High-throughput identification of regulatory elements and functional assays to uncover susceptibility genes for nasopharyngeal carcinoma.

Large-scale genetic association studies have identified multiple susceptibility loci for nasopharyngeal carcinoma (NPC), but the underlying biological mechanisms remain to be explored. To gain insights into the genetic etiology of NPC, we conducted a follow-up study encompassing 6,907 cases and 10,472 controls and identified two additional NPC susceptibility loci, 9q22.33 (rs1867277; OR = 0.74, 95% CI = 0.68-0.81, p = 3.08 × 10-11) and 17q12 (rs226241; OR = 1.42, 95% CI = 1.26-1.60, p = 1.62 × 10-8). The two additional loci, together with two previously reported genome-wide significant loci, 5p15.33 and 9p21.3, were investigated by high-throughput sequencing for chromatin accessibility, histone modification, and promoter capture Hi-C (PCHi-C) profiling. Using luciferase reporter assays and CRISPR interference (CRISPRi) to validate the functional profiling, we identified PHF2 at locus 9q22.33 as a susceptibility gene. PHF2 encodes a histone demethylase and acts as a tumor suppressor. The risk alleles of the functional SNPs reduced the expression of the target gene PHF2 by inhibiting the enhancer activity of its long-range (4.3 Mb) cis-regulatory element, which promoted proliferation of NPC cells. In addition, we identified CDKN2B-AS1 as a susceptibility gene at locus 9p21.3, and the NPC risk allele of the functional SNP rs2069418 promoted the expression of CDKN2B-AS1 by increasing its enhancer activity. The overexpression of CDKN2B-AS1 facilitated proliferation of NPC cells. In summary, we identified functional SNPs and NPC susceptibility genes, which provides additional explanations for the genetic association signals and helps to uncover the underlying genetic etiology of NPC development.

Multiplex assays reveal anti-EBV antibody profile and its implication in detection and diagnosis of nasopharyngeal carcinoma.

Epstein-Barr virus (EBV) is detected in nearly 100% of nonkeratinizing nasopharyngeal carcinoma (NPC) and EBV-based biomarkers are used for NPC screening in endemic regions. Immunoglobulin A (IgA) against EBV nuclear antigen 1 (EBNA1) and viral capsid antigen (VCA), and recently identified anti-BNLF2b antibodies have been shown to be the most effective screening tool; however, the screening efficacy still needs to be improved. This study developed a multiplex serological assay by testing IgA and immunoglobulin G (IgG) antibodies against representative EBV antigens that are highly transcribed in NPC and/or function crucially in viral reactivation, including BALFs, BNLF2a/b, LF1, LF2, and Zta (BZLF1). Among them, BNLF2b-IgG had the best performance distinguishing NPC patients from controls (area under the curve: 0.951, 95% confidence interval [CI]: 0.913-0.990). Antibodies to lytic antigens BALF2 and VCA were significantly higher in advanced-stage than in early-stage tumors; in contrast, antibodies to latent protein EBNA1 and early lytic antigen BNLF2b were not correlated with tumor progression. Accordingly, a novel strategy combining EBNA1-IgA and BNLF2b-IgG was proposed and validated improving the integrated discrimination by 15.8% (95% CI: 9.8%-21.7%, p < .0001) compared with the two-antibody method. Furthermore, we found EBV antibody profile in patients was more complicated compared with that in healthy carriers, in which stronger correlations between antibodies against different phases of antigens were observed. Overall, our serological assay indicated that aberrant latent infection of EBV in nasopharyngeal epithelial cells was probably a key step in NPC initiation, while more lytic protein expression might be involved in NPC progression.

Autoantibody repertoire profiling in tissue and blood identifies colorectal cancer-specific biomarkers.

Autoantibodies (AAbs) in the blood of colorectal cancer (CRC) patients have been evaluated for tumor detection. However, it remains uncertain whether these AAbs are specific to tumor-associated antigens. In this study, we explored the IgG and IgM autoantibody repertoires in both the in situ tissue microenvironment and peripheral blood as potential tumor-specific biomarkers. We applied high-density protein arrays to profile AAbs in the tumor-infiltrating lymphocyte supernatants and corresponding serum from four patients with CRC, as well as in the serum of three noncancer controls. Our findings revealed that there were more reactive IgM AAbs than IgG in both the cell supernatant and corresponding serum, with a difference of approximately 3-5 times. Immunoglobulin G was predominant in the serum, while IgM was more abundant in the cell supernatant. We identified a range of AAbs present in both the supernatant and the corresponding serum, numbering between 432 and 780, with an average of 53.3% shared. Only 4.7% (n = 23) and 0.2% (n = 2) of reactive antigens for IgG and IgM AAbs, respectively, were specific to CRC. Ultimately, we compiled a list of 19 IgG AAb targets as potential tumor-specific AAb candidates. Autoantibodies against one of the top candidates, p15INK4b-related sequence/regulation of nuclear pre-mRNA domain-containing protein 1A (RPRD1A), were significantly elevated in 53 CRC patients compared to 119 controls (p < 0.0001). The project revealed that tissue-derived IgG AAbs, rather than IgM, are the primary source of tumor-specific AAbs in peripheral blood. It also identified potential tumor-specific AAbs that could be applied for noninvasive screening of CRC.

