Strategy for synchronous and multiple liver metastasis.

BACKGROUND/AIMS: Surgical indications for resection of synchronous metastasis from colorectal cancer (CRC) and the optimal timing of hepatectomy are still controversial and widely debated. METHODOLOGY: Synchronous and multiple metastatic liver tumors were detected in 57 patients since May 2005. Our treatment policy was to perform hepatectomy if the resection could be done with no limit on size and number of tumors. However, if curative resection could not be done, chemotherapy was begun and timing for the possibility of a radical operation was planned immediately. RESULTS: In 37 patients whose tumors were located only in the liver, primary tumor resection was performed in 16 patients and after tumor-decreasing by chemotherapy, in 7 patients. In 20 patients in whom chemotherapy was performed first, after controlling the distant metastasis, hepatectomy was performed in 3 patients and staged hepatectomy was performed in 10. Recurrence was detected after hepatectomy in 75.0% of simultaneous resection cases and in 70.0% of staged cases. In the recurrence cases, early detection after tumor resection occurred in 58.3% of the simultaneous and 14.2% of the staged. CONCLUSIONS: The present data show that neoadjuvant chemotherapy does not increase the risk of postoperative complications or the surgical difficulties of hepatectomy for colorectal metastases.

Mucinous cystic neoplasm of the pancreas in a male patient.

Mucinous cystic neoplasms (MCNs) make up a morphologic family of similar appearing tumors arising in the ovary and various extraovarian organs such as pancreas, hepatobiliary tract and mesentery. MCNs of the pancreas occur almost exclusively in women. Here, we report a rare case of MCN in a male patient. A 39-year-old man was admitted to our hospital with the chief complaint of back pain. Abdominal computed tomography revealed a multilocular cyctic mass 6.3 cm in diameter in the pancreatic tail. In addition, the outer wall and septae with calcification were demonstrated in the cystic lesion. On magnetic resonance imaging , the cystic fluid had low intensity on T1-weighted imaging and high intensity on T2-weighted imaging. Endoscopic retrograde cholangio-pancreatography (ERCP) showed neither communication between the cystic lesion and the main pancreatic duct nor encasement of the main pancreatic duct. Endoscopic ultrasonography revealed neither solid component nor thickness of the septae in the cystic lesion. Consequently, we performed distal pancreatectomy with splenectomy under the diagnosis of cystic neoplasia of the pancreas. Histopathologically, the cystic lesion showed two distinct component: an inner epithelial layer and an outer densely cellular ovarian-type stromal layer. Based on these findings, the cystic lesion was diagnosed as MCN.

Aberrant methylation of heparan sulfate glucosamine 3-O-sulfotransferase 2 genes as a biomarker in colorectal cancer.

AIM: The first aim was to determine whether hypermethylation of certain tumor related genes, including 3OST2, CHFR, RUNX3, and p16, could be detected in Japanese colorectal cancer (CRC) patients. The second was to utilize the most frequently hypermethylated genes as biomarkers for early detection of CRC. MATERIALS AND METHODS: We investigated the aberrant promoter methylation profile of 4 genes in 129 colorectal tumors and corresponding normal mucosa. For the second step, bowel lavage and blood of the main tumor drainage vein from 21 CRC patients were analyzed. RESULTS: The 3OST2 gene was the most frequently methylated (57%) and was methylated frequently (9/21, 43%) in bowel lavage but rarely (1/21; 4.7%) in the venous drainage. The concordance between 3OST2 methylation in bowel lavage and corresponding tumor samples was 71.4%. CONCLUSION: These results may show the possibility of early detection for CRC by examining 3OST2 gene methylation status in DNA extracted from stool.

Contribution of thymidylate synthase to gemcitabine therapy for advanced pancreatic cancer.

