External biliary drainage and liver regeneration after major hepatectomy.

BACKGROUND: Bile acid signalling and farnesoid X receptor activation are assumed to be essential for liver regeneration. This study was designed to investigate the association between serum bile acid levels and extent of liver regeneration after major hepatectomy. METHODS: Patients who underwent left- or right-sided hemihepatectomy between 2006 and 2009 at the authors' institution were eligible for inclusion. Patients were divided into two groups: those undergoing hemihepatectomy with external bile drainage by cystic duct tube (group 1) and those having hemihepatectomy without drainage (group 2). Serum bile acid levels were measured before and after hepatectomy. Computed tomography was used to calculate liver volume before hepatectomy and remnant liver volume on day 7 after surgery. RESULTS: A total of 46 patients were enrolled. Mean(s.d.) serum bile acid levels on day 3 after hemihepatectomy were significantly higher in group 2 than in group 1 (11·6(13·5) versus 2·7(2·1) µmol/l; P = 0·003). Regenerated liver volumes on day 7 after hepatectomy were significantly greater in group 2 138·1(135·9) ml versus 40·0(158·8) ml in group 1; P = 0·038). Liver regeneration volumes and rates on day 7 after hemihepatectomy were positively associated with serum bile acid levels on day 3 after hemihepatectomy (P = 0·006 and P < 0·001 respectively). The incidence of bile leakage was similar in the two groups. CONCLUSION: Initial liver regeneration after major hepatectomy was less after biliary drainage and was associated with serum bile acid levels. External biliary drainage should be used judiciously after liver resection.

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.

Effect of saw dust on borate removal from groundwater in bench-scale simulation of permeable reactive barriers including magnesium oxide.

Effective immobilization of boron in groundwater is a major challenge. Permeable reactive barrier (PRB) column tests for removal of borate have been investigated using MgO agglomerates as the primary reactive material over 40 weeks. Additionally, saw dust was also blended with MgO agglomerates to facilitate for borate removal in this system. Boron accumulation was more than 1.6 times greater in the presence of saw dust, although MgO alone performed well. Increased boron accumulation in the presence of saw dust was primarily due to higher porosity of the PRB column, decreasing the impact of secondary Mg(OH)(2) passivating layers and leaving more reactive sites on MgO agglomerates. In addition, Mg(2+) ions released from MgO agglomerates are complexed with carboxylic acids leached from saw dusts. This sequestration prevents the formation of bulky Mg(OH)(2) which is an ineffective sorbent for borate and covers the surfaces and passivating reactive sites on the MgO agglomerates. The morphologies of Mg(OH)(2) precipitated in the PRB column were also significantly affected by the presence of saw dust, with crystallization of needle-like particles of Mg(OH)(2) was prevented by Mg(2+) ions-organic ligand complexation.

Evaluation of the efficacy of combined continuous arterial infusion and systemic chemotherapy for the treatment of advanced pancreatic carcinoma.

PURPOSE: To evaluate the effects of combined continuous transcatheter arterial infusion (CTAI) and systemic chemotherapy in patients with advanced pancreatic carcinoma. METHODS: CTAI was performed in 17 patients with stage IV pancreatic cancer with (n = 11) or without (n = 6) liver metastasis. The reservoir was transcutaneously implanted with the help of angiography. The inferior pancreatic artery (IPA) was embolized to achieve delivery of the pancreatic blood supply through only the celiac artery. The systemic administration of gemcitabine was combined with the infusion of 5-fluorouracil via the reservoir. Treatment effects were evaluated based on the primary tumor size, liver metastasis, and survival time and factors such as tumor size, tumor location, and stage of pancreatic carcinoma; the embolized arteries were analyzed with respect to treatment effects and prognosis. RESULTS: A catheter was fixed in the gastroduodenal artery and splenic artery in 10 and 7 patients, respectively. Complete peripancreatic arterial occlusion was successful in 10 patients. CT showed a decrease in tumor size in 6 of 17 (35%) patients and a decrease in liver metastases in 6 of 11 (55%) patients. The survival time ranged from 4 to 18 months (mean +/- SD, 8.8 +/- 1.5 months). Complete embolization of arteries surrounding the pancreas was achieved in 10 patients; they manifested superior treatment effects and prognoses (p < 0.05). CONCLUSION: In patients with advanced pancreatic cancer, long-term CTAI with systemic chemotherapy appeared to be effective not only against the primary tumor but also against liver metastases. Patients with successfully occluded peripancreatic arteries tended to survive longer.

