predicted to alter the protein stability of POLN in silico. Further assays demonstrated that POLN carrying any of the three mutations displayed reduced protein stability and decreased expression levels, thereby impairing its ability to promote complete EBV lytic replication and facilitate cell survival. Interpretation: We identified a susceptibility gene POLN for familial NPC and elucidated its function. Funding: This study was funded by the National Key Research and Development Program of China (2021YFC2500400); the National Key Research and Development Program of China (2020YFC1316902); the Basic and Applied Basic Research Foundation of Guangdong Province, China (2021B1515420007); the National Natural Science Foundation of China (81973131); the National Natural Science Foundation of China (82003520); the National Natural Science Foundation of China (81903395).

BackgroundIncidental exposure of the heart to ionizing irradiation is associated with an increased risk of ischemic heart disease and subsequent fatality in patients with breast cancer after radiotherapy. Proton beam therapy can limit the heart dose in breast irradiation to a negligible level. However, compared with conventional photon modality, proton breast irradiation is more expensive. In this study, we performed cost-effectiveness analyses to identify the type of patients who would be more suitable for protons.MethodsA Markov decision model was designed to evaluate the cost-effectiveness of protons vs. photons in reducing the risk of irradiation-related ischemic heart disease. A baseline evaluation was performed on a 50-year-old woman patient without the preexisting cardiac risk factor. Furthermore, risk-stratification analyses for photon mean heart dose and preexisting cardiac risk were conducted on 40-, 50-, and 60-year-old women patients under different proton cost and willingness-to-pay (WTP) settings.ResultsUsing the baseline settings, the incremental effectiveness (protons vs. photons) increased from 0.043 quality-adjusted life-year (QALY) to 0.964 QALY when preexisting cardiac risk increased to 10 times its baseline level. At a proton cost of 50,000 US dollars ($), protons could be cost-effective for ≤ 60-year-old patients with diabetes and ≤50-year-old patients with grade II–III hypertension at the WTP of China ($37,653/QALY); for ≤ 60-year-old patients with diabetes and ≤ 50-year-old patients with grade II–III hypertension or ≥ 2 major cardiac risk factors at a WTP of $50,000/QALY; and for ≤ 60-year-old patients with diabetes, grade II–III hypertension or ≥ 2 major cardiac risk factors and ≤ 50-year-old patients with total cholesterol ≥ 240 mg/dL at a WTP of $100,000/QALY.ConclusionPatients' preexisting cardiac risk status was a key factor affecting the cardiac benefits gained from protons and should therefore be a major consideration for the clinical decision of using protons; cost-effective scenarios of protons exist in those patients with high risk of developing cardiac diseases.

ObjectiveThis study aimed to establish a prognostic stratified model of chemotherapy-based comprehensive treatment for patients with locoregional recurrent nasopharyngeal carcinoma (lrNPC), to help individualized treatment decision-making.Materials and MethodsThis study retrospectively reviewed patients with lrNPC who received chemotherapy-based comprehensive treatment from January 1, 2010, to December 31, 2018. A total of 422 eligible patients were divided into test (n = 338) and validation (n = 84) cohorts. A LASSO cox regression model was used to identify significant prognostic factors for overall survival (OS) in the test cohort. A nomogram was then developed based on a combined consideration of clinically meaningful prognostic factors and statistically significant prognostic factors. The performance of the nomogram was assessed with Harrell’s concordance index (C-index) and calibration plots.ResultsFive significant factors were identified: age, albumin (ALB), T stage after recurrent (rT), neutrophil to lymphocyte ratio (NLR), and systematic immune-inflammation index (SII). The nomogram was established with these five factors. C-index was 0.636 in the test cohort and 0.610 in the validation cohort. The calibration curves for the OS rate at 3, and 5 years showed an excellent agreement in both cohorts. In addition, the corresponding risk classification system successfully classified patients into low- and high-risk groups and performed well in stratification (P < 0.001).ConclusionsThe nomogram shows well prognostic performance for lrNPC patients receiving chemotherapy-based comprehensive treatment.

