The prognostic value of neuromedin U in patients with hepatocellular carcinoma.

BACKGROUND: Neuromedin U (NMU) is a neuropeptide belonging to the neuromedin family. Recently, significant associations between NMU and several cancers have been reported. However, no studies have examined the association between NMU and hepatocellular carcinoma (HCC). The purpose of this study was to examine the role of NMU in HCC. METHODS: An enzyme-linked immunosorbent assay was used to measure the level of NMU protein in the sera of patients with hepatic hemangioma and HCC. NMU and cytokine mRNA expression was assessed in HCC samples via RT-qPCR. A tissue microarray consisting of 228 HCC peri- and intra-tumor tissues was used to detect NMU expression via immunohistochemical analysis. The association between NMU expression and overall survival (OS) and disease-free survival (DFS) was analyzed by Kaplan-Meier curves, the log-rank test, and Cox proportional hazard model. RESULTS: The level of NMU protein was increased in the sera of HCC patients (p = 0.006). NMU was expressed in intercellular space, rather than in hepatocytes or HCC cells. The prognosis of HCC patients with high NMU expression in peri-tumor tissue was significantly poorer than that of patients with low NMU expression (OS: p = 0.002, DFS: p = 0.033). Peri-tumor NMU expression was also a significant independent prognostic factor for OS (hazard ratio: 1.541, 95% confidence interval: 1.092-2.175, p = 0.014). The level of NMU expression was positively associated with M2 macrophage percentage and the levels of type-2 inflammatory cytokines in HCC tissue. CONCLUSIONS: NMU may serve as a novel prognostic biomarker for HCC patients, although further validation is needed in the future. The activation of M2 macrophages and a type-2 inflammatory response may involve in the role of NMU in patients with HCC.

Perioperative blood transfusion has distinct postsurgical oncologic impact on patients with different stage of hepatocellular carcinoma.

BACKGROUND: The influence of perioperative blood transfusion (PBT) on postsurgical survival of patients with different stage of hepatocellular carcinoma (HCC) is not well clarified. This study aimed to evaluate the impact of PBT on survival outcomes of different stage of HCC patients. METHODS: Consecutive patients who underwent liver resection for HCC between January 2009 and November 2015 were identified from an HCC prospective database in authors' center. The survival outcomes were compared between patients receiving PBT and those without PBT before and after propensity score matching (PSM) in different stage subsets. Cox regression analysis was performed to verify the impact of PBT on outcomes of HCC. RESULTS: Among 1255 patients included, 804 (64.1%) were Barcelona Clinic Liver Cancer (BCLC) stage 0-A, and 347 (27.6%) received PBT. Before PSM, patients with PBT had worse disease free survival (DFS) and overall survival (OS) compared with those without PBT in both BCLC 0-A subset and BCLC B-C subset (all P < 0.05). After PSM, 288 pairs of patients (with and without PBT) were created. In the subset of BCLC 0-A, the median DFS of patients with PBT was shorter than those without PBT (12.0 months vs. 36.0 months, P = 0.001) Similar result was observed for OS (36.0 months vs. 96.0 months, P = 0.001). In the subset of BCLC B-C, both DFS and OS were comparable between patients with PBT and those without PBT. Cox regression analysis showed that PBT involved an increasing risk of DFS (HR = 1.607; P < 0.001) and OS (HR = 1.756; P < 0.001) for this subset. However, PBT had no impact on DFS (P = 0.126) or OS (P = 0.139) for those with stage B-C HCC. CONCLUSIONS: PBT negatively influenced oncologic outcomes of patient with BCLC stage 0-A HCC, but not those with stage B-C after curative resection.

Hornerin promotes tumor progression and is associated with poor prognosis in hepatocellular carcinoma.

