Vascular endothelial growth factor is associated with hepatocellular carcinoma recurrence, independent of folate and glutathione-related antioxidant enzymes: A follow-up study.

The associations of tumor angiogenesis with folate and antioxidant capacities in patients with hepatocellular carcinoma (HCC) and their effects on HCC recurrence have not yet been investigated. We investigated the changes and relationships of VEGF, folate, GSH, and GSH-related antioxidant enzymes in patients with HCC before tumor resection, as well as 1 month, 1 year, and 3 years after tumor resection, and their effects on HCC recurrence. 95 HCC patients who underwent tumor resection were recruited. Patients were followed up before tumor resection (pre-resection), 1 month after tumor resection (post-resection), 1 year, and 3 years of follow-up. The recurrence and survival status of patients were evaluated. Plasma VEGF concentrations decreased slightly during follow-up. Serum folate and GSH concentrations and plasma GPx and GR activities increased significantly from pre-resection to post-resection and remained stable at follow-up. Pre-resection plasma VEGF was positively correlated with GSH, GPx, and GR, but negatively correlated with folate and GST. The high pre-resection plasma VEGF was a significant predictor of a high HCC rate (hazard ratio = 1.05, p = 0.035), remaining significant after adjustments for folate, GSH, GPx, GR, and GST to diminish their interference with VEGF. Pre-tumor-resection plasma VEGF constitutes a potential independent marker for predicting HCC recurrence. However, the associations of plasma VEGF with folate and GSH-related antioxidant capacities in HCC patients cannot be ignored.

Surgical Outcomes of Pancreatic Solid Pseudopapillary Neoplasm: Experiences of 24 Patients in a Single Institute.

Background and Objectives: The pancreatic solid pseudopapillary neoplasm (SPN), a rare tumor predominantly affecting young women, has seen an increased incidence due to improved imaging and epidemiological knowledge. This study aimed to understand the outcomes of different interventions, possible complications, and associated risk factors. Materials and Methods: This study retrospectively analyzed 24 patients who underwent pancreatic surgery for SPNs between September 1998 and July 2020. Results: Surgical intervention, typically required for symptomatic cases or pathological confirmation, yielded favorable outcomes with a 5-year survival rate of up to 97%. Despite challenges in standardizing preoperative evaluation and follow-up protocols, aggressive complete resection showed promising long-term survival and good oncological outcomes. Notably, no significant differences were found between conventional and minimally invasive (MI) surgery in perioperative outcomes. Histopathological correlations were lacking in prognosis and locations. Among the patients, one developed diffuse liver metastases 41 months postoperatively but responded well to chemotherapy and transcatheter arterial chemoembolization, with disease stability observed at 159 postoperative months. Another patient developed nonalcoholic steatohepatitis after surgery and underwent liver transplantation, succumbing to poor medication adherence 115 months after surgery. Conclusions: These findings underscore the importance of surgical intervention in managing SPNs and suggest the MI approach as a viable option with comparable outcomes to conventional surgery.

Immediate postoperative parenteral anticoagulant therapy in patients with mesenteric ischemia after intestinal resection: a retrospective cohort study at a single institute.

BACKGROUND: Bowel gangrene represents a major fatal event in acute mesenteric ischemia. Intestinal resection is inevitable in patients with peritonitis and bowel gangrene. This retrospective study aimed to elucidate the benefit of postoperative parenteral anticoagulation in patients with intestinal resection. METHODS: Patients with acute mesenteric ischemia and bowel gangrene were recruited retrospectively between January 2007 and December 2019. All patients underwent bowel resection. They were categorized into two groups: patients without immediate parenteral anticoagulant therapy (Group A) and those with immediate parenteral anticoagulant therapy (Group B). Thirty-day mortality and survival were analyzed. RESULTS: A total of 85 patients were included, with 29 patients in Group A and 56 patients in Group B. Patients in Group B had lower 30-day mortality (16.1%) and a higher 2-year survival rate (45.4%) than patients in Group A (30-day mortality: 51.7%, p = 0.001; 2-year survival rate: 19.0%, p = 0.001). In the 30-day mortality multivariate analysis, patients in Group B had a better outcome (odds ratio = 0.080, 95% confidence interval between 0.011 and 0.605, p = 0.014). Patients in Group B also had a better outcome in the survival multivariate analysis (hazard ratio: 0.435, 95% confidence interval between 0.213 and 0.887, p = 0.022). CONCLUSIONS: Immediate postoperative parenteral anticoagulant therapy improves prognosis in patients with acute mesenteric ischemia treated by intestinal resection. Trial registration This research was retrospectively approved by the Institutional Review Board (IRB) I&II of Taichung Veterans General Hospital (TCVGH-IRB No.CE21256B) on July 28th, 2021. The informed consent waiver was also approved by IRB I&II of Taichung Veterans General Hospital. The Declaration of Helsinki and ICH-GCP guidelines were followed during this study.