Abstract Background Cost-effectiveness is a pivotal consideration for clinical decision making of high-tech cancer treatment in developing countries. Intensity-modulated proton radiation therapy (IMPT, the advanced form of proton beam therapy) has been found to improve the prognosis of the patients with paranasal sinus and nasal cavity cancers compared with intensity-modulated photon-radiation therapy (IMRT). However, the cost-effectiveness of IMPT has not yet been fully evaluated. This study aimed at evaluating the cost-effectiveness of IMPT versus IMRT for treatment decision making of paranasal sinus and nasal cavity cancers in Chinese settings. Methods A 3-state Markov model was designed for cost-effectiveness analysis. A base case evaluation was performed on a patient of 47-year-old (median age of patients with paranasal sinus and nasal cavity cancers in China). Model robustness was examined by probabilistic sensitivity analysis, Markov cohort analysis and Tornado diagram. Cost-effective scenarios of IMPT were further identified by one-way sensitivity analyses and stratified analyses were performed for different age levels. The outcome measure of the model was the incremental cost-effectiveness ratio (ICER). A strategy was defined as cost-effective if the ICER was below the societal willingness-to-pay (WTP) threshold of China (30,828 US dollars ($) / quality-adjusted life year (QALY)). Results IMPT was identified as being cost-effective for the base case at the WTP of China, providing an extra 1.65 QALYs at an additional cost of $38,928.7 compared with IMRT, and had an ICER of $23,611.2 / QALY. Of note, cost-effective scenarios of IMPT only existed in the following independent conditions: probability of IMPT eradicating cancer ≥0.867; probability of IMRT eradicating cancer ≤0.764; or cost of IMPT ≤ $52,163.9. Stratified analyses for different age levels demonstrated that IMPT was more cost-effective in younger patients than older patients, and was cost-effective only in patients ≤56-year-old. Conclusions Despite initially regarded as bearing high treatment cost, IMPT could still be cost-effective for patients with paranasal sinus and nasal cavity cancers in China. The tumor control superiority of IMPT over IMRT and the patient’s age should be the principal considerations for clinical decision of prescribing this new irradiation technique.

Summary: The sluggish oxygen reduction reaction (ORR) has becoming the bottleneck of largescale implementation of proton exchange membrane fuel cells. However, when it comes to the ORR activity assessing of platinum group metals (PGMs) with rotating disk electrode, the corresponding potential conversion vs. reversible hydrogen electrode, test protocols, and activity calculation processes are still in chaos in many published literatures. In this work, two standard calculation processes for PGM ORR activities are demonstrated, followed by a specification for the usage of reference electrodes. Then a 4-fold discrepancy in ORR activities obtained via different test protocols is found for the same Pt/C, and an average adsorption model and the “coverage effects” are proposed to illustrate the hysteresis loop between negative and positive-going ORR polarization plots. Finally, four motions over appropriate assessment of PGM ORR activity are emphasized, hoping to bring a fair communication platform for researchers from different groups.

Abstract Background Promising efficacy and manageable toxicity of docetaxel-based concurrent chemoradiotherapy (CCRT) were reported in head and neck cancer. In addition, the effect of CCRT in combination with cisplatin and/or 5-fluorouracil on both locoregionally advanced and metastatic/recurrent nasopharyngeal carcinoma (NPC) was verified. However, CCRT with docetaxel for locoregionally advanced NPC are not well studied. This study aimed to compare effectiveness and toxicities of CCRT with weekly docetaxel versus tri-weekly cisplatin for locoregionally advanced NPC. Methods Clinical data of patients with locoregionally advanced NPC newly diagnosed between January 2010 and December 2014 receiving CCRT with either weekly docetaxel (15 mg/m2) or tri-weekly cisplatin (80–100 mg/m2) were reviewed. Propensity score matching at a 1:1 ratio was performed to balance baseline characteristics. Adverse events and survival were compared between the two groups. Results A total of 962 patients were included as the whole cohort, and 448 patients were matched and were regarded as the matched cohort. The median follow-up duration was 48 months for the whole cohort. The 3-year nodal recurrence-free survival rate was significantly increased for patients treated with docetaxel in both the whole (hazard ratio [HR] = 0.37, 95% confidence interval [CI] 0.19–0.72, P = 0.030) and matched cohorts (HR = 0.33, 95% CI 0.14–0.79, P = 0.023). However, no significant differences were observed in overall survival, local recurrence-free survival, and distant metastasis-free survival between the two groups in both cohorts. Significantly higher rates of grade 3 radiodermatitis (6.7% vs. 1.8%, P = 0.001), mucositis (74.5% vs. 37.9%, P

