Machine learning and new insights for breast cancer diagnosis.

Breast cancer (BC) is the most prominent form of cancer among females all over the world. The current methods of BC detection include X-ray mammography, ultrasound, computed tomography, magnetic resonance imaging, positron emission tomography and breast thermographic techniques. More recently, machine learning (ML) tools have been increasingly employed in diagnostic medicine for its high efficiency in detection and intervention. The subsequent imaging features and mathematical analyses can then be used to generate ML models, which stratify, differentiate and detect benign and malignant breast lesions. Given its marked advantages, radiomics is a frequently used tool in recent research and clinics. Artificial neural networks and deep learning (DL) are novel forms of ML that evaluate data using computer simulation of the human brain. DL directly processes unstructured information, such as images, sounds and language, and performs precise clinical image stratification, medical record analyses and tumour diagnosis. Herein, this review thoroughly summarizes prior investigations on the application of medical images for the detection and intervention of BC using radiomics, namely DL and ML. The aim was to provide guidance to scientists regarding the use of artificial intelligence and ML in research and the clinic.

Design, Synthesis, and Evaluation of [18F]BIBD-300 as a Positron Emission Tomography Tracer for Poly(ADP-Ribose) Polymerase-1.

Compounds 8a-j were designed to adjust the mode of interaction and lipophilicity of FTT by scaffold hopping and changing the length of the alkoxy groups. Compounds 8a, 8d, 8g, and BIBD-300 were screened for high-affinity PARP-1 through enzyme inhibition assays and are worthy of further evaluation. PET imaging of MCF-7 subcutaneous tumors with moderate expression of PARP-1 showed that compared to [18F]FTT, [18F]8a, [18F]8d, and [18F]8g exhibited greater nonspecific uptake, a lower target-to-nontarget ratio, and severe defluorination, while [18F]BIBD-300 exhibited lower nonspecific uptake and a greater target-to-nontarget ratio. PET imaging of 22Rv1 subcutaneous tumors, which highly express PARP-1, confirmed that the uptake of [18F]BIBD-300 in normal organs, such as the liver, muscle, and bone, was lower than that of [18F]FTT, and the ratio of tumor-to-muscle and tumor-to-liver [18F]BIBD-300 was greater than that of [18F]FTT. The biodistribution results in mice with MCF-7 and 22Rv1 subcutaneous tumors further validated the results of PET imaging. Unlike [18F]FTT, which mainly relies on hepatobiliary clearance, [18F]BIBD-300, which has lower lipophilicity, undergoes a partial shift from hepatobiliary to renal clearance, providing the possibility for [18F]BIBD-300 to indicate liver cancer. The difference in the PET imaging results for [18F]FTT, [18F]BIBD-300, and [18F]8j in 22Rv1 mice and the corresponding molecular docking results further confirmed that subtle structural modifications in lipophilicity greatly optimize the properties of the tracer. Cell uptake experiments also demonstrated that [18F]BIBD-300 has a high affinity for PARP-1. Metabolized and unmetabolized [18F]FTT and [18F]BIBD-300 were detected in the brain, indicating that they could not accurately quantify the amount of PARP-1 in the brain. However, PET imaging of glioma showed that both [18F]FTT and [18F]BIBD-300 could accurately localize both in situ to C6 and U87MG tumors. Based on its potential advantages in the diagnosis of breast cancer, prostate cancer, and glioma, as well as liver cancer, [18F]BIBD-300 is a new option for an excellent PARP-1 tracer.

18F-Labeled PET Tracers Specific for Adenosine A2A Receptor: Design, Synthesis, and Biological Evaluation.

