Induction-concurrent chemoradiotherapy with or without sintilimab in patients with locoregionally advanced nasopharyngeal carcinoma in China (CONTINUUM): a multicentre, open-label, parallel-group, randomised, controlled, phase 3 trial.

BACKGROUND: Anti-PD-1 therapy and chemotherapy is a recommended first-line treatment for recurrent or metastatic nasopharyngeal carcinoma, but the role of PD-1 blockade remains unknown in patients with locoregionally advanced nasopharyngeal carcinoma. We assessed the addition of sintilimab, a PD-1 inhibitor, to standard chemoradiotherapy in this patient population. METHODS: This multicentre, open-label, parallel-group, randomised, controlled, phase 3 trial was conducted at nine hospitals in China. Adults aged 18-65 years with newly diagnosed high-risk non-metastatic stage III-IVa locoregionally advanced nasopharyngeal carcinoma (excluding T3-4N0 and T3N1) were eligible. Patients were randomly assigned (1:1) using blocks of four to receive gemcitabine and cisplatin induction chemotherapy followed by concurrent cisplatin radiotherapy (standard therapy group) or standard therapy with 200 mg sintilimab intravenously once every 3 weeks for 12 cycles (comprising three induction, three concurrent, and six adjuvant cycles to radiotherapy; sintilimab group). The primary endpoint was event-free survival from randomisation to disease recurrence (locoregional or distant) or death from any cause in the intention-to-treat population. Secondary endpoints included adverse events. This trial is registered with ClinicalTrials.gov (NCT03700476) and is now completed; follow-up is ongoing. FINDINGS: Between Dec 21, 2018, and March 31, 2020, 425 patients were enrolled and randomly assigned to the sintilimab (n=210) or standard therapy groups (n=215). At median follow-up of 41·9 months (IQR 38·0-44·8; 389 alive at primary data cutoff [Feb 28, 2023] and 366 [94%] had at least 36 months of follow-up), event-free survival was higher in the sintilimab group compared with the standard therapy group (36-month rates 86% [95% CI 81-90] vs 76% [70-81]; stratified hazard ratio 0·59 [0·38-0·92]; p=0·019). Grade 3-4 adverse events occurred in 155 (74%) in the sintilimab group versus 140 (65%) in the standard therapy group, with the most common being stomatitis (68 [33%] vs 64 [30%]), leukopenia (54 [26%] vs 48 [22%]), and neutropenia (50 [24%] vs 46 [21%]). Two (1%) patients died in the sintilimab group (both considered to be immune-related) and one (<1%) in the standard therapy group. Grade 3-4 immune-related adverse events occurred in 20 (10%) patients in the sintilimab group. INTERPRETATION: Addition of sintilimab to chemoradiotherapy improved event-free survival, albeit with higher but manageable adverse events. Longer follow-up is necessary to determine whether this regimen can be considered as the standard of care for patients with high-risk locoregionally advanced nasopharyngeal carcinoma. FUNDING: National Natural Science Foundation of China, Key-Area Research and Development Program of Guangdong Province, Natural Science Foundation of Guangdong Province, Overseas Expertise Introduction Project for Discipline Innovation, Guangzhou Municipal Health Commission, and Cancer Innovative Research Program of Sun Yat-sen University Cancer Center. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

MRI-based radiomic models to predict surgical margin status and infer tumor immune microenvironment in breast cancer patients with breast-conserving surgery: a multicenter validation study.

OBJECTIVES: Accurate preoperative estimation of the risk of breast-conserving surgery (BCS) resection margin positivity would be beneficial to surgical planning. In this multicenter validation study, we developed an MRI-based radiomic model to predict the surgical margin status. METHODS: We retrospectively collected preoperative breast MRI of patients undergoing BCS from three hospitals (SYMH, n = 296; SYSUCC, n = 131; TSPH, n = 143). Radiomic-based model for risk prediction of the margin positivity was trained on the SYMH patients (7:3 ratio split for the training and testing cohorts), and externally validated in the SYSUCC and TSPH cohorts. The model was able to stratify patients into different subgroups with varied risk of margin positivity. Moreover, we used the immune-radiomic models and epithelial-mesenchymal transition (EMT) signature to infer the distribution patterns of immune cells and tumor cell EMT status under different marginal status. RESULTS: The AUCs of the radiomic-based model were 0.78 (0.66-0.90), 0.88 (0.79-0.96), and 0.76 (0.68-0.84) in the testing cohort and two external validation cohorts, respectively. The actual margin positivity rates ranged between 0-10% and 27.3-87.2% in low-risk and high-risk subgroups, respectively. Positive surgical margin was associated with higher levels of EMT and B cell infiltration in the tumor area, as well as the enrichment of B cells, immature dendritic cells, and neutrophil infiltration in the peritumoral area. CONCLUSIONS: This MRI-based predictive model can be used as a reliable tool to predict the risk of margin positivity of BCS. Tumor immune-microenvironment alteration was associated with surgical margin status. CLINICAL RELEVANCE STATEMENT: This study can assist the pre-operative planning of BCS. Further research on the tumor immune microenvironment of different resection margin states is expected to develop new margin evaluation indicators and decipher the internal mechanism. KEY POINTS: • The MRI-based radiomic prediction model (CSS model) incorporating features extracted from multiple sequences and segments could estimate the margin positivity risk of breast-conserving surgery. • The radiomic score of the CSS model allows risk stratification of patients undergoing breast-conserving surgery, which could assist in surgical planning. • With the help of MRI-based radiomics to estimate the components of the immune microenvironment, for the first time, it is found that the margin status of breast-conserving surgery is associated with the infiltration of immune cells in the microenvironment and the EMT status of breast tumor cells.

