Toripalimab Plus Chemotherapy for Recurrent or Metastatic Nasopharyngeal Carcinoma: The JUPITER-02 Randomized Clinical Trial.

Importance: There are currently no therapies approved by the US Food and Drug Administration for nasopharyngeal carcinoma (NPC). Gemcitabine-cisplatin is the current standard of care for the first-line treatment of recurrent or metastatic NPC (RM-NPC). Objective: To determine whether toripalimab in combination with gemcitabine-cisplatin will significantly improve progression-free survival and overall survival as first-line treatment for RM-NPC, compared with gemcitabine-cisplatin alone. Design, Setting, and Participants: JUPITER-02 is an international, multicenter, randomized, double-blind phase 3 study conducted in NPC-endemic regions, including mainland China, Taiwan, and Singapore. From November 10, 2018, to October 20, 2019, 289 patients with RM-NPC with no prior systemic chemotherapy in the RM setting were enrolled from 35 participating centers. Interventions: Patients were randomized (1:1) to receive toripalimab (240 mg [n = 146]) or placebo (n = 143) in combination with gemcitabine-cisplatin for up to 6 cycles, followed by maintenance with toripalimab or placebo until disease progression, intolerable toxicity, or completion of 2 years of treatment. Main Outcome: Progression-free survival as assessed by a blinded independent central review. Secondary end points included objective response rate, overall survival, progression-free survival assessed by investigator, duration of response, and safety. Results: Among the 289 patients enrolled (median age, 46 [IQR, 38-53 years; 17% female), at the final progression-free survival analysis, toripalimab treatment had a significantly longer progression-free survival than placebo (median, 21.4 vs 8.2 months; HR, 0.52 [95% CI, 0.37-0.73]). With a median survival follow-up of 36.0 months, a significant improvement in overall survival was identified with toripalimab over placebo (hazard ratio [HR], 0.63 [95% CI, 0.45-0.89]; 2-sided P = .008). The median overall survival was not reached in the toripalimab group, while it was 33.7 months in the placebo group. A consistent effect on overall survival, favoring toripalimab, was found in subgroups with high and low PD-L1 (programmed death-ligand 1) expression. The incidence of all adverse events, grade 3 or greater adverse events, and fatal adverse events were similar between the 2 groups. However, adverse events leading to discontinuation of toripalimab or placebo (11.6% vs 4.9%), immune-related adverse events (54.1% vs 21.7%), and grade 3 or greater immune-related adverse events (9.6% vs 1.4%) were more frequent in the toripalimab group. Conclusions and Relevance: The addition of toripalimab to chemotherapy as first-line treatment for RM-NPC provided statistically significant and clinically meaningful progression-free survival and overall survival benefits compared with chemotherapy alone, with a manageable safety profile. These findings support the use of toripalimab plus gemcitabine-cisplatin as the new standard of care for this patient population. Trial Registration: ClinicalTrials.gov Identifier: NCT03581786.

Predictive and prognostic role of early apolipoprotein A-I alteration in recurrent or metastatic nasopharyngeal carcinoma patients treated with anti-PD-1 therapy.

BACKGROUND: The primary objective of this study was to evaluate the predictive and prognostic value of serum lipids in recurrent or metastatic nasopharyngeal carcinoma (R/M NPC) patients received anti-PD-1 therapy. MATERIALS AND METHODS: Patients treated with anti-PD-1 therapy (monotherapy or combined with chemotherapy) from two clinical trials (CAPTAIN and CAPTAIN-1st study) were included. Serum lipids were measured at baseline and after two cycles of treatment. We examined the impact of both baseline and post-treatment lipid levels on objective response rate (ORR), progression-free survival (PFS), and duration of response (DOR). RESULTS: Of 106 patients, 89 patients (84%) were male. The patients' median age was 49 years. An early elevated (after two cycles of treatment) cholesterol (CHO), low-density lipoprotein cholesterol (LDL-C), apolipoprotein A-I (ApoA-I), and apolipoprotein B (ApoB) were significantly associated with better ORR. Moreover, early elevated CHO, LDL-C, and ApoA-I were also positively correlated with DOR and PFS. Further multivariate analysis showed that only early change in ApoA-I could independently predict PFS (HR, 2.27; 95% CI, 1.11-4.61; p = 0.034). The median PFS for patients with early elevated and reduced ApoA-I was 11.43 and 1.89 months, respectively. However, baseline lipids levels do not play a significant role in the prognosis and prediction of patients with anti-PD-1 treatment. CONCLUSION: Collectively, an early elevation in ApoA-I was correlated with better outcomes for anti-PD-1 therapy in patients with R/M NPC, suggesting that clinicians should consider the early alteration of ApoA-I as a useful marker in treating R/M NPC patients with anti-PD-1.

