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Purpose The risk psychological distress (PD) confers on mortality due to specific chronic diseases compared to suicide is unclear. Using the National Health Interview Survey (NHIS), we investigated the association between PD levels and risk of all-cause and chronic disease-specific mortality and compared the contribution of chronic disease-related mortality to that of suicide. Methods Data from 195, 531 adults, who participated in the NHIS between 1997 and 2004, were linked to the National Death Index records through to 2006. Multivariable Cox regression models were used to estimate hazard ratios (HRs) and their 95% confidence intervals (CIs) across four levels of PD, measured using the Kessler-6 scale. Outcomes included all-cause mortality, and mortality due to all CVDs and subtypes, all cancers and subtypes, diabetes mellitus, alcoholic liver disease and suicide. Results During a mean follow-up time of 5.9 years, 7665 deaths occurred. We found a dose–response association between levels of PD and all-cause mortality, with the adjusted HRs (95% CI) elevated for all levels of PD, when compared to asymptomatic levels: subclinical 1.10 (1.03–1.16), symptomatic 1.36 (1.26–1.46) and highly symptomatic 1.57 (1.37–1.81). A similar association was found for all CVDs and certain CVD subtypes, but not for cancers, cerebrovascular diseases diabetes mellitus. Excess mortality attributable to suicide and alcoholic liver disease was evident among those with levels of PD only. Conclusion PD symptoms, of all levels, were associated with an increased risk of all-cause and CVD-specific mortality while higher PD only was associated with suicide. These findings emphasise the need for lifestyle interventions targeted towards improving physical health disparities among those with PD. Supplementary Information The online version contains supplementary material available at 10.1007/s00127-021-02116-7.

Chemotherapy resistance is a bottleneck for ovarian cancer treatment; therefore, revealing its regulatory mechanism is critical. In the present study, we found that prostate tumor overexpressed-1 (PTOV1) was upregulated significantly in ovarian cancer cells and tissues. Patients with high PTOV1 levels had a poor outcome. In addition, PTOV1 overexpression increased CDDP (cisplatin) resistance, while PTOV1 knockdown inhibited CDDP resistance, as determined using cell viability assays, apoptosis assays, and an animal model. Mechanistic analysis showed that PTOV1 increased nuclear factor kappa B (NF-κB) pathway activity, reflected by increased nuclear translocation of its p65 subunit and the phosphorylation of inhibitor of nuclear factor kappa-B kinase subunits alpha and beta, which are markers of NF-κB pathway activation. Inhibition of the NF-κB pathway in PTOV1-overexpressing ovarian cancer cells increased CDDP-induced apoptosis, suggesting that PTOV1 promoted chemotherapy resistance by activating the NF-κB pathway. In summary, we identified PTOV1 as a prognostic factor for patients with ovarian cancer. PTOV1 might be a target for inhibition of chemotherapy resistance., Graphical Abstract, Chemotherapy resistance is a bottleneck of ovarian cancer treatment. In this study, we found PTOV1 not only served as a prognostic factor for ovarian cancer patients but also was a novel target for inhibition of cisplatin resistance.

Microvascular invasion (MVI) is a key pathological factor that severely affects the postoperative prognosis of patients with hepatocellular carcinoma (HCC). However, no MVI classification schemes based on standardized gross sampling protocols of HCC are available at present. 119 HCC specimens were sampled at multiple sites (3-, 7-, and 13 points) for the optimum MVI detection rate. 16,144 resected HCCs were graded as M0, M1 or M2 by adopting three-tiered MVI grading (MVI-TTG) scheme based on the seven-point sampling protocol (SPSP). Survival analyses were performed on 2573 patients to explore the advantages of MVI-TTG. The MVI detection rate determined by SPSP was significantly higher than that determined by the 3-point sampling method (34.5% vs. 47.1%, p = 0.048), but was similar to that determined by the 13-point sampling method (47.1% vs. 51.3%, p = 0.517). Among 16,144 resected HCCs, the proportions of M0, M1 and M2 specimens according to SPSP were 53.4%, 26.2% and 20.4%, respectively. Postoperative survival analysis in 2573 HCC patients showed that the 3-year recurrence rates in M0, M1 and M2 MVI groups were 62.5%, 71.6% and 86.1%, respectively (p

Background: Inhibition of cancer cell growth and low in vivo toxicity are two important criteria for the development of anti-cancer drugs. Curcumin is a promising candidate for developing novel anti-cancer drug analogs. The research group designed the 3,5-bis-(3,4,5- trimethoxybenzylidene)-1-methyl-piperidin-4-one analog of curcumin that significantly inhibited the growth of esophageal cancer cells in vivo. In this study, 81 curcumin analogs were synthesized, analyzed both in vitro and in vivo, and their structure activity relationships (SARs) were determined. Methods: Based on the parent structure of curcumin, 81 analogs of 3,5-bis(substitutedbenzylidene)- piperidin-4-one compounds were designed and synthesized. Their anti-cancer activity in the human cancer cell lines was evaluated using the MTT assay, and in vivo toxicity was evaluated in mice. The SARs of selected compounds were analyzed. Results and Discussion: Among the designed curcumin analogs, 61 compounds exerted anti-cancer effects higher than the parent compound in vitro; 23 compounds inhibited cell growth in the human cancer cell line at low concentrations (IC50 values below 1 μM). The acute toxicity of curcumin analogs was tested in mice; 13 compounds were selected, which did not show any obvious toxicity at doses as high as 25.0 mg/kg. The SARs of these shortlisted curcumin analogs were determined. Conclusion: Twenty-three curcumin analogs exhibiting promising in vitro anti-cancer activity and low in vivo toxicity were designed. SAR analysis indicated the optimal functional groups in the molecule required for anti-cancer activity. This study not only suggested a useful strategy to design curcumin analogs for the development of anti-cancer drugs, but also revealed a group of curcumin analogs which could be further explored.

Purpose: Adults with T-cell lymphoblastic lymphoma (T-LBL) generally benefit from treatment with acute lymphoblastic leukemia (ALL)-like regimens, but approximately 40% will relapse after such treatment. We evaluated the value of CpG methylation in predicting relapse for adults with T-LBL treated with ALL-like regimens. Experimental Design: A total of 549 adults with T-LBL from 27 medical centers were included in the analysis. Using the Illumina Methylation 850K Beadchip, 44 relapse-related CpGs were identified from 49 T-LBL samples by two algorithms: least absolute shrinkage and selector operation (LASSO) and support vector machine–recursive feature elimination (SVM-RFE). We built a four-CpG classifier using LASSO Cox regression based on association between the methylation level of CpGs and relapse-free survival in the training cohort (n = 160). The four-CpG classifier was validated in the internal testing cohort (n = 68) and independent validation cohort (n = 321). Results: The four-CpG–based classifier discriminated patients with T-LBL at high risk of relapse in the training cohort from those at low risk (P < 0.001). This classifier also showed good predictive value in the internal testing cohort (P < 0.001) and the independent validation cohort (P < 0.001). A nomogram incorporating five independent prognostic factors including the CpG-based classifier, lactate dehydrogenase levels, Eastern Cooperative Oncology Group performance status, central nervous system involvement, and NOTCH1/FBXW7 status showed a significantly higher predictive accuracy than each single variable. Stratification into different subgroups by the nomogram helped identify the subset of patients who most benefited from more intensive chemotherapy and/or sequential hematopoietic stem cell transplantation. Conclusions: Our four-CpG–based classifier could predict disease relapse in patients with T-LBL, and could be used to guide treatment decision.

Background The prognosis of patients with biliary atresia (BA) after Kasai portoenterostomy (KPE) varies, and precisely predicting the outcomes of KPE before surgery is still challenging. Methods A total of 158 patients who underwent KPE in our hospital were included in this study. The patients in the training cohort were recruited from January 2012 to October 2017 (n = 118), and then, those in the validation cohort were recruited from November 2017 to April 2019 (n = 40). Combined nomogram models were developed based on two-dimensional shear wave elastography (2D SWE) values and other biomarkers. The utility of the proposed models was evaluated by C-index. Results 2D SWE played a potentially important role in predicting native liver survival (NLS) of BA patients with a C-index of 0.69 (0.63 to 0.75) in the training cohort and 0.76 (0.67 to 0.85) in the validation cohort. The nomogram A based on 2D SWE values, age, gamma-glutamyl transferase (GGT) and aspartate aminotransferase-to-platelet ratio (APRI) had a better C-index in the training cohort [0.74 (0.68-0.80) vs. 0.66 (0.60-0.73), P = 0.017] and in the validation cohort [0.78 (0.70-0.86) vs. 0.60 (0.49-0.71), P = 0.002] than the nomogram B (without 2D SWE). Using risk score developed from nomogram A, we successfully predicted 88.0% (22/25) of patients in the training cohort and 75.0% (9/12) in the validation cohort to have survival time of less than 12 months after KPE. Conclusion The combined nomogram model based on 2D SWE values, age, GGT and APRI prior to KPE can effectively predict NLS in BA infants.

