Quantitative image features of gadoxetic acid-enhanced MRI for predicting glypican-3 expression of small hepatocellular carcinoma ≤3 cm.

AIM: To explore the value of quantitative image features of gadoxetic acid-enhanced magnetic resonance imaging (MRI) for predicting Gglypican-3 (GPC3) expression of single hepatocellular carcinoma (HCC) ≤3 cm. MATERIALS AND METHODS: One hundred and forty-nine patients with histopathologically confirmed HCC were included retrospectively. Quantitative image features and clinicopathological parameters were analysed. The significant predictors for GPC3 expression were identified using multivariate logistic regression analyses. Nomograms were constructed from the prediction model and the progression-free survival (PFS) rate was evaluated by the Kaplan-Meier method. RESULTS: The tumour-to-liver signal intensity (SI) ratio on the hepatobiliary phase (HBP; odds ratio [OR] = 0.004; p=0.001), serum alpha-fetoprotein (AFP) > 20 ng/ml (OR=6.175; p<0.001), and non-smooth tumour margin (OR=4.866; p=0.002) were independent significant factors for GPC3 expression. When the three factors were combined, the diagnostic specificity was 97.7% (42/43). The nomogram based on the predictive model performed satisfactorily (C-index: 0.852). Kaplan-Meier curves showed that patients with GPC3-positive HCCs have lower PFS rates than patients with GPC3-negative HCCs (Log-rank test, p=0.006). CONCLUSION: The tumour-to-liver SI ratio on the HBP combined with serum AFP >20 ng/ml and non-smooth tumour margin are potential predictive factors for GPC3 expression of small HCC ≤3cm. GPC3 expression is correlated with a poor prognosis in HCC patients.

[Analysis of MRI features of hepatocyte nuclear factor 1α-inactivated hepatocellular adenoma].

Objective: To investigate the MRI imaging features of hepatocyte nuclear factor 1α- inactivated hepatocellular adenoma (H-HCA). Methods: Clinical data and MRI images of 19 H-HCA cases who were pathologically confirmed at Zhongshan Hospital Affiliated to Fudan University between August 2014 and July 2020 were retrospectively analyzed. Among them, there were 15 females and 4 males, aged 16-47 (32± 7) years old. Tumor number, location, shape, size, boundary, MRI plain scan signal intensity, dynamic enhancement features of each phase, presence or absence of intratumoral fat content, pseudocapsule, and others were analyzed. The differences in apparent diffusion coefficient (ADC) values between the lesion and the surrounding normal liver parenchyma were compared for statistical significance. t-test was used for statistical analysis. Results: There were a total of 24 lesions in 19 cases. 14 cases had solitary lesions, and five cases had multiple lesions. 15 and nine lesions were located in the right and left lobes of the liver, respectively. 20 lesions were round or quasi-round, and four were irregular or lobulated. The tumor's maximal diameter was 0.6-8.6 (3.5 ± 2.4) cm. T(1)-weighted image (WI) showed hyperintense to iso-intense signals in 20 lesions and hypointense signals in four. T(2)WI showed iso-to-slightly high signal intensity in 16 lesions, with two hyperintense and six hypointense signals. Diffusion-weighted image (DWI) revealed hyperintense to iso-intense signals. Lesions mean ADC value was (1.289 ± 0.222)×10(-3) mm(2)/s, while the adjacent normal liver parenchyma's mean ADC value was (1.307 ± 0.236)×10(-3) mm(2)/s, with no statistically significant difference between the two (P > 0.05). During the arterial phase, 15 of the 18 lesions that underwent dynamic contrast-enhanced scanning with gadoxetate disodium (Gd-DTPA) were mildly to moderately enhanced and three were strongly enhanced. The portal and hepatic venous phases had no continuous enhancement, while the delayed phase showed a hypointense signal. During the arterial phase, two of the six lesions scanned by gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid ((Gd-EOB-DTPA) dynamic enhancement were mildly to moderately enhanced, while four were strongly enhanced. The portal and hepatic venous phases had no continuous enhancement, while the transition and hepatobiliary-specific phases showed hypointense signals. Intracellular steatosis occurred in 21 lesions, of which 19 were diffuse steatosis and 16 formed pseudocapsules in the delayed phase. Conclusion: H-HCA often occurs in young females as solitary lesions and has certain MRI features. T1WI anti-phase diffuse signal reduction and post-enhanced hypovascular withdrawal enhancement patterns can aid in accurately diagnosing the disease condition.

[MRI features of lymphoepithelioma-like intrahepatic cholangiocarcinoma].