Value of radiological depth of invasion in non-pT4 Oral tongue squamous cell carcinoma: implication for preoperative MR T-staging.

OBJECTIVE: The prognostic stratification for oral tongue squamous cell carcinoma (OTSCC) is heavily based on postoperative pathological depth of invasion (pDOI). This study aims to propose a preoperative MR T-staging system based on tumor size for non-pT4 OTSCC. METHODS: Retrospectively, 280 patients with biopsy-confirmed, non-metastatic, pT1-3 OTSCC, treated between January 2010 and December 2017, were evaluated. Multiple MR sequences, including axial T2-weighted imaging (WI), unenhanced T1WI, and axial, fat-suppressed coronal, and sagittal contrast-enhanced (CE) T1WI, were utilized to measure radiological depth of invasion (rDOI), tumor thickness, and largest diameter. Intra-class correlation (ICC) and univariate and multivariate analyses were used to evaluate measurement reproducibility, and factors' significance, respectively. Cutoff values were established using an exhaustive method. RESULTS: Intra-observer (ICC = 0.81-0.94) and inter-observer (ICC = 0.79-0.90) reliability were excellent for rDOI measurements, and all measurements were significantly associated with overall survival (OS) (all p < .001). Measuring the rDOI on axial CE-T1WI with cutoffs of 8 mm and 12 mm yielded an optimal MR T-staging system for rT1-3 disease (5-year OS of rT1 vs rT2 vs rT3: 94.0% vs 72.8% vs 57.5%). Using multivariate analyses, the proposed T-staging exhibited increasingly worse OS (hazard ratio of rT2 and rT3 versus rT1, 3.56 [1.35-9.6], p = .011; 4.33 [1.59-11.74], p = .004; respectively), which outperformed pathological T-staging based on nonoverlapping Kaplan-Meier curves and improved C-index (0.682 vs. 0.639, p < .001). CONCLUSIONS: rDOI is a critical predictor of OTSCC mortality and facilitates preoperative prognostic stratification, which should be considered in future oral subsite MR T-staging. CLINICAL RELEVANCE STATEMENT: Utilizing axial CE-T1WI, an MR T-staging system for non-pT4 OTSCC was developed by employing rDOI measurement with optimal thresholds of 8 mm and 12 mm, which is comparable with pathological staging and merits consideration in future preoperative oral subsite planning. KEY POINTS: • Tumor morphology, measuring sequences, and observers could impact MR-derived measurements and compromise the consistency with histology. • MR-derived measurements, including radiological depth of invasion (rDOI), tumor thickness, and largest diameter, have a prognostic impact on OS (all p < .001). • rDOI with cutoffs of 8 mm and 12 mm on axial CE-T1WI is an optimal predictor of OS and could facilitate risk stratification in non-pT4 OTSCC disease.

Radiomics-based nomogram guides adaptive de-intensification in locoregionally advanced nasopharyngeal carcinoma following induction chemotherapy.

OBJECTIVES: This study aimed to construct a radiomics-based model for prognosis and benefit prediction of concurrent chemoradiotherapy (CCRT) versus intensity-modulated radiotherapy (IMRT) in locoregionally advanced nasopharyngeal carcinoma (LANPC) following induction chemotherapy (IC). MATERIALS AND METHODS: A cohort of 718 LANPC patients treated with IC + IMRT or IC + CCRT were retrospectively enrolled and assigned to a training set (n = 503) and a validation set (n = 215). Radiomic features were extracted from pre-IC and post-IC MRI. After feature selection, a delta-radiomics signature was built with LASSO-Cox regression. A nomogram incorporating independent clinical indicators and the delta-radiomics signature was then developed and evaluated for calibration and discrimination. Risk stratification by the nomogram was evaluated with Kaplan-Meier methods. RESULTS: The delta-radiomics signature, which comprised 19 selected features, was independently associated with prognosis. The nomogram, composed of the delta-radiomics signature, age, T category, N category, treatment, and pre-treatment EBV DNA, showed great calibration and discrimination with an area under the receiver operator characteristic curve of 0.80 (95% CI 0.75-0.85) and 0.75 (95% CI 0.64-0.85) in the training and validation sets. Risk stratification by the nomogram, excluding the treatment factor, resulted in two groups with distinct overall survival. Significantly better outcomes were observed in the high-risk patients with IC + CCRT compared to those with IC + IMRT, while comparable outcomes between IC + IMRT and IC + CCRT were shown for low-risk patients. CONCLUSION: The radiomics-based nomogram can predict prognosis and survival benefits from concurrent chemotherapy for LANPC following IC. Low-risk patients determined by the nomogram may be potential candidates for omitting concurrent chemotherapy during IMRT. CLINICAL RELEVANCE STATEMENT: The radiomics-based nomogram was constructed for risk stratification and patient selection. It can help guide clinical decision-making for patients with locoregionally advanced nasopharyngeal carcinoma following induction chemotherapy, and avoid unnecessary toxicity caused by overtreatment. KEY POINTS: • The benefits from concurrent chemotherapy remained controversial for locoregionally advanced nasopharyngeal carcinoma following induction chemotherapy. • Radiomics-based nomogram achieved prognosis and benefits prediction of concurrent chemotherapy. • Low-risk patients defined by the nomogram were candidates for de-intensification.