BACKGROUND: The function of hornerin (HRNR), a member of the S100 protein family, is poorly clarified in the development of human tumors. The role of HRNR in hepatocellular carcinoma (HCC) progression is investigated in the study. METHODS: The expression levels of HRNR were assessed in tumor samples from a cohort of 271 HCC patients. The effect of HRNR on proliferation, colony formation and invasion of tumor cells was examined. We further determined the role of HRNR in tumor growth in vivo by using xenograft HCC tumor models. The possible mechanism of the HRNR promotion of HCC progression was explored. RESULTS: We found that HRNR was overexpressed in HCC tissues. The high expression of HRNR in HCCs was significantly associated with vascular invasion, poor tumor differentiation, and advanced TNM stage. The disease-free survival (DFS) and overall survival (OS) of HCC patients with high HRNR expression were poorer than those in the low HRNR expression group. HRNR expression was an independent risk factor linked to both poor DFS (HR = 2.209, 95% CI = 1.627-2.998,P <  0.001) and OS (HR = 2.459,95% CI = 1.736-3.484, P <  0.001). In addition, the knockdown of HRNR by shRNAs significantly inhibited the proliferation, colony formation, migration and invasion of HCC tumor cells. HRNR silencing led to the decreased phosphorylation of AKT signaling. Notably, tumor growth was markedly inhibited by HRNR silencing in a xenograft model of HCC. CONCLUSIONS: HRNR promotes tumor progression and is correlated with a poor HCC prognosis. HRNR may contribute to HCC progression via the regulation of the AKT pathway.

Low expression of c-Myc protein predicts poor outcomes in patients with hepatocellular carcinoma after resection.

BACKGROUND: Embryonic Liver Fodrin (ELF) is an adaptor protein of transforming growth factor (TGF-ß) signaling cascade. Disruption of ELF results in mislocalization of Smad3 and Smad4, leading to compromised TGF-ß signaling. c-Myc is an important oncogenic transcription factor, and the disruption of TGF-ß signaling promotes c-Myc-induced hepatocellular carcinoma (HCC) carcinogenesis. However, the prognostic significance of c-Myc in HCC is less understood METHODS: The expression of c-Myc protein and mRNA were measured by immunohistochemistry (IHC) and qRT- PCR, respectively. IHC was performed to detect TGF-ß1 and ELF expression in HCC tissues. Their relationship with clinicopathological factors and overall survival (OS) and disease free survival (DFS) were examined. RESULTS: The expression of c-Myc protein and mRNA in HCC tissues were significantly higher in HCC area than those in normal liver tissues. However, the expression were low compared with those adjacent to HCC area. c-Myc protein was independently predictive of DFS and OS, and it was negatively correlated with tumor size (P = 0.031), tumor number (P = 0.038), and recurrence (P = 0.001). Low c-Myc expression was associated with short-term recurrence and poor prognosis. The predictive value of c-Myc combined with TGF-ß1 or/and ELF was higher than that of any other single marker. Low c-Myc, high TGF-ß1 or/and low ELF expression was associated with the worst DFS and OS. CONCLUSIONS: Low expression of c-Myc protein predicts poor outcomes in patients with HCC with hepatectomy. The combination of the expression of c-Myc, TGF-ß1, and ELF can be used to accurately predict outcomes of patients with HCC.

Thrombocytopenia and the outcomes of hepatectomy for hepatocellular carcinoma: a meta-analysis.

BACKGROUND: Recently, increasing studies have revealed the association of inflammatory parameters, such as preoperative platelet count, and the prognosis of hepatocellular carcinoma (HCC). However, the link between the platelet count and the prognosis of patients with HCC after hepatic resection is still controversial. METHODS: We searched PubMed, Web of Science, EMBASE, and CBM for relevant trials and analyzed outcomes with random-effects model. The hazard ratio (HR) and its 95% confidence interval (CI) were calculated. RESULTS: In total, 31 studies, including a total of 10,730 patients, met our criteria. The results showed that thrombocytopenia in HCC patients was associated with poor overall survival (HR = 1.47, 95% CI: 1.21-1.78), disease-free survival (HR = 1.36, 95% CI: 1.08-1.72), and a high risk of cancer recurrence (HR = 1.41, 95% CI: 1.22-1.62), but a low risk of extrahepatic metastasis (HR = 0.55, 95% CI: 0.47-0.63). CONCLUSIONS: The meta-analysis revealed that preoperative platelet count could act as a significant biomarker in the prognosis of HCC, especially a platelet count of <100 × 103/mm3. Additional high-quality trials are needed, considering the low-quality studies analyzed.

Prognostic value of combined preoperative prognostic nutritional index and body mass index in HCC after hepatectomy.