Objective: To investigate the MRI manifestations of lymphoepithelioma-like intrahep cholangiocarcinoma (LEL-ICC). Methods: MR images of 26 cases with LEL-ICC confirmed pathologically at Zhongshan Hospital Affiliated with Fudan University between March 2011 and March 2021 were retrospectively analyzed. The number, location, size, morphology, edges of lesions, non-scan signal intensity, cystic necrosis, enhancement mode, peak, and capsule, vascular invasion, lymph node metastasis, and other MR images were included for analysis. The apparent diffusion coefficient (ADC) value of the lesion and the surrounding normal liver parenchyma were measured. A paired-sample t-test was used to statistically analyze the measurement data. Results: All 26 cases of LEL-ICC had solitary lesions. Mass-type LEL-ICC was the most common [n=23, lesion size (4.02±2.32) cm] with distribution along the bile duct [n=3, lesion size (7.23±1.40 cm)]. Among the 23 lesions of mass type LEL-ICC, most of the lesions were close to the liver capsule (n=20), round (n=22), clearly bordered (n=13), and cystic necrosis (n=22). In the three lesions of LEL-ICC distributed along the bile duct, most of them were close to the liver capsule (n=2), irregular (n=3), blurred edges (n=3), and cystic necrosis (n=3). All 26 lesions showed a low/slightly low signal on T1WI, a high/slightly high signal on T2WI, and a slightly high or high signal on DWI. Three lesions showed fast-in and fast-out enhancement modes, and 23 lesions showed continuous enhancement. Twenty-five lesions showed peak enhancement in the arterial phase, and one lesion appeared in the delayed phase. The ADC value of 26 lesions and adjacent normal liver parenchyma was (1.112±0.274)×10-3 mm2/s and (1.482±0.346)×10-3 mm2/s, respectively, and the both had a statistically significant difference (P<0.05). Conclusion: Certain manifestations of LEL-ICC in magnetic resonance imaging are advantageous for diagnosis and differential diagnosis.

[Nodular regenerative hyperplasia of liver caused by chemotherapy: magnetic resonance imaging features].

Objective: To investigate the MRI features of hepatic nodular regenerative hyperplasia (NRH) induced by chemotherapy. Methods: The clinical data and MRI of 20 cases with hepatic NRH induced by chemotherapy and confirmed by pathology in Zhongshan Hospital Fudan University from August 2014 to May 2019 were retrospectively analyzed. There were 13 males and 7 females, with an average age of 49.8 ± 9.7 years. Contrast-enhanced MR scan with Gd-DTPA was performed eighteen patients, and two patients underwent contrast-enhanced MR scan with hepatobiliary specific contrast (Gd-EOB-DTPA). The image analysis includes the number, location, size, shape, signal intensity in plain scan and enhancement pattern of lesions. The apparent diffusion coefficient (ADC) values of the lesions and adjacent hepatic parenchyma were measured on the ADC map, and the difference was compared with paired sample t test. Results: A total of 36 lesions in 20 patients were rounded or oval, including 23 (63.9%) lesions in the right lobe, 12 (33.3%) in the left lobe and 1 (2.8%) in the caudate lobe. The average diameter of all lesions was 15.4 ± 6.4 (7.0-37.0) mm. The boundary was clear in 9 (25.0%) lesions and blurred in 27 (75%) lesions. In T1WI, 35 (97.2%) lesions showed slightly hypointensity, and in 1 (2.8%) lesion was iosintensity. All 36 lesions showed slightly hyperintensity in T2WI. 33 (91.7%) lesions showed slightly hyperintensity in DWI, and 3 (8.3%) lesions showed iosintensity. 31 lesions with Gd-DTPA enhanced MR scan were significantly enhanced in the arterial phase and showed slightly high signal intensity in early portal vein phase, late portal vein phase and equilibrium phase. 5 lesions with Gd-EOB-DTPA enhanced MR scan were also significantly enhanced in the arterial phase and showed slightly high signal intensity in early portal vein phase, late portal vein phase and equilibrium phase, then all lesions showed circular high signal intensity in hepatobiliary specific phase. The average ADC value of 29 lesions was (1.471 ± 0.253) × 10(-3) mm(2)/s, and that of adjacent liver parenchyma was (1.460 ± 0.235) ×10(-3) mm(2)/s. There was no significant difference between the two groups (P > 0.05). Conclusion: MR findings of NRH induced by chemotherapy have certain characteristics, and the morphological manifestations, diffusion-weighted imaging, enhanced imaging and hepatobiliary specific phase features of the lesions can help to diagnose the disease.

[The value of 3.0T magnetic resonance -diffusion kurtosis imaging in the differential diagnosis of rectal mucinous adenocarcinoma and common adenocarcinoma].

