Surgery for Hepatocellular Carcinoma With Macroscopic Vascular Invasion in the Era of Modern Molecular Therapy.

It has been reported that patients with macroscopic vascular invasion accompanying hepatocellular carcinoma have a poor prognosis. Modern molecular therapy with multitargeted tyrosine kinase inhibitors and immune checkpoint inhibitors has shown promising results in patients with metastatic hepatocellular carcinoma; however, molecular therapy is limited to patients with Child-Pugh class A disease. This review summarizes the present status of surgical therapies, including conversion hepatectomy, for patients with MVI in the developing era of novel molecular therapy. Phase III studies showed patients with macroscopic vascular invasion had significant survival benefits from sorafenib [hazard ratio (HR)=0.68] and regorafenib (HR=0.67) versus placebo, and nivolumab (HR=0.74) versus sorafenib. Lenvatinib and atezolizumab plus bevacizumab showed marginal effects. It is currently widely assumed that molecular therapy alone will not cure the disease but that additional conversion hepatectomy will be required. A response other than progressive disease is essential but a pathological complete response is not always required. A significant randomized controlled trial has already started in China to assess the necessity for conversion hepatectomy after effective atezolizumab plus bevacizumab treatment, and the results are still awaited. According to Japanese national data, upfront hepatectomy can be recommended for patients with initially resectable disease and macroscopic vascular invasion other than for those with tumors in the main portal vein and the inferior vena cava. In addition, adequate adjuvant therapies with hepatic arterial chemotherapy and transarterial chemoembolization may be beneficial but an effective adjuvant molecular therapy is currently unavailable. In conclusion, novel molecular therapies with higher response rates customized to the oncologic characteristics of each hepatocellular carcinoma with macroscopic vascular invasion are needed to increase the likelihood of conversion surgery and improve long-term outcomes.

Hepatocyte-Specific ß-Catenin Deletion During Severe Liver Injury Provokes Cholangiocytes to Differentiate Into Hepatocytes.

Liver regeneration after injury is normally mediated by proliferation of hepatocytes, although recent studies have suggested biliary epithelial cells (BECs) can differentiate into hepatocytes during severe liver injury when hepatocyte proliferation is impaired. We investigated the effect of hepatocyte-specific ß-catenin deletion in recovery from severe liver injury and BEC-to-hepatocyte differentiation. To induce liver injury, we administered choline-deficient, ethionine-supplemented (CDE) diet to three different mouse models, the first being mice with deletion of ß-catenin in both BECs and hepatocytes (Albumin-Cre; Ctnnb1flox/flox mice). In our second model, we performed hepatocyte lineage tracing by injecting Ctnnb1flox/flox ; Rosa-stopflox/flox -EYFP mice with the adeno-associated virus serotype 8 encoding Cre recombinase under the control of the thyroid binding globulin promoter, a virus that infects only hepatocytes. Finally, we performed BEC lineage tracing via Krt19-CreERT ; Rosa-stopflox/flox -tdTomato mice. To observe BEC-to-hepatocyte differentiation, mice were allowed to recover on normal diet following CDE diet-induced liver injury. Livers were collected from all mice and analyzed by quantitative real-time polymerase chain reaction, western blotting, immunohistochemistry, and immunofluorescence. We show that mice with lack of ß-catenin in hepatocytes placed on the CDE diet develop severe liver injury with impaired hepatocyte proliferation, creating a stimulus for BECs to differentiate into hepatocytes. In particular, we use both hepatocyte and BEC lineage tracing to show that BECs differentiate into hepatocytes, which go on to repopulate the liver during long-term recovery. Conclusion: ß-catenin is important for liver regeneration after CDE diet-induced liver injury, and BEC-derived hepatocytes can permanently incorporate into the liver parenchyma to mediate liver regeneration.

Impact of surgical treatment after sorafenib therapy for advanced hepatocellular carcinoma.

BACKGROUND: For advanced hepatocellular carcinoma (HCC), surgical treatment after sorafenib induction has rarely been reported. We examined the survival benefit of additional surgical treatment in sorafenib-treated patients. METHODS: Thirty-two advanced HCC patients were given sorafenib from July 2009 to July 2012, and we statistically analyzed the relevant predictive factors of the long-term survival. The institutional review board of Kumamoto University Hospital approved this study (Approval number 1038). RESULTS: The median duration of sorafenib administration was 56.5 days (range 5-945). The cumulative overall survival rate was 44.6, 33.4, 26.0 and 17.8% at 1, 2, 3 and 5 years, respectively. The median survival time was 11.2 months. A survival of more than 3 years after the initiation of sorafenib induction was observed in seven patients, five of whom were subjected to additional surgical intervention. Additional surgery was the most significant factor predicting a survival exceeding 3 years (P < 0.0001) and represents an independent prognostic factor [hazard ratio (HR) 0.07; P = 0.01], followed by the total dose of sorafenib. The surgical interventions comprised two hepatic resections ± radiofrequency ablation, two radiofrequency ablations and one lung resection. CONCLUSIONS: A long-term survival might be obtained for select HCC patients given adequate additional surgical treatment, even after sorafenib induction.

