Preoperative serum hyaluronic acid level as a prognostic factor in patients undergoing hepatic resection for hepatocellular carcinoma.

BACKGROUND: Hyaluronic acid (HA) probably plays a critical role in tumorigenesis. The clinical significance of serum HA concentration in patients with hepatocellular carcinoma (HCC) remains to be elucidated. This study analysed the relationship between preoperative serum HA levels and prognosis after hepatic resection in patients with HCC. METHODS: Consecutive patients who underwent hepatic resection for HCC between September 1999 and March 2012 were included in this retrospective study. Serum HA levels were measured within 4 weeks before surgery by an immunoturbidimetric automated latex assay. The cut-off level for preoperative serum HA was validated using a time-dependent receiver operating characteristic (ROC) curve analysis. The prognostic impact of preoperative serum HA levels was analysed using Cox proportional hazards models. RESULTS: A total of 506 patients of median age 66 years (405 men, 80·0 per cent) were analysed. The median length of follow-up was 32 months. High serum HA levels (100 ng/ml or above) were associated with shorter recurrence-free survival (P < 0·001) (hazard ratio (HR) 1·50, 95 per cent confidence interval 1·17 to 1·93; P = 0·002) and overall survival (P = 0·001) (HR 1·46, 1·03 to 2·07; P = 0·033). In patients with HCC without severe liver fibrosis, serum HA level was correlated with multiple tumours (P = 0·039), early recurrence (P = 0·033), and poor recurrence-free (P < 0·001) and overall (P = 0·024) survival. CONCLUSION: High preoperative serum HA levels predict poor prognosis in patients with HCC after hepatic resection, and may serve as a future biomarker.

CD44s signals the acquisition of the mesenchymal phenotype required for anchorage-independent cell survival in hepatocellular carcinoma.

BACKGROUND: Circulating tumour cells (CTCs) have an important role in metastatic processes, but details of their basic characteristics remain elusive. We hypothesised that CD44-expressing CTCs show a mesenchymal phenotype and high potential for survival in hepatocellular carcinoma (HCC). METHODS: Circulating CD44(+)CD90(+) cells, previously shown to be tumour-initiating cells, were sorted from human blood and their genetic characteristics were compared with those of tumour cells from primary tissues. The mechanism underlying the high survival potential of CD44-expressing cells in the circulatory system was investigated in vitro. RESULTS: CD44(+)CD90(+) cells in the blood acquired epithelial-mesenchymal transition, and CD44 expression remarkably increased from the tissue to the blood. In Li7 and HLE cells, the CD44(high) population showed higher anoikis resistance and sphere-forming ability than did the CD44(low) population. This difference was found to be attributed to the upregulation of Twist1 and Akt signal in the CD44(high) population. Twist1 knockdown showed remarkable reduction in anoikis resistance, sphere formation, and Akt signal in HLE cells. In addition, mesenchymal markers and CD44s expression were downregulated in the Twist1 knockdown. CONCLUSIONS: CD44s symbolises the acquisition of a mesenchymal phenotype regulating anchorage-independent capacity. CD44s-expressing tumour cells in peripheral blood are clinically important therapeutic targets in HCC.

Distal pancreatectomy using a no-touch isolation technique.

BACKGROUND AND AIMS: Distal pancreatectomy is the only effective treatment for cancers of the pancreatic body and tail. The recurrence rate after DP has remained high. In an effort to over-come this problem, we developed a no-touch surgical technique for DP. This is a pilot study to see if distal pancreatectomy can be technically done using a no-touch surgical technique with-out deteriorating the post-operative prognosis. PATIENTS AND METHODS: From November 2000 through May 2011, 16 pancreatic ductal adeno-carcinoma patients have been operated on using a no-touch technique by a single operator. We described the surgical technique, and we reported our preliminary experience. During the procedure, the pancreatic body and tail is neither grasped nor squeezed by the surgeon. And all drainage vessels from the pancreatic body and tail are ligated and divided during the early phase of the operation. Furthermore, for improved dissection of the retroperitoneal tissue (rightward and posterior margins), we use a hanging and clamping maneuver and dissection behind Gerota's fascia. RESULTS: In the current series, the posterior and rightward resection margins were free in all patients, although seven were positive for anterior serosal invasion. The post-operative prognosis was not deteriorated with this technique. CONCLUSION: No-touch distal pancreatectomy technique may have some theoretical advantages, which merit future investigation in randomized controlled trials.