Objective: To investigate the value of 3.0T MRI diffusion kurtosis imaging (DKI) quantitative histogram parameters in the differential diagnosis of rectal mucinous adenocarcinoma (MC) and common adenocarcinoma (AC). Methods: One hundred and ten patients from Department of Radiology, the Second Affiliated Hospital of Soochow University between September 2015 and September 2019 with complete magnetic resonance imaging (MRI) and DKI results confirmed by surgery and pathology were retrospectively analyzed, including 16 patients in MC group and 94 patients in AC group. Two physicians outlined the region of interest (ROI) on the DKI image with b=1 000 s/mm(2), and obtained quantitative DKI parameters, including the diffusion coefficient (D value) and kurtosis coefficient (K value) corrected for non-Gaussian distribution. The apparent diffusion coefficient (ADC) values of quantitative parameters of diffusion-weighted imaging (DWI) were obtained through image registration, and histogram analysis was performed to obtain the mean value, 25th percentile, 50th percentile, 75th percentile, skewness and kurtosis of the above parameters, respectively. The difference between the quantitative histogram parameter analysis results of the rectal MC group and the AC group was evaluated, and the main indicators and multivariate comprehensive analysis indicators was screened, and the effectiveness of quantitative histogram parameters related to histopathological classification in the differential diagnosis of rectal MC and AC was evaluated. Results: There was no significant differences in gender, age, lesion location, T stage or N stage between MC group and AC group (all P>0.05). The multivariate binary logistic stepwise regression screening showed that D50th percentile and K25th percentile are statistically significant indicators (B values were 2 966.166 and -4.550, respectively; Wals values were 9.000 and 15.720, respectively; and P values were 0.003 and <0.001, respectively). The combined area under the curve of the two indictors was 0.85, but there was no statistically significant difference in pairwise comparison using DeLong method (P>0.05). The results of histogram analysis of quantitative parameters measured by the two physicians were consistent, and the inter-group correlation coefficient ranged from 0.880 to 0.981. Conclusions: The quantitative parameter histogram analysis of the DKI double-index model is helpful for the differentiation of rectal MC and AC, in which the D50th percentile and K25th percentile have differential diagnosis significance, and are superior to the ADC value of the single-index model.

[Gadoxetic disodium-enhanced MRI to characterize T1 relaxation values and expression level of organic anion transporters and multidrug resistance protein on hepatocyte surface membrane of normal C57BL/6 mice].

Objective: The characteristics of T1 relaxation values and the expression levels of organic anion transport system (OATP) and multidrug resistance protein carrier (MRP) on hepatocyte surface membrane were quantitatively studied to evaluate liver function in normal C57BL/6 mice with gadoxetic disodium-enhanced MRI. Methods: Ten 6-weeks-old, normal C57BL/6 mice were included in this study. Gadoxetic disodium- enhanced MRI examination was performed. Longitudinal relaxation time images before and 20 min after contrast injection (hepatobiliary-specific phase) were acquired. T1-relaxation time, T1 relaxation time decline rate (△T) and rapid initial enhancement slope percentage in the first-pass study of the liver parenchyma before and after administration of gadoxetate disodium were measured. Liver parenchyma specimens were detected by Western blotting and the values ​​of OATP1, MRP2, and MRP3 were recorded. Statistical results were expressed in mean. Results: The mean T1 relaxation time of 10 normal C57BL/6 mice before and after enhancement was 659.13 ± 24.07, and 408.87 ± 27.21 ms. The mean T1 relaxation time decline rate and rapid initial enhancement slope percentage in the first-pass study was 37.12% ± 4.95% and 4.14% ± 0.96% ms. Furthermore, the mean value of OATP1, MRP2 and MRP3 were 29 952.1 ± 11 475.2, 34 376.4 ± 33 228.4 and 357 308.9 ± 64 646.5. Conclusion: T1-relaxation values, T1 relaxation time decline rate and rapid initial enhancement slope percentage in the first-pass study before and after gadoxetic disodium-enhanced MRI were determined in normal C57BL/6 mice as well as quantitative values of OATP1, MRP2 and MRP3 at the molecular level on the hepatocyte surface membrane were helpful for liver injury model with control study.

[Magnetic resonance imaging and diffusion weighted imaging features of focal peliosis hepatis].

