Diacylglycerol kinase alpha is a proliferation marker of intrahepatic cholangiocarcinoma associated with the prognosis.

BACKGROUND: Intrahepatic cholangiocarcinoma (ICC) has a high recurrence rate and a poor prognosis. Thus, the development of effective treatment and prognostic biomarkers is required. High expression of diacylglycerol kinase alpha (DGKα) is a prognostic factor for the recurrence of hepatocellular carcinoma. However, the relationship between DGKα expression and prognosis in ICC has not been reported. METHODS: Immunohistochemistry (IHC) with anti-DGKα antibody was performed on surgical specimens of ICC (n = 69). First, DGKα expression in cancer cells was qualitatively classified into four groups (-, 1+, 2+, 3+) and divided into two groups (DGKα- and DGKα+1 + to 3+). The relationship between clinical features and DGKα expression was analyzed. Second, Ki-67 expression was evaluated as a cell proliferation marker. The number of Ki-67-positive cells was counted, and the relationship with DGKα expression was examined. RESULTS: DGKα IHC divided the patients into a DGKα+ group (1+: n = 15; 2+: n = 5; 3+: n = 5) and a DGKα- group (-: n = 44). In the DGKα+ group, patients were older and had advanced disease. Both overall survival and recurrence-free survival (RFS) were significantly worse in the DGKα+ patients. DGKα+ was identified as an independent prognostic factor for RFS by multivariate analysis. Furthermore, the number of Ki-67-positive cells increased in association with the staining levels of DGKα. CONCLUSION: Pathological DGKα expression in ICC was a cancer proliferation marker associated with recurrence. This suggests that DGKα may be a potential therapeutic target for ICC.

Expression of Wnt5a and ROR2, Components of the Noncanonical Wnt-Signaling Pathway, is Associated with Tumor Differentiation in Hepatocellular Carcinoma.

BACKGROUND: Wnt5a is the key ligand of the noncanonical Wnt pathway, and receptor tyrosine kinase-like orphan receptor 2 (ROR2) is a receptor associated with Wnt5a. The association between the noncanonical Wnt-signaling pathway and carcinogenesis in hepatocellular carcinoma (HCC) is unclear. This study investigated the significance of ROR2 expression in HCC. METHODS: The study examined ROR2 expression in liver cancer cell lines. Immunohistochemical staining of ROR2 was performed on 243 resected HCC specimens. The study investigated ROR2 expression and its association with clinicopathologic factors and prognosis. RESULTS: Findings showed that ROR2 was expressed in well-differentiated Huh7 and HepG2 cells, but not in poorly differentiated HLE and HLF cells. Expression of ROR2 was positive in 147 (60.5%) and negative in 96 (39.5%) HCC specimens. A significant association was shown between ROR2 negativity and high alpha-fetoprotein (AFP) level (P = 0.006), poor differentiation (P = 0.015), and Wnt5a negativity (P = 0.024). The 5-year overall survival (OS) rate for the ROR2-negative group (64.2 %) tended to be worse than for the ROR2-positive group (73.8%), but the difference was not significant (P = 0.312). The 5-year OS rate was 78.7% for the ROR2+Wnt5a+ group, 71.3 % for the ROR2+Wnt5a- group, 80.8% for the ROR2-Wnt5a+ group, and 60.5 % for the ROR2-Wnt5a- group. The OS in the ROR2-Wnt5a- group was significantly poorer than in the ROR2+Wnt5a+ group (P = 0.030). The multivariate analysis showed that Wnt5a-ROR2- was an independent prognostic factor (hazard ratio, 2.058; 95% confidence interval, 1.013-4.180; P = 0.045). CONCLUSIONS: The combination of ROR2 and Wnt5a may be a prognostic indicator for HCC. The Wnt5a/ROR2 signal pathway may be involved in the differentiation of HCC. This pathway may be a new therapeutic target for HCC.

Novel Benchmark Values for Open Major Anatomic Liver Resection in Non-cirrhotic Patients: A Multicentric Study of 44 International Expert Centers.

