The correlation and prognostic value of serum levels of soluble programmed death protein 1 (sPD-1) and soluble programmed death-ligand 1 (sPD-L1) in patients with hepatocellular carcinoma.

BACKGROUND: Blocking the programmed death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) pathway in hepatocellular carcinoma (HCC) is a very promising approach in immunotherapy. However, the correlation and prognostic values of serum soluble PD-1 and PD-L1 (sPD-1/sPD-L1) have not been explored conjointly in HCC patients. METHODS: This study retrospectively included 120 HCC patients receiving radical resection. The serum levels of sPD-1/sPD-L1 and inflammatory cytokines were measured by antibody array assay. Immunohistochemistry was applied to assess both the expression of membrane-bound PD-L1, and the number of CD4+ tumor-infiltrating lymphocytes (TILs) and CD8+ TILs. RESULTS: The best cut-off values of sPD-1 and sPD-L1 for predicting disease-free survival (DFS) were 33.0 µg/ml and 11.2 µg/ml, respectively. Multivariable analysis showed that sPD-L1 was a negative independent prognostic factor [DFS, Hazard Ratio (HR) 2.58, 95% CI 1.14-5.84, P = 0.023; overall survival (OS), HR 1.77, 95% CI 1.01-3.12, P = 0.048], while sPD-1 was a favorable independent prognostic factor (DFS, HR 0.32, 95% CI 0.14-0.74, P = 0.007; OS, HR 0.54, 95% CI 0.30-0.98, P = 0.044) in HCC patients. We also observed some similar associations between inflammatory cytokines (IL-10, IL-17, TNF-α) and sPD-1 or sPD-L1, as well as a close positive association between sPD-1 and sPD-L1. No significant associations of sPD-1/sPD-L1 with either intra-tumoral PD-L1 expression, or the numbers of CD4+ TILs and CD8+ TILs were determined. CONCLUSIONS: Our findings indicate that sPD-1 and sPD-L1 are independent prognostic factors with opposite prognostic roles in predicting both DFS and OS in HCC patients.

High number of PD-1 positive intratumoural lymphocytes predicts survival benefit of cytokine-induced killer cells for hepatocellular carcinoma patients.

BACKGROUND & AIMS: Adjuvant cytokine-induced killer (CIK) cells treatment has shown potential in reducing the recurrence rate and prolonging the survival of patients with hepatocellular carcinoma (HCC). We aimed to identify the best predictive biomarker for adjuvant CIK cells treatment in patients with HCC after curative resection. METHODS: This study retrospectively included 145 pairs of HCC patients by one-to-one propensity score matching. One group received CIK cells transfusion after surgery (surgery-CIK group); the other one group underwent surgery only (surgery-only group). Immunohistochemistry (IHC) was used to measure PD-1, PD-L1, CD4, CD8 and Foxp3 expression in tumour tissues of surgery-CIK group; IHC of PD-1 and PD-L1 was conducted in the surgery-only group. RESULTS: The surgery-CIK group had a significantly higher disease-free survival (DFS) and overall survival (OS) rates compared to the surgery-only group. Of all the intratumoural biomarkers, in the surgery-CIK group, multivariate analysis showed that a high number of PD-1+ tumour infiltrative lymphocytes (TILs) was the only factor that independently predicted favourable OS and DFS. By contrast, in the surgery-only group, no significant correlations between PD-1/PD-L1 expression and survival of patients were identified. Further correlation analysis showed a high number of PD-1+ TILs associated with a high number of both CD4+ and CD8+ TILs in surgery-CIK group. CONCLUSIONS: A high number of PD-1+ TILs can serve as a potent biomarker for adopting CIK cells therapy in HCC patients after curative resection.

PRL-3 promotes migration and invasion and is associated with poor prognosis in salivary adenoid cystic carcinoma.

