Nutritional Status and Incidence of Radiation-Induced Oral Mucositis in Nasopharyngeal Carcinoma Patients Treated with Chemoradiotherapy.

Malnutrition is prevalent among patients with nasopharyngeal carcinoma undergoing radiotherapy. This study examined the nutritional status and incidence of radiation-induced oral mucositis (RIOM) in patients with nasopharyngeal carcinoma. A retrospective analysis was conducted to compare the incidence of RIOM, Nutritional Risk Screening (NRS) 2002 score, weight, body mass index (BMI), and hemoglobin levels in 338 patients treated with induction chemotherapy (IC) plus concurrent chemoradiotherapy (CCRT) or treated with CCRT alone. The IC + CCRT group exhibited an increase in weight and BMI but a decrease in hemoglobin levels after IC compared with baseline (p < 0.001). Both groups showed differences in weight at Week 0 and BMI at Weeks 0-2 of radiotherapy (p < 0.05). The IC + CCRT group experienced an increase in NRS 2002 scores from Week 2 to Week 6 (p < 0.05). The hemoglobin levels of the IC + CCRT group were consistently lower throughout radiotherapy (p < 0.001). However, no significant difference was observed in the incidence of RIOM between the two groups (p = 0.246). Patients treated with IC + CCRT exhibited a higher nutritional risk during radiotherapy. Although the incidence of Grade III RIOM was high, no significant difference was found between the groups.

Serum and urine metabolomics analyses reveal metabolic pathways and biomarkers in relation to nasopharyngeal carcinoma.

RATIONALE: Nasopharyngeal carcinoma (NPC) is a malignant tumor that is endemic in Southeast Asia, North Africa, and southern China. There is an urgent need for effective early diagnosis and treatment of this disease since NPC is currently often detected at advanced stages. METHODS: To reveal the underlying metabolic mechanisms and discover potential diagnostic biomarkers of NPC, we employed ultrahigh-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF-MS) and UHPLC-Q-Exactive Orbitrap MS, respectively, to analyze 54 serum samples and 54 urine samples from 27 patients with NPC and 27 healthy control individuals. RESULTS: A total of 1230 metabolites were determined in serum samples, and 181 of the 1230 metabolites were significantly changed in NPC patients. The 181 metabolites were enriched in 16 pathways, including biosynthesis of unsaturated fatty acids, cholesterol metabolism, and ferroptosis. A total of 2509 metabolites were detected in the urine samples. Among them, 179 metabolites were significantly altered in NPC patients, and these metabolites were enriched in eight pathways, including the tricarboxylic acid (TCA) cycle and caffeine metabolism. Seven metabolites, including creatinine and paraxanthine, were found to be significantly changed in both NPC serum and urine samples. Based on them, further biomarker analysis revealed that the panel of three serum metabolites, octanoylcarnitine, creatinine, and decanoyl-l-carnitine, displayed a perfect diagnostic performance (area under the curve [AUC] = 0.973) to distinguish NPC patients from controls, while the other three-metabolite biomarker panel, consisting of stachydrine, decanoyl-l-carnitine, and paraxanthine, had an AUC = 0.809 to distinguish NPC and control in urine samples. CONCLUSION: This work highlights the key metabolites and metabolic pathways disturbed in NPC and presents potential biomarkers for effective diagnosis of this disease.

Comparison of an in-house hybrid DIR method to NiftyReg on CBCT and CT images for head and neck cancer.