A new method to establish the rational extent of hepatic resection for advanced gallbladder cancer using dye injection through the cystic artery.

BACKGROUND: Hepatic resection has been indicated to eliminate cancer at the surgical margin in cases of advanced gallbladder carcinoma, but there is considerable controversy about the reasonable extent of liver resection. A new on-table dye injection technique has been introduced to determine the venous drainage of the gallbladder and ascertain the amount of liver to remove. METHODS: In four hepatic resections for pT2 gallbladder cancer, indocyanine green solution (25 mg/20 ml) was injected over a period of 30 seconds through the cystic artery. The stained area of the liver surface was completely resected, maintaining a margin of at least 2 cm from the gallbladder. RESULTS: The entire serosal surface of the gallbladder takes on a light green stain immediately after dye injection, and then the liver surface around the gallbladder gradually becomes stained with a clear demarcation line. The distance between the demarcation line and the gallbladder ranged from 1.0 to 5.0 cm. The extent of the stained area differed from one individual to another. Histopathological examination of resected liver specimens revealed that one of the four resected livers had micrometastasis in the portal area 27 mm from the gallbladder wall and there were no cancer cells at the surgical margins. No recurrence has been seen in any of our 4 patients at 16-26 months after operation. DISCUSSION: The dye injection method is useful in determining the appropriate extent of hepatic resection for advanced gallbladder cancer, as it is possible to determine the necessary and sufficient amount of liver parenchyma that should be removed according to the perfusion area of the cystic veins in each individual patient.

Quiet MRI with novel acoustic noise reduction.

Fast scan techniques, which are used to reduce scanning times, have raised scanning noise levels in magnetic resonance imaging (MRI) systems, resulting in greater patient discomfort and stress. It is well known that this noise is caused by vibration of the gradient coil due to the Lorentz forces generated by the current in the gradient coil, which is placed in a static magnetic field. We have confirmed that MRI noise can be substantially reduced by sealing the gradient coil in a vacuum chamber to block airborne vibration propagation, by supporting the gradient coil independently to block solid vibration propagation and by decreasing the eddy currents induced in RF coils, the RF shield and the static-field-magnet cryostat. Based on these findings, we have developed a silent MRI system in which scanning noise is markedly reduced under a wide range of scanning conditions.

Human CC chemokine liver-expressed chemokine/CCL16 is a functional ligand for CCR1, CCR2 and CCR5, and constitutively expressed by hepatocytes.

Liver-expressed chemokine (LEC)/CCL16 is a human CC chemokine selectively expressed in the liver. Here, we investigated its receptor usage by calcium mobilization and chemotactic assays using mouse L1.2 pre-B cell lines stably expressing a panel of 12 human chemokine receptors. At relatively high concentrations, LEC induced calcium mobilization and chemotaxis via CCR1 and CCR2. LEC also induced calcium mobilization, but marginal chemotaxis via CCR5. Consistently, LEC was found to bind to CCR1, CCR2 and CCR5 with relatively low affinities. The binding of LEC to CCR8 was much less significant. In spite of its binding to CCR5, LEC was unable to inhibit infection of an R5-type HIV-1 to activated human peripheral blood mononuclear cells even at high concentrations. In human liver sections, hepatocytes were strongly stained by anti-LEC antibody. HepG2, a human hepatocarcinoma cell line, was found to constitutively express LEC. LEC was also present in the plasma samples from healthy adult donors at relatively high concentrations (0.3--4 nM). Taken together, LEC is a new low-affinity functional ligand for CCR1, CCR2 and CCR5, and is constitutively expressed by liver parenchymal cells. The presence of LEC in normal plasma at relatively high concentrations may modulate inflammatory responses.