BACKGROUND: PRL-3 had been found to be involved in tumorigenesis in various malignancies. In this study, we investigated the role of PRL-3 in the development, migration, and invasion of salivary adenoid cystic carcinoma (SACC). METHODS: Immunohistochemistry (IHC) was used to analyze the role of PRL-3 in the development and prognosis of SACC. Then, we overexpressed or inhibited the expression of PRL-3 in paired SACC cells to analyze the role of PRL-3 in the migration and invasion of SACC. In vitro migration and invasion assays were used. Western blotting was used to detect metastasis-related protein levels. RESULTS: IHC results confirmed that the deregulation of PRL-3 was a frequent event in SACC; the upregulation of PRL-3 was related to clinical stages, vital status, and distant metastasis, which was associated with reduced overall survival and disease-free survival. SACC-LM cells with higher migratory and invasive abilities had more robust PRL-3 protein expression than SACC-83 cells with lower migratory and invasive abilities. PRL-3 overexpression promoted cell migration, invasion, and proliferation, led to simultaneous upregulation of phosphorylated PRL-3, pERK1/2, Slug, vimentin, and downregulation of E-cadherin in SACC-83 cells. However, the inhibition of PRL-3 by PRL-3 inhibitor or PRL-3 siRNA in SACC-LM cells inhibited cell migration, invasion, and proliferation, resulted in simultaneous downregulation of phosphorylated PRL-3, pERK1/2, Slug, vimentin, and upregulation of E-cadherin. CONCLUSIONS: Our results confirm that PRL-3 plays an important role in the development of SACC and contributes to the migratory and invasive abilities of SACC.

Deregulation of Bmi-1 is associated with enhanced migration, invasion and poor prognosis in salivary adenoid cystic carcinoma.

BACKGROUND: Bmi-1 had been found to involve in self renewal of stem cells and tumorigenesis in various malignancies. In this study, we investigated the role of Bmi-1 in the development of salivary adenoid cystic carcinoma (SACC). METHODS: At first, we confirmed that the deregulation of Bmi-1 was a frequent event in SACC; up-regulation of Bmi-1 was correlated with clinical stages, vital status and distant metastasis and associated with reduced overall survival and disease free survival. SACC-LM cells, higher migration and invasion abilities, elevated the expression of Bmi-1 protein, epithelial-mesenchymal transition (EMT) related proteins (Snail, Slug and Vimentin) and cancer stem cells (CSCs) related proteins (ABCG2, Notch, ALDH-1, Oct-4, Nanog and Epcam) compared to the SACC-83 cells (lower migration and invasion abilities). The migration and invasion abilities were inhibited in SACC-LM cells upon Bmi-1 knockdown. Meanwhile, Bmi-1 knockdown resulted in simultaneous loss of stem cell markers and EMT markers in SACC-LM cells. CONCLUSION: Our studies confirm that Bmi-1 deregulation plays an important role in the development of SACC and contributes to the migration and the invasion abilities of SACC, which is involved in EMT and CSCs. GENERAL SIGNIFICANCE: To our knowledge, this is the first study revealing that Bmi-1 deregulation is associated with enhanced migration, invasion and poor prognosis in salivary adenoid cystic carcinoma.

MTUS1/ATIP3a down-regulation is associated with enhanced migration, invasion and poor prognosis in salivary adenoid cystic carcinoma.

BACKGROUND: Microtubule-associated tumor suppressor gene (MTUS1) has been identified as tumor suppressor gene in many malignant tumors. In this study, we investigated the role of MTUS1 in the development of salivary adenoid cystic carcinoma (SACC) and its functional effect on the migration and invasion of SACC. METHODS: Archival clinical samples including 49 primary SACC were examined for MTUS1 expression by immunohistochemistry. Statistical analyses were performed to evaluate the correlation between MTUS1 with histopathological features and survival. The expression of MTUS1/ATIP (AT2 receptor-interacting protein) isoforms was determined in SACC tissue samples and cell lines using quantitative RT-PCR assays. Then we investigated whether the migration and invasion of SACC were mediated by MTUS1/ATIP3a using in vitro cell migration and invasion assay. RESULTS: We confirmed that the down-regulation of MTUS1 was a frequent event in SACC, and was correlated with distant metastasis and associated with reduced overall survival and disease free survival. Isoform specific quantitative RT-PCR assays revealed that ATIP1, ATIP3a and ATIP3b were the major isoforms of the MTUS1 gene products in SACC, and were significant down-regulation in SACC as compared to matching normal tissues. For functional analyses, we found that SACC-LM cells (SACC cell line with higher migration and invasion ability) possessed a lower expression level of ATIP3a compared to SACC-83 cells (lower migration and invasion ability). Restoration of ATIP3a expression in SACC-LM cells induced anti-proliferative activity and inhibited the migration and invasion ability. Knockdown of ATIP3a promoted the proliferation, migration and invasion ability of SACC-83 cells. Restoration of ATIP3a inhibited the phosphorylation of ERK (extracellular-regulated kinase) 1/2, the expression of Slug and Vimentin in SACC-LM cells, while knockdown of ATIP3a increased the phosphorylation of ERK1/2, the expression of Slug and Vimentin in SACC-83 cells. CONCLUSIONS: Our studies confirm that MTUS1 plays an important role in the progression of SACC, and may serve as a biomarker or therapeutic target for patients with SACC. MTUS1/ATIP3a down-regulation contributes to the proliferation, migration and the invasion abilities of SACC.