Objective: To investigate the MRI and diffusion weighted imaging (DWI) features of focal peliosis hepatis. Methods: The clinical data and MRI of 19 cases with focal peliosis hepatis confirmed by pathology from January 2012 to March 2018 in Zhongshan Hospital of Fudan University were retrospectively analyzed. The number, location, size, shape, signal intensity of plain scan of lesions, enhancement pattern of lesions, vessels within lesions, and perfusion disorders of hepatic parenchyma were analyzed. The apparent diffusion coefficient (ADC) values of the lesions and adjacent hepatic parenchyma were measured, then the differences between them were explored statistically. All 24 lesions were categorized into group A with tumor-related chemotherapy and group B without tumor-related chemotherapy. The differences of MR features between the two groups were explored statistically. Results: In all 24 lesions, 22 lesions were located in the right lobe, 2 lesions in the left lobe. The median size was 7.5-72.0 (24.4±17.2) mm.On T(1)WI,21 lesions showed slightly hypointensity, 1 lesion showed slightly hyperintensity and 2 lesions were isointensity; all 24 lesions showed slightly hyperintensity on T(2)WI, and isointensity or slightly hyperintensity on DWI. The mean ADC value was (1.511±0.415)×10(-3) mm(2)/s in the lesions and (1.769±0.690)×10(-3) mm(2)/s in the adjacent hepatic parenchyma, which showed no difference between the two groups (P>0.05). On dynamic MR images, 20 lesions showed gradually filling enhancement, 4 lesions showed markedly and persistent enhancement. Punctiform or filiform vessels were found in 9 lesions. Adjacent hepatic perfusion disorders showed in 8 lesions. The median lesion size was 7.5-38.5(17.6±9.8) mm in the tumor-related-chemotherapy group and 9.0-72.0(33.8±21.2) mm in the no chemotherapy group.There was significant difference between the two groups (P<0.05). Conclusions: The MRI performance of focal peliosis hepatis had a certain characteristic. MRI combined with diffusion weighted imaging could help to make diagnoses.

[Study on diagnostic value of extracellular volume imaging by magnetic resonance imaging for liver fibrosis of hepatitis B].

Objective: To investigate the diagnostic value of extracellular volume (ECV) imaging by magnetic resonance imaging for liver fibrosis of hepatitis B. Methods: A retrospective analysis was recruited in patients with chronic hepatitis B, who underwent liver surgery from April to October 2017 for pathological evaluation of liver tissues, and all patients underwent Gd-EOB-DTPA-enhanced T1 mapping to calculate the liver ECV score. The correlation between ECV and staging of hepatic fibrosis and inflammatory activity were compared to clarify the diagnostic value of staging of fibrosis. Results: 66 patients were enrolled in this study. Concerning the staging of liver fibrosis, there were 13, 4, 13, 10, and 26 cases with F0, F1, F2, F3 and F4 stages, respectively. ECV values had high interobserver consistency (correlation coefficient 0.860). The ECV difference between different stages of liver fibrosis was statistically significant (F = 15.02, P < 0.001). There was a significant positive correlation between ECV and fibrosis stage (r = 0.622, P < 0.001), and weak correlation with inflammatory activity (r = 0.332, P = 0.007). Fibrosis staging was an independent factor influencing ECV (P < 0.001). The area under the receiver operator characteristic curve for the diagnosis of liver fibrosis staging F≥1, F≥3 and F4 were 0.760, 0.846 and 0.873, respectively. The diagnostic sensitivity and specificity were 64.15%, 92.31%, 77.78%, 80.00% and 88.46, 72.50%, respectively. Conclusion: MRI-ECV imaging has great value for staging hepatic fibrosis of hepatitis B, and it can provide an effective method for diagnosis, staging, and evaluating the curative effect of fibrosis.

[Value of gadoxetate disodium-enhanced magnetic resonance on hepatobiliary phase T1 mapping for predicting liver injury].

Objective: To evaluate the measured value of gadoxetic disodium - enhanced T1-weighted magnetic resonance for the prediction of liver damage (LD) including liver fibrosis and inflammation. Methods: Retrospectively analyzed laboratory data of 115 patients with pathological results including prothrombin time (PT), albumin, serum total bilirubin level (TBil), alanine aminotransferase (ALT), aspartate aminotransferase (AST), and magnetic resonance measurements (T1 measurement before and after enhancement and hepatobiliary specific phase T1pre, T1post, and changes in T1 relaxation time before and after enhancement were measured). The correlation between LD and magnetic resonance measurements was assessed by Spearman's correlation. All cases were divided into two groups: LD < 1 and LD≥1 (n1 = 26, n2 = 89), and the mean value of both groups was compared by t-test or Mann-Whitney U test. The independent influence factors of LD were obtained by binary logistic regression model. The area under receiver operating characteristics (AUROC) curve was performed on T1pre, T1post, and variation values. Results: Spearman's correlation test showed that T1post and variation values ​​were significantly associated with LD, and the correlation coefficients were 0.435, -0.353 and P < 0.05, respectively. The mean values ​​of T1post, variation values, PT, albumin, ALT and AST were statistically significant (P < 0.05). Binary logistic regression model showed T1post (P = 0.006), PT (P = 0.003), and AST (P = 0.032) were independent influencing factors of LD. T1- post contrast was good predictor of liver damage (AUC = 0.800). Conclusion: T1-post contrast predicts the existence of liver damage and provides useful information for clinical diagnosis and treatment.

