OBJECTIVETo investigate the effects of artificial ligand of peroxisome proliferators activated receptors (PPARs), rosiglitazone (RGZ) and all trans-retinoic acid (ATRA) on human myeloma cell line growth in vitro and in vivo.

METHODSU266 and RPMI 8226 cells were treated with different concentration of RGZ in the presence or absence of ATRA and the results were studied by 3H-TdR thymidine incorporation (for cells proliferation), Annexin V-PI staining and caspase-3 activity assay (for cells apoptosis), RT-PCR (for FLIP, XIAP and survivin mRNA expression), and tumor formation test in BALB/c nude mice.

RESULTSExposure to RGZ induced proliferation inhibition in a dose-dependent manner in both U266 (r = 0.991, P < 0.01) and RPMI 8226 cells (r = 0.961, P < 0.01). A combination of RGZ with ATRA could enhance the inhibition effect (P < 0.001 in U266, P < 0.01 in RPMI8226). 10 micromol/L of RGZ induced apoptosis of (9.8 +/- 1.7)% in U266 cells and (10.7 +/- 3.3)% in RPMI8226 cells, in a time and dose dependent manner and combined with ATRA intensified the apoptosis induction effects (P < 0.01 in both cell lines). The FLIP, XIAP and survivin mRNAs were expressed in both cell lines and their levels decreased significantly after cultured with RGZ. The addition of RGZ + ATRA in the culture further decreased the levels. Caspase-3 activity increased substantially with the increase of RGZ concentration and the addition of RGZ + ATRA in the culture medium showed similar synergism effect on caspase-3 activation (P < 0.01). The xenograft of U266 cells in BALB/c nude mice were inhibited by RGZ and so did more by the combination of RGZ and ATRA (P < 0.01).

CONCLUSIONThe down-regulation of FLIP, XIAP and Survivin induced by RGZ can activate caspase-3, whereby induced apoptosis and proliferation inhibition in myeloma cells. ATRA can enhance these effects of RGZ.

Animals ; Antineoplastic Agents ; pharmacology ; Apoptosis ; drug effects ; Caspase 3 ; metabolism ; Cell Line, Tumor ; Cell Proliferation ; drug effects ; Female ; Humans ; Inhibitor of Apoptosis Proteins ; metabolism ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Multiple Myeloma ; metabolism ; pathology ; Signal Transduction ; drug effects ; Thiazolidinediones ; pharmacology ; Tretinoin ; pharmacology

OBJECTIVETo investigate the effects of PPARgamma ligand (rosiglitazone, RGZ) as well as combined with all trans-retinoic acid (ATRA) on human myeloma cells and try to explore the possible mechanism.

METHODSHuman myeloma cell lines U266 and RPMI-8226 cells were treated with RGZ in the presence or absence of ATRA. Cell proliferation was evaluated by [(3)H] thymidine incorporation, cell cycle distribution and CD49e expression were analyzed by flow cytometry, morphology changes were evaluated by Wright-Giemsa staining, and p27(Kip1) and p21(Waf1) expression was detected by Western blotting.

RESULTSThe exposure to RGZ induced proliferation inhibition in both cell lines in a dose-dependent manner. After cultured with 5 micromol/L RGZ, the proportion of U266 and RPMI-8226 cells in phase G(0)/G(1) was (45.2 +/- 6.7)% and (40.3 +/- 7.3)%, respectively (P < 0.05). The proportion of the cells in phase G(2)/M and S was (52.2 +/- 7.4)% and (57.4 +/- 9.5)%, respectively (P < 0.05). These changes were more evident when the RGZ concentration was increased to 10 micromol/L. A combination of RGZ with ATRA enhanced the growth inhibition and cell cycle arrest effects of RGZ. The RGZ-treated myeloma cells displayed morphological characteristics of cell differentiation, and more evident signs of differentiation were observed when RGZ was combined with ATRA. These changes were confirmed by the detection of CD49e expression. The expression of p27(Kip1) and p21(Waf1) in myeloma cells was up-regulated by RGZ and this change was more apparent when RGZ was used in combination with ATRA.

CONCLUSIONRGZ can induce cell cycle arrest and cell differentiation in myeloma cells which maybe caused by up-regulation of p27(Kip1) and p21(Waf1) expression. ATRA can enhance these effects of RGZ on multiple myeloma cells and combined use of these two drugs may show a synergistic effect on myeloma cells.

