Trajectories of α-fetoprotein and unresectable hepatocellular carcinoma outcomes receiving atezolizumab plus bevacizumab: a secondary analysis of IMbrave150 study.

BACKGROUND: α-fetoprotein (AFP) response has been demonstrated as a biomarker for unresectable hepatocellular carcinoma (uHCC) patients receiving immunotherapy, but its definition is still unclear. This exploratory study investigated the AFP trajectory and clinical outcomes of receiving atezolizumab plus bevacizumab (Atez/Bev) therapy. METHODS: This secondary analysis used the Atez/Bev arm data of phase III IMbrave150 study to distinguish potential AFP changing rate trajectories through latent class trajectory models. The multivariable Cox models were applied to calculate adjusted hazard ratios (HRs) and 95% CIs for clinical outcomes. RESULTS: Three distinct trajectories were identified among the uHCC patients with 7 times (range, 3 to 28) of AFP measurements: low-stable (50.0%, n = 132), sharp-falling (13.3%, n = 35), and high-rising (36.7%, n = 97). Compared with the high-rising class, HRs of disease progression were 0.52 (95% CI: 0.39, 0.70) and 0.26 (95% CI: 0.16, 0.43) for the low-stable class and sharp-falling class, respectively. In contrast, HRs of death were 0.59 (95% CI: 0.40, 0.81) and 0.30 (95% CI: 0.16, 0.57) for the two groups after propensity score adjustment. Besides, AFP trajectories had the highest relative importance of each covariate to survival. DISCUSSION: There are three distinct AFP trajectories in uHCC patients receiving Atez/Bev, and it is an independent biomarker for clinical outcomes.

The aMAP Score is an Independent Risk Factor for Intermediate-stage Hepatocellular Carcinoma: A Large Retrospective Cohort Study.

Background: A less effective nomogram for patients with intermediate-stage hepatocellular carcinoma (HCC) to predict overall survival (OS) is available. This study aimed to investigate the role of age-male-albumin-bilirubin-platelet (aMAP) scores in the prognosis of patients with intermediate-stage HCC and develop an aMAP score-based nomogram to predict OS. Methods: Data on newly diagnosed intermediate-stage patients with HCC at Sun Yat-sen University Cancer Center between January 2007 and May 2012 were retrospectively collected. Independent risk factors affecting prognosis were selected by multivariate analyses. The optimal cut-off value for the aMAP score was determined using X-tile. The survival prognostic models were presented by the nomogram. Results: For the 875 patients with intermediate-stage HCC included, the median OS was 22.2 months (95% CI 19.6-25.1). Patients were classified into three groups by X-tile plots (aMAP score < 49.42; 49.42 ≤ aMAP score < 56; aMAP score ≥ 56). Alpha-fetoprotein, lactate dehydrogenase, aMAP score, diameter of main tumor, number of intrahepatic lesions, and treatment regimen were independent risk factors for prognosis. A predicted model was constructed with a C-index of 0.70 (95% CI: 0.68-0.72) in the training goup, and its 1-, 3-, and 5-year area under the receiver operating curve were: 0.75, 0.73, and 0.72. The validation group of the C-index is 0.82. Calibration graphs showed good consistency between the actual and predicted survival rates. The decision curve analysis suggested the clinical utility of the model, which may help clinicians guide clinical decision-making. Conclusion: The aMAP score was an independent risk factor for intermediate-stage HCC. The aMAP score-based nomogram has good discrimination, calibration, and clinical utility.

Impact of prior cancer on the overall survival of patients with nasopharyngeal carcinoma.

