A Significant Increase in the Serum Carbohydrate Antigen 19-9 Level Accompanied by Acute Cholecystitis and Choledocholithiasis: A Case Report and Review of the Literature.

An 80-year-old man with jaundice and fatigue was referred to our hospital. A laboratory examination revealed increased levels of hepatobiliary enzymes, and CA19-9 levels increased to 29,512 U/mL. Based on the findings of imaging examination and laboratory data, the patient was diagnosed with acute cholecystitis and choledocholithiasis. The possibility of malignancy could not be ruled out because of the high levels of CA19-9. Antibiotic administration was commenced, and the common bile duct stone was endoscopically removed. One month after treatment, the CA19-9 level decreased to within the normal range. One year after treatment, imaging examinations did not reveal any malignancy.

Deterioration of liver function and aging disturb sequential systemic therapy for unresectable hepatocellular carcinoma.

This study aimed to investigate the clinical characteristics of patients with unresectable hepatocellular carcinoma (HCC), who were eligible for sequential systemic therapy. We evaluated 365 patients with HCC who underwent systemic therapy after 2017. The overall survival (OS) was 13.7 months, 19.2 months, and 35.6 months in the first-line, second-line, and third-line or later therapy groups, respectively. Multivariate analysis revealed that the modified-albumin-bilirubin (m-ALBI) grade, macrovascular invasion, extrahepatic spread, discontinuation due to adverse events (AEs), and sequential therapy were independent factors for OS. At the end of each therapy, the ALBI score was significantly worse among patients with discontinuation due to AEs than among those without. The conversion rate to second-line and third-line therapy among patients with discontinuation due to AEs was significantly lower than that among patients without (30.4% vs. 69.2%, p < 0.001; 6.7% vs. 58.3%; p < 0.001, respectively). In the decision tree analysis, m-ALBI grade 1 or 2a and non-advanced age were selected splitting variables, respectively, for sequential systemic therapy. In conclusion, sequential therapy prolonged the OS of unresectable HCC. Additionally, good hepatic function and non-advanced age were clinically eligible characteristics for sequential systemic therapy.

Final Results of TACTICS: A Randomized, Prospective Trial Comparing Transarterial Chemoembolization Plus Sorafenib to Transarterial Chemoembolization Alone in Patients with Unresectable Hepatocellular Carcinoma.

Introduction: Several clinical trials comparing the efficacy and safety of transarterial chemoembolization (TACE) plus molecular-targeted agents versus TACE alone revealed no clinical benefits in progression-free survival (PFS) or overall survival (OS). Here, we report the final OS analysis from the TACTICS trial, which previously demonstrated significant improvement in PFS with TACE plus sorafenib in patients with unresectable hepatocellular carcinoma (HCC) (NCT01217034). Methods: Patients with unresectable HCC were randomized to a TACE plus sorafenib group (N = 80) or a TACE alone group (N = 76). Patients in the combination treatment group received sorafenib 400 mg once daily for 2-3 weeks before TACE, followed by 800 mg once daily during on-demand conventional TACE sessions until time to untreatable progression. In this trial, TACE-specific PFS was used. TACE-specific PFS is defined as the time from randomization to progressive disease (PD) or death from any cause, and PD was defined as untreatable progression, caused by the inability of a patient to further receive or benefit from TACE for reasons that include intrahepatic tumor progression (25% increase vs. baseline) according to response evaluation criteria in cancer of the liver, the detection of extrahepatic spread, vascular invasion, or transient deterioration of liver function to Child-Pugh C after TACE. Results: At the cut-off date of July 31, 2020, 131 OS events were observed. The median OS was 36.2 months with TACE plus sorafenib and 30.8 months with TACE alone (hazard ratio [HR] = 0.861; 95% confidence interval [CI], 0.607-1.223; p = 0.40, ΔOS, 5.4 months). The updated PFS was 22.8 months with TACE plus sorafenib and 13.5 months with TACE alone (HR = 0.661; 95% CI, 0.466-0.938; p = 0.02). Post-trial treatments with active procedures/agents were received by 47 (58.8%) patients in the TACE plus sorafenib group and 58 (76.3%) in the TACE alone group (p = 0.01). In post hoc analysis, PFS and OS benefit were shown in HCC patients with tumor burden beyond up-to-7 criteria. Conclusions: In TACTICS trial, TACE plus sorafenib did not show significant OS benefit over TACE alone; however, clinical meaningful OS prolongation and significantly improved PFS was observed. Thus, the TACE plus sorafenib can be considered a choice of treatment in intermediate-stage HCC, especially in patients with high tumor burden. Trial Registration: NCT01217034.