We aimed to establish a discriminative gene-expression-based classifier to predict survival outcomes of T-cell lymphoblastic lymphoma (T-LBL) patients. After exploring global gene-expression profiles of progressive (n = 22) vs. progression-free (n = 28) T-LBL patients, 43 differentially expressed mRNAs were identified. Then an eleven-gene-based classifier was established using LASSO Cox regression based on NanoString quantification. In the training cohort (n = 169), high-risk patients stratified using the classifier had significantly lower progression-free survival (PFS: hazards ratio 4.123, 95% CI 2.565–6.628; p

Pathological MVI diagnosis could help to determine the prognosis and need for adjuvant therapy in hepatocellular carcinoma (HCC). However, narrative reporting (NR) would miss relevant clinical information and non-standardized sampling would underestimate MVI detection. Our objective was to explore the impact of innovative synoptic reporting (SR) and seven-point sampling (SPRING) protocol on microvascular invasion (MVI) rate and patient outcomes. In retrospective cohort, we extracted MVI status from NR in three centers and re-reviewed specimen sections by SR recommended by the College of American Pathologists (CAP) in our center. In prospective cohort, our center implemented the SPRING protocol, and external centers remained traditional pathological examination. MVI rate was compared between our center and external centers in both cohorts. Recurrence-free survival (RFS) before and after implementation was calculated by Kaplan-Meier method and compared by the log-rank test. In retrospective study, we found there was no significant difference in MVI rate between our center and external centers [10.3% (115/1112) vs. 12.4% (35/282), P=0.316]. In our center, SR recommended by CAP improved the MVI detection rate from 10.3 to 38.6% (Pvs. 17%, P

Background Hydatidiform moles exhibit a distinctive gross appearance of multiple vesicles in the placenta. The advances in cytogenetic technologies have helped uncover novel entities of hydatidiform moles and enabled elaborate diagnoses. However, management of a vesicular placenta with a coexistent live fetus poses a bigger challenge beyond hydatidiform moles. Case presentation A 33-year-old woman was referred to our department for suspected hydatidiform mole coexistent with a live fetus at 24 weeks’ gestation. The patient had conceived through double embryo transplantation, and first-trimester ultrasonography displayed a single sac. Mid-trimester imaging findings of normal placenta parenchyma admixed with multiple vesicles and a single amniotic cavity with a fetus led to suspicion of a singleton partial molar pregnancy. After confirmation of a normal diploid by amniocentesis and close surveillance, the patient delivered a healthy neonate. Preliminary microscopic examination of the placenta failed to clarify the diagnosis until fluorescence in situ hybridization showed a majority of XXY sex chromosomes. The patient developed suspected choriocarcinoma and achieved remission for 5 months after chemotherapy, but relapsed with suspected intermediate trophoblastic tumor. Conclusion We report a rare case of twin pregnancy comprising a partial mole and a normal fetus that resembled a singleton partial molar pregnancy. Individualized care is important in conditions where a vesicular placenta coexists with a fetus. We strongly recommend ancillary examinations in addition to traditional morphologic assessment in such cases.

Background: The consistency in steatosis grading between magnetic resonance imaging-based proton density fat fraction (MRI-PDFF) and controlled attenuation parameter (CAP) before and after treatment remains unclear. This study aimed to compare the diagnostic accuracy of steatosis grading between MRI-PDFF and CAP using liver biopsy as standard and to evaluate the value of monitoring changes in steatosis grading with CAP during follow-up utilizing MRI-PDFF as a reference. Methods: Consecutive patients from a biopsy cohort and a randomized controlled trial were included in this study and classified into 3 groups (the biopsy, orlistat treatment, and routine treatment subgroups). Hepatic steatosis was measured via MRI-PDFF and CAP at baseline and at the 6th month; the accuracy and cutoffs were assessed in the liver biopsy cohort at baseline. Results: A total of 209 consecutive patients were enrolled. MRI-PDFF and CAP showed comparable diagnostic accuracy for detecting pathological steatosis [⩾S1, area under the receiver operating characteristic curve (AUC) = 0.984 and 0.972, respectively]; in contrast, CAP presented significantly lower AUCs in grades S2–3 and S3 (0.820 and 0.815, respectively). The CAP values correlated well with the MRI-PDFF values at baseline and at the 6th month ( r = 0.809 and 0.762, respectively, both p Conclusions: CAP has decreased value for the initial screening of moderate-severe steatosis and is limited in monitoring changes in steatosis during treatment. The confirmation of steatosis grading with MRI-PDFF remains necessary.

Jing Ye,1,* Bing Liao,2,* Xiaohua Jiang,1 Zhihuai Dong,1 Sunhong Hu,1 Yuehui Liu,2 Mang Xiao1 1Department of Otolaryngology Head and Neck Surgery, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, People’s Republic of China; 2Department of Otorhinolaryngology Head and Neck Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yuehui Liu; Mang Xiao Email liuyuehuiclark@21cn.com; joelxm@zju.edu.cnBackground: Peripheral blood inflammation factor neutrophil-lymphocyte ratio (NLR), platelet count (PLT) and nutritional factor serum albumin (ALB) have been proposed as prognostic markers of head and neck squamous carcinoma cancer (HNSCC) in recent years. In the current study, nomogram predict models based on pre-treatment hematological parameters and a modified risk-stratified score system have been built.Methods: A total of 197 patients with oropharyngeal, hypopharyngeal and laryngeal cancers receiving multimodality treatment between 2012 and 2014 were included. The pre-treatment ALB, neutrophil, lymphocyte and platelet count (PLT) were detected. Cancer-specific survival and locoregional recurrence (LRC) by 5 years’ follow-up in the cases were obtained. To integrate clinical characteristics, we propose a modified risk-stratified score system. Kaplan–Meier method, proportional hazards COX model, logistic models were used to establish nomograms within external validation.Results: Five-year LRC was decreased (p=0.004) for 140 patients with pre-treatment NLR < 2.77. Five-year LRC and 5-year cancer-specific survival were decreased (p=0.031, p=0.021) with pre-treatment PLT ≥ 248× 109/L. Comparison of univariate parametric models demonstrated that pre-treatment NLR evaluation and PLT> 248× 109/L were better among tested models. On Bayesian information criteria (BIC) analysis, the optimal prognostic model was then used to develop nomograms predicting 3- and 5-year LRC. The external validation of this predictive model was confirmed in 57 patients from another hospital.Conclusion: Pre-treatment NLR elevation and PLT> 248× 109/L are promising predictors of prognosis in patients with operable HNSCC. Nomograms based on the pre-treatment hematological markers and modified risk-stratified score system provide distinct risk stratifications. There results provided the feasibility of anti-inflammatory and antiplatelet treatments for HNSCC patients.Keywords: head and neck squamous cell carcinoma, neutrophil-lymphocyte ratio, platelet count, albumin, nomogram

Intraductal papillary neoplasms of the bile duct (IPNBs) are a group of rare lesions with uncertain clinical findings and imaging features. We aim to investigate the clinicopathological features and imaging findings of IPNBs on contrast-enhanced ultrasound (CEUS) and contrast-enhanced computed tomography (CECT). From February 2005 to March 2018, 30 patients with pathologically confirmed IPNBs were retrospectively identified in our hospital. Demographic, clinical, and pathological data, CEUS and CECT features and surgical strategies were analyzed. The most common clinical manifestations were abdominal pain (53.3%), jaundice (23.3%), and acute cholangitis (10.0%). Among all lesions, 5/30 (16.7%) lesions presented as dilated bile ducts only, while 13/30 (43.3%) lesions presented as dilated bile ducts with intraductal papillary masses, and 12/30 (40.0%) presented as solid masses with dilated bile ducts. For the 20 patients who underwent both CEUS and CECT, 18 lesions were hyperenhanced on CEUS, and 17 lesions were hyperenhanced on CECT in the arterial phase. In total, 16 and 18 lesions showed washout in the portal and late phases on CEUS, while the corresponding number of lesions that showed washout in the portal and late phases on CECT were 11 and 13. Twelve lesions (40.0%) showed atypical hyperplasia, while 16/30 (53.3%) lesions underwent malignant transformations. There are 3 major forms of IPNBs on grayscale ultrasound, including diffusely dilated bile ducts without visible mass; focal dilated bile duct with intraductal papillary masses; and solid mass surrounded by dilated bile ducts. The enhancement patterns of IPNBs on CEUS and on CECT were consistent. IPNB has a high malignant potential, and patients should be treated with surgical resection after the diagnosis is established.