Whole-liver graft without the retrohepatic inferior vena cava for sequential (domino) living donor liver transplantation.

Grafts used in Domino liver transplantation (LT) obtained from living donor liver transplantation (LDLT) for familial amyloid polyneuropathy (FAP) patients have been mainly used as reduced grafts. Because of small-for-size problems seen in LDLT, using whole liver grafts could improve post-LT outcome. Eight consecutive Domino LDLT using whole livers without retrohepatic inferior vena cava (IVC) from FAP patients were retrospectively analyzed. The graft weight/recipient's body weight ratio (GWRW) in the domino recipients ranged from 1.28% to 2.4% (mean: 1.52). Multiple vascular reconstructions in the whole-liver domino LT resulted in longer than usual warm ischemia time (mean: 64 min); however immediate post-operative recovery of hepatic function was uneventful. At 8-40 months after the transplant, all the FAP patients are well and all of the domino recipients are alive. Domino LT using a whole FAP liver from a LDLT for a FAP patient presents satisfactory results, even though the transplant procedure is technically complicated.

Constitutive IL-8 expression in cancer cells is associated with mutation of p53.

We previously reported that most cancer cell lines constitutively express various cytokines including IL-8. But how IL-8 gene expression is regulated in cancer cells is still unclear. p53 tumor suppressor gene plays an important role in the regulation of transcription and is mutated in cancer cell lines. We investigated whether p53 status affects the constitutive expression of IL-8 in human cancer cells. SUIT-2 and RERF-LCOK cancer cells constitutively produced high levels of IL-8 in culture medium. Both cell lines were shown to carry a p53 mutation, and constitutive NF-kappaB transcriptional activity. To analyze whether p53 status mediates IL-8 expression, the effect of wild-type p53 (wt-p53) gene transfer on activation of NF-kappaB was determined in both cell lines. ELISA showed that the IL-8 concentration in medium decreased dose dependently by transient expression of wt-p53. Western-blot analysis showed no marked change in NF-kappaB protein levels in cell nuclei. EMSA showed no repression of NF-kappaB binding activity after transient expression of wt-p53. In contrast, luciferase reporter studies indicated that transcriptional activity of NF-kappaB is suppressed by transfection of wt-p53. These results show that wt-p53 gene transfer inhibits IL-8 production and NF-kappaB transcription activity in cancer cells and suggest that constitutive IL-8 production in cancer cells is associated with mutation of p53.

Total hip arthroplasty: the relationship between posterolateral reconstruction, abductor muscle strength, and femoral offset.

PURPOSE: To evaluate the relationship between posterolateral reconstruction, abductor muscle strength, and femoral offset following total hip arthroplasty. METHODS: Of 28 patients (56 limbs) we assessed, 12 underwent posterolateral reconstruction (reconstruction group) and 16 did not (non-reconstruction group). Isometric abductor muscle strength was measured with a handheld dynamometer. Each patient's muscle strength was converted into a force to body weight ratio, and this ratio was used in the comparisons. RESULTS: The reconstruction group showed a higher value in abductor muscle strength than the non-reconstruction group (p<0.05). Significant correlation between abductor muscle strength and femoral offset was found in the reconstruction group (p=0.016; r=0.674). CONCLUSION: Posterolateral reconstruction and appropriate reconstruction of femoral offset following total hip arthroplasty are important to improve the abductor muscle strength.

[A promising new treatment strategy for advanced hepatocellular carcinoma--"multi-ablation therapy" consisting of radio-frequency ablation (RFA), microwave coagulation therapy (MCT) and ethanol injection therapy (EIT)].

We introduce a new treatment strategy (multi-ablation therapy) for advanced hepatocellular carcinoma (HCC). The therapy consists of radio-frequency ablation (RFA), microwave coagulation therapy (MCT) and ethanol injection therapy (EIT). We assessed the efficacy of the therapy in 20 patients with advanced HCCs, including 10 patients with stage III and 10 patients with stage IV. The average tumor diameter was 3.6 cm (max: 6.6 cm) and the average tumor number was 3.6 (max: 11). RFA, MCT and EIT were performed in 20, 14 and 9 cases, respectively. A percutaneous, endoscopic and open approach was applied in 2, 11 and 7 cases, respectively. The average number of times treated on initial admission was 1.1. The response rate, calculated by the tumor necrosis effect, was 100%. The cumulative two-year recurrent rate in the treated sites was 33% and the 2-year cumulative survival rate was 90%. Complications were encountered in two patients (liver failure and pyothorax). Multi-ablation therapy provides an excellent prognosis for advanced HCC patients whose condition could not be controlled with conventional therapeutic modalities.

