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Background: The Japanese guideline for therapeutic strategy in HCC does not recognize any benefit of preoperative chemotherapy for potentially resectable hepatocellular carcinoma (HCC), and only upfront resec tion is recommended even for an advanced HCC. Data on preoperative chemotherapy for advanced HCC is still limited. Poor prognostic factors of HCC after resection are tumor more than 5 cm in diameter, multiple lesions, and gross tumor thrombosis, which constitute UICC7 Stage IIIA and IIIB HCC. There are no prospective studies about preoperative chemotherapy in these patients., Aim: To evaluate the benefit of preoperative chemotherapy for UICC7 Stage IIIA and IIIB potentially resectable HCC., Discussion: Our recent study demonstrated that the 5-year overall survival rate (OS) of patients diagnosed as UICC7 Stage IIIA and IIIB who had received upfront resection was only 16.5%. In contrast, the 5-year OS of UICC7 Stage IIIA and IIIB initially unresectable patients who had achieved conversion from unresectable to resect able status under successful hepatic infusion chemotherapy prior to resection was as high as 61.3%. Additionally, recent studies reported transarterial chemoembolization achieved outcomes comparable with those of resection. Therefore, we believe that patients with UICC7 Stage IIIA and IIIB should be considered borderline resectable. To evaluate this hypothesis we registered the present phase II clinical trial to assess the benefit of preoperative chemo therapy followed by hepatectomy in potentially resectable UICC7 Stage IIIA and IIIB HCC patients.

Background/aim: The aim of this study was to evaluate hepatectomy cases that underwent preoperative chemotherapy to examine the relationship between the development of desmoplastic histopathological growth pattern (dHGP) and prognosis and recurrence and determine whether it is useful for evaluating preoperative chemotherapy., Patients and Methods: A total of 133 cases with hepatic metastasis for colorectal cancer that underwent surgical resection., Results: Of the 102 cases that underwent preoperative chemotherapy, 34 (33%) were determined to be dHGP positive, which was statistically significantly higher than the 2 of 31 cases (6.5%) that had not undergone preoperative chemotherapy. Regarding the 5-year recurrence-free survival, the dHGP group had a value of 50.3%, whereas the non-dHGP group had a value of 7.1%. For the 5-year overall survival, the dHGP group had a better prognosis than the non-dHGP group (57.6% vs. 37.1%, respectively), with a statistically significant difference. Univariate analysis of recurrence-free survival showed that the number of tumours, the Response Evaluation Criteria in Solid Tumors, and the presence or absence of dHGP were prognostic factors, whereas multivariate analysis showed that the presence or absence of dHGP was an independent prognostic factor. Univariate analysis of the overall survival showed that the number of tumours, the Response Evaluation Criteria in Solid Tumors, and presence or absence of dHGP were prognostic factors. Multivariate analysis showed that the presence or absence of dHGP was an independent prognostic factor., Conclusion: dHGP is useful as a new evaluation method for evaluating the efficacy of preoperative chemotherapy., (Copyright © 2023 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Several studies have reported that interferon (IFN) therapy improves the prognosis of patients with hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC), especially for patients who have achieved a sustained virological response (SVR). We retrospectively evaluated the clinicopathological outcomes of patients who acquired an SVR through IFN therapy pre- or post-hepatectomy for treatment naïve HCC., Method: Among the 305 HCV-related HCC patients entered in this study, 59 patients (SVR group) achieved an SVR after IFN therapy and received hepatectomy either after or before achieving an SVR (n=36 and n=23, respectively), while the remaining 179 patients (control group) did not receive IFN therapy, or did not achieve an SVR through IFN therapy (n=67)., Results: In the SVR group, the overall survival (OS) and disease-free survival (DFS) rates were significantly higher than in the control group. We evaluated the prognosis of patients with an SVR achieved pre- or post-hepatectomy separately. There were no significant differences in OS and DFS., Conclusion: This result suggests that the prognosis of naïve HCC may be improved by additional INF therapy to achieve SVR status after hepatectomy.

