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The most frequent location of metastatic EBV+ nasopharyngeal carcinoma (NPC) is the bone marrow, an adipocyte-dominant region. Several EBV-associated lymphoepithelioma-like carcinoma (LELC) types also grow in the anatomical vicinity of fat tissues. Here we show that in an adipose tissue-rich tumor setting, EBV targets adipocytes and remodels the tumor microenvironment. Positive immunoreactivity for EBV-encoded early antigen D was detected in adipose tissue near tumor beds of bone marrow metastatic NPC. EBV was capable of infecting primary human adipocytes in vitro, triggering expression of multiple EBV-encoded mRNA and proteins. In infected adipocytes, lipolysis was stimulated through enhanced expression of lipases and the AMPK metabolic pathway. The EBV-mediated imbalance in energy homeostasis was further confirmed by increased release of free fatty acids, glycerol, and expression of proinflammatory adipokines. Clinically, enhanced serum levels of free fatty acids in patients with NPC correlated with poorer recurrence-free survival. EBV-induced delipidation stimulated dedifferentiation of adipocytes into fibroblast-like cells expressing higher levels of S100A4, a marker protein of cancer-associated fibroblasts (CAF). IHC analyses of bone marrow metastatic NPC and salivary LELC revealed similar structural changes of dedifferentiated adipocytes located at the boundaries of EBV+ tumors. S100A4 expression in adipose tissues near tumor beds correlated with fibrotic response, implying that CAFs in the tumor microenvironment are partially derived from EBV-induced dedifferentiated adipocytes. Our data suggest that adipose tissue serves as an EBV reservoir, where EBV orchestrates the interactions between adipose tissues and tumor cells by rearranging metabolic pathways to benefit virus persistence and to promote a protumorigenic microenvironment.Significance:This study suggests that Epstein–Barr virus hijacks adipocyte lipid metabolism to create a tumor-promoting microenvironment from which reactivation and relapse of infection could potentially occur.

Supplementary Figures, Tables, and Methods

Supplementary Data from Macrophage Inflammatory Protein-3α Is a Novel Serum Marker for Nasopharyngeal Carcinoma Detection and Prediction of Treatment Outcomes

Purpose: We herein examine whether macrophage inflammatory protein-3α (MIP-3α) is a biomarker for nasopharyngeal carcinoma (NPC) and whether it is involved in modulating NPC cell functions.Experimental Design: The study population comprises 275 NPC patients and 250 controls. MIP-3α levels in tissues and sera were examined by immunohistochemistry and ELISA, respectively. EBV DNA load and EBV viral capsid antigen IgA were measured by quantitative real-time PCR and immunofluorescence assay, respectively. Effects of MIP-3α on NPC cell motility were investigated by Transwell migration/invasion assays and RNA interference.Results: MIP-3α was overexpressed in NPC tumor cells. Serum MIP-3α levels were significantly higher in untreated patients, recurrent patients and patients with distant metastases versus non-NPC controls, patients with complete remission, and long-term disease-free patients. In the prospective cohort, serum MIP-3α levels were significantly higher in untreated NPC patients with advanced tumor-node-metastasis stage versus early stage and also correlated with EBV DNA load. Measurement of MIP-3α, EBV DNA, and viral capsid antigen IgA levels in serial serum/plasma samples from treated patients at 6-month intervals revealed a high association between MIP-3α level, EBV DNA load, and disease status. Among 155 consecutive NPC patients, subjects with pretreated MIP-3α serum levels over 65 pg/mL had worse prognoses for overall survival and distant metastasis-free survival in univariate and multivariate analysis. Additionally, cell functional assays showed that MIP-3α contributed to migration and invasion of NPC cells, which could be effectively inhibited by MIP-3α knockdown.Conclusions: MIP-3α may be a novel biomarker and prognosticator for NPC and is involved in migration and invasion of NPC cells.

BACKGROUND/AIM The clinical significance of frailty status on treatment outcome in patients with esophageal cancer (EC) has been seldom explored. This study aimed to evaluate the impact of pretreatment frailty on treatment-related toxicity and survival outcome in patients with EC undergoing concurrent chemoradiotherapy (CCRT). PATIENTS AND METHODS Patients aged ≥20 years and with newly diagnosed locally advanced EC receiving neoadjuvant radiotherapy and concurrent chemotherapy with weekly administration of carboplatin and paclitaxel for 5 weeks were prospectively enrolled. A pretreatment frailty assessment was performed within 7 days before CCRT initiation. The primary endpoint was treatment-related toxicity and complications of CCRT while the secondary endpoint was overall survival. RESULTS A total of 87 patients were enrolled, 41 (47%) and 46 (53%) of whom were allocated in the frail and fit group, respectively. Frail patients had a significantly higher incidence of having at least one severe hematological adverse event (63.4% vs. 19.6%, p