An in-house hybrid deformable image registration (DIR) method, which combines free-form deformation (FFD) and the viscous fluid registration method, is proposed. Its results on the planning computed tomography (CT) and the day 1 treatment cone-beam CT (CBCT) image from 68 head and neck cancer patients are compared with the results of NiftyReg, which uses B-spline FFD alone. Several similarity metrics, the target registration error (TRE) of annotated points, as well as the Dice similarity coefficient (DSC) and Hausdorff distance (HD) of the propagated organs at risk are employed to analyze their registration accuracy. According to quantitative analysis on mutual information, normalized cross-correlation, and the absolute pixel value differences, the results of the proposed DIR are more similar to the CBCT images than the NiftyReg results. Smaller TRE of the annotated points is observed in the proposed method, and the overall mean TRE for the proposed method and NiftyReg was 2.34 and 2.98 mm, respectively (p < 0.001). The mean DSC in the larynx, spinal cord, oral cavity, mandible, and parotid given by the proposed method ranged from 0.78 to 0.91, significantly higher than the NiftyReg results (ranging from 0.77 to 0.90), and the HD was significantly lower compared to NiftyReg. Furthermore, the proposed method did not suffer from unrealistic deformations as the NiftyReg did in the visual evaluation. Meanwhile, the execution time of the proposed method was much higher than NiftyReg (96.98 ± 11.88 s vs. 4.60 ± 0.49 s). In conclusion, the in-house hybrid method gave better accuracy and more stable performance than NiftyReg.

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.

A randomized, double-blind, placebo-controlled trial of probiotics to reduce the severity of oral mucositis induced by chemoradiotherapy for patients with nasopharyngeal carcinoma.

BACKGROUND: The objective of this study was to evaluate the effect of a probiotic combination on the severity of oral mucositis (OM), which is a common, unpreventable complication induced by radiochemotherapy in patients with nasopharyngeal carcinoma who undergo concurrent radiochemotherapy (CCRT). METHODS: Eligible patients (n = 99) with locally advanced nasopharyngeal carcinoma who were undergoing CCRT were randomly assigned (2:1) to receive a probiotic combination or placebo during radiochemotherapy, and the incidence of severe OM (grade 3 or higher) was the primary endpoint. RESULTS: Patients taking the probiotic combination showed a significant reduction in the severity of OM. The incidences of grade 0, 1, 2, and 3 OM in the placebo group and the probiotic combination group were 0% and 12.07%, 0% and 55.17%, 54.29% and 17.24%, and 45.71% and 15.52%, respectively. Furthermore, CCRT greatly lowered the number of immune cells, whereas the probiotic combination markedly lowered the reduction rates of CD4+ T cells (76.59% vs 52.85%; P < .05), CD8+ T cells (62.94% vs 29.76%; P < .05), and CD3+ T cells (69.72% vs 45.49%; P < .05) in an A-CCRT-P (after treatment with radiotherapy plus chemotherapy plus the probiotic combination) group. High-throughput sequencing results indicated that CCRT had obviously disturbed the intestinal diversity of patients in an A-CCRT (after treatment with radiotherapy plus chemotherapy plus a placebo) group, whereas the probiotic combination distinctly restored the microbial diversity in the A-CCRT-P group toward that of healthy people and a B-CCRT-P (before the treatment of radiotherapy plus chemotherapy plus the probiotic combination) group. CONCLUSIONS: A probiotic combination significantly enhances the immune response of patients and reduces the severity of OM through modification of gut microbiota.

Induction chemotherapy plus concurrent chemoradiotherapy versus concurrent chemoradiotherapy alone in locoregionally advanced nasopharyngeal carcinoma: a phase 3, multicentre, randomised controlled trial.