Optimal Size Threshold for MRI-Detected Retropharyngeal Lymph Nodes to Predict Outcomes in Nasopharyngeal Carcinoma: A Two-Center Study.

BACKGROUND. Retropharyngeal lymph node (RLN) metastases have profound prognostic implications in patients with nasopharyngeal carcinoma (NPC). However, the AJCC staging system does not specify a size threshold for determining RLN involvement, resulting in inconsistent thresholds in practice. OBJECTIVE. The purpose of this article was to determine the optimal size threshold for determining the presence of metastatic RLNs on MRI in patients with NPC, in terms of outcome predictions. METHODS. This retrospective study included 1752 patients (median age, 46 years; 1297 men, 455 women) with NPC treated by intensity-modulated radiotherapy (RT) from January 2010 to March 2014 from two hospitals; 438 patients underwent MRI 3-4 months after treatment. Two radiologists measured the minimal axial diameter (MAD) of the largest RLN for each patient using a consensus process. A third radiologist measured MAD in 260 randomly selected patients to assess interobserver agreement. Initial ROC and restricted cubic spline (RCS) analyses were used to derive an optimal MAD threshold for predicting progression-free survival (PFS). The threshold's predictive utility was assessed in multivariable Cox regression analyses, controlling for standard clinical predictors. The threshold's utility for predicting PFS and overall survival (OS) was compared with a 5-mm threshold using Kaplan-Meier curves and log-rank tests. RESULTS. The intraclass correlation coefficient for MAD was 0.943. ROC and RCS analyses yielded an optimal threshold of 6 mm. In multivariable analyses, MAD of 6 mm and greater independently predicted PFS in all patients (HR = 1.35, p = .02), patients with N0 or N1 disease (HR = 1.80, p = .008), and patients who underwent posttreatment MRI (HR = 1.68, p = .04). In patients with N1 disease without cervical lymph node involvement, 5-year PFS was worse for MAD greater than or equal to 6 mm than for MAD that was greater than or equal to 5 mm but less than 6 mm (77.2% vs 89.7%, p = .03). OS was significantly different in patients with stage I and stage II disease defined using a 6-mm threshold (p = .04), but not using a 5-mm threshold (p = .09). The 5-year PFS rate was associated with a post-RT MAD of 6 mm and greater (HR = 1.68, p = .04) but not a post-RT MAD greater than or equal to 5 mm (HR = 1.09, p = .71). CONCLUSION. The findings support a threshold MAD of 6 mm for determining RLN involvement in patients with NPC. CLINICAL IMPACT. Future AJCC staging updates should consider incorporation of the 6-mm threshold for N-category and tumor-stage determinations.

Integrating Postradiotherapy MRI-Detected Lymph Node Necrosis and Pre- and Posttreatment Epstein-Barr Virus-DNA for Risk Stratification in Nasopharyngeal Carcinoma.

BACKGROUND: Residual lymphadenopathy and detectable Epstein-Barr virus (EBV) DNA after radiotherapy (RT) are known negative prognostic factors for nasopharyngeal carcinoma (NPC). However, there is a need to distinguish between patients with residual disease that will metastasize and those who will not. PURPOSE: To develop a prognostic model to improve the risk stratification of NPC patients after RT. STUDY TYPE: Retrospective. POPULATION: Three hundred eighty-seven NPC patients treated with RT between January 2010 and January 2013. FIELD STRENGTH/SEQUENCE: T1-, T2-weighted and enhanced T1-weighted imaging at 1.5 or 3.0 T pretreatment and 3-4 months post-RT. ASSESSMENT: Post-RT central nodal necrosis (CNN) and other nodal characteristics on MRI were assessed by three radiologists independently. EBV DNA was measured by quantitative polymerase chain reaction. The association between these variables and the primary endpoint (5-year distant metastasis-free survival [DMFS], time from the day of diagnosis to any distant metastasis) was analyzed. Nomograms A (pre-/posttreatment EBV-DNA + N stage + post-RT retropharyngeal lymph node [RLN] CNN), B (tumor-node-metastasis [TNM] stage + pretreatment EBV-DNA), and C (TNM stage + post-RT EBV-DNA) were developed. STATISTICAL TESTS: Univariate and multivariate analyses were performed with the Cox regression model. Nomograms were developed based on the Cox regression model and two prognostic models. The concordance index (C-index) and calibration curve were used to evaluate the discriminative ability of the nomograms and TNM stage. P-values < 0.05 were considered statistically significant. RESULTS: Post-RT RLN CNN was an independent prognostic factor for 5-year DMFS (hazard ratio, 2.88 [1.48-5.62]). Nomogram A (C-index 0.728 [0.660-0.797]) demonstrated better risk discrimination than nomogram B (0.638 [0.571-0.705]), nomogram C (0.707 [0.636-0.778]), and the TNM stage (0.587 [0.515-0.659]) for 5-year DMFS in NPC. DATA CONCLUSION: Nomogram A combining pretreatment EBV-DNA and N stage with post-RT EBV-DNA and RLN CNN improved the prognostic risk stratification for DMFS in NPC. EVIDENCE LEVEL: 4 TECHNICAL EFFICACY: Stage 2.

