Preoperative estimation of asialoglycoprotein receptor expression in the remnant liver from CT/99mTc-GSA SPECT fusion images correlates well with postoperative liver function parameters.

BACKGROUND: Accurate preoperative estimation of remnant liver function is critically important for hepatic surgery, and the expression of asialoglycoprotein receptors (ASGPR) is associated with hepatic function. METHODS: Thirty-two patients with hepatocellular carcinoma who underwent surgical resection were studied. To estimate the expression of ASGPR in the remnant liver, simulated surgery was performed on fusion images that combined data from (99m)technetium-galactosyl human serum albumin ((99m)Tc-GSA)/single photon emission computed tomography (SPECT) and computed tomography (CT) scanning. The liver uptake ratio (LUR) of (99m)Tc-GSA and the functional liver volume (FLV) in the remnant liver were predicted and were compared with postoperative liver function parameters. RESULTS: The LUR of (99m)Tc-GSA was strongly correlated with the extent of hepatic ASGPR expression (r = 0.944, p = 5.01 x 10(-16)), being confirmed to be a reliable parameter for the evaluation of liver function. The estimated remnant LUR, but not the estimated remnant FLV, was significantly correlated with postoperative liver function parameters, such as serum total bilirubin (r = -0.430, p < 0.05), prothrombin activity (r = 0.515, p < 0.01), and serum cholinesterase activity (r = 0.546, p < 0.01) at 1 week. CONCLUSION: Preoperative estimation of the extent of ASGPR expression in the remnant liver on CT/GSA-SPECT fusion images correlated well with postoperative liver function parameters, suggesting its usefulness for surgical decisions.

The impact of 3-D virtual hepatectomy simulation in living-donor liver transplantation.

BACKGROUND/PURPOSE: In living-donor liver transplantation, accurate assessments of liver graft volume and anatomical variation are mandatory for the preoperative planning of safe donor hepatectomy and successful recipient implantation. The aim of this study was to assess the feasibility and accuracy of novel three-dimensional (3-D) virtual hepatectomy simulation software in living-donor liver transplantation. METHODS: We developed the hepatectomy simulation software, which was programmed to analyze detailed 3-D vascular structure and to predict liver graft volume, based on hepatic circulation. RESULTS: In 101 individuals, including 4 living donors, the predicted liver resection volumes revealed a significant correlation with the actual value (P < 0.0001), with a mean difference of 7.9 ml. The drainage area by the individual hepatic vein branch was quantified to achieve reconstruction of the corresponding venous branch. The application of multidetector computed technology scanning and virtual cholangioscopy facilitated more detailed visualization of the 3-D hilar anatomy in a left trisectoral graft transplantation. CONCLUSIONS: This hepatectomy simulation software reliably predicted accurate liver graft volume and the drainage volume of hepatic vein branches. This software may contribute to the preoperative planning of safe donor hepatectomy and implantation with satisfactory graft viability.

Growth factor-mediated interaction between tumor cells and stromal fibroblasts in an experimental model of human small-cell lung cancer.

Malignant tumors induce development of their own stromal tissues during the processes of growth, progression and metastasis. Since the vascular architecture among the various stromal elements is well known to facilitate tumor growth and has been a target of therapy, the importance of stromal fibroblasts has recently been established. To elucidate the interaction between the tumor and its stromal fibroblasts, the present study took advantage of a unique experimental model consisting of a human small-cell lung cancer cell line, WA-ht, and its mouse stromal fibroblast cell line, WA-mFib, both originally derived from a xenograft tumor in a mouse subcutis. Co-culture with the WA-mFib cells significantly augmented the plating efficiency of WA-hT cells in vitro, and their co-inoculation in nude mice shortened latency and tumor doubling time. Histochemical detection of beta-gal, transfected into WA-mFib cells, demonstrated their contribution to the nude mouse xenograft tumor formation as its tumor stroma. Elevated hepatocyte growth factor (HGF) from fibroblasts followed by elevated production of vascular endothelial growth factor (VEGF) from both tumor cells and fibroblasts were demonstrated by ELISA in supernatants of their co-culture, accompanied by enhanced colonogenicity of the tumor cells; these enhanced features were not observed in their respective monocultures. Antisense oligonucleotides to HGF cancelled these augmentation effects with co-culture. The findings highlight the substantial roles of tumor stromal fibroblasts, interacting with soluble growth factors, in promoting the malignant propensity of the tumor.