OBJECTIVES: Thymidylate synthase (TS) inhibitors activate human equilibrative nucleoside transporter 1. We evaluated the contribution of TS expression to determine a treatment method providing an effect from gemcitabine (GEM). METHODS: The expression of 5-fluorouracil (5-FU) and GEM metabolic factors (5-FU: TS, dihydropyrimidine dehydrogenase, orotate phosphoribosyltransferase; GEM: human equilibrative nucleoside transporter 1, deoxycytidine kinase, cytidine deaminase, 5'-nucleotidase) were studied in 7 pancreatic cancer cell lines by Western blotting, and drug resistance was evaluated by 3-[4,5-dimethylthiazol]-2,5-dephenyl tetrazolium bromide assay. The expression of 5-FU factors was observed immunohistochemically in resected pancreatic cancer specimens. RESULTS: Gemcitabine concentrations that inhibited colony formation by 50% correlated with TS protein expression (P = 0.0169). With a 5-FU non-growth-inhibiting dose, GEM concentrations that inhibited colony formation by 50% were significantly reduced by one fourth to one tenth. Knockout of TS expression by small interfering RNA decreased resistance to GEM in the cell lines (P = 0.0019). Immunohistochemically, TS expression related to disease-free survival time of patients treated with GEM (P = 0.0224). A high expression of 5-FU factors was detected: orotate phosphoribosyltransferase: differentiated cases (P = 0.0137), lower T factor (P = 0.0411); dihydropyrimidine dehydrogenase: nerve invasion (P = 0.0188), lymph node recurrence (P = 0.0253); TS, positive N factor (P = 0.0061). CONCLUSIONS: The expression of TS provides an alternative source of substrate for DNA synthesis and positively correlates with GEM resistance and shortened patient survival.

Liver abscess after common hepatic artery embolization for delayed hemorrhage following pancreaticoduodenectomy: a case report.

A 55-year-old man underwent pancreaticoduodenectomy for bile duct carcinoma in March 2009. The patient developed anastomotic leakage and had a short episode of hemorrhage from the drainage tubes with spontaneous disappearance. CT and upper endoscopy did not reveal the source of bleeding. A massive life-threatening hemorrhage occurred on the 18th postsurgical day. Emergency angiography showed a 2.7-cm pseudoaneurysm of the gastroduodenal artery stump, and hepatic artery embolization was performed. After embolization, an abscess appeared in segments 2/3 of the liver without involving the right lobe. We treated conservatively by drainage and antibiotics. During the course of therapy after embolization, the patient experienced several episodes of high fever but did not develop hepatic failure. On the 68th day after embolization, the abscess had penetrated to the lesser sac, which was immediately treated by percutaneous drainage. Anastomotic leakage was treated by continuous irrigation from the drain, for which complete resolution was achieved by the 34th day after embolization. The patient was discharged 101 days after embolization. Imaging and the clinical course demonstrate a unique mechanism of abscess formation after embolization.

Effect of hepatocyte growth factor on progression of liver metastasis in colorectal cancer.

BACKGROUND/AIMS: Colorectal cancer (CRC) is one of the most common cancers worldwide, and a strategy to assess and control liver metastasis will be critical to control patient prognosis. To evaluate therapeutic approaches, the biological responses associated with hepatectomy were studied with a focus on hepatocyte growth factor (HGF). METHODOLOGY: In 54 patients with metastatic liver tumors due to CRC, c-Met expression was estimated by western blotting from resected tissue specimens. Serum HGF levels were measured by an ELISA method and compared with other liver function serum factors. RESULTS: The preoperative serum level of HGF was found to be related to ICGR15, ALP, CHE and AST, but after hepatectomy, the change was not correlated with other liver function factors. From an evaluation of pre-operative liver condition using ICGR15, an increasing rate (post/pre) of AST, ALT, ALP and HGF was observed to be higher in cases with positive outcomes. In cases with normal pre-operative levels of serum HGF, the increasing rate (post/pre) of HGF after surgery was higher than in cases with abnormally high pre operative values (3.07 +/- 0.87 and 2.38 +/- 0.74, respectively; p = 0.0102). In cases where tumors recurred within 6 months (early recurrence cases), the c-Met value in tumor tissue was higher than in cases with no recurrence, even in cases where there was no tendency for an increasing rate of HGF. In addition, multiplying data serum HGF increasing rate by c-Met value in tissue was significantly higher in early recurrence cases than in cases with no recurrence, (3.96 +/- 0.62 and 3.00 +/- 1.16 respectively; p = 0.0135). A similar finding was also detected following curative operations involving multiple tumor resection (3.93 +/- 0.64 vs. 2.84 +/- 1.24 for early and no recurrence, respectively; p = 0.0147). CONCLUSION: The present study demonstrated that cancer with high c-Met expression and under high level of its ligand, HGF, led to recurrence soon after hepatectomy, leading to unfavorable patient prognosis. If pathological or biochemical factors from resected specimens could help identify patients with a high risk of relapse, innovative adjuvant chemotherapy protocols could be initiated.