Diagnostic Value of Clear Cell Likelihood Score v1.0 and v2.0 for Common Subtypes of Small Renal Masses: A Multicenter Comparative Study.

BACKGROUND: Clear cell likelihood score (ccLS) is reliable for diagnosing small renal masses (SRMs). However, the diagnostic value of Clear cell likelihood score version 1.0 (ccLS v1.0) and v2.0 for common subtypes of SRMs might be a potential score extension. PURPOSE: To compare the diagnostic performance and interobserver agreement of ccLS v1.0 and v2.0 for characterizing five common subtypes of SRMs. STUDY TYPE: Retrospective. POPULATION: 797 patients (563 males, 234 females; mean age, 53 ± 12 years) with 867 histologically proven renal masses. FIELD STRENGTH/SEQUENCES: 3.0 and 1.5 T/T2 weighted imaging, T1 weighted imaging, diffusion-weighted imaging, a dual-echo chemical shift (in- and opposed-phase) T1 weighted imaging, multiphase dynamic contrast-enhanced imaging. ASSESSMENT: Six abdominal radiologists were trained in the ccLS algorithm and independently scored each SRM using ccLS v1.0 and v2.0, respectively. All SRMs had definite pathological results. The pooled area under curve (AUC), accuracy, sensitivity, and specificity were calculated to evaluate the diagnostic performance of ccLS v1.0 and v2.0 for characterizing common subtypes of SRMs. The average κ values were calculated to evaluate the interobserver agreement of the two scoring versions. STATISTICAL TESTS: Random-effects logistic regression; Receiver operating characteristic analysis; DeLong test; Weighted Kappa test; Z test. The statistical significance level was P < 0.05. RESULTS: The pooled AUCs of clear cell likelihood score version 2.0 (ccLS v2.0) were statistically superior to those of ccLS v1.0 for diagnosing clear cell renal cell carcinoma (ccRCC) (0.907 vs. 0.851), papillary renal cell carcinoma (pRCC) (0.926 vs. 0.888), renal oncocytoma (RO) (0.745 vs. 0.679), and angiomyolipoma without visible fat (AMLwvf) (0.826 vs. 0.766). Interobserver agreement for SRMs between ccLS v1.0 and v2.0 is comparable and was not statistically significant (P = 0.993). CONCLUSION: The diagnostic performance of ccLS v2.0 surpasses that of ccLS v1.0 for characterizing ccRCC, pRCC, RO, and AMLwvf. Especially, the standardized algorithm has optimal performance for ccRCC and pRCC. ccLS has potential as a supportive clinical tool. EVIDENCE LEVEL: 4. TECHNICAL EFFICACY: Stage 2.

Clinical and genome-wide association analysis of chemoradiation-induced hearing loss in nasopharyngeal carcinoma.

Chemoradiation-induced hearing loss (CRIHL) is one of the most devasting side effects for nasopharyngeal carcinoma (NPC) patients, which seriously affects survivors' long-term quality of life. However, few studies have comprehensively characterized the risk factors for CRIHL. In this study, we found that age at diagnosis, tumor stage, and concurrent cisplatin dose were positively associated with chemoradiation-induced hearing loss. We performed a genome-wide association study (GWAS) in 777 NPC patients and identified rs1050851 (within the exon 2 of NFKBIA), a variant with a high deleteriousness score, to be significantly associated with hearing loss risk (HR = 5.46, 95% CI 2.93-10.18, P = 9.51 × 10-08). The risk genotype of rs1050851 was associated with higher NFKBIA expression, which was correlated with lower cellular tolerance to cisplatin. According to permutation-based enrichment analysis, the variants mapping to 149 hereditary deafness genes were significantly enriched among GWAS top signals, which indicated the genetic similarity between hereditary deafness and CRIHL. Pathway analysis suggested that synaptic signaling was involved in the development of CRIHL. Additionally, the risk score integrating genetic and clinical factors can predict the risk of hearing loss with a relatively good performance in the test set. Collectively, this study shed new light on the etiology of chemoradiation-induced hearing loss, which facilitates high-risk individuals' identification for personalized prevention and treatment.

