Hepatic Volume Research Articles

Total and segmental liver volume variations: Implications for liver surgery

Background Liver remnant volumes after major hepatic resection and graft volumes for liver transplantation correlate with surgical outcome. The relative contributions of the hepatic segments to total liver volume (TLV) are not well established. Methods TLV and hepatic segment volumes were measured with computed tomography (CT) in 102 patients without liver disease who underwent CT for conditions unrelated to the liver or biliary tree. Results TLV ranged from 911 to 2729 cm 3. On average, the right liver (segments V, VI, VII, and VIII) contributed approximately two thirds of TLV (997±279 cm 3), and the left liver (segments II, III and IV) contributed approximately one third of TLV (493±127 cm 3). Bisegment II+III (left lateral section) contributed about half the volume of the left liver (242±79 cm 3), or 16% of TLV. Liver volumes varied significantly between patients—the right liver varied from 49% to 82% of TLV, the left liver, 17% to 49% of TLV, and bisegment II+III (left lateral section) 5% to 27% of TLV. Bisegment II+III contributed less than 20% of TLV in more than 75% of patients and the left liver contributed 25% or less of TLV in more than 10% of patients. Discussion There is clinically significant interpatient variation in hepatic volumes. Therefore, in the absence of appreciable hypertrophy, we recommend routine measurement of the future liver remnant before extended right hepatectomy (right trisectionectomy) and in selected patients before right hepatectomy if a small left liver is anticipated.

Preoperative imaging in adult-to-adult living related liver transplant donors: what surgeons want to know.

Because of an overwhelming demand for cadaveric livers in the United States that far outstrips supply, living related liver transplantation is increasingly being performed to help treat a cohort of patients with severe end-stage liver disease. This procedure demands careful preoperative evaluation to minimize morbidity to the healthy donor and recipient, however. As a part of the workup, radiologic assessment of the donor hepatic vascular and biliary anatomy, hepatic volume, and hepatic parenchyma (with regard to focal and diffuse liver disease) is essential. In this pictorial essay, the experience of a group of investigators at the University of California at Los Angeles is reviewed, and the essential radiologic components of the preoperative evaluation of hepatic vascular and biliary anatomy, hepatic parenchyma, and lobar volume are described. The roles of high-field magnetic resonance (MR) imaging, MR angiography, MR cholangiopancreatography, multidetector-row computed tomography (CT) angiography, and CT cholangiography in the workup are discussed.

Predictive value of 3D computed tomography in assessing hepatic volumes prior to resection

Predictive value of 3D computed tomography in assessing hepatic volumes prior to resection

3D CT modeling of hepatic vessel architecture and volume calculation in living donated liver transplantation.

The aim of this study was to evaluate a software tool for non-invasive preoperative volumetric assessment of potential donors in living donated liver transplantation (LDLT). Biphasic helical CT was performed in 56 potential donors. Data sets were post-processed using a non-commercial software tool for segmentation, volumetric analysis and visualisation of liver segments. Semi-automatic definition of liver margins allowed the segmentation of parenchyma. Hepatic vessels were delineated using a region-growing algorithm with automatically determined thresholds. Volumes and shapes of liver segments were calculated automatically based on individual portal-venous branches. Results were visualised three-dimensionally and statistically compared with conventional volumetry and the intraoperative findings in 27 transplanted cases. Image processing was easy to perform within 23 min. Of the 56 potential donors, 27 were excluded from LDLT because of inappropriate liver parenchyma or vascular architecture. Two recipients were not transplanted due to poor clinical conditions. In the 27 transplanted cases, preoperatively visualised vessels were confirmed, and only one undetected accessory hepatic vein was revealed. Calculated graft volumes were 1110 +/- 180 ml for right lobes, 820 ml for the left lobe and 270 +/- 30 ml for segments II+III. The calculated volumes and intraoperatively measured graft volumes correlated significantly. No significant differences between the presented automatic volumetry and the conventional volumetry were observed. A novel image processing technique was evaluated which allows a semi-automatic volume calculation and 3D visualisation of the different liver segments.