Critical role of c-Met and Ki67 in progress of biliary carcinoma.

The purpose of this study was to evaluate the pattern of expression of c-Met and Ki67 in several components of biliary carcinoma. Fourteen surgically resected samples, including five intrahepatic cholangiocarcinomas, five gallbladder carcinomas, and four extrahepatic bile duct carcinomas, were subjected to immunohistochemistry with primary antibodies. In all 13 cases, intraductal neoplastic components showed diffuse staining for c-Met localized in the cell membrane, whereas 10 of the 14 cases lacked expression of c-Met in the corresponding invasive components. In four cases, invasive components composed of undifferentiated carcinoma (n = 2), signet-ring cell carcinoma (n = 1), and squamous cell carcinoma (n = 1) showed nuclear or perinuclear staining for c-Met. Conversely, 11 of the 13 cases did not express Ki67 in intraductal neoplastic components, whereas corresponding invasive components showed diffuse nuclear staining in all 14 cases. A comparison of the patterns of expression between c-Met and Ki67 at the boundary between intraductal and invasive components clearly demonstrated the complementary expression of c-Met and Ki67. Our results suggested that c-Met is involved in early events of carcinogenesis and Ki67 is involved in the formation of invasive carcinoma. However, exceptional cases were also observed, which might be associated with specificity for histologic subtypes and malignant potential.

A Case Report of Intraductal Papillary-Mucinous Neoplasm of the Pancreas Showing Morphologic Transformation during Followup Periods.

A 64-year-old man underwent MRCP for further examination of gallbladder stones and IPMN of branch-type (IPMN-Br) was pointed out. Yearly MRCP had revealed the gradual increase of the cystic components, marked dilation of the main pancreatic duct (MPD), and filling defects in the MPD. After follow-up for three years, he underwent pancreatoduodenectomy. Histologically, the dilated MPD and connecting dilated branch ducts were filled with nodular growth of tumor cells consisting of gastric-type adenoma with pyloric gland-like structures. In the MPD, a transition from gastric-type adenoma to intestinal-type carcinoma was observed. In addition, in a dilated branch duct, some components of intestinal-type carcinoma with marked arborizing structures were observed. A minimally invasion was observed around branch ducts. Immunohistochemistry revealed diffuse nuclear accumulation of PCNA and Ki67 in the tumor cells of branch dusts. Our observations suggest that the secondary infiltration to the MPD of IPMN-Br and IPMN-Br possesses malignant potential for microinvasion.

Clinical evaluation of modified reconstruction method after pancreatoduodenectomy.

BACKGROUND/AIMS: The new reconstruction procedure after pancreatoduodenectomy (PD) is described to evaluate its usefulness. METHODOLOGY: The jejunum was made for an end-to-side choledochojejunostomy, and the cut proximal jejunum for approximately 20 cm was led to the pancreatic stump for end-to-end anastomosis with telescoping. Approximately 20 cm of jejunum was created with a side-to-end anastomosis with the stomach, and end-to-side jejuno-jejunostomy for Roux-en Y reconstruction. As a postoperative course, separated loop method (SL, n=38) was evaluated by comparing pancreatogastrostomy (PG, n=31) and Imanaga method (IM, n=26). RESULTS: On SL, PG and IM cases, the high amylase level in drainage fluid was noted in 2.6%, 6.5% and 19.2%, respectively. The delayed gastric emptying was seen in PG and IM, but not in SL. Serum albumin levels were similar, but cholinesterase and total cholesterol levels were significant better in SL. CONCLUSIONS: SL method is safe for complications after PD.

