Distribution of tumor stage and initial treatment modality in patients with primary hepatocellular carcinoma.

OBJECTIVE: This study reviewed the distribution of each tumor stage and each type of initial treatment modality among patients with primary hepatocellular carcinoma (HCC) treated at a tertiary tumor hospital between January 2003 and October 2013. METHODS: Baseline data of patients with primary hepatocellular carcinoma treated between January 2003 and October 2013 were retrospectively collected. Tumor stage was determined according to the Barcelona Clinic Liver Cancer (BCLC) staging system and Hong Kong Clinic Liver Cancer (HKLC) staging system. RESULTS: A total of 6241 patients with primary hepatocellular carcinoma were included in the analysis. In accordance with the BCLC, 28.9% of patients were in stage 0/A, 16.2% in stage B, 53.6% in stage C, and 1.3% in stage D. According to the HKLC stage system, 8.4% patients were in stage I, 1.5% in stage IIa, 29.0% in stage IIb, 10.0% in stage IIIa, 33.6% in stage IIIb, 3.4% in stage IVa, 2.5% in stage IVb, 0.2% in stage Va, and 11.4% in stage Vb. Treatment modalities applied to this patient group were as follows: 33.3% of patients underwent hepatic resection, 36.7% underwent transarterial chemoembolization (TACE), 2.2% underwent radiotherapy, 0.9% underwent local ablated therapy, 8.8% underwent systemic chemotherapy, 4.2% underwent traditional herbal medicine therapy, 0.1% underwent targeted drug therapy, and 13.8% received no treatment. Hepatic resection was the most frequent therapy for patients with BCLC 0/A/B disease, and TACE was the initial therapy for patients with BCLC C disease. In the Hong Kong Clinic Liver Cancer staging system, the main treatments for HKLC I to IIIb disease is hepatic resection and TACE. Systemic chemotherapy was the initial therapy for patients with HKLC IVa/IVb disease. Most HKLC Va/Vb patients received traditional Chinese medicine treatment. CONCLUSION: Prevalence of stage BCLC B and C disease was high among our hepatocellular carcinoma patients. In Hong Kong Clinic Liver Cancer staging system, HKLC I to IIIb disease was high among our HCC patients. Hepatic resection and TACE are initial therapies.

[Comparison of the prognosis after hepatic resection for patients with Barcelona Clinical Liver Cancer Stage B hepatocellular carcinoma].

Objective: To compare the efficacy of hepatic resection (HR) in patients with Barcelona Clinical Liver Cancer (BCLC) Stage B hepatocellular carcinoma (HCC) and examine how that efficacy has changed over time in a large medical center. Methods: A consecutive sample of 918 patients with preserved liver function and large and/or multinodular HCC who were treated by initial HR were divided into three groups: those with a single tumor ≥5 cm in diameter (n=582), 2-3 tumors with a maximum diameter>3 cm (n=223), or>3 tumors of any diameter (n=113). Hospital mortality and overall survival (OS) in each group were compared for the years 2001-2007 and 2008-2013. Results: Patients with >3 tumors showed the highest incidence of hospital mortality of all groups (P<0.05). Kaplan-Meier survival analysis showed that OS varied across the three groups as follows: single tumor>2-3 tumors >3+ tumors (all P<0.05). OS rate at 5 years ranged from 24% to 41% in all three groups for the period 2001-2007, and from 35% to 46% for the period 2008-2013. OS was significantly higher during the more recent 6-year period in the entire patient population, those with single tumor, and those with 3+ tumors (all P<0.05). However, in patients with 2-3 tumors, OS was only slightly higher during the more recent 6-year period (P=0.084). Conclusions: Prognosis of three types of HCC was different. Patients with >3 tumors show the highest hospital mortality and lowest OS after HR. OS has been improving for all three types of HCC at our medical center as a consequence of improvements in surgical technique and perioperative management.

[Role of PI3K/AKT signaling pathway in clonogenicity and tumorigenicity of CD90+ stem-like cells of the hepatocellular carcinoma cell line MHCC-97H].