Transarterial Chemoembolization (TACE) Combined with Lenvatinib versus TACE Alone in Intermediate-Stage Hepatocellular Carcinoma Patients Beyond Up-To-Seven Criteria: A Retrospective, Propensity Score-Matched Analysis.

RATIONALE AND OBJECTIVES: To compare the treatment efficacy and safety of transarterial chemoembolization (TACE) combined with lenvatinib versus TACE alone in patients with intermediate-stage hepatocellular carcinoma (HCC) beyond up-to-seven criteria. MATERIALS AND METHODS: A total of 107 newly diagnosed HCC patients with Barcelona Clinic Liver Cancer stage B HCC beyond up-to-seven criteria were included in this retrospective cohort study. These patients were divided into two groups: TACE-Lenv group and TACE alone group. Propensity score matching was used to account for potential confounding factors. Overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), downstaging rate, liver function, and adverse events (AEs) were recorded and evaluated. RESULTS: Both the median OS and median PFS were significantly longer in the TACE-Lenv group compared to the TACE alone group (median OS: 28.0 vs 12.0 months, P = 0.017; median PFS [mRECIST]: 8.2 vs 3.7 months, P = 0.018; median PFS [RECIST v1.1]: 8.9 vs 3.7 months, P = 0.003). Furthermore, the ORR and DCR were also significantly higher in TACE-Lenv group (ORR: 94% [30/32] vs 47% [15/32], P < 0.001; DCR: 97% [31/32] vs 62% [20/32], P < 0.001). There were no significant differences in terms of liver function and grade 3 or 4 AEs rate between two groups. CONCLUSION: The combination of TACE and lenvatinib provides clinical benefits for patients with intermediate HCC beyond the up-to-seven criteria, has an acceptable safety profile, shows a trend towards improving liver function, and does not increase the occurrence of grade 3-4 AEs. KEY POINTS: The efficacy of transarterial chemoembolization in intermediate-stage hepatocellular carcinoma patients is partially unsatisfactory. Addition of lenvatinib to transarterial chemoembolization improves OS, PFS, ORR, and DCR for patients with intermediate-stage hepatocellular carcinoma beyond the up-to-seven criteria. This combination therapy is a superior treatment option for intermediate-stage hepatocellular carcinoma patients with high tumor burden.

Three E2F target-related genes signature for predicting prognosis, immune features, and drug sensitivity in hepatocellular carcinoma.

Background: Hepatocellular carcinoma (HCC) is extremely malignant and difficult to treat. The adenoviral early region 2 binding factors (E2Fs) target pathway is thought to have a major role in tumor growth. This study aimed to identify a predictive E2F target signature and facilitate individualized treatment for HCC patients. Methods: We constructed an E2F target-related gene profile using univariate COX and LASSO regression models and proved its predictive efficacy in external cohorts. Furthermore, we characterized the role of the E2F target pathway in pathway enrichment, immune cell infiltration, and drug sensitivity of HCC. Results: Lasso Cox regression created an E2F target-related gene signature of GHR, TRIP13, and CDCA8. HCC patients with high risk were correlated with shorter survival time, immune evasion, tumor stem cell characteristics and high sensitivity to Tipifarnib and Camptothecin drugs. Conclusion: Hepatocellular carcinoma prognosis was predicted by an E2F target signature. This finding establishes the theoretical usefulness of the E2F target route in customized identification and treatment for future research.