Abstract Background Whether PD-L1/PD-1 expression plays a significant role in the prognosis of NPC is still controversial. The present study mainly aimed to investigate the prognostic significance of PD-L1/PD-1 expression in patients with NPC. Methods A systematical research was performed in the PubMed, Web of Science, EMBASE, and the Cochrane Library databases up to January 06, 2019. Eighteen studies met eligible criteria were included in the meta-analysis. Quality assessment of included articles was evaluated by Newcastle–Ottawa quality assessment scale (NOS). Pooled hazard ratios (HRs) and their corresponding 95% confidence intervals (95% CIs) were used to elucidated the primary endpoint, overall survival (OS), and the secondary endpoints. Furthermore, the relationship between clinicopathological features of NPC and PD-L1/PD-1 expression was estimated by relative ratios (RRs) and 95% CIs. Results A total of 1836 patients from 15 included studies concerning PD-L1 and 678 patients from six studies regarding PD-1 were included in the meta-analysis. Pooled results revealed that PD-L1 expression in NPC did not correlate with OS (HR 1.34 95% CI 0.93–1.93, p = 0.11), DFS (HR 1.82, 95% CI 0.86–3.85, p = 0.12), PFS (HR 1.19, 95% CI 0.46–3.08, p = 0.72), and DMFS (HR 2.26, 95% CI 0.60–8.56, p = 0.23). Meanwhile, no statistically significant differences existed between the expression level of PD-1 in tumor infiltrating lymphocytes (TILs) and the OS in NPC, with the pooled HR 1.29 (95% CI 0.68–2.42, p = 0.44). In subgroup analysis, higher expression of PD-L1 in immune cells correlated with better OS in patients with NPC, with a pooled HR 0.68 (95% CI 0.47–0.99, p = 0.04). Among the clinicopathological features included in our study, we found that the positive expression of PD-L1 in NPC associated with the higher expression of PD-1 (RR 1.25, 95% CI 1.02–1.52, p = 0.03). Conclusions Our meta-analysis indicated that higher/positive expression of PD-L1/PD-1 may not serve as suitable biomarkers for the prognosis of NPC, which was not in consistent with some previous studies about the prognostic value of PD-L1/PD-1 in other types of tumors. Despite the positive results in subgroup analysis and study about clinicopathological features, it may still need corroboration of prospective and large-scale studies.

Abstract Background The male predominance in the incidence of nasopharyngeal carcinoma (NPC) suggests the contribution of the X chromosome to the susceptibility of NPC. However, no X-linked susceptibility loci have been examined by genome-wide association studies (GWASs) for NPC by far. Methods To understand the contribution of the X chromosome in NPC susceptibility, we conducted an X chromosome-wide association analysis on 1615 NPC patients and 1025 healthy controls of Guangdong Chinese, followed by two validation analyses in Taiwan Chinese (n = 562) and Malaysian Chinese (n = 716). Results Firstly, the proportion of variance of X-linked loci over phenotypic variance was estimated in the discovery samples, which revealed that the phenotypic variance explained by X chromosome polymorphisms was estimated to be 12.63% (non-dosage compensation model) in males, as compared with 0.0001% in females. This suggested that the contribution of X chromosome to the genetic variance of NPC should not be neglected. Secondly, association analysis revealed that rs5927056 in DMD gene achieved X chromosome-wide association significance in the discovery sample (OR = 0.81, 95% CI 0.73–0.89, P = 1.49 × 10−5). Combined analysis revealed rs5927056 for DMD gene with suggestive significance (P = 9.44 × 10−5). Moreover, the female-specific association of rs5933886 in ARHGAP6 gene (OR = 0.62, 95%CI: 0.47–0.81, P = 4.37 × 10−4) was successfully replicated in Taiwan Chinese (P = 1.64 × 10−2). rs5933886 also showed nominally significant gender × SNP interaction in both Guangdong (P = 6.25 × 10−4) and Taiwan datasets (P = 2.99 × 10−2). Conclusion Our finding reveals new susceptibility loci at the X chromosome conferring risk of NPC and supports the value of including the X chromosome in large-scale association studies.