New prognostic factors are needed to establish indications for haematopoietic stem cell transplantation (HSCT) in first complete remission (CR1) for T-cell lymphoblastic lymphoma (T-LBL) patients. We used microarray to compare T-LBL tissue samples (n = 75) and fetal thymus tissues (n = 20), and identified 35 differentially expressed miRNAs. Using 107 subjects as the training group, we developed a five-miRNA-based classifier to predict patient survival with LASSO Cox regression: lower risk was associated with better prognosis (disease-free survival (DFS): hazard ratio (HR) 4.548, 95% CI 2.433–8.499, p

Summary Background Identification of high-risk localised renal cell carcinoma is key for the selection of patients for adjuvant treatment who are at truly higher risk of reccurrence. We developed a classifier based on single-nucleotide polymorphisms (SNPs) to improve the predictive accuracy for renal cell carcinoma recurrence and investigated whether intratumour heterogeneity affected the precision of the classifier. Methods In this retrospective analysis and multicentre validation study, we used paraffin-embedded specimens from the training set of 227 patients from Sun Yat-sen University (Guangzhou, Guangdong, China) with localised clear cell renal cell carcinoma to examine 44 potential recurrence-associated SNPs, which were identified by exploratory bioinformatics analyses of a genome-wide association study from The Cancer Genome Atlas (TCGA) Kidney Renal Clear Cell Carcinoma (KIRC) dataset (n=114, 906 600 SNPs). We developed a six-SNP-based classifier by use of LASSO Cox regression, based on the association between SNP status and patients' recurrence-free survival. Intratumour heterogeneity was investigated from two other regions within the same tumours in the training set. The six-SNP-based classifier was validated in the internal testing set (n=226), the independent validation set (Chinese multicentre study; 428 patients treated between Jan 1, 2004 and Dec 31, 2012, at three hospitals in China), and TCGA set (441 retrospectively identified patients who underwent resection between 1998 and 2010 for localised clear cell renal cell carcinoma in the USA). The main outcome was recurrence-free survival; the secondary outcome was overall survival. Findings Although intratumour heterogeneity was found in 48 (23%) of 206 cases in the internal testing set with complete SNP information, the predictive accuracy of the six-SNP-based classifier was similar in the three different regions of the training set (areas under the curve [AUC] at 5 years: 0·749 [95% CI 0·660–0·826] in region 1, 0·734 [0·651–0·814] in region 2, and 0·736 [0·649–0·824] in region 3). The six-SNP-based classifier precisely predicted recurrence-free survival of patients in three validation sets (hazard ratio [HR] 5·32 [95% CI 2·81–10·07] in the internal testing set, 5·39 [3·38–8·59] in the independent validation set, and 4·62 [2·48–8·61] in the TCGA set; all p Interpretation Our six-SNP-based classifier could be a practical and reliable predictor that can complement the existing staging system for prediction of localised renal cell carcinoma recurrence after surgery, which might enable physicians to make more informed treatment decisions about adjuvant therapy. Intratumour heterogeneity does not seem to hamper the accuracy of the six-SNP-based classifier as a reliable predictor of recurrence. The classifier has the potential to guide treatment decisions for patients at differing risks of recurrence. Funding National Key Research and Development Program of China, National Natural Science Foundation of China, Guangdong Provincial Science and Technology Foundation of China, and Guangzhou Science and Technology Foundation of China.

To retrospectively assess the value of the combination of conventional ultrasound and shear-wave elastography (SWE) in evaluating the segmental heterogeneity of liver fibrosis in biliary atresia (BA) patients after Kasai portoenterostomy. A total of 35 BA patients with liver segmental deformation were enrolled. The segmental deformation was assessed by conventional ultrasound followed with SWE examinations for evaluating the liver stiffness. Liver biopsy was performed in 11 patients in the region of SWE measurement and liver fibrosis was assessed using the Metavir classification. Aminotransferase to platelet ratio index (APRI) was calculated for comparison. The correlations between serum biochemical tests with SWE values were evaluated. Spearman’s rank coefficient test was performed to evaluate the correlation between variables. The SWE values of the biopsy segments had significant positive correlations with liver fibrosis severity (r = 0.828, p = 0.001), which was better than APRI (r = 0.366, p = 0.242). The levels of bilirubin and transaminase showed significant correlations with the SWE values at hypertrophic segments in all patients (r from 0.336 to 0.576, all p

PurposeTo analyze the outcomes and toxicities of induction chemotherapy (ICT) followed by concurrent chemoradiotherapy (CCRT) plus adjuvant chemotherapy (ACT) in patients with locoregionally advanced nasopharyngeal carcinoma (LA-NPC).MethodsRetrospective analysis of 163 patients with LA-NPC referred from August 2015 to December 2018 was carried out. All patients underwent platinum-based ICT followed by CCRT plus ACT.ResultsThe median follow-up time was 40 months, ranging from 5 to 69 months. The 3-year disease-free survival (DFS), overall survival (OS), locoregional recurrence-free survival (LRRFS), and distant metastasis-free survival (DMFS) rates were 80.8, 90.0, 91.6, and 87.4%, respectively. The most frequent acute grade 3/4 adverse events were leukopenia (66.8%), neutropenia (55.8%), mucositis (41.1%), thrombocytopenia (27.0%), and anemia (14.7%).ConclusionICT followed by CCRT plus ACT did not seemingly enhance DFS and OS in LA-NPC patients compared to the addition of ICT to CCRT (historical controls). In contrast, ICT followed by CCRT plus ACT had more acute adverse events than ICT followed by CCRT. Longer-term clinical studies are required to examine the treatment outcomes and late toxicities.

Higher mortality in asthmatics has been shown previously. However, evidence on different asthma phenotypes on long-term mortality risk is limited. The aim was to evaluate the impact of asthma phenotypes on mortality in general population. Data from the National Health and Nutrition Examination Survey from 2001–2002 to 2013–2014 linked mortality files through December 31, 2015, were used (N = 37,015). Cox proportional hazards regression was used to estimate the risk of all-cause and cause-specific mortality adjusting for sociodemographic characteristics, smoking, body mass index, and chronic conditions. During the mean follow-up time of 7.5 years, 4326 participants died from a variety of causes. Current asthma, but not former asthma was associated with increased all-cause mortality (current asthma: HR = 1.37; 95% CI 1.20–1.58; Former asthma: HR = 0.93; 95% CI 0.73–1.18); as well as mortality from cardiovascular disease (HRCurrent = 1.41; 95% CI 1.08–1.85) and chronic lower respiratory diseases (HRCurrent = 3.17; 95% CI 1.96–5.14). In addition, we found that the HR for cardiovascular disease (CVD) mortality was slightly greater in people with childhood-onset asthma than those with adult-onset asthma. The HR for chronic lower respiratory diseases (CLRD) mortality was greater in people with adult-onset asthma than those with childhood-onset asthma. However, the differences were not statistically significant. Our study suggested that current asthma but not former asthma was associated with increased all-cause, CLRD and CVD mortality. Future well-designed studies with larger sample are required to demonstrate the association and clarify the potential mechanisms involved.

Accumulating evidence has indicated that lncRNAs regulate various biological and pathological processes in diverse malignant tumors. The roles of LINC00667 in cancer development have been explored in glioma, hepatocellular carcinoma and non-small cell lung cancer, but not in nasopharyngeal carcinoma (NPC). In the present study, we characterize the role and molecular mechanism of LINC00667 in NPC progression. It was found that LINC00667 was overexpressed in NPC cells compared to normal cells. Silencing LINC00667 suppressed the proliferation, migration, invasion and epithelial mesenchymal transition (EMT) in NPC cells. In addition, bioinformatics analysis revealed that LINC00667 acted as a ceRNA to absorb miR-4319. Further investigations illustrated that miR-4319 had low expression in NPC cells and functioned as a tumor suppressor in the progression of NPC. Mechanistic study identified forkhead box Q1 (FOXQ1) as a functional target of miR-4319. The effect of LINC00667 in NPC development was mediated by the miR-4319/FOXQ1 axis. Analysis on tumorxenograft mouse model demonstrated that knockdown of LINC00667 repressed NPC tumor growth in vivo and confirmed the in vitro results. Our present study suggested that LINC00667 promoted the malignant phenotypes of NPC cells by competitively binding to miR-4319 to up-regulate FOXQ1 expression. Our results reveled that LINC00667 could be a diagnostic and therapeutic target for NPC patients.