Genomic Landscapes of Epstein-Barr Virus in Pulmonary Lymphoepithelioma-Like Carcinoma.

Epstein-Barr virus (EBV) infection is associated with multiple malignancies, including pulmonary lymphoepithelioma-like carcinoma (pLELC), a particular subtype of primary lung cancer. However, the genomic characteristics of EBV related to pLELC remain unclear. Here, we obtained the whole-genome data set of EBV isolated from 78 pLELC patients and 37 healthy controls using EBV-captured sequencing. Compared with the reference genome (NC_007605), a total of 3,995 variations were detected across pLELC-derived EBV sequences, with the mutational hot spots located in latent genes. Combined with 180 published EBV sequences derived from healthy people in Southern China, we performed a genome-wide association study and identified 32 variations significantly related to pLELC (P < 2.56 × 10-05, Bonferroni correction), with the top signal of single nucleotide polymorphism (SNP) coordinate T7327C (OR = 1.22, P = 2.39 × 10-15) locating in the origin of plasmid replication (OriP). The results of population structure analysis of EBV isolates in East Asian showed the EBV strains derived from pLELC were more similar to those from nasopharyngeal carcinoma (NPC) than other EBV-associated diseases. In addition, typical latency type-II infection were recognized for EBV of pLELC at both transcription and methylation levels. Taken together, we defined the global view of EBV genomic profiles in pLELC patients for the first time, providing new insights to deepening our understanding of this rare EBV-associated primary lung carcinoma. IMPORTANCE Pulmonary lymphoepithelioma-like carcinoma (pLELC) is a rare, distinctive subtype of primary lung cancer closely associated with Epstein-Barr virus (EBV) infection. Here, we gave the first overview of pLELC-derived EBV at the level of genome, methylation and transcription. We obtained the EBV sequences data set from 78 primary pLELC patients, and revealed the sequences diversity across EBV genome and detected variability in known immune epitopes. Genome-wide association analysis combining 217 healthy controls identifies significant variations related to the risk of pLELC. Meanwhile, we characterized the integration landscapes of EBV at the genome-wide level. These results provided new insight for understanding EBV's role in pLELC tumorigenesis.

Peptidome-wide association analysis of Epstein-Barr virus identifies epitope repertoires associated with nasopharyngeal carcinoma.

Human leukocyte antigen (HLA) molecules are essential for presenting Epstein-Barr virus (EBV) antigens and are closely related to nasopharyngeal carcinoma (NPC). This study aims to systematically investigate the association between HLA-bound EBV peptides and NPC risk through in silico HLA-peptide binding prediction. A total of 455 NPC patients and 463 healthy individuals in NPC endemic areas were recruited, and HLA-target sequencing was performed. HLA-peptide binding prediction for EBV, followed by peptidome-wide logistic regression and motif analysis, was applied. Binding affinity changes for EBV peptides carrying high-risk mutations were analyzed. We found that NPC-associated EBV peptides were significantly enriched in immunogenic proteins and core linkage disequilibrium (LD) proteins related to evolution, especially those binding HLA-A alleles (p = 3.10 × 10-4 for immunogenic proteins and p = 8.10 × 10-5 for core LD proteins related to evolution). These peptides were clustered and showed binding motifs of HLA supertypes, among which supertype A02 presented an NPC-risk effect (padj = 3.77 × 10-4 ) and supertype A03 presented an NPC-protective effect (padj = 4.89 × 10-4 ). Moreover, a decreased binding affinity toward risk HLA supertype A02 was observed for the peptide carrying the NPC-risk mutation BNRF1 V1222I (p = 0.0078), and an increased binding affinity toward protective HLA supertype A03 was observed for the peptide carrying the NPC-risk mutation BALF2 I613V (p = 0.022). This study revealed the distinct preference of EBV peptides for binding HLA supertypes, which may contribute to shaping EBV population structure and be involved in NPC development.

The interaction and mediation effects between the host genetic factors and Epstein-Barr virus VCA-IgA in the risk of nasopharyngeal carcinoma.

