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.

Effect of Helicobacter Pylori Infection on Glucose Metabolism, Lipid Metabolism and Inflammatory Cytokines in Nonalcoholic Fatty Liver Disease Patients.

Objective: To probe into the influence of Helicobacter pylori (Hp) infection on glucose metabolism, lipid metabolism, and inflammatory cytokines in patients with nonalcoholic fatty liver disease (MASLD). Methods: A total of 140 MASLD patients admitted to our Hospital between June 2020 and May 2021 were selected as the research objects. Based on the presence or absence of Hp infection, they were divided into the study group (73 cases with infection) and control group (67 cases without infection). Glucose metabolism indicators [fasting blood glucose (FBG), 2-hour postprandial glucose (2hPG), fasting insulin (FINS), glycated hemoglobin (HbAlc)], lipid metabolism indicators [total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C)], and inflammatory indicators [interleukin-37 (IL-37), interleukin-18 (IL-18)] were measured and compared between the two groups. Results: In terms of glucose metabolism indicators, the study group exhibited higher levels of FBG (5.84±0.49 vs 5.40±0.51, t=2.535, P=0.012), 2hPG (7.26±1.30 vs 6.50±1.53, t=3.321, P<0.001), and FINS (11.13±4.13 vs 9.12±3.72, t=3.224, P<0.001), and Insulin resistance index (HOMA-IR) (2.97±0.35 VS 2.13±0.54, t=3.761, P<0.001) and a lower level of HbAlc (5.25±0.56 vs 6.12±0.57, t=5.473, P<0.001) compared to the control group. Regarding lipid metabolism indicators, the study group exhibited higher levels of TC (5.64±1.49 vs 5.01±1.32, t=3.332, P<0.001), TG (1.89±0.34 vs 1.32±0.43, t=3.411, P<0.001), and LDL-C (3.31±0.43 vs 2.12±0.29, t=4.142, P<0.001), and a lower level of HDL-C (1.45±0.21 vs 1.78±0.42, t=4.347, P<0.001) compared to the control group. As for the inflammatory indicators, the study group exhibited higher levels of IL-37 (45.56±6.02 vs 34.02±3.28, t=9.332, P<0.001) and IL-18 (73.57±5.82 vs 60.34±4.84, t=10.141, P<0.001) compared to the control group. Conclusion: It is crucial to place appropriate emphasis on the impact of Hp infection on the glucose metabolism, lipid metabolism, and inflammatory response in MASLD patients, warranting careful consideration during the treatment of these patients.

Identification of a seven autophagy-related gene pairs signature for the diagnosis of colorectal cancer using the RankComp algorithm.

Based on the colorectal cancer microarray sets gene expression data series (GSE) GSE10972 and GSE74602 in colon cancer and 222 autophagy-related genes, the differential signature in colorectal cancer and paracancerous tissues was analyzed by RankComp algorithm, and a signature consisting of seven autophagy-related reversal gene pairs with stable relative expression orderings (REOs) was obtained. Scoring based on these gene pairs could significantly distinguish colorectal cancer samples from adjacent noncancerous samples, with an average accuracy of 97.5% in two training sets and 90.25% in four independent validation GSE21510, GSE37182, GSE33126, and GSE18105. Scoring based on these gene pairs also accurately identifies 99.85% of colorectal cancer samples in seven other independent datasets containing a total of 1406 colorectal cancer samples.

Observation of Anomalous Orbital Angular Momentum Transfer in Parametric Nonlinearity.

Orbital angular momentum (OAM) conservation plays an important role in shaping and controlling structured light with nonlinear optics. The OAM of a beam originating from three-wave mixing should be the sum or difference of the other two inputs because no light-matter OAM exchange occurs in parametric nonlinear interactions. Here, we report anomalous OAM transfer in parametric upconversion, in which a Hermite-Gauss mode signal interacts with a specially engineered pump capable of astigmatic transformation, resulting in Laguerre-Gaussian mode sum-frequency generation (SFG). The anomaly here refers to the fact that the pump and signal both carry no net OAM, while their SFG does. We reveal experimentally that there is also an OAM inflow to the residual pump, having the same amount of that to the SFG but with the opposite sign, and thus holds system OAM conservation. This unexpected OAM selection rule improves our understanding of OAM transfer among interacting waves and may inspire new ideas for controlling OAM states via nonlinear optics.

CT-based radiomics in predicting pathological response in non-small cell lung cancer patients receiving neoadjuvant immunotherapy.