Lymphatic spreading pattern of intrahepatic cholangiocarcinoma.

BACKGROUND: There have been very few reports on the pattern of lymphatic spread of intrahepatic cholangiocarcinoma. This pattern was elucidated to help define the rational extent of radical lymph node dissection. METHODS: Thirty-nine consecutive patients who underwent hepatectomy with radical lymph node dissection were reviewed retrospectively. RESULTS: Lymph node metastases were detected in 24 of the 39 patients (62%). The metastatic nodes were found in the hepatoduodenal ligament, along the common hepatic artery, around the abdominal aorta, on the posterior surface of the pancreas head, along the left gastric artery, along the superior mesenteric artery, around the celiac artery, along the lesser curvature of the stomach, and around the cardia. The nodal involvements along the left gastric artery, along the lesser curvature, or around the cardia were recognized only in the left peripheral and hilar types of cholangiocarcinoma, while all other sites included both the left or right peripheral type and the hilar type cholangiocarcinoma. CONCLUSIONS: Intrahepatic cholangiocarcinomas, irrespective of their intrahepatic location, mainly spread to the nodes in the hepatoduodenal ligament, then to the para-aortic nodes, retropancreatic nodes, or common hepatic artery nodes. In addition to these spreading routes, the left peripheral type or hilar type of cholangiocarcinoma tends to spread along the left gastric nodes through the lesser curvature.

Genetic variation and correlations among responses to five insecticides within natural populations of Drosophila melanogaster (Diptera: Drosophilidae).

To investigate the genetic basis of cross-resistance to insecticides, natural populations of Drosophila melanogaster (Meigen) were first collected from four different locations in Japan. After 10-80 isofemale lines of each population had been established in a laboratory, the susceptibility of each line to each of the insecticides permethrin, malathion, fenitrothion, prothiophos, and DDT was examined. Broad ranges of continuous variation in susceptibility to all the chemicals were observed within each natural population as a whole. In addition, highly significant correlations among responses to organophosphates were observed. However, based on the coefficients of determination, about less than half of variation in responses to one insecticide could be explained by variation in responses to another insecticide, suggesting that not only a common resistance factor but also other factors could be involved in a natural population. Genetic analyses by using resistant and susceptible inbred lines from the same natural population demonstrated that resistance to organophosphates in some resistant lines could be due to a single or tightly linked factors, and that resistance in the other line may be due to more than one major factor. These observations could suggest that several resistance factors may be involved within each natural population, and that some of major factors could contribute to correlations among responses to organophosphates. These major factors could then contribute to the broad ranges of continuous variation observed at the level of the populations.

Autocrine growth effect of IL-8 and GROalpha on a human pancreatic cancer cell line, Capan-1.

A human pancreatic cancer cell line, Capan-1, secretes the chemokines interleukin-8 (IL-8) and growth-related oncogene alpha (GROalpha). Capan-1 cells also express the chemokine receptor 2 (CXCR2), which is a Gialpha-protein coupled receptor. Growth of Capan-1 cells was inhibited when anti-IL-8 or anti-GROalpha monoclonal antibody was added into the culture medium. Pertussis toxin, which blocks Gialpha also demonstrated a growth-inhibitory effect on Capan-1 cells. These results indicated that IL-8 and GROalpha act on Capan-1 cells as growth factors in an autocrine manner through CXCR2.

Point mutation causing constitutive signaling of CXCR2 leads to transforming activity similar to Kaposi's sarcoma herpesvirus-G protein-coupled receptor.