Background The progression of nasopharyngeal carcinoma (NPC) is profoundly affected by Epstein-Barr virus (EBV) infection. However, the role of EBV in the intercommunication between NPC and surrounding stromal cells has yet to be explored. Methods NPC biopsies were obtained for immunohistochemical (IHC) analyses. Clinical correlations between the expression of active YAP1/FAPα and the fibrotic response and between YAP1/FAPα and the density of cytotoxic CD8a+ T lymphocytes were determined. Survival times based on IHC scores were compared between groups using Kaplan-Meier survival and log-rank tests. Independent prognostic factors for metastasis/recurrence-free survival and overall survival were identified using univariate and multivariate Cox regression models. Fibroblasts were isolated from human nasopharyngeal biopsies. Exosomes were purified from culture supernatants of EBV+-positive NPC cells. The effects of EBV product-containing exosomes on fibroblast activation, fibrotic response, tumor growth, immune response, and correlations between the expression of featured genes were investigated using gel contraction assays, ELISAs, EdU incorporation assays, real-time impedance assays, RNA sequencing, immunostaining, 3D cancer spheroid coculture systems, and an NPC xenograft model. Results NPC patients who developed metastasis had significantly higher levels of active YAP1 and FAPα in their tumor stroma, which was further correlated with tumor fibrosis and poorer metastasis-free survival. Exosomes released from EBV+-NPC cells contained abundant FAPα protein and EBV-encoded latent membrane protein 1. Viral product-containing exosomes markedly enhanced the fibrotic response and tumor growth in a mouse xenograft model. IHC analyses of human NPC and NPC xenografts revealed positive correlations between levels of active YAP1 and FAPα, YAP1 and the fibrotic response, and FAPα and the fibrotic response. Mechanistic studies showed that treatment of fibroblasts with viral product-containing exosomes promoted the characteristics of cancer-associated fibroblasts by stimulating YAP1 signaling and the production of the immunosuppressive cytokines IL8, CCL2, and IL6. Inhibition of YAP1 activation markedly reversed these exosome-mediated protumoral effects, resulting in reduced contractility, inactivation of YAP1 signaling, and decreased production of immunosuppressive cytokines in fibroblasts. Furthermore, fibroblasts stimulated with these viral product-containing exosomes promoted NPC resistance to T cell-mediated cytotoxicity within tumor spheroids. In NPC tissues, a significant negative correlation was found between YAP1/FAPα and the density of CD8a+ T lymphocytes with a granzyme B signature. Conclusion EBV orchestrates interactions with the host and surrounding stroma by stimulating the functions of YAP1 and FAPα in fibroblasts through exosome cargos to create a more immunosuppressive, proinvasive microenvironment.

Background We sought to compare the prognostic significance of different preoperative complete blood count cell ratios in patients with oral cavity squamous cell carcinoma (OSCC) treated with surgery and postoperative radiotherapy (PORT). Methods We retrospectively reviewed the clinical records of 890 patients with OSCC who were treated with surgery and PORT. The following preoperative complete blood count cell ratios were collected: neutrophil‐to‐lymphocyte ratio (NLR), platelet‐to‐lymphocyte ratio (PLR), and lymphocyte‐to‐monocyte ratio (LMR). Overall survival (OS), local control, regional control, and distant control (DC) served as the main outcomes of interest. Results The results of multivariate analysis in the entire study cohort revealed that a low NLR was the only independently favorable marker of both OS (adjusted hazard ratio [HR]: 0.794, 95% confidence interval (CI): 0.656–0.961, bootstrap p = 0.028) and DC (adjusted HR: 0.659, 95% CI: 0.478–0.909, bootstrap p = 0.015). Both LMR and PLR were not retained in the model as independent predictors. Subgroup analyses in high‐risk patients (i.e., those bearing T4 disease, N3 disease, or poor differentiation) revealed that a high NLR was a significant adverse risk factor for both OS and DC (all p, This relatively large cohort reports a comparative result: pretreatment high neutrophil‐to‐lymphocyte ratio (NLR) was an independent unfavorable risk factor for both overall survival and distant metastasis in patients with oral cavity squamous cell carcinoma (OSCC) who underwent surgery and postoperative radiotherapy. Lymphocyte‐to‐monocyte ratio (LMR) and platelet‐to‐lymphocyte ratio (PLR) were not significant.

Objectives To investigate the prognostic value of the preoperative systemic immune‐inflammation index (SII) in patients with oral cavity squamous cell carcinoma (OC‐SCC) treated with curative surgery followed by adjuvant radiotherapy (RT) or chemoradiotherapy (CCRT). Materials and Methods We retrospectively reviewed the clinical records of patients with OC‐SCC who received surgery and postoperative adjuvant RT/CCRT between January 2005 and December 2012. Blood samples were drawn in the 2 weeks preceding surgery. SII was calculated by multiplying the absolute neutrophil and platelet counts, and then, divided by the absolute lymphocyte count, and its optimal cutoff value was identified using the Youden’s index. The study endpoints included overall survival (OS), local control (LC), regional control (RC), and distant control (DC). Results The study sample consisted of 993 patients (58.8% of them treated with CCRT). The optimal cutoff value for SII was 810.6. A total of 347 (34.9%) study participants had high preoperative SII values. After allowance for potential confounders in multivariable analysis, high SII values were independently associated with less favorable DC (adjusted hazard ratio [HR] = 1.683, p = 0.001) and OS (adjusted HR = 1.466, p, The SII is defined as platelet × neutrophil/lymphocyte counts. Increased SII values predict poor distant control and overall survival in patients with oral cancer treated with curative resection and adjuvant RT/CCRT. Owing to the higher risk of systemic failure in this patient group, a tight follow‐up surveillance schedule or adjuvant systemic treatment may be advisable pending independent confirmation of our data.