BACKGROUND: The value of adding cisplatin, fluorouracil, and docetaxel (TPF) induction chemotherapy to concurrent chemoradiotherapy in locoregionally advanced nasopharyngeal carcinoma is unclear. We aimed to compare TPF induction chemotherapy plus concurrent chemoradiotherapy with concurrent chemoradiotherapy alone in a suitably powered trial. METHODS: We did an open-label, phase 3, multicentre, randomised controlled trial at ten institutions in China. Patients with previously untreated, stage III-IVB (except T3-4N0) nasopharyngeal carcinoma, aged 18-59 years without severe comorbidities were enrolled. Eligible patients were randomly assigned (1:1) to receive induction chemotherapy plus concurrent chemoradiotherapy or concurrent chemoradiotherapy alone (three cycles of 100 mg/m2 cisplatin every 3 weeks, concurrently with intensity-modulated radiotherapy). Induction chemotherapy was three cycles of intravenous docetaxel (60 mg/m2 on day 1), intravenous cisplatin (60 mg/m2 on day 1), and continuous intravenous fluorouracil (600 mg/m2 per day from day 1 to day 5) every 3 weeks before concurrent chemoradiotherapy. Randomisation was by a computer-generated random number code with a block size of four, stratified by treatment centre and disease stage (III or IV). Treatment allocation was not masked. The primary endpoint was failure-free survival calculated from randomisation to locoregional failure, distant failure, or death from any cause; required sample size was 476 patients (238 per group). We did efficacy analyses in our intention-to-treat population. The follow-up is ongoing; in this report, we present the 3-year survival results and acute toxic effects. This trial is registered with ClinicalTrials.gov, number NCT01245959. FINDINGS: Between March 1, 2011, and Aug 22, 2013, 241 patients were assigned to induction chemotherapy plus concurrent chemoradiotherapy and 239 to concurrent chemoradiotherapy alone. After a median follow-up of 45 months (IQR 38-49), 3-year failure-free survival was 80% (95% CI 75-85) in the induction chemotherapy plus concurrent chemoradiotherapy group and 72% (66-78) in the concurrent chemoradiotherapy alone group (hazard ratio 0·68, 95% CI 0·48-0·97; p=0·034). The most common grade 3 or 4 adverse events during treatment in the 239 patients in the induction chemotherapy plus concurrent chemoradiotherapy group versus the 238 patients in concurrent chemoradiotherapy alone group were neutropenia (101 [42%] vs 17 [7%]), leucopenia (98 [41%] vs 41 [17%]), and stomatitis (98 [41%] vs 84 [35%]). INTERPRETATION: Addition of TPF induction chemotherapy to concurrent chemoradiotherapy significantly improved failure-free survival in locoregionally advanced nasopharyngeal carcinoma with acceptable toxicity. Long-term follow-up is required to determine long-term efficacy and toxicities. FUNDING: Shenzhen Main Luck Pharmaceuticals Inc, Sun Yat-sen University Clinical Research 5010 Program (2007037), National Science and Technology Pillar Program during the Twelfth Five-year Plan Period (2014BAI09B10), Health & Medical Collaborative Innovation Project of Guangzhou City (201400000001), Planned Science and Technology Project of Guangdong Province (2013B020400004), and The National Key Research and Development Program of China (2016YFC0902000).

Channel-wise attention enhanced and structural similarity constrained cycleGAN for effective synthetic CT generation from head and neck MRI images.

BACKGROUND: Magnetic resonance imaging (MRI) plays an increasingly important role in radiotherapy, enhancing the accuracy of target and organs at risk delineation, but the absence of electron density information limits its further clinical application. Therefore, the aim of this study is to develop and evaluate a novel unsupervised network (cycleSimulationGAN) for unpaired MR-to-CT synthesis. METHODS: The proposed cycleSimulationGAN in this work integrates contour consistency loss function and channel-wise attention mechanism to synthesize high-quality CT-like images. Specially, the proposed cycleSimulationGAN constrains the structural similarity between the synthetic and input images for better structural retention characteristics. Additionally, we propose to equip a novel channel-wise attention mechanism based on the traditional generator of GAN to enhance the feature representation capability of deep network and extract more effective features. The mean absolute error (MAE) of Hounsfield Units (HU), peak signal-to-noise ratio (PSNR), root-mean-square error (RMSE) and structural similarity index (SSIM) were calculated between synthetic CT (sCT) and ground truth (GT) CT images to quantify the overall sCT performance. RESULTS: One hundred and sixty nasopharyngeal carcinoma (NPC) patients who underwent volumetric-modulated arc radiotherapy (VMAT) were enrolled in this study. The generated sCT of our method were more consistent with the GT compared with other methods in terms of visual inspection. The average MAE, RMSE, PSNR, and SSIM calculated over twenty patients were 61.88 ± 1.42, 116.85 ± 3.42, 36.23 ± 0.52 and 0.985 ± 0.002 for the proposed method. The four image quality assessment metrics were significantly improved by our approach compared to conventional cycleGAN, the proposed cycleSimulationGAN produces significantly better synthetic results except for SSIM in bone. CONCLUSIONS: We developed a novel cycleSimulationGAN model that can effectively create sCT images, making them comparable to GT images, which could potentially benefit the MRI-based treatment planning.