MRI-Based Metastatic Nodal Number and Associated Nomogram Improve Stratification of Nasopharyngeal Carcinoma Patients: Potential Indications for Individual Induction Chemotherapy.

BACKGROUND: Metastatic lymph nodal number (LNN) is associated with the survival of nasopharyngeal carcinoma (NPC); however, counting multiple nodes is cumbersome. PURPOSE: To explore LNN threshold and evaluate its use in risk stratification and induction chemotherapy (IC) indication. STUDY TYPE: Retrospective. POPULATION: A total of 792 radiotherapy-treated NPC patients (N classification: N0 182, N1 438, N2 113, N3 59; training group: 396, validation group: 396; receiving IC: 390). FIELD STRENGTH/SEQUENCE: T1-, T2- and postcontrast T1-weighted fast spin echo MRI at 1.5 or 3.0 T. ASSESSMENT: Nomogram with (model B) or without (model A) LNN was constructed to evaluate the 5-year overall (OS), distant metastasis-free (DMFS), and progression-free survival (PFS) for the group as a whole and N1 stage subgroup. High- and low-risk groups were divided (above vs below LNN- or model B-threshold); their response to IC was evaluated among advanced patients in stage III/IV. STATISTICAL TESTS: Maximally selected rank, univariate and multivariable Cox analysis identified the optimal LNN threshold and other variables. Harrell's concordance index (C-index) and 2-fold cross-validation evaluated discriminative ability of models. Matched-pair analysis compared survival outcomes of adding IC or not. A P value < 0.05 was considered statistically significant. RESULTS: Median follow-up duration was 62.1 months. LNN ≥ 4 was independently associated with decreased 5-year DMFS, OS, and PFS in entire patients or N1 subgroup. Compared to model A, model B (adding LNN, LNN ≥ 4 vs <4) presented superior C-indexes in the training (0.755 vs 0.727) and validation groups (0.676 vs 0.642) for discriminating DMFS. High-risk patients benefited from IC with improved post-IC response and OS, but low-risk patients did not (P = 0.785 and 0.690, respectively). CONCLUSIONS: LNN ≥ 4 is an independent risk stratification factor of worse survival in entire or N1 staging NPC patients. LNN ≥ 4 or the associated nomogram has potential to identify high-risk patients requiring IC. EVIDENCE LEVEL: 4 TECHNICAL EFFICACY: 4.

Prognostic value of quantitative cervical nodal necrosis burden on MRI in nasopharyngeal carcinoma and its role as a stratification marker for induction chemotherapy.

OBJECTIVES: This study aimed to assess the prognostic value of quantitative cervical nodal necrosis (CNN) burden in N staging risk stratification in patients with nasopharyngeal carcinoma. METHODS: Univariate and multivariate Cox regression models evaluated the association between lymph node variables based on MRI images and survival. Revisions for the N classification system were proposed and compared to the 8th edition AJCC staging system using Harrell's concordance index (C-index). The survival outcomes of induction chemotherapy plus concurrent chemoradiotherapy (CCRT) and CCRT alone in patients with multiple CNNs were compared. RESULTS: In 1319 patients enrolled, CNN was not an independent prognostic factor for the main survival outcomes, but multiple CNNs (three or more necrotic nodes) were independent prognostic factors for distant metastasis-free survival (DMFS) (adjusted hazard ratio [HR], 2.05; p = 0.020) and progression-free survival (PFS) (HR, 1.78; p = 0.004), surpassing other nodal variables. On upgrading patients with multiple CNNs to revised N3 disease, the proposed N staging widened the differences in DMFS and PFS between N2 and N3 disease. The overall survival of patients with multiple CNNs who received CCRT plus induction chemotherapy was improved compared to that of those who received CCRT alone (76.1% vs. 55.7%; adjusted p = 0.030). CONCLUSIONS: Upgrading patients with multiple CNNs to stage N3 may improve prognostication of the current AJCC staging system. Multiple CNNs might be a potential marker for stratifying patients who would benefit from induction chemotherapy. KEY POINTS: • Quantitatively assessed the prognostic value of CNN burden in patients with NPC. • Upgrading patients with multiple CNNs to stage N3 may improve prognostication. • Multiple CNNs may be used as a stratification marker for induction chemotherapy.

Value of skull base invasion subclassification in nasopharyngeal carcinoma: implication for prognostic stratification and use of induction chemotherapy.

OBJECTIVES: Prognoses for nasopharyngeal carcinoma (NPC) between categories T2 and T3 in the Eighth American Joint Committee on Cancer (AJCC) staging system were overlapped. We explored the value of skull base invasion (SBI) subclassification in prognostic stratification and use of induction chemotherapy (IC) to optimize T2/T3 categorization for NPC patients. METHODS: We retrospectively reviewed 1752 NPC patients from two hospitals. Eight skull base bone structures were evaluated. Survival differences were compared between slight SBI (T3 patients with pterygoid process and/or base of the sphenoid bone invasion only) and severe SBI (T3 patients with other SBIs) with or without IC using random matched-pair analysis. We calculated the prognosis and Harrel concordance index (C-index) for the revised T category and compared IC outcomes for the revised tumor stages. RESULTS: Compared to severe SBI, slight SBI showed better 5-year overall survival (OS) (81.5% vs. 92.3%, p = 0.001) and progression-free survival (PFS) (71.5% vs. 83.0%, p = 0.002). Additional IC therapy did not significantly improve OS and PFS in slight SBI. The proposed T category separated OS, PFS, and locoregional recurrence-free survival in T2 and T3 categories with statistical significance. An improved C-index for OS prediction was observed in the proposed T category with combined confounding factors, compared to the AJCC T staging system (0.725 vs. 0.713, p = 0.046). The survival benefits of IC were more obvious in the advanced stage. CONCLUSIONS: NPC patients with slight SBI were recommended to downstage to T2 category. The adjustment for T category enabled better prognostic stratification and guidance for IC use. KEY POINTS: • For nasopharyngeal carcinoma (NPC) patients in T3 category, slight skull base invasion was a significant positive predictor for OS and PFS. • NPC patients with slight SBI might not gain significant survival benefits from induction chemotherapy. • Downstaging slight SBI NPC patients to T2 category would make a more accurate risk stratification, improve the predicting performance in OS, and have a better guidance in the use of IC for patients in advanced stage.