The chemokine receptor CXCR2 is the closest homologue to Kaposi's sarcoma herpesvirus-G protein-coupled receptor (KSHV-GPCR), which is known to be constitutively activated and able to cause oncogenic transformation. Among G protein-coupled receptors, a DRY sequence in the second intracellular loop is highly conserved. However, the KSHV-GPCR shows a VRY sequence instead. In this study, we exchanged Asp138 of the DRY sequence in the CXCR2 with a Val (D138V), the corresponding amino acid in KSHV-GPCR, or with a Gln (D138Q), and investigated the functional consequences of these mutations. In focus formation and soft agar growth assays in NIH 3T3 cells, the D138V mutant exhibited transforming potential similar to the KSHV-GPCR. Surprisingly, the CXCR2 wild type itself showed transforming activity, although not as potently, due to continuous autocrine stimulation, whereas the D138Q mutant formed no foci. In agreement with these results were high levels of inositol phosphate accumulation in the D138V mutant and the KSHV-GPCR, indicating constitutive activity. These data emphasize the importance of the DRY sequence for G protein-coupled signaling of the CXCR2. Either constitutive activation or persistent autocrine stimulation of the CXCR2 causes transformation similar to KSHV-GPCR-transfected cells, probably activating the same signal transduction cascade that can abrogate normal growth control mechanisms.

Bronchoalveolar lavage with KL4-surfactant in models of meconium aspiration syndrome.

As a model of the meconium aspiration syndrome (MAS) of human infants, adult rabbits and newborn rhesus monkeys received intratracheal instillation of human meconium to induce pulmonary injury. Injured rabbits were ventilated with 100% O2 and divided into four treatment groups, receiving: 1) bronchoalveolar lavages (BAL) with dilute KL4-Surfactant; 2) lavages with equal volumes of sterile saline; 3) a single intratracheal bolus of KL4-Surfactant, 100 mg/kg; and 4) no treatment. The untreated rabbits developed atelectasis, a fall in pressure-volume levels and in partial pressure of O2 in arterial blood (PaO2) from approximately 500 to < 100 mm Hg, and severe pulmonary inflammation between 3 and 5 h after instillation of meconium. Rabbits treated by BAL with dilute KL4-Surfactant showed rapid and sustained recovery of PaO2 to approximately 300 mm Hg within minutes, a return toward normal pressure-volume levels, and diminished inflammation. Rabbits receiving BAL with saline failed to show recovery, and rabbits treated with a bolus of surfactant intratracheally exhibited a transient response by 1-2 h after treatment, but then returned to the initial atelectatic state. Newborn rhesus monkeys, after receiving human meconium intratracheally before the first breath, developed severe loss of pulmonary function. Treatment of these monkeys 1-5 h after birth with BAL with dilute KL4-Surfactant produced clearing of chest radiographs and a rapid improvement in pulmonary function with ratios of partial pressure of O2 in arterial blood to the fraction of O2 in the inspired air rising into the normal range where they remained through the 20-h period of study. The studies indicate that pulmonary function in two models of severe meconium injury respond rapidly to BAL with dilute KL4-Surfactant.

Modulation of bone mass, strength, and turnover by a new benzamide compound, DU-6712, in adjuvant-induced arthritic rats.