PURPOSE: Prior cancer history is an important exclusion criterion from clinical trials and may decrease their generalizability. This study aimed to investigate the impact of prior cancer on the prognosis of patients with nasopharyngeal carcinoma and to describe their characteristics. MATERIALS AND METHODS: Data of patients with nasopharyngeal carcinoma diagnosed between 2010 and 2015 were collected from the Surveillance, Epidemiology, and End Results database. The discrepancy in baseline characteristics was adjusted by propensity score matching. Kaplan-Meier and Cox regression analyses were performed to assess the impact of prior cancer on overall survival. RESULTS: A total of 3412 individuals were identified, of which 418 (12.25%) had prior cancer. Prostate cancer was the most frequently detected type of prior cancer (18.42%). Nearly 45% of the prior cancers were diagnosed within 5 years before the nasopharyngeal carcinoma. Patients with prior cancer had an inferior survival compared to those without prior cancer (p < 0.001). Notably, patients with prior prostate, breast, hematological, and nasopharyngeal cancers had a non-inferior overall survival. Prior cancer history was an independent factor of poor overall survival (hazard ratio = 1.329, p = 0.003). CONCLUSIONS: This is the first study to provide the comprehensive insight that patients with nasopharyngeal carcinoma and prior cancer have lower overall survival. Different prior cancer types had a different impact on the clinical outcome, suggesting that the exclusion criteria should be individually defined by unique cancer types.

Neoadjuvant chemotherapy plus intensity-modulated radiotherapy versus neoadjuvant chemotherapy plus concurrent chemoradiotherapy for ascending or descending types of nasopharyngeal carcinoma: A retrospective study.

PURPOSE: This study aimed to compare the efficacy between neoadjuvant chemotherapy (NACT) plus intensity-modulated radiotherapy (IMRT) and NACT plus concurrent chemoradiotherapy (CCRT) in patients with nasopharyngeal carcinoma (NPC). MATERIALS AND METHODS: Data from 603 patients with ascending (T4 and N0-1) or descending (T1-2&N3) NPC who were treated at Sun Yat-sen University Cancer Center between October 2009 and February 2012 were retrospectively analyzed. These patients were divided into two groups: NACT+IMRT (n = 302) and NACT+CCRT (n = 301). The primary endpoint was overall survival (OS), which was analyzed using the Kaplan-Meier method, log-rank test, Cox proportional hazards model, and landmark analysis. RESULTS: In univariate analysis, there was no significant difference in 5-year OS between the NACT+IMRT and NACT+CCRT groups (hazard ration [HR]: 0.69; 95% confidence interval [CI]: 0.47-1.01; P = 0.057). However, after adjustment for age (<45 years, ≥45 years), gender, histological stage (I/II, III), T stage (1/2, 3, 4), and N stage (0/1, 2/3), NACT+IMRT was more effective in improving OS, with a 33% decrease in the risk of death than NACT+CCRT (HR: 0.67; 95%CI: 0.45-0.99). Furthermore, landmark analysis indicated that patients in the NACT+IMRT group had higher OS rates within 24 months (HR: 1.83; 95%CI: 1.00-3.34), whereas those treated with NACT+CCRT had higher OS rates after 24 months (HR, 0.47; 95% CI, 0.29-0.77). We also found significant survival benefits of NACT+IMRT regimen in patients younger than 45 years old (HR: 0.27; 95%CI: 0.14-0.49), and in those at stage T3 (HR: 0.50; 95%CI: 0.27-0.93) and stage N2/3 (HR: 0.52; 95%CI: 0.32-0.83). CONCLUSION: Patients with ascending or descending NPC who are treated with NACT+IMRT may have better long-term survival outcomes than those treated with NACT+CCRT, especially the patients younger than 45 years old or in stage T3/N2/N3. Additionally, NACT+IMRT may be a better option than NACT+CCRT in patients within the first 24 months.

Hepatic Resection Versus Transarterial Chemoembolization for Intermediate-Stage Hepatocellular Carcinoma: A Cohort Study.

