Shingi Imaoka

AXIN1 mutations in hepatocellular carcinomas, and growth suppression in cancer cells by virus-mediated transfer of AXIN1

The Wnt signalling pathway is essential for development and organogenesis. Wnt signalling stabilizes β-catenin, which accumulates in the cytoplasm, binds to T-cell factor (TCF; also known as lymphocyte enhancer-binding factor, LEF) and then upregulates downstream genes. Mutations in CTNNB1 (encoding β-catenin) or APC (adenomatous polyposis coli) have been reported in human neoplasms including colon cancers and hepatocellular carcinomas (HCCs). Because HCCs tend to show accumulation of β-catenin more often than mutations in CTNNB1 , we looked for mutations in AXIN1, encoding a key factor for Wnt signalling, in 6 HCC cell lines and 100 primary HCCs. Among the 4 cell lines and 87 HCCs in which we did not detect CTNNB1 mutations, we identified AXIN1 mutations in 3 cell lines and 6 mutations in 5 of the primary HCCs. In cell lines containing mutations in either gene, we observed increased DNA binding of TCF associated with β-catenin in nuclei. Adenovirus mediated gene transfer of wild-type AXIN1 induced apoptosis in hepatocellular and colorectal cancer cells that had accumulated β-catenin as a consequence of either APC, CTNNB1 or AXIN1 mutation, suggesting that axin may be an effective therapeutic molecule for suppressing growth of hepatocellular and colorectal cancers.

Practical usefulness of lymphatic and connective tissue clearance for the carcinoma of the pancreas head

We performed a retrospective review of 59 pancreatic resections for ductal carcinoma of the pancreas head performed between 1971 and 1983. In addition to pancreaticoduodenectomy, 37 consecutive patients (from 1971 to 1981) received lymphatic dissection adjacent to the pancreatic head (Group R1), whereas another 22 patients (from 1981 to 1983) received a wider range of lymphatic and soft tissue dissection, including the para-aortic region (Group R2). These groups did not differ with regard to operative mortality rate or background factors in the patients who tolerated operation. The 3-year cumulative survival rate was 13% in the R1 group vs. 38% in the R2 group (p < 0.05). Almost all of the deaths from cancer recurrence occurred within 3 years after operation; the cumulative rate of death from local recurrence decreased from 67 to 16% (p < 0.05) at 3 years. Among the patients with nodal involvement, there was no 3-year survivor in the Rl group, but four (27%) in the R2 group (p < 0.05) survived. Among the patients whose tumor size exceeded 4 cm with retroperitoneal invasion, there was no 3-year survivor in either group and most patients died of distant metastasis. Extended clearance of regional lymph nodes and soft tissue appears to benefit patients with ductal carcinoma of the pancreatic head whose tumor size is less than 4 cm without severe invasion to the retroperitoneal space.

A new approach to chemoembolization therapy for hepatoma using ethiodized oil, cisplatin, and gelatin sponge

This article reports on a new approach to hepatic arterial chemoembolization therapy using ethiodized oil (Lipiodol, Ultra Fluide), cisplatin, and gelatin sponge (Gelfoam, Upjohn, Kalamazoo, MI) for hepatocellular carcinoma (HCC). The anticancer effects of this therapy on 20 patients who underwent subsequent hepatic resection were evaluated mainly by histologic examination. All main tumors were reduced in size following this therapy. It is notable that in 65% of the patients the tumor size was reduced to less than 50% of that before therapy. All the values of serum α‐fetoprotein (AFP) in the patients who exhibited pretreatment levels exceeding 100 ng/ml dropped by more than 50%, and in 55% of them it fell below 20 ng/ml. The concentration of platinum in the tumor tissue was significantly higher than that in the nontumorous tissue. In 15 of 20 patients (75%), the main nodules were completely necrotic. Thirteen of the patients had daughter nodules and/or small intrahepatic metastases (Group A); nine had tumor emboli in the portal (hepatic) vein (Group B); 17 had intracapsular invasions (Group C); and ten had extracapsular invasions (Group D). The ratios of patients with completely necrotic cancer cells in Group A were nine of 13 (69%); in Group B, seven of nine (78%); in Group C, 11/17 (65%); and in Group D, four of 10 (40%). In eight of the 20 patients (40%) no viable cancer cells were recognized at any foci. Lesions other than those with extracapsular invasion could be considerably eliminated with this form of therapy. It is expected that this method will become the therapy of choice not only for palliative treatment but also for preoperative treatment.