Previous studies have demonstrated strong associations between host genetic factors and Epstein-Barr virus (EBV) VCA-IgA with the risk of nasopharyngeal carcinoma (NPC). However, the specific interplay between host genetics and EBV VCA-IgA on NPC risk is not well understood. In this two-stage case-control study (N = 4804), we utilized interaction and mediation analysis to investigate the interplay between host genetics (genome-wide association study-derived polygenic risk score [PRS]) and EBV VCA-IgA antibody level in the NPC risk. We employed a four-way decomposition analysis to assess the extent to which the genetic effect on NPC risk is mediated by or interacts with EBV VCA-IgA. We consistently found a significant interaction between the PRS and EBV VCA-IgA on NPC risk (discovery population: synergy index [SI] = 2.39, 95% confidence interval [CI] = 1.85-3.10; replication population: SI = 3.10, 95% CI = 2.17-4.44; all pinteraction < 0.001). Moreover, the genetic variants included in the PRS demonstrated similar interactions with EBV VCA-IgA antibody. We also observed an obvious dose-response relationship between the PRS and EBV VCA-IgA antibody on NPC risk (all ptrend < 0.001). Furthermore, our decomposition analysis revealed that a substantial proportion (approximately 90%) of the genetic effects on NPC risk could be attributed to host genetic-EBV interaction, while the risk effects mediated by EBV VCA-IgA antibody were weak and statistically insignificant. Our study provides compelling evidence for an interaction between host genetics and EBV VCA-IgA antibody in the development of NPC. These findings emphasize the importance of implementing measures to control EBV infection as a crucial strategy for effectively preventing NPC, particularly in individuals at high genetic risk.

Design and Screening of Fluorescent Probes Based upon Hemicyanine Dyes to Sensitively Respond to HSO3- in Living Cells.

SO2, a gas signaling molecule, can be produced endogenously in mitochondria. Its hydrolysate, HSO3-, plays a key role in food preservation, cardiovascular relaxation, and other fields, suggesting that it is important to achieve its detection. Here, based on the Michael addition mechanism, four hemicyanine dye fluorescent probes (ETN, ETB, STB, and EIB) were designed and synthesized for responding to HSO3-. We evaluated the reaction ability of different probes with HSO3- and tried to explain the reasons for the significantly different response effects between probes and HSO3- according to the structure-activity relationship. The influence of different substituents of probes on the properties of mitochondria-targeting was also discussed. Finally, we screened out ETN as the optimal HSO3- probe due to its high sensitivity, rapid reactivity, and good mitochondria-targeting, and it could sensitively respond to HSO3- in living cells. The LODs of ETN for HSO3- were calculated by both absorption and fluorescence methods, respectively, which were 2.727 and 0.823 µM. Our work provided valuable references for designing strategies and potential tools for response to SO2 derivatives in biosystems.

Proxalutamide for the treatment of COVID-19 rebound following Paxlovid treatment: Report of four cases and review of the literature.

BACKGROUND: The pandemic the coronavirus disease 2019 (COVID-19) has created a global health crisis. Although Paxlovid is recommended for the early-stage treatment of mild-to-moderate COVID-19 in patients at increased risk of progression to severe COVID-19, more and more cases are reported a COVID-19 rebound after Paxlovid treatment. Currently, information on the additional treatment for COVID-19 rebound following Paxlovid treatment is limited. CASE REPORT: Here, we present four cases with COVID-19 who were mild on admission. All cases experienced a COVID-19 rebound and progressed to severe COVID-19, following treatment with Paxlovid (300 mg of nirmatrelvir with 100 mg ritonavir, twice daily for 5 days). After being treated with proxalutamide (300 mg/day), all cases finally turned real-time reverse transcription polymerase chain reaction (RT-PCR) negative. CONCLUSION: Our cases suggested that proxalutamide might be an effective remedial treatment option for patients experiencing a COVID-19 rebound after Paxlovid treatment.

Genomic landscape of Epstein-Barr virus in familial nasopharyngeal carcinoma.

To better understand the genomic characteristics of Epstein-Barr virus (EBV) in familial nasopharyngeal carcinoma (NPC), we sequenced the EBV genomes by whole-genome capture in 38 unrelated patients with NPC family history in first-degree relatives and 47 healthy controls, including 13 with family history and 34 without. Compared with type 1 reference genome, mutation hotspots were observed in the latent gene regions of EBV in familial NPC cases. Population structure analysis showed that one cluster has a higher frequency in familial cases than in controls (OR=5.33, 95 % CI 2.50-11.33, P=1.42×10-5), and similar population structure composition was observed among familial and sporadic NPC cases in high-endemic areas. By genome-wide association analysis, four variants were found to be significantly associated with familial NPC. Consistent results were observed in the meta-analysis integrating two published case-control EBV sequencing studies in NPC high-endemic areas. High-risk haplotypes of EBV composed of 34 variants were associated with familial NPC risk (OR=13.85, 95 % CI 4.13-46.44, P=2.06×10-5), and higher frequency was observed in healthy blood-relative controls with NPC family history (9/13, 69.23 %) than those without family history (16/34, 47.06%). This study suggested the potential contribution of EBV high-risk subtypes to familial aggregation of NPC.