Disrupting G6PD-mediated Redox homeostasis enhances chemosensitivity in colorectal cancer.

Glucose-6-phosphate dehydrogenase (G6PD) is a key enzyme that generates NADPH to maintain reduced glutathione (GSH), which scavenges reactive oxygen species (ROS) to protect cancer cell from oxidative damage. In this study, we mainly investigate the potential roles of G6PD in colorectal cancer (CRC) development and chemoresistance. We discover that G6PD is overexpressed in CRC cells and patient specimens. High expression of G6PD predicts poor prognosis and correlated with poor outcome of oxaliplatin-based first-line chemotherapy in patients with CRC. Suppressing G6PD decreases NADPH production, lowers GSH levels, impairs the ability to scavenge ROS levels, and enhances oxaliplatin-induced apoptosis in CRC via ROS-mediated damage in vitro. In vivo experiments further shows that silencing G6PD with lentivirus or non-viral gene delivery vector enhances oxaliplatin anti-tumor effects in cell based xenografts and PDX models. In summary, our finding indicated that disrupting G6PD-mediated NADPH homeostasis enhances oxaliplatin-induced apoptosis in CRC through redox modulation. Thus, this study indicates that G6PD is a potential prognostic biomarker and a promising target for CRC therapy.

Far upstream element-binding protein 1 is a prognostic biomarker and promotes nasopharyngeal carcinoma progression.

Nasopharyngeal carcinoma (NPC) is a malignant epithelial tumor with tremendous invasion and metastasis capacities, and it has a high incidence in southeast Asia and southern China. Previous studies identified that far upstream element-binding protein 1 (FBP1), a transcriptional regulator of c-Myc that is one of the most frequently aberrantly expressed oncogenes in various human cancers, including NPC, is an important biomarker for many cancers. Our study aimed to investigate the expression and function of FBP1 in human NPC. Quantitative real-time RT-PCR (qRT-PCR), western blot and immunohistochemical staining (IHC) were performed in NPC cells and biopsies. Furthermore, the effect of FBP1 knockdown on cell proliferation, colony formation, side population tests and tumorigenesis in nude mice were measured by MTT, clonogenicity analysis, flow cytometry and a xenograft model, respectively. The results showed that the mRNA and protein levels of FBP1, which are positively correlated with c-Myc expression, were substantially higher in NPC than that in nasopharyngeal epithelial cells. IHC revealed that the patients with high FBP1 expression had a significantly poorer prognosis compared with the patients with low expression (P=0.020). In univariate analysis, high FBP1 and c-Myc expression predicted poorer overall survival (OS) and poorer progression-free survival. Multivariate analysis indicated that high FBP1 and c-Myc expression were independent prognostic markers. Knockdown of FBP1 reduced cell proliferation, clonogenicity and the ratio of side populations, as well as tumorigenesis in nude mice. These data indicate that FBP1 expression, which is closely correlated with c-Myc expression, is an independent prognostic factor and promotes NPC progression. Our results suggest that FBP1 can not only serve as a useful prognostic biomarker for NPC but also as a potential therapeutic target for NPC patients.

Liver fibrosis staging using T1 mapping on gadoxetic acid-enhanced MRI compared with DW imaging.

AIM: To evaluate the utility of T1 mapping on gadoxetic acid-enhanced magnetic resonance imaging (MRI) and diffusion-weighted imaging (DWI) for staging liver fibrosis. MATERIALS AND METHODS: This retrospective study was approved by the institutional review board and included 145 patients (mean age: 54 years old; 115 men and 30 women). Necro-inflammatory activity grade (G) and liver fibrosis stage (S) were histopathologically determined. T1 relaxation time and apparent diffusion coefficient (ADC) of the liver were measured and the reduction rate of the T1 relaxation time (Δ%) was calculated. T1 relaxation time measurements were compared with ADC values according to S/G scores. RESULTS: Unenhanced hepatobiliary phase (HBP) and Δ% of T1 relaxation times showed significant correlations with S/G scores (rho: 0.28, 0.51, -0.35 for the S score, 0.26, 0.39, -0.26 for the G score, respectively, p<0.05). ADC values showed significant correlation with the S score (rho: -0.17, p = 0.04) and did not correlate significantly with the G score (rho: -0.07, p = 0.39). The areas under receiver operator characteristics (AUC) curve of unenhanced HBP, Δ% T1 relaxation time, and the ADC value were 0.68, 0.82, 0.71, 0.61 for the identification of S ≥ 3, and 0.63, 0.68, 0.62, 0.52 for the identification of G ≥ 3, respectively. The HBP T1 relaxation time was better than that of ADC for identification of S ≥ 3 (p = 0.0005) and G ≥ 3 (p = 0.014). CONCLUSIONS: The HBP T1 relaxation time measurement on gadoxetic acid-enhanced MRI images might be a potential biomarker in the staging of hepatic fibrosis, and was more accurate than the ADC measurement.

