Kenichi Matsuo

Anatomic versus limited nonanatomic resection for solitary hepatocellular carcinoma

BACKGROUND Although anatomic liver resection is preferred when treating hepatocellular carcinoma (HCC), evidence that it improves survival when compared with an adequate nonanatomic resection is lacking. The purpose of this study was to compare the survival impact of anatomic versus nonanatomic resection in patients with solitary HCC. PATIENTS AND METHODS Clinicopathologic data were available for 125 patients who underwent hepatectomy for a solitary HCC confined to 1 or 2 Couinauds segments. These patients were divided into 2 groups based on the hepatectomy procedure: anatomic (n = 83) and nonanatomic (n = 42) resection. RESULTS No differences were detected either in the hepatic recurrence rates (P = .38) or in the overall survival rates (P = .34) between the anatomic group and the nonanatomic group. The hepatectomy procedure (anatomic vs nonanatomic resection) did not affect survival in either univariate (P = 0.34) or multivariate analysis (relative risk, 1.574; P = .22). The proportion of patients who survived after recurrence was greater in the nonanatomic (15/42) than the anatomic group (13/83; P = .049), and the median survival time after recurrence was greater in patients who underwent nonanatomic resection (991 days; range, 131-4073 days) than in patients with anatomic resection (310 days; range, 48-1887 days; P = .045). CONCLUSIONS No superiority was seen in survival when HCC was treated by anatomic resection. Maintaining adequate liver function regardless of whether the resection is anatomic or not may be of greater importance.

Activation of human multidrug resistance-1 gene promoter in response to heat shock stress

The multidrug resistance (MDR1) gene encodes a P-glycoprotein, which catalyzes the energy-dependent efflux of anticancer agents. Various environmental stresses including heat shock can induce the expression of endogenous MDR1 genes. In order to study the regulatory mechanisms of MDR1 gene expression, we have established human cancer KB cell lines which could stably integrate bacterial chloramphenicol acetyltransferase (CAT) gene driven by various lengths of the MDR1 promoter. Kst-6 has an integrated plasmid, pMDRCAT1, containing the human MDR1 promoter of -2 kilobases. The MDR1 gene promoter contains a typical heat shock element (HSE) motif located -152 bp to -178 bp from the initiation site. Heat shock at 45 degrees C for 90 min significantly induced CAT activity in Kst-6 cells. Northern blot analysis showed a 4-5 fold increase in CAT mRNA levels in Kst-6 cells. Deletion analysis of the MDR1 promoter demonstrated that the induction of CAT activity was observed in Kxh-14 cells containing a HSE-deleted MDR1 promoter construct, pMDRCAT7. However, further deletion analysis showed that heat shock could not induce CAT activity in Khp-1 cells containing -76 approximately +121 base sequence of the promoter, suggesting that a new heat shock responsible element was located at between -136 and -76. Gel shift assay showed that the heat shock factor (HSF) could bind to the HSE motif located at -152 bp to -178 bp in the MDR1 promoter. We also found that one distinct DNA-protein complex formed specifically within the MDR1 promoter region -99 to -66 was not significantly increased, but relatively more stabilized under mild denaturing condition in the nuclear extract of heat-shocked cells. In our present assay system, activation of the MDR1 promoter in response to heat shock appears to be mediated through both a new heat shock responsive element and MDR1 specific transcription factor.

