The m6A reader HNRNPC promotes glioma progression by enhancing the stability of IRAK1 mRNA through the MAPK pathway.

Glioma is the most common and aggressive type of primary malignant brain tumor. The N6-methyladenosine (m6A) modification widely exists in eukaryotic cells and plays an important role in the occurrence and development of human tumors. However, the function and mechanism of heterogeneous nuclear ribonucleoprotein C (HNRNPC), an RNA-binding protein and m6A reader in gliomas remains to be comprehensively and extensively explored. Herein, we found that HNRNPC mRNA and protein overexpression were associated with a poor prognosis for patients with gliomas, based on the data from TCGA, the CGGA, and the TMAs. Biologically, HNRNPC knockdown markedly repressed malignant phenotypes of glioma in vitro and in vivo, whereas ectopic HNRNPC expression had the opposite effect. Integrative RNA sequencing and MeRIP sequencing analyses identified interleukin-1 receptor-associated kinase 1 (IRAK1) as a downstream target of HNRNPC. The glioma public datasets and tissue microarrays (TMAs) data indicated that IRAK1 overexpression was associated with poor prognosis, and IRAK1 knockdown significantly repressed malignant biological behavior in vitro. Mechanistically, HNRNPC maintains the mRNA stability of IRAK1 in an m6A-dependent manner, resulting in activation of the mitogen-activated protein kinase (MAPK) signaling pathway, which was necessary for the malignant behavior of glioma. Our findings demonstrate the HNRNPC-IRAK1-MAPK axis as a crucial carcinogenic factor for glioma and the novel underlying mechanism of IRAK1 upregulation, which provides a rationale for therapeutically targeting epitranscriptomic modulators in glioma.

Simultaneous integrated boost intensity-modulated radiotherapy post breast-conserving surgery: clinical efficacy, adverse effects, and cosmetic outcomes in breast cancer patients.

BACKGROUND: Simultaneous integrated boost intensity-modulated radiotherapy (SIB-IMRT) is an innovative technique delivering a higher dose to the tumor bed while irradiating the entire breast. This study aims to assess the clinical outcomes, adverse effects, and cosmetic results of SIB-IMRT following breast-conserving surgery in breast cancer patients. METHODS: We conducted a retrospective analysis of 308 patients with stage 0-III breast cancer who underwent breast-conserving surgery and SIB-IMRT from January 2016 to December 2020. The prescribed doses included 1.85 Gy/27 fractions to the whole breast and 2.22 Gy/27 fractions or 2.20 Gy/27 fractions to the tumor bed. Primary endpoints included overall survival (OS), local-regional control (LRC), distant metastasis-free survival (DMFS), acute and late toxicities, and cosmetic outcomes. RESULTS: The median follow-up time was 36 months. The 3-year OS, LRC, and DMFS rates were 100%, 99.6%, and 99.2%, respectively. Five patients (1.8%) experienced local recurrence or distant metastasis, and one patient succumbed to distant metastasis. The most common acute toxicity was grade 1-2 skin reactions (91.6%). The most common late toxicity was grade 0-1 skin and subcutaneous tissue reactions (96.7%). Five patients (1.8%) developed grade 1-2 upper limb lymphedema, and three patients (1.1%) had grade 1 radiation pneumonitis. Among the 262 patients evaluated for cosmetic outcomes at least 2 years post-radiotherapy, 96.9% achieved excellent or good results, while 3.1% had fair or poor outcomes. CONCLUSIONS: SIB-IMRT after breast-conserving surgery in breast cancer patients demonstrated excellent clinical efficacy, mild acute and late toxicities, and satisfactory cosmetic outcomes in our study. SIB-IMRT appears to be a feasible and effective option for breast cancer patients suitable for breast-conserving surgery.

Anatomic prognostic factors and their potential roles in refining M1 classification for de novo metastatic nasopharyngeal carcinoma.

BACKGROUND AND PURPOSE: To identify anatomic prognostic factors and their potential roles in refining M1 classification for de novo metastatic nasopharyngeal carcinoma (M1-NPC). MATERIALS AND METHODS: All M1-NPC treated with chemotherapy and/or radiotherapy between 2010 and 2019 from two centers (training and validation cohort) were included. The prognostic value of metastatic disease extent and involved organs for overall survival (OS) were assessed by several multivariable analyses (MVA) models. A new M1 classification was proposed and validated in a separate cohort who received immuno-chemotherapy. RESULTS: A total of 197 M1-NPC in the training and 307 in the validation cohorts were included for M1 subdivision study with median follow-up of 46 and 57 months. MVA model with "≤2 organs/≤5 lesions" as the definition of oligometastasis had the highest C-index (0.623) versus others (0.606-0.621). Patients with oligometastasis had better OS versus polymetastasis (hazard ratio [HR] 0.47/0.63) while liver metastases carried worse OS (HR 1.57/1.45) in MVA in the training/validation cohorts, respectively. We proposed to divide M1-NPC into M1a (oligometastasis without liver metastases) and M1b (liver metastases or polymetastasis) with 3-year OS of 66.5%/31.7% and 64.9%/35.0% in the training/validation cohorts, respectively. M1a subset had a better median progress-free survival (not reach vs. 17 months, p < 0.001) in the immuno-chemotherapy cohort (n = 163). CONCLUSION: Oligometastasis (≤2 organs/≤5 lesions) and liver metastasis are prognostic for M1-NPC. Subdivision of M1-NPC into M1a (oligometastasis without liver metastasis) and M1b (liver metastasis or polymetastasis) depicts the prognosis well in M1-NPC patients who received immuno-chemotherapy.