First-line sorafenib sequential therapy and liver disease etiology for unresectable hepatocellular carcinoma using inverse probability weighting: A multicenter retrospective study.

BACKGROUND AND AIMS: Sequential therapy with molecular-targeted agents (MTAs) is considered effective for unresectable hepatocellular carcinoma (HCC) patients. This study purposed to evaluate the efficacy of sequential therapy with sorafenib (SORA) as a first-line therapy and to investigate the therapeutic impact of SORA in nonalcoholic fatty liver disease (NAFLD) or nonalcoholic steato hepatitis (NASH)-related HCC. METHODS: We evaluated 504 HCC patients treated with SORA (Study-1). The times of administration for sorafenib from 2009 to 2015, 2016 to 2017, and 2018 and later were defined as the early-, mid-, and late-term periods, respectively. Among them, 180 HCC patients treated with SORA in addition to MTAs in the mid- and late-term periods were divided into groups based on disease etiology (NAFLD or NASH [n = 37] and viral or alcohol [n = 143]), and outcomes were compared after inverse probability weighting (IPW) (Study-2). RESULTS: Overall survival (OS) of HCC patients who received sequential MTA therapy after first-line SORA was significantly longer. The median survival times (MST) were 12.6 versus 17.6 versus 17.4 months in the early-term group, mid-term group, and the later-time group (early vs. mid, p = 0.014, early vs. later. p = 0.045), respectively. (Study-1). In Study-2, there was no significant differences in OS between the Virus/alcohol group and the NAFLD/NASH group in patients who received sequential therapy (MST was 23.4 and 27.0 months p = 0.173, respectively). The NAFLD or NASH, female sex, albumin-bilirubin (ALBI) grade 2b, and major Vp (Vp3/Vp4) were significant factors for OS treated with SORA. CONCLUSIONS: Sequential therapy with SORA as the first-line treatment improved the prognosis of unresectable HCC patients and was effective regardless of HCC etiology.

Survival Benefit of Hepatic Arterial Infusion Chemotherapy over Sorafenib in the Treatment of Locally Progressed Hepatocellular Carcinoma.

BACKROUND: Not all patients with hepatocellular carcinoma (HCC) benefit from treatment with molecular targeted agents such as sorafenib. We investigated whether New-FP (fine-powder cisplatin and 5-fluorouracil), a hepatic arterial infusion chemotherapy regimen, is more favorable than sorafenib as an initial treatment for locally progressed HCC. METHODS: To avoid selection bias, we corrected the data from different facilities that did or did not perform New-FP therapy. In total, 1709 consecutive patients with HCC initially treated with New-FP or sorafenib; 1624 (New-FP, n = 644; sorafenib n = 980) were assessed. After propensity score matching (PSM), overall survival (OS) and prognostic factors were assessed (n = 344 each). Additionally, the patients were categorized into four groups: cohort-1 [(without macrovascular invasion (MVI) and extrahepatic spread (EHS)], cohort-2 (with MVI), cohort-3 (with EHS), and cohort-4 (with MVI and EHS) to clarify the efficacy of each treatment. RESULTS: New-FP prolonged OS than sorafenib after PSM (New-FP, 12 months; sorafenib, 7.9 months; p < 0.001). Sorafenib treatment, and severe MVI and EHS were poor prognostic factors. In the subgroup analyses, the OS was significantly longer the New-FP group in cohort-2. CONCLUSIONS: Local treatment using New-FP is a potentially superior initial treatment compared with sorafenib as a multidisciplinary treatment in locally progressed HCC without EHS.

Randomised, multicentre prospective trial of transarterial chemoembolisation (TACE) plus sorafenib as compared with TACE alone in patients with hepatocellular carcinoma: TACTICS trial.

