TCF3 alternative splicing controlled by hnRNP H/F regulates E-cadherin expression and hESC pluripotency.

Alternative splicing (AS) plays important roles in embryonic stem cell (ESC) differentiation. In this study, we first identified transcripts that display specific AS patterns in pluripotent human ESCs (hESCs) relative to differentiated cells. One of these encodes T-cell factor 3 (TCF3), a transcription factor that plays important roles in ESC differentiation. AS creates two TCF3 isoforms, E12 and E47, and we identified two related splicing factors, heterogeneous nuclear ribonucleoproteins (hnRNPs) H1 and F (hnRNP H/F), that regulate TCF3 splicing. We found that hnRNP H/F levels are high in hESCs, leading to high E12 expression, but decrease during differentiation, switching splicing to produce elevated E47 levels. Importantly, hnRNP H/F knockdown not only recapitulated the switch in TCF3 AS but also destabilized hESC colonies and induced differentiation. Providing an explanation for this, we show that expression of known TCF3 target E-cadherin, critical for maintaining ESC pluripotency, is repressed by E47 but not by E12.

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.

Hyperfractionation compared with standard fractionation in intensity-modulated radiotherapy for patients with locally advanced recurrent nasopharyngeal carcinoma: a multicentre, randomised, open-label, phase 3 trial.

BACKGROUND: Reirradiation in standard fractionation for locally advanced recurrent nasopharyngeal carcinoma after a previous course of high-dose radiotherapy is often associated with substantial late toxicity, negating its overall benefit. We therefore aimed to investigate the efficacy and safety of hyperfractionation compared with standard fractionation in intensity-modulated radiotherapy. METHODS: This multicentre, randomised, open-label, phase 3 trial was done in three centres in Guangzhou, China. Eligible patients were aged 18-65 years with histopathologically confirmed undifferentiated or differentiated, non-keratinising, advanced locally recurrent nasopharyngeal carcinoma. Participants were randomly assigned (1:1) to either receive hyperfractionation (65 Gy in 54 fractions, given twice daily with an interfractional time interval of at least 6 h) or standard fractionation (60 Gy in 27 fractions, given once a day). Intensity-modulated radiotherapy was used in both groups. A computer program generated the assignment sequence and randomisation was stratified by treatment centre, recurrent tumour stage (T2-T3 vs T4), and recurrent nodal stage (N0 vs N1-N2), determined at the time of randomisation. The two primary endpoints were the incidence of severe late complications defined as the incidence of grade 3 or worse late radiation-induced complications occurring 3 months after the completion of radiotherapy until the latest follow-up in the safety population, and overall survival defined as the time interval from randomisation to death due to any cause in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT02456506. FINDINGS: Between July 10, 2015, and Dec 23, 2019, 178 patients were screened for eligibility, 144 of whom were enrolled and randomly assigned to hyperfractionation or standard fractionation (n=72 in each group). 35 (24%) participants were women and 109 (76%) were men. After a median follow-up of 45·0 months (IQR 37·3-53·3), there was a significantly lower incidence of grade 3 or worse late radiation-induced toxicity in the hyperfractionation group (23 [34%] of 68 patients) versus the standard fractionation group (39 [57%] of 68 patients; between-group difference -23% [95% CI -39 to -7]; p=0·023). Patients in the hyperfractionation group had better 3-year overall survival than those in the standard fractionation group (74·6% [95% CI 64·4 to 84·8] vs 55·0% [43·4 to 66·6]; hazard ratio for death 0·54 [95% CI 0·33 to 0·88]; p=0·014). There were fewer grade 5 late complications in the hyperfractionation group (five [7%] nasal haemorrhage) than in the standard fractionation group (16 [24%], including two [3%] nasopharyngeal necrosis, 11 [16%] nasal haemorrhage, and three [4%] temporal lobe necrosis). INTERPRETATION: Hyperfractionated intensity-modulated radiotherapy could significantly decrease the rate of severe late complications and improve overall survival among patients with locally advanced recurrent nasopharyngeal carcinoma. Our findings suggest that hyperfractionated intensity-modulated radiotherapy could be used as the standard of care for these patients. FUNDING: Key-Area Research and Development of Guangdong Province, the National Natural Science Foundation of China, the Special Support Program for High-level Talents in Sun Yat-sen University Cancer Center, the Guangzhou Science and Technology Plan Project, and the National Ten Thousand Talents Program Science and Technology Innovation Leading Talents, Sun Yat-Sen University Clinical Research 5010 Program.