By modifying the structures of targeted A2AR antagonists and tracers, novel compounds 3, 7a, 9, 12c, and BIBD-399 were designed and synthesized. In vitro inhibition experiments demonstrated that 3, 12c, and BIBD-399 have high affinity for A2AR. [18F]3 and [18F]BIBD-399 were successfully synthesized. In terms of biological distribution, the brain uptake of [18F]MNI-444 exhibits greater than that of [18F]3 and [18F]BIBD-399. PET imaging shows that [18F]3 is off-target in the brain, while [18F]BIBD-399 and [18F]MNI-444 can be specifically imaged in regions with high A2AR expression. Differently, [18F]BIBD-399 could quickly reach equilibrium in the targeted region within 10 min after administration, while [18F]MNI-444 shows a slowly increasing trend within 2 h of administration. [18F]BIBD-399 is mainly metabolized by the liver and kidney, and there is no obvious defluorination in vivo. Additional in vitro autoradiography showed that the striatal signals of [18F]BIBD-399 and [18F]MNI-444 were inhibited by the A2AR antagonist SCH442416 but not by the A1R antagonist DPCPX, demonstrating the high A2AR binding specificity of [18F]BIBD-399. Molecular docking further confirms the high affinity of MNI-444 and BIBD-399 for A2AR. Further tMCAo imaging showed that [18F]BIBD-399 can sensitively distinguish between infarcted and noninfarcted sides, a capability not observed with [18F]MNI-444. Given its pharmacokinetic properties and the ability to identify lesion regions, [18F]BIBD-399 has potential advantages in monitoring A2AR changes, meriting further clinical investigation.

T2-weighted Imaging Features of the Fetal Thymus in the Middle and Late Pregnancy: A Post-mortem Study based on Magnetic Resonance Imaging.

BACKGROUND: Fat-suppressed (FS) T2-weighed turbo spin-echo (TSE) sequence was used to detect the signal of the thymus and the characteristics of the thymus location, measure the two-dimensional diameter at specific levels, and analyze the association with gestational weeks. METHODS: This study involved 51 fetal specimens. Post-mortem MRI scanning was implemented with a 3.0-T MRI system. T2-weighted imaging (T2WI) features of the thymus in fetuses were quantitatively investigated with DICOM images. Statistical analysis was done with the Chi-Square test, oneway ANOVA, and Student's t-test. RESULTS: There was heterogeneity in the morphology of the fetal thymus. FS T2-weighted TSE sequence clearly exhibited the microstructure of the fetal thymus. The thymus extensively showed a lobulated appearance. The central signal is much higher than the peripheral signal in each lobule. In addition, FS-T2WI images can clearly show the interlobular septum, which is filled with fluid and presents a linear high signal. The signal intensity of fetal thymus increased with gestational weeks. The diameter measured in a particular plane was highly correlated with gestational week. CONCLUSION: FS T2-weighted TSE sequence provides high-resolution images of the fetal thymus. The change in signal intensity, location, and two-dimensional diameter in a specific plane can be used as a research direction for the fetal thymus.

Predictive value of infiltrating tumor border configuration of rectal cancer on MRI.