Multiport staging laparoscopy in esophageal and cardiac carcinoma

Between February 1993 and September 2000, 320 patients with esophageal cancer were referred to our oesophagogastric unit. One hundred and thirty-three consecutive patients with histologically proven carcinoma of the esophagus were assessed with a view to resection using multiport staging laparoscopy. Multiport staging laparoscopy was performed as a short stay/day case procedure in 133 patients with esophageal and oesophagogastric junctional carcinoma. Multiple ports were used to inspect the liver, omentum, peritoneal surfaces, coeliac/left gastric lymph nodes and obtain biopsies and cytology. Satisfactory assessment was possible in 127 cases (95%). Laparoscopy detected incurable disease in 31 patients (24%), some of whom had more than one contraindication to surgery, including hepatic metastases (n = 10), peritoneal metastases (n = 12) and malignant small volume ascites (n = 5). Lymph node metastases were confirmed histologically by biopsy at laparoscopy in 26 patients (fixed nodes, n = 14; mobile nodes, n = 12). Sensitivity for the detection of liver and peritoneal metastases was 100%, and lymph node metastases were 83%. Specificity for detection of hepatic metastases was 99%, 100% for peritoneal metastases and 82% for lymph node metastases. Ninety-nine patients proceeded to definitive surgery and only two were unresectable. Multiport laparoscopic assessment of metastases in patients with esophageal carcinoma avoids unnecessary surgery and allows for more efficient use of theatre and intensive care time.

Attenuated Salmonella typhimurium prevents the establishment of unresectable hepatic metastases and improves survival in a murine model

Purpose The authors investigated the utility of attenuated Salmonella typhimurium for preventing the establishment of hepatic metastases in a murine model. Methods A single, oral 10 8 cfu dose of attenuated S typhimurium was given 8 days before the establishment of a model of unresectable hepatic metastases. Animals were assessed for hepatic tumor number and volume, hepatic lymphocyte population analysis, and survival. Results Pretreatment with Salmonella provided a 10-fold reduction in hepatic tumor burden compared with saline-treated controls. The antitumor effect is associated with markedly elevated natural killer (NK), CD8+ and CD4+ hepatic lymphocytes. Pretreatment with Salmonella provided a 90-day survival rate of 30%, whereas control animals were dead by 30 days. All long-term survivors were devoid of hepatic tumor. Conclusions Attenuated S typhimurium effectively prevents the establishment of hepatic metastases in a murine model, providing a clear survival benefit. Thus, it may represent a novel form of in vivo immunotherapy for the prevention of hepatic metastases for patients with locally advanced colorectal cancer.

Donor safety in adult-to-adult living donor liver transplantation

LIVING DONOR liver transplantation (LDLT) is becoming an important treatment option for adult patients with progressive liver disease, due to the shortage of cadaveric donors. The procedure obviously shortens the waiting time, allowing for a better selection for and ideal timing of transplantation. The key to success of the enterprise depends on donor safety. The major concern is delivering an adequate liver volume to the recipient, on the one hand, while the remaining liver volume determines the donor’s postoperative outcome, on the other hand. Graft size is one important factor to avoid postoperative recipient liver failure. Application of LDLT for adult recipients has increased by using right lobe grafts, a procedure first described by Hashikura et al in 1994. Although a right hepatic lobe consists of about 50% to 60% of the donor’s total hepatic volume, the graft may still be too small for the recipient. In the present study, we analyzed the postoperative course of right lobe donor surgery on the basis of the residual hepatic volume.

Massive subcapsular hematoma of liver graft after living donor liver transplantation: a case report

