Combination gemcitabine plus S-1 versus gemcitabine plus cisplatin for advanced/recurrent biliary tract cancer: the FUGA-BT (JCOG1113) randomized phase III clinical trial.

BACKGROUND: Gemcitabine plus cisplatin (GC) is the standard treatment of advanced biliary tract cancer (BTC); however, it causes nausea, vomiting, and anorexia, and requires hydration. Gemcitabine plus S-1 (GS) reportedly has equal to, or better, efficacy and an acceptable toxicity profile. We aimed to confirm the non-inferiority of GS to GC for patients with advanced/recurrent BTC in terms of overall survival (OS). PATIENTS AND METHODS: We undertook a phase III randomized trial in 33 institutions in Japan. Eligibility criteria included chemotherapy-naïve patients with recurrent or unresectable BTC, an Eastern Cooperative Oncology Group Performance Status of 0 - 1, and adequate organ function. The calculated sample size was 350 with a one-sided α of 5%, a power of 80%, and non-inferiority margin hazard ratio (HR) of 1.155. The primary end point was OS, while the secondary end points included progression-free survival (PFS), response rate (RR), adverse events (AEs), and clinically significant AEs defined as grade ≥2 fatigue, anorexia, nausea, vomiting, oral mucositis, or diarrhea. RESULTS: Between May 2013 and March 2016, 354 patients were enrolled. GS was found to be non-inferior to GC [median OS: 13.4 months with GC and 15.1 months with GS, HR, 0.945; 90% confidence interval (CI), 0.78-1.15; P = 0.046 for non-inferiority]. The median PFS was 5.8 months with GC and 6.8 months with GS (HR 0.86; 95% CI 0.70-1.07). The RR was 32.4% with GC and 29.8% with GS. Both treatments were generally well-tolerated. Clinically significant AEs were observed in 35.1% of patients in the GC arm and 29.9% in the GS arm. CONCLUSIONS: GS, which does not require hydration, should be considered a new, convenient standard of care option for patients with advanced/recurrent BTC. CLINICAL TRIAL NUMBER: This trial has been registered with the UMIN Clinical Trials Registry (http://www.umin.ac.jp/ctr/index.htm), number UMIN000010667.

Factors predicting survival in advanced T-staged hepatocellular carcinoma patients treated with reduction hepatectomy followed by transcatheter arterial chemoembolization.

AIMS: To evaluate the efficacy of reduction hepatectomy followed by transcatheter arterial chemoembolization (TACE) for advanced T-Staged hepatocellular carcinomas (HCCs). METHODS: A retrospective analysis of 39 consecutive patients who underwent reduction hepatectomy followed by TACE for advanced T-Staged HCCs was undertaken. RESULTS: Reduction hepatectomies, including 20 major ones, were performed. After a median interval of 30 days, the hepatectomies were followed by TACE using farmorubicin. Actual overall 3-year survival after surgery was 32%. Indocyanine green R(15) > or =15%, preoperative AFP > or =2000 ng/ml, and tumour reduction rate <98% were predictive of decreased overall survival. When the three prognostic factors were used in a scoring system, with one point assigned for each factor, the 3-year survival rates of patients with scores of 0, 1, 2, and 3 were 71%, 40%, 0%, and 0% respectively. CONCLUSIONS: Reduction hepatectomy followed by TACE is effective in patients with advanced T-Staged HCCs who have none of the 3 poor prognostic factors. Reduction surgery followed by TACE is one of the options for controlling advanced T-Staged HCCs in patients who are not candidates for curative resection or TACE alone.

Importance of intra-individual variation in tumour volume of hepatic colorectal metastases.

AIMS: The efficacy of surgical resection for multiple colorectal hepatic metastases (MCHM) has been controversial. We examined the survival of patients who received surgery for MCHM and examined the factors associated with survival. METHODS: A retrospective analysis was performed of 50 consecutive patients who received hepatic resections for MCHM, defined as four or more metastatic lesions of colorectal cancer. RESULTS: Overall survival after hepatic resection for MCHM was 48% at 3years and 43% at 5years (median survival, 22.3months). Multivariate analyses revealed that a coefficient of variation (CV) in volume of hepatic metastases in each individual patient above 1.8 (P=0.01, HR=4.08, 95% CI=1.33-12.5) was the only poor prognostic factor after resection of MCHM. CONCLUSIONS: A CV in volume of hepatic metastases in each individual patient above 1.8 predicts poor survival after hepatectomy of MCHM. Thus, the CV in volume of hepatic metastases in each individual patient might be useful in planning the therapeutic strategy for patients with MCHM.