MiR-34c suppresses tumor growth and metastasis in nasopharyngeal carcinoma by targeting MET.

Our previous microarray analysis indicated that miR-34c was downregulated in nasopharyngeal carcinoma (NPC). However, little is known about the function and molecular mechanism of miR-34c in NPC. In this study, miR-34c was found to be significantly downregulated in NPC cell lines and clinical tissues. Ectopic expression of miR-34c suppressed NPC cell viability, colony formation, anchorage-independent growth, cell migration and invasion in vitro, and inhibited xenograft tumor growth and lung metastasis in vivo. MET proto-oncogene (MET) was identified as a direct target of miR-34c using luciferase reporter assays, quantitative RT-PCR, western blotting and immunofluorescent staining. Overexpression of miR-34c markedly reduced MET expression at both the mRNA and protein levels. Knockdown of MET suppressed NPC cell proliferation, migration and invasion, whereas the restoration of MET rescued the suppressive effects of miR-34c. The demethylation agent 5-aza-2'-deoxycytidine (DAC) restored the expression of miR-34c in NPC cell lines. The promoter region of miR-34c was hypermethylated in NPC cells. In conclusion, miR-34c suppresses tumor growth and metastasis in NPC by targeting MET. The newly identified miR-34c/MET pathway provides further insights into the development and progression of NPC, and may represent a novel therapeutic target for NPC treatment.

The impact of plasma Epstein-Barr virus DNA and fibrinogen on nasopharyngeal carcinoma prognosis: an observational study.

BACKGROUND: The impact of combining plasma fibrinogen levels with Epstein-Barr Virus DNA (EBV DNA) levels on the prognosis for patients with nasopharyngeal carcinoma (NPC) was evaluated. METHODS: In this observational study, 2563 patients with non-metastatic NPC were evaluated for the effects of circulating plasma fibrinogen and EBV DNA levels on disease-free survival (DFS), distant metastasis-free survival (DMFS), and overall survival (OS). RESULTS: Compared with the bottom biomarker tertiles, TNM stage-adjusted hazard ratios (HR, 95% confidence intervals (CIs)) for predicting DFS in fibrinogen tertiles 2 to 3 were 1.26 (1.00 to 1.60) and 1.81 (1.45 to 2.26), respectively; HR for EBV DNA tertiles 2 to 3 were 1.49 (1.12 to 1.98) and 4.24 (3.27 to 5.49), respectively. After additional adjustment for established risk factors, both biomarkers were still associated (P for trend <0.001) with reduced DFS (HR: 1.79, 95% CI, 1.43 to 2.25 for top fibrinogen tertiles; HR: 4.04, 95% CI: 3.10 to 5.27 for top EBV DNA tertiles compared with the bottom tertiles). For patients with advanced-stage disease, those with high fibrinogen levels (3.34 g l(-1)) presented with worse DFS, regardless of EBV DNA 4000 or <4000 copies ml(-1) subgroup. Similar findings were observed for DMFS and OS. CONCLUSIONS: Circulating fibrinogen and EBV DNA significantly correlate with NPC patients survival. Combined fibrinogen and EBV DNA data lead to improved prognostic prediction in advanced-stage disease.

Comparison of radiological and clinical features of temporal lobe necrosis in nasopharyngeal carcinoma patients treated with 2D radiotherapy or intensity-modulated radiotherapy.