Adult living donor liver transplantation (ALDLT) is an accepted procedure to overcome the organ shortage. The advantages of ALDLT must be balanced against the first concern of donor safety. We analyzed the results of our early experience among a series of eight ALDLT performed between April 2001 and October 2003. All patients were listed as United Network for Organ Sharing UNOS status 2b and 3. Transplant recipients consisted of four men and four women. The living donors included four sons, three daughters, and one son-in-law (ages 20 to 45 years). One donor was anti-HBc-positive and negative for hepatitis B virus-DNA by polymerase chain reaction analysis in serum and in liver tissue. GR/WR >0.8 and fatty liver <10% were considered suitable for the hepatectomy. Residual left lobe volume was at least 33%. No exogenous blood and blood products were transfused into the donors and a cell-saver device was used in all donors (blood loss 490 ± 160 mL). All procedures were right lobe hepatectomy; in one case the middle hepatic vein was withdrawn with the right graft. The mean ischemia time was 1.5 ± 0.5 hours. All donors survived the procedure. Median hospital stay was 8.5 ± 2.1 days in all donors but one who had a long stay because of drug-related hepatitis. One graft was lost and one donor aborted because of preoperative overestimated volumetry. Complications were experienced by two donors (25%). Five recipients (62.5%) experienced major complications; one patient underwent retransplantation because of donor graft loss. Two biliary and two vascular complications (33.3%) occurred in three patients. No perioperative death occurred. Two patients died at 9 and 10 months after transplant because of heart and respiratory failure in the first case and tumor recurrence in the second. One-year actuarial survival is 75%. ALDLT using right lobe has gained acceptance to overcome the organ shortage. Donor selection criteria must be stringent with respect to residual donor hepatic volume, steatosis, and liver function.

Capillarization of the sinusoids in liver fibrosis: noninvasive assessment with contrast-enhanced MRI in the rabbit.

Sinusoidal capillarization induces microcirculatory changes in liver cirrhosis and fibrosis. The purpose of this study was to assess whether contrast-enhanced MRI can be used to demonstrate the effects of sinusoidal capillarization in liver fibrosis. Dynamic MRI after injection of a low-molecular-weight contrast agent of 0.56 kDa (Gd-DOTA), and two high-molecular-weight contrast agents of 6.47 kDa and 52 kDa (P792 and P717) was performed in rabbits with liver fibrosis induced by cholesterol and diethylstilbestrol. The hepatic distribution volume accessible to the high-molecular-weight agents decreased in the rabbits with liver fibrosis (P792: 7.8% +/- 1.7% vs. 10.1% +/- 1.8% in normal rabbits, P =.038; P717: 6.2% +/- 2.1% vs. 9.7% +/- 1.6% in normal rabbits, P =.007), whereas the hepatic mean transit time (MTT) of the low-molecular-weight agent was increased (15.9 +/- 8.0 s vs. 8.8 +/- 2.6 s in normal rabbits, P =.015). In rabbits with liver fibrosis, the clearance of indocyanine green (ICG) was correlated with the volume accessible to the high-molecular-weight agents (P792: r = 0.810, P =.015; P717: r = 0.857, P =.007). The collagen content of the liver was inversely correlated with the distribution volume of P717 (r = -.833, P =.010) and with the ICG clearance (r = -.810, P =.015). It was concluded that the microcirculatory changes induced by sinusoidal capillarization in liver fibrosis can be demonstrated noninvasively with MRI.

Mesure semi-automatique des différents lobes hépatiques. Application à la recherche d’une corrélation entre volumes des lobes du foie. Une étude sur 50 angioscanners de foies sains

Objective. – Healthy and pathological hepatic volumetry can be of great interest in Liver pathology and treatment. We studied the hepatic segmentation in order to verify if it is possible to estimate the volume of one lobe, when the volume of the other lobe or the total liver is known. Patients and Methods. – We studied 50 normal hepatic angiotomographies. For each exam and using the Couinaud classification, we measured the total hepatic volume, the right lobe, the left lobe and the caudate lobe volumes. We used a software called “Hepato” developed in order to quantify automatically CTScan images of the liver. We performed a linear regression analysis (least squares method) and calculated the determination coefficient to study the correlation between the different volumes. Results. – The mean total hepatic volume was 1497 cm 3. We obtained for the right lobe 1231 cm 3, 226 cm 3 for left lobe, and 39 cm 3 for the caudate lobe. Moreover there was a weak correlation between these volumes. Conclusion. – Exact volume estimation of an hepatic lobe in one patient can not be obtained from the total hepatic volume. However, theses volumes can only be measured from three-dimensional images. Since classical image editing tools are time request, it becomes impossible to utilize them in a clinical routine to get the different volumes of the Liver. Thus, a software dedicated for liver parenchyma recognition is necessary.