A Novel Prognostic Model Predicts Outcomes in Non-Metastatic Nasopharyngeal Carcinoma Based on Inflammation, Nutrition, and Coagulation Signature.

Purpose: This study aimed to assess the prognostic and predictive value of a circulating hematological signature (CHS) and to develop a CHS-based nomogram for predicting prognosis and guiding individualized chemotherapy in non-metastatic nasopharyngeal carcinoma (NPC) patients. Patients and Methods: NPC patients were recruited between January 2014 and December 2017 at the Jiangxi Cancer Hospital. The CHS was constructed based on a series of hematological indicators. The nomogram was developed by CHS and clinical factors. Results: A total of 779 patients were included. Three biomarkers were selected by least absolute shrinkage and selection operator regression, including prognostic nutritional index, albumin-to-fibrinogen ratio, and prealbumin-to-fibrinogen ratio, were used to construct the CHS. The patients in the low-CHS group had better 5-year DMFS and OS than those in the high-CHS group in the training (DMFS: 85.0% vs 56.6%, p<0.001; OS: 90.3% vs 65.4%, p<0.001) and validation cohorts (DMFS: 92.3% vs 43.6%, p<0.001; OS: 92.1% vs 65.5%, p<0.001). The nomogram_CHS showed better performance than clinical stage in predicting distant metastasis (concordance index: 0.728 vs 0.646). In the low-TRS (total risk scores) group, the patients received RT alone, CCRT and IC plus CCRT had similar 5-year DMFS and OS (p>0.05). In the middle-TRS group, the patients received RT alone had worse 5-year DMFS (58.7% vs 80.8% vs 90.8%, p=0.002) and OS (75.0% vs 94.1% vs 95.0%, p=0.001) than those received CCRT or IC plus CCRT. In the high-TRS group, the patients received RT alone and CCRT had worse 5-year DMFS (18.6% vs 31.3% vs 81.5%, p<0.001) and OS (26.9% vs 53.2% vs 88.8%, p<0.001) than those received IC plus CCRT. Conclusion: The developed nomogram_CHS had satisfactory prognostic accuracy in NPC patients and may individualize risk estimation to facilitate the identification of suitable IC candidates.

MRI-based deep learning model predicts distant metastasis and chemotherapy benefit in stage II nasopharyngeal carcinoma.

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.

A two-stage genome-wide association study identifies novel germline genetic variations in CACNA2D3 associated with radiotherapy response in nasopharyngeal carcinoma.

BACKGROUND: Radiotherapy (RT) is the standard treatment for nasopharyngeal carcinoma (NPC). However, due to individual differences in radiosensitivity, biomarkers are needed to tailored radiotherapy to cancer patients. However, comprehensive genome-wide radiogenomic studies on them are still lacking. The aim of this study was to identify genetic variants associated with radiotherapy response in patients with NPC. METHODS: This was a large­scale genome-wide association analysis (GWAS) including a total of 981 patients. 319 individuals in the discovery stage were genotyped for 688,783 SNPs using whole genome-wide screening microarray. Significant loci were further genotyped using MassARRAY system and TaqMan SNP assays in the validation stages of 847 patients. This study used logistic regression analysis and multiple bioinformatics tools such as PLINK, LocusZoom, LDBlockShow, GTEx, Pancan-meQTL and FUMA to examine genetic variants associated with radiotherapy efficacy in NPC. RESULTS: After genome-wide level analysis, 19 SNPs entered the validation stage (P < 1 × 10- 6), and rs11130424 ultimately showed statistical significance among these SNPs. The efficacy was better in minor allele carriers of rs11130424 than in major allele carriers. Further stratified analysis showed that the association existed in patients in the EBV-positive, smoking, and late-stage (III and IV) subgroups and in patients who underwent both concurrent chemoradiotherapy and induction/adjuvant chemotherapy. CONCLUSION: Our study showed that rs11130424 in the CACNA2D3 gene was associated with sensitivity to radiotherapy in NPC patients. TRIAL REGISTRATION NUMBER: Effect of genetic polymorphism on nasopharyngeal carcinoma chemoradiotherapy reaction, ChiCTR-OPC-14005257, Registered 18 September 2014, http://www.chictr.org.cn/showproj.aspx?proj=9546 .