MRI of nasopharyngeal carcinoma: parapharyngeal subspace involvement has prognostic value and influences T-staging in the IMRT era.

OBJECTIVES: To identify the prognosis of parapharyngeal space involvement (PPSI) based on the number of subspaces involved (pre-styloid space, carotid space (CS), areas outside the CS) and explore its significance for current T-staging in patients with nasopharyngeal carcinoma (NPC). METHODS: PPSI was retrospectively identified in 1224 patients with non-disseminated NPC at two centers on MRI and separated into four invasion patterns: pattern A (only post-styloid space), pattern B (post-styloid space, CS extension), pattern C (post-styloid space, pre-styloid space extension), and pattern D (all spaces). The Kaplan-Meier analysis and multivariate Cox regression models were used. RESULTS: PPSI was diagnosed in 63.4% of cases, with patterns A, B, C, and D in 14.3%, 3.8%, 25.3%, and 18.6% of cases, respectively. No prognostic heterogeneity was observed between pattern B and pattern C (p > 0.05). Thus, the degree of PPSI was based on the number of subspaces involved: grade 0 (none), grade 1 (one), grade 2 (two), and grade 3 (three), which could independently predict overall survival (OS) (p < 0.001). T3 patients with grade 0/1 PPSI (slight-T3) had a better prognosis than those with grade 2/3 PPSI (severe-T3) in terms of OS, locoregional-free survival (LRFS), and progression-free survival (PFS) (all p < 0.001), whose hazard ratios were higher and lower than those with T1 and T2, respectively. Combining the T2 and slight-T3 groups as the proposed T2 provided significant differences in OS, LRFS, and PFS between T2 and T3 (all p < 0.05). CONCLUSIONS: The risk of death increased with the number of parapharyngeal subspaces involved. The degree of PPSI is recommended to optimize T3 heterogeneity. KEY POINTS: • Parapharyngeal space involvement was proposed to differentiate patient risk groups based on the number of involved subspaces: grade 0 (none), grade 1 (one), grade 2 (two), or grade 3 (three). • The degree of parapharyngeal space involvement was an independent negative prognosticator for OS. • The degree of parapharyngeal space involvement may influence T-staging in patients with nasopharyngeal carcinoma.

Predicting response to immunotherapy plus chemotherapy in patients with esophageal squamous cell carcinoma using non-invasive Radiomic biomarkers.

OBJECTIVES: To develop and validate a radiomics model for evaluating treatment response to immune-checkpoint inhibitor plus chemotherapy (ICI + CT) in patients with advanced esophageal squamous cell carcinoma (ESCC). METHODS: A total of 64 patients with advance ESCC receiving first-line ICI + CT at two centers between January 2019 and June 2020 were enrolled in this study. Both 2D ROIs and 3D ROIs were segmented. ComBat correction was applied to minimize the potential bias on the results due to different scan protocols. A total of 788 features were extracted and radiomics models were built on corrected/uncorrected 2D and 3D features by using 5-fold cross-validation. The performance of the radiomics models was assessed by its discrimination, calibration and clinical usefulness with independent validation. RESULTS: Five features and support vector machine algorithm were selected to build the 2D uncorrected, 2D corrected, 3D uncorrected and 3D corrected radiomics models. The 2D radiomics models significantly outperformed the 3D radiomics models in both primary and validation cohorts. When ComBat correction was used, the performance of 2D models was better (p = 0.0059) in the training cohort, and significantly better (p < 0.0001) in the validation cohort. The 2D corrected radiomics model yielded the optimal performance and was used to build the nomogram. The calibration curve of the radiomics model demonstrated good agreement between prediction and observation and the decision curve analysis confirmed the clinical utility. CONCLUSIONS: The easy-to-use 2D corrected radiomics model could facilitate noninvasive preselection of ESCC patients who would benefit from ICI + CT.

Differences in Radiomics Signatures Between Patients with Early and Advanced T-Stage Nasopharyngeal Carcinoma Facilitate Prognostication.