miR-135b-5p Targets SIRT1 to Inhibit Deacetylation of c-JUN and Increase MMP7 Expression to Promote Migration and Invasion of Nasopharyngeal Carcinoma Cells.

NPC is a type of cancer with a poor prognosis. We aim to excavate the regulatory roles of miR-135b-5p in NPC and uncover the underlying mechanism. The levels of miR-135b-5p and Sirtuin 1 (SIRT1) in NPC and normal tissues and cells were tested via quantitative real-time PCR, western blotting, and immunohistochemistry, respectively. The binding relationship between them was predicted with ENCORI databases and validated with dual-luciferase reporter assay. The impact of miR-135b-5p and SIRT1 on the expressions of matrix metalloproteinase 7 (MMP7) and epithelial-mesenchymal transformation (EMT) proteins in NPC cells was evaluated by western blotting. Metastasis of NPC cells was evaluated by Transwell assay. The binding of c-JUN at the MMP7 promoter and deacetylation of c-JUN were examined using chromatin-immunoprecipitation and co-immunoprecipitation, respectively. The level of miR-135b-5p was increased and SIRT1 was decreased in NPC tissues and cells. miR-135b-5p was validated to target SIRT1. Silencing of miR-135b-5p accelerated EMT and metastasis of NPC cells, whereas knockdown of SIRT1 showed opposite results. Notably, knockdown of SIRT1 partially reversed the miR-135b-5p-induced change of EMT markers and metastasis of NPC cells. Mechanistically, miR-135b-5p disrupted SIRT1-induced deacetylation of c-JUN to promote the activation of MMP7 in NPC cells. miR-135b-5p targeted SIRT1 to inhibit deacetylation of c-JUN and increase MMP7 expression to promote malignancy of NPC cells.

Efficacy, safety, and biomarker analysis of Camrelizumab in Previously Treated Recurrent or Metastatic Nasopharyngeal Carcinoma (CAPTAIN study).

BACKGROUND: This study aimed to evaluate the antitumor activity of camrelizumab, an antiprogrammed cell death-1 antibody, in pretreated recurrent or metastatic nasopharyngeal carcinoma (NPC) and to explore predictive biomarkers. METHODS: Patients with recurrent (not amenable to locally curative treatment) or metastatic NPC who had failed at least two lines of chemotherapy were eligible to receive camrelizumab (200 mg intravenously every 2 weeks) for 2 years or until disease progression, intolerable adverse events, withdrawal of consents, or investigator decision. The primary endpoint was objective response rate (ORR) assessed by an independent review committee (IRC). Programmed cell death-ligand 1 (PD-L1) expression was assessed by immunohistochemistry. Other immune-related biomarkers including major histocompatibility complex class I and major histocompatibility complex class II (MHC-II) were assessed by multiplex immunofluorescence staining. RESULTS: Between August 14, 2018, and December 30, 2019, a total of 156 patients were enrolled. The IRC-assessed ORR was 28.2% (95% CI 21.3% to 36.0%). The median progression-free survival was 3.7 months (95% CI 2.0 to 4.1) per IRC, and the median overall survival was 17.4 months (95% CI 15.2 to 21.9). The ORRs were 35.2% (95% CI 25.3% to 46.1%) vs 19.4% (95% CI 10.4% to 31.4%) in patients with tumor PD-L1 expression of ≥10% and<10%, respectively. Patients with durable clinical benefit (DCB), which was defined as complete response, partial response or stable disease of ≥18 weeks, had higher density of MHC-II+ cell in stroma than patients without DCB (median 868.1 (IQR 413.4-2854.0) cells/mm2 vs median 552.4 (IQR 258.4 to 1242.1) cells/mm2). MHC-II+ cell density did not correlate with PD-L1 expression, and a composite of high stromal MHC-II+ cell density and tumor PD-L1 expression further enriched patients who could benefit from camrelizumab. CONCLUSIONS: Camrelizumab had clinically meaningful antitumor activity in patients with recurrent or metastatic NPC. The composition of both MHC-II+ cell density and PD-L1 expression could result in better patient selection.