OBJECTIVE: This trial compared the efficacy and safety of transarterial chemoembolisation (TACE) plus sorafenib with TACE alone using a newly established TACE-specific endpoint and pre-treatment of sorafenib before initial TACE. DESIGN: Patients with unresectable hepatocellular carcinoma (HCC) were randomised to TACE plus sorafenib (n=80) or TACE alone (n=76). Patients in the combination group received sorafenib 400 mg once daily for 2-3 weeks before TACE, followed by 800 mg once daily during on-demand conventional TACE sessions until time to untreatable (unTACEable) progression (TTUP), defined as untreatable tumour progression, transient deterioration to Child-Pugh C or appearance of vascular invasion/extrahepatic spread. Co-primary endpoints were progression-free survival (PFS), which is not a conventional one but defined as TTUP, or time to any cause of death plus overall survival (OS). Multiplicity was adjusted by gatekeeping hierarchical testing. RESULTS: Median PFS was significantly longer in the TACE plus sorafenib than in the TACE alone group (25.2 vs 13.5 months; p=0.006). OS was not analysed because only 73.6% of OS events were reached. Median TTUP (26.7 vs 20.6 months; p=0.02) was also significantly longer in the TACE plus sorafenib group. OS at 1 year and 2 years in TACE plus sorafenib group and TACE alone group were 96.2% and 82.7% and 77.2% and 64.6%, respectively. There were no unexpected toxicities. CONCLUSION: TACE plus sorafenib significantly improved PFS over TACE alone in patients with unresectable HCC. Adverse events were consistent with those of previous TACE combination trials. TRIAL REGISTRATION NUMBER: NCT01217034.

Prognostic impact of transcatheter arterial chemoembolization (TACE) combined with radiofrequency ablation in patients with unresectable hepatocellular carcinoma: Comparison with TACE alone using decision-tree analysis after propensity score matching.

AIMS: The prognosis of hepatocellular carcinoma (HCC) patients treated with transcatheter arterial chemoembolization (TACE) is still poor. We aimed to evaluate the impact of TACE combined with radiofrequency ablation (TACE+RFA) on the prognosis of HCC patients using decision-tree analysis after propensity score matching. METHODS: This was a retrospective study. We enrolled 420 patients with HCC treated with TACE alone (n = 311) or TACE+RFA (n = 109) between 1998 and 2016 (median age, 72 years; male / female, 272/148; Barcelona Clinic Liver Cancer (BCLC) stage A / B, 215/205). The prognosis of patients who underwent TACE+RFA was compared to patients who underwent TACE alone after propensity score matching. Decision-tree analysis was used to investigate the profile for prognosis of the patients. RESULTS: After propensity score matching, there was no significant difference in age, sex, BCLC stage, or albumin-bilirubin (ALBI) score between both groups. The survival rate of the TACE+RFA group was significantly higher than the TACE alone group (median survival time [MST] 57.9 months vs. 33.1 months, P < 0.001). In a stratification analysis according to BCLC stage, the overall survival rate of the TACE+RFA group was significantly higher than the TACE alone group in BCLC stage A and B (MST 57.9 and 50.7 months vs. 39.8 and 24.5 months [P = 0.007 and 0.001], respectively). Decision-tree analysis showed that TACE+RFA was the third distinguishable factor for survival in patients with α-fetoprotein level >7 ng/mL and ALBI <-2.08. CONCLUSION: Decision-tree analysis after propensity score matching showed that TACE+RFA could prolong the survival of HCC patients compared to TACE alone.

Diffusion-weighted magnetic resonance imaging predicts malignant potential in small hepatocellular carcinoma.