To assess the reductions in bone mass, strength, and turnover in adjuvant-induced arthritic rats and to examine the effect of a new benzamide compound, DU-6712, on these parameters, a 28-day dosing experiment was performed using 8-week-old female Lewis rats. Arthritis was induced by injecting the adjuvant into the hind paw. The age-dependent increases in the body weight, lumbar bone mineral content and density (BMC and BMD) and compressive strength were disturbed in the arthritic rats. At 14 days, the histomorphometric parameters of bone formation (BFR/BS and BFR/BV) and the serum osteocalcin levels were significantly reduced compared with the baseline controls. However, the BMC values corrected for body weight did not differ significantly between the arthritic and normal rats, and the bone minerals were not reduced compared with the baseline controls. At 28 days, the parameters of bone minerals and strength of the lumbar body in the arthritic rats, both with and without correction for body weight, were significantly reduced compared with the baseline controls. The trabecular mineralizing surface remained significantly reduced and the osteoclast numbers were increased. DU-6712 at the doses of 5, 15, and 45 mg/kg, orally administered daily from the start of the experiment, significantly prevented the development of the chronic paw edema at 28 days. The reductions in the parameters of bone minerals, strength, and trabecular bone formation, and the increase in osteoclast number were alleviated by this agent. Age-dependent increases in the lumbar height, disturbed by the adjuvant injection, were also maintained. These data indicated that a 28-day period is necessary to obtain sufficient reductions in the bone mass and strength of the lumbar body concerning the model of secondary osteoporosis in adjuvant arthritic rats. DU-6712 was able to prevent these reductions by modulating the bone turnover in this arthritis model.

Importance of the carboxy-terminus of the CXCR2 for signal transduction.

The CXCR2 is phosphorylated at the C-terminal intracytoplasmic portion within 15 sec following the addition of IL-8 or MGSA. Cells transfected with a truncated form of the receptor missing the last 12 amino acids (T3) showed normal binding affinity, but were no longer phosphorylated; individual alanine replacement indicated that Ser346 and 348 were the primary sites of phosphorylation. In studies of the importance of phosphorylation in CXCR2 desensitization, cells expressing wild type CXCR2 lost GTP gamma S binding above basal rate after the first exposure to IL-8, while cells with the T3 mutant retained 60% of their capacity to induce GTP gamma S exchange upon a second exposure to IL-8. In contrast, receptor internalization was not affected by the loss of phosphorylation of the T3 mutant. Further receptor truncation led to decreasing binding affinities for IL-8 and MGSA and a decreased rate of GTP gamma S exchange following addition of excess ligand which suggests involvement of this region in G-protein coupling.

Expression of tumor-associated carbohydrate antigens correlates with hepatic metastasis of pancreatic cancer: clinical and experimental studies.

BACKGROUND/AIMS: This study was designed to detect an useful indicator to prognose postoperative hepatic metastases of pancreatic cancer. MATERIALS AND METHODS: We analyzed clinical and histological data in thirty patients. RESULTS: Of the ten items analyzed, only preoperative serum CA 19-9 level was indicative of postoperative hepatic metastases. When the patients were classified into two groups in regard to the CA 19-9 level making a boundary at 50 U/ml, the group of CA 19-9 level equal to, or over, 50 U/ml possessed a significantly higher frequency of the hepatic metastases. With a design based on these clinical results, we experimentally studied a correlation between expression of three carbohydrate antigens (CA 19-9, DUPAN-2 and Span-1) and incidence of blood-borne hepatic metastases in nude mice by using six human pancreatic, cancer cell lines. These antigens were immunocytochemically detectable in four cell lines (SUIT-2, AsPC-1, HPAF and Capan-2) and were undetectable in two cell lines (MIA PaCa-2 and BxPC-3). All of the former cell lines formed metastatic lesions in the liver. In contrast, the latter two did not cause hepatic metastases at all. Moreover, these antigens were expressed more intensely in the metastatic foci than in the primary transplanted tumor lesion in the spleen. CONCLUSION: There is a positive correlation between expression of the carbohydrate antigens and metastatic potential of pancreatic cancer.

The combination of lovastatin and enalapril in a model of progressive renal disease.