Selectively recommend 18F-FDG PET/CT for patients with de novo nasopharyngeal carcinoma in endemic areas.

INTRODUCTION: To identify the subset of patients with de novo nasopharyngeal carcinoma (NPC) for whom [18F] fluorodeoxyglucose positron emission tomography and computed tomography (18F-FDG PET/CT) should be recommended, and to determine whether PET/CT is a cost-effective decision for precise M staging in endemic areas. MATERIALS AND METHODS: Retrospective analysis of data of 4469 patients diagnosed with de novo NPC between January 2014 and December 2019. The detection rate of distant metastasis was compared between different groups. Univariate and multiple logistic regression analysis was applied to identify the risk factors for distant metastasis. The cost-effectiveness of the diagnostic strategies was assessed. RESULTS: The detection rate of distant metastasis in the whole cohort was 5.46%. In multivariate analysis, male sex, T3-4 stage, N2-3 stage, and high plasma Epstein-Barr virus (EBV) DNA (≥ 14,650 copies/mL) were risk factors for distant metastases. NPC patients with T3-4 stage combined with N2-3 stage, high EBV DNA combined with male sex, or N2-3 stage combined with high EBV DNA were defined as recommended group with relatively higher tendency for metastasis. Distant metastasis incidence in recommended group and unrecommended group were 10.25% and 1.75%, respectively (P < 0.001). In the recommended group, PET/CT significantly improved the detection rate of distant metastasis (13.25% vs 9.02%, P = 0.005). Cost-effectiveness analysis revealed that additional cost for every one percent increase in distant metastasis detection rate was $22,785.58 in the recommended group (< Willingness-to-pay (WTP) threshold of $32,700.00) and $310,912.90 in the unrecommended group. CONCLUSIONS: In patients with de novo NPC, the tendency for metastasis can be predicted based on clinical parameters. 18F-FDG PET/CT should be selectively recommended for the subset of patients with a relatively higher tendency for metastasis.

Expression of ANCR in nasopharyngeal carcinoma patients and its clinical significance.

ABSTRACT: Anti-differentiation non-coding RNA (ANCR), a long non-coding RNA, is involved in the development, progression and metastasis of various human cancers. However, its clinical significance in nasopharyngeal carcinoma (NPC) still remains unknown. This study aimed to investigate ANCR expression and its clinical significance in NPC.Totally, 96 NPC tissues and 24 non-cancerous nasopharyngeal mucosa tissues were used. The levels of ANCR were determined by qRT-PCR. Relationship of ANCR with patient clinical characteristics, disease-free survival and overall survival (OS) was evaluated.ANCR expression was increased in NPC tissues compared to non-cancerous nasopharyngeal mucosae. ANCR expression was significantly related to lymph node metastasis, clinical stage, and tumor differentiation (P < .05). Kaplan-Meier survival analysis revealed that high level of ANCR expression was significantly associated with poor disease-free survival but not with OS in NPC patients. Univariate analysis showed a significant association between increased ANCR expression and adverse OS (P < .05), but multivariate analysis suggested that ANCR could not be used as an independent prognostic factor for NPC patients.ANCR is involved in the development and progression of NPC, but whether it can be used as an effective therapeutic target for NPC needs further study.

Neoantigen landscape in metastatic nasopharyngeal carcinoma.