Incidence rate of occult lymph node metastasis in clinical T1-2N0M0 small cell lung cancer patients and radiomic prediction based on contrast-enhanced CT imaging: a multicenter study : Original research.

BACKGROUND: This study aimed to explore the incidence of occult lymph node metastasis (OLM) in clinical T1 - 2N0M0 (cT1 - 2N0M0) small cell lung cancer (SCLC) patients and develop machine learning prediction models using preoperative intratumoral and peritumoral contrast-enhanced CT-based radiomic data. METHODS: By conducting a retrospective analysis involving 242 eligible patients from 4 centeres, we determined the incidence of OLM in cT1 - 2N0M0 SCLC patients. For each lesion, two ROIs were defined using the gross tumour volume (GTV) and peritumoral volume 15 mm around the tumour (PTV). By extracting a comprehensive set of 1595 enhanced CT-based radiomic features individually from the GTV and PTV, five models were constucted and we rigorously evaluated the model performance using various metrics, including the area under the curve (AUC), accuracy, sensitivity, specificity, calibration curve, and decision curve analysis (DCA). For enhanced clinical applicability, we formulated a nomogram that integrates clinical parameters and the rad_score (GTV and PTV). RESULTS: The initial investigation revealed a 33.9% OLM positivity rate in cT1 - 2N0M0 SCLC patients. Our combined model, which incorporates three radiomic features from the GTV and PTV, along with two clinical parameters (smoking status and shape), exhibited robust predictive capabilities. With a peak AUC value of 0.772 in the external validation cohort, the model outperformed the alternative models. The nomogram significantly enhanced diagnostic precision for radiologists and added substantial value to the clinical decision-making process for cT1 - 2N0M0 SCLC patients. CONCLUSIONS: The incidence of OLM in SCLC patients surpassed that in non-small cell lung cancer patients. The combined model demonstrated a notable generalization effect, effectively distinguishing between positive and negative OLMs in a noninvasive manner, thereby guiding individualized clinical decisions for patients with cT1 - 2N0M0 SCLC.

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.

Feasible CT features to distinguish incidental rib enhancement from sclerotic metastasis in patients with malignancies.

OBJECTIVE: To investigate the CT features of incidental rib enhancement (RE) and to summarize the CT characteristics for distinguishing the RE from sclerotic metastasis (SM) in patients with malignancies. MATERIAL AND METHODS: This retrospective observational study enrolled 79 patients with RE (involved 133 ribs) during October 2014 and December 2021. Another 53 patients with SM (160 SM) in the same period were selected randomly for comparison. The location, enhancement patterns of RE were reviewed. The CT values of RE regions and SM were measured and statistically analyzed. RESULTS: Most REs (70 patients, 88.6%) were in the 1st to 6th ribs. 50 patients had solitary RE and 29 with multiple REs in a regional distribution. All the REs were closely connected to the intercostal venous plexus (ICVP) ipsilateral to the injection site. No visible abnormalities on unenhanced scans were detected in all REs. One hundred and twenty REs (90.2%) had nodular/patchy enhancement. The CT value of RE regions in the venous phase was lower than that in the arterial phase (589.8 ± 344.2 HU versus 1188.5 ± 325.3 HU, p < 0.001). During the venous phase, most REs (125, 94.0%) shrank or disappeared. SM appeared similar on both contrast-enhanced and unenhanced scans in terms of shape and CT values. CONCLUSION: The RE demonstrated characteristic CT features. The manifestations of nodular/patchy enhancement in the arterial phase, decreased density and shrinkage or disappearance during the venous phase, and no abnormality on unenhanced scans, as well as a close connection with the ICVP, may help differentiate RE from SM.

HPODNets: deep graph convolutional networks for predicting human protein-phenotype associations.