The Prognostic Role of Glutathione and Its Related Antioxidant Enzymes in the Recurrence of Hepatocellular Carcinoma.

The imbalance of high oxidative stress and low antioxidant capacities is thought to be a significant cause of the development and progression of hepatocellular carcinoma (HCC). However, the impact of oxidative stress, glutathione (GSH), and its related antioxidant enzymes on the recurrence of HCC has not been investigated. The purpose of this study was to compare the changes to oxidative stress and GSH-related antioxidant capacities before and after tumor resection in patients with HCC recurrence and non-recurrence. We also evaluated the prognostic significance of GSH and its related enzymes in HCC recurrence. This was a cross-sectional and follow-up study. Ninety-two HCC patients who were going to receive tumor resection were recruited. We followed patients' recurrence and survival status until the end of the study, and then assigned patients into the recurrent or the non-recurrent group. The tumor recurrence rate was 52.2% during the median follow-up period of 3.0 years. Patients had significantly lower plasma malondialdehyde level, but significantly or slightly higher levels of GSH, glutathione disulfide, trolox equivalent antioxidant capacity, glutathione peroxidase (GPx), and glutathione reductase (GR) activities after tumor resection compared to the respective levels before tumor resection in both recurrent and non-recurrent groups. GSH level in HCC tissue was significantly higher than that in adjacent normal tissue in both recurrent and non-recurrent patients. Decreased plasma GPx (HR = 0.995, p = 0.01) and GR (HR = 0.98, p = 0.04) activities before tumor resection, and the increased change of GPx (post-pre-resection) (HR = 1.004, p = 0.03) activity were significantly associated with the recurrence of HCC. These findings suggest there might be a possible application of GPx or GR as therapeutic targets for reducing HCC recurrence.

Locoregional therapies in patients with recurrent intrahepatic cholangiocarcinoma after curative resection.

BACKGROUND: Hepatectomy is one potential treatment for intrahepatic cholangiocarcinoma (IHCC). Recurrent rate is high after curative resection and most recurrences occur within residual liver parenchyma. The aim of this study was to elucidate the impact of different treatment modalities on recurrent diseases in patients with IHCC after primary liver resection. METHODS: Between February 1999 and December 2015, we retrospectively identified patients who received curative resection for IHCC. Patients who experienced recurrences were included. Locoregional therapies included re-hepatectomy, radiofrequent ablation, and transhepatic arterial chemoembolization. These patients were categorized into three groups: intrahepatic recurrence without locoregional therapies (group A), intrahepatic recurrence with locoregional therapies (group B) and extrahepatic metastases (group C). RESULTS: Forty-three patients were included and there were 12, 15, and 16 patients in groups A, B, and C, respectively. The median disease-free survival times were 8.3, 9.1, and 8.7 months in groups A, B, and C (p = 0.099). The median after-recurrence overall survival times (period between recurrence and death/censor) were 6.4, 34.0, and 8.3 months in groups A, B, and C (p = 0.001). Locoregional therapies showed favorable benefit in multivariant analysis (hazard ratio: 0.274, confidence interval: 0.083-0.908, p = 0.010). CONCLUSION: Locoregional therapies offered favorable benefits for patients with recurrent intrahepatic cholangiocarcinoma.

Impact of Glutathione and Vitamin B-6 in Cirrhosis Patients: A Randomized Controlled Trial and Follow-Up Study.