Objectives: In radiomics, high-throughput algorithms extract objective quantitative features from medical images. In this study, we evaluated CT-based radiomics features, clinical features, in-depth learning features, and a combination of features for predicting a good pathological response (GPR) in non-small cell lung cancer (NSCLC) patients receiving immunotherapy-based neoadjuvant therapy (NAT). Materials and methods: We reviewed 62 patients with NSCLC who received surgery after immunotherapy-based NAT and collected clinicopathological data and CT images before and after immunotherapy-based NAT. A series of image preprocessing was carried out on CT scanning images: tumor segmentation, conventional radiomics feature extraction, deep learning feature extraction, and normalization. Spearman correlation coefficient, principal component analysis (PCA), and least absolute shrinkage and selection operator (LASSO) were used to screen features. The pretreatment traditional radiomics combined with clinical characteristics (before_rad_cil) model and pretreatment deep learning characteristics (before_dl) model were constructed according to the data collected before treatment. The data collected after NAT created the after_rad_cil model and after_dl model. The entire model was jointly constructed by all clinical features, conventional radiomics features, and deep learning features before and after neoadjuvant treatment. Finally, according to the data obtained before and after treatment, the before_nomogram and after_nomogram were constructed. Results: In the before_rad_cil model, four traditional radiomics features ("original_shape_flatness," "wavelet hhl_firer_skewness," "wavelet hlh_firer_skewness," and "wavelet lll_glcm_correlation") and two clinical features ("gender" and "N stage") were screened out to predict a GPR. The average prediction accuracy (ACC) after modeling with k-nearest neighbor (KNN) was 0.707. In the after_rad_cil model, nine features predictive of GPR were obtained after feature screening, among which seven were traditional radiomics features: "exponential_firer_skewness," "exponential_glrlm_runentropy," "log- sigma-5-0-mm-3d_firer_kurtosis," "logarithm_skewness," "original_shape_elongation," "original_shape_brilliance," and "wavelet llh_glcm_clustershade"; two were clinical features: "after_CRP" and "after lymphocyte percentage." The ACC after modeling with support vector machine (SVM) was 0.682. The before_dl model and after_dl model were modeled by SVM, and the ACC was 0.629 and 0.603, respectively. After feature screening, the entire model was constructed by multilayer perceptron (MLP), and the ACC of the GPR was the highest, 0.805. The calibration curve showed that the predictions of the GPR by the before_nomogram and after_nomogram were in consensus with the actual GPR. Conclusion: CT-based radiomics has a good predictive ability for a GPR in NSCLC patients receiving immunotherapy-based NAT. Among the radiomics features combined with the clinicopathological information model, deep learning feature model, and the entire model, the entire model had the highest prediction accuracy.

Assessment of Survival Model Performance Following Inclusion of Epstein-Barr Virus DNA Status in Conventional TNM Staging Groups in Epstein-Barr Virus-Related Nasopharyngeal Carcinoma.

Importance: Nonanatomic prognostic factors complement the traditional anatomic staging system and could be incorporated into the tumor-node-metastasis (TNM) framework. Several diseases have incorporated nonanatomic prognostic factors into the determination of TNM staging groups. Objective: To refine TNM staging groups for Epstein-Barr virus (EBV)-related nonmetastatic nasopharyngeal carcinoma (NPC) by incorporating EBV DNA status. Design, Setting, and Participants: This multicenter prognostic study included patients with NPC treated with radiotherapy at 2 hospitals in China from January 2008 to December 2016. Progression-free survival and overall survival according to EBV DNA status and the TNM staging system were compared. Recursive partitioning analysis (RPA) combined with supervised clustering was applied to derive prognostic groupings, and then a refined RPA staging schema was developed, validated, and compared with existing staging schemes. Statistical analyses were conducted from October 1, 2020, to June 15, 2021. Exposures: Curative intensity-modulated radiotherapy with or without platinum-based chemotherapy. Main Outcomes and Measures: The primary end point was progression-free survival. The performance of the staging system was assessed using the time-dependent area under the receiver operating characteristic curves and the TNM stage system's evaluation methodology. Results: A total of 2354 patients (1709 men [72.6%]; median [interquartile range] age, 45 [38-53] years) were split into training (1372 [58.3%]), internal validation (672 [28.5%]), and external validation (310 [13.2%]) cohorts. Pretreatment EBV DNA was detected in 1338 (56.8%) patients. EBV DNA status was an independent prognostic factor: lower survival probability by higher TNM stage was evident in EBV DNA-positive patients but not in those with EBV DNA-negative disease. After integrating EBV DNA status and TNM stage, nonmetastatic NPC cases were categorized into RPA-I (T1-3N0 or EBV DNA-negative T1-3N1 cancers), RPA-II (EBV DNA-positive T1-3N1-2 or EBV DNA-negative T1-3N2-3/T4N0-3 cancers), and RPA-III (EBV DNA-positive T4N0-3/T1-3N3 cancers) groups, each with distinctly different prognosis. This system of RPA staging outperformed the current TNM stage system and 2 reported RPA staging schemes. These results were internally and externally validated. Conclusions and Relevance: An RPA-based staging system for EBV-related NPC cases was associated with improved outcomes. This staging system may facilitate prognostic stratification and clinical trial designs.