BACKGROUND: Malnutrition and immunological status are associated with survival in many cancers. Prognostic nutritional index (PNI) and body mass index (BMI) are recognized immune-nutritional indices and associated with postoperative outcome in hepatocellular carcinoma (HCC) patients. However, this association is still controversial. Our aim was to determine whether the combination of PNI and BMI is better than either alone in HCC patients' prognosis. MATERIAL AND METHODS: Preoperative PNI and BMI, patient demographics, clinical and pathological data from 322 HCC patients were collected and analyzed. RESULTS: Low PNI was correlated with age, cirrhosis, total bilirubin (TBIL) ≥34.2 µmol/L, and recurrence. Likewise, low BMI was associated with TBIL ≥34.2 µmol/L, portal vein tumor thrombi (PVTT), tumor size, tumor differentiation, TNM stage, and recurrence. Multivariate analysis identified TNM stage, PVTT, tumor size, PNI, and BMI as independent predictors of outcome in HCC patients. Low PNI combined with BMI (PNI + BMI) accurately predicted poorer outcome, particularly in patients with TNM stage I HCC. The predictive range of PNI + BMI was more sensitive than that of either alone. CONCLUSIONS: preoperative PNI/BMI is an independent predictor of outcome for HCC patients, especially in patients with early stage HCC. Intriguingly, the PNI + BMI combination can enhance the accuracy of prognosis.

Prognostic value of preoperative serum gamma-glutamyltranspeptidase in patients with hepatocellular carcinoma after hepatectomy.

Gamma-glutamyltranspeptidase (γ-GGT), an oxidative stress marker, is correlated with inflammation in the extracellular hepatic microenvironment. This study aimed to evaluate the prognostic value of serum γ-GGT levels in patients with hepatocellular carcinoma (HCC) after hepatectomy. Three hundred and eight patients who underwent hepatic resection for HCC were included in the study. Preoperative serum γ-GGT levels, as well as demographic, clinical, and pathologic data, were analyzed. The optimal cutoff value of γ-GGT was 88 U/L. All patients were divided into γ-GGT ≤ 88 U/L group (n = 146) and γ-GGT > 88 U/L group (n = 162). The disease-free survival (DFS) and overall survival (OS) rates of patients in the γ-GGT > 88 U/L group were poorer than those in γ-GGT ≤ 88 U/L group. Preoperative serum γ-GGT levels, associating with gender, HBsAg status, tumor size, capsulation, tumor number, and vascular invasion, was an independent prognostic predictor of disease-free survival [hazard ratio (HR) = 1.616; 95 % confidence interval (CI), 1.223-2.135; P = 0.001] and overall survival (HR = 2.043; 95 % CI, 1.509-2.766; P < 0.001). Furthermore, γ-GGT was also associated with DFS and OS in small HCC (tumor size ≤5 cm) and alpha-fetoprotein (AFP) ≤ 200 ng/mL subgroup. In conclusion, γ-GGT is a promising and reliable prognostic biomarker in HCC patients after hepatic resection, especially for patients with small HCC or AFP ≤ 200 ng/mL.

A novel and accurate predictor of survival for patients with hepatocellular carcinoma after surgical resection: the neutrophil to lymphocyte ratio (NLR) combined with the aspartate aminotransferase/platelet count ratio index (APRI).

BACKGROUND: The occurrence and development of hepatocellular carcinoma (HCC) depends largely on such non-tumor factors as inflammatory condition, immune state, viral infection and liver fibrosis. Various inflammation-based prognostic scores have been associated with survival in patients with HCC, such as the neutrophil/lymphocyte ratio (NLR), the platelet/lymphocyte ratio (PLR) and the prognostic nutritional index (PNI). The aspartate aminotransferase/platelet count ratio index (APRI) is thought to be a biomarker of liver fibrosis and cirrhosis. This study aims to evaluate the ability of these indices to predict survival in HCC patients after curative hepatectomy, and probe the increased prognostic accuracy of APRI combined with established inflammation-based prognostic scores. METHODS: Data were collected retrospectively from 321 patients who underwent curative resection for HCC. Preoperative NLR, PLR, PNI, APRI and clinico-pathological variables were analyzed. Univariate and multivariate analyses were performed to identify the predictive value of the above factors for disease-free survival (DFS) and overall survival (OS). RESULTS: Univariate analysis showed that NLR, PLR, PNI and APRI were significantly associated with DFS and OS in HCC patients with curative resection. Multivariate analysis showed that NLR and APRI were superior to PLR and PNI, and both were independently correlated with DFS and OS. Preoperative NLR >2 or APRI >1.68 predicted poor prognosis of patients with HCC after hepatectomy. Furthermore, the predictive range of NLR combined with APRI was more sensitive than that of either measure alone. CONCLUSIONS: Preoperative NLR and APRI are independent predictors of DFS and OS in patients with HCC after surgical resection. Higher levels of NLR or APRI predict poorer outcomes in HCC patients. Intriguingly, combining NLR and APRI increases the prognostic accuracy of testing.