The role of radiologic extranodal extension in predicting prognosis and chemotherapy benefit for T1-2 N1 nasopharyngeal carcinoma: A multicenter retrospective study.

BACKGROUND AND PURPOSE: This multicenter retrospective study aimed to investigated the prognostic value of unequivocal radiologic extranodal extension (rENE) and the efficacy of chemotherapy for stage T1-2 N1 nasopharyngeal carcinoma (NPC) in the IMRT era. MATERIALS AND METHODS: We included 1,082 patients treated in 2005-2017 from three centers. rENE was recorded as G1 (coalescent nodal mass comprising ≥ 2 inseparable nodes) or G2 (invading beyond perinodal fat to frankly infiltrate adjacent structures). Multivariable analysis (MVA) evaluated the prognostic value of rENE. The value of chemotherapy was assessed in rENE-positive (rENE + ) and rENE-negative (rENE - ) subset separately. RESULTS: Centers 1, 2, and 3 had 139/515 (27.0 %), 100/365 (27.4 %), and 43/202 (21.3 %) cN + patients with rENE, respectively. Compared to rENE-, rENE + patients had a worse distant metastasis-free survival (DMFS) and overall survival (OS) (all p < 0.001). MVA confirmed the prognostic of both G1-rENE and G2-rENE for distant metastasis [G1: hazard ratio (HR): 2.933, G2: HR: 6.942, all p < 0.001] and death (G1: HR: 1.587, p = 0.040; G2: HR: 6.162, p < 0.001). There was no significant difference for DMFS and OS between chemo-radiotherapy and radiotherapy alone in rENE + and rENE - groups (all p > 0.1). However, rENE + patients with a cumulative cisplatin/nedaplatin dose (CCND) of > 160 mg/m2 had an improved DMFS (p = 0.033) but no OS (p = 0.197). CONCLUSION: Unequivocal rENE is prognostic in patients with T1-2 N1 NPC. Addition of chemotherapy to radiotherapy did not affect DMFS and OS in rENE - patients. Chemotherapy with a CCND of > 160 mg/m2 improved DMFS in rENE + patients.

Adjuvant Capecitabine Following Concurrent Chemoradiotherapy in Locoregionally Advanced Nasopharyngeal Carcinoma: A Randomized Clinical Trial.

Importance: Induction or adjuvant chemotherapy with concurrent chemoradiotherapy (CCRT) are first-line treatment options for treatment of locoregionally advanced nasopharyngeal carcinoma (LA-NPC). Adjuvant platinum regimens are, however, poorly tolerated, highlighting the unmet need for an efficacious, tolerable adjuvant regimen. Objective: To investigate the efficacy and safety of adjuvant capecitabine with CCRT for the treatment of patients with LA-NPC. Design, Setting, and Participants: This open-label randomized clinical trial recruited patients from March 31, 2014, to July 27, 2018, at 3 institutions in China, with at least 3 years of follow-up. The data collection cutoff date was February 9, 2022. Eligibility included stage III-IVb nasopharyngeal carcinoma and at least 1 of the following: T3-4N2 or T1-4N3; plasma Epstein-Barr virus DNA titer higher than 20 000 copies/mL; primary gross tumor volume larger than 30.0 cm3; fluorodeoxyglucose F 18 positron emission tomography/computed tomography maximum standard uptake value of the primary gross tumor volume larger than 10.0; or multiple nodal metastases and any larger than 4.0 cm. Interventions: Patients were randomly assigned 1:1 to receive either capecitabine (1000 mg/m2 twice daily for 14 days every 3 weeks for 8 cycles) or observation following CCRT (100 mg/m2 cisplatin every 3 weeks for 2 to 3 cycles, depending on duration of radiotherapy). Main Outcomes and Measures: Failure-free survival in the intention-to-treat cohort was assessed using Kaplan-Meier survival curves compared with the log-rank test. Unstratified Cox proportional hazards regression models were used to estimate hazard ratios, with corresponding 95% CIs based on the Wald test. Results: There were 180 patients enrolled (median [IQR] age, 47 [40-55] years; 143 [79.4%] men). Among 90 patients in the capecitabine group, 76 (84.4%) had at least 2 high-risk factors; among 90 patients in the control group, 80 (88.9%) had at least 2 high-risk factors. All patients completed CCRT, except 1 patient in the capecitabine group who received 1 cycle of cisplatin. Of the 90 patients in the capecitabine group, 85 (94.4%) received capecitabine, with 71 (78.9%) completing 8 cycles. With a median (IQR) follow-up of 58.0 (49.5-80.1) months, 18 events were recorded in the capecitabine group vs 31 events in the control group. Failure-free survival was improved with adjuvant capecitabine (3 years, 83.3% vs 72.2%; 5 years, 78.5% vs 65.9%; hazard ratio, 0.53 [95% CI, 0.30-0.94]; P = .03). The incidence of grade 3 treatment-related adverse events (TRAEs) was higher in the capecitabine group than in the control group (54 of 90 patients [60.0%] vs 46 of 90 patients [51.1%]). Treatment-related adverse events included xerostomia (17 [18.9%] vs 9 [10.0%] patients), mucositis (21 [23.3%] vs 15 [16.7%] patients), and anorexia (8 [8.9%] vs 4 [4.4%] patients). The incidence of grade 3 delayed treatment-related adverse events was comparable in both groups (9 of 83 [10.8%] vs 7 of 81 [8.6%] patients). Conclusions and Relevance: In this randomized clinical trial, adjuvant capecitabine at the full dose following CCRT was well tolerated and improved failure-free survival among patients with LA-NPC and high-risk factors. Further investigations assessing optimal dose and duration are warranted. Trial Registration: ClinicalTrials.gov Identifier: NCT02143388.