[Lymph node excision with laparotomy and chemo-radiation therapy for a hepatocellular carcinoma patient with multiple lymph node metastases].

We reported a case of hepatocellular carcinoma (HCC) with multiple lymph node metastases. The patient was a 67-year-old male with C type liver cirrhosis. He underwent microwave coagulation therapy (MCT) for HCC (5 cm and 1.5 cm) 1.5 years before admission. Abdominal CT scan revealed a well-enhanced tumor (2 cm) in caudate lobe of the liver and excessive lymph node metastases, locating in the inferior phrenic, periportal and para-aortic area. The preoperative serum AFP and AFP-L3 levels were 41.9 ng/ml and 93.1%, respectively. At laparotomy, systematic dissection of the enlarged lymph nodes and MCT of the hepatic tumor was performed. After operation, residual inferior phrenic lymph node was treated with irradiation therapy (total 50.4 Gy). The lymph node showed complete response (CR) for about a year and the AFP-L3 level returned to the normal range. After 9 months, a supra-clavicular lymph node was detected on abdominal CT scan. Irradiation therapy (total 45 Gy) in combination with CDDP (100 mg) and 5-FU (4,000 mg) was applied. The lymph node had been assessed as partial response for 6 months. The patient lived quite well after these therapies, but died of hepatic failure 32 months after the initial operation. In conclusion, we recommend this therapeutic strategy using operative excision and chemo-radiation therapy for HCC with multiple lymph node metastases.

[A case report of advanced hepatocellular carcinoma successfully treated with surgical multi-ablation therapy based on radio-frequency thermal ablation].

We report a patient with advanced hepatocellular carcinoma (HCC) who was successfully treated with multi-ablation therapy by the surgical method of laparotomy and partial thoracotomy. A 67-year-old man, who had undergone transcatheter arterial embolization (TAE) three times for advanced HCC with hepatitis C, presented at our hospital in May 2001. Although TAE had been performed 3 times starting 2 years earlier, interventional therapy for recurrent tumors is difficult because of stenosis and obstruction of regional hepatic arteries. Computed tomography of the liver revealed five tumors in both lobes and the tumor in segment VIII presented difficulty for percutaneous ablation treatment due to its closeness to the trunk of the hepatic vein. Multi-ablation therapy consisting of radio-frequency ablation, microwave ablation and ethanol injection was selected for this patient. By laparotomy and partial thoracotomy, we performed multi-ablation therapy safely and accurately for each tumor. After this treatment, 5 tumors in both lobes showed no viability on dynamic CT and the patency of the right hepatic vein was preserved. Six months after the treatment, one remnant mass appeared in segment V. An additional two sessions of percutaneous RFA were performed for this tumor. At the end of these treatments, enhanced CT revealed no viability of the tumors, and serum alpha-fetoprotein and PIVKA-II level dropped to the normal range. This case suggests that multiple ablation therapy with a surgical method is feasible and useful in cases of advanced hepatocellular carcinoma.

[Complete response (CR) in a case of advanced hepatocellular carcinoma by percutaneous multi-ablation therapy].

A 56-year-old male patient was diagnosed with hepatocellular carcinoma by abdominal ultrasonography. The tumor was located in segment 7-1 and was 7 cm in diameter. Two transcatheter arterial chemoembolizations (TACE) were not effective. The patient had experienced more than ten fractures because of fibrous dysplasia of the bone. Laparotomy was very risky, so we decided to perform multi-ablation therapy. This therapy consists of percutaneous radiofrequency ablation (RFA) and percutaneous ethanol injection therapy (PEIT). PEIT was applied to the lesion where extrahepatic the Glisson's capsule was near the tumor. After two sessions with these therapies, the tumor with the surrounding liver parenchyma turned necrotic. A complete response was obtained and the patient has been disease-free for 6 months. We conclude that our multi-ablation therapy is effective for patients with advanced hepatocellular carcinoma who have therapeutic limitations because of some preoperative complications.

[Efficacy of local ablation therapy for liver metastasis from colorectal cancer--radiofrequency ablation and microwave coagulation therapy].