Background: Reportedly, nasopharyngeal carcinoma (NPC) patients with MHC I Class aberration are prone to poor survival outcomes, which indicates that the deficiency of tumor neoantigens might represent a mechanism of immune surveillance escape in NPC. Methods: To clearly delineate the landscape of neoantigens in NPC, we performed DNA and RNA sequencing on paired primary tumor, regional lymph node metastasis and distant metastasis samples from 26 patients. Neoantigens were predicted using pVACseq pipeline. Subtype prediction model was built using random forest algorithm. Results: Portraying the landscape of neoantigens in NPC for the first time, we found that the neoantigen load of NPC was above average compared to that of other cancers in The Cancer Genome Atlas program. While the quantity and quality of neoantigens were similar among primary tumor, regional lymph node metastasis and distant metastasis samples, neoantigen depletion was more severe in metastatic sites than in primary tumors. Upon tracking the clonality change of neoantigens, we found that neoantigen reduction occurred during metastasis. Building a subtype prediction model based on reported data, we observed that subtype I lacked T cells and suffered from severe neoantigen depletion, subtype II highly expressed immune checkpoint molecules and suffered from the least neoantigen depletion, and subtype III was heterogenous. Conclusions: These results indicate that neoantigens are conducive to the guidance of clinical treatment, and personalized therapeutic vaccines for NPC deserve deeper basic and clinical investigations to make them feasible in the future.

Circulating Epstein-Barr virus DNA level post induction chemotherapy contributes to prognostication in advanced-stage nasopharyngeal carcinoma.

BACKGROUND: To investigate the value of post-induction chemotherapy (IC) cell-free Epstein-Barr virus DNA (cfEBV DNApostIC) for prognostication in locally advanced nasopharyngeal carcinoma (LA-NPC). METHODS: A total of 910 histologically proven LA-NPC undergoing radical IC + concurrent chemo-radiotherapy (CCRT) or targeted radiotherapy (CTRT) or both (CTCRT) were involved. The concentration of cfEBV DNA was measured by quantitative polymerase chain reaction pre-IC (cfEBV DNApreIC) and at IC completion. CfEBV DNApostIC was classified as undetectable (0 copy/ml) and detectable (>0 copy/ml). Recursive partitioning analysis (RPA) with respect to the overall survival (OS) was applied to construct a risk stratification system incorporating cfEBV DNApostIC and critical risk factors. RESULTS: We observed that 660 (72.5%) and 250 (27.5%) patients had cfEBV DNApostIC undetectable and detectable respectively. CfEBV DNApostIC positive was associated with a significant inferior 5-year OS (76.2% versus 85.9%), metastasis-free survival (DMFS, 71.7% versus 86.4%) and disease-free survival (DFS, 57.7% versus 80.1%) than cfEBV DNApostIC negative (P < 0.001 for all). Additionally, cfEBV DNApostIC was independently significant for OS (hazard ratio [HR] 1.90, 95% CI 1.40-2.59), DMFS (1.99, 1.45-2.71) and DFS (2.38, 1.86-3.06) in multivariate analyses (P < 0.001 for all). RPA modelling yielded three distinct risk groups: low-risk (N0-1 and undetectable cfEBV DNApostIC or N2-3 and pre-treatment cfEBV DNA [cfEBV DNApreIC] <7000), median-risk (N0-1 and detectable cfEBV DNApostIC or N2-3 and cfEBV DNApreIC ≥7000 with undetectable cfEBV DNApostIC) and high-risk (N2-3 and cfEBV DNApreIC ≥7000 with detectable cfEBV DNApostIC), with 5-year OS of 88.1%, 79.2% and 66.9%, respectively. Our risk stratification outperformed TNM classification for predicting death (AUC, 0.631 versus 0.562; P = 0.012) and distant metastasis (0.659 versus 0.562; P = 0.004). CONCLUSIONS: CfEBV DNApostIC represents an effective indicator of prognostication in LA-NPC. We developed a risk classification system that provides improved OS prediction over the current staging system by combining cfEBV DNApostIC, cfEBV DNApreIC and N-stage classification in LA-NPC.

Copy number loss in granzyme genes confers resistance to immune checkpoint inhibitor in nasopharyngeal carcinoma.