BACKGROUND: Infiltrating tumor border configuration (iTBC) is assessed by postoperative pathological examination, thus, is not helpful for preoperative treatment strategies. The study aimed to detect iTBC by magnetic resonance imaging (MRI) and evaluate its predictive value. MATERIALS AND METHODS: A total of 153 patients with rectal cancer were retrospectively analyzed. Clinicopathological and MRI data mainly including tumor border configuration (TBC) on MRI, MRI-detected extramural vascular invasion (MEMVI), tumor length, tumor growth pattern, maximal extramural depth, pathology-proven lymph node metastasis (PLN) and pathology-proven extramural vascular invasion (PEMVI) were analyzed. The correlation of MRI factors with PEMVI and PLN was analyzed by univariate and multivariate logistic regression analyses. The nomograms were established based on multivariate logistic regression analysis and were confirmed by Bootstrap self-sampling. The receiver operating characteristic (ROC) curve analysis and area under the curve (AUC) were used to evaluate the diagnostic efficiency. RESULTS: Fifty cases of PEMVI and 48 cases of PLN were found. Forty cases of PEMVI and 34 cases of PLN in 62 cases of iTBC were also found. iTBC, MEMVI and maximal extramural depth were significantly associated with PEMVI and PLN (P < 0.05). iTBC (odds ratio = 3.84 and 3.02) and MEMVI (odds ratio = 7.27 and 3.22) were independent risk factors for PEMVI and PLN. The C-indices of the two nomograms for predicting PEMVI and PLN were 0.863 and 0.752, respectively. The calibration curves and ROC curves of the two nomograms showed that the correlation between the predicted and the actual incidence of PEMVI and PLN was good. The AUCs of iTBC for predicting PEMVI and PLN were 0.793 (95% CI: 0.714-0.872) and 0.721 (95% CI: 0.632-0.810), respectively. The DeLong test showed that the predictive efficiency of the nomogram in predicting PEMVI was better than that of iTBC (P = 0.0009) and MEMVI (P = 0.0095). CONCLUSION: iTBC and MEMVI are risk factors for PEMVI and pelvic lymph node metastasis. The nomograms based on iTBC show a good performance in predicting PEMVI and pelvic lymph node metastasis, possessing a certain clinical reference value. TRIAL REGISTRATION: This study was approved by the Ethics Committee of Beijing Friendship Hospital, and individual consent was waived for this retrospective analysis.

Typical metabolic pattern of 18F-FDG PET in Anti-NMDAR encephalitis in the acute and subacute phases and its correlation with T2 FLAIR-MRI features.

BACKGROUND/AIMS: Early diagnosis of Anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis with non-invasive imaging modalities benefiting is crucial to guarantee prompt treatments decision-making and good prognosis for patients. The present study aimed to explore the correlation of MRI features with brain metabolism characteristics of 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) and to describe the metabolic patterns in Anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis at acute and subacute phases. Twenty-four patients with anti-NMDAR encephalitis confirmed by serum and/or CSF tests at acute and subacute phases, 9 females and 15 males, with an age range of 6-80 years, were enrolled in this retrospective study as encephalitis group. 18F-FDG PET and MRI findings of all patients were investigated and interpreted with visual analysis. Chi-square test was performed to compare the diagnostic sensitivity between MRI and PET. Independent sample t-test was used to compare the standardized uptake value ratio (SUVR) of each ROI between the encephalitis group and control group, which consisted of 24 healthy volunteers of the same age and gender. RESULTS: There was no statistical difference in the diagnostic sensitivity between FDG PET (23/24, 95.83%) and MRI (18/24, 75.00%) in anti-NMDAR encephalitis patients (P > 0.05). Three categories of abnormalities shown on T2 FLAIR, including shallow of sulci and swelling of brain tissue, increased signal in the sulci, increased signal on brain gray matter or adjacent white matter presented hypermetabolism on PET, excepting increased signal in brain linear structure with hypometabolism of the basal ganglia on PET. We identified 19 brain regions with hypermetabolism and 16 brain regions with hypometabolism that exhibited statistically significant changes in SUVRs between anti-NMDAR encephalitis group and control group (FDR P < 0.05). CONCLUSION: Anteroposterior glucose metabolism gradient (frontal-temporal/parietal-occipital) is proved to be a typical pattern of anti-NMDAR encephalitis at the acute and subacute phases in both visual and statistical testing. Interestingly, the pattern is also commonly found in the anterior and posterior portions of the parietal lobe and cingular cortex, which may be a potential indicator for the diagnosis of this disorder. In addition, MRI is an important and reliable neuroimaging modality to assist in the correct evaluation of activity changes on individual 18F-FDG PET.

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.

Cortical metabolic characteristics of anti-leucine-rich glioma-inactivated 1 antibody encephalitis based on 18F-FDG PET.