Highlights • The first study to develop and validate an MRI-derived radiomic signature (RS) for the prediction of 1-year locoregional failure in HPSCC patients receiving OPT. • The RS-based model (RS of 0.0326 as the cut-off value) provides a novel and convenient approach for the prediction of the 1-year clinical outcomes. • The proposed RS-based model can help physicians characterize and facilitate decision-making for the clinical management of patients with locally advanced HPSCC., Background and purpose To develop and validate a magnetic resonance imaging (MRI)-derived radiomic signature (RS) for the prediction of 1-year locoregional failure (LRF) in patients with hypopharyngeal squamous cell carcinoma (HPSCC) who received organ preservation therapy (OPT) Material and methods A total of 800 MRI-based features of pretreatment tumors were obtained from 116 patients with HPSCC who received OPT from two independent cohorts. The least absolute shrinkage and selection operator regression model were used to select the features used to develop the RS. Harrell’s C-index and corrected C-index were used to evaluate the discriminative ability of RS. The Youden index was used to select the optimal cut-point for risk category. Results The RS yielded 1000 times bootstrapping corrected C-index of 0.8036 and 0.78235 in the experimental (n = 82) and validation cohorts (n = 34), respectively. With respect to the subgroup of patients with stage III/IV and cT4 disease, the RS also showed good predictive performance with corrected C-indices of 0.760 and 0.754, respectively. The dichotomized risk category using an RS of 0.0326 as the cut-off value yielded a 1-year LRF predictive accuracy of 79.27%, 79.41%, 76.74%, and 71.15% in the experimental, validation, stage III/IV, and cT4a cohorts, respectively. The low-risk group was associated with a significantly better progression-free laryngectomy-free and overall survival outcome in two independent institutions, stage III/IV, and cT4a cohorts. Conclusion The RS-based model provides a novel and convenient approach for the prediction of the 1-year LRF and survival outcome in patients with HPSCC who received OPT.

Purpose This study aimed to identify vulnerable patients with head and neck cancer undergoing concurrent chemoradiation therapy (CCRT) who are susceptible to higher treatment-related adverse effects and have poorer treatment tolerance. This study also aimed to determine whether comprehensive geriatric assessment, developed in the geriatric population, can predict vulnerability to treatment-related adverse events and survival even in nongeriatric patients with head and neck cancer, as well as the prevalence of vulnerability and its effect on toxicities and survival among these patients. Methods and Materials This prospective cohort study examined 461 patients with primary head and neck cancer who underwent definitive CCRT during 2016 to 2017 at 3 medical centers across Taiwan. Vulnerability is defined as susceptibility to cancer- and treatment-related adverse events that result in poor treatment tolerance and unexpected emergent medical needs, such as hospitalization and emergency room visits. Vulnerability was assessed as impairment with ≥2 dimensions on comprehensive geriatric assessment, 7 days before CCRT. The association of vulnerability with treatment-related adverse events and survival was analyzed. Results The prevalence of vulnerability was 22.2%, 27.3%, 30.2%, and 27.9% among patients aged 20 to 34, 35 to 49, 50 to 64, and >65 years, respectively. Survival was poorer in vulnerable patients than in nonvulnerable patients (hazard ratio, 1.97; 95% confidence interval, 1.26-3.07; P = .003). Vulnerable patients showed a higher tendency toward CCRT incompletion (19.5% vs 6.1%, P Conclusions Vulnerability, which is an urgent concern when it presents among patients with head and neck cancer, was independently associated with poorer survival and severe treatment-related complications. Vulnerability assessment should be routinely evaluated in all patients with primary head and neck cancer who are undergoing definitive CCRT, not only in such patients who are geriatric.

Nutritional counseling is frequently overlooked in cancer patients with normal nutritional status. This study aimed to evaluate the impact of nutritional counseling in head and neck cancer (HNC) patients with normal nutritional status prior to concurrent chemoradiotherapy (CCRT). A total of 243 patients with pretreatment normal nutritional status and locally advanced HNC receiving concurrent chemoradiotherapy (CCRT) at three medical centers were enrolled. All patients were retrospectively allocated into the early (≤ 2 weeks, n = 105, 43.2%), late (> 2 weeks, n = 102, 42.0%), and no nutritional counseling groups (n = 36, 14.8%) according to the time interval between the date of CCRT initiation and the first date of nutritional counseling for comparison. The 1-year overall survival rates were 95.0%, 87.5%, and 81.3% in the early, late, and no nutritional counseling groups (p = 0.035), respectively. The median body weight changes at end of CCRT were − 4.8% (range, − 13.3 to 8.7%), − 5.6% (range, − 21.9 to 5.6%), and − 8.6% (range, − 20.3 to 2.4%) in patients in the early, late, and no nutritional counseling groups, respectively. The early termination of chemotherapy rates and the incompletion rates of planned radiotherapy were 1.9% and 1.9%, 2.9%, and 2.0%, 13.9%, and 19.4% in patients in the early, late, and no nutritional counseling groups, respectively. Our findings strongly suggest that while some HNC patients may have pretreatment normal nutritional status, early nutritional counseling is nevertheless essential for the improvement of treatment tolerance and survival outcome.