Importance of Complete Pathologic Response to Prehepatectomy Chemotherapy in Treating Colorectal Cancer Metastases

Objective:We studied the influence of complete pathologic response of colorectal cancer liver metastases to prehepatectomy chemotherapy on long-term survival after hepatectomy. Summary Background Data:Although complete response seen on imaging may be a useful criterion for evaluating efficacy of chemotherapy, complete clinical response by imaging has shown limited predictive value for complete pathologic response in treating colorectal liver metastases. Methods:We retrospectively analyzed data from 63 patients who received preoperative chemotherapy and underwent hepatectomy. Results:Of 472 liver metastases evaluated, 86 were no more visible from images after chemotherapy. We excluded 14 of these metastasis treated with local ablation. Of the remaining 72 metastasis, 22 (30.6%) were microscopically persistent metastases or recurrences in situ. Liver metastases with complete pathologic response had smaller diameters at diagnosis than others (P < 0.001), and microscopic cancer deposits surrounding macroscopic tumors were less frequent in patients with complete pathologic response than others (P < 0.05). Outcomes were favorable in patients whose liver metastases all showed a complete pathologic response. Even patients with complete pathologic response in only some metastases showed higher overall and disease-free survival rates than pathologic nonresponders (P = 0.001 and P = 0.002, respectively). Presence or absence of metastases showing complete pathologic response was an independent prognostic factor (relative risk, 4.464; P = 0.0099). Conclusions:Little correlation was observed between imaging response of colorectal cancer liver metastases to chemotherapy and pathologic response. Liver surgery should be undertaken even after a complete response by imaging. Outcome after hepatectomy was favorable in patients showing complete pathologic response of least one metastasis.

Management of Massive Arterial Hemorrhage After Pancreatobiliary Surgery: Does Embolotherapy Contribute to Successful Outcome?

Massive arterial hemorrhage is, although unusual, a life-threatening complication of major pancreatobiliary surgery. Records of 351 patients who underwent major surgery for malignant pancreatobiliary disease were reviewed in this series. Thirteen patients (3.7%) experienced massive hemorrhage after surgery. Complete hemostasis by transcatheter arterial embolization (TAE) or re-laparotomy was achieved in five patients and one patient, respectively. However, 7 of 13 cases ended in fatality, which is a 54% mortality rate. Among six survivors, one underwent selective TAE for a pseudoaneurysm of the right hepatic artery (RHA). Three patients underwent TAE proximal to the proper hepatic artery (PHA): hepatic inflow was maintained by successful TAE of the gastroduodenal artery in two and via a well-developed subphrenic artery in one. One patient had TAE of the celiac axis for a pseudoaneurysm of the splenic artery (SPA), and hepatic inflow was maintained by the arcades around the pancreatic head. One patient who experienced a pseudoaneurysm of the RHA after left hemihepatectomy successfully underwent re-laparotomy, ligation of RHA, and creation of an ileocolic arterioportal shunt. In contrast, four of seven patients with fatal outcomes experienced hepatic infarction following TAE proximal to the PHA or injury of the common hepatic artery during angiography. One patient who underwent a major hepatectomy for hilar bile duct cancer had a recurrent hemorrhage after TAE of the gastroduodenal artery and experienced hepatic failure. In the two patients with a pseudoaneurysm of the SPA or the superior mesenteric artery, an emergency re-laparotomy was required to obtain hemostasis because of worsening clinical status. Selective TAE distal to PHA or in the SPA is usually successful. TAE proximal to PHA must be restricted to cases where collateral hepatic blood flow exists. Otherwise or for a pseudoaneurysm of the superior mesenteric artery, endovascular stenting, temporary creation of an ileocolic arterioportal shunt, or vascular reconstruction by re-laparotomy is an alternative.

Drug resistance to cis-diamminedichloroplatinum(II) in Chinese hamster ovary cell lines transfected with glutathione S-transferase pi gene