Hepatic Resection Followed by Hepatic Arterial Infusion Chemotherapy for Hepatocellular Carcinoma with Intrahepatic Dissemination.

BACKGROUND/AIM: To investigate the utility of adjuvant hepatic arterial infusion chemotherapy (HAIC) following hepatectomy for patients with hepatocellular carcinoma (HCC) with intrahepatic dissemination (IHD) after local ablation therapy. PATIENTS AND METHODS: Twelve patients with HCC with IHD were divided into two groups: HAIC group (n=6) underwent hepatectomy followed by HAIC; and the non-HAIC group (n=6) underwent hepatectomy alone. HAIC with cisplatin and 5-fluorouracil was started within a month and was continued for a month: Results: At the first local ablation, tumors close to the major portal vein and insufficient ablation were recognized in eight (67.7%) and six (58.3%) of the patients, respectively. In the HAIC group, the 1-, 3-, and 5-year disease-free and overall survival rates were 50.0%, 16.7%, and 16.7%, and 83.3%, 83.3% and 62.5%, respectively. Three patients in the HAIC group remain alive after 10 years of follow-up. CONCLUSION: Hepatic resection with short-term postoperative HAIC may provide excellent outcomes in patients with HCC and IHD.

A long-term survivor of hilar cholangiocarcinoma with resection of recurrent peritoneal dissemination after R0 surgery: a case report.

BACKGROUND: Although hilar cholangiocarcinoma (HCCA) has a very poor prognosis, there are cases in which long-term survival is rarely obtained by multidisciplinary treatment. CASE PRESENTATION: A 61-year-old man diagnosed with HCCA was referred to our hospital. We performed an extended left hemi-hepatectomy and caudate lobectomy with extrahepatic bile duct resection. The tumor stage was T2aN0M0, stage II, based on the TNM classification, seventh edition. R0 resection was successfully performed. Adjuvant chemotherapy was not administered. After 38 months, computed tomography revealed peritoneal dissemination. The patient received chemotherapy with tegafur-gimeracil-oteracil-potassium (S-1) and gemcitabine. The peritoneal dissemination was successfully controlled for more than 50 months. During the treatment, levels of CEA and CA19-9 kept rising slowly, which was followed by bowel obstruction due to peritoneal dissemination of HCCA. The patient underwent resection of transverse colon with tumor nodules, and the tumor was pathologically diagnosed as metastasis of HCCA. Tumor markers decreased to normal levels, and the patient has been free from tumor relapse for 6 months. CONCLUSIONS: We here report a rare case of HCCA patient with recurrent peritoneal dissemination 3 years after R0 surgery which was sensitive to chemotherapy. The patient successfully received resection of peritoneal dissemination 50 months after the induction of chemotherapy and survived for 10 years.

Statin attenuates cell proliferative ability via TAZ (WWTR1) in hepatocellular carcinoma.

Diabetes and obesity are associated with non-alcoholic steatohepatitis and an increased incidence of hepatocellular carcinoma (HCC). TAZ and YAP are equivalently placed downstream effectors of the Hippo pathway with oncogenic roles in human cancers. Statins are commonly used to patients with metabolic problems as hypercholesterolemia. Statins also have anti-cancer properties, and the cross-talk between mevalonate pathway and Hippo pathway was known. The aim of this study is to confirm the statin's anti-cancer effects on HCC cells and its survival benefits in HCC patients with curative surgery. TAZ expression level in HCC cell lines was analyzed by western blot. Two cell lines (HLF and HuH1) were used in this study. Then the mechanism of statin's anti-proliferative effect was examined in HLF and HuH1 cells. In clinical setting, overall survival and recurrence-free survival (RFS) rate were examined in comparison between statin intake and statin non-intake group. The proliferation assay using four different statins (atorvastatin, pravastatin, fluvastatin, simvastatin). Simvastatin and fluvastatin showed very strong growth suppressive effects, and induced apoptosis in HLF cells, but not HuH1 cells. TAZ expression was suppressed in HLF cells by fluvastatin and simvastatin treatment. The similar change pattern was confirmed in p-ERK1/2 and ERK. In HuH1 cells, such expression change was not confirmed. In clinical setting, statin intake was significantly associated with longer RFS in the HCC patients with hepatectomy (P = 0.038). The statin had the anti-proliferative effects and induced apoptosis in HCC cells and improved the prognosis of HCC patients.