A two-stage genome-wide association study to identify novel genetic loci associated with acute radiotherapy toxicity in nasopharyngeal carcinoma.

BACKGROUND: Genetic variants associated with acute side effects of radiotherapy in nasopharyngeal carcinoma (NPC) remain largely unknown. METHODS: We performed a two-stage genome-wide association analysis including a total of 1084 patients, where 319 individuals in the discovery stage were genotyped for 688,783 SNPs using whole genome-wide screening microarray. Significant variants were then validated in an independent cohort of 765 patients using the MassARRAY system. Gene mapping, linkage disequilibrium, genome-wide association analysis, and polygenic risk score were conducted or calculated using FUMA, LDBlockShow, PLINK, and PRSice software programs, respectively. RESULTS: Five SNPs (rs6711678, rs4848597, rs4848598, rs2091255, and rs584547) showed statistical significance after validation. Radiotherapy toxicity was more serious in mutant minor allele carriers of all five SNPs. Stratified analysis further indicated that rs6711678, rs4848597, rs4848598, and rs2091255 correlated with skin toxicity in patients of EBV positive, late stage (III and IV), receiving both concurrent chemoradiotherapy and induction/adjuvant chemotherapy, and with OR values ranging from 1.92 to 2.66. For rs584547, high occurrence of dysphagia was found in A allele carriers in both the discovery (P = 1.27 × 10- 6, OR = 1.55) and validation (P = 0.002, OR = 4.20) cohorts. Furthermore, prediction models integrating both genetic and clinical factors for skin reaction and dysphagia were established. The area under curve (AUC) value of receiver operating characteristic (ROC) curves were 0.657 (skin reaction) and 0.788 (dysphagia). CONCLUSIONS: Rs6711678, rs4848597, rs4848598, and rs2091255 on chromosome 2q14.2 and rs584547 were found to be novel risk loci for skin toxicity and dysphagia in NPC patients receiving radiotherapy. TRIAL REGISTRATION: Chinese Clinical Trial Register (registration number: ChiCTR-OPC-14005257 and CTXY-140007-2).

Final Overall Survival Analysis of Gemcitabine and Cisplatin Induction Chemotherapy in Nasopharyngeal Carcinoma: A Multicenter, Randomized Phase III Trial.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically on the based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.We previously reported significantly improved failure-free survival using gemcitabine plus cisplatin induction chemotherapy in locoregionally advanced nasopharyngeal carcinoma. Here, we present the final overall survival (OS) analysis. In this multicenter, randomized trial, patients were assigned to be treated with concurrent chemoradiotherapy alone (standard therapy, n = 238) or gemcitabine and cisplatin induction chemotherapy before concurrent chemoradiotherapy (n = 242). With a median follow-up of 69.8 months, the induction chemotherapy group had a significantly higher 5-year OS (87.9% v 78.8%, hazard ratio, 0.51 [95% CI 0.34 to 0.78]; P = .001) and a comparable risk of late toxicities (≥ grade 3, 11.3% v 11.4%). Notably, the depth of the tumor response to induction chemotherapy correlated significantly and positively with survival (complete response v partial response v stable/progressive disease, 5-year OS, 100% v 88.4% v 61.5%, P = .005). Besides, patients with a low pretreatment cell-free Epstein-Barr virus DNA load (< 4,000 copies/mL) might not benefit from induction chemotherapy (5-year OS, 90.6% v 91.4%, P = .77). In conclusion, induction chemotherapy before concurrent chemoradiotherapy improved OS significantly in patients with locally advanced nasopharyngeal carcinoma, without increasing the risk of late toxicities. Tumor response to induction chemotherapy and pretreatment cell-free Epstein-Barr virus DNA might be useful to guide individualized treatment.