Burden, trends, and risk factors for breast cancer in China from 1990 to 2019 and its predictions until 2034: an up-to-date overview and comparison with those in Japan and South Korea.

BACKGROUND: The difference in epidemiological characteristics of breast cancer (BC) across countries is valuable for BC management and prevention. The study evaluated the up-to-date burden, trends, and risk factors of BC in China, Japan and South Korea during 1990-2019 and predicted the BC burden until 2034. METHODS: Data on incident cases, deaths, disability-adjusted life-years (DALYs) and age-standardized rate (ASR) of BC were extracted from the Global Burden of Disease Study 2019. Trend analysis and prediction until 2034 were conducted by estimated annual percentage change and a Bayesian age-period-cohort model, respectively. Besides, the attributable burden to BC risk factors was also estimated. RESULTS: In 2019, the number of BC incident cases, deaths and DALYs in China were 375,484, 96,306 and 2,957,453, respectively. The ASR of incidence increased, while that of death and DALYs decreased for Chinese females and Japanese and South Korean males during 1990-2019. High body-mass-index (BMI) was the largest contributor to Chinese female BC deaths and DALYs, while alcohol use was the greatest risk factor for Japanese and South Korean as well as Chinese males. The incident cases and deaths were expected to continue increase during 2020-2034 (except for Japanese female incident cases). CONCLUSIONS: China had the greatest burden of BC among the three countries. Incident cases and deaths of BC were projected to increase over the next 15 years in China, particularly among Chinese males. Effective prevention and management strategies are urgently necessary for BC control in China.

Preoperatively predicting early response of HCC to TACE using clinical indicators and MRI features.

BACKGROUND: We aimed to evaluate the value of using preoperative magnetic resonance imaging (MRI) features and clinical indicators to predict the early response of hepatocellular carcinoma (HCC) to transcatheter arterial chemoembolization (TACE). We also aimed to establish a preoperative prediction model. METHODS: We retrospectively reviewed data of 111 patients with HCC who underwent magnetic resonance imaging (MRI) before the first TACE and underwent MRI or computed tomography between 30 and 60 days after TACE. We used the modified response evaluation criteria in solid tumors for evaluating the TACE response. We used univariate and multivariate logistic regression analyses to identify independent predictors based on MRI features and clinical indicators. Moreover, receiver operating characteristic (ROC) curve analyses were performed to assess the diagnostic performance of the prediction model and each independent predictor. RESULTS: Among the 111 included patients, 85 were men (76.6%). Patient age was 31-86 years (average age, 61.08 ± 11.50 years). After the first treatment session, 56/111 (50.5%) patients showed an objective response (complete response + partial response), whereas the remaining showed non-response (stable disease + local progressive disease). In the univariate analysis, we identified irregular margins, number of nodules, and satellite nodules as predictors of early objective response. However, in the multivariate logistic regression analysis, irregular margins, number of nodules and pretreatment platelet were identified as the independent predictors of early objective response. A combined prediction model was then established, which factored in irregular margins, the number of nodules, and the pretreatment platelet count. This model showed good diagnostic performance (area under the ROC curve = 0.755), with the sensitivity, specificity, positive predictive value, and negative predictive value being 78.6%, 69.1%, 72.1%, and 76.0%, respectively. CONCLUSIONS: Irregular margins, the number of nodules and the pretreatment platelet count are independent predictors of the early response of HCC to TACE. Our clinical combined model can provide a superior predictive power to a single indicator.

Association between HLA alleles and Epstein-Barr virus Zta-IgA serological status in healthy males from southern China.