BackgroundWe sought to investigate the prognostic impact of missed RT sessions in patients who had undergone surgery for oral cavity squamous cell carcinoma (OCSCC).MethodsThe study sample consisted of 905 patients with surgically treated OCSCC who fulfilled criteria of RT course ≤8 weeks. The study participants were divided into three groups based on the characteristics of missed RT, as follows: 1) early missed RT, 2) late missed RT, and 3) RT as scheduled.ResultsThe 5-year overall survival (OS) rates in the early missed RT, late missed RT, and RT as scheduled groups were 53.0, 58.1, and 64.5%, respectively (p = 0.046). In multivariate analysis, early missed RT was independently associated with both OS (hazard ratio (HR) = 1.486; 95% confidence interval (CI): 1.122–1.966;p = 0.006) and the occurrence of distant metastasis (HR = 1.644; 95% CI: 1.047–2.583;p = 0.031).ConclusionEarly missed RT was independently associated with a higher occurrence of distant metastasis and less favorable OS in patients who had undergone surgery for OCSCC.

Objectives This study aimed to investigate the association between preoperative glycated hemoglobin (HbA1c) levels and the treatment outcomes of oral cavity squamous cell carcinoma (OSCC). Methods Three hundred and fifty-eight OSCC patients were consecutively enrolled between July 2004 and July 2016. Clinicopathological parameters and survival outcomes were analyzed following HbA1c stratification of 6.5% (HbA1c ≥ 6.5%: n = 74, 20.6%) and 7.0% (HbA1c ≥ 7.0%: n = 53, 14.8%). Results Higher HbA1c levels were associated with elevated body mass index, lower albumin levels, wider surgical margins, and prolonged hospital stays (HbA1c 6.5%: p = .001, .048, .030, .009, respectively; HbA1c 7.0%: p = .092, .032, .009, .015, respectively). Survival rates stratified by HbA1c 6.5% were as follows: locoregional recurrence-free survival, p = .014; distant metastasis-free survival, p = .013; second primary cancer-free survival, p = .015; overall survival, p = .014; disease-specific survival, p = .002 and HbA1c 7.0%: locoregional recurrence-free survival, p = .013; distant metastasis-free survival, p = .013; second primary cancer-free survival, p = .014; overall survival, p = .015; disease-specific survival, p = .004. Multivariate analyses identified HbA1c as an independent prognostic factor for overall and disease-specific survival (HbA1c 6.5%: p = .014 and .002, respectively; HbA1c 7.0%: p = .036 and .013, respectively). Conclusions Oral squamous cell carcinoma patients with higher preoperative HbA1c levels had longer hospitalization and worse survival outcomes.

The aim of this study is to develop a computer-aided diagnosis method to help classify medical images of neck lymph nodes in head and neck cancer patients. According to the current practice guidelines, the classification of lymph node status is critical for patient stratification before treatment. Take extra-nodal extension (ENE) of metastatic neck lymph nodes, the status of ENE has been considered a single factor affecting the decision of whether systemic treatment with toxicity should be given to patients with otherwise non-advanced cancer status. Medical imaging prior to surgery serves as tools for clinical staging and determining the extent of neck lymph node dissection during the tumor resection surgery. The information contained in these images may also help determine the status of ENE and thus stratify patients for more precise treatment. In the current practice, there has been not a reliable computer-aided tool for this task. In this study, we used open-source software to investigate radiomic features that help distinguish malignant from benign and ENE from non-ENE lymph nodes. We have identified 89 features that can differentiate malignant from benign and 4 features that can differentiate ENE from non-ENE lymph nodes. Furthermore, we fed the significant features to a multilayer perceptron neural network to predict malignancy and ENE of lymph nodes and achieved 84% and 77% of accuracy in each task, respectively.

Background/aim We compared the adequacy of five nutrition assessment tools with respect to their predictive value in patients with locally advanced gastric cancer (GC) receiving radical surgery. Patients and methods Five nutrition assessment tools-Glasgow prognostic score (GPS), malnutritional universal screening tool (MUST), nutritional risk screening, patient generated subjective global assessment (PG-SGA), and prognostic nutritional index (PNI)-were assessed preoperatively for stage III GC patients. The correlation between postoperative events and nutritional status was further analyzed. Results Most of the nutritional tools accurately predicted length of hospital stay and grade 3 or higher surgical complications, while only the GPS correlated with 30-day readmission and surgical complications. The PG-SGA performed the poorest among the five tools and failed to predict any postoperative event. Conclusion The application of GPS is recommended as a prognostic index for patients with locally advanced GC prior to radical surgery.