Intercellular transfer of activated STING triggered by RAB22A-mediated non-canonical autophagy promotes antitumor immunity.

STING, an endoplasmic reticulum (ER) transmembrane protein, mediates innate immune activation upon cGAMP stimulation and is degraded through autophagy. Here, we report that activated STING could be transferred between cells to promote antitumor immunity, a process triggered by RAB22A-mediated non-canonical autophagy. Mechanistically, RAB22A engages PI4K2A to generate PI4P that recruits the Atg12-Atg5-Atg16L1 complex, inducing the formation of ER-derived RAB22A-mediated non-canonical autophagosome, in which STING activated by agonists or chemoradiotherapy is packaged. This RAB22A-induced autophagosome fuses with RAB22A-positive early endosome, generating a new organelle that we name Rafeesome (RAB22A-mediated non-canonical autophagosome fused with early endosome). Meanwhile, RAB22A inactivates RAB7 to suppress the fusion of Rafeesome with lysosome, thereby enabling the secretion of the inner vesicle of the autophagosome bearing activated STING as a new type of extracellular vesicle that we define as R-EV (RAB22A-induced extracellular vesicle). Activated STING-containing R-EVs induce IFNß release from recipient cells to the tumor microenvironment, promoting antitumor immunity. Consistently, RAB22A enhances the antitumor effect of the STING agonist diABZI in mice, and a high RAB22A level predicts good survival in nasopharyngeal cancer patients treated with chemoradiotherapy. Our findings reveal that Rafeesome regulates the intercellular transfer of activated STING to trigger and spread antitumor immunity, and that the inner vesicle of non-canonical autophagosome originated from ER is secreted as R-EV, providing a new perspective for understanding the intercellular communication of organelle membrane proteins.

Dynamic monitoring of serum soluble programmed cell death ligand 1 as a response predictor to chemotherapy in metastatic or recurrent gastrointestinal cancer.

BACKGROUND: Biomarkers in serum may have important clinical implications for personalized medicine, including therapeutic guidance, and monitoring of recurrence. The role of programmed cell death ligand 1 (PD-L1) expression as a tumor biomarker remains controversial. In this study, we aimed at determining the changes of soluble PD-L1 (sPD-L1) during first-line chemotherapy and assessing the association with treatment response and progression-free survival (PFS) of patients with advanced gastrointestinal cancer. METHODS: Blood samples from 115 gastrointestinal cancer patients who have not received any previous systemic chemotherapy for recurrent or metastatic disease were collected at the time of diagnosis and each response evaluation. Serum of sPD-L1 expression was tested by enzyme-linked immunosorbent assay (ELISA). The associations between the baseline level of serum sPD-L1 and clinical-pathological characteristics and prognosis were analyzed. we further dynamically monitored the level change of serum sPD-L1 during treatment and analyzed its relationship with clinical-pathological characteristics, chemotherapy response and prognosis. RESULTS: Among 115 metastatic gastrointestinal patients, the median serum sPD-L1 level was 0.777 (range, <0.156-6.680) ng/mL. In most cases, changes in sPD-L1 level correlated with treatment response. Patients with values of serum sPD-L1 decreasing after chemotherapy had better tumor response and median PFS compared with patients with values increasing after chemotherapy (ORR, 88.3% vs. 54.0% P=0.000005 and PFS, not reached vs. 27 months, P=0.00026). D-values of sPD-L1 in patients with progressive disease (PD) were observed increasing from 0.406 to 1.097 ng/mL between pre- and post-chemotherapy, while in those with better tumor response D-values decreased from 1.153 to 0.791 ng/mL after chemotherapy compared with baseline. In the logistic regression analysis, the change of sPD-L1 levels in serum after chemotherapy were found to be a prognostic factor for treatment response and PFS in the multivariate analysis. CONCLUSIONS: These results showed for the first time that sPD-L1 in serum samples of patients with advanced gastrointestinal cancer were changed after chemotherapy and increased serum sPD-L1 levels were poor prognostic factors for both tumor response and PFS of patients. Dynamic monitoring of serum sPDL1 after treatment may be served as a potential predictor to treatment response in gastrointestinal cancer patients.