Cell Cycle ; drug effects ; Cell Line, Tumor ; Cell Proliferation ; drug effects ; Cyclin-Dependent Kinase Inhibitor p21 ; metabolism ; Cyclin-Dependent Kinase Inhibitor p27 ; Dose-Response Relationship, Drug ; Drug Synergism ; Humans ; Integrin alpha5 ; metabolism ; Intracellular Signaling Peptides and Proteins ; metabolism ; Multiple Myeloma ; metabolism ; pathology ; PPAR gamma ; agonists ; Thiazolidinediones ; administration & dosage ; pharmacology ; Tretinoin ; pharmacology ; Up-Regulation

UNLABELLEDThe aim of this paper was to study the efficacy, side effects and complications of radiofrequency (RF) ablation of primary and metastatic liver malignancies.

MATERIALS AND METHODSWe retrospectively reviewed 57 patients (39 men, 18 women; mean age, 63 years; age range, 44 to 83 years) who underwent RF ablation for liver malignancies from January 2002 to December 2004. A total of 87 tumours were ablated - 71 (81.6%) hepatocellular carcinomas and 16 (18.4%) metastases (from primaries in the colon, stomach and pancreas). RF ablation was performed either percutaneously (n = 71) under conscious sedation or intraoperatively (n = 16) under general anaesthesia. Follow-up ranged from 1 month to 41 months (mean, 15.2) and included computed tomography (CT) 1 day, 1 month and 3 months after ablation, and half-yearly thereafter. Patients were observed for local tumour progression and for the emergence of new tumours.

RESULTSFour patients with a total of 5 tumours were lost to follow-up. Of the remaining 82 tumours treated, complete ablation was attained in 66 tumours after a single procedure, giving a primary effectiveness rate of 80.5%. Seven (8.5%) required 2 procedures to achieve complete ablation, giving a secondary effectiveness rate of 89% after 2 ablations. One tumour (1.2%) required 3 procedures to achieve complete ablation. One tumour required 4 procedures to date, with the latest follow-up CT still demonstrating incomplete ablation. Two tumours (2.4%) had an initial RF ablation and subsequent transarterial chemoembolisation (TACE). One tumour had an initial RF ablation followed by 32Phosphorus-biosilicon (BrachySil) injection, the latter as part of a Phase IIA trial. One tumour required 2 RF ablations and a subsequent TACE. Lastly, 3 tumours received initial RF ablation but subsequent local tumour progression was not treated as the patients were deemed unfit for repeat ablation. No procedure-related deaths or major complications were encountered. Minor complications were reported in 2 patients (3.8%) - subcapsular haematoma and thermal injury to the adjacent gastric antrum, both not necessitating surgical intervention.

CONCLUSIONSRF ablation is an effective, safe and relatively simple procedure for the treatment of unresectable liver malignancies.

Adult ; Aged ; Aged, 80 and over ; Carcinoma, Hepatocellular ; mortality ; secondary ; surgery ; therapy ; Catheter Ablation ; Chemoembolization, Therapeutic ; Combined Modality Therapy ; Female ; Hospitals, General ; Humans ; Liver Neoplasms ; mortality ; secondary ; surgery ; therapy ; Male ; Middle Aged ; Retreatment ; Retrospective Studies ; Singapore ; Surgery, Computer-Assisted

INTRODUCTIONThe 2005 American Association for Study of Liver Diseases (AASLD) diagnostic criteria allow non-invasive diagnosis of hepatocellular carcinoma (HCC) based on their enhancement pattern but we have observed a high incidence of atypical enhancement characteristics in HCC associated with portal vein thrombosis. This study seeks to examine the radiological features of this particular subgroup.

MATERIALS AND METHODSPatients with HCC and portal vein thrombosis who underwent pre-treatment multiphasic CT imaging were drawn from a surgical database. The arterial, portal venous and delayed phase images were assessed qualitatively and quantitatively (with region of interest [ROI] analysis) for lesion hypervascularity and washout. The background enhancement of the left and right lobes of the liver was also quantifi ed by ROI analysis.

RESULTSTwenty-fi ve lesions in 25 patients were selected for analysis. Qualitative analysis showed that 10/25 (40%) lesions demonstrated arterial hypervascularity while 16/25 (64%) lesions showed washout. Ten out of 25 (40%) lesions demonstrated both arterial hypervascularity and washout. Quantitative analysis showed that the average absolute lesion enhancement from precontrast to arterial phases was 49.1 (± 17.1) HU for hypervascular lesions compared to 23.8 (± 16.6) HU for non-hypervascular lesions (P <0.01). The mean absolute enhancement of the background liver parenchyma in the arterial phase was 13.79 (± 7.9) HU for hypervascular lesions compared to 36.6 (± 30.6) HU for non-hypervascular lesions (P = 0.03).

CONCLUSIONA large proportion of HCC with portal vein thrombosis lack characteristic arterial hypervascularity, which may be secondary to compensatory increased arterial supply to the background liver. This is a potential pitfall when applying imaging criteria for diagnosis of HCC.