Objective To investigate the clinical outcomes and failure patterns of patients with unresectable cholangiocarcinoma (CC) who had been treated with proton beam therapy (PBT). Methods The authors retrospectively examined 30 patients with unresectable CC who had undergone PBT between November 2015 and December 2017. Survival curves were plotted with the Kaplan-Meier method. Independent predictors of survival were identified by multivariate Cox proportional hazard regression analyses. Complications were assessed using the Common Terminology Criteria for Adverse Events v4.0. Results The median tumor size was 7 cm. Seventeen patients (56.7%) had regional lymph node metastases. The median radiation dose was 72.6 cobalt gray equivalents, and 23 patients (76.7%) received concurrent chemotherapy. The 1-year local control, regional control, and distant metastases-free rates were 88%, 86%, and 68%, respectively. The median overall survival and progression-free survival were 19.3 and 10.4 months, respectively. The median jaundice-free survival was 13 months, with a 1-year biliary tract infection (BTI)-free rate of 58%. Patients who received concurrent chemotherapy had a better median progression-free survival (12.1 vs. 4.7 mo). The most common form of acute toxicity from PBT was acute skin reactions which were rarely severe (grade III: 7% of patients). Three and 2 patients had grade III-IV toxicities and radiation-induced liver disease. There were no deaths caused by PBT or concurrent chemotherapy. Conclusions PBT is clinically useful in patients with unresectable CC, even in the presence of large tumors or regional nodal metastases. Its use may induce durable symptom relief, without increasing acute or late toxicity.

Background The prognostic relevance of extranodal extension (ENE) for salivary gland carcinoma (SGC) remains unclear. The present study is undertaken to investigate the predictive significance of pathological nodal parameters in surgically treated patients with nodal metastatic SGC. Methods This multicenter cohort included 114 patients with pathologically proven node-positive SGC between 2000 and 2014. Possible correlations of clinicopathological parameters and outcomes were examined. Results The median follow-up was 69 months (range, 11-173 months). The multivariate analysis identified metastatic node number (1-2 vs 3-6; 1-2 vs ≥7) as an independent predictor for regional control (P = 0.005; P = 0.02), locoregional control (P = 0.008; P = 0.04), distant metastasis-free survival (P = 0.17; P = 0.006), disease-free survival (P = 0.05; P = 0.002), and overall survival (P = 0.18; P = 0.009), whereas ENE was not associated with survival outcomes. Conclusions Metastatic node number, not ENE, is an independent node-related prognosticator for SGC. Integration of ENE into the American Joint Committee on Cancer 8th edition staging criteria may not improve prognostic performance.

Background/aim This study was designed to clarify the value of routine alpha-fetoprotein (AFP) testing for patients with gastric cancer (GC). Patients and methods A total of 905 patients with newly diagnosed GC and available pretreatment carcinoembryonic antigen (CEA), cancer-related antigen 19-9 (CA19-9), and AFP data from 2010 to 2016 were collected for comparison of tumor stage and survival. Results In total, 139 patients (15.4%), 155 patients (17.1%), and 27 patients (3.0%) had elevated CEA, CA19-9, and AFP levels, respectively. The c-index values of elevated AFP levels in predicting stage IV disease and the 1-year mortality rate were 0.564 (95%CI=0.520-0.608) and 0.594 (95%CI=0.553-0.635), respectively, which were significantly lower than those of CEA (0.673 and 0.665) and CA19-9 (0.619 and 0.618). Conclusion Elevated AFP is rare in patients with newly diagnosed GC. Routine AFP sampling would not provide a higher survival prediction in GC patients than CEA or CA19-9.

Concurrent chemoradiotherapy (CCRT) treatment incompletion is a known negative prognosticator for patients with head and neck cancer (HNC). Malnutrition is a common phenomenon which leads to treatment interruption in patients with HNC. We aimed to compare the performance of three nutritional tools in predicting treatment incompletion in patients with HNC undergoing definitive CCRT. Three nutritional assessment tools, Mini Nutritional Assessment-Short Form (MNA-SF), Malnutritional Universal Screening Tool (MUST), and Nutritional Risk Screening 2002 (NRS-2002), were prospectively assessed prior to CCRT for HNC patients. Patients were stratified into either normal nutrition or malnourished groups using different nutrition tools. Treatment incompletion and treatment-related toxicities associated with CCRT were recorded. A total of 461 patients were included in the study; malnourished rates ranged from 31.0 to 51.0%. The CCRT incompletion rates were 4.9–6.3% and 14.5–18.2% for normal nutrition patients and malnourished patients, respectively. The tools had significant correlations with each other (Pearson correlation 0.801–0.837, p