Pretreatment evaluation of tumor biology and microenvironment is important to predict prognosis and plan treatment. We aimed to develop nomograms based on gadoxetic acid-enhanced MRI to predict microvascular invasion (MVI), tumor differentiation, and immunoscore. This retrospective study included 273 patients with HCC who underwent preoperative gadoxetic acid-enhanced MRI. Patients were assigned to two groups: training (N = 191) and validation (N = 82). Univariable and multivariable logistic regression analyses were performed to investigate clinical variables and MRI features’ associations with MVI, tumor differentiation, and immunoscore. Nomograms were developed based on features associated with these three histopathological features in the training cohort, then validated, and evaluated. Predictors of MVI included tumor size, rim enhancement, capsule, percent decrease in T1 images (T1D%), standard deviation of apparent diffusion coefficient, and alanine aminotransferase levels, while capsule, peritumoral enhancement, mean relaxation time on the hepatobiliary phase (T1E), and alpha-fetoprotein levels predicted tumor differentiation. Predictors of immunoscore included the radiologic score constructed by tumor number, intratumoral vessel, margin, capsule, rim enhancement, T1D%, relaxation time on plain scan (T1P), and alpha-fetoprotein and alanine aminotransferase levels. Three nomograms achieved good concordance indexes in predicting MVI (0.754, 0.746), tumor differentiation (0.758, 0.699), and immunoscore (0.737, 0.726) in the training and validation cohorts, respectively. MRI-based nomograms effectively predict tumor behaviors in HCC and may assist clinicians in prognosis prediction and pretreatment decisions. • This study developed and validated three nomograms based on gadoxetic acid-enhanced MRI to predict MVI, tumor differentiation, and immunoscore in patients with HCC. • The pretreatment prediction of tumor microenvironment may be useful to guide accurate prognosis and planning of surgical and immunological therapies for individual patients with HCC.

The aim of this work is to explore the impact of the number of sampling sites (NuSS) and sampling location on microvascular invasion (MVI) detection rate and long-term survival of hepatocellular carcinoma (HCC), and determine the minimum NuSS for sufficient MVI detection. From January 2008 to March 2017, 1144 HCC patients who underwent hepatectomy were retrospectively enrolled. Associations between NuSS and MVI positive rates and overall survival were investigated. NuSS thresholds were determined by Chow test and confirmed prospectively in 305 patients from April 2017 to February 2019. In the prospective cohort, the distribution of MVI in different sampling locations and its prognostic effect was evaluated. MVI positive rates increased as NuSS increased, steadily reaching a plateau when NuSS reached a threshold. A threshold of four, six, eight, and eight sampling sites within paracancerous parenchyma ≤ 1 cm from tumor was required for detecting MVI in solitary tumors measuring 1.0–3.0, 3.1–4.9, and ≥ 5.0 cm and multiple tumors. Patients with adequate NuSS achieved longer survival than those with inadequate NuSS [hazard ratio (HR) = 0.75, P = 0.043]. For all MVI-positive patients, MVI could be detected positive in paracancerous parenchyma ≤ 1 cm from tumor. Patients with MVI positive in paracancerous parenchyma > 1 cm had higher recurrence risk than those with MVI positive only in parenchyma ≤ 1 cm (HR = 6.05, P

Background Limb girdle muscular dystrophy type 2Y (LGMD2Y) is a rare subgroup of limb girdle muscular dystrophy featuring limb-girdle weakness, tendon contracture and cardiac involvement. It is caused by the mutation of TOR1AIP1, which encodes nuclear membrane protein LAP1 (lamina-associated polypeptide 1) and comprises heterogeneous phenotypes. The present study reported a patient with a novel homozygous TOR1AIP1 mutation that presented with selective muscle weakness, which further expanded the phenotype of LGMD2Y- and TOR1AIP1-associated nuclear envelopathies. Case presentation A 40-year-old male presented with Achilles tendon contracture and muscle weakness that bothered him from 8 years old. While the strength of his distal and proximal upper limbs was severely impaired, the function of his lower limbs was relatively spared. Muscle pathology showed dystrophic features, and electron microscopy showed ultrastructural abnormalities of disrupted muscle nuclei envelopes. Whole-exome sequencing showed a frameshift mutation in TOR1AIP1 (c.98dupC). Conclusion We reported a novel mild phenotype of LGMD2Y with relatively selective distal upper limb weakness and joint contracture and revealed the heterogeneity of LGDM2Y and the role of the LAP1 isoform by literature review.

OBJECTIVE This study aimed to evaluate the role of preoperative two-dimensional (2D) shear wave elastography (SWE) in assessing the stages of liver fibrosis in patients with suspected biliary atresia (BA) and compared its diagnostic performance with those of serum fibrosis biomarkers. MATERIALS AND METHODS This study was approved by the ethical committee, and written informed parental consent was obtained. Two hundred and sixteen patients were prospectively enrolled between January 2012 and October 2018. The 2D SWE measurements of 69 patients have been previously reported. 2D SWE measurements, serum fibrosis biomarkers, including fibrotic markers and biochemical test results, and liver histology parameters were obtained. 2D SWE values, serum biomarkers including, aspartate aminotransferase to platelet ratio index (APRi), and other serum fibrotic markers were correlated with the stages of liver fibrosis by METAVIR. Receiver operating characteristic (ROC) curves and area under the ROC (AUROC) curve analyses were used. RESULTS The correlation coefficient of 2D SWE value in correlation with the stages of liver fibrosis was 0.789 (p < 0.001). The cut-off values of 2D SWE were calculated as 9.1 kPa for F1, 11.6 kPa for F2, 13.0 kPa for F3, and 15.7 kPa for F4. The AUROCs of 2D SWE in the determination of the stages of liver fibrosis ranged from 0.869 to 0.941. The sensitivity and negative predictive value of 2D SWE in the diagnosis of ≥ F3 was 93.4% and 96.0%, respectively. The diagnostic performance of 2D SWE was superior to that of APRi and other serum fibrotic markers in predicting severe fibrosis and cirrhosis (all p < 0.005) and other serum biomarkers. Multivariate analysis showed that the 2D SWE value was the only statistically significant parameter for predicting liver fibrosis. CONCLUSION 2D SWE is a more effective non-invasive tool for predicting the stage of liver fibrosis in patients with suspected BA, compared with serum fibrosis biomarkers.

To examine the cross-sectional relationship between sleep duration and 11 chronic diseases (risk of obesity, depression, diabetes, asthma, COPD, arthritis, kidney, CHD, stroke, and cancer [excluding skin cancer]) by using data from Behavioral Risk Factor Surveillance System.Using data from the 2013, 2014 and 2016 Behavioral Risk Factor Surveillance System, a total sample consisted of 1,191,768 participants. Logistic regression models were constructed to calculate OR and 95% confidence intervals (CI) for the association between sleep duration and 11 chronic diseases. In addition, we also conducted subgroup analysis based on age and gender.In multi-adjusted model, the positive association between extremely short or long sleep duration and risk of chronic diseases was significant (P 0.05) with the exception of skin cancer (P = 0.14 and P = 0.43). There are stronger association between extremely short or long sleep duration and obesity, diabetes, asthma, chronic obstructive pulmonary disease, arthritis, kidney, coronary heart disease, stroke, and cancer in women and aged 18-64 years old.Our results indicated a higher risk of common chronic diseases due to short or long sleep duration in women and aged 18-64 years. Further studies are needed to demonstrate these association.

Objective: Pituicytomas and granular cell tumours (GCTs) of the neurohypophysis are considered non-adenomatous neoplasms in the sellar region. The association between hormone hypersecretion and the...

Summary Castleman disease (CD) is a rare lymphoproliferative disorder. To assess the clinical features, outcomes, and prognostic factors of this disease, we retrospectively analyzed 185 HIV-negative CD patients from four medical centers in southern China. The median age was 37 years. 121 patients (65.4%) were classified as unicentric CD (UCD) and 64 patients (34.6%) were classified as multicentric CD (MCD). The histology subtype was hyaline-vascular for 132 patients (71.4%), plasma cell for 50 patients (27%) and mixed type for 3 patients (1.6%). The 5-year overall survival (OS) of 185 CD cases was 80.3%. All UCD patients underwent surgical excision, while the treatment strategies of MCD patients were heterogeneous. The outcome for UCD patients was better than MCD patients, with 5-year OS rates of 93.6% and 51.2%, respectively. In further analysis of the MCD subgroup, a multivariate analysis using a Cox regression model revealed that age, splenomegaly and pretreatment serum albumin level were independent prognostic factors for OS. This multicenter study comprising the largest sample size to date suggested that MCD is a distinct entity from UCD with a significantly worse outcome. Older age (≥40 years), splenomegaly and hypoalbuminemia were risk factors for poorer MCD prognosis. This article is protected by copyright. All rights reserved.

We previously identified the important role of RIN1 expression in the prognosis of clear cell renal cell carcinoma (ccRCC). The role of RIN1 in ccRCC malignancy and underlying molecular mechanisms remain unclear. Here we report that ccRCC cells and tissues expressed more RIN1 than normal controls. Gain-of-function and loss-of-function studies demonstrated that RIN1 enhanced ccRCC cell growth, migration and invasion abilities in vitro and promoted tumor growth and metastasis in vivo. Mechanistic studies revealed that RIN1 has an activating effect on EGFR signaling in ccRCC. In addition, we unveil Rab25, a critical GTPase in ccRCC malignancy, as a functional RIN1 interacting partner. Knockdown of Rab25 eliminated the augmentation of carcinoma cell proliferation, migration and invasion by ectopic RIN1. We also confirmed that RIN1 and Rab25 expression correlates with the overall-survival of ccRCC patients from TCGA. These findings suggest that RIN1 plays an important oncogenic role in ccRCC malignancy by activation of EGFR signaling through interacting with Rab25, and RIN1 could be employed as an effective therapeutic target for ccRCC.