MOTIVATION: Deciphering the relationship between human genes/proteins and abnormal phenotypes is of great importance in the prevention, diagnosis and treatment against diseases. The Human Phenotype Ontology (HPO) is a standardized vocabulary that describes the phenotype abnormalities encountered in human disorders. However, the current HPO annotations are still incomplete. Thus, it is necessary to computationally predict human protein-phenotype associations. In terms of current, cutting-edge computational methods for annotating proteins (such as functional annotation), three important features are (i) multiple network input, (ii) semi-supervised learning and (iii) deep graph convolutional network (GCN), whereas there are no methods with all these features for predicting HPO annotations of human protein. RESULTS: We develop HPODNets with all above three features for predicting human protein-phenotype associations. HPODNets adopts a deep GCN with eight layers which allows to capture high-order topological information from multiple interaction networks. Empirical results with both cross-validation and temporal validation demonstrate that HPODNets outperforms seven competing state-of-the-art methods for protein function prediction. HPODNets with the architecture of deep GCNs is confirmed to be effective for predicting HPO annotations of human protein and, more generally, node label ranking problem with multiple biomolecular networks input in bioinformatics. AVAILABILITY AND IMPLEMENTATION: https://github.com/liulizhi1996/HPODNets. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

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.

Matted Lymph Nodes on MRI in Nasopharyngeal Carcinoma: Prognostic Factor and Potential Indication for Induction Chemotherapy Benefits.

BACKGROUND: Lymph node characteristics markedly affect nasopharyngeal carcinoma (NPC) prognosis. Matted node (MN), an important characteristic for lymph node, lacks explored MRI-based prognostic implications. PURPOSE: Investigate MRI-determined MNs' prognostic value in NPC, including 5-year overall survival (OS), distant metastasis-free survival (DMFS), local recurrence-free survival (LRFS), progression-free survival (PFS), and its role in induction chemotherapy (IC). STUDY TYPE: Retrospective cohort survival study. POPULATION: Seven hundred ninety-two patients with non-metastatic NPC (female: 27.3%, >45-year old: 50.1%) confirmed by biopsy. FIELD STRENGTH/SEQUENCE: 5-T/3.0-T, T1-, T2- and post-contrast T1-weighted fast spin echo sequences acquired. ASSESSMENT: MNs were defined as ≥3 nodes abutting with intervening fat plane replaced by extracapsular nodal spread (ENS). Patients were observed every 3 months for 2 years and every 6 months for 5 years using MRI. Follow-up extended from treatment initiation to death or final follow-up. MNs were evaluated by three radiologists with inter-reader reliability calculated. A 1:1 matched-pair method compared survival differences between MN-positive patients with or without IC. Primary endpoints (OS, DMFS, LRFS, PFS) were calculated from therapy initiation to respective event. STATISTICAL TESTS: Kappa values assessed inter-reader reliability. Correlation between MN, ENS, and LNN was studied through Spearman's correlation coefficient. Clinical characteristics were calculated via Fisher's exact, Chi-squared, and Student's t-test. Kaplan-Meier curves and log-rank tests analyzed all time-to-event data. Confounding factors were included in Multivariable Cox proportional hazard models to identify independent prognostic factors. P-values <0.05 were considered statistically significant. RESULTS: MNs incidence was 24.6%. MNs independently associated with decreased 5-year OS, DMFS, and PFS; not LRFS (P = 0.252). MN-positive patients gained significant survival benefit from IC in 5-year OS (88.4% vs. 66.0%) and PFS (76.4% vs. 53.5%), but not DMFS (83.1% vs. 69.9%, P = 0.145) or LRFS (89.9% vs. 77.8%, P = 0.140). DATA CONCLUSION: MNs may independently stratify NPC risk and offer survival benefit from IC. EVIDENCE LEVEL: 3 TECHNICAL EFFICACY: Stage 2.

Head and neck MRI-based T stage and [18F]FDG PET/CT-based N/M stage improved prognostic stratification in primary nasopharyngeal carcinoma.