Preoperative indications for extended pancreatectomy for locally advanced pancreas cancer involving the portal vein.

This retrospective study attempted to determine the indications for extended pancreatectomy for locally advanced carcinoma of the pancreas, in terms of postoperative prognosis. An extended pancreatectomy with portal vein or superior mesenteric vein (PV/ SMV) resection and regional lymphadenectomy was performed in 35 of 50 consecutive cancers that extended into the retroperitoneal spaces and involved the PV or SMV. Among the many background factors in the 35 resected specimens, the degree of PV/SMV invasion by the cancer was most closely associated with prognosis, despite resection of all involved PV/SMV. This factor generally correlated with the preoperative findings on the portal phase of superior mesenteric arteriograph. In 17 selected patients in whom PV/SMV invasion had been angiographically both semicircular or less and 1.2 cm (1.4 cm on the film) or less in length, the 3-year survival rate was 59%. This survival rate was significantly higher than the 29% 3-year survival rate in all 35 patients (p < 0.05). Conversely, among the 18 patients in whom invasion was angiographically either beyond semicircular or more than 1.2 cm (1.4 cm on the film) in length, there were no 1.5-year survivors, and this result was even worse than that of 15 nonresectable cases. Based on postoperative survival, the degrees of PV/SMV invasion on preoperative angiography (narrowing pattern and length) are good indicators for aggressive pancreatectomy for locally advanced pancreatic cancer.

The detection of breast carcinoma micrometastases in axillary lymph nodes by means of reverse transcriptase‐polymerase chain reaction

Background. The development of a sensitive method for the detection of breast carcinoma micrometastases in axillary lymph nodes is reported.

A novel image-guided surgery of hepatocellular carcinoma by indocyanine green fluorescence imaging navigation.

The clear delineation between tumor and normal tissue is ideal for real‐time surgical navigation imaging. We present a novel indocyanine green (ICG) fluorescence imaging technique to visualize hepatocellular carcinoma (HCC).

A Prospective Randomized Trial of the Preventive Effect of Pre‐operative Transcatheter Arterial Embolization against Recurrence of Hepatocellular Carcinoma

To clarify whether pre‐operalive transcatheter arterial embolization (TAE) improves survival after hepatectomy, a prospective randomized comparative study was done. Of a total of 115 registered patients having solitary hepatocellular carcinoma (HCC) 2 to 5 cm in diameter, 18 (15.7%) were excluded after randomization. As a result, 97 patients were chosen as subjects and divided into two groups: hepatectomy with (group A: n = 50) and without (group B: n=47) pre‐operative TAE. The period of observation of the patients who survived the surgery was between 4.0 and 6.6 years. The randomization appeared to have provided well‐balanced groups of patients and the clinico‐pathological characteristics of the two groups were quite similar. The necrotic part of the cancerous lesions, as confirmed by operative specimens, amounted to 74.8 ±33.4% (mean±SD) in group A and 6.8 ±7.2% in group B (P<0.01). However, the cancer‐free survival rates after hepatectomy in both groups showed little difference (39.1±7.0 (%±SE) and 31.1±0.1, respectively). We speculate that TAE is not effective against such HCC accessory lesions as minute intrahepatic metastasis and tumor thrombus and that pre‐operative TAE does not improve post‐operative survival.

Detection of Sentinel Node in Gastric Cancer Surgery by Indocyanine Green Fluorescence Imaging: Comparison with Infrared Imaging

BackgroundSecure methods for clinical detection of the sentinel node (SN) are in great demand to avoid unnecessary resection. This was a clinical exploration/feasibility study of a novel detection system for SN biopsy using indocyanine green (ICG) fluorescence imaging in gastric cancer surgery.MethodsSN biopsy using ICG dye was performed in three patients who had gastric cancer. ICG fluorescence images were obtained using a detection system comprising a charge-coupled device (CCD) camera with a cut filter as the detector and light emitting diodes (LED) as the light source. The nodes were also examined simultaneously by an infrared (IR) imaging videoscope.ResultsImmediately after intraoperative ICG injection, the fluorescence imaging system allowed easy visualization of the lymphatic vessels draining from the primary gastric tumor toward the lymph nodes and tracing of the moving injected dye. Some lymph vessels and nodes were hardly recognized by ICG green color or IR imaging. The ICG fluorescence system also allowed visualization of the lymph node when ICG was injected the day before surgery, similar to the radio-guided method.ConclusionsDetection of SNs in gastric cancer surgery using the ICG fluorescence imaging system is a promising novel technique and may perhaps prove useful for laparoscopic surgery.