BACKGROUND: The selection criteria for hepatic resection (HR) in intermediate-stage (IM) hepatocellular carcinoma (HCC) are still controversial. We used real-world data to evaluate the overall survival (OS) in treatment with HR or transarterial chemoembolization (TACE). METHODS: In total, 942 patients with IM-HCC were categorized into the HR group and the TACE group. OS was analyzed using the Kaplan-Meier method, log-rank test, Cox proportional hazards models, and propensity score-matched (PSM) analysis. Curve smoothing was performed through the generalized additive model. The interaction test was performed to evaluate the impact of HR on OS concerning risk factors. Also, we used multiple imputation to deal with missing data. RESULTS: In total, 23.0% (n = 225) of patients received HR. At a median OS of 23.7 months, HR was associated with improved OS in the multivariate analysis [hazard ratio (HzR) = 0.45, 95%CI = 0.35-0.58; after PSM: HzR = 0.56, 95%CI = 0.41-0.77]. Landmark analyses limited to long-term survivors of ≥6 months, ≥1 year, and ≥2 years demonstrated better OS with HR in all subsets (all p < 0.05). After PSM analysis, however, HR increased the risk of death by 20% (HzR = 1.20, 95%CI = 0.67-2.15) in the subgroup of patients with lactate dehydrogenase (LDH) ≤192 U/L (p for interaction = 0.037). Furthermore, the significant interaction was robust between the LDH and HR with respect to the 1-, 3-, and 5-year observed survival rates (all p < 0.05). CONCLUSION: HR was superior to TACE for intermediate-stage HCC in patients with LDH levels >192 U/L. Moreover, TACE might be suitable for patients with LDH levels ≤192 U/L.

Association between platelet count and hepatocellular carcinoma overall survival: a large retrospective cohort study.

OBJECTIVES: To explore the non-linear relationship between platelet count (PLT) and hepatocellular carcinoma (HCC) overall survival (OS). SETTING: The study was done in Sun Yat-sen University Cancer Center (SYSUCC) from January 2007 to May 2012, a total of 5005 consecutive participants at SYSUCC were retrospectively reviewed, and 979 patients with Barcelona clinic liver cancer (BCLC) stage B were selected for the final analysis. PARTICIPANTS: A total of 979 newly diagnosed patients with HCC with BCLC stage B were identified for the secondary analysis. Eight cases were excluded for missing data of PLT. MAIN OUTCOME MEASURES: Cox proportional hazard regression models were used to calculate multivariable-adjusted HRs and 95% CIs for HCC. The non-linear relationship was estimated through a restricted cubic spline regression, and a two-piecewise Cox proportional hazards model was further performed to calculate the threshold effect. We used multiple imputation to deal with the missing data. RESULTS: In the multivariate analysis, Log PLT was associated with a 91% risk increase in death (HR 1.91; 1.28 to 2.85) with adjustment for gender, Child-Pugh class, age × diameter of main tumour, both lobe with lesions × number of the intrahepatic lesions, alpha-fetoprotein (<25, ≥25) and lactic dehydrogenase (<245, ≥245). We also found a U-shape relationship between PLT and HCC OS at the inflexion point of 67.6×109/L. The HR was 0.12 (95% CI 0.03 to 0.52) for Log PLT≤10.83 and 3.07 (CI 1.91 to 4.92) for Log PLT>10.83 after adjusting for potential confounders. The core results were consistent with those from the sensitivity analysis. Besides, a significantly higher hazard risk was found in the patients with age <55, both lobes with lesions, tumour diameter >50, haemoglobin ≥120 and C reactive protein >10. CONCLUSION: PLT was nonlinearly associated with HCC OS.

Elevated Platelet Count is Associated with Poor Survival After Transarterial Chemoembolization Treatment in Patients with Hepatocellular Carcinoma: A Cohort Study.