Epstein-Barr virus (EBV) infection is intimately associated with type III nasopharyngeal carcinoma (NPC). Most NPCs respond well to chemoradiation. Nevertheless, approximately 20% of patients experience recurrence and distant metastasis. Tumor desmoplastic responses and high densities of cancer-associated fibroblasts (CAFs) within tumors have been correlated with poorer prognosis. In this study, we demonstrate that EBV activates fibroblasts via exosomes to remodel a pro-tumoral microenvironment. Exosomes derived from NPC cells contained a high level of fibroblast activation protein alpha (FAPα) and EBV-encoded latent membrane protein 1 (LMP1). Treating primary fibroblasts with these exosomes induced functional changes resembling CAFs. Transcriptomic analysis on exosome-treated fibroblasts revealed genes involved in fibrosis-associated pathways were enriched. Noticeably, treating with EBV products-containing exosomes in fibroblasts enhanced the production of several immune-suppressive cytokines, including IL6, IL8, and MCP-1. Moreover, stimulation with these exosomes enhanced activation of YAP1 signaling, a key pathway linking to fibrosis. The in vivo mouse xenografted NPC studies showed that EBV products-containing exosomes markedly enhanced the severity of tissue fibrosis and tumor growth. IHC analysis on mouse NPC xenografts and human NPC biopsies showed a positive correlation between levels of nuclear YAP1 and FAPα, which were further correlated with an enhanced fibrotic response within tumors. Pharmaceutical intervention with YAP1 inhibitors blocked the exosome-mediated effects on fibroblasts. Collectively, our data suggest that EBV products-containing exosome is a causal factor in CAF formation, which constitutes a pro-tumoral microenvironment to benefit the survival of both tumor and virus itself. Citation Format: Po-Ju Lee, Yun-Hua Sui, Chen-Han Huang, Tzu-Tung Liu, Ngan-Ming Tsang, Shu-Chen Liu. EBV-products containing exosomes remodel NPC tumor microenvironment by activating fibroblasts [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3192.

The most frequent location of metastatic EBV+ nasopharyngeal carcinoma (NPC) is the bone marrow, an adipocyte-dominant region. Several EBV-associated lymphoepithelioma-like carcinoma (LELC) types also grow in the anatomical vicinity of fat tissues. Here we show that in an adipose tissue-rich tumor setting, EBV targets adipocytes and remodels the tumor microenvironment. Positive immunoreactivity for EBV-encoded early antigen D was detected in adipose tissue near tumor beds of bone marrow metastatic NPC. EBV was capable of infecting primary human adipocytes in vitro, triggering expression of multiple EBV-encoded mRNA and proteins. In infected adipocytes, lipolysis was stimulated through enhanced expression of lipases and the AMPK metabolic pathway. The EBV-mediated imbalance in energy homeostasis was further confirmed by increased release of free fatty acids, glycerol, and expression of proinflammatory adipokines. Clinically, enhanced serum levels of free fatty acids in patients with NPC correlated with poorer recurrence-free survival. EBV-induced delipidation stimulated dedifferentiation of adipocytes into fibroblast-like cells expressing higher levels of S100A4, a marker protein of cancer-associated fibroblasts (CAF). IHC analyses of bone marrow metastatic NPC and salivary LELC revealed similar structural changes of dedifferentiated adipocytes located at the boundaries of EBV+ tumors. S100A4 expression in adipose tissues near tumor beds correlated with fibrotic response, implying that CAFs in the tumor microenvironment are partially derived from EBV-induced dedifferentiated adipocytes. Our data suggest that adipose tissue serves as an EBV reservoir, where EBV orchestrates the interactions between adipose tissues and tumor cells by rearranging metabolic pathways to benefit virus persistence and to promote a protumorigenic microenvironment. Significance: This study suggests that Epstein–Barr virus hijacks adipocyte lipid metabolism to create a tumor-promoting microenvironment from which reactivation and relapse of infection could potentially occur.

Nutritional counseling is frequently overlooked in cancer patients with normal nutritional status. This study aimed to evaluate the impact of nutritional counseling in head and neck cancer (HNC) patients with normal nutritional status prior to concurrent chemoradiotherapy (CCRT).A total of 243 patients with pretreatment normal nutritional status and locally advanced HNC receiving concurrent chemoradiotherapy (CCRT) at three medical centers were enrolled. All patients were retrospectively allocated into the early (≤ 2 weeks, n = 105, 43.2%), late (2 weeks, n = 102, 42.0%), and no nutritional counseling groups (n = 36, 14.8%) according to the time interval between the date of CCRT initiation and the first date of nutritional counseling for comparison.The 1-year overall survival rates were 95.0%, 87.5%, and 81.3% in the early, late, and no nutritional counseling groups (p = 0.035), respectively. The median body weight changes at end of CCRT were - 4.8% (range, - 13.3 to 8.7%), - 5.6% (range, - 21.9 to 5.6%), and - 8.6% (range, - 20.3 to 2.4%) in patients in the early, late, and no nutritional counseling groups, respectively. The early termination of chemotherapy rates and the incompletion rates of planned radiotherapy were 1.9% and 1.9%, 2.9%, and 2.0%, 13.9%, and 19.4% in patients in the early, late, and no nutritional counseling groups, respectively.Our findings strongly suggest that while some HNC patients may have pretreatment normal nutritional status, early nutritional counseling is nevertheless essential for the improvement of treatment tolerance and survival outcome.