The prognostic value of combined TGF-ß1 and ELF in hepatocellular carcinoma.

BACKGROUND: Tumor suppression of Transforming Growth Factor (TGF-ß) signaling pathway requires an adaptor protein, Embryonic Liver Fodrin (ELF). Disruption of ELF expression resulted in miscolocalization of Smad3 and Smad4, then disruption of TGF-ß signaling. However, the prognostic significance of ELF for hepatocellular carcinoma (HCC) hasn't been clarified. This study aimed to investigate whether measuring both TGF-ß1 and ELF provides a more powerful predictor for HCC prognosis than either marker alone. METHODS: TGF-ß1 and ELF protein were detected by immunohistochemistry. The relationship between TGF-ß1/ELF expression and patients' clinicopathologic factors was analyzed. The association between TGF-ß1/ELF expression and disease-free survival and overall survival was analyzed by Kaplan-Meier curves, the log-rank test, and Multivariate Cox regression analyses. RESULTS: The expression of TGF-ß1 in HCC tissues was significantly higher than that in normal liver tissues. Conversely, the expression of ELF in HCC tissues declined markedly. ELF protein was correlated with HBsAg, tumor size, tumor number, TNM and recurrence. Data also indicated a significant negative correlation between ELF and TGF-ß1. Patients with high TGF-ß1 expression or/and low ELF expression appeared to have a poor postoperative disease-free survival and overall survival compared with those with low TGF-ß1 expression or/and high ELF expression. Furthermore, the predictive range of ELF combined with TGF-ß1 was more sensitive than that of either one alone. CONCLUSIONS: TGF-ß1 and ELF protein are potential and reliable biomarkers for predicting prognosis in HCC patients after hepatic resection. Our current study has demonstrated that the prognostic accuracy of testing can be enhanced by their combination.

Combined vascular resection and analysis of prognostic factors for hilar cholangiocarcinoma.

BACKGROUND: Hilar cholangiocarcinoma (HCCA) is a devastating malignancy arising from the bifurcation of the hepatic duct, whether combined vascular resection benefits HCCA patients is controversial. This study was undertaken to assess the effect of combined vascular resection in HCCA patients and to analyze the prognostic factors. METHODS: Clinical data of 154 HCCA patients who had been treated from January 2005 to December 2012 were retrospectively analyzed. The patients were divided into three groups based on vascular resection: those without vascular resection; those with portal vein resection alone and those with hepatic artery resection. The survival and complication rates were compared among the three groups. Multivariate analysis was made to determine prognostic factors. RESULTS: No significant differences were found in survival and complication rates among the three groups (P>0.05). Multivariate analysis showed that 3 factors were related to survival: lymph node metastasis, tumor size (>2.5 cm), and positive resection margin. CONCLUSIONS: Vascular resection improved the survival rate of patients with HCCA involving the hepatic artery or portal vein. Lymph node metastasis, tumor size (>2.5 cm) and positive resection margin were poor prognostic factors in patients with HCCA.

Risk factors and outcomes of postoperative pancreatic fistula after pancreatico-duodenectomy: an audit of 532 consecutive cases.

BACKGROUND: Pancreatic fistula (PF) remains the most challenging complication after pancreaticoduodenectomy (PD). The purpose of this study was to identify the risk factors of PF and delineate its impact on patient outcomes. METHODS: We retrospectively reviewed clinical data of 532 patients who underwent PD and divided them into PF group and no PF group. Risk factors and outcomes of PF following PD were examined. RESULTS: PF was found in 65 (12.2%) cases, of whom 11 were classified into ISGPF grade A, 42 grade B, and 12 grade C. Clinically serious postoperative complications in the PF versus no PF group were mortality, abdominal bleeding, bile leak, intra-abdominal abscess and pneumonia. Univariate and multivariate analysis showed that blood loss ≥ 500 ml, pancreatic duct diameter ≤ 3 mm and pancreaticojejunostomy type were independent risk factors of PF after PD. CONCLUSIONS: Blood loss ≥ 500 ml, pancreatic duct diameter ≤ 3 mm and pancreatico-jejunostomy type were independent risk factors of PF after PD. PF was related with higher mortality rate, longer hospital stay, and other complications.

Preoperative aspartate aminotransferase to platelet ratio is an independent prognostic factor for hepatitis B-induced hepatocellular carcinoma after hepatic resection.