Generating synthesized computed tomography from CBCT using a conditional generative adversarial network for head and neck cancer patients.

Purpose: To overcome the imaging artifacts and Hounsfield unit inaccuracy limitations of cone-beam computed tomography, a conditional generative adversarial network is proposed to synthesize high-quality computed tomography-like images from cone-beam computed tomography images. Methods: A total of 120 paired cone-beam computed tomography and computed tomography scans of patients with head and neck cancer who were treated during January 2019 and December 2020 retrospectively collected; the scans of 90 patients were assembled into training and validation datasets, and the scans of 30 patients were used in testing datasets. The proposed method integrates a U-Net backbone architecture with residual blocks into a conditional generative adversarial network framework to learn a mapping from cone-beam computed tomography images to pair planning computed tomography images. The mean absolute error, root-mean-square error, structural similarity index, and peak signal-to-noise ratio were used to assess the performance of this method compared with U-Net and CycleGAN. Results: The synthesized computed tomography images produced by the conditional generative adversarial network were visually similar to planning computed tomography images. The mean absolute error, root-mean-square error, structural similarity index, and peak signal-to-noise ratio calculated from test images generated by conditional generative adversarial network were all significantly different than CycleGAN and U-Net. The mean absolute error, root-mean-square error, structural similarity index, and peak signal-to-noise ratio values between the synthesized computed tomography and the reference computed tomography were 16.75 ± 11.07 Hounsfield unit, 58.15 ± 28.64 Hounsfield unit, 0.92 ± 0.04, and 30.58 ± 3.86 dB in conditional generative adversarial network, 20.66 ± 12.15 Hounsfield unit, 66.53 ± 29.73 Hounsfield unit, 0.90 ± 0.05, and 29.29 ± 3.49 dB in CycleGAN, and 16.82 ± 10.99 Hounsfield unit, 58.68 ± 28.34 Hounsfield unit, 0.92 ± 0.04, and 30.48 ± 3.83 dB in U-Net, respectively. Conclusions: The synthesized computed tomography generated from the cone-beam computed tomography-based conditional generative adversarial network method has accurate computed tomography numbers while keeping the same anatomical structure as cone-beam computed tomography. It can be used effectively for quantitative applications in radiotherapy.

The Chinese Society of Clinical Oncology (CSCO) clinical guidelines for the diagnosis and treatment of nasopharyngeal carcinoma.

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.

Gemcitabine and Cisplatin Induction Chemotherapy in Nasopharyngeal Carcinoma.

BACKGROUND: Platinum-based concurrent chemoradiotherapy is the standard of care for patients with locoregionally advanced nasopharyngeal carcinoma. Additional gemcitabine and cisplatin induction chemotherapy has shown promising efficacy in phase 2 trials. METHODS: In a parallel-group, multicenter, randomized, controlled, phase 3 trial, we compared gemcitabine and cisplatin as induction chemotherapy plus concurrent chemoradiotherapy with concurrent chemoradiotherapy alone. Patients with locoregionally advanced nasopharyngeal carcinoma were randomly assigned in a 1:1 ratio to receive gemcitabine (at a dose of 1 g per square meter of body-surface area on days 1 and 8) plus cisplatin (80 mg per square meter on day 1), administered every 3 weeks for three cycles, plus chemoradiotherapy (concurrent cisplatin at a dose of 100 mg per square meter every 3 weeks for three cycles plus intensity-modulated radiotherapy) or chemoradiotherapy alone. The primary end point was recurrence-free survival (i.e., freedom from disease recurrence [distant metastasis or locoregional recurrence] or death from any cause) in the intention-to-treat population. Secondary end points included overall survival, treatment adherence, and safety. RESULTS: A total of 480 patients were included in the trial (242 patients in the induction chemotherapy group and 238 in the standard-therapy group). At a median follow-up of 42.7 months, the 3-year recurrence-free survival was 85.3% in the induction chemotherapy group and 76.5% in the standard-therapy group (stratified hazard ratio for recurrence or death, 0.51; 95% confidence interval [CI], 0.34 to 0.77; P = 0.001). Overall survival at 3 years was 94.6% and 90.3%, respectively (stratified hazard ratio for death, 0.43; 95% CI, 0.24 to 0.77). A total of 96.7% of the patients completed three cycles of induction chemotherapy. The incidence of acute adverse events of grade 3 or 4 was 75.7% in the induction chemotherapy group and 55.7% in the standard-therapy group, with a higher incidence of neutropenia, thrombocytopenia, anemia, nausea, and vomiting in the induction chemotherapy group. The incidence of grade 3 or 4 late toxic effects was 9.2% in the induction chemotherapy group and 11.4% in the standard-therapy group. CONCLUSIONS: Induction chemotherapy added to chemoradiotherapy significantly improved recurrence-free survival and overall survival, as compared with chemoradiotherapy alone, among patients with locoregionally advanced nasopharyngeal carcinoma. (Funded by the Innovation Team Development Plan of the Ministry of Education and others; ClinicalTrials.gov number, NCT01872962.).