BACKGROUND: Accurately predicting the risk of death, recurrence, and metastasis of patients with nasopharyngeal carcinoma (NPC) is potentially important for personalized diagnosis and treatment. Survival outcomes of patients vary greatly in distinct stages of NPC. Prognostic models of stratified patients may aid in prognostication. PURPOSE: To explore the prognostic performance of MRI-based radiomics signatures in stratified patients with NPC. STUDY TYPE: Retrospective. POPULATION: Seven hundred and seventy-eight patients with NPC (T1-2 stage: 298, T3-4 stage: 480; training cohort: 525, validation cohort: 253). FIELD STRENGTH/SEQUENCE: Fast-spin echo (FSE) axial T1-weighted images, FSE axial T2-weighted images, contrast-enhanced FSE axial T1-weighted images at 1.5 T or 3.0 T. ASSESSMENT: Radiomics signatures, clinical nomograms, and radiomics nomograms combining the radiomic score (Radscore) and clinical factors for predicting progression-free survival (PFS) were constructed on T1-2 stage patient cohort (A), T3-4 stage patient cohort (B), and the entire dataset (C). STATISTICAL TESTS: Least absolute shrinkage and selection operator (LASSO) method was applied for radiomics modeling. Harrell's concordance indices (C-index) were employed to evaluate the predictive power of each model. RESULTS: Among 4,410 MRI-extracted features, we selected 16, 16, and 14 radiomics features most relevant to PFS for Models A, B, and C, respectively. Only 0, 1, and 4 features were found overlapped between models A/B, A/C, and B/C, respectively. Radiomics signatures constructed on T1-2 stage and T3-4 stage patients yielded C-indices of 0.820 (95% confidence interval [CI]: 0.763-0.877) and 0.726 (0.687-0.765), respectively, which were larger than those on the entire validation cohort (0.675 [0.637-0.713]). Radiomics nomograms combining Radscore and clinical factors achieved significantly better performance than clinical nomograms (P < 0.05 for all). DATA CONCLUSION: The selected radiomics features and prognostic performance of radiomics signatures differed per the type of NPC patients incorporated into the models. Radiomics models based on pre-stratified tumor stages had better prognostic performance than those on unstratified dataset. LEVEL OF EVIDENCE: 4 Technical Efficacy Stage: 5.

Prognostic Value of Nodal Matting on MRI in Nasopharyngeal Carcinoma Patients.

BACKGROUND: Nodal (N) stage is one of the most important predictors for distant metastasis in nasopharyngeal carcinoma (NPC) patients. It may ignore potentially useful nodal features, such as nodal matting (three or more lymph nodes abutting together with the absence of intervening fat planes). PURPOSE: To explore the prognostic value of nodal matting in NPC patients and construct a nomogram with nodal matting for predicting distant metastasis-free survival (DMFS). STUDY TYPE: Retrospective. POPULATION: In all, 792 NPC patients treated with intensity modulated radiation therapy from 2010 to 2013 were enrolled with 2:1 training (n = 527) and validation (n = 65) cohorts. FIELD STRENGTH/SEQUENCE: T1 - and T2 -weighted imaging at 1.5 or 3.0T. ASSESSMENT: Nodal matting and other nodal characteristics were assessed with MRI. MR images were evaluated separately by three radiologists. The association between nodal matting and DMFS was analyzed. STATISTICAL TESTS: Univariate and multivariate analyses were performed using the Cox proportional hazards regression model. Nomograms were constructed from a multivariate logistic regression model with and without nodal matting. The predictive accuracy and discriminative ability of the nomograms were determined by concordance index (C-index) and calibration curves. The results were validated using bootstrap resampling and validation cohort. RESULTS: The incidence of nodal matting was 24.6% (195/792) in all patients. In the training cohort, nodal matting was independently associated with DMFS (hazard ratio [HR] = 1.97 [1.05-3.69], P < 0.05). N1 patients with nodal matting had worse DMFS than N1 patients without (P < 0.05). However, no significant difference was observed when comparing N1 patients with nodal matting to N2 patients (P = 0.464). The C-index of the nomogram with nodal matting was higher than the nomogram without (0.717 vs. 0.699, P = 0.084). DATA CONCLUSION: Nodal matting was an independent prognostic factor for DMFS in NPC patients. It may help to select patients at high risk of distant metastasis.

Grading Soft Tissue Involvement in Nasopharyngeal Carcinoma Using Network and Survival Analyses: A Two-Center Retrospective Study.

BACKGROUND: Soft tissue involvement (STI) indicates poor prognosis in nasopharyngeal carcinoma (NPC). However, only a few studies have systematically assessed this extension using network analysis. PURPOSE: To investigate the prognostic value of STI and to propose an improved STI grading system for NPC therapy. STUDY TYPE: Retrospective study. POPULATION: A total of 1225 consecutive patients with pathologically confirmed NPC treated with intensive-modulated radiotherapy from January 2010 to March 2014 were enrolled from two centers. FIELD STRENGTH/SEQUENCE: T1- and T2-weighted imaging and enhanced T1-weighted imaging with fast spin echo sequence at 1.5 or 3.0 T. ASSESSMENT: The levator veli palatini and tensor veli palatini involvement were graded "mild," prevertebral muscle involvement, "moderate," medial pterygoid, lateral pterygoid, and the infratemporal fossa involvement, "severe" STI. The above STI sites were evaluated separately by three radiologists using MRI images and graded using network analysis. Overall survival (OS) and progression-free survival (PFS) were assessed. STATISTICAL TESTS: Kaplan-Meier method, Cox's proportional hazards model, and concordance index (C-index) were used. RESULTS: Five-year OS and PFS rates between mild and moderate groups (90.5% vs. 81.7%, P < 0.05 and 82.9% vs. 72.5%, P < 0.05, respectively) and between moderate and severe groups (81.7% vs. 70.4%, P < 0.05 and 72.5% vs. 61.2%, P < 0.05, respectively) revealed significant differences. The C-index of the nomogram with STI grading was higher compared with current T-classification (OS 0.641 vs. 0.604, P < 0.05 and PFS 0.605 vs. 0.581, P < 0.05, respectively). Significant OS differences were observed between patients with severe STI who underwent induction chemotherapy (IC) and those who did not (84.5% vs. 70.7%, P < 0.05). DATA CONCLUSION: STI grading was an independent prognostic factor for OS and PFS in NPC patients and it may be help to improve the accuracy in predicting survival outcomes. Patients with severe STI might benefit from IC to improve OS. LEVEL OF EVIDENCE: 4 TECHNICAL EFFICACY: Stage 2.