Dr. Gary J. Becker Young Investigator Award: Intraarterial Adenovirus for Metastatic Gastrointestinal Cancer: Activity, Radiographic Response, and Survival

To determine the antitumoral activity and radiographic response pattern of intraarterial administration of a selective replication-competent adenovirus in patients with hepatic metastases from gastrointestinal carcinomas. Thirty-five patients were treated, seven in the dose-escalation phase and 28 at high doses. Inclusion criteria allowed mild laboratory value and performance status abnormalities and as much as 50% replacement of hepatic volume by tumor. An attenuated adenovirus that selectively replicates in p53-deficient cells (Onyx-015) was administered by hepatic arterial infusion at doses as high as 2 x 10(12) particles for two cycles. Subsequent cycles (maximum of eight total) were administered in combination with intravenous 5-fluorouracil (5-FU) and leucovorin. Tumor responses were demonstrated in combination with chemotherapy, even in 5-FU-resistant patients. The 15 patients who responded radiographically showed a pattern of acute tumor enlargement despite normalization of laboratory and clinical parameters, followed by very slow regression of tumor size. Radiographic response did not correlate with p53 status. Median survival of radiographic responders (475 days) was significantly longer than that of nonresponders (143 days). Hepatic arterial infusion of the replication-selective adenovirus Onyx-015 in combination with chemotherapy resulted in tumor regressions in select patients, including some in whom previous chemotherapy had failed. A biphasic radiographic response pattern was demonstrated. The mechanism of action appears to be more complex than that seen in vitro.

The significance of hepatic vein outflow volume in adult-to-adult living donor liver transplantation evaluated by Doppler ultrasound

The significance of hepatic vein outflow volume in adult-to-adult living donor liver transplantation evaluated by Doppler ultrasound

Functional significance of hepatic arterial flow reserve in patients with cirrhosis

In cirrhosis, hepatic arterial vasodilatation occurs in response to reduced portal venous blood flow. However, although the hepatic arterial flow reserve is high in patients with cirrhosis, its impact on hepatic function is unknown. This study investigated the effect of adenosine-induced hepatic arterial vasodilatation on different markers of liver function. In 20 patients with cirrhosis (Child-Pugh class A/B/C: n = 2/7/11) adenosine (2-30 μg · min −1 · kg body wt −1) was infused into the hepatic artery and hepatic arterial average peak flow velocities (APV), pulsatility indices (PI), and blood flow volumes (HABF) were measured using digital angiography and intravascular Doppler sonography. Indocyanine green (ICG), lidocaine, and galactose were administered intravenously in doses of 0.5, 1.0, and 500 mg/kg body weight in the presence of adenosine-induced hepatic arterial vasodilatation and, on a separate study day, without adenosine. ICG disappearance, galactose elimination capacity (GEC), and formation of the lidocaine metabolite monoethylglycinxylidide (MEGX) were assessed. Adenosine markedly increased APV and HABF and markedly decreased PI. Serum MEGX concentrations were 63.7 ± 18.2 (median, 62; range, 36-107) and 99.0 ± 46.3 (82.5; 49-198) ng/mL in the absence and presence of adenosine infusion, respectively ( P = .001). Adenosine-induced changes in MEGX concentrations were correlated inversely to changes in APV ( r = −0.5, P = .02) and PI ( r = −0.55, P = .01) and were more marked in Child-Pugh class C compared with Child-Pugh class A patients (57.4 ± 49.9 [44; −14 to 140] vs. 8.4 ± 16.5 [13; −11 to 35] ng/mL, P < .01). In conclusion, hepatic arterial vasodilatation provides substantial functional benefit in patients with cirrhosis. The effect does not depend directly on hepatic arterial macroperfusion and is observed preferentially in patients with decompensated disease. (H EPATOLOGY 2003;37:385-392.)