Background: The anticancer drug, Lenvima (lenvatinib), has severe side effects. Therapeutic drug monitoring helps ensure its efficacy and safety. Regular and optimally timed blood sampling is tough, especially when lenvatinib is self-medicated. Microsampling using the easy to handle Microsampling Wing (MSW) may help circumvent this problem. However, current lenvatinib detection methods are not sensitive enough to detect its concentrations in microsamples (<50-250 μL). Thus, the aim of this study was 2-fold (1) develop an analytic method to estimate plasma lenvatinib concentrations in microsamples and (2) verify whether this method works on micro (5.6 μL) blood plasma samples obtained clinically through MSW from patients with unresectable hepatocellular carcinoma (HCC)., Methods: A simple, highly sensitive, and specific liquid chromatography-electrospray ionization tandem mass spectrometry method was developed. Using this novel protocol, the trough blood plasma concentration of lenvatinib was measured for both blood sampled conventionally and that using MSW. Thirty-five venous whole blood samples were obtained from 11 patients with HCC. Furthermore, the stability of lenvatinib in MSW samples during storage was evaluated., Results: The mean plasma lenvatinib concentration estimates were not significantly different between the MSW and conventional venous blood samples. CV for interday and intraday assays was low. Up to day 5, the lenvatinib concentration in the MSW samples was 85%-115% of the initial day concentration (when stored at 25°C or 4°C). The interference of endogenous matrix components in the human plasma was low., Conclusions: These results indicate that the novel mass spectrometry protocol accurately measures lenvatinib in human plasma and is reproducible. Thus, MSW could be a useful microsampling device for lenvatinib therapeutic drug monitoring in patients with HCC when used in combination with this novel liquid chromatography-electrospray ionization tandem mass spectrometry detection method., Competing Interests: M. Kikuchi, Y. Sato, T. Sato, M. Maekawa, and N. Mano received research funding from Shimadzu Corporation. Masafumi Kikuchi received JSPS KAKENHI (Grant Number JP21K06708). The remaining authors declare no conflict of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Nucleos(t)ide analogues (NAs) suppress hepatitis B virus (HBV) replication, but the risk of hepatocellular carcinoma still remains. The presence of detectable HBV DNA in the serum during NA therapies for chronic hepatitis B patients has been reported to be associated with the risk of hepatocellular carcinoma. In this study, we investigated the antiviral effect of switching from entecavir (ETV) to tenofovir alafenamide fumarate (TAF) in chronic hepatitis B patients who had detectable HBV DNA in the serum at least once within a year. Among a total of 77 cases in 7 hospitals that switched NAs from ETV to TAF, 23 patients with detectable HBV DNA in a year before switching were analyzed. When the detection frequencies of HBV DNA in the 1st and 2nd years after switching to TAF were analyzed, they were significantly lower than those in the year before switching (68.8% vs. 34.1% for the 1st year and 21.3% for the 2nd year, P < 0.001 for both). The HBsAg decline tended to be larger after switching than before (-2.5% vs. -3.0% for 1st year and -3.1% for 2nd year), but the difference was not significant. One patient died of a cardiovascular event 11 months after the treatment switch, but no adverse effects due to TAF including renal function were observed. In conclusion, it was suggested that switching from ETV to TAF might be effective to suppress the HBV DNA level further in patients whose HBV DNA is detectable, even if at a very low level.

