Kuniya Tanaka

Liver Resection for Colorectal Metastases: The Third Hepatectomy

Objective: To determine the risk, the benefit, and the main factors of prognosis of third liver resections for recurrent colorectal metastases Summary Background Data: Recurrence following liver resection is frequent after a first as after a second hepatectomy. Second liver resections yield a similar survival to that obtained with first liver resection, but little is known about third hepatectomy. Methods: This study reports a retrospective analysis of 60 patients who underwent a third liver resection for colorectal metastases in a 16-year experience (1984–2000). Patients were identified from a prospective database that collected 615 consecutive patients who cumulated 883 hepatectomies (615 first, 199 second, 60 thirds, and 9 fourths). Third hepatic resections were compared with first and second procedures, in terms of risk and benefit for the patient. Prognostic factors of survival after third hepatic resection were determined by univariate and multivariate analysis Results: A third hepatic resection was attempted in 68 of 115 of liver recurrences following a second hepatectomy (59%) and achieved in 88% of the cases (60 of 68). There was no intraoperative mortality or postoperative deaths within the 2 months. Fifteen patients developed postoperative complications (25%), a rate similar to that of first and second hepatectomies. Overall 5-year survival was 32% and disease-free survival was 17% after the third resection. Survival compared favorably to that of patients with recurrence following a second hepatectomy who could not be operated (5% at 3 years) or who failed to be resected (15% at 2 years, P = 0.0001). It also compared favorably to that of patients who underwent only two hepatectomies (5-year survival, 27%). When estimated from the time of first hepatectomy, survival was 65% at 5 years for the 60 patients who underwent three hepatic resections. Concomitant extrahepatic tumor was treated in 16 patients (27%) by 11 abdominal procedures and 5 pulmonary resections. By multivariate analysis, tumor size >30 mm for first liver metastases, presence of extrahepatic tumor at second hepatectomy, and noncurative pattern of third liver resection were independent prognostic factors of reduced survival. Conclusions: Third hepatectomy is safe and provides an additional benefit of survival similar to that of first and second liver resections. It is worthwhile when curative and integrated into an intended multimodal strategy of tumoral eradication.

Role of neoadjuvant chemotherapy in the treatment of multiple colorectal metastases to the liver

The role of neoadjuvant chemotherapy for patients with multiple (five or more) bilobar hepatic metastases irrespective of initial resectability is still under scrutiny. The purpose of this study was to compare the outcome of hepatectomy alone with that of hepatectomy after neoadjuvant chemotherapy for multiple bilobar hepatic metastases from colorectal cancer.

Risk Factors and Management of Bile Leakage after Hepatic Resection

The aim of this study was to identify the perioperative risk factors for postoperative bile leakage after hepatic resection and to propose a treatment strategy for such leakage when it does occur. Between 1992 and 2000 a total of 313 hepatic resections without choledocojejunal anastomosis were performed at our institute. Risk factors related to bile leakage were identified with univariate analysis, and strategies were evaluated in relation to the findings of postoperative fistulography. Postoperative bile leakage developed in 17 patients (5.4%). Univariate analysis identified high risk factors as advanced age, a wide surface area of the incision (bile leakage group versus no bile leakage group: 102.1 vs. 66.4 cm2, p < 0.05), and exposure of Glisson’s sheath at the cut surface (e.g., central bisegmentectomy, S4, S8 subsegmentectomy). Groupings of patients by their postoperative fistulography results showed that patients with involvement of the proximal bile duct were slower to heal than those with no demonstrable bile duct involvement. The one patient whose fistulogram demonstrated peripheral bile duct involvement had uncontrollable leakage and required reoperation. Hepatectomies with a wide surface area and those that expose the major Glisson’s sheath present serious risk factors for bile leakage. When the fistulogram shows proximal bile duct involvement, endoscopic nasobiliary tube drainage is necessary; when the fistulogram shows peripheral bile duct involvement, reoperation is needed.

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.

Matrilysin is associated with progression of colorectal tumor

Matrilysin and gelatinase A, B mRNA expressions were examined in colorectal tumors. Matrilysin mRNA was observed exclusively in tumors, while the others were also found in normal mucosa surrounding tumors. Further analysis revealed that colorectal adenomas with severe dysplasia, not with mild dysplasia, expressed matrilysin with lower levels than cancers. The level of matrilysin mRNA expression increased with the advancement of stages of colorectal cancers, consequently a relatively higher expression was observed in liver metastatic tumors than primary tumors. These results suggest that matrilysin mRNA expression was correlated with the progression of colorectal tumors, and this enzyme may also play a role in developing metastatic tumors in liver.