BACKGROUND: Anti-programmed death (PD)-1 therapy has recently been used in recurrent or metastatic (R/M) nasopharyngeal carcinoma (NPC). The long-term survival and its biomarkers responding to anti-PD-1 treatment in patients with R/M NPC remain unclear. METHODS: Patients with R/M NPC were enrolled between March 2016 and January 2018 from two phase I clinical trials. The median follow-up period was 24.7 months. Eligible patients progressed on standard chemotherapy had measurable disease by Response Evaluation Criteria in Solid Tumor V.1.1. Non-obligatory contemporaneous tumor samples were collected for whole-exome sequencing. The primary outcome was objective response rate (ORR). Duration of response (DOR), progression-free survival (PFS), and overall survival (OS) were secondary outcomes assessed in all patients. RESULTS: Among 124 evaluable patients, anti-PD-1 therapy achieved an ORR of 29.8% and a durable clinical benefit rate of 60.5%. The median OS (mOS) was 17.1 months (95% CI 14.2 to 24.7), median PFS (mPFS) was 3.8 months (95% CI 3.4 to 6.0), and median DOR was 9.5 months. Significant OS benefit from treatment was observed in patients without liver metastasis (23.8 vs 13.3 months, p=0.006). Copy number deletion in genes encoding granzyme B or granzyme H (GZMB/H) was associated with poor treatment outcome (mPFS altered vs wildtype: 1.7 vs 3.6 months, p=0.03; mOS altered vs wildtype: 10.1 vs 18 months, p=0.012). CONCLUSIONS: Anti-PD-1 treatment provided promising clinical benefit in pretreated patients with R/M NPC. Copy number loss in either GZMB or GZMH genes was associated with reduced survival.

Perifocal edema volume is not associated with immunohistochemical features reflecting proliferation potential, microvessel density, neoangiogenesis and invasiveness in brain metastasis.

OBJECTIVE: Perifocal edema of brain tumors is associated with survival and neurological symptoms. Our aim was to analyze associations between perifocal edema and immunohistochemical features including proliferation potential, microvessel density, neoangiogenesis and invasiveness in brain metastasis (BM). METHODS: 35 patients with BM were included into the retrospective study. The tumors were localized supratentorial in 25 lesions (71.4%) and infratentorial in 10 lesions (28.6%). The following immunohistochemical features were calculated on histopathological specimens: microvessel density, proliferation index Ki 67, matrix-metallopeptidase 9 (MMP9) extracellular matrix metalloproteinase inducer (EMMPRIN) and vascular endothelial growth factor (VEGF) expression. Tumor and edema volumes were estimated semiautomatically on magnetic resonance images. RESULTS: There were no correlations between tumor volume and edema volume. Moreover, no correlation was identified between the investigated immunohistochemical features and tumor/edema volume. In the non-small cell lung cancer subgroup, a positive correlation between tumor volume and VEGF expression was observed (r = 0.52, P = 0.02) and edema volume correlated inversely with MMP9 expression (r = -0.53, P = 0.02). CONCLUSION: In BM, no linear associations exist between tumor volumes, edema volumes and immunohistochemical features reflecting proliferation potential, neoangiogenesis, microvessel density and MMP9 expression. However, in the subgroup of non-small cell lung cancer, there might be associations between MMP9 expression and edema volume as well as between tumor volume and angiogenesis.

Long-term recurrence and brain metastasis of nasopharyngeal carcinoma mimicking cystic radiation encephalopathy relapse: a case report.

BACKGROUND: During medical imaging, cystic radiation encephalopathy and brain metastasis are difficult to differentiate, and hence they are easily misdiagnosed. To our knowledge, a nasopharyngeal carcinoma recurrence after more than seven years with cerebral metastasis that mimicked cystic radiation encephalopathy has not been reported. CASE PRESENTATION: A 52-year-old man was admitted to the hospital owing to weakness of the right limb for one month, which increased in intensity for three days. He had been diagnosed with nasopharyngeal carcinoma in 2011, which was treated by radiotherapy. The patient successively developed cystic radiation encephalopathy and brain metastasis from the nasopharyngeal carcinoma, which mimicked cystic radiation encephalopathy relapse. Left frontotemporal craniotomy, surgical resection of brain metastasis, and repair of the skull base and dura were performed. Postoperative computed tomography showed that midline deviation recovered, and brain edema was reduced. CONCLUSIONS: This report is significant because brain metastasis from nasopharyngeal carcinoma can masquerade as a benign entity and cause fatal consequences. In patients presenting with cystic radiation encephalopathy, brain metastasis should be considered as a differential diagnosis.