OBJECTIVE: This study aims at establishing benchmark values for best achievable outcomes following open major anatomic hepatectomy for liver tumors of all dignities. BACKGROUND: Outcomes after open major hepatectomies vary widely lacking reference values for comparisons among centers, indications, types of resections, and minimally invasive procedures. METHODS: A standard benchmark methodology was used covering consecutive patients, who underwent open major anatomic hepatectomy from 44 high-volume liver centers from 5 continents over a 5-year period (2016-2020). Benchmark cases were low-risk non-cirrhotic patients without significant comorbidities treated in high-volume centers (≥30 major liver resections/year). Benchmark values were set at the 75th percentile of median values of all centers. Minimum follow-up period was 1 year in each patient. RESULTS: Of 8044 patients, 2908 (36%) qualified as benchmark (low-risk) cases. Benchmark cutoffs for all indications include R0 resection ≥78%; liver failure (grade B/C) ≤10%; bile leak (grade B/C) ≤18%; complications ≥grade 3 and CCI ® ≤46% and ≤9 at 3 months, respectively. Benchmark values differed significantly between malignant and benign conditions so that reference values must be adjusted accordingly. Extended right hepatectomy (H1, 4-8 or H4-8) disclosed a higher cutoff for liver failure, while extended left (H1-5,8 or H2-5,8) were associated with higher cutoffs for bile leaks, but had superior oncologic outcomes, when compared to formal left hepatectomy (H1-4 or H2-4). The minimal follow-up for a conclusive outcome evaluation following open anatomic major resection must be 3 months. CONCLUSION: These new benchmark cutoffs for open major hepatectomy provide a powerful tool to convincingly evaluate other approaches including parenchymal-sparing procedures, laparoscopic/robotic approaches, and alternative treatments, such as ablation therapy, irradiation, or novel chemotherapy regimens.

Lymphaticovenous anastomosis for treatment of refractory chylous ascites: A case report.

Chylous ascites, the leakage of lymphatic fluid into the abdominal cavity caused by lymphatic fluid stasis or lymphatic vessel damage, can be treated by lymphaticovenous anastomosis (LVA). We report rarely performed abdominal LVA to treat a case of refractory ascites possibly caused by ligation of the thoracic duct and pleurodesis in a man aged 60 years requiring weekly ascites drainage. Ligation was abandoned because the leakage site was not determined. The greater omentum (GO) was generally edematous and showed lymphatic effusion by gross appearance, and was considered suitable for LVA. We performed once LVA in the lymphatic vessels and veins of the GO using common microsurgical instrumentation and lateral anastomosis. Lymphatic vessels in the omentum were dilated to 2-3 mm, and LVA was simple. After LVA, GO edema improved. Postoperatively, the patient developed paralytic ileus, which improved within a few days, and the patient was discharged without any increase in ascites after starting to diet. One year post-surgery, there was no recurrence of ascites. LVA at the GO may be effective for the treatment of refractory chylous ascites because of its absorptive lymphatic draining capabilities and large transverse vessels.

Conversion surgery after lenvatinib treatment for multiple lung metastases from hepatocellular carcinoma.

Although systemic treatment for hepatocellular carcinoma has advanced after the development of tyrosine kinase inhibitors such as sorafenib and lenvatinib, the effectiveness of a single tyrosine kinase inhibitor in survival extension of unresectable hepatocellular carcinoma is limited to a few months. Therefore, novel treatment options are required for unresectable hepatocellular carcinomas, including those with multiple lung metastases. This case report describes a hepatocellular carcinoma patient with a recurrence of multiple lung metastases, which was successfully treated with conversion pneumonectomy after treatment with tyrosine kinase inhibitors. A 79-year-old man underwent right hepatectomy for hepatocellular carcinoma, along with removal of the tumor thrombus in the inferior vena cava. Multiple lung metastases were detected 4 months after hepatectomy. Treatment with tyrosine kinase inhibitors, mainly lenvatinib, resulted in complete remission of the lung metastases, except for one lesion in segment 3 of the right lung which gradually enlarged. Twenty-three months after hepatectomy, partial resection of the right lung was performed using video-assisted thoracic surgery for this residual lesion in the right lung. The patient remained disease-free for 11 months after conversion pneumonectomy, without any adjuvant therapies. This is the first case report of multiple lung metastases originating from hepatocellular carcinoma which were successfully treated with conversion pneumonectomy after treatment with tyrosine kinase inhibitors. Conversion pneumonectomy after systemic therapy with tyrosine kinase inhibitors should be considered as a treatment strategy for patients with unresectable multiple lung metastases from hepatocellular carcinomas.

Study of hepatic toxicity in small liver tumors after photon or proton therapy based on factors predicting the benefits of proton.