Risk of bile duct carcinogenesis after excision of extrahepatic bile ducts in pancreaticobiliary maljunction.

BACKGROUND: A reflux of pancreatic juice into the biliary tract caused by pancreaticobiliary maljunction (PBM) has been considered important in the development of biliary tract carcinogenesis in choledochal cysts. We excised extrahepatic bile ducts in patients with choledochal cysts to terminate the reflux of pancreatic juice. We investigated whether this surgery could stop the development of the residual bile duct carcinoma. METHODS: Fifty-six patients with a diagnosis of PBM with choledochal dilatation underwent surgical excision of extrahepatic bile ducts. We applied a person-year method to compare the relative risks (observed number/expected number) of biliary tract carcinoma before and after surgery. RESULTS: In 3 patients, bile duct carcinoma developed in residual dilated segments 19 years 6 months, 8 years 8 months, and 2 years 5 months, respectively, after surgery. Although the relative risk in the post-surgery group was slightly decreased by surgery, it was still high compared with that of the general population. CONCLUSIONS: The incidence of bile duct carcinoma is still high, even after excision of extrahepatic bile ducts in PBM patients with choledochal dilatation. For these patients, careful long-term follow-up is necessary, especially after operations that leave the dilated bile ducts, such as cases of Todani's type IV-A.

Inhibition of growth and invasive activity of human pancreatic cancer cells by a farnesyltransferase inhibitor, manumycin.

The effects of manumycin, a competitive farnesyltransferase (FTase) inhibitor, on pancreatic cancer cell lines with or without K-ras mutation were studied. Manumycin inhibited the growth of human pancreatic cancer cells (SUIT-2, MIA PaCa-2, AsPC-1, BxPC-3) in a dose-dependent manner. The 50% inhibitory concentration (IC50) in cell lines with a mutant K-ras gene (SUIT-2, MIA PaCa-2, AsPC-1) was lower than that in BxPC-3 with a wild-type ras. Both mitogen-activated protein kinase activity after growth stimuli and the ability for chemotactic invasion were markedly more inhibited by manumycin in SUIT-2 than in BxPC-3. These results suggest that mutated Ras is more sensitive to manumycin than the wild type. Furthermore, tumor growth and liver metastasis in nude mice inoculated with manumycin-treated SUIT-2 cells were inhibited dose dependently. Inhibition of Ras activity might be a new anticancer strategy in pancreatic cancer in which Ras plays a role.

Application of high energy shock waves to cancer treatment in combination with cisplatin and ATX-70.

BACKGROUND: The anti-tumor effects of high-energy shock waves (HESW) in combination with cisplatin (CDDP) and ATX-70, as a photosensitizer, were investigated in vitro and in vivo. METHODS: Active oxygen generation by HESW was studied by means of electron spin resonance (ESR) system. The anti-tumor effects of HESW in combination with cisplatin (CDDP) and ATX-70 was investigated in vitro and in vivo. RESULTS: HESW exposure induced singlet oxygen or hydroxyl radical. Adding ATX-70 enhanced the cell damage induced by HESW dose-dependently. Ascorbic acid inhibited the combined effect of HESW and ATX-70. Adding CDDP did not enhanced cell damage by HESW. The combined therapy of HESW, CDDP and ATX-70 showed further inhibition of tumor growth in vivo. CONCLUSIONS: These results indicate that HESW activated ATX-70, and that the anti-tumor effect of HESW and ATX-70 was caused by active oxygen generation. HESW is able to be utilized with any other cancer treatment.

Intraductal papillary mucinous tumors of the pancreas.