Successful Fluorescence-Guided Surgery on Human Colon Cancer Patient-Derived Orthotopic Xenograft Mouse Models Using a Fluorophore-Conjugated Anti-CEA Antibody and a Portable Imaging System

BACKGROUND Fluorescence-guided surgery (FGS) can enable successful cancer surgery where bright-light surgery often cannot. There are three important issues for FGS going forward toward the clinic: (a) proper tumor labeling, (b) a simple portable imaging system for the operating room, and (c) patient-like mouse models in which to develop the technology. The present report addresses all three. MATERIALS AND METHODS Patient colon tumors were initially established subcutaneously in nonobese diabetic (NOD)/severe combined immune deficiency (SCID) mice immediately after surgery. The tumors were then harvested from NOD/SCID mice and passed orthotopically in nude mice to make patient-derived orthotopic xenograft (PDOX) models. Eight weeks after orthotopic implantation, a monoclonal anti-carcinoembryonic antigen (CEA) antibody conjugated with AlexaFluor 488 (Molecular Probes Inc., Eugene, OR) was delivered to the PDOX models as a single intravenous dose 24 hours before laparotomy. A hand-held portable fluorescence imaging device was used. RESULTS The primary tumor was clearly visible at laparotomy with the portable fluorescence imaging system. Frozen section microscopy of the resected specimen demonstrated that the anti-CEA antibody selectively labeled cancer cells in the colon cancer PDOX. The tumor was completely resected under fluorescence navigation. Histologic evaluation of the resected specimen demonstrated that cancer cells were not present in the margins, indicating successful tumor resection. The FGS animals remained tumor free for over 6 months. CONCLUSIONS The results of the present report indicate that FGS using a fluorophore-conjugated anti-CEA antibody and portable imaging system improves efficacy of resection for CEA-positive colorectal cancer. These data provide the basis for clinical trials.

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.

Hepatic Resection Combined with Portal Vein or Hepatic Artery Reconstruction for Advanced Carcinoma of the Hilar Bile Duct and Gallbladder

Hepatectomy with vascular reconstruction for biliary malignancy remains controversial. This study aimed to clarify the indications for surgery. Patients with advanced hilar bile duct cancer (HBDC) (n = 26) and gallbladder cancer (GBC) involving the hepatoduodenal ligament (n = 13) who underwent hepatectomy were enrolled. They were divided into two groups on the basis of whether vascular reconstruction was performed (HBDC, 10 yes vs. 16 no; GBC, 5 yes vs. 8 no). Portal vein (PV) reconstruction was performed on the right branch in seven patients and on the left branch in two; hepatic artery (HA) reconstruction was done on the right branch in 11 patients and on the left branch in 1. Five patients with HBDC and one with GBC underwent both PV and HA reconstruction. Patency rates were 88.0% and 83.3% for PV and HA reconstructions, respectively. Vascular reconstruction-related morbidity occurred in one patient with fatal liver failure owing to a portal thrombus and in two patients with multiple liver abscesses caused by arterial obstruction. Microsurgery eliminated reconstruction-related morbidity. Mortality in vascular reconstruction cases was 13.3% (2/15), and in those without reconstruction it was 8.3% (2/24). Curability rates (R0 and R1+R2) were 50.0% and 56.0% for HBDC and 40.0% and 62.5% for GBC, respectively. The 3-year survivals of HBDC patients were, respectively, 33% and 42%, and the 5-year survivals were 18% and 25%, whereas for GBC the 1-year survivals were 20% and 60% and the 2-year survivals 0% and 25%. Two patients with vascular involvement who underwent PV with HA reconstruction survived more than 3 years. Hepatectomy with vascular reconstruction for selected HBDC patients offers low surgical risk and increased survival by curable resection, but it is not recommended for advanced GBC.

Efficacy of Salmonella typhimurium A1-R versus chemotherapy on a pancreatic cancer patient-derived orthotopic xenograft (PDOX)

The aim of this study is to determine the efficacy of tumor‐targeting Salmonella typhimurium A1‐R (A1‐R) on pancreatic cancer patient‐derived orthotopic xenografts (PDOX). The PDOX model was originally established from a pancreatic cancer patient in SCID‐NOD mice. The pancreatic cancer PDOX was subsequently transplanted by surgical orthotopic implantation (SOI) in transgenic nude red fluorescent protein (RFP) mice in order that the PDOX stably acquired red fluorescent protein (RFP)‐expressing stroma for the purpose of imaging the tumor after passage to non‐transgenic nude mice in order to visualize tumor growth and drug efficacy. The nude mice with human pancreatic PDOX were treated with A1‐R or standard chemotherapy, including gemcitabine (GEM), which is first‐line therapy for pancreatic cancer, for comparison of efficacy. A1‐R treatment significantly reduced tumor weight, as well as tumor fluorescence area, compared to untreated control (P = 0.011), with comparable efficacy of GEM, CDDP, and 5‐FU. Histopathological response to treatment was defined according to Evanss criteria and A1‐R had increased efficacy compared to standard chemotherapy. The present report is the first to show that A1‐R is effective against a very low‐passage patient tumor, in this case, pancreatic cancer. The data of the present report suggest A1‐1 will have clinical activity in pancreatic cancer, a highly lethal and treatment‐resistant disease and may be most effectively used in combination with other agents. J. Cell. Biochem. 115: 1254–1261, 2014.