OBJECTIVES: In a previous study of hepatic toxicity, the following three factors were identified to predict the benefits of proton beam therapy (PBT) for hepatocellular carcinomas (HCCs) with a maximum diameter of ≤5 cm and Child-pugh grade A (CP-A): number of tumors (1 vs ≥2), the location of tumors (hepatic hilum or others), and the sum of the diameters of lesions. The aim of this study is to analyze the association between these three factors and hepatic toxicity. METHODS: We retrospectively reviewed patients of CP-A treated with PBT or photon stereotactic body radiotherapy (X-ray radiotherapy, XRT) for HCC ≤5 cm. For normal liver dose, the V5, V10, V20 (volumes receiving 5, 10, and 20 Gy at least), and the mean dose was evaluated. The albumin-bilirubin (ALBI) and CP score changes from the baseline were evaluated at 3 and 6 months after treatment. RESULTS: In 89 patients (XRT: 48, PBT: 41), those with two or three (2-3) predictive factors were higher normal liver doses than with zero or one (0-1) factor. In the PBT group, the ALBI score worsened more in patients with 2-3 factors than those with 0-1 factor, at 3 months (median: 0.26 vs 0.02, p = 0.032) and at 6 months (median: 0.35 vs 0.10, p = 0.009). The ALBI score change in the XRT group and CP score change in either modality were not significantly different in the number of predictive factors. CONCLUSION: The predictive factor numbers predicted the ALBI score change in PBT but not in XRT. ADVANCES IN KNOWLEDGE: This study suggest that the number of predictive factors previously identified (0-1 vs 2-3) were significantly associated with dosimetric parameters of the normal liver in both modalities. In the proton group, the number of predictive factors was associated with a worsening ALBI score at 3 and 6 months, but these associations were not found in the photon SBRT group.

Hepatectomy is Beneficial in Select Patients with Multiple Hepatocellular Carcinomas.

BACKGROUND: A single hepatocellular carcinoma (HCC) is a good indication for hepatic resection regardless of tumor size, but the surgical indications for cases with multiple HCCs remain unclear. METHODS: We retrospectively reviewed the outcomes of hepatectomies for Barcelona Clinic Liver Cancer (BCLC) stage 0, A, and B HCCs. We further subclassified stage A and B into A1 (single nodule <5 cm, or three or fewer nodules ≤3 cm), A2 (single nodule 5-10 cm), A3 (single nodule ≥10 cm), B1 (two to three nodules >3 cm), and B2 (four or more nodules). RESULTS: A total of 1088 patients were enrolled, comprising 88 stage 0, 750 stage A (A1: 485; A2: 190; A3: 75), and 250 stage B (B1: 166; B2: 84) cases. The 5-year overall survival (OS) rates for stage 0, A1, A2, A3, B1, and B2 patients were 70.4%, 74.2%, 63.8%, 47.7%, 47.5%, and 31.9%, respectively (p < 0.0001). Significant differences in OS were found between stages A1 and A2 (p = 0.0118), A2 and A3 (p = 0.0013), and B1 and B2 (p = 0.0050), but not between stages A3 and B1 (p = 0.4742). In stage B1 patients, multivariate analysis indicated that Child-Pugh B cirrhosis was the only independent prognostic factor for the OS outcome. CONCLUSIONS: A hepatectomy should be considered for multiple HCCs if the number of tumors is three or fewer, especially in patients with no cirrhosis or in Child-Pugh A cases, because the long-term results are equivalent to those for a single HCC.

Impact of comorbid renal dysfunction in patients with hepatocellular carcinoma on long-term outcomes after curative resection.