Successful surgical resection for peritoneal implantation of hepatocellular carcinoma at the paracardial portion.

Peritoneal implantation from hepatocellular carcinoma has been rarely reported. It may occur at various sites. Here we present a surgically resected case of peritoneal implantation to the diaphragm from hepatocellular carcinoma. A 50-year-old woman underwent right hemihepatectomy extended to a medial part of Couinaud segment IV for hepatocellular carcinoma in May 2000. In December 2008, the elevation of alpha-phetoprotein and the appearance of a heterogeneously enhanced mass, with dimensions of 9 x 7 cm, and adjacent to the remnant liver and pericardium suggested intrahepatic recurrence with markedly enhanced growth. After transcatheter arterial embolization, surgical resection under laparotomy combined with median sternotomy was selected. Samples of pericardial fluid showed no malignancy after cytological examination. At the superior border of the tumor, the confluence of pericardium and diaphragm was displaced, but the tumor itself showed a generally expanding but not invasive growth. The resected tumor showed moderately differentiated hepatocellular carcinoma whose pathology revealed a peritoneal implantation to the diaphragm. The patient is in good health without any postoperative complications or any further sign of recurrence.

The utility of vitamin K3 (menadione) against pancreatic cancer.

BACKGROUND: To evaluate the efficacy of vitamin K3 (VK3) against pancreatic cancer, the molecular mechanism of VK3 or gemcitabine (GEM)-induced inhibition of proliferation was characterized. MATERIALS AND METHODS: The cell viability was determined using the 3-[4,5-dimethylthiazol]-2,5-diphenyl tetrazolium bromide (MTT) test method. The expressions of cellular proteins were evaluated by Western blot analysis. For morphological studies of the in vivo transplanted cancer cells, the tissues were stained with hematoxylin and eosin. RESULTS: The IC50 of VK3 for pancreatic cancer cells was calculated for 42.1 +/- 3.5 microM. Western blot analysis showed that VK3 induced rapid phosphorylation of extracellular signal-regulated kinase (ERK) and c-Jun NH2-terminal kinase (JNK) 30 minutes after application. ERK but not JNK phosphorylation was maintained for at least 12 hours. Activation of apoptosis by VK3, as shown by molecular weight shifts of the pro-activated 32-kDa form of caspase-3 and poly(ADP-ribose)polymerase (PARP) cleavage of the 112-kDa form, was found. Treatment with the thiol antioxidant, L-cysteine (>0.2 mM), completely abrogated the VK3-induced phosphorylation of ERK, but not the JNK, and inhibition of proliferation. A caspase-3 inhibitor antagonized caspase-3 activation, but had no inhibitory effect on the proliferative activity of VK3. GEM at concentrations >0.1 microg/ml was found to inhibit cell proliferation after 24 hours. GEM also induced phosphorylation of JNK, activation of caspase-3 and accumulation of cyclin B1. Local application of VK3 was found to induce extensive tumor tissue necrosis, but slight hematemesis without necrosis was observed 48 hours after GEM injection. In Western blot, ERK but not JNK phosphorylation, was clearly detected in response to VK3 injection into the tumor tissue. CONCLUSION: The action of VK3 may lead to a favorable outcome against pancreatic cancer, and the detection of ERK phosphorylation in the tissue is important for predicting this effect.

Extracellular signal-regulated kinase phosphorylation due to menadione-induced arylation mediates growth inhibition of pancreas cancer cells.