Vitamin B-6 and glutathione (GSH) are antioxidant nutrients, and inadequate vitamin B-6 may indirectly limit glutathione synthesis and further affect the antioxidant capacities. Since liver cirrhosis is often associated with increased oxidative stress and decreased antioxidant capacities, we conducted a double-blind randomized controlled trial to assess the antioxidative effect of vitamin B-6, GSH, or vitamin B-6/GSH combined supplementation in cirrhotic patients. We followed patients after the end of supplementation to evaluate the association of vitamin B-6 and GSH with disease severity. In total, 61 liver cirrhosis patients were randomly assigned to placebo, vitamin B-6 (50 mg pyridoxine/d), GSH (500 mg/d), or B-6 + GSH groups for 12 weeks. After the end of supplementation, the condition of patient's disease severity was followed until the end of the study. Neither vitamin B-6 nor GSH supplementation had significant effects on indicators of oxidative stress and antioxidant capacities. The median follow-up time was 984 d, and 21 patients were lost to follow-up. High levels of GSH, a high GSH/oxidized GSH ratio, and high GSH-St activity at baseline (Week 0) had a significant effect on low Child-Turcotte-Pugh scores at Week 0, the end of supplementation (Week 12), and the end of follow-up in all patients after adjusting for potential confounders. Although the decreased GSH and its related enzyme activity were associated with the severity of liver cirrhosis, vitamin B-6 and GSH supplementation had no significant effect on reducing oxidative stress and increasing antioxidant capacities.

Possible Synergistic Effects of Glutathione and C-Reactive Protein in the Progression of Liver Cirrhosis.

Liver cirrhosis is often associated with increased inflammatory responses and changes of glutathione (GSH) status. The possible interactions between these two factors in mediating damages of liver function remain unclear. Here, we measured the inflammatory responses and GSH status in liver cirrhotic patients and compared them with healthy subjects. In addition, we assessed the relationship of the GSH status and levels of inflammatory markers with the severity of the disease. This was a cross-sectional study. In total, we recruited 63 liver cirrhotic patients with Child⁻Turcotte⁻Pugh class A scores, and 12 patients with class B⁻C scores, together with 110 healthy subjects. Patients with class B⁻C scores showed the highest level of high-sensitivity C-reactive protein (hs-CRP) when compared with class A patients or healthy subjects. Patients in class A group had significantly higher GSH levels when compared with class B⁻C group or healthy subjects. After adjusting for potential confounders and each other, serum hs-CRP levels showed positive association with the Child⁻Turcotte⁻Pugh scores, while GSH levels showed negative association with Child⁻Turcotte⁻Pugh scores. Interactions were found between levels of plasma GSH and serum hs-CRP (ß = 0.004, p = 0.016). CRP and GSH levels, which had showed interactions, were associated with the severity of liver cirrhosis.

Changes of Oxidative Stress, Glutathione, and Its Dependent Antioxidant Enzyme Activities in Patients with Hepatocellular Carcinoma before and after Tumor Resection.

The changes in and relationship between oxidative stress and the glutathione (GSH) antioxidant system in the plasma and tissues of patients with hepatocellular carcinoma (HCC) before and after tumor resection have not been clearly determined. We investigated the changes in oxidative stress, GSH status and its dependent antioxidant enzyme activities in HCC patients before and after tumor resection, and to determine the association of oxidative stress with GSH and its dependent antioxidant enzyme activities in plasma and tissues. This study employed a cross-sectional design. Forty-four men and 16 women with HCC were recruited. Fasting blood was drawn on the day before the tumor resection and one month after the tumor resection. HCC tissue and adjacent normal liver tissue were obtained at the time of surgical resection. Patients had significantly increased plasma malondialdehyde (MDA) and oxidized-low density lipoprotein levels but decreased GSH and oxidized GSH levels before tumor resection compared with the corresponding post-resection values. GSH and trolox equivalent antioxidant capacity (TEAC) levels and activities of GSH peroxidase were significantly increased while MDA level was significantly lower in HCC tissue when compared with the adjacent normal tissue. The pre-resection plasma MDA level was significantly correlated with pre-resection plasma GSH concentration, and MDA level in HCC and adjacent normal tissues. Pre-resection plasma GSH concentration was significantly correlated with GSH and TEAC level in HCC tissue. HCC patients had increased oxidative stress, decreased GSH, and lower dependent antioxidant capacities before tumor resection. However, hepatocellular tumor had increased GSH and TEAC levels as well as GSH peroxidase activities which might protect itself against increased oxidative stress.