// Jun Lu 1, * , Jin-Huan Wei 1, * , Zi-Hao Feng 1, * , Zhen-Hua Chen 1, * , Yong-Qian Wang 2 , Yong Huang 1 , Yong Fang 1 , Yan-Ping Liang 1 , Jun-Jie Cen 1 , Yi-Hui Pan 1 , Bing Liao 3 , Wen-Fang Chen 3 , Wei Chen 1 , Jun-Hang Luo 1 1 Department of Urology, First Affiliated Hospital, Sun Yat-sen University, Guangdong, China 2 Department of Musculoskeletal Oncology, First Affiliated Hospital, Sun Yat-sen University, Guangdong, China 3 Department of Pathology, First Affiliated Hospital, Sun Yat-sen University, Guangdong, China * These authors contributed equally to this work Correspondence to: Jun-Hang Luo, email: luojunh@mail.sysu.edu.cn Keywords: miR-106b-5p, stemness, Wnt signalling, tumorigenesis, renal cell carcinoma Received: October 29, 2016 Accepted: February 06, 2017 Published: February 21, 2017 ABSTRACT Purpose: To examine the role of miR-106b-5p in regulating the cancer stem-cell-like phenotype in clear cell renal cell carcinomas (ccRCC). Experimental Design: Real-time PCR was performed to evaluate miR-106b-5p levels in ccRCC cell lines and patients specimens. A series of in vivo and in vitro assays were performed to confirm the effect of miR-106b-5p on ccRCC stemness phenotype. Results: ccRCC cells and tissues expressed more miR-106b-5p than normal controls. Gain- and loss-of-function studies demonstrated that overexpression of miR-106b-5p in ccRCC cells increased the spheres formation ability and the proportion of side population cells. Ectopic expression of miR-106b-5p in ccRCC cells increased tumour growth rates and the number of metastatic colonies in the lungs by using an orthotopic kidney cancer model and a tail vein injection model, respectively. Mechanistic studies revealed that, miR-106b-5p has an activating effect on Wnt/β-catenin signalling. miR-106p-5p overexpression simultaneously targets multiple negative regulators of the Wnt/β-catenin pathway, namely, LZTFL1, SFRP1 and DKK2. In addition, we also confirmed that miR-106b-5p and its targets expression correlates with the overall-survival of ccRCC patients from TCGA. Conclusions: These findings suggest that miR-106b-5p mediates the constitutive activation of Wnt/β-catenin signalling, likely serving as a potential therapeutic target for ccRCC.

Background The predictive model of postsurgical recurrence for solitary early hepatocellular carcinoma (SE-HCC) is not well established. The aim of this study was to develop a novel model for prediction of postsurgical recurrence and survival for patients with hepatitis B virus (HBV)-related SE-HCC ≤10 cm. Patients and Methods Data from 1,081 patients with HBV-related SE-HCC ≤10 cm who underwent curative liver resection from 2003 to 2016 in our center were collected retrospectively and randomly divided into the derivation cohort (n = 811) and the internal validation cohort (n = 270). Eight hundred twenty-three patients selected from another four tertiary hospitals served as the external validation cohort. Postsurgical recurrence-free survival (RFS) and overall survival (OS) predictive nomograms were generated. The discriminatory accuracies of the nomograms were compared with six conventional hepatocellular carcinoma (HCC) staging systems. Results Tumor size, differentiation, microscopic vascular invasion, preoperative α-fetoprotein, neutrophil-to-lymphocyte ratio, albumin-to-bilirubin ratio, and blood transfusion were identified as the risk factors associated with RFS and OS. RFS and OS predictive nomograms based on these seven variables were generated. The C-index was 0.83 (95% confidence interval [CI], 0.79–0.87) for the RFS-nomogram and 0.87 (95% CI, 0.83–0.91) for the OS-nomogram. Calibration curves showed good agreement between actual observation and nomogram prediction. Both C-indices of the two nomograms were substantially higher than those of the six conventional HCC staging systems (0.54–0.74 for RFS; 0.58–0.76 for OS) and those of HCC nomograms reported in literature. Conclusion The novel nomograms were shown to be accurate at predicting postoperative recurrence and OS for patients with HBV-related SE-HCC ≤10 cm after curative liver resection.

Increasing evidences have revealed that long noncoding RNAs (lncRNAs) are frequently involved in various cancers. However, the expression and function of lncRNA DRAIC in nasopharyngeal carcinoma (NPC) remain unknown. In this study, we found that DRAIC was significantly increased in NPC tissues. Increased expression of DRAIC was positively correlated with advanced clinical stages of NPC patients. Functional assays revealed that ectopic expression of DRAIC enhances NPC cell growth, migration and invasion. DRAIC knockdown represses NPC cell growth, migration and invasion. Mechanistically, we identified two miR-122 binding sites on DRAIC. RNA pull-down, RNA immunoprecipitation, and dual-luciferase reporter assays confirmed the binding of DRAIC to miR-122. Via binding of miR-122, DRAIC upregulated the expression of miR-122 target SATB1, which was abolished by the mutation of miR-122 binding sites on SATB1. Moreover, the oncogenic roles of DRAIC on NPC were reversed by the mutation of miR-122 binding sites on SATB1, simultaneous overexpression of miR-122, or depletion of SATB1. In addition, the expression of SATB1 was also increased and positively associated with that of DRAIC in NPC tissues. In conclusion, these findings revealed the important roles of DRAIC-miR-122-SATB1 axis in NPC and suggested that DRAIC may be a potential therapeutic target for NPC.

The present study aimed to evaluate the utility of the extent of change (C) and change rate (Cr) of cardiac troponin I (cTnI) and hypersensitive C-reactive protein (hs-CRP) prior to and after treatment in evaluating the early therapeutic efficacy of acute myocardial infarction (AMI) treatment. A total of 145 patients with AMI who received regular MI treatment were enrolled in the present study. Patients were divided into the effective group and the ineffective group based on the early therapeutic efficacy. The values of two parameters, namely the serum levels of cTnI and hs-CRP, were collected prior to and after AMI treatment. Data were analyzed by using the t-test, Chi-squared test, logistic regression and receiver operating characteristic (ROC) curve analysis. Compared with those in the ineffective group, the values of cTnI and hs-CRP after treatment [cTnI(post) and hs-CRP(post)], as well as their C and Cr values, were significantly decreased in the effective group (P

// Yi Lin 1, * , Ertao Zhai 2, * , Bing Liao 3, * , Lixia Xu 1 , Xinhua Zhang 2 , Sui Peng 1 , Yulong He 2 , Shirong Cai 2 , Zhirong Zeng 1 , Minhu Chen 1 1 Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P.R.China 2 Department of Gastrointestinal Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P.R.China 3 Department of Pathology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P.R.China * These authors have contributed equally to this work Correspondence to: Shirong Cai, email: caisrteam@163.com Zhirong Zeng, email: zengzhirong@vip.163.com Keywords: autocrine, VEGF, proliferation, Apatinib, gastric cancer Received: December 16, 2015 Accepted: December 25, 2016 Published: January 03, 2017 ABSTRACT Background: Tumor cells produce vascular endothelial growth factor (VEGF) which interact with the membrane or cytoplasmic VEGF receptors (VEGFRs) to promote cell growth in an angiogenesis-independent fashion. Apatinib, a highly selective VEGFR2 inhibitor, is the only effective drug for patients with terminal gastric cancer (GC) who have no other chemotherapeutic options. However, its treatment efficacy is still controversy and the mechanism behind remains undetermined. In this study, we aimed to investigate the role of autocrine VEGF signaling in the growth of gastric cancer cells and the efficacy of Apatinib treatment. Methods: The expression of phosphor VEGFR2 in gastric cancer cell lines was determined by real-time PCR, immunofluorescence, and Western blot. The gastric cancer cells were administrated with or without recombination human VEGF (rhVEGF), VEGFR2 neutralizing antibody, U73122, SU1498, and Apatinib. The nude mice were used for xenograft tumor model. Results: we found that autocrine VEGF induced high VEGFR2-expression, promoted phosphorylation of VEGFR2, and further enhanced internalization of pVEGFR2 in gastric cancer cells. The autocrine VEGF was self-sustained through increasing VEGF mRNA and protein expression. It exerted pro-proliferative effect through a PLC-ERK1/2 dependent pathway. Furthermore, we demonstrated that in VEGFR2 overexpressing gastric cancer cells, Apatinib inhibited cell proliferation in vitro and delayed xenograft tumor growth in vivo . However, these effects were not observed in VEGFR2 low expressing gastric cancer cells. Conclusion: These results suggested that autocrine VEGF signaling promotes gastric cancer cell proliferation and enhances Apatinib treatment outcome in VEGFR2 overexpression gastric cancer cells both in vitro and in vivo . This study would enable better stratification of gastric cancer patients for clinical treatment decision.