BACKGROUND: There is conflicting evidence concerning platelet status and hepatocellular carcinoma (HCC) prognosis. We evaluated the prognostic value of platelet-based indices, including platelet count, platelet/lymphocyte ratio (PLR), and aspartate aminotransferase to platelet ratio index (APRI) in HCC after hepatic resection. METHODS: We retrospectively reviewed 332 patients with HCC treated with hepatectomy between 2006 and 2009. Preoperative platelet count, as well as demographic, clinical, and pathologic data, were analyzed. RESULTS: Both disease-free survival (DFS) and overall survival (OS) were significantly improved for patients with low platelet count, PLR, and APRI compared to patients with elevated values. On multivariate analysis, APRI, tumor size ≥5 cm, noncapsulation, and multiple tumors were all associated with both poor DFS and OS. The 1-, 3-, and 5-year DFS rates were 52, 36, and 32 % for patients with APRI <0.62 and were 35, 22, and 19 % for patients with APRI ≥0.62. Correspondingly, the 1-, 3-, and 5-year OS rates were 77, 51, and 42, and 63, 35, and 29 % for both groups. Both DFS and OS of patients with APRI <0.62 were significantly better compared to patients with an elevated APRI (P = 0.009 and 0.002, respectively). Patients with elevated APRI tended to have cirrhosis, hepatitis B virus (HBV) infection, surgical margin <1 cm, and noncapsulated tumors. CONCLUSIONS: Elevated platelets based inflammatory indices, especially APRI, was associated with adverse characteristic features and poor prognosis in HCC, especially for patients with HBV infection or cirrhosis. Antiplatelet treatment may represent a potential therapy for HBV-induced HCC recurrence.

Elevated preoperative peripheral blood monocyte count predicts poor prognosis for hepatocellular carcinoma after curative resection.

BACKGROUND: Peripheral blood monocyte count is an easily assessable parameter of systemic inflammatory response. The aim of this study was to determine whether monocyte count was prognostic in hepatocellular carcinoma (HCC) following hepatic resection. METHODS: We retrospectively reviewed 351 patients with HCC treated with hepatic resection from 2006 to 2009. Preoperative absolute peripheral monocyte count, demographics, and clinical and pathological data were analyzed. RESULTS: On univariate and multivariate analysis, elevated monocyte counts (≥ 545/mm(3)), tumor size ≥ 5 cm, non-capsulation, and multiple tumors were associated with poor disease-free survival (DFS) and overall survival (OS). The 1-, 3- and 5-year DFS rates were 58%, 41% and 35%, respectively, for patients with monocyte counts <545/mm(3), and 36%, 23% and 21% for patients with monocyte counts ≥ 545/mm(3). Correspondingly, the 1-, 3- and 5-year OS rates were 79%, 53% and 46% for monocyte counts <545/mm(3), and 64%, 36% and 29% for monocyte counts ≥ 545/mm(3). Subgroup analysis indicated that DFS after hepatic resection in hepatitis B virus (HBV)-infected patients was significantly better in those with a peripheral blood monocyte counts <545/mm(3), but it did not differ between patients without HBV infection. In addition, DFS was significantly better for patients with a peripheral blood monocyte count <545/mm(3), whether or not cirrhosis was present. Patients with elevated monocyte counts tended to have larger tumors. CONCLUSIONS: Elevated preoperative monocyte count is an independent predictor of worse prognosis for patients with HCC after hepatic resection, especially for those with HBV infection. Postoperative adjuvant treatment might be considered for patients with elevated preoperative monocyte counts.

Adjuvant Transarterial Chemoembolization With Sorafenib for Portal Vein Tumor Thrombus: A Randomized Clinical Trial.