This systematic review aims to identify prognostic molecular biomarkers which demonstrate strong evidence and a low risk of bias in predicting the survival of nasopharyngeal carcinoma (NPC) patients. The literature was searched for on PubMed to identify original clinical studies and meta-analyses which reported associations between molecular biomarkers and survival, including ≥150 patients with a survival analysis, and the results were validated in at least one independent cohort, while meta-analyses must include ≥1000 patients with a survival analysis. Seventeen studies fulfilled these criteria—two studies on single nucleotide polymorphisms (SNPs), three studies on methylation biomarkers, two studies on microRNA biomarkers, one study on mutational signature, six studies on gene expression panels, and three meta-analyses on gene expressions. The comparison between the hazard ratios of high-risk and low-risk patients along with a multivariate analysis are used to indicate that these biomarkers have significant independent prognostic values for survival. The biomarkers also indicate a response to certain treatments and whether they could be used as therapeutic targets. This review highlights that patients’ genetics, epigenetics, and signatures of cancer and immune cells in the tumor microenvironment (TME) play a vital role in determining their survival.

Abstract Germline polymorphisms are linked with differential survival outcomes in cancers but are not well studied in nasopharyngeal carcinoma (NPC). Here, a two‐phase association study is conducted to discover germline polymorphisms that are associated with the prognosis of NPC. The discovery phase includes two consecutive hospital cohorts of patients with NPC from Southern China. Exome‐wide genotypes at 246 173 single nucleotide polymorphisms (SNPs) are determined, followed by survival analysis for each SNP under Cox proportional hazard regression model. Candidate SNP is replicated in another two independent cohorts from Southern China and Singapore. Meta‐analysis of all samples (n = 5553) confirms that the presence of rs1131636‐T, located in the 3′‐UTR of RPA1, confers an inferior overall survival (HR = 1.33, 95% CI = 1.20–1.47, P = 6.31 × 10−8). Bioinformatics and biological assays show that rs1131636 has regulatory effects on upstream RPA1. Functional studies further demonstrate that RPA1 promotes the growth, invasion, migration, and radioresistance of NPC cells. Additionally, miR‐1253 is identified as a suppressor for RPA1 expression, likely through regulation of its binding affinity to rs1131636 locus. Collectively, these findings provide a promising biomarker aiding in stratifying patients with poor survival, as well as a potential drug target for NPC.

Abstract Background Although the prognostic impact of body mass index (BMI) in patients with non-metastatic nasopharyngeal carcinoma (NPC) had been extensively studied, its effect among metastatic NPC patients remains unknown. The purpose of this study was to evaluate the prognostic effect of BMI in patients with metastatic NPC. Methods We retrospectively studied 819 patients who were diagnosed with distant metastasis from NPC and received treatment between 1998 and 2007. The patients were divided into three subgroups according to the World Health Organization classifications for Asian populations: underweight (BMI

Abstract Background Nasal-type extranodal natural killer/T-cell lymphoma (ENKTCL) originates primarily in the nasal cavity or extra-nasal sites within the upper aerodigestive tract. However, it is unclear whether the primary site can serve as an independent prognostic factor or whether the varying clinical outcomes observed with different primary sites can be attributed merely to their propensities of regional lymph node involvement. The aim of this study was to investigate the prognostic implications of the primary site and regional lymph node involvement in patients with early-stage nasal-type ENKTCL. Methods To develop a nomogram, we reviewed the clinical data of 215 consecutively diagnosed patients with early-stage nasal-type ENKTCL who were treated in Sun Yat-sen University Cancer Center with chemotherapy and radiotherapy between 2000 and 2011. The predictive accuracy and discriminative ability of the nomogram were determined using a concordance index (C-index) and calibration curve. Results The 5-year overall survival (OS) and progression-free survival (PFS) rates of patients with nasal ENKTCL were higher than those of patients with extra-nasal ENKTCL (OS: 68.2% vs. 46.0%, P = 0.030; PFS: 53.4% vs. 26.6%, P = 0.010). The 5-year OS and PFS rates of patients with Ann Arbor stage IE ENKTCL were higher than those of patients with Ann Arbor stage IIE ENKTCL (OS: 66.3% vs. 59.2%, P = 0.003; PFS: 51.4% vs. 40.3%, P = 0.009). Multivariate analysis showed that age >60 years, ECOG performance status score ≥2, elevated lactate dehydrogenase (LDH) level, extra-nasal primary site, and regional lymph node involvement were significantly associated with lower 5-year OS rate; age >60 years, elevated LDH level, extra-nasal primary site, and regional lymph node involvement were significantly associated with lower 5-year PFS rate. The nomogram included the primary site and regional lymph node involvement based on multivariate analysis. The calibration curve showed good agreement between the predicted and actual 5-year OS and PFS rates, and the C-indexes of the nomogram for the OS and PFS rates were 0.697 and 0.634, respectively. Conclusions The primary site and regional lymph node involvement are independent prognostic factors for early-stage ENKTCL treated with chemotherapy followed by definitive radiotherapy.