Low concentrations of imatinib (IM) in bone marrow cells have been linked with poor prognosis in patients with chronic myeloid leukemia (CML), which may be caused by the emergence of ATP-binding cassette transporter B1 (ABCB1) mutations. The aim of present study was to investigate how clinical outcomes vary among patients with different single nucleotide polymorphisms (SNPs) of ABCB1. A total of 48 adult patients with CML and higher than median ABCB1 mRNA levels were selected for testing of ABCB1 SNPs. In 28 of the 48 patients, the IM concentration and expression levels of human organic cation transporter 1 (hOCT1) and ABCB1 in bone marrow mononuclear cells (BMMCs) were also tested. Correlations between treatment outcomes and IM concentration or the SNP status of ABCB1 were analyzed. Patients were classified by therapeutic response as major molecular response (MMR) (n=11), complete cytogenetic response (CCyR) (n=19) and non-CCyR (n=18) groups. It was found that the concentration of IM in BMMCs of the CCyR group was significant higher than that of the resistant groups (P=0.013). In addition, the IM concentration was positively correlated with the expression of hOCT1 mRNA (R=0.456, P=0.033), but negatively correlated with the expression of ABCB1 mRNA (R=−0.491, P=0.015). Furthermore, the mRNA expression level of ABCB1 was not associated with therapeutic response, but SNPs of the ABCB1 gene were associated with the response to IM. In conclusion, the concentration of IM in BMMCs may be regulated by the ABCB1 gene, and SNPs of the ABCB1 gene predict the therapeutic response to IM in patients with CML.

Background: Peripheral blood inflammation factor neutrophil-lymphocyte Ratio (NLR), platelet and nutritional factor albumin (ALB) have recently been proposed as prognostic markers in solid tumors. The current study the impact of those hematological parameters and oncologic outcomes in patients with operable head and neck squamous carcinoma cancer (HNSCC) using database approach were evaluated. Methods: 198 patients with oropharyngeal, hypopharyngeal and laryngeal cancers receiving multimodality protocols between 2012 and 2014 were included. Neutrophil, lymphocyte, platelet and albumin from the last phlebotomy before treatment were identified. Patients were risk-stratified and were tested for association with survival and disease-control outcomes. Results: 5-year LRC were decreased (p=0.004, respectively) for 140 patients with NLRpre-treatment 248×109/L were better among tested models. On Bayesian information criteria (BIC) analysis, the optimal prognostic model was then used to develop nomograms predicting 3- and 5-year locoregional recurrence (LRC). External validity evaluated by studying another 57 patients from other hospital confirmed the reliability of prediction model. Conclusion: Pre-treatment NLR elevation and platelet >248×109/L are promising predictors of prognosis in patients with operable HNSCC. The analyses performed show that pre-treatment hematological inflammatory markers and platelet-based Nomograms provide a distinct risk stratification. Further works should be complete to elucidate the utility of anti-inflammatory and anti- platelet treatments in modifying risk in peri-operation HNSCC patients. Funding Statement: This study is sponsored by grants from Medical Health Science and Technology Project of Zhejiang Provincial Health Commission (Grant No.2019336033). Medical Health Science Project of Hangzhou (Grant No. OO20190775). Declaration of Interests: The authors declare no conflict of interest. Ethics Approval Statement: This study was in accordance with Declaration of Helsinki and approved by the Research Ethic Committees of Affiliated Sir Run Run Shaw Hospital, Zhejiang University medical college and The Second Affiliated Hospital of Nanchang University Medical College. Both the institutional review board approved data extraction was performed from an existing HNSCC.

Background: Adults with T-cell lymphoblastic lymphoma (T-LBL) generally benefit from treatment with acute lymphoblastic leukemia (ALL)-like regimens, but approximately 40% will relapse after such treatment. We evaluated the value of CpG methylation in predicting relapse for adults with T-LBL treated with ALL-like regimens. Methods: A total of 549 adults with T-LBL from 27 medical centers were included in the analysis. Using the Illumina Methylation 850K Beadchip, 44 relapse-related CpGs were identified from 49 T-LBL samples by two algorithms, Least Absolute Shrinkage and Selector Operation (LASSO) and Support Vector Machine-Recursive Feature Elimination (SVM-RFE). We built a four-CpG classifier using LASSO Cox regression based on association between the methylation level of CpGs and relapse-free survival (RFS) in the training cohort (n=160).The four-CpG classifier was validated in the internal testing cohort (n=68) and independent validation cohort (n=321). Findings: The four-CpG-based classifier discriminated T-LBL patients at high risk of relapse in the training cohort from those at low risk (p

Background: Pretreatment evaluation of tumor biology and microenvironment of hepatocellular carcinoma (HCC) are important to predict prognosis and plan treatment. We aimed to develop nomograms based on Gd-EOB-DTPA-enhanced magnetic resonance imaging (MRI) to predict microvascular invasion (MVI), tumor differentiation, and immunoscore. Methods: This retrospective study included 273 patients with HCC who underwent preoperative Gd-EOB-DTPA-enhanced MRI. Patients were assigned to two groups: training (N = 191) and validation (N = 82). Univariable and multivariable logistic regression analyses were performed to investigate clinical variables and MRI features' associations with MVI, tumor differentiation and immunoscore. Nomograms were developed based on features associated with these histopathological features in the same training cohort, then validated, and evaluated. Findings: Predictors of MVI included tumor size (P = 0.002), rim enhancement (P = 0.017), percent reduction in T1 images (T1D%; P = 0.043), and standard deviation of apparent diffusion coefficient (P = 0.028), while capsule (P = 0.007), mean relaxation time on the hepatocellular phase (T1E; P < 0.001), and alpha-fetoprotein levels (P = 0.003) predicted tumor differentiation. Predictors of immunoscore included the radiologic score (P = 0.001) constructed by tumor number, intratumoral vessel, margin, capsule, rim enhancement, T1D%, relaxation time on plain scan (T1P) and T1E, and serum alpha-fetoprotein (P = 0.027) and alanine aminotransferase levels (P = 0.028). Three nomograms achieved high C-index in predicting MVI (0.754, 0.746), tumor differentiation (0.758, 0.699) and immunoscore (0.737, 0.726) in the training and validation cohorts, respectively. Interpretation:MRI-based nomograms effectively predict tumor behaviors in HCC and may assist clinicians in prognosis prediction. Funding: This work was funded by the National Natural Science Foundation of China (No. 81771908, 81571750, 81801703), the National Science Fund for Distinguished Young Scholars (No. 81825013) and the Guangdong Natural Science Foundation of Guangdong Province (No. 2018A030310282). Declaration of Interest: The authors declare that they have no competing interests. Ethical Approval: The Institutional Ethic Review Board has approved our study, and informed consent was waived due to the retrospective nature of the study.

To investigate the feasibility of prediction for targeted therapy-related gene expression in hepatocellular carcinoma (HCC) using preoperative gadoxetic acid-enhanced magnetic resonance imaging (MRI). Ninety-one patients (81 men, mean age 53.9 ± 12 years) with solitary HCC who underwent preoperative enhanced MRI were retrospectively analyzed. Features including tumor size, signal homogeneity, tumor capsule, tumor margin, intratumoral vessels, peritumor enhancement, peritumor hypointensity, signal intensity ratio on DWI, T1 relaxation times, and the reduction rate between pre- and post-contrast enhancement images were assessed. The operation and histopathological evaluation were performed within 2 weeks after MRI examination (mean time 7 days). The expression levels of BRAF, RAF1, VEGFR2, and VEGFR3 were evaluated. The associations between these imaging features and gene expression levels were investigated. Tumor incomplete capsules or non-capsules (p = 0.001) and intratumoral vessels (p = 0.002) were significantly associated with BRAF expression, and tumor incomplete capsules or non-capsules (p = 0.001) and intratumoral vessels (p = 0.013) with RAF1 expression. There was no significant association between the expression of VEGFR2, VEGFR3, and all examined MRI features. Multivariate logistic regression showed that incomplete tumor capsule (p = 0.002) and non-capsule (p = 0.004) were independent risk factors of HCC with high BRAF expression; incomplete tumor capsule (p

To prospectively investigate the usefulness of acoustic structure quantification (ASQ) for noninvasive assessment of liver fibrosis in patients with chronic hepatitis B (CHB). Consecutive patients with CHB scheduled for liver biopsy or partial liver resection underwent standardized ASQ examinations. The ASQ parameter, named focal disturbance (FD) ratio, were compared with METAVIR scores. The analysis was based on receiver operating characteristic (ROC) curves and multiple regression analysis. A total of 114 patients were enrolled in the final analysis. The area under the ROC curve for the FD ratio was 0.84 for significant fibrosis (≥ F2), 0.86 for severe fibrosis (≥ F3), and 0.83 for cirrhosis (= F4). The optimal cutoff values for the FD ratio were 0.25, 0.30 and 0.50 for fibrosis stages ≥ F2, ≥ F3 and = F4, respectively. The prevalence of a difference of at least two stages between the FD ratio and the histological stage was 12.3 % (14 of 114). The fibrosis stage (P