Importance: Certain patients with hepatocellular carcinoma with portal vein tumor thrombus could benefit from surgical resection, and postoperative adjuvant therapy may lower the incidence of tumor recurrence. Objective: To compare the efficacy and safety of sorafenib plus transarterial chemoembolization vs sorafenib alone as postoperative adjuvant therapy for patients with hepatocellular carcinoma with portal vein tumor thrombus. Design, Setting, and Participants: This was a phase 3, multicenter, randomized clinical trial conducted in 5 hospitals in China. A total of 158 patients were enrolled and randomized from October 2019 to March 2022, with a median follow-up of 28.4 months. Portal vein tumor thrombus was graded by the Cheng classification. Eligible patients with hepatocellular carcinoma with Cheng grade I to III portal vein tumor thrombus (ie, involving segmental or sectoral branches, right- or left-side branch, or main trunk of portal vein) were included. Interventions: Patients were randomly assigned 1:1 to receive transarterial chemoembolization with sorafenib or sorafenib alone as postoperative adjuvant therapy. Sorafenib treatment was started within 3 days after randomization, with an initial dose of 400 mg orally twice a day. In the transarterial chemoembolization with sorafenib group, transarterial chemoembolization was performed 1 day after the first administration of sorafenib. Main Outcomes and Measures: The primary end point was recurrence-free survival. Efficacy was assessed in the intention-to-treat population and safety was assessed in patients who received at least 1 dose of study treatment. Results: Of 158 patients included, the median (IQR) age was 54 (43-61) years, and 140 (88.6%) patients were male. The median (IQR) recurrence-free survival was significantly longer in the transarterial chemoembolization with sorafenib group (16.8 [12.0-NA] vs 12.6 [7.8-18.1] months; hazard ratio [HR], 0.57; 95% CI, 0.39-0.83; P = .002). The median (IQR) overall survival was also significantly longer with transarterial chemoembolization with sorafenib than with sorafenib alone (30.4 [20.6-NA] vs 22.5 [15.4-NA] months; HR, 0.57; 95% CI, 0.36-0.91; P = .02). The most common grade 3/4 adverse event was hand-foot syndrome (23 of 79 patients in the transarterial chemoembolization with sorafenib group [29.1%] vs 24 of 79 patients in the sorafenib alone group [30.4%]). There were no treatment-related deaths in either group. The transarterial chemoembolization with sorafenib group did not show additional toxicity compared with the sorafenib monotherapy group. Conclusion and Relevance: In this study, the combination of sorafenib and transarterial chemoembolization as postoperative adjuvant therapy in patients with hepatocellular carcinoma with portal vein tumor thrombus resulted in longer recurrence-free survival and overall survival than sorafenib alone and was well tolerated. Trial Registration: ClinicalTrials.gov Identifier: NCT04143191.

Toripalimab Plus Bevacizumab as First-line Treatment for Advanced Hepatocellular Carcinoma: A Prospective, Multicenter, Single-Arm, Phase II Trial.

PURPOSE: This phase II, multicenter, prospective, single-arm study aimed to evaluate the efficacy and safety of toripalimab plus bevacizumab for treating advanced hepatocellular carcinoma (HCC). PATIENTS AND METHODS: Treatment-naïve patients with advanced HCC received toripalimab 240 mg plus bevacizumab 15 mg/kg every 3 weeks. The primary endpoints included safety and tolerability and objective response rate (ORR) assessed by the investigator per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. RESULTS: Fifty-four patients were enrolled between April 17, 2020, and December 11, 2020. As assessed by the investigator according to RECIST v1.1, the ORR was 31.5% [95% confidence interval (CI), 19.5-45.6] and the lower bound of the 95% CI was above the prespecified boundary of 10%. The independent review committee (IRC) assessed ORR according to the modified RECIST (mRECIST), which was 46.3% (95% CI, 32.6-60.4). The median progression-free survival was 8.5 (95% CI, 5.5-11.0) and 9.8 months (95% CI, 5.6 to not evaluable) as assessed by the investigator according to RECIST v1.1 and IRC according to mRECIST criteria, respectively. The median overall survival (OS) was not reached, and the 12- and 24-month OS rates were 77.3% and 63.5%, respectively. Grade 3 or higher treatment-emergent adverse events (TEAEs) occurred in 27 patients (50.0%). The most common TEAEs were proteinuria (59.3%), hypertension (38.9%), increased aspartate aminotransferase (33.3%), increased amylase (29.6%), decreased platelet count (27.8%), and increased bilirubin levels (27.8%). CONCLUSIONS: Toripalimab plus bevacizumab showed a favorable efficacy and safety profile, supporting further studies on this combination regimen as a first-line treatment for advanced HCC.

Profile of regulatory T cells and interferon γ secretion in the tumor-draining lymph node from mouse Hepa1-6 cells.