Involvement of carbohydrate antigen sialyl Lewisx in colorectal cancer metastasis

PURPOSE: Recognition of metastatic tumor cells with distinct biochemical phenotypes predominant in the primary tumors should be useful not only for establishment of new therapeutic approaches but also for identification of highrisk or low-risk patients for relapse. We examined whether carbohydrate antigens, sialyl Lewisx (sLex) and sialyl Lewisa (sLea) are involved in colorectal cancer metastasis. METHODS: Metastatic abilities of human colon cancer cell variants that were selected for their high or low cell surface levels of sLex (KM12-HX and KM12-LX, respectively) were analyzed. Also, immunohistochemical expressions of sLex and sLea in 159 primary colorectal cancers were examined to determine the clinical significance of increased expression of these antigens. RESULTS: KM12-HX cells adhered more readily to tumor necrosis factor-α activated endothelial cells than did KM12-LX cells. Increased adhesion of KM12-HX cells to activated endothelial cells was inhibited by antibodies against E-selectin and sLex and by modification of cell surface carbohydrates. KM12-HX cells showed more invasive ability in vitro and more metastatic potential in the liver of nude mice than KM12-LX cells. Although no difference was seen in the expression of six messenger ribonucleic acids corresponding to progression or metastasis of colorectal cancer, expression of fucosyltransferase was found to be responsible for the higher expression of sLex in KM12-HX cells. Clinical records of patients showed that disease-free survival rate of patients with sLex-positive tumors was significantly poorer than that of those with sLex-negative tumors. Coxs multivariate analysis revealed that the sLex status was an independent predictive factor for disease recurrence (P = 0.004), depth of invasion (P = 0.0005), and histologic type> (P = 0.037), but sLea status, age, gender, tumor location, N stage, and vessel invasion were not. CONCLUSION: Increased expression of sLex could be involved in establishment of colorectal cancer metastasis. It appears that examining sLex expression may serve as a potent marker of the recurrence in patients with colorectal cancer.

Risk of recurrence in a long-term follow-up after surgery in 417 patients with hepatitis B- or hepatitis C-related hepatocellular carcinoma.

Objective:The aim of this study is to clarify the difference of risk of recurrence after hepatic resection between patients with hepatitis B- and hepatitis C-related hepatocellular carcinoma (HCC). Summary and Background Data:HCC is a highly recurrent carcinoma. However, consensus has not yet been reached about the relationship between hepatitis virus types and risk of recurrence in a long-term follow-up for HCC patients who underwent hepatic resection. Patients and Methods:From the beginning of January 1990 to the end of December 1999, of 469 HCC patients who underwent curative hepatic resection, 66 (14%) patients with positive hepatitis B virus surface antigen (HBs-Ag) and negative hepatitis C virus antibody (HCV-Ab) were regarded to have B-type hepatitis (HB)-related HCC (HB-HCC) and 351 (75%) with negative HBs-Ag and positive HCV-Ab were regarded to have C-type hepatitis (HC)-related HCC (HC-HCC). A clinical follow-up was performed to assess the existence of recurrence with the median follow-up periods of 11.0 and 10.1 years for HB- and HC-HCC patients, respectively. Results:The 3-, 5-, and 10-year disease-free survival (DFS) rates of HC-HCC (40%, 24%, and 12%, respectively) were significantly shorter than those of HB-HCC (57%, 54%, and 28%, respectively) (P = 0.0001). In multivariate Cox proportional hazard analysis, viral type, TNM stage, surgical margin, and Edmondsons grade were significantly associated with risk of recurrence. The risk of recurrence from the initial HCC increased to 1.93 times (95% confidence interval, 1.27–2.93) greater in HC-HCC patients than in HB-HCC patients. Conclusion:Hepatitis viral type is an independent factor for recurrence of HCC in a long-term clinical follow-up. This finding suggests that we may need a different strategy to control postoperative recurrence by the viral types in HCC patients.