BACKGROUND: Cytotoxicity of Vitamin K3 (VK3) is indicated to have the same mechanism with oxidative stress (H(2)O(2)). In the present study, we analyzed the differences and/or similarities in the cellular responses to oxidative stress and VK3 to clarify the mechanism of growth inhibition. METHODS: Cell viability was determined by a test method with 3-[4, 5-dimethyl-thiazol]-2, 5-dephenyl tetrazolium bromide (MTT). Expressions of cellular proteins were evaluated by Western blot analysis. RESULTS: The IC50 was calculated to be 47.3 +/- 4.1 microM for VK3 and 2.2 +/- 1.2 microM for H(2)O(2). By Western blot analysis, VK3 or H(2)O(2) was shown to induce rapid phosphorylation of extracellular signal-regulated kinase (ERK), and c-Jun N-terminal kinases (JNKs). H(2)O(2)-induced phosphorylation of ERK and JNK was almost complete inhibited by more than 100-muM genistein. VK3-induced JNK phosphorylation was blocked by 100-microM genistein, but ERK phosphorylation was not inhibited completely even if 400-microM genistein was used. H(2)O(2)-induced inhibition of cell proliferation was completely blocked by 400-microM genistein, but the VK3 effect was reduced 72.8 +/- 5.4% by the same concentration of genistein. H(2)O(2)-induced JNK phosphorylation and ERK phosphorylation were inhibited by staurosporine, protein kinase C (PKC) inhibitor. VK3-induced JNK phosphorylation was also blocked, but ERK phosphorylation was not affected. Staurosporine had no effect on VK3- or H(2)O(2)-induced growth inhibition. Treatment with a non-thiol antioxidant agent, catalase, completely abrogated H(2)O(2)-induced JNK and ERK phosphorylation, but a thiol antioxidant, L: -cystein, had no effect on phosphorylation of them. The VK3-induced JNK phosphorylation was inhibited by catalase, but not L: -cystein. But ERK phosphorylation was not inhibited by catalase and was abrogated completely by the thiol antioxidant. Catalase, but not L: -cystein, blocked H(2)O(2)-induced growth inhibition, and L: -cystein, but not catalase, blocked VK3-induced effects on cell proliferation completely. CONCLUSION: VK3-induced ERK phosphorylation occurs by a different mechanism from oxidative stress, and it might have an important role to induce growth inhibition.

Clinicopathological features of hepatocellular carcinoma evaluated by vascular endothelial growth factor expression.

AIM: To evaluate the significance of the expression of vascular endothelial growth factor (VEGF), its correlation with clinicopathological variables were studied in the tissue of hepatocellular carcinoma (HCC) and surrounding liver. METHODS: In 56 samples (tumor and non-tumor liver tissue) collected from 28 patients, VEGF expression was examined by immunohistochemistry and western blot analysis. RESULTS: The value of VEGF expression by western blotting was correlated with immunohistochemical staining grade. In tumor tissue, the value of VEGF expression correlated with tumor size (P = 0.034), á-fetoprotein (P = 0.036) and protein induced by vitamin K absence-II by simple regression, and histological grade (P = 0.0132) by the unpaired t-test. The level of VEGF expression in non-tumor liver was found to correlate with the value of serum albumin (P = 0.008), cholinesterase (P = 0.012) and prothrombin activity (P = 0.046). The frequency of simple nodular type in gross appearance decreased in cases with high tumor/non-tumor (T/N) ratio (P = 0.022), and the degree of portal vein invasion progressed with an increase in the T/N ratio (P = 0.008). The T/N ratio was significantly higher in early recurrence cases (P = 0.0081). CONCLUSION: This study on the expression of VEGF might be useful to estimate the liver condition and the clinicopathological features of HCC.

Serum cytokine levels in response to hepatic cryoablation.