BACKGROUND: Poor differentiation and microvascular invasion are indicators of poor outcome after hepatectomy for patients with small hepatocellular carcinoma (HCC). AIMS: We investigated whether gadoxetic acid-enhanced and diffusion-weighted magnetic resonance imaging (MRI) could predict these factors before hepatectomy. METHODS: Between July 2008 and April 2012, 75 patients who underwent hepatectomy for small HCCs (diameter: ≤3cm, tumor number: ≤3) were consecutively enrolled. In gadoxetic acid-enhanced MRI, the signal intensity in the tumor was corrected to that in the paraspinous muscles, and the relative enhancement was calculated. In diffusion-weighted imaging, we measured the apparent diffusion coefficient (ADC). We then investigated the correlations between relative enhancement or ADC and histological grade, microvascular invasion and recurrence-free survival. RESULTS: Poorly differentiated HCCs showed significantly lower ADC than well-differentiated and moderately differentiated HCCs. There was no significant difference in the hepatobiliary phase. Only ADC was an independent predictor of microvascular invasion, and the best cut-off point of its prediction was 1.175×10(-3)mm(2)/s. Additionally, the recurrence-free survival was significantly shorter in low-ADC group than in high-ADC group. CONCLUSION: ADC is useful for predicting poorly differentiated HCCs and microvascular invasion, and low ADC is associated with increased recurrence risk for small HCCs after hepatectomy.

The systemic inflammatory response as a prognostic factor for advanced hepatocellular carcinoma with extrahepatic metastasis.

Several indices have been proposed to evaluate the systemic inflammatory response (SIR), which has been reported to be a useful prognostic factor in various types of cancer. We investigated the usefulness of the Glasgow Prognostic Score (GPS), neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) as prognostic factors in patients with advanced hepatocellular carcinoma (HCC) with extrahepatic metastasis (stage IVB). Between April, 1997 and March, 2013, a total of 434 HCC patients who developed extrahepatic metastasis were enrolled in the present study. The GPS was defined on the basis of pretreatment C-reactive protein (CRP) and albumin (Alb) levels, and the subjects were grouped according to GPS 0-2. The NLR was calculated as the neutrophil count/lymphocyte count, and the PLR was calculated as the platelet count/lymphocyte count. A comparative examination was performed using a survival analysis with approximate median values to determine the cut-off value for both ratios. The median survival time (MST) of the 434 patients overall was 7.3 months, with cumulative survival rates of 31.8, 14.5 and 7.7% at 1, 2 and 3 years, respectively. The patient backround was as follows: The male:female ratio was 363:71, with a median age of 67.0 years (range, 15.0-92.0 years). Hepatitis B virus patients:hepatitis C virus patients:non-B, non-C hepatitis patients = 75:303:56. Child-Pugh class A:B:C = 218:153:63. As regards T stage, ≤T2:T3:T4 = 60:190:181. The median white blood cell count was 4,650/l (range, 1,400-20,500/l); the platelet count was 11.1×104/µl (range, 3.1×104-45.5×104/µl); the aspartate aminotransferase level was 40.0 U/l (range, 7.0-338.0 U/l) and the alanine aminotransferase level 64.5 U/l (range, 16.0-407.0 U/l); the α-fetoprotein level was 622.1 ng/ml (range, 1.5-3,311,794.0 ng/ml); and the des-gamma-carboxyprothrombin level was 1,285.0 mAU/ml (range, 8.0->75,000 mAU/ml). The principal sites of metastasis included the lungs (53.9%), bone (38.9%), lymph nodes (21.4%) and adrenal glands (10.1%). The survival analysis revealed that hepatic functional reserve [Child-Pugh class B+C; hazard ratio (HR)=2.055; 95% confidence interval (CI): 1.592-2.651, P<0.001], T stage (T3; HR=2.359; 95% CI: 1.648-3.376, P<0.001), AFP (≥200 ng/ml; HR=1.416; 95% CI: 1.125-1.783, P=0.003), NLR (≥3; HR=1.569; 95% CI: 1.253-1.963, P<0.001) and GPS (1+2; HR=1.410; 95% CI: 1.060-1.874, P=0.018) were independent risk factors. A total of 136 patients were included in the GPS 0 group, 169 patients in the GPS 1 group and 129 patients in the GPS 2 group. The low together with the high NLR groups comprised 217 patients. The MST was 480 days in the GPS 0 group, 154 days in the GPS 1 and 2 groups, 115 days in the high NLR group and 321 days in the low NLR group; a significant difference in survival was observed for the GPS and NLR groups. Therefore, we consider GPS and NLR to be useful prognostic factors in patients with stage IVB HCC.