BACKGROUND: Nasopharyngeal carcinoma (NPC), an Epstein-Barr virus (EBV) associated cancer, exhibits an extremely high incidence in southern Chinese. Given that human leukocyte antigen (HLA) plays critical roles in antigen presentation and relates to NPC susceptibility, it is speculated that certain HLA variants may affect EBV reactivation, which is a key pathogenic factor of NPC. Therefore, we attempted to identify HLA alleles associated with the indicator of EBV reactivation, Zta-IgA, in healthy males from NPC endemic area. METHODS: HLA alleles of 1078 healthy males in southern China from the 21-RCCP study were imputed using genome-wide single nucleotide polymorphism data. EBV Zta-IgA in blood samples were measured using an enzyme-linked immunosorbent assay. Multiple logistic regression analysis was used to evaluate the effect of HLA allele on Zta-IgA serological status and its potential joint association with smoking. The binding affinity for Zta-peptide was predicted using NetMHCIIpan 4.0. RESULTS: HLA-DRB1*09:01 was found to be associated with a higher risk of Zta-IgA seropositivity (odds ratio = 1.80, 95% confidence interval = 1.32-2.45; p = 1.82 × 10-4 ). Compared with non-smokers without HLA-DRB1*09:01, the effect size increased to 2.19- and 3.70-fold for the light and heavy smokers carrying HLA-DRB1*09:01, respectively. Furthermore, HLA-DRB1*09:01 showed a stronger binding affinity to Zta peptide than other HLA-DRB1 alleles. CONCLUSIONS: Our study highlighted the pivotal role of genetic HLA variants in EBV reactivation and the etiology of NPC. Smokers with HLA-DRB1*09:01 have a significantly higher risk of being Zta-IgA seropositive, which indicates the necessity of smoking cessation in certain high-risk populations and also provide clues for further research on the etiology of NPC.

A fecal-based test for the detection of advanced adenoma and colorectal cancer: a case-control and screening cohort study.

BACKGROUND: Colorectal cancer (CRC) is the leading cause of cancer death worldwide. Screening is a confirmed way to reduce the incidence and mortality rates of CRC. This study aimed to identify a fecal-based, noninvasive, and accurate method for detection of colorectal cancer (CRC) and advanced adenoma (AA). METHODS: Through detection in tissue (n = 96) and fecal samples (n = 88) and tested in an independent group of fecal samples (n = 294), the methylated DNA marker ITGA4 and bacterial markers Fusobacterium nucleatum (Fn) and Pepetostreptococcusanaerobius (Pa) were identified from the candidate biomarkers for CRC and AA detection. A prediction score (pd-score) was constructed using the selected markers and fecal immunochemical test (FIT) for distinguishing AA and CRC from healthy subjects by logistic regression method. The diagnostic performance of the pd-score was compared with FIT and validated in the external validation cohort (n = 117) and in a large CRC screening cohort. RESULTS: The pd-score accurately identified AA and CRC from healthy subjects with an area under the curve (AUC) of 0.958, at a specificity of 91.37%; the pd-score showed sensitivities of 95.38% for CRC and 70.83% for AA, respectively. In the external validation cohort, the sensitivities of the pd-score for CRC and AA detection were 94.03% and 80.00%, respectively. When applied in screening, the pd-score identified 100% (11/11) of CRC and 70.83% (17/24) of AA in participants with both colonoscopy results and qualified fecal samples, showing an improvement by 41.19% compared to FIT. CONCLUSIONS: The current study developed a noninvasive and well-validated approach for AA and CRC detection, which could be applied widely as a diagnostic and screening test.

Does Training in LI-RADS Version 2018 Improve Readers' Agreement with the Expert Consensus and Inter-reader Agreement in MRI Interpretation?

BACKGROUND: The Liver Imaging Reporting and Data System (LI-RADS) was established for noninvasive diagnosis for hepatocellular carcinoma (HCC). However, whether training can improve readers' agreement with the expert consensus and inter-reader agreement for final categories is still unclear. PURPOSE: To explore training effectiveness on readers' agreement with the expert consensus and inter-reader agreement. STUDY TYPE: Prospective. SUBJECTS: Seventy lesions in 61 patients at risk of HCC undergoing liver MRI; 20 visiting scholars. FIELD STRENGTH/SEQUENCE: 1.5 T or 3 T, Dual-echo T1 WI, Fast spin-echo T2 WI, SE-EPI DWI, and Dynamic multiphase fast gradient-echo T1 WI. ASSESSMENT: Seventy lesions assigned LI-RADS categories of LR1-LR5, LR-M, and LR-TIV by three radiologists in consensus were randomly selected, with 10 cases for each category. The consensus opinion was the standard reference. The third radiologist delivered the training. Twenty readers reviewed images independently and assigned each an LI-RADS category both before and after the training. STATISTICAL TESTS: Accuracy, sensitivity, specificity, positive predictive value, negative predictive value, positive likelihood ratio, negative likelihood ratio, receiver operating characteristic (ROC) analysis, simple and weighted kappa statistics, and Fleiss kappa statistics. RESULTS: Before and after training: readers' AUC (areas under ROC) for LR-1-LR-5, LR-M, and LR-TIV were 0.898 vs. 0.913, 0.711 vs. 0.876, 0.747 vs. 0.860, 0.724 vs. 0.815, 0.844 vs. 0.895, 0.688 vs. 0.873, and 0.720 vs. 0.948, respectively, and all improved significantly (P < 0.05), except LR-1(P = 0.25). Inter-reader agreement between readers for LR-1-LR-5, LR-M, LR-TIV were 0.725 vs. 0.751, 0.325 vs. 0.607, 0.330 vs. 0.559, 0.284 vs. 0.488, 0.447 vs. 0.648, 0.229 vs. 0.589, and 0.362 vs. 0.852, respectively, and all increased significantly (P < 0.05). For training effectiveness on both AUC and inter-reader agreement, LR-TIV, LR-M, and LR-2 improved most, and LR-1 made the least. DATA CONCLUSION: This study shows LI-RADS training could improve reader agreement with the expert consensus and inter-reader agreement for final categories. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY STAGE: 2.