Ultrasound Assessment of Muscle Injury Associated with Closed Limb Fracture.

OBJECTIVE: The aim of this study was to assess muscle injury associated with upper and lower closed limb fracture using ultrasound, and to develop ultrasound classification criteria for muscle injury. PATIENTS AND METHODS: Thirty patients with limb fracture and muscle injury participated in this study. Ultrasonography was used to assess muscle fibre, hematoma, vascular injury, and diameter growth rate. Injury was classified into three grades according to the ultrasound imaging: scores of less than, equal to, or greater than 9. RESULTS: Of 30 patients, focal fibre rupture was observed in 11 cases; in 9 cases, the injured area exceeded 30% of the muscle area. Six patients had muscle hematoma (the largest reaching 39 mm); in 4 patients, the hematoma showed a honeycombed pattern. Vascular rupture was observed in 6 patients, of which 2 had decreased main arterial diameter and blood flow. The greatest increase in muscle thickness was 17 mm. Of all patients, 11 showed an increase in the diameter growth rate of the muscle exceeding 50%. In addition, among the 30 patients, 11 patients with scores ranging from 4 to 8 received conservative treatment; 9 patients with scores ranging from 10 to 14 received operative treatment; and 10 patients with scores equal to 9 received either conservative or operative treatment. CONCLUSIONS: Ultrasonography is useful for diagnosing muscle injury associated with closed limb fracture. The ultrasound classification criteria for muscle injury can be used to assess the severity of injury and guide the decision of treatment.

An exploratory study of CT-guided percutaneous radiofrequency ablation for stage I thymoma.

BACKGROUND: Thymoma is a rare tumor that originates from thymic epithelial cells and is usually associated with myasthenia gravis. Radiofrequency ablation (RFA) is a minimally invasive and curative treatment for other tumors, but RFA has not been used for the early treatment of thymoma. METHODS: The current study included 13 patients with stage I thymoma who were not candidates for surgical resection or video-assisted thoracoscopic surgery (VATS). All patients underwent first-line CT-guided percutaneous RFA. The feasibility and therapeutic effects of the intervention were thoroughly documented. RESULTS: All tumors were completely ablated (13 / 13, 100%). During follow-up (median 80.5 months, range, 64.6-116.9 months), only 1 of the 13 patients had recurrence of thymoma (1 / 13, 7.7%) at 35.5 months after the initial ablation. There were no surgery-related deaths after RFA treatment. The most common complications were fever (13 / 13, 100%) and pain (13 / 13, 100%). There was only one patient who occurred severe puncture-related bleeding during the procedure that needed blood transfusion and intravascular embolization of the punctured-injured vessel. CONCLUSION: CT-guided percutaneous RFA for treatment of stage I thymoma is associated with minor trauma, few complications and good treatment outcomes.

TFAP4 Promotes Hepatocellular Carcinoma Invasion and Metastasis via Activating the PI3K/AKT Signaling Pathway.

Transcription factor activating enhancer binding protein 4 (TFAP4) is established as a regulator of human cancer genesis and progression. Overexpression of TFAP4 indicates poor prognosis in various malignancies. The current study was performed to quantify TFAP4 expression as well as to further determine its potential prognostic value and functional role in patients with hepatocellular carcinoma (HCC). We identified that the expression of TFAP4 mRNA in 369 tumor tissues was higher than that in 160 normal liver tissues. Upregulated TFAP4 expressions were discovered in HCC cell lines compared to the healthy liver cell line, and similarly, the levels of TFAP4 were higher in tumor tissues than its expression in paratumor tissues. High mRNA and protein expression of TFAP4 was associated with worse overall survival (OS) and disease-free survival (DFS). Additionally, TFAP4 expression emerged as a risk factor independently affecting both OS and DFS of HCC patients. Functional studies demonstrated that TFAP4 increased HCC cell migration and invasion. Further investigations found that TFAP4 promotes invasion and metastasis by inducing epithelial-mesenchymal transition (EMT) and regulating MMP-9 expression via activating the PI3K/AKT signaling pathway in HCC. In conclusion, our study demonstrated that TFAP4 is a valuable prognostic biomarker in determining the likelihood of tumor metastasis and recurrence, as well as the long-term survival rates of HCC patients. Exploring the regulatory mechanism of TFAP4 will also contribute to the development of new prevention and treatment strategies for HCC.