Hepatic arterial infusion chemoembolization therapy for advanced hepatocellular carcinoma: multicenter phase II study.

PURPOSE: Portal vein tumor thrombosis is a critical complication in patients with hepatocellular carcinoma (HCC). This prospective multicenter trial assessed the efficacy of hepatic arterial infusion chemoembolization therapy with cisplatin suspended in lipiodol combined with 5-fluorouracil for HCC patients with portal vein tumor thrombosis. METHODS: We enrolled 52 HCC patients with portal vein tumor thrombosis. They received hepatic arterial infusion chemoembolization therapy with cisplatin suspension in lipiodol and 5-fluorouracil. The primary efficacy endpoint was progression-free survival (PFS), while the secondary endpoints were overall survival (OS), tumor response rate, safety, and tolerability. Independent factors for survival were also evaluated. RESULTS: The median PFS and OS were 8.6 and 27.0 months, respectively. Ten patients showed complete response, while 29 had partial response (response rate, 75.0 %). The median survival time of 10 patients with complete response and 29 with partial response was 32 months, while that of 15 patients with partial response who later showed disappearance of HCC following additional therapies was 50 months. Multivariate analysis identified response to treatment and disappearance of viable HCC as independent predictors of survival. The treatment was well tolerated, and the only encountered Grade 3 toxicities were thrombocytopenia and hyperbilirubinemia. CONCLUSIONS: Hepatic arterial infusion chemoembolization therapy with cisplatin suspension in lipiodol combined with 5-fluorouracil is effective treatment for unresectable HCC with portal vein tumor thrombosis.

Sorafenib for the treatment of advanced hepatocellular carcinoma with extrahepatic metastasis: a prospective multicenter cohort study.

Sorafenib, an oral multikinase inhibitor, is approved for advanced hepatocellular carcinoma (HCC) treatment. However, its therapeutic effect in advanced HCC patients with extrahepatic metastasis remains uncertain. This study aimed to prospectively assess the efficacy, safety, and survival risk factors and evaluate the prognostic impact of sorafenib treatment in advanced HCC patients with or without extrahepatic metastasis. Between May 2009 and March 2014, 312 consecutive advanced HCC patients who received sorafenib were enrolled in this study. We evaluated their characteristics and compared the clinical outcomes of those with and without extrahepatic metastasis. Of the enrolled patients, 245 (81%) received sorafenib treatment for more than 1 month, with a median duration of 3.6 months. Eighteen patients demonstrated partial response to sorafenib therapy, 127 had stable disease, and 134 had progressive disease at the first radiologic assessment. The median survival time (MST) and progression-free survival (PFS) were 10.3 and 3.6 months, respectively. Multivariate analysis identified gender, Child-Pugh class, baseline serum des-gamma-carboxy prothrombin level, and treatment duration as independent risk factors for survival. Extrahepatic metastasis was detected in 178 patients. However, the MST, PFS, and therapeutic effect were comparable between patients with and without extrahepatic metastasis. The independent risk factors for decreased overall survival in patients with extrahepatic metastasis were similar to those affecting all patients. Our results indicated that sorafenib could be administered for hepatic reserve and as long-term treatment for advanced HCC patients regardless of their extrahepatic metastasis status.

Clinical characteristics and prognostic factors for advanced hepatocellular carcinoma with extrahepatic metastasis.

Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide. The aim of this study was to evaluate whether there are differences in the clinical characteristics and survival between patients with advanced HCC with extrahepatic metastasis who received and those who did not receive previous treatment. Between April, 1998 and April, 2012, a total of 419 HCC patients with extrahepatic metastasis (81 previously untreated and 338 previously treated) were enrolled in this study. The differences in the clinical characteristics, including metastatic sites, were compared between the two groups. In addition, the prognostic predictors among all the patients and among the 81 previously untreated patients were analyzed. The distribution of the major metastatic sites was similar in the two groups; the most frequent site of extrahepatic metastasis was the lungs, followed by the bones, lymph nodes and adrenal glands. The median survival time (MST) among the 419 patients was 6.8 months. The 1-, 2-, 3- and 5-year survival rates were 31.6, 15.3, 9.5 and 2.3%, respectively. No significant differences in survival were observed between patients who received and those who did not receive previous treatment. The multivariate analysis revealed that the Child-Pugh classification, white blood cell count, neutrophil-lymphocyte ratio (NLR) and primary tumor stage were independent predictors of survival for all the patients and for the 81 previously untreated patients. Differences in the clinical characteristics of patients with advanced HCC with extrahepatic metastasis were identified between patients who received and those who did not receive previous treatment. Furthermore, intrahepatic tumor status, Child-Pugh classification, white blood cell count and NLR were demonstrated to be independent predictors of survival in HCC patients with extrahepatic metastasis.