BACKGROUND: To compare the imaging and clinical features of temporal lobe necrosis (TLN) in nasopharyngeal carcinoma (NPC) patients treated with two-dimensional radiotherapy (2D-RT) or those with intensity-modulated radiotherapy (IMRT). METHODS: We retrospectively analysed NPC patients who underwent 2D-RT (72 patients, 128 temporal lobes) or IMRT (36 patients, 50 lobes) and developed radiation-induced, MRI-confirmed TLN. RESULTS: White-matter lesions (WMLs), contrast-enhanced lesions, cysts and local mass effects were present in 128 out of 128 vs 48 out of 50 (P=0.078), 123 out of 128 vs 47 out of 50 (P=0.688), 10 out of 128 vs 1 out of 50 (P=0.185) and 57 out of 128 vs 13 out of 50 (P=0.023) temporal lobes, respectively, in the 2D-RT and IMRT groups. The WMLs were more extensive in the 2D-RT group (P<0.001). The maximum diameter of contrast-enhanced lesions was greater in the 2D-RT group (P<0.001), and these lesions tended to extend far away from the nasopharynx. The WMLs and enhancement had no impact on cyst development (both P=1). Local mass effects were always accompanied with contrast-enhanced lesions (P=0.024) but were not correlated with WMLs or cysts (P=0.523 and 0.341, respectively). There were no between-group differences in clinical features (all P-values>0.05), whereas the difference in the incidence of severe debility was of marginal significance (18.1% vs 5.6%, P=0.077). CONCLUSIONS: The IMRT-induced TLN was less extensive and milder than 2D-RT-induced TLN, but both had similar clinical features.

Longikaurin A, a natural ent-kaurane, induces G2/M phase arrest via downregulation of Skp2 and apoptosis induction through ROS/JNK/c-Jun pathway in hepatocellular carcinoma cells.

Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer, and is also highly resistant to conventional chemotherapy treatments. In this study, we report that Longikaurin A (LK-A), an ent-kaurane diterpenoid isolated from the plant Isodon ternifolius, induced cell cycle arrest and apoptosis in human HCC cell lines. LK-A also suppressed tumor growth in SMMC-7721 xenograft models, without inducing any notable major organ-related toxicity. LK-A treatment led to reduced expression of the proto-oncogene S phase kinase-associated protein 2 (Skp2) in SMMC-7721 cells. Lower Skp2 levels correlated with increased expression of p21 and p-cdc2 (Try15), and a corresponding decrease in protein levels of Cyclin B1 and cdc2. Overexpression of Skp2 significantly inhibited LK-A-induced cell cycle arrest in SMMC-7721 cells, suggesting that LK-A may target Skp2 to arrest cells at the G2/M phase. LK-A also induced reactive oxygen species (ROS) production and apoptosis in SMMC-7721 cells. LK-A induced phosphorylation of c-Jun N-terminal kinase (JNK), but not extracellular signal-regulated kinase and P38 MAP kinase. Treatment with, the JNK inhibitor SP600125 prevented LK-A-induced apoptosis in SMMC-7721 cells. Moreover, the antioxidant N-acetylcysteine prevented phosphorylation of both JNK and c-Jun. Taken together, these data indicate that LK-A induces cell cycle arrest and apoptosis in cancer cells by dampening Skp2 expression, and thereby activating the ROS/JNK/c-Jun signaling pathways. LK-A is therefore a potential lead compound for development of antitumor drugs targeting HCC.

Defining prognostic factors of survival after external beam radiotherapy treatment of hepatocellular carcinoma with lymph node metastases.

PURPOSE: To identify independent predictors of survival in patients with lymph node (LN) metastases from hepatocellular carcinoma (HCC) after external beam radiotherapy (EBRT). METHODS: There were 191 patients with LN metastases from HCC received EBRT enrolled in the study cohort. EBRT was designed to focus on the LNs and a median dose of 50 Gy (range 40-60 Gy) was delivered. Treatment response was assessed by the WHO response criteria. Factors such as demographic data, tumor characteristics, and treatment modalities were determined before EBRT. Predictors of survival were identified by univariate and multivariate analysis. RESULTS: The median survival was 8.0 months for all patients. Factors including Child-Pugh status (p = 0.009), intrahepatic tumor control (p = 0.015), LN location (p = 0.015), and response to EBRT (p < 0.001) were significant prognostic factors predicting for survival by multivariate analysis. The objective regression rate (ORR), which is the sum of complete and partial response rates, was as high as 79.1 %. As determined by multivariate analysis, the factors of LN location near liver (p = 0.002), smaller LN size (p = 0.021), and higher EBRT dose (p < 0.001) were associated with higher ORR values. CONCLUSION: This study provides detailed information about survival outcomes and prognostic factors. Child-Pugh B value, uncontrolled intrahepatic tumor, LN location far from liver, and no response to EBRT are the unfavorable independent predictors.

Homogeneous high attenuation renal cysts and solid masses--differentiation with single phase dual energy computed tomography.