Chiral ruthenium(II) complex Δ-[Ru(bpy)2(o-FMPIP)] (bpy = bipyridine, o-FMPIP = 2-(2'-trifluoromethyphenyl) imidazo[4,5-f][1,10]phenanthroline) as potential apoptosis inducer via DNA damage.

Chiral ruthenium(II) complexes have long been considered as potential anticancer agents. Herein, in vivo inhibitory activity of a chiral ruthenium(II) complex coordinated by ligand 2-(2'-trifluoromethyphenyl) imidazo [4,5-f][1,10]phenanthroline, Δ-[Ru(bpy)2(o-FMPIP)] (D0402) on Kunming(KM) mice bearing tumor (H22 hepatic cancer) has been evaluated, and the results showed that the tumor weight of mice treated with 0.22 mg/(kg·day) D0402 via i.v. administration for 7 days decreased about 31.79% compared to the control group, while the body weight, as well as the thymus, spleen, liver, lung, and kidney indices of mice treated with D0402 observed almost no loss compared to the control group. Furthermore, the mechanism studies on anti-angiogenic showed that D0402 could inhibit the formation of angiogenesis in the transgenic Tg(fli1a: EGFP) zebrafish. After treated with D0402, the sub-intestinal vessels(SIVs) of the zebrafish became disordered and chaotic, and was dosage dependent. Moreover, the TUNEL analysis and comet assays revealed that D0402 can induce apoptosis of HepG2 cell through DNA damage, and this was further demonstrated by immunofluorescence analysis with the number of γ-H2AX increased following the increasing amount of D0402. Besides, in vivo toxicity of D0402 has also been investigated on the development of zebrafish embryo, and the results showed that there were no death or development delay occurred for zebrafish embryo treated with D0402 up to concentration of 60 µM. All in together, this study suggested that D0402 can be developed as a potential inhibitor against liver cancer through co-junction of anti-angiogenesis and apoptosis-inducing via DNA damage in the near future.

Oxymatrine prevents synovial inflammation and migration via blocking NF-κB activation in rheumatoid fibroblast-like synoviocytes.

The fibroblast-like synoviocytes (FLSs) has the aggressive phenotype, which is very important for cartilage destruction in rheumatoid arthritis (RA). To the pathology of RA, the increased FLSs migration, activation and proliferation are essential factors. Oxymatrine is a traditional Chinese herb, which is the extraction from the root of Sophora flavescens and regarded as quinolizidine alkaloid compounds and has been shown to inhibit inflammation, proliferation and migration in vitro or vivo. However, whether oxymatrine effects in the treatment of RA FLSs is undefined. In our study, the inhibition of oxymatrine in RA FLSs inflammation, proliferation and migration in RA FLS are evaluated. We found that oxymatrine decreased the IL-6 and IL-8 expression and the proliferation, migration and invasion of RA FLSs. We also evaluated the molecular mechanisms and we found the effect of oxymatrine on NF-κB activation. The results showed that oxymatrine inhibited the activity of NF-κB. And the treatment activity of oxymatrine on collagen-induced arthritis (CIA) was further explored by us. Thus, we conclude that oxymatrine may protect joint destruction of RA by inhibiting synoviocyte activation, migration, invasion, and proliferation.

A Prognostic Nomogram Incorporating Depth of Tumor Invasion to Predict Long-term Overall Survival for Tongue Squamous Cell Carcinoma With R0 Resection.