Recurrence-free survival of a hepatocellular carcinoma patient with tumor thrombosis of the inferior vena cava after treatment with sorafenib and hepatic resection.

Sorafenib (Nexabar, Bayer, Berlin, Germany), one of multikinase inhibitors, can infrequently downstage advanced hepatocellular carcinoma (HCC). There are some reports that sorafenib in combination with other modalities, such as transcatheter arterial chemoembolization (TACE) or radiation therapy, could represent a bridge to surgery. We have observed a progressive HCC case with hepatic vein tumor thrombosis proceeding to the inferior vena cava (IVC-HVTT) convert to a state of feasible curative resection after a multidisciplinary treatment which included sorafenib. The patient underwent a successful resection in consequence of this therapy. A 45-year-old male with Hepatitis B Virus-associated chronic hepatitis was diagnosed as HCC with IVC-HVTT. To obtain oncological curative resection, we performed TACE, radiation therapy followed by administration of sorafenib (800 mg per day, total 72 g). The tumor including IVC-HVTT remarkably shrank, therefore, an extended posterior sectionectomy and total removal of the IVC-HVTT was successfully performed. The operation time was 736 minutes and the amount of intraoperative hemorrhage was 805 mL. No postoperative complication occurred. Adjuvant therapy with sorafenib was started four weeks after the operation and continued for 6 months (800 mg per day, total 144 g). The patient is alive without recurrence for about 4 years from the initial therapy. Multidisciplinary therapy including sorafenib, TACE, radiation, and hepatic resection may be an effective strategy to treat HCC patients with IVC-HVTT.

Effect of branched-chain amino acid supplementation on functional liver regeneration in patients undergoing portal vein embolization and sequential hepatectomy: a randomized controlled trial.

BACKGROUND: Portal vein embolization (PVE) can decrease the resection ratio for major hepatectomy. (99m)Tc-galactosyl human serum albumin (GSA) scintigraphy is useful for evaluating quantitative functional liver volume. Branched chain amino acids (BCAAs) modulate liver function and regeneration. We analyzed the effects of BCAAs, in terms of liver function and regeneration after PVE, in combination with major hepatectomy. METHODS: This randomized controlled trial was conducted for patients receiving PVE through to complete hepatectomy from September, 2011 to June, 2013. BCAA granules were added two times a day to a conventional diet in the BCAA administration group (BCAA group). The primary end point was functional liver regeneration of the future remnant liver after PVE followed by hepatic resection. Functional liver regeneration was assessed by the liver uptake value obtained from (99m)Tc-GSA scintigraphy single-photon-emission computed tomography/computed tomography fusion images. The secondary end points were volumetric liver regeneration and changes in liver function and laboratory data. RESULTS: A BCAA group (n = 13) and a non-BCAA group (control group; n = 15) were included. The primary end point was partially met: the liver uptake value significantly increased in the BCAA group compared with the control group 6 months after hepatic resection (266.7% vs 77.6%, P = 0.04) and marginally increased after PVE (43.8% vs 17.4%, P = 0.079). Following PVE, the increment of the uptake ratio of the liver to the liver plus heart at 15 min was significantly less in the BCAA group than in the control group (0.0 and 0.01, P = 0.023). CONCLUSIONS: BCAA supplementation improved functional liver regeneration and function in patients undergoing PVE followed by major hepatic resection.

Feasibility and short-term outcome of adjuvant FOLFOX after resection of colorectal liver metastases.