Allograft rejection has been an obstacle for long-term survival of patients for many years. Current strategies for transplant rejection are not as optimal as we expected, especially for long-term treatments. Trichinella spiralis, a nematode parasitized in mammalian muscle and as an invader, maintains harmonious with host in the long term by evading host immune attack. To determine whether T. spiralis infection impacts on allograft rejection, we performed mice cardiac allograft transplantation model by using BALB/c (H-2(b)) mice as donors and C57BL/6 (H-2(b)) mice orally infected with 300 muscle larvae for 28 days as recipients. Graft survival was monitored by daily palpation of the abdomen; histologic change was observed by HE stain; and CD4(+), CD8(+), CD4(+)IFN-γ(+), and CD4(+)IL-17(+) T cells and regulatory T cells were examined with the use of flow cytometry. Serum cytokine levels were measured by Luminex. Finally, we found that mean survival time of cardiac allografts in T. spiralis group was 23.40 ± 1.99 days, while the vehicle control group was 10.60 ± 0.75 days. Furthermore, we observed alleviated histological changes in the heart allograft, decreased corresponding CD8(+) T cells, suppressed Th1 and Th17 responses, and increased regulatory T cell frequency in a murine cardiac transplantation model at day 7 post-transplantation in experimental group. These data suggest that T. spiralis infection resulted in prolonged allograft survival following murine cardiac transplantation, with suppressed Th1/Th17 responses and augmented regulatory T cells.

Ischemia and reperfusion injury (IRI) is an inevitable event in conventional organ transplant procedure and is associated with significant mortality and morbidity post-transplantation. We hypothesize that IRI is avoidable if the blood supply for the organ is not stopped, thus resulting in optimal transplant outcomes. Here we described the first case of a novel procedure called ischemia-free organ transplantation (IFOT) for patients with end-stage liver disease. The liver graft with severe macrovesicular steatosis was donated from a 25-year-old man. The recipient was a 51-year-old man with decompensated liver cirrhosis and hepatocellular carcinoma. The graft was procured, preserved, and implanted under continuous normothermic machine perfusion. The recipient did not suffer post-reperfusion syndrome or vasoplegia after revascularization of the allograft. The liver function test and histological study revealed minimal hepatocyte, biliary epithelium and vascular endothelium injury during preservation and post-transplantation. The inflammatory cytokine levels were much lower in IFOT than those in conventional procedure. Key pathways involved in IRI were not activated after allograft revascularization. No rejection, or vascular or biliary complications occurred. The patient was discharged on day 18 post-transplantation. This marks the first case of IFOT in humans, offering opportunities to optimize transplant outcomes and maximize donor organ utilization.

Aim: To confirm whether cirrhosis is indispensable for the non-invasive diagnostic criteria for hepatocellular carcinoma (HCC) in hepatitis B virus (HBV)-endemic areas. Methods: Between January 2014 and December 2014, a total of 409 patients with pathologically proven focal liver lesions who underwent contrast-enhanced ultrasound (CEUS) were recruited from our institution. Clinical liver cirrhosis, HBV/HCV infection and HCC-typical vascular pattern of the targeted lesion on CEUS were evaluated. The following 3 criteria were applied to these patients to diagnose HCC: criterion 1, clinical liver cirrhosis and HCC-typical vascular pattern; criterion 2, HBV/HCV infection and HCC-typical vascular pattern; criterion 3, HBV/HCV infection or clinical liver cirrhosis and HCC-typical vascular pattern. Pathological reports were considered the gold standard. Results: A total of 311 patients had confirmed HCC by pathology. The sensitivity, specificity, accuracy, positive predictive value, negative predictive value and area under the ROC curve for criterion 1 were 29.6, 90.8, 44.3, 91.1, 28.9, and 0.60% respectively. For criterion 2, they were 83.3, 74.5, 81.2, 91.2, 58.4, and 0.79%, respectively, and for criterion 3, they were 86.2, 72.5, 82.9, 90.9, 62.3, and 0.79% respectively. Conclusions: In HBV-endemic areas, when using the HBV/HCV infection instead of cirrhosis as the precondition of the non-invasive diagnostic criteria for HCC, we should be aware of the potential false positive. Cirrhosis still plays an important role in the non-invasive diagnostic criteria for HCC because of the high specificity.

Objective. To investigate the imaging features observed in preoperative Gd-EOB-DTPA-dynamic enhanced MRI and correlated with the presence of microvascular invasion (MVI) in hepatocellular carcinoma (HCC) patients. Methods. 66 HCCs in 60 patients with preoperative Gd-EOB-DTPA-dynamic enhanced MRI were retrospectively analyzed. Features including tumor size, signal homogeneity, tumor capsule, tumor margin, peritumor enhancement during mid-arterial phase, peritumor hypointensity during hepatobiliary phase, signal intensity ratio on DWI and apparent diffusion coefficients (ADC), T1 relaxation times, and the reduction rate between pre- and postcontrast enhancement images were assessed. Correlation between these features and histopathological presence of MVI was analyzed to establish a prediction model. Results. Histopathology confirmed that MVI were observed in 17 of 66 HCCs. Univariate analysis showed tumor size (p=0.003), margin (p=0.013), peritumor enhancement (p=0.001), and hypointensity during hepatobiliary phase (p=0.004) were associated with MVI. A multiple logistic regression model was established, which showed tumor size, margin, and peritumor enhancement were combined predictors for the presence of MVI (α=0.1). R2 of this prediction model was 0.353, and the sensitivity and specificity were 52.9% and 93.0%, respectively. Conclusion. Large tumor size, irregular tumor margin, and peritumor enhancement in preoperative Gd-EOB-DTPA-dynamic enhanced MRI can predict the presence of MVI in HCC.

e15657 Background: Microvascular invasion (MVI) is an important risk factor of recurrence for hepatocellular carcinoma (HCC). We aimed to explore the relationship of the number of sampling sites (NuSS) and sampling location with positive rate of MVI, and investigate cut-off values for NuSS. Methods: From May 2010 to Feb 2017, 910 HCC patients undergone hepatectomy with well-preserved tissue blocks were retrospectively enrolled. Associations between NuSS and positive rates of MVI were investigated. The thresholds of NuSS according to different factors were determined by Chow test and Breakpoints function, and validated prospectively in 118 patients. In validation cohort, MVI positive rates in different sampling locations were estimated. Results: The positive rates of MVI increased as NuSS increased ( P < 0.001). Tumor size and number were two factors influencing NuSS. A minimum of four, six, eight and eight sampling sites were required for detecting MVI in solitary tumors measuring 1.0-3.0 cm, 3.1-4.9 cm and ≥ 5.0 cm and multiple tumors. The positive rates of MVI as per developed thresholds were significantly higher in all the tumor subgroups of validation cohort than those in routine clinical practice in training cohort (46.7% vs. 20.6%, P= 0.048; 44.4% vs. 24.4%, P= 0.025; 73.3% vs. 50.3%, P= 0.004; 67.7% vs. 45.4%, P= 0.026). The positive rates of MVI in tumor interface were higher than those in proximal and distal paracancerous and normal liver parenchyma. Conclusions: The different thresholds of NuSS according to tumor size and number, and sampling distribution according to location provided evidences of standardized sample collection of liver cancer specimen for accurate MVI diagnosis.

Ipilimumab is a novel FDA-approved recombinant human monoclonal antibody that blocks cytotoxic T-lymphocyte antigen-4 and has been used to treat patients with metastatic melanoma. Immune-related neurological adverse effects include inflammatory myopathy, aseptic meningitis, posterior reversible encephalopathy syndrome, Guillain-Barré syndrome, myasthenia gravis-type syndrome, sensorimotor neuropathy, and inflammatory enteric neuropathy. To date, there is no report for ipilimumab-induced chronic inflammatory demyelinating polyneuropathy (CIDP), transverse myelitis (TM), or concurrent myositis and myasthenia gravis-type syndrome. Our objective is to raise early recognition of atypical neurological adverse events and to share our therapeutic approach.We report 3 cases of metastatic melanoma treated with ipilimumab in which the patients developed CIDP, TM, and concurrent myositis and myasthenia gravis-type syndrome, respectively, at the MD Anderson Cancer Center between July 2012 and June 2013. Patients consented to release of medical information for publication/educational purposes.Our 3 cases of metastatic melanoma treated with ipilimumab developed CIDP, TM, and concurrent myositis and myasthenia gravis-type syndrome, respectively. The median time to onset of immune-related adverse events following ipilimumab treatment ranged from 1 to 2 weeks. Ipilimumab was discontinued due to the severe neurological symptoms. Plasmapheresis was initiated in the patients with CIDP and concurrent myositis and myasthenia gravis-type syndrome; high-dose intravenous steroids were given to the patient with TM, and significant clinical response was demonstrated.Ipilimumab could induce a wide spectrum of neurological adverse effects. Our findings support the standard treatment of withholding or discontinuing ipilimumab. Plasmapheresis or high-dose intravenous steroids may be considered as the initial choice of treatment for severe ipilimumab-related neurological adverse events. Improvement of neurological symptoms may be seen within 2 weeks.