Umbilical flow distribution to the liver and the ductus venosus in human fetuses during gestation: an anatomy-based mathematical modeling

The partitioning of umbilical vein blood flow between fetal liver and ductus venosus may be an indicator of the fetal well-being, because the goal of the ductus venosus is to supply oxygen and nutrients to heart and brain. Both distribution and blood flow rate of the umbilical vein are functions of the local vascular impedances that, in turn, depend on the anatomical features of the related vessels. In order to investigate the venous blood flows in human fetuses during a normal gestation, a simple lumped parameter mathematical model was developed on the basis of some information achievable by ultrasonographic techniques. Particularly, the diameter and length of umbilical vein and ductus venosus and the volume of the liver were used to derive the vascular impedances. Three different impedance models were adopted for the umbilical vein, the ductus venosus and the hepatic circulation. A linear model described viscous hydraulic dissipations through the umbilical vein, while a quadratic pressure-flow relationship was used for the ductus venosus due to the irregular local hemodynamics at its inlet. Finally, the equivalent impedance of the whole hepatic network was related to the hepatic volume assuming a tree-like, symmetric and self-similar fractal geometry. The hepatic vascular resistances predicted according to the fractal analysis were quite consistent with some experimental measurements in fetal lambs. In agreement with clinical observations, the model predicted blood flows through the ductus venosus and umbilical vein increasing (from about 25 to 75 ml/min and from about 45 to 370 ml/min, respectively) throughout the gestation (20–40 weeks), while the flow fraction shunted via the ductus venosus diminishes (from about 50 to 20%).

Role of preoperative selective portal vein embolization in two-step curative hepatectomy for hepatocellular carcinoma.

To determine the feasibility and role of ultrasound-guided preoperative selective portal vein embolization (POSPVE) in the two-step hepatectomy of patients with advanced primary hepatocellular carcinoma (HCC). Fifty patients with advanced HCC who were not suitable for curative hepatectomy were treated by ultrasound-guided percutaneous transhepatic POSPVE with fine needles. The successful rate, side effects and complications of POSPVE, changes of hepatic lobe volume and two-step curative hepatectomy rate after POSPVE were observed. POSPVE was successfully performed in 47 (94.0 %) patients. In patients whose right portal vein branches were embolized, their right hepatic volume decreased and left hepatic volume increased gradually. The ratio of right hepatic volume to total hepatic volume decreased from 62.4 % before POSPVE to 60.5 %, 57.2 % and 52.8 % after 1, 2 and 3 weeks respectively. The side effects included different degree of pain in liver area (38 cases), slight fever (27 cases), nausea and vomiting (9 cases). The level of aspartate alanine transaminase (AST), alanine transaminase (ALT) and total bilirubin (TBIL) increased after POSPVE, but returned to preoperative level in 1 week. After 2-4 weeks, two-step curative hepatectomy for HCC was successfully performed on 23 (52.3 %) patients. There were no such severe complications as ectopic embolization, local hemorrhage and bile leakage. Ultrasound-guided percutaneous transhepatic POSPVE with fine needles is feasible and safe. It can extend the indications of curative hepatectomy of HCC, and increase the safety of hepatectomy.

Evaluation of liver functional reserve by combining D-sorbitol clearance rate and CT measured liver volume.