Abstract Background With the improved overall survival (OS) of nasopharyngeal carcinoma (NPC) patients, the importance of quality of life (QoL) is increasingly being recognized. For some radiosensitive NPC patients, whether low-dose radiotherapy can improve the QoL without affecting clinical efficacy is unknown. This study aimed to assess the survival rates and QoL of NPC patients treated with 50 Gy radiotherapy plus hematoporphyrin derivative (HPD). Methods Forty-six newly diagnosed NPC patients treated with 50 Gy radiotherapy plus HPD between June 1988 and July 1992 were analyzed. All patients were restaged according to the 7th edition of the American Joint Committee on Cancer staging system. The radiotherapy plan was designed on the basis of pretreatment computed tomography. The OS, local recurrence-free survival (LRFS), distant metastasis-free survival (DMFS), and disease-free survival (DFS) rates were estimated using the Kaplan–Meier method. QoL was assessed using the Late Radiation Morbidity Scoring Criteria of the Radiation Therapy Oncology Group. Results The 5-year OS, LRFS, DMFS, and DFS rates were 74.3%, 72.6%, 82.1%, and 61.2%, respectively. The corresponding 10-year rates were 38.4%, 62.9%, 78.5%, and 49.8%, respectively, and the 20-year rates were 27.7%, 51.4%, 78.5%, and 40.7%, respectively. None of the patients developed severe radiation-related complications, such as radiation-induced temporal lobe necrosis, hearing loss, trismus, and dysphagia. Conclusion Some NPC patients were sensitive to 50 Gy radiotherapy plus HPD, and this sensitivity was characterized by long-term survival without significant late treatment morbidities.

In the original publication of this article [1], the first affiliation name in the Author details section should be updated to ‘Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen 518116, China’ because the affiliation has been renamed from Jun. 15th, 2019.

PURPOSE:To investigate the prognostic value of cavernoussinus invasion (CSI) in patients with nasopharyngeal carcinoma (NPC) treated with intensity-modulated radiotherapy (IMRT). PATIENTS AND METHODS:Retrospective review of data from 1,087 patients with biopsy-proven, non-metastatic NPC. All patients were diagnosed using magnetic resonance imaging (MRI) scans and received IMRT as the primary treatment. RESULTS:The incidence of cavernoussinus invasion in this cohort was 12.1%. In univariate analysis, 5-year overall survival (OS) (70.6% vs. 88.5%, P < 0.001) and distant metastasis-free survival (DMFS) (71.4% vs. 87.7%, P < 0.001), but not locoregional relapse-free survival (LRFS) (93.9% vs. 93.7%, P = 0.341), were significantly different between patients with and without cavernoussinus invasion. In the T4 subgroup, the 5-year OS, DMFS, and LRFS of patients with and without cavernoussinus extension were 70.6% vs. 81.9% (P = 0.011), 71.4% vs. 84.1% (P = 0.011), and 91.2% vs. 89.7% (P = 0.501), respectively. In multivariate analysis, cavernoussinus invasion was an independent prognostic factor for poorer OS (HR = 1.782; P = 0.013) and DMFS (HR = 1.771; P = 0.016), but not LRFS (HR = 0.632; P = 0.294). In patients with lymph node metastasis, the DMFS rates of patients with and without cavernoussinus invasion were significantly different (P < 0.001). Preliminaryanalysis indicated that neoadjuvant chemotherapy led to better DMFS and OS in patients with cavernoussinus invasion than concurrent chemotherapy or radiotherapy alone; however, the differences were not significant. CONCLUSIONS:In the IMRT era, cavernoussinus invasion remains a prognostic factor for poor DMFS and OS in NPC, even in patients with T4 disease.