Background/aim: Right hepatectomy and extended right hepatectomy (Rt-Hr) are identified as risk factors for the development of post-hepatectomy liver failure (PHLF). Although portal vein embolization (PVE) has made it possible to safely perform extended hepatectomy, to ensure safety, in our department, PVE is performed prior to Rt-Hr for hepatocellular carcinoma (HCC) regardless of the resection rate. This study aimed to retrospectively investigate the clinical course of PVE prior to Rt-Hr for HCC cases resected in our department and the appropriateness of our policy by clarifying complications and deaths., Patients and Methods: The target period was from 2005 to 2020. Among the HCC cases resected at our hospital, those in which PVE was performed prior to Rt-Hr were included in this study. For PHLF, the definition of the International Study Group of Liver Surgery was used. The Clavien-Dindo classification was used for postoperative complications. Perioperative mortality was defined as the overall mortality within 30 days following surgery and surgery-related deaths within 90 days following surgery., Results: A total of 79 cases were included. Rt-Hr was possible in all cases after PVE and there were no cases in which serious complications occurred after PVE. PHLF was found in 14 cases (17.7%)/5 cases (6.4%)/0 cases (0%) of Grade A/B/C, respectively. Regarding postoperative complications, there were no Grade IV, and Grade IIIa/IIIb were found in 13 cases (16.5%). There were no perioperative deaths., Conclusion: Our department's policy of performing PVE prior to all Rt-Hr was considered to be a safe and reasonable treatment strategy., (Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

A 71-year-old man who underwent laparoscopic partial liver resection for local recurrence hepatocellular carcinoma (HCC)in segment 4 one year after percutaneous radiofrequency ablation(RFA)for HCC. About 3 years after treatment, the patient showed elevation of serum level of tumor marker and a mass lesion in the round ligament on CT and EOB-MRI. We made a diagnosis of peritoneal dissemination of HCC. Laparoscopic extirpation of peritoneal dissemination using indocyanine green(ICG)imaging was performed and no other tumors were observed in the peritoneal cavity. A lesion was diagnosed as peritoneal dissemination of HCC, and postoperative course was uneventful. This patient underwent repeated RFA and partial resection for recurrence of HCC. The patient was died for intrahepatic multiple recurrence of HCC without peritoneal dissemination 25 months after extirpation of peritoneal dissemination. In the field of hepatobiliary surgery, ICG imaging can be used for the intraoperative real-time visualization of hepatic malignancies. The ICG imaging is restricted to detection of fluorescence for liver tumors 5-10 mm from the liver surface. In the detection of peritoneal dissemination, however, there are no such limitations. Laparoscopic extirpation using ICG imaging is useful for the detection of peritoneal dissemination of HCC and may improve the prognosis in selected patients.

Cisplatin (CDDP) is one of the chemotherapeutic drugs being used to treat various cancers. Although effective in many cases, as high doses of CDDP cause cytotoxic effects that may worsen patients' condition, therefore, a marker of sensitivity to CDDP is necessary to enhance the safety and efficiency of CDDP administration. This study focused on adipose most abundant 2 (APM2) to examine its potential as a marker of CDDP sensitivity. The relationship of APM2 expression with the mechanisms of CDDP resistance was examined in vitro and in vivo using hepatocellular carcinoma (HCC) cells, tissues and serum of HCC patients (n = 71) treated initially with intrahepatic arterial infusion of CDDP followed by surgical resection. The predictability of serum APM2 for CDDP sensitivity was assessed in additional 54 HCC patients and 14 gastric cancer (GC) patients. APM2 expression in CDDP-resistant HCC was significantly higher both in serum and the tissue. Bioinformatic analyses and histological analyses demonstrated upregulation of ERCC6L (DNA excision repair protein ERCC6-like) by APM2, which accounts for the degree of APM2 expression. The serum APM2 level and chemosensitivity for CDDP were assessed and cut-off value of serum APM2 for predicting the sensitivity to CDDP was determined to be 18.7 µg/mL. The value was assessed in HCC (n = 54) and GC (n = 14) patients for its predictability of CDDP sensitivity, resulted in predictive value of 77.3% and 100%, respectively. Our study demonstrated that APM2 expression is related to CDDP sensitivity and serum APM2 can be an effective biomarker of HCC and GC for determining the sensitivity to CDDP.Trial registration: This study was registered with the University Hospital Medical Information Network Clinical Trials Registry (UMIN000028487).