A novel 3D hepatectomy simulation based on liver circulation: application to liver resection and transplantation.

Hepatectomy is a complicated operative procedure because of its anatomical complexity, vascular variability, and impaired hepatic function due to associated hepatitis or cirrhosis. Thus preoperative detailed topography and precise liver resection volume measurements should be obtained for a curative hepatectomy. The aim of this study was to assess the feasibility and accuracy of a novel three-dimensional (3D) virtual hepatectomy simulation software in patients who underwent liver resection or living donor liver transplantation. We developed the hepatectomy simulation software, which was programmed to analyze detailed 3D vascular structure and to predict liver resection volume and margins. In 72 patients receiving hepatectomy, the predicted liver resection volumes and margins revealed a significant correlation with the actual value with a mean difference of 9.3 mL (P < .0001) and 1.6 mm (P < .01), respectively. The drainage area by hepatic veins was quantified to achieve reconstruction of the corresponding venous branch. In conclusion, this hepatectomy simulation software reliably predicted an accurate liver resection volume, the cancer-free margin, and the drainage volume of hepatic vein branches. This software may promote curative hepatectomy and may be used for other interventional therapies in the treatment of liver disease.

[A case of the multiple peripheral pulmonary artery branch stenosis].

A 31-year-old woman in whom primary pulmonary hypertension had been diagnosed at age 18, was admitted because of dyspnea on exertion and for evaluation of pregnancy risk. The perfusion scanning was not diagnostic, but chest CT suggested stenosis of pulmonary arteries instead of primary pulmonary hypertension. Echocardiograms and cardiac catheterization revealed pulmonary hypertension of pulmonary arterial pressure 71/13 (mean 39) mmHg with no cardiac defects. Selective pulmonary angiograms showed multiple stenosis of pulmonary arteries with poststenotic dilatations. We diagnosed multiple peripheral pulmonary artery branch stenosis with the pulmonary hypertension because systemic vasculitis was excluded because there were no signs of inflammation or any systemic arterial invlolvement This case was thought to be congenital, considering her history of over 30 years. In reports from western countries, maternal rubella and familial factors were important etiologic factors of this disease. Few cases have been reported in Japan and all cases, including the present case, were unrelated to the specific etiological factors. We recommended her to use birth control and have been observing her very carefully since the progression of the pulmonary hypertension is the major determinant of her prognosis.

Interleukin 18 acts on memory T helper cells type 1 to induce airway inflammation and hyperresponsiveness in a naive host mouse.

Interleukin (IL)-18 was originally regarded to induce T helper cell (Th)1-related cytokines. In general, factors favoring interferon (IFN)-gamma production are believed to abolish allergic diseases. Thus, we tested the role of IL-18 in regulation of bronchial asthma. To avoid a background response of host-derived T cells, we administered memory type Th1 or Th2 cells into unsensitized mice and examined their role in induction of bronchial asthma. Administration of antigen (Ag) induced both airway inflammation and airway hyperresponsiveness (AHR) in mice receiving memory Th2 cells. In contrast, the same treatment induced only airway inflammation but not AHR in mice receiving memory Th1 cells. However, these mice developed striking AHR when they were coadministered with IL-18. Furthermore, mice having received IFN-gamma-expressing Th1 cells sorted from polarized Th1 cells developed severe airway inflammation and AHR after intranasal administration of Ag and IL-18. Thus, Th1 cells become harmful when they are stimulated with Ag and IL-18. Newly polarized Th1 cells and IFN-gamma-expressing Th1 cells, both of which express IL-18 receptor alpha chain strongly, produce IFN-gamma, IL-9, IL-13, granulocyte/macrophage colony-stimulating factor, tumor necrosis factor alpha, regulated on activation, normal T cell expressed and secreted, and macrophage inflammatory protein 1alpha upon stimulation with Ag, IL-2, and IL-18 in vitro. Thus, Ag and IL-18 stimulate memory Th1 cells to induce severe airway inflammation and AHR in the naive host.