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide. However, the number of patients with chronic kidney disease (CKD) is on the rise because of the increase in lifestyle-related diseases. AIM: To establish a tailored management strategy for HCC patients, we evaluated the impact of comorbid renal dysfunction (RD), as stratified by using the estimated glomerular filtration rate (EGFR), and assessed the oncologic validity of hepatectomy for HCC patients with RD. METHODS: We enrolled 800 HCC patients who underwent hepatectomy between 1997 and 2015 at our university hospital. We categorized patients into two (RD, EGFR < 60 mL/min/1.73 m2; non-RD, EGFR ≥ 60 mL/min/1.73 m2) and three groups (severe CKD, EGFR < 30 mL/min/1.73 m2; mild CKD, 30 ≤ EGFR < 60 mL/min/1.73 m2; control, EGFR ≥ 60 mL/min/1.73 m2) according to renal function as defined by the EGFR. Overall survival (OS) and recurrence-free survival (RFS) were compared among these groups with the log-rank test, and we also analyzed survival by using a propensity score matching (PSM) model to exclude the influence of patient characteristics. The mean postoperative observation period was 64.7 ± 53.0 mo. RESULTS: The RD patients were significantly older and had lower serum total bilirubin, aspartate aminotransferase, and aspartate aminotransferase levels than the non-RD patients (P < 0.0001, P < 0.001, P < 0.05, and P < 0.01, respectively). No patient received maintenance hemodialysis after surgery. Although the overall postoperative complication rates were similar between the RD and non-RD patients, the proportions of postoperative bleeding and surgical site infection were significantly higher in the RD patients (5.5% vs 1.8%; P < 0.05, 3.9% vs 1.8%; P < 0.05, respectively), and postoperative bleeding was the highest in the severe CKD group (P < 0.05). Regardless of the degree of comorbid RD, OS and RFS were comparable, even after PSM between the RD and non-RD groups to exclude the influence of patient characteristics, liver function, and other causes of death. CONCLUSION: Comorbid mild RD had a negligible impact on the prognosis of HCC patients who underwent curative hepatectomy with appropriate perioperative management, and close attention to severe CKD is necessary to prevent postoperative bleeding and surgical site infection.

Liver metastasis 13 years after the resection of a malignant triton tumor originating in the duodenum.

This is an additional case report of a malignant triton tumor arising in the duodenum that was removed by pancreatoduodenectomy. Liver and gallbladder dysfunctions were detected in a regular blood examination during a follow-up for hypertension in a 62-year-old woman with a previous surgical history for a malignant Triton tumor in the duodenum 13 years ago. Further examinations revealed a metastatic liver tumor originating from the malignant triton tumor in the duodenum. Since the progression of the liver tumor was detected after radiation therapy, complete resection was performed by right hepatectomy. Curative hepatectomy resulted in disease-free survival for 1 year and 5 months in an extremely rare case of liver metastasis derived from a malignant triton tumor in the duodenum.

A case of alveolar echinococcosis in the liver that ruptured into the pericardium treated by a combination of hepatectomy and albendazole.

BACKGROUND: Alveolar echinococcosis (AE) is a rare parasitic disease caused by the larva of Echinococcus multilocularis. It nearly always occurs in the liver, and cardiac involvement is extremely rare. Liver resection is the most effective intervention for AE because the only potentially curative treatment is removal of the lesion. Even when complete resection is not performed, long-term survival can be expected after surgical removal of most of the lesion with lifelong administration of albendazole (ABZ). CASE PRESENTATION: A 64-year-old man who lived in Hokkaido was referred to our hospital due to abnormalities in biliary enzymes. According to the findings from enhanced computed tomography and magnetic resource imaging of the abdomen, transthoracic echocardiography and serologic tests, he was diagnosed with hepatic AE with rupture into the pericardium. He underwent extended left hemi-hepatectomy with reconstruction of the inferior vena cava and opening of the pericardium with drainage as reduction surgery. Pathological examination revealed echinococcal infection in the pericardium as well as the liver. He started chemotherapy with 400 mg ABZ per Day 67 days after surgery. Although the surgical margin was positive in the pathological findings, he was alive 19 months later with no regrowth of the echinococcal lesion. CONCLUSION: AE with cardiac involvement is extremely rare. Even if the complete removal of cardiac-involved AE is not possible, surgical debulking with lifelong ABZ treatment can successfully manage the disease.

Laparoscopic liver resection for liver metastasis of leiomyosarcoma of the thigh: a case report.

BACKGROUND: Although there is no established treatment strategy for liver metastasis of leiomyosarcoma, liver resection has been reported to be effective in some cases. However, almost all liver resections performed for liver metastasis of primary leiomyosarcoma are reported to be open resections, and there are few reports of liver resection performed by laparoscopy. Here, we report a case of laparoscopic liver resection for liver metastasis of a leiomyosarcoma in the right thigh. CASE PRESENTATION: An 80-year-old man was diagnosed with leiomyosarcoma of the right thigh with liver metastasis. The primary tumor was first resected, and he was discharged on the 25th postoperative day. Four months after primary tumor resection, a laparoscopic right posterior sectionectomy was performed. There were no postoperative complications, and the patient was discharged on the 11th postoperative day with a histopathological diagnosis of liver metastasis of leiomyosarcoma and negative resection margins. Currently, 9 months have passed since the resection of the primary tumor, and 5 months have passed since the laparoscopic liver resection; there is no recurrence. CONCLUSIONS: The liver metastasis of leiomyosarcoma was successfully removed, with good short-term outcomes after the laparoscopic liver resection. Laparoscopic liver resection seems to be effective for liver metastasis of leiomyosarcoma, which is characterized by a high recurrence rate after surgery. However, more case studies may be necessary to examine the effectiveness and long-term results of laparoscopic liver resection for the treatment of liver metastasis of leiomyosarcoma.