Purpose: A general glucose metabolism pattern is observed in patients with anti-leucine-rich glioma-inactivated 1 (LGI1) antibody encephalitis; however, it is unclear whether further subregional metabolic differences exist. Therefore, the present study aimed to conduct an in-depth exploration of the features of glucose metabolism within specific brain areas using 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET). Materials and methods: This retrospective study enrolled thirteen patients confirmed with LGI1 antibody encephalitis who were admitted to Beijing Tiantan Hospital from June 2021 to September 2022. All patients underwent 18F-FDG PET before initiating clinical treatment. Changes in glucose metabolism in specific brain areas were analyzed using Cortex ID software. The laterality of 18F-FDG uptake was assessed, and differences in specific brain areas were compared using paired t-tests. Results: Significant metabolic changes in at least one brain region in 11 out of 13 patients (84.6%) were revealed by semi-quantitative analysis (z-score > 2). A bilateral decrease in the 18F-FDG metabolic pattern was revealed in almost all brain regions of interest; in contrast, a hypermetabolic pattern was observed in the medial temporal region, with mean z-scores of 1.75 ± 3.27 and 2.36 ± 5.90 on the left and right sides, respectively (p = 0.497). In the prefrontal and temporal lobes, 18F-FDG metabolism was significantly lower in the lateral region than in the medial region on both sides. For the cingulate cortex, significant hypometabolism was also observed in the posterior part compared to the anterior counterpart on both the left (z-score: -1.20 ± 1.93 vs. -0.42 ± 1.18, respectively; p = 0.047) and right (z-score: -1.56 ± 1.96 vs. -0.33 ± 1.63, respectively; p = 0.001) sides. However, a significant difference in regional metabolism was observed only on the left side (p = 0.041). Conclusion: An asymmetric 18F-FDG metabolic pattern exists in patients with anti-LGI1 encephalitis. Meanwhile, varied regional metabolic differences were revealed bilaterally in specific cerebral areas, which could be associated with the clinical manifestations.

Development and validation of a polygenic hazard score to predict prognosis and adjuvant chemotherapy benefit in early-stage non-small cell lung cancer.

Background: It remains controversial who would benefit from adjuvant chemotherapy (ACT) in patients with early-stage non-small cell lung cancer (NSCLC). We aim to construct a polygenic hazard score (PHS) to predict prognosis and ACT benefit among NSCLC patients. Methods: We conducted a retrospective study including 1,395 stage I-II NSCLC patients. We performed a genome-wide association study (GWAS) on overall survival (OS) in patients treated with ACT (SYSUCC ACT set, n=404), and then developed a PHS using LASSO Cox regression in a random subset (training, n=202) and tested it in the remaining set (test, n=202). The PHS was further validated in two independent datasets (SYSUCC surgery set, n=624; PLCO cohort, n=367). Results: The GWAS-derived PHS consisting of 37 single-nucleotide polymorphisms (SNPs) was constructed to classify patients into high and low PHS groups. For patients treated with ACT, those with low PHS had better clinical outcomes than high PHS (test set: HR =0.21, P<0.001; PLCO ACT set: HR =0.33, P=0.260). Similar results were found in the extended validation cohorts including patients with or without ACT (SYSUCC: HR =0.48, P<0.001; PLCO: HR =0.60, P=0.033). Within subgroup analysis by treatment or clinical factors, we further observed consistent results for the prognostic value of the PHS. Notably, ACT significantly improved OS in stage II patients with low PHS (HR =0.26, P<0.001), while there was no ACT survival benefit among patients with high PHS (HR =0.97, P=0.860). Conclusions: The PHS improved prognostic stratification and could help identify patients who were most likely to benefit from ACT in early-stage NSCLC.

Whole-Exome Sequencing Study of Familial Nasopharyngeal Carcinoma and Its Implication for Identifying High-Risk Individuals.