OBJECTIVE: To investigate the influence of the PI3K/AKT signaling pathway on the proportion and characteristics of the stem-like CD90(+) subpopulation of the human hepatocellular carcinoma (HCC) cell line MHCC-97. METHODS: MHCC-97H cultures were treated with the PI3K/AKT pathway inhibitor LY294002. The proportion of the CD90(+) subpopulation was determined by flow cytometry, and the expression of related proteins was measured by Western blot. The clonogenicity of CD90(+) and CD90(-) cells was measured by plate colony formation assay. The tumorigenicity was compared between CD90(+) and CD90(-) subpopulations (with different concentrations) in xenograft experiments in nude mice, and the changes in tumorigenicity after the addition of LY294002 were evaluated. The changes in the expression of CD90, SHP2, P-AKT, and AKT in CD90(+) and CD90(-) cell xenografts after the addition of LY294002 were examined. Data were analyzed using t test. RESULTS: LY294002 was capable of reducing the proportion of CD90(+) HCC stem cells from 2.98%±0.08% to 0.78%±0.08% (t = 32.400, P < 0.01) and reducing the clonogenicity of CD90(+) subpopulation from 95.13%±3.78% to 61.82%±7.23% (t = 7.617, P < 0.01). However, it showed no significant effect on the clonogenicity of CD90(-) subpopulation. LY294002 also reduced the tumorigenicity of CD90(+) subpopulation and the expression of CD90, SHP2, and P-AKT in related HCC stem cells, but it did not significantly affect the expression of AKT. LY294002 had no significant inhibitory effect on the tumorigenicity of CD90(-) cells. CONCLUSION: The CD90(+) subpopulation of MHCC-97H cells has the characteristics of stem cells and is dependent on the PI3K/AKT signaling pathway.

Meta-analysis of microsomal epoxide hydrolase gene polymorphism and the risk of breast carcinoma.

Carcinogenesis of breast carcinoma is very complicated. Previous studies have suggested conflicting results regarding the association between Tyr113His and His139Arg microsomal epoxide hydrolase (mEH) gene polymorphisms and risk of breast carcinoma. We conducted a meta-analysis to examine the relationship between these polymorphisms and breast carcinoma risk. We searched the PubMed, EMBASE, and Google Scholar databases to identify relevant studies. After extracting relevant data, the association between mEH polymorphisms and susceptibility to breast carcinoma was examined by meta-analysis. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to assess the strength of the association. Seven studies were identified that included 6357 cases and 8090 controls. The mEH His-allele was not associated with the risk of breast carcinoma based on the allelic contrast model (OR = 0.99, 95%CI = 0.94-1.04, P = 0.58), dominant genetic model (OR = 1.14, 95%CI = 0.88-1.48, P = 0.33), or recessive genetic model (OR = 1.03, 95%CI = 0.96-1.10, P = 0.43). Similarly, the mEH Arg-allele was not associated with breast carcinoma risk based on the allelic contrast model (OR = 0.97, 95%CI = 0.91-1.04, P = 0.44), dominant genetic model (OR = 1.01, 95%CI = 0.84-1.21, P = 0.94), or recessive genetic model (OR = 1.04, 95%CI = 0.96-1.12, P = 0.35). Subgroup analysis based on ethnicity showed no association between the polymorphisms and risk of breast carcinoma. Thus, the Tyr113His and His139Arg mEH polymorphisms may not be risk factors for breast carcinoma.

Isotropic and nematic phases of the hard spheroid fluid: a virial approach.

We use a high level virial expansion to investigate the properties of the isotropic and nematic phases of the hard spheroid fluid. We use the Monte Carlo techniques described previously to calculate the virial coefficients up to seventh order and we represent the dependence of these coefficients on particle orientations via a spherical harmonic expansion. The expansion coefficients are determined using Lebedev quadrature which carries out the angular integration required exactly. For fairly spherical spheroids (1/3

Adjuvant therapy options following curative treatment of hepatocellular carcinoma: a systematic review of randomized trials.

AIMS: Numerous postoperative therapies for preventing recurrence of hepatocellular carcinoma (HCC) have been reported, but their efficacy remains controversial and knowledge about adverse effects is limited. A systematic review of randomized controlled trials (RCTs) was performed to gain a comprehensive picture of the efficacy and risks of these therapies. METHODS: MEDLINE, EMBASE and the Cochrane Library were systematically searched through July 2011. Risk ratios (RRs) and 95% confidence intervals (CIs) were calculated. RESULTS: A total of 2989 patients from 28 RCTs involving 10 postoperative therapies were included. For interferon therapy, the estimated RR for the 2-year recurrence rate was 0.84 (95% CI 0.73-0.97, P = 0.02) and the overall survival (OS) was 1.15 (95% CI 1.07-1.22, P < 0.001). Postoperative therapy with the vitamin K2 analog did not lead to a significant reduction in the 1-year recurrence rate, with a pooled RR of 0.60 (95% CI 0.28-1.27, P = 0.18). However, it did slightly improve the 1-year OS, with a pooled RR of 1.03 (95% CI 1.00-1.05, P = 0.03). Transarterial chemotherapy with or without embolization, adoptive immunotherapy and heparanase inhibitor PI-88 therapy may delay tumor recurrence. The effects of acyclic retinoid, lipiodol-iodine-131 and tumor vaccine treatment were promising but require further study. All postoperative therapies except interferon administered intramuscularly were well tolerated by the majority of patients. CONCLUSIONS: Use of adjuvant interferon is definitely associated with an increase in OS. Postoperative therapies involving acyclic retinoid, lipidol-iodine-131, or tumor vaccine may improve the OS of patients with HCC after curative treatment.