Background: Intrahepatic cholangiocarcinoma (ICC) is primary cancer of the liver with poor prognosis because of its high potential for recurrence and metastasis. We experienced a rare case of ICC with hematogenous metastasis to the falciform ligament. We aimed to clarify the route of metastasis to the mesentery by increasing the accuracy of preoperative imaging and establish a hepatectomy to control cancer., Case Presentation: An 85-year-old woman was referred to our hospital for a detailed study of progressively increasing liver tumors. She had no subjective symptoms. Her medical history showed hypertension, aneurysm clipping for cerebral hemorrhage, and gallstones. A detailed physical examination and laboratory data evaluation included tumor markers but did not demonstrate any abnormalities. On computed tomography scan, contrast-enhanced ultrasound, and magnetic resonance imaging with gadolinium ethoxybenzyl diethylenetriamine penta-acetic acid, the tumor appeared to be located in liver segment IV, protruding outside the liver. It appeared to contain two distinct components; we suspected ICC in the intrahepatic tumor component. Laparoscopic observation revealed that the extrahepatic lesion was an intra-falciform ligament mass; laparoscopic left hepatectomy was performed. Microscopically, the main tumor in segment IV was 15 mm in diameter and was diagnosed as moderately and poorly differentiated ICC. The tumor of the intra-falciform ligament was not continuous with the main intrahepatic nodule and was also diagnosed as ICC with extensive necrosis. There were no infiltrates in the round ligament of the liver, and several tumor thrombi were found in the small veins of the falciform ligament., Conclusions: To date, there have been a few reports of metastases of primary liver cancer to the falciform ligament. At the time of preoperative imaging and pathological diagnosis, this case was suggestive of considering that the malignant liver tumor might be suspected of metastasizing to the falciform ligament. Our case improves awareness of this pathology, which can be useful in the future when encountered by hepatic specialists and surgeons.

Background: The success of laparoscopic liver resection (LLR) depends on stable and full exposure of the parenchymal transection plane. We evaluated the efficacy of LLR using a silicone band retraction method for lesions in the anterolateral and posterosuperior segments., Methods: We retrospectively analyzed 189 consecutive patients who had undergone LLR in our hospital between July 2010 and July 2020. They were divided into 2 groups according to whether LLR was performed before (conventional group; n=64) or after (silicone band group; n=125) the introduction of the silicone band retraction method., Results: The silicone band group demonstrated significantly less blood loss than that by the conventional group. The mean operative time and the hospital stay in the silicone band group were obviously shorter than that in the conventional group. The open conversion rate and the major complication rate were significantly lower in the silicone band group than that in the conventional group., Conclusion: The silicone band retraction method is a useful approach that results in a safe LLR., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background/aim: We investigated the anti-proliferative effect of quercetin on liver cancer cell lines., Materials and Methods: Thirteen liver cancer cell lines were cultured followed by treatment with varying concentrations of quercetin (0-100 μM) or quercetin and 5-FU, and the cell viability was analysed by the MTT assay. Flow cytometry was also used to examine cell cycle progression after treatment with quercetin., Results: The addition of quercetin resulted in a dose- and time-dependent suppression of cell proliferation. In some cell lines, treatment with quercetin and 5-FU caused an additional or synergistic effect. Most cell lines displayed cell cycle arrest at different phases of the cell cycle., Conclusion: Quercetin inhibits the proliferation of liver cancer cells via induction of apoptosis and cell cycle arrest., (Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Metformin is the first-line treatment for type 2 diabetes. Inhibition of hepatic gluconeogenesis is the primary contributor to its anti-diabetic effect. Metformin inhibits complex I and α-glycerophosphate shuttle, and the resultant increase in cytoplasmic NADH/NAD + ratio diverts glucose precursors away from gluconeogenesis. These actions depend on metformin-mediated activation of AMP kinase (AMPK). Here we report on a hitherto unknown mechanism. Metformin inhibits the expression of the plasma membrane citrate transporter NaCT in HepG2 cells and decreases cellular levels of citrate. 5-Aminoimidazole-4-carboxamide ribonucleotide (AICAR), an AMPK activator, elicits a similar effect. The process involves a decrease in maximal velocity with no change in substrate affinity. The decrease in NaCT expression is associated with decreased mRNA levels. AMPK inhibits mTOR, and the mTOR inhibitor rapamycin also decreases NaCT expression. The transcription factor downstream of AMPK that is relevant to cAMP signaling is CREB; decreased levels of phospho-CREB seem to mediate the observed effects of metformin on NaCT. Citrate is known to suppress glycolysis by inhibiting phosphofructokinase-1 and activate gluconeogenesis by stimulating fructose-1,6-bisphophatase; therefore, the decrease in cellular levels of citrate would stimulate glycolysis and inhibit gluconeogenesis. These studies uncover a novel mechanism for the anti-diabetic actions of metformin.