BACKGROUND: Platelet count (PLT) has been proved as an essential biomarker for the survival of hepatocellular carcinoma (HCC). However, the prognostic value of PLT change (ΔPLT) is still uncertain. The aim of this study was to explore the relationship between ΔPLT and HCC survival after transarterial chemoembolization (TACE) treatment. METHODS: Cox proportional hazard regression models were used to calculate multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for HCC. The non-linear relationship between ΔPLT and OS was estimated through a restricted cubic spline regression analysis, and a two-piece-wise Cox proportional hazard model was further performed to calculate the threshold effect. RESULTS: A total of 597 HCC patients treated with TACE were selected for the secondary analysis. Compared with the ΔPLT within ±20 (×109/L), ΔPLT≥20 (×109/L) was significantly associated with an 64% increase in risk of death (HR, 1.64; 95% CI: 1.21 to 2.22) after adjustment for confounding variables, but the association was not significant in the group of ΔPLT≤-20 (HR, 1.23; 95% CI: 0.92 to 1.63). We also found a U-shape relationship between ΔPLT and HCC survival at the turning point of ΔPLT as 0 (20×109/L). The HR for the death was 1.12 (95% CI: 1.06, 1.18) with ΔPLT≥0 (20×109/L) while 0.95 (95% CI: 0.92, 0.98) with ΔPLT<0 (20×109/L). After potential confounding factors were adjusted, the non-linear relationship between ΔPLT and OS was still significant (P=0.013). Besides, ΔPLT≥20 (×109/L) was associated with new lesions (OR, 2.74; 95% CI: 1.38 to 5.45). CONCLUSION: Elevated PLT was associated with poor overall survival of HCC patients after TACE treatment.

Capn4 is induced by and required for Epstein-Barr virus latent membrane protein 1 promotion of nasopharyngeal carcinoma metastasis through ERK/AP-1 signaling.

Capn4, also known as CapnS1, is a member of the calpain family, which plays a crucial role in maintaining the activity and function of calpain. We previously reported that Capn4 also plays an essential role in the migration of nasopharyngeal carcinoma (NPC) cells through regulation of (MMP-2) by nuclear factor-kappa B activation. Epstein-Barr virus latent membrane protein 1 (LMP1) is closely related to the malignant functions of NPC; however, the relationship between LMP1 and Capn4 in NPC remain unclear. Immunohistochemical studies showed that the level of LMP1 and Capn4 expression was high in both primary and metastatic NPC tissues, with a significantly positive correlation. We further found that LMP1 was able to upregulate the Capn4 promoter in a dose-dependent way through the C-terminal activation region (CTAR)1 and CTAR2 domains to activate AP-1. Moreover, we also found that LMP1 activated AP-1 through ERK/JNK phosphorylation. These findings indicate that Capn4 coordination with LMP1 promotes actin rearrangement and, ultimately, cellular migration. These results show that Capn4 coordination with LMP1 enhances NPC migration by increasing actin rearrangement involving ERK/JNK/AP-1 signaling. Therapeutically, additional and more specific LMP1 and Capn4 targeted inhibitors could be exploited to treat NPC.

BTG1 low expression in pancreatic ductal adenocarcinoma is associated with a poorer prognosis.

OBJECTIVE: BTG1 is a member of the TOB/BTG protein family, which is a transducer of ErbB-2 and TOB2. It is known to inhibit tumor genesis, but its role in pancreatic ductal adenocarcinoma (PDAC) is still unknown. The purpose of this study is to investigate the expression of BTG1 protein in PDAC and to determine its prognostic significance. METHODS: Immunohistochemistry is used to determine the protein expression of the BTG1 gene in 79 surgically resected PDAC. The association of BTG1 expression with all the patients' clinicopathologic parameters, including survival, was analyzed using statistical software. RESULTS: High BTG1 expression was observed in 27.8% (22/79) of the PDAC tissues, which was significantly lower than the 58.2% (46/79) of corresponding normal adjacent noncancerous tissues by immunohistochemical staining (p<0.001).Through the stratified analysis, we found a significant difference of BTG1 expression in peri-neural invasion (p = 0.002), T stage (p = 0.000), N stage (p = 0.018), and tumor, node, and metastasis stage (p = 0.000). Univariate and multivariate Cox analysis revealed that BTG1 expression status was an independent prognostic factor in PDAC (p = 0.027). Moreover, overall survival was better in PDAC cases with higher rather than lower BTG1 expression (p = 0.027). CONCLUSIONS: This study demonstrated for the first time that lower expression of BTG1 might be involved in the progression of PDAC, suggesting that BTG1 might be a novel prognostic marker and a target for therapy.