Design of a microfluidic chip consisting of micropillars and its use for the enrichment of nasopharyngeal cancer cells.

The aim of the present study was to discuss the design of a microfluidic chip consisting of columns, and its use for the enrichment of nasopharyngeal cancer (NPC) cells. A microfluidic chip experiment was simulated using FLUENT software. Within the microfluidic chip, aptamers were bound to the reaction chamber (consisting of columns) using a biotin-avidin system. Cell suspension was introduced into the reaction chamber to capture NPC cells. NPC cells were subsequently eluted, and the capture rate of the cells was calculated. The modified aptamer-bound microfluidic chip was able to capture NPC cells with a capture rate of ~90%. The modified aptamer-bound microfluidic chip has a wide range of potential applications for the diagnosis of NPC.

Concurrent chemoradiotherapy with/without induction chemotherapy in locoregionally advanced nasopharyngeal carcinoma: Long-term results of phase 3 randomized controlled trial.

To report long-term results of a randomized controlled trial that compared cisplatin/fluorouracil/docetaxel (TPF) induction chemotherapy (IC) plus concurrent chemoradiotherapy (CCRT) with CCRT alone in locoregionally advanced nasopharyngeal carcinoma (NPC). Patients with stage III-IVB (except T3-4 N0) NPC were randomly assigned to receive IC plus CCRT (n = 241) or CCRT alone (n = 239). IC included three cycles of docetaxel (60 mg/m2 d1), cisplatin (60 mg/m2 d1), and fluorouracil (600 mg/m2 /d civ d1-5) every 3 weeks. Patients from both groups received intensity-modulated radiotherapy concurrently with three cycles of 100 mg/m2 cisplatin every 3 weeks. After a median follow-up of 71.5 months, the IC plus CCRT group showed significantly better 5-year failure-free survival (FFS, 77.4% vs. 66.4%, p = 0.019), overall survival (OS, 85.6% vs. 77.7%, p = 0.042), distant failure-free survival (88% vs. 79.8%, p = 0.030), and locoregional failure-free survival (90.7% vs. 83.8%, p = 0.044) compared to the CCRT alone group. Post hoc subgroup analyses revealed that beneficial effects on FFS were primarily observed in patients with N1, stage IVA, pretreatment lactate dehydrogenase ≥170 U/l, or pretreatment plasma Epstein-Barr virus DNA ≥6000 copies/mL. Two nomograms were further developed to predict the potential FFS and OS benefit of TPF IC. The incidence of grade 3 or 4 late toxicities was 8.8% (21/239) in the IC plus CCRT group and 9.2% (22/238) in the CCRT alone group. Long-term follow-up confirmed that TPF IC plus CCRT significantly improved survival in locoregionally advanced NPC with no marked increase in late toxicities and could be an option of treatment for these patients.

Risk factors and distribution features of level IB lymph nodes metastasis in nasopharyngeal carcinoma.

OBJECTIVE: The objective of this study is to investigate the risk factors and distribution features for level IB metastasis in nasopharyngeal carcinoma (NPC) and provide clinical evidence for defining the indications and clinical target volume (CTV) of prophylactic level IB irradiation. METHODS: We retrospectively analyzed 798 patients with newly-diagnosed, non-metastatic and histologically confirmed NPC underwent intensity-modulated radiation therapy (IMRT). Two sides of neck in each patient have been analyzed separately. The correlations of level IB metastasis and the clinical risk factors were analyzed with Chi-square test and logistic regression model. The risk score model (RSM) of level IB metastasis was calculated by totaling up the scores of each independent variable. We divided level IB into three areas, including anterolateral space of submandibular glands, medial space of the submandibular glands and submandibular glands. RESULTS: Maximal axial diameter (MAD) of level IIA nodes >20mm or extra capsular spread (ES) of level IIA nodes, anterior half of nasal cavity involvement and submandibular gland involvement/compression were independently significantly risk factors for level IB lymph nodes (LNs) metastasis at diagnosis. Two groups based on RSM were obtained: low risk (total score=0-2.5); high risk (4-8.5). The incidence of IB LNs metastasis at diagnosis of the two groups were 0.9% and 6.3%, respectively (P<0.001). The cervical lymph nodes of level IB were distributed in the anterolateral space of submandibular glands. There was no positive/negative LNs inside or medial space of the submandibular glands. CONCLUSION: Level IB LNs metastasis is associated with MAD of level IIA nodes >20mm or ES of level IIA nodes, anterior half of nasal cavity involvement and submandibular gland involvement/compression in NPC patients. Omission of level IB irradiation may be feasible for patients with low-risk IB LNs metastasis at diagnosis. The submandibular gland should not be included in level IB.