Preoperative prediction of axillary sentinel lymph node burden with multiparametric MRI-based radiomics nomogram in early-stage breast cancer.

OBJECTIVES: To develop and validate a multiparametric MRI-based radiomics nomogram for pretreatment predicting the axillary sentinel lymph node (SLN) burden in early-stage breast cancer. METHODS: A total of 230 women with early-stage invasive breast cancer were retrospectively analyzed. A radiomics signature was constructed based on preoperative multiparametric MRI from the training dataset (n = 126) of center 1, then tested in the validation cohort (n = 42) from center 1 and an external test cohort (n = 62) from center 2. Multivariable logistic regression was applied to develop a radiomics nomogram incorporating radiomics signature and predictive clinical and radiological features. The radiomics nomogram's performance was evaluated by its discrimination, calibration, and clinical use and was compared with MRI-based descriptors of primary breast tumor. RESULTS: The constructed radiomics nomogram incorporating radiomics signature and MRI-determined axillary lymph node (ALN) burden showed a good calibration and outperformed the MRI-determined ALN burden alone for predicting SLN burden (area under the curve [AUC]: 0.82 vs. 0.68 [p < 0.001] in training cohort; 0.81 vs. 0.68 in validation cohort [p = 0.04]; and 0.81 vs. 0.58 [p = 0.001] in test cohort). Compared with the MRI-based breast tumor combined descriptors, the radiomics nomogram achieved a higher AUC in test cohort (0.81 vs. 0.58, p = 0.005) and a comparable AUC in training (0.82 vs. 0.73, p = 0.15) and validation (0.81 vs. 0.65, p = 0.31) cohorts. CONCLUSION: A multiparametric MRI-based radiomics nomogram can be used for preoperative prediction of the SLN burden in early-stage breast cancer. KEY POINTS: • Radiomics nomogram incorporating radiomics signature and MRI-determined ALN burden outperforms the MRI-determined ALN burden alone for predicting SLN burden in early-stage breast cancer. • Radiomics nomogram might have a better predictive ability than the MRI-based breast tumor combined descriptors. • Multiparametric MRI-based radiomics nomogram can be used as a non-invasive tool for preoperative predicting of SLN burden in patients with early-stage breast cancer.

Differentiation Between Benign and Nonbenign Meningiomas by Using Texture Analysis From Multiparametric MRI.

BACKGROUND: It is difficult to prospectively differentiate between benign (World Health Organization [WHO] I) and nonbenign (WHO II and III) meningiomas. PURPOSE: To evaluate the feasibility of preoperative differentiation between benign and nonbenign meningiomas by using texture analysis from multiparametric MR data. STUDY TYPE: Retrospective. SUBJECTS: In all, 184 patients with meningioma (139 benign and 45 nonbenign) were included as the training cohort and 79 patients with meningioma (60 benign and 19 nonbenign) were included as the external validation cohort. FIELD STRENGTH/SEQUENCE: T1 -weighted, T2 -weighted, and contrast-enhanced T1 -weighted imaging were performed on 1.5 or 3.0T MR systems from two centers. ASSESSMENT: Tumor segmentation and radiological characteristic (RC) evaluation were performed by experienced radiologists. The texture features were extracted from preprocessed images and combined with RCs, and then the combined features were reduced by using a two-step feature selection. Three single-sequence models and a multiparametric MRI (the combination of single sequences) model were constructed and then evaluated with the external validation cohort. STATISTICAL TESTS: Area under receiver operating characteristic curve (AUC), accuracy (Acc), f1-score (F1), sensitivity (Sen), and specificity (Spec), were calculated to quantify the performance of the models. RESULTS: Among the four texture models, the multiparametric MRI model demonstrated the best performance for differentiating between benign and nonbenign meningiomas in both the training and external validation cohorts (AUC 0.91, Acc 89%, F1 0.88, Sen 0.93, and Spec 0.87 in the training cohort; AUC 0.83, Acc 80%, F1 0.77, Sen 0.84, and Spec 0.78 in the validation cohort). DATA CONCLUSION: Nonbenign meningiomas might be preoperatively differentiated from benign meningiomas by using texture analysis from multiparametric MR data. LEVEL OF EVIDENCE: 3 Technical Efficacy Stage: 2 J. Magn. Reson. Imaging 2020;51:1810-1820.

Nodal grouping in nasopharyngeal carcinoma: prognostic significance, N classification, and a marker for the identification of candidates for induction chemotherapy.