BACKGROUND AND OBJECTIVES: Cryogenic treatment sometimes stimulates the immune system by releasing intracellular antigens. We evaluated anti-tumor immune response by analyzing alterations in serum cytokine levels. METHODS: Percutaneous cryosurgery was performed in 13 patients with unresectable tumors. Serum levels of interleukin (IL) -4, -6, and -10, tumor necrosis factor (TNF)-alpha, and interferon (IFN)-gamma were measured by enzyme-linked immunosorbent assay (ELISA). The Th1/Th2 ratio was estimated from the IFN-gamma/IL-4 ratio. RESULTS: Levels of serum factors in the immune reaction (IR) group, in which tumor necrosis was identified not only in the treated area but also away from the treated area, were compared with those in the local effect (LE) group. Serum amyloid A (SAA), C-reactive protein (CRP), and IL-6 levels were increased in both groups after three treatments. The serum IL-10 level tended to increase with the number of treatments. Pretreatment IL-10 levels in the LE group were significantly greater than those in the IR group, and the maximum value in the LE group (59.5 +/- 13.2 pg/ml) was greater than that in the IR group (47.0 +/- 15.0 pg/ml). The TNF-alpha level was increased in the IR group. Pretreatment TNF-alpha levels and maximum levels in response to treatment were significantly greater in the IR group than in the LE group (P = 0.0313). The Th1/Th2 ratio was increased in the IR group, and the maximum ratio was significantly greater in the IR group than in the LE group. CONCLUSION: It might be possible to evaluate the appearance of immune responses to cryosurgery by monitoring serum cytokine levels.

A modified reconstruction method to prevent critical complications after pancreatoduodenectomy.

BACKGROUND/AIMS: A new method of reconstructing the pancreatic stump after pancreatoduodenectomy (PD) is necessary to improve the postoperative mortality rate. Thus, we modified the pancreatoenteric procedure to reduce anastomotic leakage from the pancreatic stump after PD, and we conducted a study to evaluate the usefulness of the new procedure on the basis of patients' postoperative condition. METHODOLOGY: We compared the postoperative condition of 21 patients who underwent PD with the new separated loop (SL) reconstruction (6 men, 11 women; mean age, 67.7+/-7.2 years) to that of 31 patients (12 men, 19 women; mean age, 66.8+/-10.3 years) who underwent PD with pancreatogastrostomy (PG). In the SL reconstruction procedure, the proximal jejunum is brought up behind the colon, and an end-to-side choledochojejunostomy is made with a single layer of interrupted sutures. Approximately 20cm of the jejunum is fitted with a fixed stomach tube for postoperative enteral feeding, and the cut proximal jejunum is positioned next to the pancreatic stump. A pancreatic tube is inserted into the lumen of the pancreatic duct and fixed without closing the pancreatic duct. Pancreatojejunostomy is achieved as an end-to-end anastomosis with the pancreatic stump telescoping into the proximal jejunum. Approximately 20cm of the jejunum is anastomosed side-to-end to the stomach, and end-to-side jejunojejunostomy is made to complete a Y-type reconstruction. Each patient's postoperative condition was also assessed on the basis of serum albumin (ALB), cholinesterase and total cholesterol (T-CHO) levels on postoperative days (PODs) 14 and 28. RESULTS: A high level of amylase in drainage fluid was noted in two (6.5%) and delayed gastric emptying in four (12.9%) of the patients in the PG group. There were no complications in the SL group. Postoperative levels of ALB on POD 14 and T-CHO on POD 28 were significantly higher than in the PG group. CONCLUSIONS: The SL method is safe and does not induce complications after PD. Our results indicate that this method may provide a favored outcome.

Ileal perforation in a patient with high spinal cord injury: report of a case.

Assessing abdominal complications in patients who have previously suffered high spinal cord injury is very difficult because the resultant loss of sensory, motor, and reflux function of the abdominal wall can mask the typical signs of acute abdomen such as tenderness, muscle rigidity, and peritoneal rebound pain. We recently diagnosed a small intestinal perforation in a 77-year-old man with a C6-7 spinal cord injury sustained 14 years earlier. The patient was correctly diagnosed as having an acute abdominal condition, despite palsy of abdominal wall sensation. An emergency laparotomy was done and a 40-cm length of affected ileum, about 180 cm distal to the Treitz ligament, including a 1-cm perforation, was resected, followed by an end-to-end anastomosis. We report this case to raise awareness of the need for appropriate diagnosis and early surgical treatment of abdominal complications in spinal-cord-injured patients.