Our research attempted to evaluate the overall functional reserve of cirrhotic liver by combination of hepatic functional blood flow, liver volume, and Child-Pugh's classification, and to discuss its value of clinical application. Ninety two patients with portal hypertension due to hepatic cirrhosis were investigated. All had a history of haematemesis and hematochezia, esophageal and gastric fundus varices, splenomegaly and hypersplenia. A 2-year follow-up was routinely performed and no one was lost. Twenty two healthy volunteers were used as control group. Blood and urine samples were collected 4 times before and after intravenous D-sorbitol infusion. The hepatic clearance (CL(H)) of D-sorbitol was then calculated according to enzymatic spectrophotometric method while the total blood flow (Q(TOTAL)) and intrahepatic shunt (R(INS)) were detected by multicolor Doppler ultrasound, and the liver volume was measured by spiral CT. Data were estimated by t-test, variance calculation and chi-squared test. The relationships between all these parameters and different groups were investigated according to Child-Pugh classification and postoperative complications respectively. Steady blood concentration was achieved 120 mins after D-sorbitol intravenous infusion, which was (0.358+/-0.064) mmol x L(-1) in cirrhotic group and (0.189+/-0.05) mmol x L(-1) in control group (P<0.01). CL(H) =(812.7+/-112.4) ml x min(-1), Q(TOTAL) =(1280.6+/-131.4) ml x min(-1), and R(INS) =(36.54+/-10.65) % in cirrhotic group and CL(H)=(1248.3+/-210.5) ml x min(-1), Q(TOTAL)=(1362.4+/-126.9) ml x min(-1), and R(INS)=(8.37+/-3.32) % in control group (P<0.01). The liver volume of cirrhotic group was 1057+/-249 cm(3), 851+/-148 cm(3) and 663+/-77 cm(3) in Child A, B and C group respectively with significant difference (P<0.001). The average volume of cirrhotic liver in Child B, C group was significantly reduced in comparison with that in control group (P<0.001). The patient, whose liver volume decreased by 40 % with the CLH below 600 ml x min(-1), would have a higher incidence of postoperative complications. There was no strict correspondent relationship between CL(H), liver volume and Child-Pugh's classification. The hepatic clearance of D-sorbitol, CT measured liver volume can be reliably used for the evaluation of hepatic functional blood flow and liver metabolic volume. Combined with the Child-Pugh's classification, it could be very useful for further understanding the liver functional reserve, therefore help determine reasonable therapeutic plan, choose surgical procedures and operating time.

Predictors of successful hepatic resection: prognostic usefulness of hepatic asialoglycoprotein receptor analysis.

To test the clinical usefulness of hepatic asialogycoprotein receptor analysis in liver surgery, we have conducted univariate and multivariate analysis for the detection of cirrhotic patients and prediction of morbidity after hepatic resection. Liver scintigraphy using technetium 99m-labeled asialoglycoprotein analog (TcGSA), ICG test, and CT hepatic volumetry were undertaken in 158 surgical patients including 111 who underwent hepatic resection. Hepatic functional parameters including Child-Pugh score, indocyanine green retention at 15 minutes (ICG-R15), clearance index (HH15), receptor index (LHL15), receptor concentration ([R]0), total hepatic receptor amount (R0) and hepatic parenchymal volume (HPV) were compared among patients with normal, cirrhotic, and non-cirrhotic damaged liver. Preoperative hepatic functional parameters, resected parenchymal fraction (RPf), operative blood loss, and total receptor amount of the remnant liver (R0-remnant) were compared between patients with and without signs of postoperative liver failure. All parameters but HPV were significantly different among patients with normal, cirrhotic, and noncirrhotic damaged liver. The multivariate analysis selected two significant (p <0.05) parameters, [R]0 and Child-Pugh score for the detection of liver cirrhosis. Of the 111 patients who underwent resection, 14 developed transient signs of postoperative liver failure. Of the parameters tested, presence of liver cirrhosis, LHL15, R0, intraoperative blood loss, and R0-remnant were significantly different between patients with and without signs of postoperative liver failure (p <0.05). The multivariate logistic regression analysis selected only R0-remnant as a significant (p = 0.022) parameter for the prediction of liver failure. The morbidity rate in patients with R0-remnant under 0.05 mmoles was 100%, and the rate decreased in inverse proportion to R0-remnant. In conclusion, combining the ASGP-R concentration ([R]0) and the Child-Pugh score best detected liver cirrhosis in surgical candidates. Cirrhotic patients and patients with a low R0-remnant are at higher risk for postoperative liver failure. The present study confirms the usefulness of hepatic asialogycoprotein receptor analysis in liver surgery.