OBJECTIVES: This study aimed to evaluate the value of nodal grouping (NG), defined as the presence of at least three contiguous lymph nodes (LNs) within one LN region, in staging and management of patients with non-metastatic nasopharyngeal carcinoma (NPC). METHODS: MR images were reviewed to evaluate LN variables, including NG. The Kaplan-Meier method and multivariate Cox regression models evaluated the association between the variables and survival. Harrell's concordance index (C-index) was used to measure the performance of prognostic models. The outcome of induction chemotherapy (IC) in patients with and without NG was compared using matched-pair analysis. RESULTS: In 1224 patients enrolled, NG was found to be an independent prognostic factor for overall survival (OS), progression-free survival (PFS), distant metastasis-free survival (DMFS), and regional recurrence-free survival. The hazard ratio and 95% confidence interval (CI) of NG for OS (3.86, 2.09-7.12) were higher than those of stage N2 (3.54, 1.89-6.70). On upgrading patients with NG from stages N1 to N2, the revised N staging yielded a higher C-index compared to the American Joint Committee on Cancer system in predicting PFS (0.664 vs. 0.658, p = 0.022) and DMFS (0.699 vs. 0.690, p = 0.005). Results of the matched-pair analysis revealed that for patients with NG in stages N1 and N2, IC was correlated with improved OS (p = 0.022), PFS (p = 0.007), and DMFS (p = 0.021). CONCLUSIONS: NG is a significant prognostic factor for patients with NPC. Patients with NG may be upgraded from stages N1 to N2. NG was also a marker for identifying patients who would benefit from IC. KEY POINTS: • Nodal grouping, defined as the presence of at least three contiguous LNs within one LN region on MRI, was identified as a significant prognostic factor. • In patients with nasopharyngeal carcinoma, nodal grouping may influence lymph node staging. • Nodal grouping was a marker for identifying patients who may benefit from induction chemotherapy.

Identification of Key Genes and Pathways Involved in the Heterogeneity of Intrinsic Growth Ability Between Neurons After Spinal Cord Injury in Adult Zebrafish.

In the adult central nervous system (CNS), axon regeneration is a major hurdle for functional recovery after trauma. The intrinsic growth potential of an injured axon varies widely between neurons. The underlying molecular mechanisms of such heterogeneity are largely unclear. In the present study, the adult zebrafish dataset GSE56842 were downloaded. Differentially expressed genes (DEGs) were sorted and deeply analyzed by bioinformatics methods. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis of DEGs were performed with the DAVID. A DEGs-associated protein-protein interaction network was constructed from the STRING database and visualized with Cytoscape software. In total, 621 DEGs were identified. GO analysis showed that the biological processes of DEGs focused mainly on the Notch signaling pathway, cell differentiation and positive regulation of neuron differentiation. The molecular functions mainly included calcium-transporting ATPase activity and calcium ion binding and structural constituents of the cytoskeleton. The cellular components included the plasma membrane, spectrin, and cytoplasmic and membrane-bound vesicles. KEGG pathway analysis showed that these DEGs were mainly involved in the metabolic pathway and Notch signaling pathway, and subnetworks revealed that genes within modules were involved in the metabolic pathway, Wnt signaling pathway, and calcium signaling pathway. This study identified DEG candidate genes and pathways involved in the heterogeneity of the intrinsic growth ability between neurons after spinal cord injury in adult zebrafish, which could facilitate our understanding of the molecular mechanisms underlying axon regeneration, and these candidate genes and pathways could be therapeutic targets for the treatment of CNS injury.

Radiomics on multi-modalities MR sequences can subtype patients with non-metastatic nasopharyngeal carcinoma (NPC) into distinct survival subgroups.

OBJECTIVES: To explore and evaluate the feasibility of radiomics in stratifying nasopharyngeal carcinoma (NPC) into distinct survival subgroups through multi-modalities MRI. METHODS: A total of 658 patients (training cohort: 424; validation cohort: 234) with non-metastatic NPC were enrolled in the retrospective analysis. Each slice was considered as a sample and 4863 radiomics features on the tumor region were extracted from T1-weighted, T2-weighted, and contrast-enhanced T1-weighted MRI. Consensus clustering and manual aggregation were performed on the training cohort to generate a baseline model and classification reference used to train a support vector machine classifier. The risk of each patient was defined as the maximum risk among the slices. Each patient in the validation cohort was assigned to the risk model using the trained classifier. Harrell's concordance index (C-index) was used to measure the prognosis performance, and differences between subgroups were compared using the log-rank test. RESULTS: The training cohort was clustered into four groups with distinct survival patterns. Each patient was assigned to one of the four groups according to the estimated risk. Our method gave a performance (C-index = 0.827, p < .004 and C-index = 0.814, p < .002) better than the T-stage (C-index = 0.815, p = .002 and C-index = 0.803, p = .024), competitive to and more stable than the TNM staging system (C-index = 0.842, p = .003 and C-index = 0.765, p = .050) in the training cohort and the validation cohort. CONCLUSIONS: Through investigating a large one-institutional cohort, the quantitative multi-modalities MRI image phenotypes reveal distinct survival subtypes. KEY POINTS: • Radiomics phenotype of MRI revealed the subtype of nasopharyngeal carcinoma (NPC) patients with distinct survival patterns. • The slice-wise analysis method on MRI helps to stratify patients and provides superior prognostic performance over the TNM staging method. • Risk estimation using the highest risk among slices performed better than using the majority risk in prognosis.

Correction to: Radiomics on multi-modalities MR sequences can subtype patients with non-metastatic nasopharyngeal carcinoma (NPC) into distinct survival subgroups.

The original version of this article, published on 14 March 2019, unfortunately contained a mistake.