Scan Time Reduction in Intravoxel Incoherent Motion Diffusion-Weighted Imaging and Diffusion Kurtosis Imaging of the Abdominal Organs: Using a Simultaneous Multislice Technique With Different Acceleration Factors.

OBJECTIVE: To investigate the feasibility of quantitative intravoxel incoherent motion (IVIM) and diffusion kurtosis imaging (DKI) analyses in the upper abdominal organs by simultaneous multislice diffusion-weighted imaging (SMS-DWI). SUBJECTS AND METHODS: In this prospective study, a total of 32 participants underwent conventional DWI (C-DWI) and SMS-DWI sequences with acceleration factors of 2 and 3 (SMS2-DWI and SMS3-DWI, respectively) in the upper abdomen with multiple b-values (0, 10, 20, 50, 80, 100, 150, 200, 500, 800, 1000, 1500, and 2000 seconds/mm2) on a 3 T system (MAGNETOM Prisma; Siemens Healthcare, Erlangen, Germany). Image quality and quantitatively measurements of apparent diffusion coefficient (ADC), true diffusion coefficient (D), pseudodiffusion coefficient (D*), perfusion fraction (f), mean kurtosis (MK), and mean apparent diffusivity (MD) for the liver, pancreas, kidney cortex and medulla, spleen, and erector spine muscle were compared between the 3 sequences. RESULTS: The acquisition times for C-DWI, SMS2-DWI, and SMS3-DWI were 10 minutes 57 seconds, 5 minutes 9 seconds, and 3 minutes 54 seconds. For image quality parameters, C-DWI and SMS2-DWI yielded better results than SMS3-DWI (P < 0.05). SMS2-DWI had equivalent IVIM and DKI parameters compared with that of C-DWI (P > 0.05). No statistically significant differences in the ADC, D, f, and MD values between the 3 sequences (P > 0.05) were observed. The D* and MK values of the liver (P = 0.005 and P = 0.012) and pancreas (P = 0.019) between SMS3-DWI and C-DWI were significantly different. CONCLUSIONS: SMS2-DWI can substantially reduce the scan time while maintaining equivalent IVIM and DKI parameters in the abdominal organs compared with C-DWI.

Feasibility study of simultaneous multislice diffusion kurtosis imaging with different acceleration factors in the liver.

BACKGROUND: Simultaneous multislice diffusion-weighted imaging (SMS-DWI) has been used to reduce image acquisition time. The purpose of this study was to investigate the feasibility of diffusion kurtosis imaging (DKI) based on the SMS technique in the liver and the influence of this method compared with that of conventional DWI sequences on image quality and DKI-derived quantitative parameters. METHODS: Forty volunteers underwent SMS-DWI sequences with acceleration factors of 2 and 3 (SMS2-DWI, SMS3-DWI) and conventional DWI (C-DWI) of the liver with three b-values (50, 800, 2000 s/mm2) in a 3T system. Qualitative image quality parameters and quantitative measurements of the signal-to-noise ratio (SNR), mean kurtosis (MK), mean apparent diffusivity (MD) and apparent diffusion coefficient (ADC) for the liver were compared between the three sequences. RESULTS: The scan times of C-DWI, SMS2-DWI, and SMS3-DWI were 4 min 11 s, 2 min 2 s, and 1 min 34 s, respectively. For all image quality parameters, there were no significant differences observed between C-DWI and SMS2-DWI (all p > 0.05) in the images with b-values of 800 and 2000 s/mm2. C-DWI and SMS2-DWI exhibited better scores than SMS3-DWI (all p < 0.01) in the images with b-values of 2000 s/mm2. In the images with b-values of 800 s/mm2, C-DWI and SMS2-DWI exhibited better scores than SMS3-DWI for artefacts and overall image quality (all p < 0.01), and C-DWI exhibited better scores than SMS3-DWI for the visibility of intrahepatic vessels (p < 0.001). There were no significant differences in the sharpness of the right lobe edge (p = 0.144), conspicuity of the left lobe (p = 0.370) or visibility of intrahepatic vessels (p = 0.109) between SMS2-DWI and SMS3-DWI. There were no significant differences in the sharpness of the right lobe edge (p = 0.066) or conspicuity of the left lobe (p = 0.131) between C-DWI and SMS3-DWI. For the b-value of 800 s/mm2, there were no statistically significant differences between SMS2-DWI and C-DWI (p = 1.000) or between SMS2-DWI and SMS3-DWI (p = 0.059), whereas SMS3-DWI had a significantly lower SNR than C-DWI (p = 0.024). For the DKI-derived parameters (MK and MD) and ADC values, there were no significant differences between the three sequences (MK, p = 0.606; MD, p = 0.831; ADC, p = 0.264). CONCLUSIONS: SMS-DWI with an acceleration factor of 2 is feasible for the liver, resulting in considerable reductions in scan time while maintaining similar image quality, comparable DKI parameters and ADC values compared with those of C-DWI.