BACKGROUND:Although weight loss is common in nasopharyngeal carcinoma (NPC) patients receiving radiotherapy, the prognostic influence of weight loss and its impact modified by body mass index (BMI) are still unclear. METHODS:2433 NPC patients receiving radical radiotherapy at Sun Yat-sen University Cancer Center from November, 2000 to December, 2004 were enrolled. Weight change during radiation treatment was categorized into high weight loss (HWL) and low weight loss (LWL). The associations of HWL with overall survival (OS) and disease-specific survival (DSS) were analyzed by Cox regression. RESULTS:Among underweight patients, HWL was independently associated with poor OS (hazard ratio [HR], 2.06; 95% CI 1.36-3.11) and DSS (HR, 2.27; 95% CI 1.38-3.73), as compared with LWL, after adjusting for covariates. In normal weight patients, the impact of HWL on OS (HR, 1.47; 95% CI 1.19-1.80) and DSS (HR, 1.59; 95% CI 1.24-2.03) was moderate. Among overweight/obese patients, no significant association between HWL and OS (HR, 1.22; 95% CI 0.95-1.55), or DSS (HR, 1.23; 95% CI 0.93-1.64) was found. CONCLUSION:Except for overweight/obese patients, high weight loss during radiation treatment was independently associated with poor survival in NPC. This impact was more prominent in the underweight patient group.

It has been recently reported that a side population of cells in nasopharyngeal carcinoma (NPC) displayed characteristics of stem-like cancer cells. However, the molecular mechanisms underlying the modulation of such stem-like cell populations in NPC remain unclear. Epstein-Barr virus was the first identified human tumor virus to be associated with various malignancies, most notably NPC. LMP2A, the Epstein-Barr virus encoded latent protein, has been reported to play roles in oncogenic processes. We report by immunostaining in our current study that LMP2A is overexpressed in 57.6% of the nasopharyngeal carcinoma tumors sampled and is mainly localized at the tumor invasive front. We found also in NPC cells that the exogenous expression of LMP2A greatly increases their invasive/migratory ability, induces epithelial-mesenchymal transition (EMT)-like cellular marker alterations, and stimulates stem cell side populations and the expression of stem cell markers. In addition, LMP2A enhances the transforming ability of cancer cells in both colony formation and soft agar assays, as well as the self-renewal ability of stem-like cancer cells in a spherical culture assay. Additionally, LMP2A increases the number of cancer initiating cells in a xenograft tumor formation assay. More importantly, the endogenous expression of LMP2A positively correlates with the expression of ABCG2 in NPC samples. Finally, we demonstrate that Akt inhibitor (V) greatly decreases the size of the stem cell side populations in LMP2A-expressing cells. Taken together, our data indicate that LMP2A induces EMT and stem-like cell self-renewal in NPC, suggesting a novel mechanism by which Epstein-Barr virus induces the initiation, metastasis and recurrence of NPC.

Purpose This study aimed to explore the functions and mechanisms of C-C motif chemokine receptor 6 (CCR6), a gene associated with progression and metastasis of colorectal cancer (CRC), in radiosensitivity of rectal cancer (RC). Materials and Methods RNA sequencing and immunohistochemical analysis on CCR6 expression were performed in pretreatment tissues of RC patients exhibiting different therapeutic effects of radiotherapy. Colonogenic survival assay was conducted in different CRC cell lines to assess their radiosensitivity. And the impact of CCR6 expression on radiosensitivity was validated through RNA interference. The DNA damage repair (DDR) abilities of cell lines with different CCR6 expression were evaluated through immunofluorescence-based yH2AX quantification. Results The CCR6 mRNA level was higher in patients without pathologic complete remission (pCR) than in those with pCR (fold changed, 2.11; p=0.004). High-level expression of CCR6 protein was more common in the bad responders than in the good responders (76.3% vs. 37.5%, p < 0.001). The CRC cell lines with higher CCR6 expression (LoVo and sw480) appeared to be more radioresistant, compared with the sw620 cell line which had lower CCR6 expression. CCR6 knockdown made the LoVo cells more sensitive to ionizing radiation (sensitization enhancement ratio, 1.738; p < 0.001), and decreased their DDR efficiency. Conclusion CCR6 might affect the RC radiosensitivity through DDR process. These findings supported CCR6 as a predicting biomarker of radiosensitivity and a potential target of radiosensitization for RC patients. [ABSTRACT FROM AUTHOR]