BACKGROUND: The tumor-draining lymph node (TDLN) is the critical and initial site of the immune decision made between activation and tolerance to tumor antigens. Tumor-reactive lymphadenopathy in TDLN has been observed for decades, but the profiles of immune regulation in these nodes remain unclear. MATERIALS AND METHODS: Both regulatory T cells (Tregs) and effector T cells were examined using 6 × 10(5) Hepa1-6 hepatocellular carcinoma cells implanted in footpads of syngeneic C57BL/6J mice, which formed TDLN. FOXP3(+) Tregs and CD8(+) T cells in TDLN were detected by immunohistochemical staining. The frequency of CD4(+)FOXP3(+) T cells and FOXP3 mRNA expression were determined by flow cytometry and real-time quantitative polymerase chain reaction. The interferon γ secretion ability of CD8(+) T cells in TDLN was measured by enzyme-linked immunospot technique. RESULTS: There was significant expansion of Tregs and CD8(+) T cells in the tumor-draining popliteal lymph node compared with nondraining popliteal lymph node and spleen in the same mouse. Tregs were diffusely distributed in the CD8(+) T cell compartment. The CD8(+) T cells primed in TDLN showed a strong ability of interferon γ secretion via in vitro stimulation. CONCLUSIONS: These findings support the notion that Tregs suppress CD8(+) T cells by secreting cytokines such as transforming growth factor ß and interleukin 10, but do not make CD8(+) T cells lose function in the TDLN. Deletion of Tregs at the secondary lymphoid organs could be crucial for the establishment of a tumor-specific immunotherapy.

A novel nomogram based on preoperative parameters to predict posthepatectomy liver failure in patients with hepatocellular carcinoma.

BACKGROUND: Posthepatectomy liver failure is one of the main causes of death in patients after hepatectomy. This study intends to establish a prediction model to predict the risk of posthepatectomy liver failure and provide a scientific basis for further reducing the incidence of posthepatectomy liver failure. METHODS: This was a retrospective analysis of 1,172 patients with hepatocellular carcinoma undergoing partial hepatectomy. Using univariate and multivariate logistic regression analyses and stepwise regression, a prediction model for posthepatectomy liver failure was established based on the independent risk factors for posthepatectomy liver failure and validated by bootstrapping with 100 resamples, and the receiver operating characteristic curve was used to evaluate the predictive value of the prediction model. RESULTS: The incidence rate of posthepatectomy liver failure was 22.7% (266/1172). The results showed that the indocyanine green retention rate at 15 minutes (odds ratio = 1.05, P = .002), alanine transaminase (odds ratio = 1.02, P < .001), albumin rate (odds ratio = 0.92, P < .001), total bilirubin (odds ratio = 1.04, P < .001), prothrombin time (odds ratio = 2.44, P < .001), aspartate aminotransferase-neutrophil ratio (odds ratio = 0.95, P < .001), and liver fibrosis index (odds ratio = 1.35, P < .001) were associated with posthepatectomy liver failure. These 7 independent risk factors for posthepatectomy liver failure were integrated into a nomogram prediction model, the predictive efficiency for posthepatectomy liver failure (area under the curve = 0.818, 95% confidence interval 0.789-0.848) was significantly higher than in other predictive models with a liver fibrosis index (area under the curve = 0.651), indocyanine green R15 (area under the curve = 0.669), albumin-bilirubin score (area under the curve = 0.709), albumin-indocyanine green evaluation score (area under the curve = 0.706), model for end-stage liver disease score (area under the curve = 0.636), and Child‒Pugh (area under the curve = 0.551) (all P < .001). The risk of posthepatectomy liver failure in the high-risk posthepatectomy liver failure group (score ≥152) was higher than that in the posthepatectomy liver failure low-risk group (score <152). CONCLUSION: This study developed and validated a nomogram model to predict the risk of posthepatectomy liver failure before surgery that can effectively predict the risk of posthepatectomy liver failure in patients with hepatocellular carcinoma.

Outcomes of liver resection for intrahepatic stones: a comparative study of unilateral versus bilateral disease.

OBJECTIVE: This study aimed to compare the outcomes of liver resection for unilateral and bilateral intrahepatic stones. BACKGROUND: Hepatectomy is effective in treating intrahepatic stones accompanied by biliary stricture or segmental atrophy. The outcomes between unilateral and bilateral intrahepatic stones may be varied because of different complexity of these 2 subtypes of disease. METHODS: From January 1992 to December 2008, 718 consecutive patients with intrahepatic stones underwent elective hepatectomy in our center were reviewed. The outcomes of patients with unilateral stones (n = 461) and bilateral stones (n = 257) were compared. The consistency between extent of liver resection (ELR) and stone-affected segments (SAS) was classified into 2 categories: ELR = SAS and ELR < SAS. The risk factors of stone recurrence were identified by Cox regression model. RESULTS: The immediate stone clearance rates of the unilateral group and the bilateral group were 93.5% and 71.1%, respectively. Postoperative cholangioscopic lithotomy raised the clearance rates to 99.3% and 90.2%, respectively. The surgical morbidities were 20.4% and 38.5%, respectively. The hospital mortality rates of both groups were 0.4%. The 5-year stone recurrence rates were 6.2% and 16.7%, respectively. Cox regression analysis showed that stone distribution (hazard ratio [HR] = 2.462, P = 0.007) and consistency between ELR and SAS (HR = 3.100, P = 0.002) were independent prognostic factors for stone recurrence. CONCLUSIONS: Generally, patients with unilateral stones have better outcomes than those with bilateral stones after hepatectomy associated with cholangioscopic lithotomy. But for the patients with ELR equals to SAS, the stone recurrence rates of unilateral and bilateral stones are low and comparable.