Low expression of PDK1 inhibits renal cell carcinoma cell proliferation, migration, invasion and epithelial mesenchymal transition through inhibition of the PI3K-PDK1-Akt pathway.

As the most commonly occurring form of primary renal tumor, renal cell carcinoma (RCC) is a malignancy accompanied by a high mortality rate. 3-phosphoinositide-dependent protein kinase 1 (PDK1) has been established as a protein target and generated considerable interest in both the pharmaceutical and academia industry. The aim of the current study was to investigate the effect of si-PDK1 on the RCC cell apoptosis, proliferation, migration, invasion and epithelial mesenchymal transition (EMT) in connection with the PI3K-PDK1-Akt pathway. Microarray analysis from the GEO database was adopted to identify differentially expressed genes (DEGs) related to RCC, after which the positive expression of the PDK1 protein in tissue was determined accordingly. The optimal silencing si-RNA was subsequently selected and RCC cell lines 786-O and A498 were selected and transfected with either a si-PDK1 or activator of the PI3K-PDK1-Akt pathway for grouping purposes. The mRNA and protein expressions of PDK1, the PI3K-PDK1-Akt pathway-, EMT- and apoptosis-related genes were then evaluated. The effect of si-PDK1 on cell proliferation, apoptosis, invasion and migration was then analyzed. Through microarray analysis of GSE6344, GSE53757, GSE14762 and GSE781, PDK1 was examined. PDK1 was determined to be highly expressed in RCC tissues. Si-PDK1 exhibited marked reductions in relation to the mRNA and protein expression of PDK1, PI3K, AKT as well as Vimentin while elevated mRNA and protein expressions of E-cadherin were detected, which ultimately suggested that cell migration, proliferation and invasion had been inhibited coupled with enhanced levels of cell apoptosis. While a notable observation was made highlighting that the PI3K-PDK1-Akt pathway antagonized the effect of PDK1 silencing. Taken together, the key observations of this study provide evidence suggesting that high expressions of PDK1 are found in RCC, while highlighting that silencing PDK1 could inhibit RCC cell proliferation, migration, invasion and EMT by repressing the PI3K-PDK1-Akt pathway.

Patterns of Treatment Failure and Postrecurrence Outcomes Among Patients With Locally Advanced Head and Neck Squamous Cell Carcinoma After Chemoradiotherapy Using Modern Radiation Techniques.

IMPORTANCE: Even though 15% to 50% of patients with head and neck squamous cell carcinoma (HNSCC) experience recurrence, relatively little is known regarding patterns of treatment failure and postrecurrence outcomes after chemoradiotherapy using modern radiation techniques (intensity-modulated radiotherapy [IMRT]). Recurrence patterns are significantly affected by variations in the quality of radiotherapy, which may confound findings from multicenter trials. OBJECTIVE: To assess patterns of treatment failure and postrecurrence outcomes for patients with HNSCC treated with contemporary radiotherapy techniques. DESIGN, SETTING, AND PARTICIPANTS: This large single-institution cohort study reviewed the outcomes of 1000 consecutive patients with stage III to IVB oropharyngeal carcinoma (n = 703), laryngeal carcinoma (n = 126), or hypopharyngeal carcinoma (n = 46) treated with definitive IMRT with or without concurrent chemotherapy, as well as patients with oral cavity carcinoma (n = 125) treated with postoperative IMRT with or without concurrent systemic therapy, from December 1, 2001, to December 31, 2013, with a median follow-up of 65.1 months among surviving patients. Data analysis was performed from January 31, 2016, to February 17, 2017. MAIN OUTCOMES AND MEASURES: Patterns of treatment failure and overall survival following locoregional failure or distant metastasis. RESULTS: Among the 1000 patients (186 women and 814 men; mean [SD] age, 59.3 [10.8] years), there were no marginal or isolated out-of-radiation-field failures. Among subsites, the cumulative incidence of local failure was highest among patients with oral cavity carcinoma vs those with oropharyngeal carcinoma (hazard ratio, 5.2; 95% CI, 3.1-8.6; P < .001). Furthermore, patients with oral cavity carcinoma experienced significantly shorter survival following distant metastasis (hazard ratio, 3.66; 95% CI, 1.98-6.80; P < .001). Patients with oropharyngeal carcinoma positive for human papillomavirus or p16 lived longer after locoregional failure compared with patents with oropharyngeal carcinoma negative for human papillomavirus or p16 (median survival, 36.5 vs 13.6 months; P = .007) but not after distant metastasis. Salvage surgery was associated with improved overall survival following locoregional failure (hazard ratio, 0.51; 95% CI, 0.34-0.77; P = .001); oligometastatic disease (1 vs ≥2 lesions: hazard ratio, 0.32; 95% CI, 0.16-0.63; P = .001) was associated with improved overall survival following distant metastasis. CONCLUSIONS AND RELEVANCE: Overall survival after recurrence of HNSCC is influenced by the HNSCC subsite and human papillomavirus or p16 status, as well surgical and systemic interventions. An oligometastatic phenotype characterizes patients with solitary metastasis after chemoradiotherapy. These findings have important implications for clinical trial designs for HNSCC in the recurrent and oligometastatic setting.

