Efficacy and predictors of immune checkpoint inhibitors in patients with gallbladder cancer.

Immune checkpoint inhibitors (ICIs) have shown promising efficacy in multiple cancers including biliary tract cancers (BTCs). However, the data focusing on the efficacy of ICIs in patients with gallbladder cancer (GBC) is still limited. In this study, we aim to assess the efficacy of ICIs in GBC and explore the clinicopathologic and molecular markers associated with ICI benefit. We retrospective analyzed 69 GBC patients who had received ICI therapy between January 2016 and December 2020. Tumor samples were obtained for genomic sequencing and immunohistochemical analysis. The median progression-free survival (PFS) and overall survival (OS) was 4.4 months and 8.5 months, respectively. Multivariate analysis indicated that alcohol intake history, carcinoma embryonic antigen (CEA) level ≥100 U/mL, and cutaneous immune-related adverse events (irAEs) were independent prognostic factors for PFS. CEA level ≥100 U/mL and cutaneous irAEs were independent prognostic factors for OS. The objective response rate and disease control rate (DCR) were 15.9% and 37.7%, respectively. Patients with cutaneous irAEs, high CD8+ T cell infiltrated or immune inflamed GBCs had higher DCR. Patients with high CD8+ T cell infiltrated or immune inflamed GBCs also had a notably improved prognosis. These results suggest that ICIs were effective in patients with GBC. High CEA level, cutaneous irAEs, high CD8+ T cell infiltration, and immune inflamed phenotype could be useful for predicting the efficacy of ICIs in GBC.

Evaluation of nuclear PGAM2 value in hepatocellular carcinoma prognosis.

Phosphoglycerate mutase (PGAM) is a critical enzyme in glycolysis. PGAM2 is abundant in several types of tissues and malignant tumours. However, there is limited information regarding their clinicopathological significance in dysplastic nodules and hepatocellular carcinoma (HCC). This study aims to investigate the prognostic value of PGAM2 as a new biomarker for HCC. The PGAM2 expression level was evaluated by immunohistochemistry in liver cirrhosis (n = 10), low-grade dysplastic nodules (n = 15), high-grade dysplastic nodules (n = 15) and HCCs (n = 20) and 178 pairs of HCC and adjacent peritumoral liver tissues. We selected X-tile software for counting cut-point based on the outcomes for prognosis analysis, and used Kaplan-Meier analysis and Cox regression analysis can assess the prognosis of clinicopathologic parameters. Nuclear PGAM2 was significantly overexpressed in peritumoral liver tissues compared with HCC tissues (P = 0.0010). Kaplan-Meier analyses of 178 HCC samples revealed that nuclear PGAM2's high expression level, but not cytoplasmic PGAM2, was significantly related to good overall survival rate (OS). In addition, univariate and multivariate Cox analyses indicated nuclear PGAM2 expression could be regarded as valuable predictors for OS in HCC. PGAM2 was highly expressed in HCC tissues than liver cirrhosis tissues, and nuclear PGAM2's high expression might demonstrate HCC patients have poor postoperative results. Thus, nuclear PGAM2 can be regarded as valuable predictors for OS in HCC patients after surgery.

Effects of LRP1B Regulated by HSF1 on Lipid Metabolism in Hepatocellular Carcinoma.

BACKGROUND: To date, aberrated lipid metabolism has been recognized as an important feature of hepatocellular carcinoma (HCC); however, it remains poorly defined. As a large member of the low-density lipoprotein receptor family, LRP1B plays a pivotal role in maintaining lipid homeostasis. Here we investigated the expression feature of LRP1B in HCC and elucidated its effects on lipid metabolism of HCC cells. MATERIALS AND METHODS: LRP1B expression in HCC cells and tumor tissues was respectively examined by quantitative PCR, Western blotting and immunohistochemistry. Crispr-cas9 RNA inference and CRISPRa transcription activation system were used to downregulate and upregulate LRP1B expression, respectively. Oil red O staining, DiD staining combined with flow cytometry and transmission electron microscopy were used to evaluate the lipid content in HCC cells. Overall survival (OS) and time to recurrence (TTR) were calculated; meanwhile, Kaplan-Meier and the Cox proportional hazards model were used to assess the prognosis of HCC patients. RESULTS: In contrast to inactivation expression in a majority of cancers, LRP1B showed predominantly strong expression in HCC. LRP1B knockdown induced the decrease of intracellular lipid content, downregulated expressions of lipid synthesis-related enzymes and upregulated expressions of ß-oxidation-related enzymes as well as activated the AMPK signaling. Moreover, HSF1 directly regulated the transcription of LRP1B and was involved in LRP1B-mediated lipid metabolism in HCC; meanwhile, the combination of LRP1B knockdown and HSF1 inhibition suppressed synergistically the proliferation of HCC cells. In addition, simultaneous expression of HSF1 and LRP1B was an independent prognostic factor for HCC patients. CONCLUSION: Altogether, the study reveals a novel unique role of LRP1B in HCC by serving as a mediator in lipid metabolism, which provides an insight for making explorable therapeutic strategies for HCC.

The clinical significance of lipopolysaccharide binding protein in hepatocellular carcinoma.