Purpose: To establish a useful prognostic nomogram to predict long-term overall survival for patients with tongue squamous cell carcinoma (TSCC) after R0 resection. Patients and Methods: The nomogram was developed using a retrospective cohort of 235 TSCC patients from Sun Yat-sen University Cancer Center between 1 January 2000 and 31 December 2007. An independent dataset of 223 patients was used for external validation. Multivariate Cox proportional hazards model (backward selection; the Akaike information criteria) was applied to select variables for construction of the nomogram. Discrimination and calibration were performed using the area under the receiver operating characteristic (ROC) curve (AUC) and calibration plots. Results: Using the backward selection of clinically-relevant variables, depth of invasion (hazard ratio [HR], 3.55; P < 0.001), pN (HR, 3.48; P = 0.01), age (HR, 1.03; P < 0.01) and neck dissection (HR, 0.53; P = 0.04) were selected as independent predictive factors of survival. A nomogram was thus established to predict survival of TSCC patients after R0 resection. The calibration curve demonstrated that the nomogram was able to accurately predict 5-year overall survival (OS). In addition, our data showed the AUC of the nomogram were 0.78 and 0.71 based on the internal and external validation, which were significantly better than the 7th TNM stage (0.64/0.55). Conclusion: The proposed nomogram resulted in accurate prognostic prediction of the 5-year OS for TSCC patients with R0 resection.

Dynamically prognosticating patients with hepatocellular carcinoma through survival paths mapping based on time-series data.

Patients with hepatocellular carcinoma (HCC) always require routine surveillance and repeated treatment, which leads to accumulation of huge amount of clinical data. A predictive model utilizes the time-series data to facilitate dynamic prognosis prediction and treatment planning is warranted. Here we introduced an analytical approach, which converts the time-series data into a cascading survival map, in which each survival path bifurcates at fixed time interval depending on selected prognostic features by the Cox-based feature selection. We apply this approach in an intermediate-scale database of patients with BCLC stage B HCC and get a survival map consisting of 13 different survival paths, which is demonstrated to have superior or equal value than conventional staging systems in dynamic prognosis prediction from 3 to 12 months after initial diagnosis in derivation, internal testing, and multicentric testing cohorts. This methodology/model could facilitate dynamic prognosis prediction and treatment planning for patients with HCC in the future.

Combined CT-guided radiofrequency ablation with systemic chemotherapy improves the survival for nasopharyngeal carcinoma with oligometastasis in liver: Propensity score matching analysis.

The aim of this study was to retrospectively compare the treatment efficacy of systemic chemotherapy combined with sequential CT-guided radiofrequency ablation (Chemo-RFA) to chemotherapy alone (Chemo-only) in the management of nasopharyngeal carcinoma (NPC) with liver metastasis. Between 2003 and 2011, 328 NPC patients diagnosed with liver metastasis at Sun Yat-sen University Cancer Center were enrolled. One-to-one matched pairs between Chemo-RFA group with the Chemo-only group were generated using propensity score matching. The associations of treatment modality with overall survival (OS) and progression-free survival (PFS) were determined by Cox regression. Of the patients enrolled, 37 patients (11.8 %) received combined treatment, 291 (82.2) received chemotherapy alone. The patients in Chemo-RFA group were more frequently classified as lower number (≤3) of liver metastatic lesions (P<0.001), had lower rates of bi-lobar liver metastasis (P<0.001) and extra-hepatic metastasis (P<0.001) than patients in Chemo-only group. After propensity score matching, 37 pairs of well-matched liver metastatic NPC patients were selected from different treatment groups. The adjusted hazard ratio in OS and PFS of the choice for Chemo-RFA approach to Chemo-only was 0.53 (95%CI, 0.30-0.93) and 0.60 (95%CI, 0.36-0.97), respectively. In conclusion, combined CT-guided RFA and chemotherapy approach offer the chance of improved survival for NPC patients with oligometastasis in liver, and should be considered if the ablation is technically feasible.

Prognostic value of programmed death-1, programmed death-ligand 1, programmed death-ligand 2 expression, and CD8(+) T cell density in primary tumors and metastatic lymph nodes from patients with stage T1-4N+M0 gastric adenocarcinoma.