Gene delivery to the lung by means of syngeneic fibroblasts: an experimental model.

An experimental model, in which exogenous gene expression in the lung is achieved, has been established. A fibroblast cell line was transfected with the lacZ gene and was administered to syngeneic mice by either intravenous or intratracheal injection. Enzyme-linked immunosorbent assay and histochemical detection of beta-galactosidase revealed efficient gene delivery to the lung by either route. Kinetic studies demonstrated that the expression peaked immediately after the injection, and this high level was maintained for 7 days by intratracheal and for 14 days by intravenous administration. This system may have potential relevance for certain experimental models requiring specific gene delivery to the lung.

Nonredundant roles for CD1d-restricted natural killer T cells and conventional CD4+ T cells in the induction of immunoglobulin E antibodies in response to interleukin 18 treatment of mice.

Interleukin (IL)-18 synergizes with IL-12 to promote T helper cell (Th)1 responses. Somewhat paradoxically, IL-18 administration alone strongly induces immunoglobulin (Ig)E production and allergic inflammation, indicating a role for IL-18 in the generation of Th2 responses. The ability of IL-18 to induce IgE is dependent on CD4+ T cells, IL-4, and signal transducer and activator of transcription (stat)6. Here, we show that IL-18 fails to induce IgE both in CD1d-/- mice that lack natural killer T (NKT) cells and in class II-/- mice that lack conventional CD4+ T cells. However, class II-/- mice reconstituted with conventional CD4+ T cells show the capacity to produce IgE in response to IL-18. NKT cells express high levels of IL-18 receptor (R)alpha chain and produce significant amounts of IL-4, IL-9, and IL-13, and induce CD40 ligand expression in response to IL-2 and IL-18 stimulation in vitro. In contrast, conventional CD4+ T cells express low levels of IL-18Ralpha and poorly respond to IL-2 and IL-18. Nevertheless, conventional CD4+ T cells are essential for B cell IgE responses after the administration of IL-18. These findings indicate that NKT cells might be the major source of IL-4 in response to IL-18 administration and that conventional CD4+ T cells demonstrate their helper function in the presence of NKT cells.

Suppression of a DNA double-strand break repair gene, Ku70, increases radio- and chemosensitivity in a human lung carcinoma cell line.

Ku70 protein, cooperating with Ku80 and DNA-dependent protein kinase (DNA-PK) catalytic subunit (DNA-PKcs), is involved in DNA double-strand break (DNA DSB) repair and V(D)J recombination. Recent studies have revealed increased ionizing radiosensitivity in Ku70-deficient cells. The presented study, using a human squamous cell lung carcinoma cell line, demonstrated that introduction of an antisense Ku70 nucleic acid made the cells more radio- and chemosensitive than the parental cells. Ku70 protein expression was suppressed in the cells with antisense Ku70 construct when compared to the wild-type cells. A relatively small but statistically significant increase in radiosensitivity of the cells was achieved by the introduction of the antisense Ku70. The increased radiosensitivity in vitro was accompanied by an approximately two-fold increase in alpha and alpha/beta values in a linear-quadratic model. The antisense Ku70 increased the chemosensitivity of the cells to some DNA-damaging agents such as bleomycin and methyl methanesulfonate, but not to cisplatin, mitomycin C, and paclitaxel. This system provides us with partial suppression of Ku70, and will be a useful experimental model for investigating the physiological roles of the DNA DSB repair gene.