Selectively sparing of the supraclavicular area during intensity-modulated radiotherapy in nasopharyngeal carcinoma: A double-center observation study.

BACKGROUND AND PURPOSE: This study was aimed at evaluating the feasibility of sparing the supraclavicular area, namely levels IVb and Vc, during intensity-modulated radiotherapy (IMRT) in nasopharyngeal carcinoma (NPC) patients with N1-2 disease[except N1 disease with purely restropharyngeal lymph nodes(RPN) involvement], and providing a basis for the revision of International Guideline for the delineation of the clinical target volume (CTV). PATIENTS AND MATERIALS: Patients with NPC (stage TanyN1-2M0) diagnosed pathologically in Fujian Cancer Hospital (Center 1, Only Lin SJ's attending group) from January 2014 to March 2018 and Jiangxi Cancer Hospital(Center 2) from January 2014 to December 2015 were included. According to our principle, the supraclavicular area (levels IVb and Vc) were excluded from the CTVnd. Survival outcomes focused on regional recurrence-free survival (RRFS) and recurrence rates of levels IVb and Vc were analysed. RESULTS: A total of 672 eligible patients were recruited (Center 1, n = 362; Center 2, n = 310). There was no significant difference in 5-year RRFS (97.33 % vs. 97.24 %, p = 0.980), overall survival (OS) (89.14 % vs. 88.56 %, p = 0.327), local recurrence-free survival (LRFS) (94.90 % vs. 95.30 %, p = 0.593) and distant metastasis-free survival (DMFS) (89.38 % vs. 86.60 %, p = 0.130) between Center 1 and Center 2. Twenty patients developed regional failure (median: 36 months), among them, only one case (0.15 %) was recorded as levels IVb and Vc recurrence. CONCLUSION: Omitting the supraclavicular area (levels IVb and Vc) during IMRT should be safe and feasible for N1-2 disease (except N1 disease with purely RPN involvement). Well-designed multicenter prospective trials should be conducted to confirm our findings.

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.

A randomized clinical trial comparing prophylactic upper versus whole-neck irradiation in the treatment of patients with node-negative nasopharyngeal carcinoma.

BACKGROUND: This study sought to compare the clinical outcomes of upper versus whole-neck prophylactic irradiation in the treatment of patients with node-negative nasopharyngeal carcinoma (NPC). METHODS: Between November 2005 and June 2012, 301 patients with node-negative NPC were randomly assigned to receive primary plus prophylactic upper neck irradiation (UNI, 153 patients) or primary plus whole-neck irradiation (WNI, 148 patients). Patients in both groups received irradiation to the primary tumor and the upper neck nodal regions, and patients in the WNI group also received irradiation to the lower neck. The main endpoint of the study was to compare the lower neck control rate between the 2 groups. RESULTS: With a median follow-up period of 39 months (range, 6-84 months), no patient in either group had a cervical node relapse. The overall survival at 3 years was 89.5% (95% confidence interval [CI] = 84.1%-95.0%) in the UNI group and 87.4% (95% CI = 81.4%-93.5%) in the WNI group (hazard ratio [HR] = 0.866, 95% CI = 0.41-1.82; P = .70). The 3-year relapse-free survival rate was 89.8% and 89.3% (95% CI = 84.2%-95.3% and 83.7%-94.8%, HR = 0.914, 95% CI = 0.42-2.00; P = .82), and the 3-year metastasis-free survival rate was 91.7% and 90.9% (95% CI = 87.0%-96.5% and 85.7%-96.1%) for the UNI and WNI groups, respectively (HR = 1.007, 95% CI = 0.44-2.32; P = .99). CONCLUSIONS: Prophylactic upper neck irradiation is sufficient for patients with node-negative NPC.