Efficacy, Safety, and Correlative Biomarkers of Toripalimab in Previously Treated Recurrent or Metastatic Nasopharyngeal Carcinoma: A Phase II Clinical Trial (POLARIS-02).

PURPOSE: As yet, no checkpoint inhibitor has been approved to treat nasopharyngeal carcinoma (NPC). This study was aimed to evaluate the antitumor activity, safety, and biomarkers of toripalimab, a new programmed death-1 (PD-1) inhibitor for recurrent or metastatic NPC (RM-NPC) refractory to standard chemotherapy. PATIENTS AND METHODS: In this single-arm, multicenter phase II study, patients with RM-NPC received 3 mg/kg toripalimab once every 2 weeks via intravenous infusion until confirmed disease progression or unacceptable toxicity. The primary end point was objective response rate (ORR). The secondary end points included safety, duration of response (DOR), progression-free survival (PFS), and overall survival (OS). RESULTS: Among all 190 patients, the ORR was 20.5% with median DOR 12.8 months, median PFS 1.9 months, and median OS 17.4 months. Among 92 patients who failed at least two lines of systemic chemotherapy, the ORR was 23.9%. The ORRs were 27.1% and 19.4% in PD-L1+ and PD-L1- patients, respectively (P = .31). Patients with ≥ 50% decrease of plasma Epstein-Barr virus (EBV) DNA copy number on day 28 had significantly better ORR than those with < 50% decrease, 48.3% versus 5.7% (P = .0001). Tumor mutational burden had a median value of 0.95 muts/mega-base in the cohort and had no predictive value for response. Whole-exome sequencing results from 174 patients revealed that the patients with genomic amplification in 11q13 region or ETV6 genomic alterations had poor responses to toripalimab. CONCLUSION: The POLARIS-02 study demonstrated a manageable safety profile and durable clinical response of toripalimab in patients with chemorefractory metastatic NPC. An early decrease in plasma EBV DNA copy number correlated with favorable response.

Chemotherapy in Combination With Radiotherapy for Definitive-Intent Treatment of Stage II-IVA Nasopharyngeal Carcinoma: CSCO and ASCO Guideline.

PURPOSE: The aim of this joint guideline is to provide evidence-based recommendations to practicing physicians and other healthcare providers on definitive-intent chemoradiotherapy for patients with stage II-IVA nasopharyngeal carcinoma (NPC). METHODS: The Chinese Society of Clinical Oncology (CSCO) and ASCO convened an expert panel of radiation oncology, medical oncology, surgery, and advocacy representatives. The literature search included systematic reviews, meta-analyses, and randomized controlled trials published from 1990 through 2020. Outcomes of interest included survival, distant and locoregional disease control, and quality of life. Expert panel members used this evidence and informal consensus to develop evidence-based guideline recommendations. RESULTS: The literature search identified 108 relevant studies to inform the evidence base for this guideline. Five overarching clinical questions were addressed, which included subquestions on radiotherapy (RT), chemotherapy sequence, and concurrent, induction, and adjuvant chemotherapy options. RECOMMENDATIONS: Evidence-based recommendations were developed to address aspects of care related to chemotherapy in combination with RT for the definitive-intent treatment of stage II to IVA NPC.Additional information is available at www.asco.org/head-neck-cancer-guidelines.

Nasopharyngeal carcinoma metastasis to the breast.

Breast metastases from extra-mammary neoplasms are rare, accounting for less than 2% of breast cancer cases. A 43-year-old female patient presented with a mass in her left breast and swelling in her left axillary region. A histopathological examination of the mass showed enlarged polygonal tumor cells with scant to moderate, eosinophilic to amphophilic cytoplasm and enlarged, hyperchromatic and pleomorphic nuclei with irregular nuclear membranes. An immunohistochemistry (IHC) examination was positive for pan cytokeratin and negative for CK7, CK20, S-100, LCA, HMB45, CD 20, desmin, myogenin, GCFDP-15, transcription factor-1, villin, estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2. As she was a known case of nasopharyngeal carcinoma, and based on the histopathology ndings and IHC profile, the patient was diagnosed with breast metastasis from NPC. The patient was deceased 3 months after refusing the recommended medical intervention.