Genome-wide association study identifies genetic susceptibility loci and pathways of radiation-induced acute oral mucositis.

BACKGROUND: Radiation-induced oral mucositis (OM) is one of the most common acute complications for head and neck cancer. Severe OM is associated with radiation treatment breaks, which harms successful tumor management. Radiogenomics studies have indicated that genetic variants are associated with adverse effects of radiotherapy. METHODS: A large-scale genome-wide scan was performed in 1467 nasopharyngeal carcinoma patients, including 753 treated with 2D-CRT from Genetic Architecture of the Radiotherapy Toxicity and Prognosis (GARTP) cohort and 714 treated with IMRT (192 from the GARTP and 522 newly recruited). Subgroup analysis by radiotherapy technique was further performed in the top associations. We also performed physical and regulatory mapping of the risk loci and gene set enrichment analysis of the candidate target genes. RESULTS: We identified 50 associated genomic loci and 64 genes via positional mapping, expression quantitative trait locus (eQTL) mapping, chromatin interaction mapping and gene-based analysis, and 36 of these loci were replicated in subgroup analysis. Interestingly, one of the top loci located in TNKS, a gene relevant to radiation toxicity, was associated with increased OM risk with OR = 3.72 of the lead SNP rs117157809 (95% CI 2.10-6.57; P = 6.33 × 10-6). Gene set analyses showed that the 64 candidate target genes were enriched in the biological processes of regulating telomere capping and maintenance and telomerase activity (Top P = 7.73 × 10-7). CONCLUSIONS: These results enhance the biological understanding of radiotherapy toxicity. The association signals enriched in telomere function regulation implicate the potential underlying mechanism and warrant further functional investigation and potential individual radiotherapy applications.

Nasopharyngeal Epstein-Barr virus DNA loads in high-risk nasopharyngeal carcinoma families: Familial aggregation and host heritability.

Nasopharyngeal carcinoma (NPC), the most common head and neck cancer, is characterized by distinct geographic distribution and familial aggregation. Multiple risk factors, including host genetics, environmental factor, and EBV infection, have been linked to the development of NPC, particularly in the familial clustering cases. However, the cause of NPC endemicity remains enigmatic due possibly to the complicated interplay between these risk factors. Recently, positive Epstein-Barr virus (EBV) DNA loads at nasopharyngeal (NP) cavity has been found to reflect NPC development and applied in NPC screening. To examine whether the increased NP EBV loads could aggregate in the families and be affected by host genetics and environmental factor, EBV loads were obtained by 510 NP brushing samples from eligible unaffected individuals, who have two or more relatives affected with NPC, in 116 high-risk NPC families. The correlation of relative pairs was estimated using S.A.G.E. (version 6.4, 2016), and host heritability of NP EBV loads was calculated with variance component models using SOLAR (version 8.4.2, 2019). In result, significant correlations of EBV loads were observed between parent-offspring pairs and sibling-sibling pairs (P < .001), but not in distant kin relationship pairs. Interestingly, after excluding the shared environmental factor within families, host genetics contributes significantly to NP EBV loads with a heritability of 56.41% (P = 1.00 × 10-7 ), and its effect was slightly elevated (68.86%, P = 3.40 × 10-6 ) in families with more NPC cases (≥3). These findings indicate that additional host-genetic variants involved in the EBV local NP mucosal behavior may be especially important for the development of NPC.