Radiation-induced hypothyroidism in patients with nasopharyngeal carcinoma treated with intensity-modulated radiation therapy with or without chemotherapy: Development of a nomogram based on the equivalent dose.

OBJECTIVE: The aim of this study was to establish a nomogram for predicting radiation-induced hypothyroidism (RHT) based on an equivalent dose at 2 Gy per fraction (EQD2) in patients with nasopharyngeal carcinoma (NPC) treated with intensity-modulated radiation therapy (IMRT) with or without chemotherapy. METHODS: Two hundred forty-four eligible patients with NPC were recruited for this study. Patients' clinical factors and dose-volume parameters of the thyroid gland were retrieved from medical records and the IMRT treatment planning system, respectively. The irradiation doses were converted into EQD2 for analysis. Least absolute shrinkage and selection operator (LASSO) regression analysis and multivariate logistic regression analysis were performed to identify optimal predictors of RHT for constructing the nomogram. RESULTS: With a median follow-up of 63.0 months, the cumulative incidence rates of RHT at 3 months and 1-, 2-, 3-, 4- and 5- year after IMRT were 10.2%, 36.2%, 47.6%, 54.2%, 58.8% and 69.4%, respectively. Four independent factors for predicting RHT, including gender, age, pretreatment volume of the thyroid gland and V35Gy(3Gy) of the thyroid gland, were identified and incorporated into the nomogram. The area under the ROC curve of the nomogram was 0.747 (95% confidence interval 0.685 - 0.809). Calibration curves and DCA curves showed that the nomogram was in good agreement with the actual observations and clinical usefulness. CONCLUSIONS: The nomogram proposed in this study provides a reliable estimate of RHT risk in patients with NPC after IMRT and appears to have the potential to be a useful tool for widespread clinical applications.

Deep Sequencing, Nested PCR, and Denaturing Gradient Gel Electrophoresis Reveal a Wider Distribution of Chinese Caterpillar Mushroom, Ophiocordyceps sinensis (Ascomycetes), in Native Soil Types.

Ophiocordyceps sinensis appears as stroma emerging from underground sclerotium enclosed by the skeleton of Thitarodes moth larvae. However, the actual distribution of the fungus in soil still remains unclarified. In this study, 40 soil samples were used for detection of O. sinensis to confirm its distribution in native habitats using denaturing gradient gel electrophoresis, nested internal transcribed spacer (ITS) PCR, and 454 pyrosequencing methods. The soil samples included six types: Os, where both stromata and host moth larvae were found; NL, representing no signs of stromata, but where moth larvae were found; NOs, where neither stroma nor moth larvae were found; BS, with bare soil without the presence of stroma of O. sinensis or moth larvae; AF, from soil surrounding the stroma; and MP, soil particles firmly wrapping the sclerotium of O. sinensis. Of 40 samples tested, 36 showed positive detection of O. sinensis by at least one of the three detection methods, with positive detection in all six sample types at all five sites. The results showed that traces of O. sinensis can be detected in locations with no macroscopically visible evidence of the fungus or its host and at least 100 m away from such locations.

RIP mutated ITS genes in populations of Ophiocordyceps sinensis and their implications for molecular systematics.

Different hypotheses have been proposed to interpret the observed unusual ITS (internal transcribed spacer) sequences in Ophiocordyceps sinensis. The coexistence of diverged ITS paralogs in a single genome was previously shown by amplifying the ITS region from mono-ascospore isolates using specific primers designed for different ITS paralog groups. Among those paralogs, are AT-biased ITS sequences which were hypothesized to result from repeat-induced point mutation (RIP). This is a process that detects and mutates repetitive DNA and frequently leads to epigenetic silencing, and these mutations have been interpreted as pseudogenes. Here we investigate the occurrence and frequency of ITS pseudogenes in populations of O. sinensis using large-scale sampling, and discusses the implications of ITS pseudogenes for fungal phylogenetic and evolutionary studies. Our results demonstrate a wide distribution of ITS pseudogenes amongst different geographic populations, and indicate how ITS pseudogenes can contribute to the reconstruction of the evolutionary history of the species.

Parametric upconversion of Ince-Gaussian modes.

The Ince-Gaussian (IG) mode, a recently discovered type of structured Gaussian beam, corresponds to eigenfunctions of the paraxial wave equation in elliptical coordinates. This propagation-invariant mode is of significance in various domains, in particular, its nonlinear transformation; however, there have been few relevant studies to date. In this Letter, we report the parametric upconversion of IG modes and associated full-field selection rule for the first time, to the best of our knowledge. We demonstrate that IG signals can be perfectly upconverted by a flattop-beam pump; in contrast, significant mode distortion occurred when using the most common Gaussian pump. Particular attention was given to the origin of the distortion, i.e., radial-mode degeneration induced by the sum-frequency generation excited by a Gaussian pump. This proof-of-principle demonstration has great significance in relevant areas, such as high-dimensional quantum frequency interfacing and upconversion imaging.