Puromycin-induced nephrotic syndrome is an animal model of progressive renal disease. Both angiotensin converting enzyme inhibitors and lipid-lowering agents have been used to preserve renal structure and function in this model, although neither completely prevents progression. We tested the hypothesis that the combination of the two agents would be more protective than either alone. Rats were divided into five groups; all were uninephrectomized. Four groups were given puromycin at a dose of 10 mg/100 g body weight (BW) with additional doses of 4 mg/100 g BW given intraperitoneally at 4, 5, and 6 weeks thereafter. One group was given enalapril (EN) 50 mg/l dissolved in the drinking water; the second received lovastatin (L) 15 mg/kg given daily by gavage; the third received both agents; the fourth was left untreated, and the final group received no puromycin and served as the control group. Eight weeks after the initial dose of puromycin, glomerular filtration rate (GFR), as inulin clearance, and protein excretion were determined and blood was collected for cholesterol and triglycerides. Blood pressure was not different between any of the groups. At the end of the study period, serum cholesterol [mean +/- SD, 252 +/- 185 mg/dl (L), 135 +/- 101 mg/dl (L + EN)] and triglycerides (239 +/- 200, 148 +/- 158 mg/dl) were significantly lower (P < 0.001) in the lovastatin-treated groups than in the untreated puromycin group (535 +/- 255 mg/dl and 579 +/- 561 mg/dl, cholesterol and triglyceride, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Treatment strategies for hepatic metastases from pancreatic cancer in patients previously treated with radical resection combined with intraoperative radiation therapy.

Since 1984, we have performed extended radical resection combined with extended intraoperative radiation therapy (IORT) for pancreatic cancer. This approach has provided a dramatic improvement in long-term survival and control of local recurrence. Hepatic metastases, however, remain an unsolved problem. Among patients with this combined therapy, we found hepatic metastases in 8 of 22 patients postoperatively. Four of these 8 were considered candidates for further therapy and underwent treatment for their hepatic metastases, the other 4 had too extensive disease. Two patients with multiple hepatic metastases underwent percutaneous ethanol injection therapy and chemotherapy, but they died within a year. Two patients with a solitary hepatic metastases underwent hepatic resection. One patient died two years and six months after the first operation because of multiple metastases in the liver and both lungs, while the other patient is still alive over six years after the first operation with an excellent performance status. When a patient has no local recurrence and a solitary metastasis in the liver, surgical resection of the liver metastasis should be performed.

Cell-mediated transfer of collagen-induced arthritis in mice and its application to the analysis of the inhibitory effects of interferon-gamma and cyclophosphamide.

We developed a convenient and reliable procedure for the cell-mediated passive transfer of type II collagen (CII)-induced arthritis (CA). Spleen cells from DBA/1 mice with CA were intravenously transferred into syngeneic recipient mice. Arthritis developed only in those recipients which had received whole-body x-irradiation (8 Gy) just before cell transfer and intraperitoneally given soluble CII without adjuvant immediately after transfer. Non-immunized splenocytes could not induce arthritis even in irradiated recipients given soluble CII. Development of arthritis depended on the number of cells transferred; 5 x 10(7) cells induced severe and long-lasting arthritis in every recipient approximately 10 days after transfer. Severity of this arthritis was clinically and histologically similar to classical CA in donors. Arthritogenic splenocytes were generated in donors no later than 20 days after priming with CII in Freund's complete adjuvant, when arthritis had yet to occur, and were detected for more than 5 weeks. One splenocyte population responsible for transferring arthritis was CD4+ T cells. We then applied this system to show that prophylactic treatment of CII-immunized mice with cyclophosphamide (CY, 7 mg/kg), but not interferon-gamma (IFN-gamma, 10(5) U/mouse), suppressed the arthritogenic ability of their spleen cells, although both treatments inhibited the development of CA. Treatment of recipients with IFN-gamma, however, inhibited the development of arthritis upon transfer with CII-immunized splenocytes. These results indicate that CY and IFN-gamma act at the induction and effector phases of arthritogenic lymphocytes, respectively. Thus, this system facilitates investigation of pathological mechanisms of CA, and of mechanisms of anti-arthritics.