Knowledge Mapping of Immunotherapy for Hepatocellular Carcinoma: A Bibliometric Study.

Background: Hepatocellular carcinoma (HCC) is one of the most common malignant tumors, and many patients are diagnosed with advanced disease. The treatment of advanced liver cancer has made significant strides in recent years, owing to the practice of immunotherapy drugs. Numerous studies have been published on immunotherapy for HCC; however, no relevant bibliometric study has been published. This study aims to gain a better understanding of the current situation and to identify potential new research directions by conducting a bibliometric analysis on immunotherapy for HCC. Methods: We searched the Web of Science Core Collection (WoSCC) for articles related to immunotherapy for HCC. Three software (VOSviewer, CiteSpace, and python) were primarily used to assess the contribution and co-occurrence relationships of various countries/regions, institutes, journals, and, authors as well as to identify research hotspots and promising future trends in this research field. Results: A total of 1,641 English articles published between 2011 and 2020 were collected, with the number of articles increasing nearly every year. The majority of publications originated from China (n = 893, 54.42%), followed by the United States and Japan. The Sun Yat-sen University contributed the most publications (n = 97, 5.91%). Nakatsura Tetsuya (n = 26) and Llovet JM (n = 366) were ranked first in the top ten authors and co-cited authors. Cancer Immunology Immunotherapy was the most productive academic journal on immunotherapy for HCC [n = 46, 2.80%; impact factor (IF) 2020 = 6.9679]. Aggregation and identification of critical nodes in the co-cited network demonstrated a shift in the field of HCC immunotherapy. Initially, the hotspots were predominantly "glypican-3", "cytokine-induced killer cells", and "ny-eso-1", while the emphasis has shifted in recent years to "landscape", "camrelizumab", "combination therapy", and "immune score". Conclusion: Increased attention has been paid to HCC with the advancement of immunotherapy. At the moment, the most active frontiers are focused on better understanding the immunological landscape of liver cancer, screening the population that can benefit from immunotherapy, and the clinical application of immune checkpoint inhibitors, particularly in combination with other therapeutic options (such as local therapy and targeted therapy).

Abnormal bile acid-microbiota crosstalk promotes the development of hepatocellular carcinoma.

BACKGROUND: Gut microbiota and microbe-derived metabolites are involved in the development of HCC. Bile acids (BAs) are the most important gut microbiota-modulated endogenous signaling molecules. METHODS: We tested serum bile acid levels and gut microbiome compositions in patients with HCC, chemical-induced HCC mouse models (DEN-HCC mice) and mouse orthotopic implanted liver tumor models with vancomycin treatment (vancomycin-treated mice). Then, we screened an important kind of HCC-related BAs, and verified its effect on the growth of HCC in vivo and in vitro. RESULTS: We found that the remarkably decreasing percentages of serum secondary BAs in the total bile acids of patients and DEN-HCC mice, especially, conjugated deoxycholic acids (DCA). The relative abundance of the bile salt hydrolase (BSH)-rich bacteria (Bifidobacteriales, Lactobacillales, Bacteroidales, and Clostridiales) was decreased in the feces of patients and DEN-HCC mice. Then, in vancomycin-treated mice, vancomycin treatment induced a reduction in the BSH-rich bacteria and promoted the growth of liver tumors. Similarly, the percentage of conjugated DCA after vancomycin treatment was significantly declined. We used a kind of conjugated DCA, Glyco-deoxycholic acid (GDCA), and found that GDCA remarkably inhibited the growth of HCC in vivo and in vitro. CONCLUSIONS: We conclude that the remarkably decreasing percentages of serum conjugated DCA may be closely associated with HCC, which may be induced by the reducing gut BSH-rich bacteria. The mechanisms may be correlated with conjugated DCA directly inhibiting the growth and migration of HCC cells.