Preventing Recurrence of Hepatocellular Carcinoma After Curative Hepatectomy With Active Hexose-correlated Compound Derived From Lentinula edodes Mycelia.

PURPOSE: Active hexose-correlated compound (AHCC), a standardized extract of cultured Lentinula edodes mycelia, exerts antitumor effects through anti-inflammatory and immune-modulatory functions. Adjuvant therapy for patients with hepatocellular carcinoma (HCC) who have undergone curative hepatectomy has not been established. The purpose of this study was to evaluate the efficacy and safety of AHCC as adjuvant therapy in patients with advanced HCC after curative hepatectomy. PATIENTS AND METHODS: The study design was single-armed, non-randomized, open (no one was blinded), and uncontrolled. Patients with HCC who underwent curative hepatectomy were treated with AHCC (1 g) 3 times daily orally for 2 years. The inclusion criteria were HCC diagnosed preoperatively as stages A and B of the Barcelona clinic liver cancer (BCLC) classification and alpha-fetoprotein × protein induced by vitamin K absence or antagonist II (PIVKA-II) ≥ 105 for stage A. RESULTS: A total of 29 patients were treated with AHCC, of which 25 (4 patients discontinued) were followed up. The 2-year recurrence-free survival rate after resection was 48% for those without discontinuations and 55.2% for all patients with a history of treatment. Serum albumin levels decreased to a minimum in the first postoperative month and gradually recovered to the preoperative level at 6 months. Almost no change in lymphocyte percentage was observed during follow-up. Inflammation-based prognostic scores were maintained at favorable levels after hepatectomy. Toxicity and adverse events were not observed in any patient. CONCLUSION: AHCC may be safe and effective in preventing HCC recurrence after curative hepatectomy, and further randomized trials of AHCC for its use in this setting are warranted.This clinical trial was registered in UMIN Clinical Trials Registry (ID UMIN000024396).

Outcomes of reduction hepatectomy combined with postoperative multidisciplinary therapy for advanced hepatocellular carcinoma.

BACKGROUND: The prognosis of advanced hepatocellular carcinoma (HCC) that is not indicated for curative hepatectomy remains poor, despite advances in the treatment of HCC, including the development of tyrosine kinase inhibitors (TKIs). The outcomes of reduction hepatectomy and multidisciplinary postoperative treatment for advanced HCC that is not indicated for curative hepatectomy, including those of recently treated cases, should be investigated. AIM: To examine the outcomes of combination treatment with reduction hepatectomy and multidisciplinary postoperative treatment for advanced HCC that is not indicated for curative hepatectomy. METHODS: Thirty cases of advanced HCC that were not indicated for curative hepatectomy, in which reduction hepatectomy was performed between 2000 and 2018 at the Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, were divided into postoperative complete remission (POCR) (+) and POCR (-) groups, depending on whether POCR of all evaluable lesions was achieved through postoperative treatment. The cases in the POCR (-) group were subdivided into POCR (-) TKI (+) and POCR (-) TKI (-) groups, depending on whether TKIs were administered postoperatively. RESULTS: The 5-year overall survival rate and mean survival time (MST) after reduction hepatectomy were 15.7% and 28.40 mo, respectively, for all cases; 37.5% and 56.55 mo, respectively, in the POCR (+) group; and 6.3% and 14.84 mo, respectively, in the POCR (-) group (P = 0.0041). Tumor size, major vascular invasion, and the number of tumors in the remnant liver after the reduction hepatectomy were also found to be related to survival outcomes. The number of tumors in the remnant liver was the only factor that differed significantly between the POCR (+) and POCR (-) groups, and POCR was achieved significantly more frequently when ≤ 3 tumors remained in the remnant liver (P = 0.0025). The MST was 33.52 mo in the POCR (-) TKI (+) group, which was superior to the MST of 10.74 mo seen in the POCR (-) TKI (-) group (P = 0.0473). CONCLUSION: Reduction hepatectomy combined with multidisciplinary postoperative treatment for unresectable advanced HCC that was not indicated for curative hepatectomy was effective when POCR was achieved via multidisciplinary postoperative therapy. To achieve POCR, reduction hepatectomy should aim to ensure that ≤ 3 tumors remain in the remnant liver. Even in cases in which POCR is not achieved, combined treatment with reduction hepatectomy and multidisciplinary therapy can improve survival outcomes when TKIs are administered.

