Significance of neoadjuvant therapy for borderline resectable pancreatic cancer: a multicenter retrospective study.

PURPOSE: Neoadjuvant therapy (NAT) is increasingly used to improve the prognosis of patients with borderline resectable pancreatic cancer (BRPC) albeit with little evidence of its advantage over upfront surgical resection. We analyzed the prognostic impact of NAT on patients with BRPC in a multicenter retrospective study. METHODS: Medical data of 165 consecutive patients who underwent treatment for BRPC between January 2010 and December 2014 were collected from ten institutions. We defined BRPC according to the National Comprehensive Cancer Network guidelines, and subclassified patients according to venous invasion alone (BR-PV) and arterial invasion (BR-A). RESULTS: The rates of NAT administration and resection were 35% and 79%, respectively. There were no significant differences in resection rates and prognoses between patients in the BR-PV and BR-A subgroups. NAT did not have a significant impact on prognosis according to intention-to-treat analysis. However, in patients who underwent surgical resection, NAT was independently associated with longer overall survival (OS). The median OS of patients who underwent resection after NAT (53.7 months) was significantly longer than that of patients who underwent upfront (17.8 months) or no resection (14.9 months). The rates of superior mesenteric or portal vein invasion, lymphatic invasion, venous invasion, and lymph node metastasis were significantly lower in patients who underwent resection after NAT than in those who underwent upfront resection despite similar baseline clinical profiles. CONCLUSIONS: Resection after NAT in patients with BRPC is associated with longer OS and lower rates of both invasion to the surrounding tissues and lymph node metastasis.

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.

Adjuvant hepatic arterial infusion chemotherapy after hepatic resection of hepatocellular carcinoma with macroscopic vascular invasion.

BACKGROUND: The prognosis of hepatocellular carcinoma (HCC) with macroscopic vascular invasion is extremely poor even after hepatic resection. We aimed to clarify the efficacy of adjuvant hepatic arterial infusion chemotherapy (HAI) for HCC with vascular invasion. METHODS: A total of 73 HCC patients with macroscopic vascular invasion were divided into two groups: 38 with hepatectomy with HAI (HAI group) and 35 with hepatectomy alone (non-HAI group). From 1997 to 2007, HAI was performed via an implanted injection port. The treatment comprised three courses of weekly infusion of HAI, which comprised cisplatin (10 mg daily on days 1-5) followed by 5-fluorouracil (5-FU; 250 mg daily on days 1-5) infusion. From 2007, cisplatin (60 mg/m(2)), 5-FU (600 mg/m(2)), and a mixture of mitomycin C (3 mg/m(2)) and degradable starch microspheres were administered for two courses. RESULTS: Overall, 92 % of patients completed adjuvant HAI. In the HAI and non-HAI groups, the 5-year disease-free survival (DFS) rates were 33.1 % and 11.8 %, respectively (p = 0.029), and the 5-year overall survival (OS) rates were 46.7 % and 32.7 %, respectively (p = 0.318). Among the patients with Vp3/4 or Vv3 (n = 32) in the HAI group, the 3-year DFS and OS rates were 33.7 % and 56.8 %, respectively (p = 0.049). Those in the non-HAI group were 8.3 % and 12.0 %, respectively (p = 0.023). Cox proportional multivariate analysis for DFS revealed that HAI was an independent favorable prognostic factor in all 73 patients (hazard ratio 0.536; p = 0.029). CONCLUSIONS: Adjuvant HAI for HCC patients with vascular invasion might reduce the risk of recurrence.

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.

Safety and short-term therapeutic effects of miriplatin-lipiodol suspension in transarterial chemoembolization (TACE) for hepatocellular carcinoma.

AIM: To determine the safety and usefulness of a novel anticancer drug, miriplatin, in transarterial chemoembolization (TACE) for unresectable hepatocellular carcinoma. PATIENTS AND METHODS: Patients (n=115) who underwent TACE with miriplatin-lipiodol suspension (miriplatin group), and control patients (n=131) who underwent TACE with cisplatin-lipiodol suspension (CDDP group) took part in this study. RESULTS: The overall incidence of adverse events was significantly lower in the miriplatin group. The percentage of patients attaining treatment effect 4 in both groups was not significantly different. The proportion exhibiting a >50% decrease in positive tumor markers following TACE was significantly greater in the CDDP group for alpha-fetoprotein, but not significantly different for des-gammma-carboxy prothrombin. CONCLUSION: Miriplatin-lipiodol suspension was associated with reduced intensity of adverse events and had comparable short-term therapeutic effects to cisplatin-lipiodol suspension, thereby indicating its usefulness in TACE.