BACKGROUND: Nasopharyngeal carcinoma (NPC) is closely associated with genetic factors and Epstein-Barr virus infection, showing strong familial aggregation. Individuals with a family history suffer elevated NPC risk, requiring effective genetic counseling for risk stratification and individualized prevention. METHODS: We performed whole-exome sequencing on 502 familial NPC patients and 404 unaffected relatives and controls. We systematically evaluated the established cancer predisposition genes and investigated novel NPC susceptibility genes, making comparisons with 21 other familial cancers in the UK biobank (N = 5218). RESULTS: Rare pathogenic mutations in the established cancer predisposition genes were observed in familial NPC patients, including ERCC2 (1.39%), TP63 (1.00%), MUTYH (0.80%), and BRCA1 (0.80%). Additionally, 6 novel susceptibility genes were identified. RAD54L, involved in the DNA repair pathway together with ERCC2, MUTYH, and BRCA1, showed the highest frequency (4.18%) in familial NPC. Enrichment analysis found mutations in TP63 were enriched in familial NPC, and RAD54L and EML2 were enriched in both NPC and other Epstein-Barr virus-associated cancers. Besides rare variants, common variants reported in the studies of sporadic NPC were also associated with familial NPC risk. Individuals in the top quantile of common variant-derived genetic risk score while carrying rare variants exhibited increased NPC risk (odds ratio = 13.47, 95% confidence interval = 6.33 to 28.68, P = 1.48 × 10-11); men in this risk group showed a cumulative lifetime risk of 24.19%, much higher than those in the bottom common variant-derived genetic risk score quantile and without rare variants (2.04%). CONCLUSIONS: This study expands the catalog of NPC susceptibility genes and provides the potential for risk stratification of individuals with an NPC family history.

A polygenic risk score for nasopharyngeal carcinoma shows potential for risk stratification and personalized screening.

Polygenic risk scores (PRS) have the potential to identify individuals at risk of diseases, optimizing treatment, and predicting survival outcomes. Here, we construct and validate a genome-wide association study (GWAS) derived PRS for nasopharyngeal carcinoma (NPC), using a multi-center study of six populations (6 059 NPC cases and 7 582 controls), and evaluate its utility in a nested case-control study. We show that the PRS enables effective identification of NPC high-risk individuals (AUC = 0.65) and improves the risk prediction with the PRS incremental deciles in each population (Ptrend ranging from 2.79 × 10-7 to 4.79 × 10-44). By incorporating the PRS into EBV-serology-based NPC screening, the test's positive predictive value (PPV) is increased from an average of 4.84% to 8.38% and 11.91% in the top 10% and 5% PRS, respectively. In summary, the GWAS-derived PRS, together with the EBV test, significantly improves NPC risk stratification and informs personalized screening.

A comprehensive analysis of genetic diversity of EBV reveals potential high-risk subtypes associated with nasopharyngeal carcinoma in China.

Epstein-Barr virus (EBV), a widespread oncovirus, is associated with multiple cancers including nasopharyngeal carcinoma (NPC), gastric cancer and diverse lymphoid malignancies. Recent studies reveal that specific EBV strains or subtypes are associated with NPC development in endemic regions. However, these NPC specific subtypes were only identified in a portion of infected individuals due possibly to the limited samples size studied or the complicated population structures of the virus. To identify additional high-risk EBV subtypes, we conducted a comprehensive genetic analysis of 22 critical viral proteins by using the largest dataset of 628 EBV genomes and 792 sequences of single target genes/proteins from GenBank. The phylogenetic, principal component and genetic structure analyses of these viral proteins were performed through worldwide populations. In addition to the general Asia-Western/Africa geographic segregation, population structure analysis showed a 'Chinese-unique' cluster (96.57% isolates from China) was highly enriched in the NPC patients, compared to the healthy individuals (89.6% vs. 44.5%, P < 0.001). The newly identified EBV subtypes, which contains four Chinese-specific NPC-associated amino acid substitutions (BALF2 V317M, BNRF1 G696R, V1222I and RPMS1 D51E), showed a robust positive association with the risk of NPC in China (Odds Ratio = 4.80, 20.00, 18.24 and 32.00 for 1, 2, 3 and 4 substitutions, respectively, P trend <0.001). Interestingly, the coincidence of positively selected sites with NPC-associated substitutions suggests that adaptive nonsynonymous mutation on critical proteins, such as BNRF1, may interact with host immune system and contribute to the carcinogenesis of NPC. Our findings provide a comprehensive overview of EBV genetic structure for worldwide populations and offer novel clues to EBV carcinogenesis from the aspect of evolution.