OBJECTIVES: To evaluate whether MRI-based T stage (TMRI), [18F]FDG PET/CT-based N (NPET/CT), and M stage (MPET/CT) are superior in NPC patients' prognostic stratification based on long-term survival evidences, and whether TNM staging method involving TMRI + NPET/CT + MPET/CT could improve NPC patients' prognostic stratification. METHODS: From April 2007 to December 2013, 1013 consecutive untreated NPC patients with complete imaging data were enrolled. All patients' initial stages were repeated based on (1) the NCCN guideline recommended "TMRI + NMRI + MPET/CT" ("MMP") staging method; (2) the traditional "TMRI + NMRI + Mconventional work-up (CWU)" ("MMC") staging method; (3) the single-step "TPET/CT + NPET/CT + MPET/CT" ("PPP") staging method; or (4) the "TMRI + NPET/CT + MPET/CT" ("MPP") staging method recommended in present research. Survival curve, ROC curve, and net reclassification improvement (NRI) analysis were used to evaluate the prognosis predicting ability of different staging methods. RESULTS: [18F]FDG PET/CT performed worse on T stage (NRI = - 0.174, p < 0.001) but better on N (NRI = 0.135, p = 0.004) and M stage (NRI = 0.126, p = 0.001). The patients whose N stage upgraded by [18F]FDG PET/CT had worse survival (p = 0.011). The "TMRI + NPET/CT + MPET/CT" ("MPP") method performed better on survival prediction when compared with "MMP" (NRI = 0.079, p = 0.007), "MMC" (NRI = 0.190, p < 0.001), or "PPP" method (NRI = 0.107, p < 0.001). The "TMRI + NPET/CT + MPET/CT" ("MPP") method could reclassify patients' TNM stage to a more appropriate stage. The improvement is significant in patients with more than 2.5-years follow-up according to the time-dependent NRI values. CONCLUSIONS: The MRI is superior to [18F]FDG PET/CT in T stage, and [18F]FDG PET/CT is superior to CWU in N/M stage. The "TMRI + NPET/CT + MPET/CT" ("MPP") staging method could significantly improve NPC patients' long-term prognostic stratification. CLINICAL RELEVANCE STATEMENT: The present research provided long-term follow-up evidence for benefits of MRI and [18F]FDG PET/CT in TNM staging for nasopharyngeal carcinoma, and proposes a new imaging procedure for TNM staging incorporating MRI-based T stage and [18F]FDG PET/CT-based N and M stage, which significantly improves long-term prognostic stratification for patients with NPC. KEY POINTS: • The long-term follow-up evidence of a large-scale cohort was provided to evaluate the advantages of MRI, [18F]FDG PET/CT, and CWU in the TNM staging of nasopharyngeal carcinoma. • A new imaging procedure for TNM stage of nasopharyngeal carcinoma was proposed.

A novel fusion algorithm for benign-malignant lung nodule classification on CT images.

The accurate recognition of malignant lung nodules on CT images is critical in lung cancer screening, which can offer patients the best chance of cure and significant reductions in mortality from lung cancer. Convolutional Neural Network (CNN) has been proven as a powerful method in medical image analysis. Radiomics which is believed to be of interest based on expert opinion can describe high-throughput extraction from CT images. Graph Convolutional Network explores the global context and makes the inference on both graph node features and relational structures. In this paper, we propose a novel fusion algorithm, RGD, for benign-malignant lung nodule classification by incorporating Radiomics study and Graph learning into the multiple Deep CNNs to form a more complete and distinctive feature representation, and ensemble the predictions for robust decision-making. The proposed method was conducted on the publicly available LIDC-IDRI dataset in a 10-fold cross-validation experiment and it obtained an average accuracy of 93.25%, a sensitivity of 89.22%, a specificity of 95.82%, precision of 92.46%, F1 Score of 0.9114 and AUC of 0.9629. Experimental results illustrate that the RGD model achieves superior performance compared with the state-of-the-art methods. Moreover, the effectiveness of the fusion strategy has been confirmed by extensive ablation studies. In the future, the proposed model which performs well on the pulmonary nodule classification on CT images will be applied to increase confidence in the clinical diagnosis of lung cancer.

First Principles Study of the Photoelectric Properties of Alkaline Earth Metal (Be/Mg/Ca/Sr/Ba)-Doped Monolayers of MoS2.

The energy band structure, density of states, and optical properties of monolayers of MoS2 doped with alkaline earth metals (Be/Mg/Ca/Sr/Ba) are systematically studied based on first principles. The results indicate that all the doped systems have a great potential to be formed and structurally stable. In comparison to monolayer MoS2, doping alkaline earth metals results in lattice distortions in the doped system. Therefore, the recombination of photogenerated hole-electron pairs is suppressed effectively. Simultaneously, the introduction of dopants reduces the band gap of the systems while creating impurity levels. Hence, the likelihood of electron transfer from the valence to the conduction band is enhanced, which means a reduction in the energy required for such a transfer. Moreover, doping monolayer MoS2 with alkaline earth metals increases the static dielectric constant and enhances its polarizability. Notably, the Sr-MoS2 system exhibits the highest value of static permittivity, demonstrating the strongest polarization capability. The doped systems exhibit a red-shifted absorption spectrum in the low-energy region. Consequently, the Be/Mg/Ca-MoS2 systems demonstrate superior visible absorption properties and a favorable band gap, indicating their potential as photo-catalysts for water splitting.