A 65-year-old man with sigmoid colon cancer underwent sigmoidectomy, followed by 8 courses of oral S-1 as postoperative adjuvant chemotherapy. Three years and 3 months after surgery, the patient developed liver metastasis, lymphadenopathy at the root of the inferior mesenteric artery, and bilateral hydronephrosis. The left hydronephrosis was believed to be due to invasion by lymph node metastasis at the root ofthe inferior mesenteric artery. The patient underwent laparoscopic partial resection ofsegment 5 ofthe liver, excision ofthe lymph nodes at the root ofthe inferior mesenteric artery(combined resection ofthe left ureter), bilateral ureteral stent placement, and left ureteral reconstruction. The postoperative course was without complications, and he was discharged 12 days after surgery. Follow-up observation without postoperative adjuvant chemotherapy was planned, according to the patient's wishes.

Administration of chemotherapy treating hepatocellular carcinoma (HCC) is divided into hepatic arterial infusion chemotherapy (HAIC) which delivers chemotherapeutic agents directly using a catheter, and systemic chemotherapy including oral treatment. Evidence for treatment with sorafenib has emerged indicating it is an effective drug for advanced HCC. HAIC can provide high anticancer efficacy, and it is often performed on patients with advanced HCC in our country. Since various HAIC regimens exist, the efficacy of HAIC using a reservoir system was tested in patients with advanced HCC. The overall response rate was 36%, with a median survival time of 11.9 months. Patients with controlled disease at 8 weeks had Child-Pugh classification A, and no increase in AFP levels when starting early stage in treatment, which were considered to be factors that influenced therapeutic efficacy. Comparison with other HAIC regimens, and consideration of combined treatments using sorafenib and HAIC will be needed.

Splenectomy may be a treatment option in hepatocellular carcinoma (HCC) and cirrhosis when there is no potential donor for liver transplantation. We retrospectively investigated the long-term outcome of splenectomy on survival in advanced cirrhotic patients with HCC and thrombocytopenia. Between 1999 and 2009, 46 cirrhotic patients with thrombocytopenia (Child-Pugh class B or C) who underwent splenectomy for the simultaneous or secondary treatment of HCC at our institute were evaluated. The 1-, 3-, and 5-year survival rates were 93.5, 76.0, and 37.9%, respectively. Splenectomy resulted in a significant reduction in mean portal venous pressure from 21.2 to 16.8 mmHg and improvements in liver function tests such as total bilirubin, prothrombin time, platelet count, Child-Pugh score for 3 years, and albumin for 2 years. The mean frequency of treatment for HCC recurrence after surgery was 3.0 times (range 1-11). Seven patients out of 16 scheduled for Interferon (IFN) therapy after surgery achieved a sustained virological response (SVR). Multivariate analysis identified SVR after IFN therapy as an independent significant prognostic factor (Hazard ratio 0.18, 95%CI 0.03-0.65, P=0.006). Postoperative complications including liver failure (n=1), portal thrombosis (n=7), ascites (n=5), and bacterial infections (n=4) were observed in 14 patients (30%). Splenectomy can be a feasible supportive therapy for the continuation of anticancer therapy and completion of IFN therapy based on improvements in liver function and thrombocytopenia with minimum complications in patients with HCC and advanced cirrhosis with no potential donor.