Association Between Oral Microbiota and Cigarette Smoking in the Chinese Population.

The oral microbiota has been observed to be influenced by cigarette smoking and linked to several human diseases. However, research on the effect of cigarette smoking on the oral microbiota has not been systematically conducted in the Chinese population. We profiled the oral microbiota of 316 healthy subjects in the Chinese population by 16S rRNA gene sequencing. The alpha diversity of oral microbiota was different between never smokers and smokers (P = 0.002). Several bacterial taxa were first reported to be associated with cigarette smoking by LEfSe analysis, including Moryella (q = 1.56E-04), Bulleidia (q = 1.65E-06), and Moraxella (q = 3.52E-02) at the genus level and Rothia dentocariosa (q = 1.55E-02), Prevotella melaninogenica (q = 8.48E-08), Prevotella pallens (q = 4.13E-03), Bulleidia moorei (q = 1.79E-06), Rothia aeria (q = 3.83E-06), Actinobacillus parahaemolyticus (q = 2.28E-04), and Haemophilus parainfluenzae (q = 4.82E-02) at the species level. Two nitrite-producing bacteria that can increase the acidity of the oral cavity, Actinomyces and Veillonella, were also enriched in smokers with FDR-adjusted q-values of 3.62E-06 and 1.10E-06, respectively. Notably, we observed that two acid production-related pathways, amino acid-related enzymes (q = 6.19E-05) and amino sugar and nucleotide sugar metabolism (q = 2.63E-06), were increased in smokers by PICRUSt analysis. Finally, the co-occurrence analysis demonstrated that smoker-enriched bacteria were significantly positively associated with each other and were negatively correlated with the bacteria decreased in smokers. Our results suggested that cigarette smoking may affect oral health by creating a different environment by altering bacterial abundance, connections among oral microbiota, and the microbiota and their metabolic function.

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.

Epstein-Barr virus DNA loads in the peripheral blood cells predict the survival of locoregionally-advanced nasopharyngeal carcinoma patients.

OBJECTIVE: Circulating cell-free Epstein-Barr virus (EBV) DNA has been shown to be a valuable biomarker for population screening and prognostic surveillance for nasopharyngeal carcinoma (NPC). Despite important insights into the biology of persistence, few studies have addressed the clinical significance of cell-based EBV-DNA loads in peripheral blood cells (PBCs). METHODS: A prospective observational cohort study was conducted involving 1,063 newly diagnosed, locoregionally-advanced NPC patients at Sun Yat-sen University Cancer Center from 2005 to 2007. Cox regression analysis was conducted to identify the association of PBC EBV DNA loads to overall survival (OS) and other prognostic outcomes. Prognostic nomograms were developed based on PBC EBV DNA loads to predict survival outcomes for NPC patients. RESULTS: After a median follow-up of 108 months, patients with higher PBC EBV-DNA loads had significantly worse OS [hazard ratio (HR) of medium, medium-high, and high vs. low were 1.50, 1.52, and 1.85 respectively; Ptrend < 0.001]. Similar results were found for progression-free survival and distant metastasis-free survival. The concordance index of the prognostic nomogram for predicting OS in the training set and validation set were 0.70 and 0.66, respectively. Our data showed that the PBC EBV DNA load was an independent and robust survival biomarker, which remained significant even after adjusting for plasma EBV DNA loads in a subset of 205 patients of the cohort (HR: 1.88; P = 0.025). Importantly, a combination of PBC EBV DNA load and plasma EBV DNA load improved the predicted OS. CONCLUSIONS: The EBV-DNA load in PBCs may be an independent prognosis marker for NPC patients.

Prognostic Value of Oral Epstein-Barr Virus DNA Load in Locoregionally Advanced Nasopharyngeal Carcinoma.