Establishment of Chinese hamster ovary (CHO) cell lines expressing human glutathione S-transferase-pi (GST-pi) was performed after cotransfection of pSV2-neo and human GST-pi cDNA-carrying plasmid p beta actGPi-2. About 30 G418-resistant clones were tested for their expression of GST-pi by Northern blot analysis. Two clones, beta 2-3 and beta 2-5, expressed a significant amount of GST-pi mRNA; and one clone, beta 1-1, that did not was also used for further study. Western blot analysis with anti-GST-pi antibody showed significant increases of GST-pi in beta 2-3 and beta 2-5, but not in beta 1-1. Northern blot analysis with the human GST-pi cDNA probe showed that the increase in the expression of GST-pi-mRNA in beta 2-3 and beta 2-5 was respectively 2- and 4-fold higher than that in beta 1-1. Southern blotting analysis showed that beta 1-1, beta 2-3 and beta 2-5 contained about one copy of the human GST-pi cDNA sequence. beta 2-3 and beta 2-5 were resistant to 1.4- and 3.0-fold higher doses of CDDP than CHO, respectively, but beta 1-1 was not. Increased expression of GST-pi might be associated with CDDP-resistance in CHO cells.

Relationship between intraoperative fluid administration and perioperative outcome after pancreaticoduodenectomy: results of a prospective randomized trial of acute normovolemic hemodilution compared with standard intraoperative management.

Background: Pancreaticoduodenectomy (PD) can be associated with significant blood loss and transfusion requirements, with potential adverse short- and long-term consequences. The aim of this study was to determine whether acute normovolemic hemodilution (ANH), an established blood conservation technique, reduces perioperative allogeneic transfusions in patients undergoing PD. Methods: One hundred thirty patients undergoing PD were randomized to ANH or standard management (STDM). In the ANH group, intraoperative blood collection was performed to a target hemoglobin of 8.0 g/dL; crystalloid and colloid were used for volume replacement. Strict transfusion triggers were applied during and after operation. Perioperative complications were prospectively assessed and graded for severity. Results: From July 2005 to May 2009, 209 patients were registered, 79 excluded, 65 were randomized to ANH, and 65 to STD. The groups were well matched for demographic, operative, and histopathologic variables. Patients undergoing ANH received over 2 L more fluid intraoperatively (6250 mL, range 2000–11850) compared with patients undergoing STD (3900 mL, range 2000–9000) (P < 0.001). Transfusion rates were similar (ANH = 16.9%, 30 units vs STD = 18.5%, 33 units; P = 0.82), as was overall perioperative morbidity (ANH = 49.2% vs STD = 47%, P = 0.86). There was, however, a trend toward more grade-3 complications in patients undergoing ANH (32% vs 23.1% STD, P = 0.17), and complications related to the pancreatic anastomosis (leak/fistula/abscess) were significantly higher in the ANH group (21.5% vs 7.7%, P = 0.045). The intraoperative fluid volume was higher for all patients with pancreatic anastomotic complications (n = 19), regardless of randomization arm (ANH 6000 mL, range 2800–11350 mL vs STD 5000 mL, range 2000–11850 mL, P < 0.042). Conclusion: In this randomized trial of patients undergoing PD, ANH did not reduce allogeneic transfusions and resulted in more pancreatic anastomotic complications, likely related to greater intraoperative fluid administration. The benefits of ANH do not necessarily extend to all procedures, and restrictive intravenous fluid management during PD may help improve postoperative outcome.

DNA topoisomerase-targeting antitumor agents and drug resistance

A review of the chemotherapeutic agents which have been developed by targeting DNA topoisomerase I and II is presented. Camptothecins as topoisomerase I-targeting agents and newly developed topoisomerase II-targeting agents with unique properties are expected to be promising anticancer agents in the near future. An important issue is how cellular sensitivity to these agents is controlled. One approach is to establish and characterize drug-resistant human cancer cell lines, which would provide powerful tools to understand their intracellular target sites and also the mechanisms for acquirement of drug resistance to topoisomerase inhibitors. Drug resistance to topoisomerase-targeting agents appears to be closely correlated with two events, namely decreased expression and point mutation of topoisomerase genes.