Impaired geriatric 8 score is associated with worse survival after radical intensity modulated radiation therapy in elderly patients with nasopharyngeal carcinoma.

BACKGROUND: Geriatric 8 score (G8) was an independent prognostic factor for survival and toxicities in various malignancies, but it has never been tested in nasopharyngeal carcinoma (NPC). OBJECTIVES: To evaluate the value of G8 in predicting survival in elderly patients with NPC. MATERIAL AND METHODS: Patients with NPC aged ≥70 who received intensity-modulated radiation therapy were recruited into this study. The overall survival (OS), progression-free survival (PFS), locoregional recurrence rate (LRR), and distant metastasis rate (DMR) between the patients with G8 > 14 and G8 ≤ 14 were calculated using the Kaplan-Meier method and compared with the Log-rank test. Cox proportional hazards model was applied to perform univariate and multivariate analysis. RESULTS: G8 ≤ 14 had significantly reduced OS (p = .001) and PFS (p = .032) than those with G8 > 14 by log-rank test. G8 score remained an independent prognosticator for OS (HR = 0.490, 95% CI = 0.267-0.900, p = .021) and was a borderline significance towards PFS (HR = 0.639, 95% CI = 0.386-1.058, p = .082) in multivariate analysis. Grade 3-4 acute toxicities were significantly more common in patients with G8 ≤ 14 than in those with G8 > 14. CONCLUSIONS AND SIGNIFICANCE: G8 is useful in predicting the OS in elderly patients with NPC. Further prospective study stratified by G8 is needed to explore the value of CT in elderly patients with NPC.

Multi-isocenter VMAT craniospinal irradiation using feasibility dose-volume histogram-guided auto-planning technique.

This study aims to propose a novel treatment planning methodology for multi-isocenter volumetric modulated arc therapy (VMAT) craniospinal irradiation (CSI) using the special feasibility dose-volume histogram (FDVH)-guided auto-planning (AP) technique. Three different multi-isocenter VMAT -CSI plans were created, including manually based plans (MUPs), conventional AP plans (CAPs) and FDVH-guided AP plans (FAPs). The CAPs and FAPs were specially designed by combining multi-isocenter VMAT and AP techniques in the Pinnacle treatment planning system. Specially, the personalized optimization parameters for FAPs were generated using the FDVH function implemented in PlanIQ software, which provides the ideal organs at risk (OARs) sparing for the specific anatomical geometry based on the valuable assumption of the dose fall-off. Compared to MUPs, CAPs and FAPs significantly reduced the dose for most of the OARs. FAPs achieved the best homogeneity index (0.092 ± 0.013) and conformity index (0.980 ± 0.011), while CAPs were slightly inferior to the FAPs but superior to the MUPs. As opposed to MUPs, FAPs delivered a lower dose to OARs, whereas the difference between FAPs and CAPs was not statistically significant except for the optic chiasm and inner ear_L. The two AP approaches had similar MUs, which were significantly lower than the MUPs. The planning time of FAPs (145.00 ± 10.25 min) was slightly lower than that of CAPs (149.83 ± 14.37 min) and was substantially lower than that of MUPs (157.92 ± 16.11 min) with P < 0.0167. Overall, introducing the multi-isocenter AP technique into VMAT-CSI yielded positive outcomes and may play an important role in clinical CSI planning in the future.

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.

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.

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.

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.

A Signature of N6-methyladenosine Regulator-Related Genes Predicts Prognoses and Immune Responses for Head and Neck Squamous Cell Carcinoma.