Effect of ethanolamine on liver regeneration after 90% hepatectomy in rats

SURGICAL PROCEDURES, such as extended liver resection or living-related liver transplantation may be performed because normal liver has vigorous regenerative potential. However, reduced hepatic volume can produce postoperative hepatic insufficiency, which is a serious problem. After extensive liver resection for hepatic tumor or in living-related liver donors maximum volume of liver resection or thus the minimum volume of donor liver are limited. When the volume exceeds these limits, surgical treatment is not indicated. However, a new treatment that promotes postoperative liver regeneration would extend these limits. Two approaches have been attempted to promote liver regeneration. One approach prepares the host environment for liver regeneration by plasma exchange. In recent years, favorable results also have been reported using a bioartificial liver as a bridge. The other approach is promotion of liver regeneration using hepatocyte growth factor (HGF) or ethanolamine (EA). EA is a nutrient factor derived from the small intestine. In this study, we investigated the enhancing effect of EA using a 90% partial hepatectomy (PHX) rat model.

Cyclooxygenase-2 inhibition augments the hepatic antitumor effect of oral Salmonella typhimurium in a model of mouse metastatic colon cancer.

Oral inoculation with a nontoxic, attenuated strain of Salmonella typhimurium reduces tumor burden and improves survival in a mouse model of metastatic colon cancer. These effects are likely mediated by S. typhimurium-induced increases in hepatic natural killer leukocytes. Cyclooxygenase-2 inhibitors may mediate antitumor effects through antiangiogenic, immune, or proapoptotic pathways. We hypothesized that cyclooxygenase-2 inhibitors would act synergistically with S. typhimurium, resulting in additional antitumor effects. Four groups of mice were studied: control, S. typhimurium alone, cyclooxygenase-2 inhibitor alone, and S. typhimurium plus cyclooxygenase-2 inhibitor. Mice were given normal drinking water (control, S. typhimurium alone) or water with 1,600 parts per million cyclooxygenase-2 inhibitor (cyclooxygenase-2 inhibitor alone, and S. typhimurium plus cyclooxygenase-2 inhibitor) and orally inoculated with saline (control, cyclooxygenase-2 inhibitor alone) or 10(9) S. typhimurium (S. typhimurium alone, S. typhimurium plus cyclooxygenase-2 inhibitor). Twenty-four hours later, all mice underwent laparotomy, and 5 x 10(4) MCA38 murine adenocarcinoma cells were injected into the spleen. On Day 14, hepatic tumor number and tumor volume was quantitated and hepatic leukocytes were analyzed by flow cytometry. Compared with control mice orally inoculated with saline, S. typhimurium-treated mice had fewer and smaller tumors; mice treated with cyclooxygenase-2 inhibitor alone had tumor burden similar to control mice, and mice treated with S. typhimurium plus cyclooxygenase-2 inhibitor had fewer and smaller tumors compared with all other groups. Increased liver natural killer cells and decreased CD4+ and CD8+ T cells were observed in both S. typhimurium-treated groups. No alterations in hepatic leukocyte phenotype were observed in mice receiving cyclooxygenase-2 inhibitor alone. Oral cyclooxygenase-2 inhibitor appeared to act synergistically with S. typhimurium to reduce tumor burden. This combination therapy may have clinical application in the treatment or prevention of hepatic metastases associated with colorectal cancer.

Expression and regulation of the Na +/K +/2Cl − cotransporter NKCC1 in rat liver and human HuH-7 hepatoma cells

The expression of sodium potassium chloride cotransporter 1 (NKCC1) was studied in different liver cell types. NKCC1 was found in rat liver parenchymal and sinusoidal endothelial cells and in human HuH-7 hepatoma cells. NKCC1 expression in rat hepatic stellate cells increased during culture-induced transformation in the myofibroblast-like phenotype. NKCC1 inhibition by bumetanide increased α 1-smooth muscle actin expression in 2-day-cultured hepatic stellate cells but was without effect on basal and platelet-derived-growth-factor-induced proliferation of the 14-day-old cells. In perfused rat liver the NKCC1 made a major contribution to volume-regulatory K + uptake induced by hyperosmolarity. Long-term hyperosmotic treatment of HuH-7 cells by elevation of extracellular NaCl or raffinose concentration but not hyperosmotic urea or mannitol profoundly induced NKCC1 mRNA and protein expression. This was antagonized by the compatible organic osmolytes betaine or taurine. The data suggest a role of NKCC1 in stellate cell transformation, hepatic volume regulation, and long-term adaption to dehydrating conditions.