OBJECTIVE To investigate the clinical utility of short-course induction chemotherapy followed by low-dose radiotherapy without a tumor bed boost in patients with primary central nervous system (CNS) germinomas. METHODS We retrospectively reviewed the clinical records of patients with primary CNS germinomas who received short-course induction chemotherapy (2 cycles of cisplatin 20 mg/m2 plus etoposide 40 or 100 mg/m2 for 5 days) followed by low-dose radiotherapy (dose: 2340 cGy) without a tumor bed boost. Disease-free survival and overall survival served as the main outcome measures. RESULTS Between February 2002 and June 2018, 24 patients (20 males and 4 females; median age: 14.1 y; age range: 7.9 to 21.2 y) with pathology-proven CNS germinomas were included. The median follow-up time was 106 months (range: 17 to 169 mo). Isolated and multifocal lesions were identified in 13 and 11 patients, respectively. Tumor location was as follows: pineal gland (n=17), suprasellar region (n=13), periventricular region (n=7), and basal ganglia (n=2). Five patients had increased levels (>5 mIU/mL) of beta-human chorionic gonadotropin (β-hCG), whereas alpha-fetoprotein concentrations were within the reference range in all participants. A total of 16 patients achieved remission after induction chemotherapy. The complete response rates of patients with increased and normal β-hCG levels were 40.0% and 72.2%, respectively (P=0.208). Low-dose radiotherapy without a tumor bed boost was subsequently delivered to either the whole ventricle (n=16) or the whole brain (n=8), resulting in complete remission in all participants. Compared with patients without increased β-hCG levels, those with β-hCG-secreting germinomas had less favorable 5-year disease-free survival rates (100% vs. 60%, respectively, P=0.000115). CONCLUSIONS Some children with primary CNS germinoma may benefit from short-course induction chemotherapy followed by low-dose radiotherapy to the whole ventricle without a tumor bed boost. The validity of our findings needs to be confirmed in a randomized phase II study for children with β-hCG levels

The significance of granuloma and amyloid deposition in primary nasopharyngeal carcinoma (NPC) has yet to be investigated. This study aimed to evaluate their clinicopathologic associations. The histopathologic findings of 747 consecutive patients with primary NPC were retrospectively reviewed between January 2001 and December 2015. The presence of granulomas and amyloid deposits was observed in 68 (9.1%) and 62 (8.3%) patients, respectively. Granulomas were significantly associated with lower T classification, N classification, and overall TNM stage (p = 0.014, p = 0.006, and p = 0.001, respectively). Their presence was an independent predictor of overall survival (p = 0.033), disease-free survival (p = 0.034), and recurrence-free survival (p = 0.040). Conversely, amyloid deposition was not a predictor in any survival analyses. The present study demonstrated the prevalence of granuloma and amyloid deposition in the largest single institution cohort of primary NPC patients so far. Our results provide evidence that granulomas are significantly associated with better prognosis and treatment outcome. Further studies are needed to elucidate the mechanism of action of granuloma formation on the anti-tumor immunity of NPC.

No gold standard of nutritional assessment is established among patients with head and neck cancer (HNC) receiving concurrent chemoradiotherapy (CCRT). This study aimed to evaluate the clinical significance of pre-treatment nutritional status using the Mini Nutritional Assessment-short form (MNA-SF) among HNC patients receiving CCRT. A total of 461 consecutive patients with newly diagnosed HNC treated with definitive CCRT at three medical institutes were prospectively enrolled. Nutritional status was assessed using MNA-SF within 7 days before CCRT initiation. Patients were classified as having normal nutrition, at risk of malnutrition, and malnourished groups according to MNA-SF for comparison. The 1-year overall survival rates were 89.8%, 76.8%, and 67.7% in the normal nutrition, at risk of malnutrition, and malnourished groups, respectively. Patients with normal nutrition had significantly lower rates of uncompleted radiotherapy and chemotherapy (4.5% and 4.1%, respectively) compared with patients at risk for malnutrition (14.1% and 11.5%, respectively) and those malnourished (11.1% and 11.1%, respectively). Patients with normal nutrition had significantly lower treatment-related complication rates regarding emergency room visits, hospital admission, and need for tubal feeding than those with at risk of malnutrition and malnourished. Patients with normal nutrition had significantly fewer severe hematologic toxicities (p = 0.044) and severe non-hematologic toxicities (p = 0.012) of CCRT than those malnourished. Pre-CCRT nutritional status identifies HNC patients vulnerable to treatment interruption and treatment complications. We suggest that nutritional assessment with MNA-SF should be incorporated in pre-CCRT evaluation for all HNC patients.