Hepatectomy and immune checkpoint inhibitor treatment for liver metastasis originating from non-cutaneous melanoma: a report of three cases.

The outcomes of hepatectomy alone for liver metastasis derived from non-cutaneous melanoma are insufficient, and the outcomes of systemic therapy alone are also insufficient, even since the development of immune checkpoint inhibitors (ICIs). We report the cases of three patients, in whom liver metastasis derived from non-cutaneous melanoma was treated with hepatectomy combined with ICI therapy, which was administered in various settings. One patient received ICI treatment for recurrent melanoma and survived 107 months after the first hepatectomy, one patient received both preoperative and adjuvant ICI treatment and has been disease-free for 27 months, and another patient received postoperative ICI treatment after reduction hepatectomy and has been alive with disease for 47 months. Since long-term survival is possible, hepatectomy combined with ICI therapy should be considered for the treatment of liver metastasis derived from non-cutaneous melanoma.

Acute Myocardial Infarction of the Left Main Coronary Artery Presenting with Cardiogenic Shock and Pulmonary Edema during Noncardiac Surgery.

Acute myocardial infarction (AMI) caused by severe stenosis of left main coronary artery (LMCA) presenting with cardiogenic shock and pulmonary edema during noncardiac surgery is uncommon, but a catastrophic event. A 77-year-old male with cholangiocarcinoma underwent hepatectomy. During the surgery, he presented with cardiogenic shock, which did not respond to infusion administration or vasopressor. A transesophageal echocardiogram revealed anterior, septal, and lateral severe hypokinesia and impaired left ventricular function. Emergent coronary angiogram showed severe stenosis of LMCA. The patient underwent primary percutaneous coronary intervention (PCI) under the support of intra-aortic balloon pump, followed by extracorporeal membrane oxygenation. The chest roentgenogram showed pulmonary edema. Two days after PCI, he successfully underwent hepatectomy and bile duct resection. Early identification of the cause of hemodynamic instability during noncardiac surgery and invasive strategy are important for minimizing the myocardial injury and improving clinical outcomes in AMI of LMCA.

High HbA1c is a risk factor for complications after hepatectomy and influences for hepatocellular carcinoma without HBV and HCV infection.

BACKGROUND: Currently, the population with type 2 diabetes mellitus (DM) is increasing worldwide. However, the influence of DM or hyperglycemia on the outcome of resected hepatocellular carcinoma (HCC) is unclear. METHODS: We analyzed 756 patients with HCC who underwent hepatectomy. These patients were assigned to an HbA1c ≥7.0% (H-A1c; n=100) or HbA1c <7.0% (L-A1c; n=656) group depending on their HbA1c level at admission. We investigated prognoses, clinicopathological characteristics and surgical outcomes including morbidities of HCC patients with high HbA1c, prognoses according to the treatment for DM were also investigated. RESULTS: Among all patients and those with hepatitis B virus (HBV) and hepatitis C virus (HCV) infection, overall survival (OS) and relapse-free survival (RFS) did not differ significantly between the H-A1c and L-A1c groups. In contrast, the 5-year OS rate of the H-A1c group was 55% and that of the L-A1c group 71% among patients without HBV and HCV (NBNC patients) (P=0.03). Among NBNC patients, the median RFS of the H-A1c group was 13 months, and that of the L-A1c group was 26 months (P=0.02). In addition, metformin use was an independent favorable factor for both OS and RFS. The H-A1c group had significantly higher rates of hyperbilirubinemia, wound infection, and pneumonia. CONCLUSIONS: HCC patients with high HbA1c might have poor prognoses for both survival and recurrence in NBNC-HCC. High HbA1c may also be a risk factor for morbidities after hepatectomy. Metformin use may constitute a good option for NBNC patients with HCC.