Adult ; Aged ; Aged, 80 and over ; Carcinoma, Hepatocellular ; complications ; diagnostic imaging ; Female ; Humans ; Liver Neoplasms ; complications ; diagnostic imaging ; Male ; Middle Aged ; Pattern Recognition, Automated ; Portal Vein ; diagnostic imaging ; physiopathology ; Retrospective Studies ; Tomography, X-Ray Computed ; methods ; Venous Thrombosis ; diagnostic imaging ; etiology

INTRODUCTIONAcute pancreatitis appears to be less prevalent in multi-ethnic Southeast Asia, where the aetiology also appears to be influenced by ethnicity. As with acute pancreatitis elsewhere, however, pancreatic necrosis is a cause of significant mortality and the aim of this study was to review our institutional experience with pancreatic necrosectomy.

MATERIALS AND METHODSThe records of all patients who underwent pancreatic necrosectomy from January 2000 to December 2004 were analysed. Indications for surgery were the presence of infected necrosis, unresolving sepsis attributable to ongoing pancreatitis or the presence of gas in the pancreatic bed on imaging. Surgical debridement was achieved by debridement with closure over drains or by debridement with open packing.

RESULTSThe cohort comprised 14 of 373 patients admitted for acute pancreatitis (3.8%), with an overall mortality rate of 29%. All patients had infected necrosis with positive bacteriological cultures. Eight patients (57%) underwent debridement with closure over drains and 6 patients (43%) underwent debridement with open packing. All mortalities occurred in patients who underwent open packing, who were also associated with a higher mean Acute Physiology and Chronic Health Evaluation (APACHE) II score. The mortality rate in patients who underwent debridement less than 4 weeks after admission was 33% (2 of 6), compared with 25% (2 of 8) in patients who underwent debridement after 4 weeks. There were no mortalities in patients operated on after 6 weeks.

CONCLUSIONSurgical debridement with closure of drains and a policy of performing delayed necrosectomy are viable in our population.

APACHE ; Adult ; Aged ; Asia, Southeastern ; epidemiology ; Cohort Studies ; Debridement ; methods ; Drainage ; Female ; Humans ; Male ; Middle Aged ; Pancreatectomy ; methods ; Pancreatitis, Acute Necrotizing ; diagnosis ; mortality ; surgery ; Time Factors ; Tomography, X-Ray Computed

The rapid increase in diabetes prevalence globally has contributed to large increases in health care expenditure on diabetic complications, posing a major health burden to countries worldwide. Asians are commonly observed to have poorer β-cell function and greater insulin resistance compared to the Caucasian population, which is attributed by their lower lean body mass and central obesity. This “double phenotype” as well as the rising prevalence of young onset diabetes in Asia has placed Asians with diabetes at high risk of cardiovascular and renal complications, with cancer emerging as an important cause of morbidity and mortality. The experience from Hong Kong had demonstrated that a multifaceted approach, involving team-based integrated care, information technological advances, and patient empowerment programs were able to reduce the incidence of diabetic complications, hospitalizations, and mortality. System change and public policies to enhance implementation of such programs may provide solutions to combat the burgeoning health problem of diabetes at a societal level.
Architectural Accessibility* ; Asia ; Asian Continental Ancestry Group ; Delivery of Health Care ; Diabetes Complications ; Diabetes Mellitus, Type 2 ; Health Expenditures ; Hong Kong* ; Hospitalization ; Humans ; Incidence ; Insulin Resistance ; Mortality ; Obesity, Abdominal ; Patient Participation ; Prevalence ; Public Policy

OBJECTIVETo observe the effect of rosiglitazone (RGZ) and all-trans-retinoic acid (ATRA) on the growth of myeloma xenograft in nude mice and to explore the influence of RGZ and ATRA on VEGF expression and angiogenesis in the tumor.

METHODSVEGF gene expression in myeloma cell line U266 cells was analyzed by semi-quantitative RT-PCR after incubation with RGZ, ATRA, or RGZ + ATRA for 24 h. Myeloma xenograft was established by subcutaneous injection of 10(7) U266 cells in the scapula area of 4-week old nude mice. 7 days later, the nude mice were administered with RGZ, ATRA or RGZ + ATRA, respectively, by intraperitoneal injection once every day for 21 days. The control mice were given equal volume of normal saline instead of the drug. On the 21(st) day of treatment, the mice were sacrificed and the tumors were taken off, and the tumor volume and weight were measured. The tumors were examined by histopathology with HE staining, and microvessel density (MVD), CD34 and VEGF expression in the tumors were analyzed by immunohistochemical staining.