Background Comprehensive Geriatric Assessment (CGA) is the gold standard for detecting frailty in elderly patients with cancer. Since CGA is time- and resource-consuming, many alternative frailty screening tools have been developed; however, it remains unknown whether these tools are suitable for older and adult patients with cancer. Therefore, we used the data collected for a large longitudinal study to compare the diagnostic performances of two frailty screening tools (Geriatric 8 [G8] and Flemish version of the Triage Risk Screening Tool [fTRST]) to identify frailty risk profile among patients with cancer. Material and methods Patients aged ≥20 years with newly diagnosed cancer were enrolled. Frailty screening with G8, fTRST, and CGA were performed before anti-cancer treatment. Diagnostic characteristics obtained using G8 and fTRST were analyzed by C-index, and the validity of G8 and fTRST was also determined. Results 40.9% of the 755 patients with cancer displayed frailty on CGA. Both G8 and fTRST showed high sensitivity (80.6–88.4%) and negative predictive value (81.0–81.2%). The C-index of G8 was higher than that of fTRST (0.77 vs 0.71, p = .01). Moreover, the best G8 and fTRST cut-off points were ≤13 and ≥ 2, respectively. The validities of G8 and fTRST were also confirmed; however, frailty age differences were not observed in our study. Conclusion Frailty is a common problem for patients with cancer, and routine frailty screening is essential for both older and adult patients. G8 and fTRST are simple and useful frailty screening tools, while G8 is more suitable than fTRST for Taiwanese patients with cancer.

Background Both medical education and radiation oncology have progressed significantly in the past decade, but a generalized overview of educational research for radiation oncology residents has not been produced. This study examines recent research trends in medical education for residents in radiation oncology through a scoping review. Methods We conducted a scoping review of medical education research for residents in radiation oncology to survey the research trends. We used publications available on MEDLINE, PubMed, and Scopus to conduct this scoping review. Results We screened 221 full-text articles, 146 of which met our inclusion criteria. These publications showed increased activity in medical education research for residents, most involving affiliations in the United States. We identified persistent interest in training-, contouring-, and technology-related issues. An increase in research related to career, treatment quality, and multidisciplinary training was also observed. However, no research about teacher training was identified. Conclusions This scoping review presents the trends in study interests among stakeholders of medical education research in radiation oncology. With an investigation of existing studies, this research identifies areas of high priority and a lack of studies about teacher training. This study provides potential future directions for medical education research for residents in radiation oncology.

Additional file 1 : Table S1. Distribution of the included publications by the categories and years.

Background Whether the prevalence of frailty and its clinical significance are relevant to treatment outcomes in younger (aged < 65 years) cancer patients remains uncertain. This study aimed to evaluate the impact of frailty on treatment outcomes in younger cancer patients with head and neck and esophageal malignancy. Material and methods This multicenter prospective study recruited 502 patients with locally advanced head and neck and esophageal cancer during 2016–2017 in Taiwan, aged 20–64 years who received curative-intent concurrent chemoradiotherapy (CCRT) as first-line antitumor treatment. Baseline frailty assessment using geriatric assessment (GA) was performed for each patient within 7 days before CCRT initiation. Results Frailty was observed in 169 (33.7%) of 502 middle-aged patients. Frail patients had significantly higher incidences of chemotherapy incompletion (16.6% versus 3.3%, P < .001) and radiotherapy incompletion (16.6% versus 3.6%, P < .001) than fit patients. During CCRT, frail patients had a significantly higher percentage of hospitalizations (42.0% versus 24.6%, P < .001) and a trend toward a higher percentage of emergency room visits (37.9% versus 30.0%, P = .08) than fit patients. Frail patients more likely had a significantly higher incidence of grade ≥ 3 adverse events than fit patients during CCRT. The 1-year survival rate was 68.7% and 85.2% (hazard ratio 2.56, 95% confidence interval 1.80–3.63, P < .001) for frail and fit patients, respectively. Conclusions This study demonstrated the significance of pretreatment frailty on treatment tolerance, treatment-related toxicity, and survival outcome in younger patients with head and neck and esophageal cancer undergoing CCRT. While GA is commonly targeted toward the older population, frailty assessment by GA may also be utilized in younger patients for decision-making guidance and prognosis prediction.

Metastasis remains a clinically unsolved issue in nasopharyngeal carcinoma. Here, we report that higher levels of cytoplasmic leukemia inhibitory factor (LIF) and LIF receptor are correlated with poorer metastasis/recurrence-free survival. Further, single nucleotide variations and signal peptide mutation of LIF are identified in NPC. Cytoplasmic LIF reprograms the invasive mode from collective to mesenchymal migration via acquisition of EMT and invadopodia-associated characteristics. Higher cytoplasmic LIF enhances cancer vascular dissemination and local invasion mechanistically through modulation of YAP1-FAK/PXN signaling. Immunohistochemical analyses of NPC biopsies reveal a positive correlation of cytoplasmic LIF expression with focal adhesion kinases. Pharmaceutical intervention with AZD0530 markedly reverses LIF-mediated cancer dissemination and local invasion through promotion of cytoplasmic accumulation of YAP1 and suppression of focal adhesion kinases. Given the significant role of LIF/YAP1-focal adhesion signaling in cancer dissemination, targeting of this pathway presents a promising opportunity to block metastasis., Molecular pathways regulating nasopharyngeal carcinoma (NPC) metastasis are unclear. Here they report higher levels of cytoplasmic leukemia inhibitory factor (cLIF) and LIF receptor (LIFR) to correlate with higher metastasis in NPC patients, and show cLIF to promote NPC metastasis and vascular dissemination via the YAP1-FAK/PXN axis.