BACKGROUND: The role of adjuvant chemotherapy for stage IV colorectal cancer has so far been under-investigated. The aim of this study was to assess the feasibility and short-term outcome of adjuvant chemotherapy with the FOLFOX regimen following liver resection for patients with colorectal liver metastasis (CRLM). METHODS: From May 2005 to September 2010, 86 patients with CRLM underwent hepatic resection in the Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University. Of these patients, 24 received FOLFOX4 or modified FOLFOX6 as postoperative adjuvant chemotherapy. RESULTS: Nineteen male and 5 female patients received adjuvant chemotherapy following liver resection. Twenty-one (87.5 %) of these patients completed 6 cycles of adjuvant chemotherapy. Five patients required a dose reduction due to neutropenia, and the dose intensities of oxaliplatin and 5-FU were 93.6 and 94.1 %, respectively. There were no severe adverse events from the treatments. The median follow-up period was 48.4 months. Recurrences developed in 12 patients, and 3 patients died during the follow-up period. The 3- and 5-year disease-free survival and overall survival were 51.6 and 45.1 % and 95.5 and 76.0 %, respectively. CONCLUSIONS: Adjuvant FOLFOX is feasible and might provide a good prognosis for CRLM patients who undergo liver resection.

[The possible role of sorafenib as a part of the multimodal treatment for hepatocellular carcinoma].

The role of sorafenib is unclear in multimodal treatment for hepatocellular carcinoma (HCC). We analyzed patients who underwent multimodal treatment including surgical operation for advanced HCC after administration of sorafenib. A 79- year-old man underwent extended right hepatectomy for Stage III huge HCC. Three years later, multiple recurrences observed in the liver, and an extrahepatic tumor was diagnosed. Peritoneal seeding was suspected, thus we decided to start a sorafenib administration. After 11 months, new intrahepatic lesions were detected, but extrahepatic tumor was unchanged. We considered the extrahepatic tumor was solitary and resectable, and new lesions in the liver were still treatable, then we attempted a surgical treatment with partial hepatectomy and ablation therapy. The tumor was successfully resected, and residual viable tumors were treated by radiofrequency ablation. The patient remains alive without recurrence at 7 months. We could perform a surgical treatment for another 2 patients with sorafenib treatment. These results suggested that there are cases of advance HCC in which multimodality treatment including surgical treatment can be achieved after sorafenib administration.

Histological liver injury and surgical outcome after FOLFOX followed by a hepatectomy for colorectal liver metastases in Japanese patients.

BACKGROUND: This study was performed to clarify the influence of preoperative chemotherapy on liver function and the correlation between histological hepatic injury and the postoperative outcome in patients with colorectal liver metastases who underwent a hepatic resection. METHODS: Twenty-seven patients who underwent a hepatic resection for colorectal liver metastases were included. Fifteen patients with initially unresectable colorectal liver metastases who were able to undergo a tumor resection after FOLFOX (oxaliplatin plus fluorouracil and leucovorin, with a mean number of 7.7 cycles) were compared to 12 patients who underwent a hepatectomy with no preoperative chemotherapy. The postoperative mortality, morbidity, changes in liver function tests, and pathology of the resected liver were examined. RESULTS: Preoperative FOLFOX therapy was significantly associated with the macroscopic appearance of oxaliplatin-associated blue liver (p = 0.02), and a tendency toward sinusoidal dilatation (33.3% in the FOLFOX group versus 8.3% in the no-chemotherapy group, p = 0.056). Preoperative liver function tests showed that the albumin and indocyanine green retention rate at 15 min (ICG-R15) test values were significantly worse after FOLFOX therapy; however, intraoperative events, postoperative liver function test values, and morbidity rates were similar in the two groups. There was no postoperative mortality in any of the patients. CONCLUSIONS: Although preoperative FOLFOX administration in patients with colorectal liver metastases caused macroscopic blue liver, microscopic sinusoidal dilatation in the liver parenchyma, and a significant decrease in liver function, there was no increase in the morbidity and mortality rates, in comparison to findings in patients without preoperative chemotherapy.

A new approach to percutaneous transhepatic portal embolization using ethanolamine oleate iopamidol.

PURPOSE: We aimed to examine the therapeutic efficacy of ethanolamine oleate iopamidol (EOI) as an embolic material for percutaneous transhepatic portal embolization (PTPE). METHODS: Eighty-two patients with liver tumors were treated with PTPE. Fifty-eight patients had hepatocellular carcinomas, 11 had liver metastases, and 13 had other liver tumors. A total of 55 patients (group E) were treated with 5% ethanolamine oleate after gelatin sponge administration. As a control, we evaluated 27 patients (group F) who were treated with fibrin glue and iodized oil. PTPE was mainly indicated before hepatic resection, for patients with high nontumorous volumetric resection ratios (the nontumorous volumetric resection ratio was estimated to be greater than 65% in patients with an indocyanine green retention ratio of 15 min (ICG R15) of 10% or less, and the nontumorous volumetric resection ratio was estimated to be greater than 40% in the patients with an ICG R15 of 10-20%). RESULTS: All patients were successfully treated percutaneously under local anesthesia. Balloon-occluded and ipsilateral approaches were used in 81 patients (99%) and 62 (75%) patients, respectively. The rate of insufficient embolization or recanalization was significantly lower in group E (7.3%) in comparison to group F (25.9%; p < 0.05). The volumetric resection ratios, before and after PTPE, decreased from 60 to 45% in group E and from 63 to 55% in group F. The post-PTPE resection ratio was significantly decreased in group E. Before and after PTPE, average ICG R15 values changed from 17 to 27% in group E and from 18 to 26% in group F. The complication rates in groups E and F were similar (7.3 vs. 7.4%). CONCLUSION: EOI is a safe embolic material that can be used to induce greater liver hypertrophy, in comparison to fibrin glue, in PTPE for liver tumors.