AIM: To assess the feasibility of using single-phase dual-energy computed tomography (DECT) to differentiate between homogeneous high attenuation renal cysts and solid renal masses. MATERIALS AND METHODS: Twenty-nine pathologically proven solid renal masses in 29 patients and 14 high attenuation renal cysts from 11 patients were evaluated retrospectively. Two readers independently measured CT values from each lesion using both unenhanced single-energy phase and nephrographic dual-energy phase scans. Enhancement was defined as the attenuation difference between average-weighted 120 kV images and unenhanced images. Diagnostic sensitivity, specificity and accuracy based on enhancement, D-value (CT: 80 kV-140 kV) and DE-ratio (CT: 80/140 kV) were compared by the receiver operator characteristic (ROC) curves. RESULTS: Using 17.6 HU as the cutoff value for enhancement, resulted in a sensitivity, specificity and accuracy of 96.6%, 100% and 97.7%, respectively. Corresponding values were 100%, 92.9% and 97.7% using a D-value cutoff of 15.6 HU, and 100%, 85.7% and 95.3% using a DE-ratio cutoff of 1.3. There were no significant differences in the AUCs obtained from the ROC curves for enhancement, D-value or DE-ratio. The mean effective radiation dose was 6.04 mSv with biphasic scanning compared with 2.91 mSv for single dual-energy nephrographic phase scanning. CONCLUSION: Single-phase dual-energy CT is able to differentiate high attenuation renal cysts and solid renal masses with high sensitivity, specificity and accuracy, based on either D-value or DE-ratio. Omitting unenhanced scanning reduces the radiation dose by more than 50%.

EZH2 supports nasopharyngeal carcinoma cell aggressiveness by forming a co-repressor complex with HDAC1/HDAC2 and Snail to inhibit E-cadherin.

The enhancer of zeste homolog 2 (EZH2) is upregulated and has an oncogenic role in several types of human cancer. However, the abnormalities of EZH2 and its underlying mechanisms in the pathogenesis of nasopharyngeal carcinoma (NPC) remain unknown. In this study, we found that high expression of EZH2 in NPC was associated closely with an aggressive and/or poor prognostic phenotype (P<0.05). In NPC cell lines, knockdown of EZH2 by short hairpin RNA was sufficient to inhibit cell invasiveness/metastasis both in vitro and in vivo, whereas ectopic overexpression of EZH2 supported NPC cell invasive capacity with a decreased expression of E-cadherin. In addition, ablation of endogenous Snail in NPC cells virtually totally prevented the repressive activity of EZH2 to E-cadherin, indicating that Snail might be a predominant mediator of EZH2 to suppress E-cadherin. Furthermore, co-immunoprecipitation (IP), chromatin IP and luciferase reporter assays demonstrated that in NPC cells, (1) EZH2 interacted with HDAC1/HDAC2 and Snail to form a repressive complex; (2) these components interact in a linear fashion, not in a triangular fashion, that is, HDAC1 or HDAC2 bridge the interaction between EZH2 and Snail; and (3) the EZH2/HDAC1/2/Snail complex could closely bind to the E-cadherin promoter by Snail, but not YY1, to repress E-cadherin. The data provided in this report suggest a critical role of EZH2 in the control of cell invasion and/or metastasis by forming a co-repressor complex with HDAC1/HDAC2/Snail to repress E-cadherin, an activity that might be responsible, at least in part, for the development and/or progression of human NPCs.

A prognostic scoring system based on clinical features of intrahepatic cholangiocarcinoma: the Fudan score.

BACKGROUND: The objectives of this study were to propose a clinical prognostic scoring system applicable for intrahepatic cholangiocarcinoma (ICC) and to evaluate the prognostic validity of the American Joint Committee on Cancer (AJCC) 7th edition staging system. PATIENTS AND METHODS: Retrospective univariate and multivariate survival analyses were conducted for 344 patients with ICC who underwent hepatectomy. A simple clinical prognostic scoring system (Fudan score) was developed based on the independent predictors. The prognostic validity was assessed in 74 patients with unresected tumors and compared with the AJCC 6th and 7th edition systems. RESULTS: In the training set, serum alkaline phosphatase level, carbohydrate antigen 19-9 level, tumor boundary type, tumor size, and number of intrahepatic tumors were independent predictive factors of survival in ICC and were incorporated into the Fudan score. Three hundred forty-four patients were categorized into four subsets with 5-year overall survival rates of 48.6%, 25.6%, 10.3%, and 0.0% for low-, intermediate-, high-, and extremely high-risk groups, respectively. The discriminative ability of the Fudan score was better than that of the AJCC staging system and well applied in the unresected patient set. CONCLUSIONS: A Fudan score based on clinical factors may provide a relatively accurate prognostic prediction for ICC patients regardless of resection status.