Coenzyme Q10 and Oxidative Stress: Inflammation Status in Hepatocellular Carcinoma Patients after Surgery.

(1) Background: Hepatocellular carcinoma (HCC) is the second leading cause of cancer deaths worldwide, and surgical resection is the main treatment for HCC. To date, no published study has examined the status of coenzyme Q10 in patients with HCC after surgery. Thus, the purpose of this study was to investigate the correlations between the level of coenzyme Q10, oxidative stress, and inflammation in patients with HCC after surgery; (2) Methods: 71 primary HCC patients were recruited. Levels of coenzyme Q10, vitamin E, oxidative stress (malondialdehyde), antioxidant enzymes activity (superoxidase dismutase, catalase, and glutathione peroxidase), and inflammatory markers (high sensitivity C-reactive protein; tumor necrosis factor-α; and interleukin-6) were measured; (3) Results: Patients with HCC had a significantly lower levels of coenzyme Q10 (p = 0.01) and oxidative stress (p < 0.01), and significantly higher levels of antioxidant enzymes activities and inflammation after surgery (p < 0.05). The level of coenzyme Q10 was significantly positively correlated with antioxidant capacity (vitamin E and glutathione peroxidase activity) and negatively correlated with inflammation markers after surgery; (4) Conclusion: Hepatocarcinogenesis is associated with oxidative stress, and coenzyme Q10 may be considered an antioxidant therapy for patients with HCC, particularly those with higher inflammation after surgery.

Effects of coenzyme Q10 supplementation on antioxidant capacity and inflammation in hepatocellular carcinoma patients after surgery: a randomized, placebo-controlled trial.

BACKGROUND: It has been reported that higher levels of oxidative stress and inflammation play a key role in the progression of hepatocellular carcinoma (HCC) after surgery. Coenzyme Q10 is an endogenous lipid-soluble antioxidant. To date, no intervention study has investigated coenzyme Q10 supplementation in HCC patients after surgery. The purpose of this study was to investigate oxidative stress, antioxidant enzymes activity, and inflammation levels in HCC patients after surgery following administration of coenzyme Q10 (300 mg/day). METHODS: This study was designed as a single-blinded, randomized, parallel, placebo-controlled study. Patients who were diagnosed with primary HCC (n = 41) and were randomly assign to a placebo (n = 20) or coenzyme Q10 (300 mg/day, n = 21) group after surgery. The intervention lasted for 12 weeks. Plasma coenzyme Q10, vitamin E, oxidative stress antioxidant enzymes activity and inflammatory markers levels were measured. RESULTS: The oxidative stress (p = 0.04) and inflammatory markers (hs-CRP and IL-6, p < 0.01) levels were significantly decreased, and the antioxidant enzymes activity was significantly increased (p < 0.01) after 12 weeks of coenzyme Q10 supplementation. In addition, the coenzyme Q10 level was significantly negatively correlated with the oxidative stress (p = 0.01), and positively correlated with antioxidant enzymes activity (SOD, p = 0.01; CAT, p < 0.05; GPx, p = 0.04) and vitamin E level (p = 0.01) after supplementation. CONCLUSION: In conclusion, we demonstrated that a dose of 300 mg/d of coenzyme Q10 supplementation significantly increased the antioxidant capacity and reduced the oxidative stress and inflammation levels in HCC patients after surgery. TRIAL REGISTRATION: Clinical Trials.gov Identifier: NCT01964001.

Vitamin B-6 Supplementation Could Mediate Antioxidant Capacity by Reducing Plasma Homocysteine Concentration in Patients with Hepatocellular Carcinoma after Tumor Resection.