BACKGROUND: Anti-programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) immunotherapy has been proved to be effective on gastric cancer in ongoing clinical trials. However, the value of PD-L1 in predicting responses of patients with gastric cancer to anti-PD-1/PD-L1 immunotherapy is controversial. Some studies suggested that intra- and inter-tumoral heterogeneity of PD-L1 expression might explain the controversy. This study aimed to analyze the expression of PD-L1, PD-L2, and PD-1 as well as CD8(+) T-cell density in primary tumors and lymph nodes from patients with stage T1-4N+M0 gastric adenocarcinoma to explore the heterogeneity of PD-1 signaling pathway molecules. METHODS: In primary tumors and metastatic as well as non-metastatic lymph nodes from patients with stage T1-4N+M0 gastric adenocarcinoma, we detected PD-L1 and PD-L2 expression with immunohistochemistry. CD8(+) T-cell density in primary tumors and PD-1 expression on CD8(+) T cells were detected with immunofluorescence. Univariate analysis was used to determine the prognostic values of them. Cox proportional hazard regression model was used to identify independent risk factors that affect patients' overall survival and disease-free survival. RESULTS: Among 119 eligible patients who had undergone surgical resection, the positive rate of PD-L1 was higher in metastatic lymph nodes than in primary tumors (45.4% vs. 38.7%, P = 0.005); the positive rate of PD-1 on CD8(+) T cells was significantly higher in primary tumors and metastatic lymph nodes than in tumor-free lymph nodes (both P < 0.001). The intensity of PD-1 expression on CD8(+) T cells in primary tumors and in metastatic lymph nodes were stronger than that in tumor-free lymph nodes from the same patient. Beside, the positive rate of PD-L2 did not show any differences between primary tumors and metastatic lymph nodes. In multivariate analysis, PD-L1 expression, PD-L2 expression, a low density of CD8(+) T cells in primary tumors, and PD-1 expression on CD8(+) T cells in primary tumors were associated with poor prognosis. CONCLUSION: The expression of PD-L1 is heterogeneous in primary tumors and in metastatic lymph nodes from patients with stage T1-4N+M0 gastric adenocarcinoma, which might explain the inconsistent results in assessing the prognostic value of PD-L1 expression in previous studies.

SOD2 deregulation enhances migration, invasion and has poor prognosis in salivary adenoid cystic carcinoma.

This study aimed to investigate the role of SOD2 in the progression and metastasis of salivary adenoid cystic carcinoma (SACC). We analyzed the expression of SOD2 in 50 SACC patients. Then, the effects and mechanism of SOD2 on cell metastasis in a pair of different metastatic potential cell lines was investigated. SOD2 was deregulated in patients with SACC. Up-regulation of SOD2 was associated with distant metastasis and reduced overall survival and disease free - survival. Compared to SACC-83 cells (lower metastasis ability), SACC-LM cells (higher metastasis ability) had higher SOD2 activity and intracellular H2O2 concentrations, and protein levels of pERK1/2 and Slug, but had similar catalase protein level and activity. In SACC-LM, reducing the expression of SOD2 by SiRNA inhibited the metastasis ability and reduced the SOD2 activities, intracellular H2O2 concentrations, and protein levels of pERK1/2 and Slug. These effects were revised in SACC-83 after SOD2 overexpression. Moreover, in SACC-83, treated with H2O2, the metastasis was enhanced accompanied by increased protein levels of pERK1/2 and Slug. We confirmed that SOD2 play an important role in the development and prognosis of SACC and SOD2-dependent production of H2O2 contributes to metastasis of SACC through the ERK-Slug signaling pathway.

Once-weekly subcutaneous administration of bortezomib in patients with multiple myeloma.

In patients with multiple myeloma (MM), once-weekly intravenous injection or twice-weekly subcutaneous injection (SC) of bortezomib has been proven to offer non-inferior efficacy to standard twice-weekly intravenous administration, with an improved safety profile. However, whether once-weekly SC bortezomib can further reduce the incidence rate of peripheral neuropathy (PN) and not compromise the efficacy remains to be investigated. 25 patients of MM treated with once-weekly SC bortezomib were reviewed in this study. The median treatment cycles were 4 (range, 2-9 cycles). Complete response (CR) rate was 52%, ≥very good partial response (VGPR) rate was 72%, and ≥partial response (PR) rate was 84%. 1-year and 2-year PFS rate was 63.0% and 34.3%, respectively, and 2-year OS rate was 100%. Any grade of PN was reported in 9 patients (36.0%), with 7 patients (28.0%) had grade 1 PN, and 2 patients (8.0%) had grade 2 PN. No patients reported grade 3/4 PN in this cohort. In conclusion, once-weekly subcutaneous administration of bortezomib offers excellent efficacy with a further improved safety profile, especially with regard to PN. It needs to be validated in future prospective randomized trials.