[The significance of combined treatment for hepatocellular carcinoma with partial splenic embolization and transcatheter arterial chemoembolization using IA call/lipiodol].

BACKGROUND AND AIM: Partial splenic embolization (PSE) is often performed to improve thrombocytopenia in liver cirrhotic patients. The aim of this study was to evaluate the efficacy and safety of PSE in combination with trans-catheter arterial chemoembolization (TACE) for hepatocellular carcinoma (HCC). PATIENTS AND METHODS: From January 2004 to December 2007, 8 HCC patients associated with hypersplenism caused by cirrhosis were synchronously treated with TACE and PSE. Fifteen patients with TACE alone at the same period were enrolled as a control. Follow-up examinations included a calculation of peripheral blood cells (leukocytes and platelets), liver damage, duration until recovery, and treatment-associated complications. RESULTS: Initially, there were no significant differences in sex, age, Child-Pugh grade and peripheral blood cell counts between two groups. After treatment, leukocyte and platelet counts were significantly higher in PSE combined with TACE group during the follow-up period than TACE group (p<0.01). Severe complications never occurred in both groups. CONCLUSION: PSE combined with TACE is more effective than TACE alone for patients with HCC associated with hypersplenism caused by cirrhosis.

[A long-term survival case of liver and mediastinal LN metastases from colon cancer treated with intensive multimodal therapy].

A 50-year-old man with multiple liver and mediastinal LN metastases from sigmoid colon cancer was admitted to our hospital in May 2005. In October 2002, a radical resection of the original tumor and liver metastases were performed at a previous hospital. Histologically, the tumor was diagnosed as Stage IV. He was treated with an oral anticancer agent as an adjuvant therapy. In January 2005, the CEA level was increased to 3.2 ng/ml and CT scan revealed a solitary liver metastasis. Partial resection of the liver was performed. On admission to our hospital, a systemic chemotherapy by FOLFOX4 was begun. The liver metastases showed 61% reduction in size and were judged to be PR. However, the intrathoracic lymph node size was not changed. Therefore, VATS extirpation of the mediastinal lymph node was performed. After 10 courses of FOLFOX4, abdominal CT revealed liver metastases remained to be almost the same size. In January 2006, radio frequency ablation (RFA) and partial hepatectomy were enforced and then, the tumor marker returned to normal. There were no serious adverse events or postoperative complications. He has been alive without any sign of recurrence for 42 months from the initial treatment. In conclusion, intensive combination therapies for remote metastases of colon cancer might be promising to obtain a long-term survival without ruining QOL.

[A 42-month disease free survival case of combined hepatocellular-cholangiocarcinoma with lymph node metastases treated with multimodal therapy].

Combined hepatocellular and cholangiocarcinoma (HCC-CC) is a rare type of liver cancer. We herein report a case of HCC-CC with lymph node metastases treated by multimodality therapy. The patient has been alive for more than 42 months. A 52-year-old man with a 9 cm diameter mass lesion in the liver was admitted to our hospital. The tumor was diagnosed as peripheral type of cholangiocarcinoma. Preoperative transhepatic arterial chemoenbolization (TACE) was performed. An accumulation pattern of lipiodol after TACE and an increase of serum alpha-fetoprotein led us to diagnosis of combined HCC-CC. A three segmentectomies of the liver and dissection of the local lymph nodes were performed. A histological examination of the resected specimen showed combined HCC-CC with lymph node metastases. Alpha fetoprotein, cytokeratins 7 and 19 were partially positive with immunohistochemical staining. The final diagnosis was a mixed type of combined HCC-CC. To improve a poor prognosis of combined HCC-CC, adjuvant chemotherapy with CDDP, 5 FU and radiation therapy were achieved. Fortunately, the patient is alive without any recurrence for 42 months after the operation.