HPOFiller: identifying missing protein-phenotype associations by graph convolutional network.

MOTIVATION: Exploring the relationship between human proteins and abnormal phenotypes is of great importance in the prevention, diagnosis and treatment of diseases. The human phenotype ontology (HPO) is a standardized vocabulary that describes the phenotype abnormalities encountered in human diseases. However, the current HPO annotations of proteins are not complete. Thus, it is important to identify missing protein-phenotype associations. RESULTS: We propose HPOFiller, a graph convolutional network (GCN)-based approach, for predicting missing HPO annotations. HPOFiller has two key GCN components for capturing embeddings from complex network structures: (i) S-GCN for both protein-protein interaction network and HPO semantic similarity network to utilize network weights; (ii) Bi-GCN for the protein-phenotype bipartite graph to conduct message passing between proteins and phenotypes. The core idea of HPOFiller is to repeat run these two GCN modules consecutively over the three networks, to refine the embeddings. Empirical results of extremely stringent evaluation avoiding potential information leakage including cross-validation and temporal validation demonstrates that HPOFiller significantly outperforms all other state-of-the-art methods. In particular, the ablation study shows that batch normalization contributes the most to the performance. The further examination offers literature evidence for highly ranked predictions. Finally using known disease-HPO term associations, HPOFiller could suggest promising, unknown disease-gene associations, presenting possible genetic causes of human disorders. AVAILABILITYAND IMPLEMENTATION: https://github.com/liulizhi1996/HPOFiller. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Deep learning radiomics of dual-energy computed tomography for predicting lymph node metastases of pancreatic ductal adenocarcinoma.

PURPOSE: Diagnosis of lymph node metastasis (LNM) is critical for patients with pancreatic ductal adenocarcinoma (PDAC). We aimed to build deep learning radiomics (DLR) models of dual-energy computed tomography (DECT) to classify LNM status of PDAC and to stratify the overall survival before treatment. METHODS: From August 2016 to October 2020, 148 PDAC patients underwent regional lymph node dissection and scanned preoperatively DECT were enrolled. The virtual monoenergetic image at 40 keV was reconstructed from 100 and 150 keV of DECT. By setting January 1, 2021, as the cut-off date, 113 patients were assigned into the primary set, and 35 were in the test set. DLR models using VMI 40 keV, 100 keV, 150 keV, and 100 + 150 keV images were developed and compared. The best model was integrated with key clinical features selected by multivariate Cox regression analysis to achieve the most accurate prediction. RESULTS: DLR based on 100 + 150 keV DECT yields the best performance in predicting LNM status with the AUC of 0.87 (95% confidence interval [CI]: 0.85-0.89) in the test cohort. After integrating key clinical features (CT-reported T stage, LN status, glutamyl transpeptadase, and glucose), the AUC was improved to 0.92 (95% CI: 0.91-0.94). Patients at high risk of LNM portended significantly worse overall survival than those at low risk after surgery (P = 0.012). CONCLUSIONS: The DLR model showed outstanding performance for predicting LNM in PADC and hold promise of improving clinical decision-making.

Correct Identification of the Core-Shell Structure of Cell Membrane-Coated Polymeric Nanoparticles.

Transmission electron microscopy (TEM) observations of negatively stained cell membrane (CM)-coated polymeric nanoparticles (NPs) reveal a characteristic core-shell structure. However, negative staining agents can create artifacts that complicate the determination of the actual NP structure. Herein, it is demonstrated with various bare polymeric core NPs, such as poly(lactic-co-glycolic acid) (PLGA), poly(ethylene glycol) methyl ether-block-PLGA, and poly(caprolactone), that certain observed core-shell structures are actually artifacts caused by the staining process. To address this issue, fluorescence quenching was applied to quantify the proportion of fully coated NPs and statistical TEM analysis was used to identify and differentiate whether the observed core-shell structures of CM-coated PLGA (CM-PLGA) NPs are due to artifacts or to the CM coating. Integrated shells in TEM images of negatively stained CM-PLGA NPs are identified as artifacts. The present results challenge current understanding of the structure of CM-coated polymeric NPs and encourage researchers to use the proposed characterization approach to avoid misinterpretations.

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.

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.