Rab1A promotes cancer metastasis and radioresistance through activating GSK-3ß/Wnt/ß-catenin signaling in nasopharyngeal carcinoma.

Many articles have reported that Rab1A was overexpressed in a variety of human cancers and involved in tumor progression and metastasis. However, the biological function and molecular mechanism of Rab1A in nasopharyngeal carcinoma (NPC) remained unknown until now. Here we found that Rab1A overexpression is a common event and was positively associated with distant metastasis and poor prognosis of NPC patients. Functionally, Rab1A depletion inhibited the migration and EMT phenotype of NPC cells, whereas Rab1A overexpression led to the opposite effect. Furthermore, we reveal an important role for Rab1A protein in the induction of radioresistance via regulating homologous recombination (HR) signaling pathway. Mechanistically, Rab1A activated Wnt/ß-catenin signaling by inhibiting the activity of GSK-3ß via phosphorylation at Ser9. Then Wnt/ß-catenin signaling induced NPC cells radioresistance and metastasis through nuclear translocation of ß-catenin and transcription upregulation of HR pathway-related and EMT-related genes expression. In general, this study shows that Rab1A may serve as a potential biomarker for predicting prognosis in NPC patients. Targeting Rab1A and Wnt/ß-catenin signaling may hold promise to overcome NPC radioresistance.

Pattern and prognosis of distant metastases in nasopharyngeal carcinoma: A large-population retrospective analysis.

Currently, the features and prognosis of nasopharyngeal carcinoma (NPC) with distant metastases are still rarely reported. Thus, the main purpose of our study was to investigate the metastasis patterns of different histological types of NPC and to clarify the prognostic characteristics of metastases at different sites. Patients were enrolled from the SEER program from 2010 to 2016. Chi-squared tests were used to compare features between groups. The tendency to develop combined metastases was assessed with the odds ratio. The Kaplan-Meier method was used for the survival analysis. Univariate and multivariate Cox analyses were used to select the independent prognostic risk factors for inclusion in the nomogram. In the present study, we found the following: (1) tumors are highly likely to metastasize if they have a larger volume, the regional lymph nodes are relatively large, or the regional lymph nodes are biopsied but not removed; (2) the bone and the brain were the most and least common metastatic sites among all histological types and N stages. Metastasis at two sites was the most common pattern, and bone metastasis was generally associated with metastasis to the liver or brain; (3) the prognostic analyses in metastatic patients showed that cancer-specific survival (CSS) was relatively worse in patients with multiple metastases, and in those with liver metastasis regardless of the number of other metastatic sites; (4) A nomogram was constructed for clinical use based on four independent prognostic risk indicators, including histology, radiation therapy, chemotherapy, and metastatic status. Our findings provide a reference for clinical decision-making and future diagnostic screening tests for NPC with distant metastases.

Comparison of induction chemotherapy plus concurrent chemoradiotherapy and induction chemotherapy plus radiotherapy in locally advanced nasopharyngeal carcinoma.

BACKGROUND: Induction chemotherapy plus concurrent chemoradiotherapy (IC + CCRT) is a standard treatment regimen for locally advanced nasopharyngeal carcinoma (LA-NPC). However, the increased acute toxicity of this intensified chemotherapy may counteract its efficacy. The results of studies focusing on the omission of concurrent chemotherapy (CC) regimens are controversial. Therefore, we carried out a meta-analysis to elucidate the efficacy and toxicity of IC + CCRT versus IC plus radiotherapy alone (IC + RT) for LA-NPC. METHODS: Studies available on PubMed, Embase, Cochrane Library and ClinicalTrails.gov were independently searched by two investigators from inception to March 1, 2020. Review Manager software 5.3 (RevMan 5.3) was employed to calculate pooled hazard ratios (HRs), risk ratios (RRs) and 95% confidence intervals (CIs). RESULTS: Eight studies with a total of 2605 patients were analysed. The results showed that no significant difference between IC + RT and IC + CCRT for disease-free survival (HR = 1.09, 95% CI: 0,85-1.39, P = 0.50), overall survival (HR = 0.92, 95% CI: 0.78-1.09, P = 0.34), local recurrence-free survival (HR = 1.26, 95% CI: 0.95-1.67; P = 0.10), or distant metastasis-free survival (HR = 1.03, 95% CI: 0.84-1.26, P = 0.79). Notably, the incidence of treatment-related grade 3/4 acute haematological toxicity during radiation was higher in the IC + CCRT group. Subgroup analysis showed similar survival outcomes for IC + CCRT and IC + RT with and without the two-dimensional RT technique. CONCLUSIONS: IC + RT was as effective as IC + CCRT for the management of LA-NPC. The IC + RT regimen has the possibility of replacing the IC + CCRT regimen for LA-NPC in the future due to the lower toxicity, although more high-level evidence is urgently needed for verification.