Vitamin B-6 has a strong antioxidative effect. It would be useful to determine whether vitamin B-6 supplementation had effects on antioxidant capacities in patients with hepatocellular carcinoma (HCC) who had recently undergone tumor resection. Thirty-three HCC patients were randomly assigned to either the placebo (n = 16) group or the vitamin B-6 50 mg/d (n = 17) group for 12 weeks. Plasma pyridoxal 5'-phosphate, homocysteine, indicators of oxidative stress, and antioxidant capacities were measured. Plasma homocysteine in the vitamin B-6 group was significantly decreased at week 12, while the level of trolox equivalent antioxidant capacity (TEAC) was significantly increased at the end of the intervention period. Vitamin B-6 supplementation had a significant reducing effect on the change of plasma homocysteine (ß = -2.4, p = 0.02) but not on the change of TEAC level after adjusting for potential confounders. The change of plasma homocysteine was significantly associated with the change of TEAC after adjusting for potential confounders (ß = -162.0, p = 0.03). Vitamin B-6 supplementation seemed to mediate antioxidant capacity via reducing plasma homocysteine rather than having a direct antioxidative effect in HCC patients who had recently undergone tumor resection. The clinical trial number is NCT01964001, ClinicalTrials.gov.

Unroofing hepatectomy: a facilitating approach for resection of deep-seated hepatocellular carcinoma adjacent to major intrahepatic vessels in cirrhotic patients.

BACKGROUND AND OBJECTIVES: Unroofing hepatectomy, an alternative approach to remove a deep-seated hepatocellular carcinoma (HCC) adjacent to major intrahepatic vessels by peel-off technique after sacrificing the overlying noncancerous liver, may result in tumor exposure without resection margin. The aim of the study was to examine the value of this approach in cirrhotic patients. METHODS: Between 1998 and 2012, 51 cirrhotic patients underwent unroofing hepatectomy for deep-seated newly-diagnosed HCC adjacent to major intrahepatic vessels (group A). Another 274 cirrhotic patients with similar tumor size and without gross major vessel involvement in the same period were selected as the control cohort (group B). The patients' clinicopathological characteristics, the early and long-term outcomes of the two groups were compared. RESULTS: The HCCs in group A had a significantly higher rate of tumor encapsulation, smaller number of associated satellite nodules, and smaller amount of resected liver weight. Postoperative complication and 90-day mortality rates were similar, but group A patients had a significant better 5-year disease-free (56% vs. 32%, P = 0.011) and overall survival rates (82% vs. 53%, P = 0.008). CONCLUSIONS: In selected cirrhotic patients, unroofing hepatectomy facilitates resection of deep-seated HCC adjacent to major intrahepatic vessels with acceptable early and long-term results.

Impact of severe oesophagogastric varices on liver resection for hepatocellular carcinoma in cirrhotic patients.

BACKGROUND: The aim of the present study was to clarify both short-term and long-term results of patients with concomitant hepatocellular carcinoma (HCC) and high-risk oesophagogastric varices (OGV). METHODS: This retrospective study identified 927 cirrhotic patients who underwent curative resection of HCC between 1995 and 2012 in single institution. Patients were separated into 3 groups (A, B, and C) according to general rules for recording endoscopic findings of oesophagogastric varices proposed in Japan in 1991. Groups A, B, and C consisted of patients without OGV (F0), patients with mild to moderate OGV (F1 to F2), and patients with high-risk OGV (F3 and/or red color sign), respectively. All patients in group C underwent prophylactic endoscopic variceal ligation/sclerotherapy. Post-operative complications, mortality, overall survival, and disease-free survival were compared among 3 groups. RESULTS: No patient had post-operative variceal bleeding. Complication rates of Clavien-Dindo grade II to V in three groups were 13.6, 14.0, and 6.9 %, respectively (P > 0.05). Operative mortality, 5-year overall survival rate, and disease-free survival rate among the 3 groups were not significantly different (P > 0.05). CONCLUSIONS: Prophylactic endoscopic variceal ligation/sclerotherapy effectively prevented from post-operative variceal bleeding in patients with high-risk OGV. Operative mortality, major morbidity, and survival of patients with high-risk OGV were similar to those of patients without OGV or those with mild OGV. Liver resection remains a feasible choice for cirrhotic patients with concomitant HCC and high-risk OGV.