Lipopolysaccharide binding protein (LBP) has been reported to be associated with prognosis in colorectal carcinoma and renal cell carcinoma; however, the clinical significance of LBP in human primary hepatocellular carcinoma (HCC) is inconclusive. We aimed to investigate the clinical significance and prognostic value of LBP in human primary HCC. In the present study, 346 patients with HCC who underwent curative resection were retrospectively analyzed. LBP protein expression was evaluated using western blot analysis and immunohistochemistry. LBP scores collected from immunohistochemical analysis were obtained by multiplying staining intensity and the percentage of positive cells. An outcome-based best cutoff-point was calculated by X-tile software. Moreover, Kaplan-Meier curves and Cox regressions were used for prognosis evaluation. LBP was frequently overexpressed in HCC compared with that in peritumor tissues (five pairs by western blot analysis, P=0.0533; 77 pairs by immunohistochemistry, P=0.0171), and LBP expression was positively associated with tumor-node-metastasis stage and tumor differentiation. Patients who had high LBP expression had decreased overall survival and time to recurrence compared with patients with low LBP expression. Furthermore, patients who were both serum α-fetoprotein positive and had high LBP expression had poor prognoses. Univariate and multivariate Cox analyses indicated that this combination was an independent prognostic factor [overall survival: Hazard ratio (HR), 1.458; 95% confidence interval (CI), 1.158-1.837; P=0.001; time to recurrence: HR,1.382; 95% Cl, 1.124-1.700; P=0.002]. In conclusion, LBP is highly expressed in HCC, and high LBP expression combined with serum α-fetoprotein may predict poor outcomes in patients with HCC following curative resection.

Low expression of B-Cell-Associated protein 31 is associated with unfavorable prognosis in human colorectal cancer.

Colorectal cancer (CRC) is one of the most common cancers worldwide. B cell-associated protein 31 (BAP31) was shown to participate in the apoptosis, and to be an immunotherapy target and a, prognostic factor for cancer, but its role in CRC has not been elucidated. In this study, we examined the expression of BAP31 in CRC to evaluate its prognostic values. We investigated the BAP31 expression level in 142 tissues (108 CRC and 17 paired human adjacent normal mucosa, and 17 liver metastatic CRC tissues) from 108 patients, using tissue microarray-based immunohistochemistry. We further investigated the association between BAP31 expression and overall survival (OS) and disease-free survival (DFS) in 77 CRC patients using Kaplan-Meier analysis. Univariate and multivariate Cox regression analyses were applied to evaluate the potential prognostic value of BAP31 in CRC patients. BAP31 expression level was significantly increased in CRC tissues (p = 0.0014) and liver metastatic CRC tissues (p < 0.0001) compared with corresponding adjacent normal mucosa. BAP31 expression was also significantly increased in liver metastatic CRC tissues compared with corresponding primary CRC tissues (p = 0.0116). Kaplan-Meier analyses showed that CRC patients with low BAP31 expression had significantly lower survival rate (p = 0.001) and lower disease-free survival rate (P = 0.009). Furthermore, multivariate Cox analysis showed that BAP31 was an independent prognostic factor for OS (hazard ratio = 0.410, 95% confidence interval = 0.195-0.862, p = 0.019). CONCLUSIONS: Our study demonstrated that BAP31 is a potential prognostic marker for CRC patients after surgery.

The prognostic value of Niemann-Pick C1-like protein 1 and Niemann-Pick disease type C2 in hepatocellular carcinoma.

Niemann-Pick C1-like 1 (NPC1L1) and Niemann-Pick C2 (NPC2) is a critical mediator of cholesterol absorption. The aim of the present study was to investigate the prognostic value of NPC1L1 and NPC2 in human primary hepatocellular carcinoma (HCC). The expression level of NPC1L1 and NPC2 were evaluated by Immunohistochemistry, Westen blot and Real-time Quantitative PCR. Protein expression level in tissue was represented by integral optic density (IOD). For prognosis analyses, outcome-based cut-point was calculated by X-tile software. Kaplan-Meier analysis, Cox regression analysis were used evaluate prognostic value of NPC1L1 and NPC2 and NPC1L1/NPC2 combination. Both of NPC1L1 and NPC2 were significantly decreased in HCC tissues than peritumoral liver tissues (61 pairs of tissue for Immunohistochemistry and 10 pairs of tissues for Western blot and Real-time Quantitative PCR), respectively. (n=61: p=0.0005 for NPC1L1 and p=0.0001 for NPC2; n=10: p=0.0002 for NPC1L1 and p=0.0489 for NPC2). Kaplan-Meier analyses in 265 HCC cases were showed that the low expression level of NPC1L1 and NPC2 and NPC1L1/NPC2 combination were significantly correlated with poor overall survival (OS) and shorter time to recurrence (TTR). In addition, univariate and multivariate Cox analyses showed that the expression level of NPC1L1/NPC2 combination in HCC was an independent prognostic factor for OS and TTR. Conclusion: NPC1L1 and NPC2 were lowly expressed in HCC compared with peritumoral liver tissues, and low expression of NPC1L1 and NPC2 in HCC tissues may indicate poor outcome of HCC patients after surgery. NPC1L1/NPC2 combination is an independent prognostic factor for OS and TTR in postoperative HCC patients.