Background: Plasma Epstein-Barr virus (EBV) DNA load has been widely used for nasopharyngeal carcinoma (NPC) prognostic risk stratification. However, oral EBV DNA load, a non-invasive biomarker that reflects the EBV lytic replication activity, has not been evaluated for its prognostic value in NPC yet. Methods: A total number of 1,194 locoregionally advanced NPC (LA-NPC) patients from south China were included from a prospective observational cohort (GARTC) with a median follow-up of 107.3 months. Pretreatment or mid-treatment mouthwashes were collected for EBV DNA detection by quantitative polymerase chain reaction (qPCR). The difference of pre- and mid-treatment oral EBV DNA load was tested by the Wilcoxon signed-rank test. The associations of oral EBV DNA load with overall survival (OS), progression-free survival (PFS), distant metastasis-free survival (DMFS), and locoregional relapse-free survival (LRFS) were assessed using the log-rank test and multivariate Cox regression. Results: The high level of the oral EBV DNA load (>2,100 copies/mL) was independently associated with worse OS (HR = 1.45, 95% CI: 1.20-1.74, p < 0.001), PFS (HR = 1.38, 95% CI: 1.16-1.65, p < 0.001), DMFS (HR = 1.66, 95% CI: 1.25-2.21, p = 0.001), and LRFS (HR = 1.43, 95% CI: 1.05-1.96, p = 0.023). Similar and robust associations between oral EBV DNA load and prognosis were observed for patients in both the pretreatment and mid-treatment stages. The detection rate (71.7 vs. 48.6%, p < 0.001) and the median load of oral EBV DNA (13,368 vs. 382 copies/mL, p < 0.001) for patients in the pretreatment stage were significantly higher than those in the mid-treatment stage. The combination of the oral EBV DNA load and TNM staging provided a more precise risk stratification for the LA-NPC patients. Conclusion: Oral EBV DNA load was an alternative non-invasive predictor of prognosis and may facilitate risk stratification for the LA-NPC patients.

Post-transplant lymphoproliferative disorder after paediatric liver transplantation.

OBJECTIVE: The purpose of this study was to analyse the clinical and pathological characteristics, treatments and outcomes of post-transplant lymphoproliferative disorder (PTLD) in paediatric liver transplant recipients. METHOD: A retrospective analysis of records from nine paediatric liver transplant recipients with PTLD who were treated at our Liver Transplant Center over the period from June 2013 to August 2018. RESULT: Of these nine patients, seven received liver transplantation in our centre and the remaining two patients at other hospitals. The overall incidence of PTLD in paediatric liver transplant recipients in our centre was 1.4% (7/485). The median onset of PTLD after liver transplantation was 11 months. Three cases were classified as infectious mononucleosis PTLD, one case was plasmacytic hyperplasia PTLD, one case was polymorphic PTLD and two cases were Burkitt lymphoma. One case showed diffuse large B-cell lymphoma and one was classical Hodgkin lymphoma-like PTLD. These patients presented with different clinical manifestations including fever, anaemia, diarrhoea, hypoproteinaemia, enlargement of lymph nodes, hepatosplenomegaly, jaundice, bowel obstruction and even intestinal perforation. Nine patients were positive for EBV-DNA in serum. After diagnosis, immunosuppressants were reduced or discontinued in all cases. Eight patients received anti-CD20 monoclonal antibody (Rituximab) therapy, four cases were treated with a combination of chemotherapy (R-CHOP, ABVD, COPP/ABV) and one case was combined with radiotherapy. Two cases received surgical treatment due to bowel obstruction. Eight of these patients achieved a complete remission and remained healthy when assessed at the time of final follow-up. One patient died as a result of PTLD progression. CONCLUSION: PTLD is one of the most serious and fatal complications after liver transplantation. The definitive diagnosis requires histopathology. Treatment varies and basically includes immunosuppression reduction, anti-CD20 antibody, surgery, radiotherapy and chemotherapy.