RESULTSVEGF mRNA was highly expressed in U266 cells and was decreased in a dose-dependent manner after incubation with RGZ. The VEGF mRNA level was further more decreased after RGZ + ATRA treatment. Xenografts of U266 cells were developed in all nude mice. The volume and weight of xenografts in the RGZ group were (785 ± 262) mm(3) and (1748 ± 365) mg, respectively, significantly lower than those of the control group (both P < 0.01). More significant inhibition was in the RGZ + ATRA group, (154 ± 89) mm(3) and (626 ± 102) mg, respectively, both were P < 0.05 vs. the RGZ group. RGZ inhibited the angiogenesis in U266 xenografts and immunohistochemical staining showed that the tumor MVD and VEGF expression were significantly decreased by RGZ treatment, and further more inhibited in the RGZ + ATRA group. VEGF protein was expressed in all xenografts in the nude mice. Its immunohistochemical staining intensity was 2.20 ± 0.40 in the control group, significantly higher than that of 1.48 ± 0.37 in the RGZ group (P < 0.01), and that of RGZ + ATRA group was 0.58 ± 0.26, further significantly lower than that of the RGZ group (P < 0.01). CD34 was expressed in all xenografts, most highly in the control group and lowest in the RGZ + ATRA group. The microvessel density (MVD) was highest in the control group (56.4 ± 15.2), significantly lower in the RGZ group (44.6 ± 11.2) (P < 0.05), and lowest in the RGZ + ATRA group (21.5 ± 8.6, P < 0.01).

CONCLUSIONSThe growth of myeloma cells can also be inhibited by RGZ and ATRA in nude mice in vivo. In addition to differentiation and apoptosis induction, RGZ can inhibit the formation of myeloma xenograft probably also through the downregulation of VEGF expression and subsequent angiogenesis.

Animals ; Antigens, CD34 ; metabolism ; Antineoplastic Agents ; pharmacology ; Apoptosis ; drug effects ; Cell Line, Tumor ; Cell Proliferation ; drug effects ; Dose-Response Relationship, Drug ; Drug Synergism ; Female ; Humans ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Microvessels ; pathology ; Multiple Myeloma ; metabolism ; pathology ; Neoplasm Transplantation ; Neovascularization, Pathologic ; RNA, Messenger ; metabolism ; Thiazolidinediones ; administration & dosage ; pharmacology ; Tretinoin ; pharmacology ; Tumor Burden ; drug effects ; Vascular Endothelial Growth Factor A ; genetics ; metabolism ; Xenograft Model Antitumor Assays

INTRODUCTIONThis study aims to determine if the quantitative method of region-of-interest (ROI) analysis of lesion attenuation on CT may be a useful adjunct to the conventional approach of diagnosis by visual assessment in assessing tracer wash-out in hepatocellular carcinomas.

MATERIALS AND METHODSFrom a surgical database of 289 patients from 2 institutions, all patients with complete surgical, pathological and preoperative multiphasic CT scans available for review were selected. For each phase of scanning, HU readings of lesion obtained (Lesion(arterial), Lesion(PV) and Lesion(equilibrium)) were analysed using receiver operating curves (ROC) to determine the optimal method and cut-off value for quantitative assessment of tumour wash-out (Lesion(arterial - equilibrium), Lesion(PV - equilibrium) or Lesion(peak - equilibrium)).

RESULTSNinety-four patients with one lesion each met the inclusion criteria. The area under the curve (AUC) values for Lesion(arterial - equilibrium) (0.941) was higher than the AUC for Lesion(pv - equilibrium) (0.484) and for Lesion(peak - equilibrium) (0.667). Based on ROC analysis, a cut-off of 10HU value for Lesion(arterial - equilibrium) would yield sensitivity and specificity of 91.5% and 80.9%, respectively. ROI analysis detected 9/21 (42.9%) of lesions missed by visual analysis. Combined ROI and visual analysis yields a sensitivity of 82/94 (87.2%) compared to 73/94 (77.7%) for visual analysis alone.

CONCLUSIONUsing a cut-off of 10 HU attenuation difference between the arterial and equilibrium phases is a simple and objective method that can be included as an adjunct to visual assessment to improve sensitivity for determining lesion wash-out on CT.

Adult ; Aged ; Aged, 80 and over ; Carcinoma, Hepatocellular ; diagnosis ; pathology ; surgery ; Confidence Intervals ; Databases, Factual ; Female ; Humans ; Liver ; pathology ; Liver Neoplasms ; diagnosis ; pathology ; surgery ; Male ; Middle Aged ; Preoperative Period ; ROC Curve ; Retrospective Studies ; Sensitivity and Specificity ; Tomography, X-Ray Computed ; instrumentation ; Young Adult