The predictive value of serum lipids for eye metastases in male nasopharyngeal carcinoma patients.

BACKGROUND: Nasopharyngeal carcinoma (NPC) is a tumor that is commonly found in southern China. NPC has several risk factors, such as infection with the Epstein-Barr virus. However, we know little about the risk factors for eye metastasis (EM) in male patients with NPC. Serum lipids are well recognized as risk factors for cardiovascular disease, and recent studies show that they also have a relationship with the development of NPC. PURPOSE: We designed the present study to determine whether they were relevant with the development of EM in male NPC patients by detecting the levels of several serum lipids. METHODS: A total of 1140 male patients with NPC were enrolled in this retrospective study and we divided them into two groups: the metastasis (EM) group and non-eye metastasis (NEM) group. A variety of serum lipids between the two groups were tested and compared. RESULTS: There were statistical differences in the levels of serum TG and TC between these two groups. Binary logistic regression showed that TG and TC were independent risk factors for EM in male NPC patients with P=0.004 and P<0.001, respectively. The area under the curve of TG and TC were 0.764 and 0.681, respectively, using cutoff values of 0.975 and 3.425 mmol/l, respectively. We found that TG had higher sensitivity and specificity values with 87.5% and 62.7%, respectively, than TC which were 50.0% and 87.2%. CONCLUSION: TG and TC are potential risk factors for eye metastases in male NPC patients.

Therapeutic Effect of Chemotherapy Cycle in Nasopharyngeal Carcinoma (NPC) Patients Who Developed Bone-Only Metastasis.

BACKGROUND To compare the effects of chemotherapy dose escalation on survival and prognosis of nasopharyngeal carcinoma (NPC) patients who developed bone-only metastasis. MATERIAL AND METHODS Between October 2000 to March 2017, 58 NPC patients with initial bone-only metastasis were retrospectively analyzed. Patients who received <6 or ≥6 cycles of chemotherapy were matched and grouped using receiver operating characteristic curve (ROC) analysis. Overall survival (OS) was assessed using the Kaplan-Meier method, log-rank test, and Cox regression analysis. RESULTS The median OS for the entire group was 24 months, while the 1-, 2-, and 3-year OS rates were 78.5%, 49.4%, and 26.8%, respectively. The median OS for patients who received <6 cycles of chemotherapy was 21 months, with 1-, 2-, and 3-year OS rates of 64.8%, 34.3%, and 17.2%, respectively. The median OS of patients who received ≥6 cycles of chemotherapy was 26 months, with 1-, 2-, and 3-year OS rates of 92.6%, 54.9%, and 30.9%, respectively. Multivariate analysis showed that the number of metastatic sites (≥3 vs. <3) and chemotherapy cycles (<6 vs. ≥6) were independent prognostic factors for OS. CONCLUSIONS NPC patients who had less than 3 bone metastatic sites and who received ≥6 cycles of chemotherapy had better survival and prognosis.

Acrometastasis of nasopharyngeal carcinoma: a case report.

Acrometastasis is an exceedingly rare condition and is often misdiagnosed or overlooked. We herein describe a 50-year-old patient who developed acrometastasis in the big toe from nasopharyngeal carcinoma. The treatment consisted of amputation through the proximal phalanx, and the patient recovered well. To our knowledge, only one case of acrometastasis from this origin has been reported in the literature to date. Acrometastasis indicates a poor prognosis, and we should choose appropriate treatment to relieve symptoms and benefit the patient.