Capn4 is a marker of poor clinical outcomes and promotes nasopharyngeal carcinoma metastasis via nuclear factor-κB-induced matrix metalloproteinase 2 expression.

Calpain small subunit 1 (Capn4) plays a key role in tumor migration or invasion. In this study, expression and function of Capn4 was investigated in human nasopharyngeal carcinoma (NPC). Here we report that both mRNA and protein levels of Capn4 were elevated in NPC tissues when compared to normal NP tissues. Similarly, Capn4 was also highly expressed in multiple NPC cell lines, compared to immortalized human nasopharyngeal epithelial cell line NP69. Moreover, expression of Capn4 was significantly correlated with Epstein-Barr virus infection, advanced stages, and lymph node or distant metastasis (P < 0.001). The patients with NPC displaying higher Capn4 had a significantly shorter overall survival (P = 0.002) and progression-free survival (P = 0.003). Furthermore, siRNA knockdown of Capn4 suppressed cell migration and invasion in vitro and in vivo. These events resulted from Capn4 downregulation were associated with reduced expression of matrix metalloproteinase 2 (MMP2), Snail, and Vimentin. Finally, we demonstrated that Capn4 upregulated MMP2 via nuclear factor-κB (NF-κB) activation, manifested by increased phosphorylation of p65, a subunit of NF-κB. Together, these findings argue a novel function of Capn4 in invasion and metastasis of NPC, and thereby suggest that Capn4 may represent an independent prognostic factor and a potential therapeutic target in NPC.

CacyBP/SIP enhances multidrug resistance of pancreatic cancer cells by regulation of P-gp and Bcl-2.

Our former report indicates that calcyclin-binding protein or Siah-1-interacting protein (CacyBP/SIP) is over-expressed in the SGC7901/ADR cell line. However, the potential role of CacyBP/SIP in the development of multidrug resistance (MDR) of pancreatic cancer is still uncertain. In this paper, we investigated the role of CacyBP/SIP in MDR of pancreatic cancer cells and its possible underlying mechanisms, and found that CacyBP/SIP was over-expressed in the Gemcitabine induced MDR pancreatic cancer cell PC-3/Gem compared with its parental cell PC-3. Up-regulation of CacyBP/SIP expression could enhance resistance of chemotherapy drugs on PC-3 cells and inhibit Adriamycin-induced apoptosis accompanied by decreased accumulation of intracellular Adriamycin. Furthermore, CacyBP/SIP could significantly up-regulate the expression of P-gp, Bcl-2, and the transcription of the MDR1 gene. In addition, the decrease of CacyBP/SIP expression using RNA interference or P-gp inhibitor could partially reverse CacyBP/SIP-mediated MDR. In brief, our study demonstrated that CacyBP/SIP could enhance the MDR phenotype of pancreatic cancer cells by increasing the expression of P-gp and Bcl-2, thus inhibiting apoptosis of pancreatic cancer cell.

CacyBP/SIP protein promotes proliferation and G1/S transition of human pancreatic cancer cells.

Calcyclin-binding protein or Siah-1-interacting protein (CacyBP/SIP), a component of the ubiquitin-mediated proteolysis, could participate in beta-catenin degradation, which was found to be related to the malignant phenotypes of pancreatic cancer previously. However, the role of CacyBP/SIP itself in pancreatic cancer has not been investigated. In the present study, CacyBP/SIP expression was assayed and manipulated to reveal the potential mechanism in pancreatic cancer carcinogenesis. Here, we show that CacyBP/SIP is over-expressed in pancreatic cancer cells. Down-regulation of CacyBP/SIP by small interference RNA (siRNA) severely suppresses the proliferation and tumorigenesis in pancreatic cancer. G1/S transition arrest induced by inhibition of CacyBP/SIP is at least partly mediated by down-regulation of Cyclin E and CDK2 as well as up-regulation of p27 and Rb. Collectively, CacyBP/SIP as an enhancer of pancreatic cancer malignance might develop into another possible therapeutic target.