[Decitabine Enhances the Sensitivity of Leukemia Stem Cell to Allo-NK Cell-Mediated Killing].

OBJECTIVE: To investigate the allo-NK cell-mediated killing effect enhanced by decitabine on leukemia stem cells(LSC) and the underlying mechanisms. METHODS: LSC were separated from KG1a cells by using immunomagnetic beads. Allo-NK cells were isolated and purified from PBMC of healthy donors. Cytotoxicity of allo-NK cells against LSC were measured by LDH releasing assay. The apoptosis induced by allo-NK cells in LSC and the expressions of NKG2D ligands including MICA/B and ULBP1-3 on LSC were detected by flow cytometry. RESULTS: The killing rate of allo-NK cells to LSC treated with 10 µmol/L decitabine for 24 hours was significant higher than that to LSC without treatment(60.52%±3.52% vs 22.08%±2.07%, 73.93%±2.33% vs 28. 99%±3.13%, 83.08%±1.32% vs 36.44%±2.40%, respectively)at the effector-target ratios of 5:1, 10:1, 20:1 (P<0.05). At the effector-target ratio of 10:1, decitabine significantly enhanced the apoptosis of LSC induced by allo-NK cells (7.84%±0.34% vs 3.33%±0.64%)(P<0.05). The expressions of NKG2D ligands(MICA/B,ULBP1,ULBP2,ULBP3) on LSC treated with decitabine 10 µmol/L for 24 hours were significantly increased (P<0.05). CONCLUSION: Decitabine may enhance the allo-NK cell-mediated killing effects on LSC by up-regulation of the expressions of NKG2D ligands on LSC.

Effects of gene polymorphisms in the endoplasmic reticulum stress pathway on clinical outcomes of chemoradiotherapy in Chinese patients with nasopharyngeal carcinoma.

There is considerable inter-individual variabil¬ity in chemoradiotherapy responses in nasopharyngeal carcinoma (NPC) patients receiv¬ing the same or similar treatment protocols. In this study we evaluated the association between the gene polymorphisms in endoplasmic reticulum (ER) stress pathway and chemoradiation responses in Chinese NPC patients. A total of 150 patients with histopathologically conformed NPC and treated with concurrent chemoradiotherapy were enrolled. Genotypes in ER stress pathway genes, including VCP (valosin-containing protein) rs2074549, HSP90B1 rs17034943, CANX (calnexin) rs7566, HSPA5 [heat shock protein family A (Hsp70) member 5] rs430397, CALCR (calcitonin receptor) rs2528521, and XBP1 (X-box binding protein 1) rs2269577 were analyzed by Sequenom MassARRAY system. The short-term effects of primary tumor and lymph node after radiotherapy were assessed based on the Response Evaluation Criteria in Solid Tumors (RECIST) of WHO. And acute radiation-induced toxic reactions were evaluated according to the Radiation Therapy Oncology Group or European Organization for Research and Treatment of Cancer (RTOG/EORTC). The effects of gene polymorphisms on clinical outcomes of chemoradiotherapy were assessed by chi-square test, univariate and multivariate logistic regression analyses. We found that CT and CT+CC genotypes of CANX rs7566 was significantly correlated with primary tumor treatment efficacy at 3 months after chemoradiotherapy and with occurrence of radiation-induced myelosuppression in Chinese NPC patients. CT and CT+CC genotypes of CALCR rs2528521 were significantly correlated with cervical lymph node efficacy at 3 months after chemoradiotherapy. And CC and CT+CC genotypes of VCP rs2074549 were significantly associated with occurrence of myelosuppression. In conclusion, SNPs of VCP rs2074549, CANX rs7566 and CALCR rs2528521 in ER stress pathway genes may serve as predictors for clinical outcomes of chemoradiotherapy in Chinese NPC patients.