BACKGROUND: An increasing number of intraductal papillary mucinous tumors of the pancreas have been reported in recent years. The indolent character and favorable prognosis of this neoplasm have been described. METHODS: Intraductal papillary mucinous tumors were classified into main duct type (n = 8) and branch type (n = 28) according to the dominant location of the tumor. This single-institute study examined the clinicopathological features and outcome after surgical resection in patients with intraductal papillary mucinous tumors. RESULTS: The gender, age, tumor size, and prognosis were quite similar for the main duct type and branch type groups. Branch type tumors were more frequently located in the head of the pancreas than were main duct type tumors. Histological examination revealed that 88% of main duct type tumors were adenocarcinomas; however, only 46% of branch type tumors were adenocarcinomas. Five-year survival rates for the patients with all main duct type tumors (n = 8), main duct type adenocarcinoma (n = 7), all branch type tumors (n = 28), and branch duct adenocarcinoma (n = 13) were 100%, 100%, 90.6%, and 90.9%, respectively. CONCLUSIONS: Intraductal papillary mucinous tumors had a favorable prognosis after surgical treatment. A curative pancreatectomy should be indicated for this localized malignant tumor.

Inferior head resection of the pancreas for intraductal papillary mucinous tumors.

BACKGROUND: Patients with intraductal papillary mucinous tumor have a favorable prognosis after surgical treatment. When this neoplasm is located in the head of the pancreas, resection has conventionally required pancreatoduodenectomy. Although pancreatoduodenectomy can now be performed with a low mortality rate, morbidity still occurs frequently. METHODS: Between November 1982 and January 1999, 38 intraductal papillary mucinous tumors of the pancreas were resected at the Chiba University Hospital. Seven patients (18%) underwent inferior head resection of the pancreas. In this preliminary study, the operative technique is presented, and its efficacy in improvement of quality of life is evaluated. RESULTS: Patients with intraductal papillary mucinous tumor underwent resection with no perioperative mortality. After discharge from hospital, 6 patients who underwent inferior head resection were still alive without recurrent disease after a median follow-up of 3 years. However, 1 patient developed peritoneal dissemination and died 18 months after inferior head resection. Patients had regained 98% of preoperative weight 1 year after inferior head resection. N-benzoyl-L-tyrosyl-p-amino-benzoic acid (BT-PABA) excretion test showed the same value before (73%) and after (73%) inferior head resection (n = 7). Pancreatic fistulas occurred more frequently after inferior head resection (38%), but the incidence of major complications was similar between inferior head resection and other types of pancreatic head resection. CONCLUSIONS: Pancreatic function was well preserved, and patients regained 98% of preoperative weight after inferior head resection of the pancreas. The authors concluded that the limited involvement of intraductal papillary mucinous tumors enables the surgeons to perform inferior head resection of the pancreas.

Spatial assessment by magnetic resonance cholangiopancreatography for preoperative imaging in partial pancreatic head resection.

BACKGROUND: Partial pancreatic head resection has been recommended for intraductal papillary mucinous tumor (IPMT). We report the usefulness of preoperative assessment by magnetic resonance cholangiopancreatography (MRCP) compared with endoscopic retrograde cholangiopancreatography (ERCP). METHODS: We studied 12 cases of surgically resected IPMT in the pancreatic head. The MRCP and ERCP images were interpreted, and we examined the detection rate of each imaging technique for the Wirsung duct, the Santorini duct, the entire cystic tumor, and the communication between the tumor and the ducts. RESULTS: In all cases MRCP correctly identified the entire cystic tumor, and the communication between the tumor and the pancreatic ducts was seen in 64% of cases. In contrast, the detection rate by ERCP of the entire cystic tumor and of the communication between the cystic tumor and the ducts was only 8% and 18%, respectively. CONCLUSION: MRCP clearly showed the relationship of the cystic tumor and the pancreatic ducts and was very useful for preoperative imaging for partial pancreatic head resection.

Combined therapy with radiofrequency thermal ablation and intra-arterial infusion chemotherapy for hepatic metastases from colorectal cancer.