Fetal thymus in the middle and late trimesters: Morphometry and development using post-mortem 3.0T MRI.

The present study aimed to investigate the anatomical microstructure, features and signals of the fetal thymus by 3.0T FS-T2 weighted turbo spin echo sequences, which could provide imaging evidence for the evaluation of early-stage development of fetal thymus. In addition, the T2-weighted three-dimensional (3D) sequences and the 3D processing may contribute to the establishment of reference ranges for the fetal thymus. A total of 64 specimens obtained from the fetuses of 16-39 weeks of gestational age (GA) were scanned by 3.0T MRI. Morphological changes and quantitative measurements of the fetal thymus were assessed, including the anteroposterior diameter, width, height, surface area and volume. The shape of fetal thymus varied and the majority were X-shaped, with a narrow top and wide bottom. Morphology measurements demonstrated gradual growth with increasing GA. There were high linear correlations between width, height, surface area and volume and GA. No significant differences were observed between the sexes. Post-mortem 3.0T MRI clearly demonstrated changes in external contours and internal structure with GA. The images and data obtained reflect normal development of the fetal thymus and enrich the imaging data of fetal morphometry.

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.

Association Between Serum Cotinine Level and Serological Markers of Epstein-Barr Virus in Healthy Subjects in South China Where Nasopharyngeal Carcinoma Is Endemic.

Introduction: Self-reported smoking has been associated with higher seropositivity for the IgA response to Epstein-Barr virus (EBV) viral capsid antigen (VCA-IgA) and transcription activator protein (Zta) in healthy men in southern China where nasopharyngeal carcinoma (NPC) is endemic. Results on the association of biochemically verified smoking status with EBV reactivation are scarce. We aimed to investigate the relations of serum cotinine level with serological markers of EBV in healthy women, in addition to men. Methods: We collected information on demographic, lifestyle, environmental factors, and EBV serological markers in a cross-sectional study on 2,275 healthy subjects who were recruited from physical examination centers in Guangdong Province, China. In the present analysis, 901 subjects' serum cotinine levels have been measured by enzyme-linked immunosorbent assay (ELISA). Odds ratios (seropositivity of four EBV serological markers vs. seronegativity) for categorical serum cotinine levels were calculated by unconditional logistic regression with a group-specific confidence interval (CI). Results: In women, compared with lower serum cotinine level (0-0.71 ng/ml), higher cotinine level (>0.71-1.20 ng/ml; >1.20-228.40 ng/ml) was associated but non-significantly with higher seropositivity for EBV VCA-IgA (age- and education-adjusted OR = 1.18, 95% CIs = 0.84-1.64, 1.06, 0.75-1.50). These associations remained but still non-significant after adjusting for 5-year age group, education, family history of cancer, consumption of tea, Chinese herbal tea, salted fish at childhood, and exposure to occupational dust, chemical, fume, and radiation (multivariable adjusted OR = 1.21, 95% CIs = 0.85-1.71, 1.09, 0.76-1.55). In men, compared with lower serum cotinine level (0-2.15 ng/ml), higher cotinine level (>2.15-103.6 ng/ml; >103.6-419.4 ng/ml) was significantly associated with higher seropositivity for EBV VCA-IgA and Zta-IgA (age- and education-adjusted OR = 2.16, 95% CIs = 1.37-3.41, 1.79, 1.11-2.90; 1.98, 1.17-3.34, 1.95, 1.14-3.34). The association remained significant after adjusting for potential confounders for Zta-IgA (OR = 2.32, 95% CI = 1.37-3.93 for >2.15-103.6, and 2.50, 1.43-4.38 for >103.6-419.4 ng/ml), but not for VCA-IgA (2.06, 1.29-3.27, and 1.61, 0.96-2.71). Conclusions: Higher serum cotinine level is associated with higher seropositivity for EBV serological markers in healthy men in southern China. Such positive association was also observed in women but became non-significant. If confirmed to be causal, this finding has important implications for tobacco control and prevention of EBV-related disease, particularly for NPC.