To explore an effective noninvasive tool for monitoring liver fibrosis of children with biliary atresia (BA) is important but evidences are limited. This study is to investigate the predictive accuracy of supersonic shearwave elastography (SSWE) in liver fibrosis for postoperative patients with BA and to compare it with aspartate aminotransferase to platelet ratio index (APRI) and fibrosis-4 (FIB-4). 24 patients with BA received SSWE and laboratory tests before scheduled for liver biopsy. Spearman rank coefficient and receiver operating characteristic (ROC) were used to analyze data. Metavir scores were F0 in 3, F1 in 2, F2 in 4, F3 in 7 and F4 in 8 patients. FIB-4 failed to correlate with fibrosis stage. The areas under the ROC curves of SSWE, APRI and their combination were 0.79, 0.65 and 0.78 for significant fibrosis, 0.81, 0.64 and 0.76 for advanced fibrosis, 0.82, 0.56 and 0.84 for cirrhosis. SSWE values at biopsy was correlated with platelet count (r = −0.426, P = 0.038), serum albumin (r = −0.670, P P = 0.041) and direct bilirubin levels (r = 0.518, P = 0.010) measured at 6 months after liver biopsy. Our results indicate that SSWE is a more promising tool to assess liver fibrosis than APRI and FIB-4 in children with BA.

This study aimed to compare the accuracy of CT and MRI in determining the invasion of thyroid cartilage by and the T staging of laryngeal carcinoma with anterior vocal commissure (AVC) involvement. A total of 26 cases of laryngeal carcinomas with AVC involvement from May 2012 to January 2014 underwent enhanced CT and MRI scan, out of whom 6 patients also underwent diffusion-weighted magnetic resonance imaging(DWI). T staging and thyroid cartilage involvement were evaluated. All the surgical specimens underwent serial section and were reviewed by two senior pathologists independently. When compared with pathologic staging, the accuracy was 88.46% (23/26) of MRI scan (with a 95% confidence interval 37~77%) and 57.69% (15/26) of CT scan (with a 95% confidence interval 70~98%), respectively (P

Objective To investigate the prevalence of impaired glucose regulation (IGR) in patients with anxiety disorders and the relationship with hypothalamic–pituitary–adrenal (HPA) and hypothalamic-pituitary-thyroid (HPT) axes function. Methods From September 2013 to May 2015, a total of 646 patients with anxiety disorders who matched the criteria of the 10th revision of the International Statistical Classification of Diseases and Related Health Problems participated in our study, which was conducted in the Psychiatric Inpatient Department of the West China Hospital of Sichuan University. The results from 75-g glucose tolerance tests, and morning (8:00 am) serum cortisol (PTC), adrenocorticotropic hormone༈ACTH), thyroid-stimulating hormone (TSH), TT3, TT4, FT3, and FT4 levels were collected. The Hamilton Anxiety Scale was administered to assess the severity of anxiety. SPSS 17.0 software was used for statistical analysis. Results The crude prevalence of impaired glucose regulation was 24.61% in patients with anxiety disorders patients. In the 18–40 year age group with impaired glucose regulation (IGR), both ACTH and PTC levels were higher than the control group (P

Neuroinflammation is a prominent pathological feature in the spinal cords of patients with amyotrophic lateral sclerosis (ALS), as well as in transgenic mouse models of inherited ALS, and is characterized by activated microglia. Earlier studies showed that activated microglia play important roles in both motoneuron protection and injury. More recent studies investigating the pathoprogression of disease in ALS mice have demonstrated that the in vivo activation states of microglia, including their anti- versus pro-inflammatory responses, are best characterized as a continuum between two extreme activation states which are represented as a neuro-protective M2 (alternatively-activated) phenotypic state or an injurious/toxic M1 (classically-activated) state; a more complete understanding and determination the temporal transformation of microglia activation states in the ALS disease pathoprogression is therefore warranted. In the current study, we demonstrated a phenotypic and functional transformation of adult ALS mice microglia that overexpress mutant superoxide dismutase (mSOD1). mSOD1 microglia isolated from ALS mice at disease onset expressed higher levels of Ym1, CD163 and BDNF (markers of M2) mRNA and lower levels of Nox2 (a marker of M1) mRNA compared with mSOD1 microglia isolated from ALS mice at end-stage disease. More importantly, when co-cultured with motoneurons, these mSOD1 M2 microglia were neuroprotective and enhanced motoneuron survival than similarly co-cultured mSOD1 M1 microglia; end-stage mSOD1 M1 microglia were toxic to motoneurons. Our study documents that adult microglia isolated from ALS mice at disease onset have an M2 phenotype and protect motoneurons whereas microglia isolated from end-stage disease ALS mice have adopted an M1 phenotype and are neurotoxic supporting the dual pheno-types of microglia and their transformation during disease pathoprogression in these mice. Thus, harnessing the neuroprotective potential of microglia may provide novel avenues for ALS therapies.

There are controversies regarding the histogenesis of stromal cells of hemangioblastoma, and no hypothesis has conclusively been proven. We report a case of unusual hemangioblastoma in a middle-aged man with von Hippel-Lindau disease. Neuroimaging revealed multifocal gadolinium-enhancing masses were located within both sides of the cerebellar hemisphere. Histologically, only small areas showing the typical morphology of hemangioblastoma were recognized in masses. Most areas of masses were composed of cohesive epithelioid tumor cells with abundant cytoplasm and distinct boundaries. Epithelioid tumor cells were arranged around blood vessels, exhibiting perivascular anuclear zone structures like ependymoma. The epithelioid tumor cells were diffusely positive for vimentin, CD99, neuron-specific enolase, GFAP and focally positive for epithelial membrane antigen (EMA) and D2-40 in a dot-like pattern. Variable-sized lipid droplets and glycogen particles were noted in the cytoplasm of epithelioid tumor cells under an electron microscope. A diagnosis of epithelioid cellular hemangioblastoma with possible ependymal differentiation (WHO grade I) was made. To our knowledge, only a few cases of hemangioblastoma show epithelioid appearance or EMA immunoreactivity. The present case indicates that the stromal cells of hemangioblastoma might originate from primitive neuroectodermal cells, and they have the capacity to show a distinctive sign of glial or ependymal differentiation.

Amyotrophic lateral sclerosis is a relentless and devastating adult-onset neurodegenerative disease with no known cure. In mice with amyotrophic lateral sclerosis, CD4+ T lymphocytes and wild-type microglia potentiate protective inflammatory responses and play a principal role in disease pathoprogression. Using this model, we demonstrate that endogenous T lymphocytes, and more specifically regulatory T lymphocytes, are increased at early slowly progressing stages, augmenting interleukin-4 expression and protective M2 microglia, and are decreased when the disease rapidly accelerates, possibly through the loss of FoxP3 expression in the regulatory T lymphocytes. Without ex vivo activation, the passive transfer of wild-type CD4+ T lymphocytes into amyotrophic lateral sclerosis mice lacking functional T lymphocytes lengthened disease duration and prolonged survival. The passive transfer of endogenous regulatory T lymphocytes from early disease stage mutant Cu2+/Zn2+ superoxide dismutase mice into these amyotrophic lateral sclerosis mice, again without ex vivo activation, were substantially more immunotherapeutic sustaining interleukin-4 levels and M2 microglia, and resulting in lengthened disease duration and prolonged survival; the stable disease phase was extended by 88% using mutant Cu2+/Zn2+ superoxide dismutase regulatory T lymphocytes. A potential mechanism for this enhanced life expectancy may be mediated by the augmented secretion of interleukin-4 from mutant Cu2+/Zn2+ superoxide dismutase regulatory T lymphocytes that directly suppressed the toxic properties of microglia; flow cytometric analyses determined that CD4+/CD25+/FoxP3+ T lymphocytes co-expressed interleukin-4 in the same cell. These observations were extended into the amyotrophic lateral sclerosis patient population where patients with more rapidly progressing disease had decreased numbers of regulatory T lymphocytes; the numbers of regulatory T lymphocytes were inversely correlated with disease progression rates. These data suggest a cellular mechanism whereby endogenous regulatory T lymphocytes are immunocompetent and actively contribute to neuroprotection through their interactions with microglia. Furthermore, these data suggest that immunotherapeutic interventions must begin early in the pathogenic process since immune dysfunction occurs at later stages. Thus, the cumulative mouse and human amyotrophic lateral sclerosis data suggest that increasing the levels of regulatory T lymphocytes in patients with amyotrophic lateral sclerosis at early stages in the disease process may be of therapeutic value, and slow the rate of disease progression and stabilize patients for longer periods of time.