BACKGROUND/AIMS: In this preliminary study, we investigated the efficacy of combined radiofrequency thermal ablation therapy (RFA) with hepatic arterial infusion chemotherapy (HAI) in the treatment of multiple liver metastases from colorectal cancer. METHODOLOGY: Nine patients with bilobular multiple metastases was treated. The number of nodules was 6.0 +/- 3.9 (range: 2-13), and the size was 2.1 +/- 1.0 cm (range: 0.5-4.8 cm) in diameter. RFA was performed using a RF generator operating at 460 kHz with a 15-gauge, 4-prong custom RF needle. Treatment temperature was kept at 90-110 degrees C for 5 min. 5-Fluorouracil (5-FU) was administered by weekly 750-1250 mg/body/5 h as the regimen of HAI. RESULTS: During a 15.2-month follow-up period, 6 of 9 patients survived more than 1 year. Three of the 6 survived more than 2 years. Serum CEA level in 5 patients dropped from 24.5 +/- 9.5 ng/ml to 10.3 +/- 5.5 ng/ml. Local recurrence was observed in 5 patients and new lesions in 4. Extrahepatic recurrence was observed in 5 patients. There were no serious complications but one HAI-related cerebral thrombosis. CONCLUSIONS: Combined RFA with HAI would be effective and safe. This modality provides a new option for the treatment of multiple liver metastases from colorectal cancer.

Virtual pancreatoscopy of mucin-producing pancreatic tumors.

We used computer-based virtual endoscopy techniques as a novel approach to clarify the three-dimensional (3D) surgical anatomy of the pancreas and of mucin-producing pancreatic tumors. Thirteen cases (18 lesions) of mucin-producing pancreatic tumors were investigated by virtual pancreatoscopy. Virtual endoscopic images were generated with virtual endoscopy software application on UNIX workstations. We created surface-rendered virtual endoscopic images derived from a computer reconstruction of the cross-sectional magnetic resonance imaging data. Virtual endoscopy could visualize the surfaces of the pancreatic duct and the bile duct, and also demonstrated all cystic tumors. The surfaces of malignant mucin-producing pancreatic tumors were illustrated as being more irregular than those of benign lesions. The virtual endoscopic technique could demonstrate not only a surface-rendered endoscopic image of the tumors but also a 3D reconstructed image of the pancreas. The relationship to anatomic structures located outside the surfaces is continuously maintained and displayed at the same time. Virtual pancreatoscopy was useful for surgical planning of minimally invasive resection of the pancreas.

[A case of Borrmann type 4 gastric cancer responding to sequential methotrexate and 5-fluorouracil combined with CDDP].

A case of Borrmann type 4 gastric cancer responding to sequential methotrexate and 5-fluorouracil combined with cis-diamminedichloroplatinum (CDDP) is reported. A 57-year-old woman was admitted to our hospital complaining of abdominal fullness. Upper gastrointestinal series and gastrofiberscopy revealed almost the entire stomach was involved with Borrmann type 4 cancer. Gastrectomy could not be performed because of peritoneal dissemination. However, the patient responded to sequential methotrexate and 5-fluorouracil therapy and CDDP administration. She enjoyed more than one year of hospital-free survival period and survived for almost two years.

[Hepatic protein synthesis rate as an index of hepatic functional reserve in human liver].

Hepatic protein synthesis rate (HPS) in human livers were measured to evaluate hepatic functional reserve. HPS of 34 patients who underwent operations were studied and were divided into 4 groups. Normal liver (n = 7), obstructive jaundice (n = 9), liver cirrhosis (n = 8) and other hepatic dysfunction (n = 10). HPS in normal liver was 6.9 +/- 3.0 nmol/mg wet wt./10 min. HPS in obstructive jaundice liver was 17.1 +/- 10.3, and HPS in liver cirrhosis was 47.5 +/- 17.8. There were significant differences among these three groups. HPS correlated well with cholinesterase (r = -0.6533, P less than 0.01) and ICGR15 (r = 0.7315, P less than 0.01). In 15 patients who received hepatectomy, relations between HPS and postoperative complication were studied. There were no complications in patients whose HPS were less than 20 nmol/mg wet wt./10 min. in major hepatic resection and in patient whose HPS were less than 40 in a segmentectomy. Even if HPS were elevated, the operations were safe in subsegmentectomy and partial hepatectomy. So HPS would be one of the good indices to evaluate hepatic functional reserve.