Up-regulation of Urokinase-type Plasminogen Activator and its Receptor Correlates with Enhanced Invasion Activity of Human Glioma Cells Mediated by Transforming Growth Factor-α or Basic Fibroblast Growth Factor

Glioblastoma multiforme is a highly malignant tumor that is extremely refractory to therapy. One reason is its highly invasive nature into brain tissue. Metalloproteinases and their inhibitors, plasminogen activators (PA) and their inhibitors and cathepsins are thought to be involved in invasion by tumor cells. In this study, we determined if the urokinase-type plasminogen activator (uPA) and/or the urokinase-type plasminogen activator receptor (uPAR) were responsible for the invasion activity of a human glioma cell line. We determined the invasion activity of a human glioma U251 cell line using an in vitro invasion assay system. A 2.4- to 5.8-fold increase in invasion activity was observed in the presence of basic fibroblast growth factor (bFGF) or transforming growth factor (TGF)-α. Northern blot analysis showed that bFCF and TGF-α treatment was associated with increases in cellular mRNA levels of uPA and uPAR. Zymographic activity correlated to mRNA levels of uPA and uPAR. Addition of an anti-uPAR monoclonal antibody significantly inhibited the invasion activity induced by bFGF- and TGF-α. Irsogladine, an inhibitor of uPA synthesis, also blocked the invasion activity. These observations suggest that uPA and its receptor have a role in the invasion process of human gliomas.

Results of surgical treatment for multiple (≥5 nodules) bi-lobar hepatic metastases from colorectal cancer

BackgroundThe surgery for the treatment of multiple (≥5) bi-lobar hepatic metastases from colorectal cancer is controversial. This retrospective study presents our experience in an attempt to develop reasonable treatment guidelines.MethodOne hundred sixty-one consecutive patients who underwent liver resection with curative intent were classified into three groups: H1 (unilateral), H2 (bilateral, ≤4 nodules), or H3 (bilateral, ≥5 nodules).ResultsThe overall cumulative 5-year survival rate was 46.7%. Survival was similar among patients with H1, H2, and H3 disease. Thirty-two patients with H3 disease underwent hepatectomy: straightforward hepatectomy in 12, portal vein embolization (PVE) prior to hepatectomy in eight, two-stage hepatectomy in two, and two-stage hepatectomy combined with PVE in ten. Two-stage hepatectomy with or without PVE was the standard approach in patients with synchronous liver metastases. The operating mortality in hepatectomy for H3 disease was 0%, and the morbidity was 15.2%. The overall response rate to neoadjuvant chemotherapy (NAC) was 41.7% (5/12). Patients who responded to NAC (n=5) had a better prognosis than non-responders (n=7) (P<0.05).ConclusionsExtended hepatectomy, including preoperative PVE and multi-step hepatectomy, combined with NAC, may result in a favourable prognosis, especially in patients who respond to NAC, but further studies with more patients are needed to confirm this.

Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS): Short-term outcome, functional changes in the future liver remnant, and tumor growth activity

BACKGROUND We compared clinical outcomes of associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) against those of classical 2-stage hepatectomy in treating metastatic liver disease. METHODS Short-term outcomes, serial changes in volume of the future liver remnant (FLR), functional FLR volume, and tumor growth activity during the treatment period, were compared between our first 11 consecutive patients treated with ALPPS and 54 patients treated with classical 2-stage hepatectomy. RESULTS Mortality in the ALPPS group (9%) tended to be higher than in the classical 2-stage group (2%, P = 0.341). The FLR hypertrophy ratio (FLR volume after vs. before the procedure) 1 week after the first operation in the ALPPS group (1.54 ± 0.18) exceeded that in the classical 2-stage group (1.19 ± 0.29, P = 0.005), being similar to the ratio at 3 weeks after the first procedure in the classical 2-stage group (1.40 ± 0.43). However, functional volume of the FLR in the ALPPS group 1 week after the first procedure (52.1%) tended to be smaller than that in the classical group 3 weeks after the first procedure (59.2%). CONCLUSIONS ALPPS should be used with extreme caution, giving special attention to postoperative complications and grade of functional liver regeneration.