We evaluated the efficacy of local ablation therapy in 40 patients with liver metastases from colorectal cancer. Radiofrequency ablation (RFA) and/or microwave coagulation therapy (MCT) were used. Ablation therapies were performed in percutaneous, endoscopic, and operative procedures. The regional recurrence rate at the therapeutic sites was 15% (median follow-up period of 2.5 years). The average surgical margin in the operative ablation group was 11 mm. The cumulative 5-year survival rates were 37% in the local ablation, 41% in the hepatic resection, and 5% in the regional chemotherapy groups. Major complications occurred in only two patients (one biliary fistula and one liver abscess). Together these observations indicate that local ablation therapy is a radical and safe locoregional therapy that provides adequate local control and contributes to long survival.

IL-6 and IFN-gamma regulation of IL-10 production by human colon carcinoma cells.

IL-10 has been shown to play a crucial role in immunosuppression in cancer patients. We explored the regulation of IL-10 production by TNF-alpha, IL-1 beta, IL-6, IL-8, and IFN-gamma in human colon carcinoma COLO205 cells. Northern analysis revealed a marked expression of IL-10 mRNA after stimulation by IL-6, and a marginal but significant expression by TNF-alpha, IL-1 beta or IFN-gamma. No IL-10 mRNA expression was observed when cells were untreated or incubated with IL-8. IL-10 in the culture supernatants showed good agreement with mRNA expression. In addition, IFN-gamma dose-dependently inhibited this IL-6-induced production of IL-10. MTT assay revealed that low dose IFN-gamma (1-10 ng/ml) had no effect on growth of COLO205 cells, but that high dose IFN-gamma (>100 ng/ml) significantly inhibited their proliferation. Northern analysis of COLO205 cells pretreated with IFN-gamma demonstrated that the IL-6R alpha chain was down-regulated. These results suggest that, in certain colon carcinoma cells, tumor-derived IL-10 production is directly regulated by systemic or local production of pro-inflammatory cytokines, such as IL-6 and IFN-gamma.

Function for p300 and not CBP in the apoptotic response to DNA damage.

The cellular response to ionizing radiation (IR) includes the induction of apoptosis. The p300/CBP proteins possess histone acetyltransferase activity and function as transcriptional coactivators of p53. We have prepared cells deficient in p300 or CBP to define the roles of these proteins in the cellular response to DNA damage. The present results demonstrate that p300, but not CBP, contributes to IR sensitivity of cells. The results also demonstrate that IR-induced apoptosis is impaired in the p300-, but not CBP-, deficient cells. These findings indicate that p300 functions in the apoptotic response to DNA damage.

FUT-175 inhibits the production of IL-6 and IL-8 in human monocytes.

We investigated the effect of FUT-175, a serine protease inhibitor, on the production of pro-inflammatory cytokines, interleukin-6 (IL-6) and interleukin-8 (IL-8), by monocytes stimulated with lipopolysaccharide (LPS). Monocytes isolated from healthy volunteers were incubated with LPS and various concentrations of FUT-175 for 12 hours. The productions of both IL-6 and IL-8, measured by enzyme-linked immunosorbent assay, were significantly inhibited by FUT at the concentration of 1 to 100 microg/ml in a dose-dependent manner. Furthermore, the expressions of IL-6 and IL-8 mRNAs were also inhibited by FUT-175. These data suggest that FUT-175 may reduce the pathological inflammatory conditions associated with enhanced production of proinflammatory cytokines including IL-6 and IL-8.

p73 is regulated by tyrosine kinase c-Abl in the apoptotic response to DNA damage.

The protein p73 is a structural and functional homologue of the p53 tumour-suppressor protein but, unlike p53, it is not induced in response to DNA damage. The tyrosine kinase c-Abl is activated by certain DNA-damaging agents and contributes to the induction of programmed cell death (apoptosis) by p53-dependent and p53-independent mechanisms. Here we show that c-Abl binds to p73 in cells, interacting through its SH3 domain with the carboxy-terminal homo-oligomerization domain of p73. c-Abl phosphorylates p73 on a tyrosine residue at position 99 both in vitro and in cells that have been exposed to ionizing radiation. Our results show that c-Abl stimulates p73-mediated transactivation and apoptosis. This regulation of p73 by c-Abl in response to DNA damage is also demonstrated by a failure of ionizing-radiation-induced apoptosis after disruption of the c-Abl-p73 interaction. These findings show that p73 is regulated by a c-Abl-dependent mechanism and that p73 participates in the apoptotic response to DNA damage.