Efficacy, safety, and survival factors for sorafenib treatment in Japanese patients with advanced hepatocellular carcinoma.

BACKGROUND: Sorafenib, an oral multikinase inhibitor, was approved for the treatment of advanced hepatocellular carcinoma (HCC), but has not been adequately evaluated for safety and effectiveness in Japanese patients with advanced HCC. AIMS: The purpose of this study was to prospectively assess the efficacy, safety, and risk factors for survival in patients with advanced HCC treated with sorafenib. METHODS: Between May 2009 and December 2010, 96 Japanese patients with advanced HCC (76 male, 20 female, mean age: 70.4 years) were treated with sorafenib. Eighty-eight patients had Child-Pugh class A, and 8 patients had Child-Pugh class B liver cirrhosis. Barcelona Clinic Liver Cancer stage B and C were found in 64 and 32 patients, respectively. RESULTS: Twelve patients demonstrated partial response to sorafenib therapy, 43 patients had stable disease, and 33 patients had progressive disease at the first radiologic assessment. The most frequent adverse events leading to discontinuation of sorafenib treatment were liver dysfunction (n = 8), hand-foot skin reaction (n = 7), and diarrhea (n = 4). The median survival time and time to progression were 11.6 and 3.2 months, respectively. By multivariate analysis, des-γ-carboxy prothrombin serum levels and duration of treatment were identified as independent risk factors for survival. CONCLUSIONS: This study showed that sorafenib was safe and useful in Japanese patients with advanced HCC. In addition, this study demonstrated that sorafenib should be administered as a long-term treatment for advanced HCC regardless of therapeutic effect and dosage.

Serum vascular endothelial growth factor as a predictor of response and survival in patients with advanced hepatocellular carcinoma undergoing hepatic arterial infusion chemotherapy.

BACKGROUND: Hepatic arterial infusion chemotherapy (HAIC) has been recognized as a useful therapeutic modality for patients with advanced hepatocellular carcinoma (HCC). The aim of this study was to investigate the association between serum vascular endothelial growth factor (VEGF) levels and the therapeutic effect of HAIC and the survival of patients undergoing HAIC. METHODS: Seventy-one patients with advanced HCC underwent HAIC through a subcutaneously implanted infusion port. One chemotherapy course consisted of low-dose cisplatin (10 mg/body on days 1-5) and 5-fluorouracil (250 mg/body on days 1-5), and 1 treatment cycle consisted of 2-3 courses of chemotherapy. Serum VEGF levels were measured with the Bio-Plex Suspension Array System (Bio-Rad Laboratories). RESULTS: The median survival time (MST) of all patients was 10.2 months, and the 1-, 2-, 3-, and 5-year survival rates were 46.5, 21.9, 12.8, and 3.7%, respectively. Of the 71 patients, 3 achieved a complete response (CR) and 22 achieved a partial response (PR) [response rate (CR + PR/71) = 35%]. The serum VEGF level (≥100 pg/mL, P = 0.026) was an independent predictor of therapeutic effect, and was positively correlated with the platelet count (r = 0.569, P < 0.001) and tumor size (r = 0.543, P < 0.001). Child-Pugh class (P = 0.046), serum VEGF level (P = 0.004), and therapeutic effect (P = 0.005) were identified by multivariate analysis as independent predictors of survival. CONCLUSIONS: These results demonstrate that the serum VEGF level in patients with advanced HCC undergoing HAIC is an important predictive factor for therapeutic effect and survival.