This study aimed to construct a signature of N6-methyladenosine (m6A) regulator-related genes that could be used for the prognosis of head and neck squamous cell carcinoma (HNSCC) and to clarify the molecular and immune characteristics and benefits of immune checkpoint inhibitor (ICI) therapy using the prognostic signature to define the subgroups of HNSCC. This study showed that eighteen m6A regulators were abnormally expressed in the Cancer Genome Atlas (TCGA) HNSCC tissues compared with those in normal tissues. We constructed a signature of 12 m6A regulator-related genes using the Cox risk model, combined with the least absolute shrinkage and selection operator (Lasso) variable screening algorithm. Based on the median of the signature risk score, the patients were divided into high- and low-risk groups. The Kaplan-Meier survival analyses showed that patients with high-risk scores demonstrated poorer overall survival (OS) than those with low-risk scores based on TCGA-HNSCC data (p <0.001). The OS of high-risk patients was significantly worse than that of low-risk patients in the GSE65858 (p <0.001) and International Cancer Genome Consortium (ICGC) oral cancer cohorts (p = 0.0089). Furthermore, immune infiltration analyses showed that 8 types of immune cell infiltration showed highly significant differences between the two risk groups (p <0.001). In the Imvigor210CoreBiologies dataset of patients who received ICIs, the objective response rate (ORR) of the low-risk group (32%) was significantly higher than that of the high-risk group (13%). Additionally, patients in the high-risk group presented with a more significant adverse OS than that of the low-risk group (p = 0.00032). GSE78220 also showed that the ORR of the low-risk group (64%) was higher than that of the high-risk group (43%) and the OS of low-risk patients was better than that of high-risk patients (p = 0.0064). The constructed prognostic signature, based on m6A regulator-related genes, could be used to effectively distinguish between prognoses for HNSCC patients. The prognostic signature was found to be related to the immune cell infiltration of HNSCC; it might help predict the responses and prognoses of ICIs during treatment.

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.

High Expression of Hyaluronan-Mediated Motility Receptor Predicts Adverse Outcomes: A Potential Therapeutic Target for Head and Neck Squamous Cell Carcinoma.

Background: Several studies have shown that the hyaluronan-mediated motility receptor (HMMR) is overexpressed in various cancers and could be a potential prognostic factor. However, further research is still required to determine the prognostic value and potential function of HMMR in head and neck squamous cell carcinoma (HNSCC). Materials and Methods: Transcriptomic expression data were collected from the Cancer Genome Atlas database (TCGA) and Gene Expression Omnibus and the differences in HMMR expression between normal and tumor tissues were analyzed. The correlation between the methylation level of HMMR and its mRNA expression was analyzed via cBioPortal. Additionally, the data obtained from TCGA was analyzed with MethSurv to determine the prognostic value of the HMMR methylation levels in HNSCC. Gene set enrichment analysis (GSEA) and single sample GSEA (ssGSEA) were used to explore the potential biological functions of HMMR. Results: HMMR was highly expressed in HNSCC tumor tissue compared to normal tissue (p < 0.001). Multivariate analysis (MAV) showed that high HMMR mRNA expression was an independent prognostic factor of overall survival (OS) in TCGA (HR = 1.628, 95% CI: 1.169-2.266, p = 0.004) and GSE41613 data (HR = 2.238, p = 0.013). The methylation level of HMMR negatively correlated with the HMMR expression (R = -0.12, p < 0.001), and patients with low HMMR methylation had worse OS than patients with high methylation (p < 0.001). GSEA found that HMMR expression was associated with the KARS, EMT, and G2M checkpoint pathways, as well as the interferon-gamma and interferon-alpha responses, whereas ssGSEA showed that HMMR expression positively correlated with the infiltration level of Th2 cells. MAV confirmed that high HMMR protein expression was an inferior independent factor for OS (HR = 2.288, p = 0.045) and progression-free survival (HR = 2.247, p = 0.038) in 70 HNSCC. Conclusions: This study demonstrated that the upregulation of HMMR mRNA and protein in HNSCC is a biomarker for poor prognosis. The biological functions of HMMR are potentially related to the KARS, EMT, and G2M checkpoint pathways, as well as the interferon-gamma and interferon-alpha responses. These findings help to elucidate the role of HMMR in carcinogenesis and lay a foundation for further study.