Adoptive immunotherapy for postoperative hepatocellular carcinoma: a systematic review.

The high risk of recurrence in post-operative hepatocellular carcinoma (HCC) highlights the need for an effective adjuvant treatment. A systematic review of randomised controlled trials (RCTs) was performed to evaluate the clinical efficacy of adjuvant adoptive immunotherapy (AIT) for post-operative HCC patients. Electronic (MEDLINE, EMBASE and Cochrane Library databases) and manual searches were conducted throughout May 2011 to identify RCTs evaluating postoperative AIT for patients with HCC. Methodological quality was assessed in accordance with the QUOROM statement. Four RCTs totalling 423 patients met the eligibility criteria. All RCTs reported significantly improved disease-free survival rate or reduced recurrence rate after treating with adjuvant AIT (p < 0.05). The overall survival rates of AIT group are slightly higher than those of the control group in one study. Moreover, AIT was a safe treatment, with fever as the main adverse effects. This study adds to the evidence that postoperative HCC patients treated with adjuvant AIT show an improvement in disease-free survival rate or recurrence rate.

Efficacy of low dose levobupivacaine (0.1%) for axillary plexus block using multiple nerve stimulation.

The purpose of this study was to investigate if low doses of levobupivacaine (0.1%) produce complete sensory blockade in preoperative axillary brachial plexus block and to compare the effect of different doses of levobupivacaine on sensory and motor blockade. A total of 110 patients scheduled for elective forearm or hand surgery were randomly allocated to receive 36 ml or 72 ml of levobupivacaine 0.1% or 36 ml of levobupivacaine 0.25%. In each group, volumes were equally distributed in the four nerve territories. In all patients, the sensory and motor block was assessed at five, 10, 20 and 30 minutes after the placement of axillary block. Complete sensory block was obtained in 94.4% of patients receiving 36 ml of levobupivacaine 0.1%, 92.1% of those receiving 72 ml of levobupivacaine 0.1%, and 97.1% of those receiving 36 ml of levobupivacaine 0.25%. There was no significant difference either in the onset of the sensory and motor block or duration of the sensory and motor block. This study demonstrates that 36 ml of levobupivacaine 0.1% (36 mg) is as effective as higher doses and volumes in axillary brachial plexus blockade.

The equation of state of isotropic fluids of hard convex bodies from a high-level virial expansion.

We have calculated virial coefficients up to seventh order for the isotropic phases of a variety of fluids composed of hard aspherical particles. The models studied were hard spheroids, hard spherocylinders, and truncated hard spheres, and results are obtained for a variety of length-to-width ratios. We compare the predicted virial equations of state with those determined by simulation. We also use our data to calculate the coefficients of the y expansion [B. Barboy and W. M. Gelbart, J. Chem. Phys. 71, 3053 (1979)] and to study its convergence properties. Finally, we use our data to estimate the radius of convergence of the virial series for these aspherical particles. For fairly spherical particles, we estimate the radius of convergence to be similar to that of the density of closest packing. For more anisotropic particles, however, the radius of convergence decreases with increased anisotropy and is considerably less than the close-packed density.

Suppressed smooth muscle proliferation and inflammatory cell invasion after arterial injury in elafin-overexpressing mice.

Elastases degrade the extracellular matrix, releasing growth factors and chemotactic peptides, inducing glycoproteins such as tenascin, and thereby promoting vascular cell proliferation and migration. Administration of serine elastase inhibitors reduces experimentally induced vascular disease. The ability to mount an intrinsic anti-elastase response may, therefore, protect against intimal/medial thickening after vascular injury. To investigate this, we showed that wire-induced endothelial denudation of the carotid artery is associated with transient elevation in elastase activity and confirmed that this is abolished in transgenic mice overexpressing the serine elastase inhibitor, elafin, targeted to the cardiovascular system. Ten days after injury, nontransgenic littermates show vessel enlargement, intimal thickening, increased medial area and cellularity, and 2-fold increase in tenascin. Injured vessels in transgenic mice become enlarged but are otherwise similar to sham-operated controls. Injury-induced vessel wall thickening, which is observed only in nontransgenic mice, is related to foci of neutrophils and macrophages, in addition to smooth muscle cells that fail to stain for alpha-actin and are likely dedifferentiated. Our study therefore suggests that a major determinant of the vascular response to injury is the early transient induction of serine elastase activity, which leads to cellular proliferation and inflammatory cell migration.

Effects of cytomegalovirus infection and prolonged cold ischemia on chronic rejection of rat renal allografts.

Previous studies have demonstrated that both cytomegalovirus (CMV) infection and prolonged cold ischemia of the allograft (CI) are associated with chronic rejection of renal transplants. The purpose of this study is to investigate the effect of CMV infection, of CI and of the combination of both, on the progression of chronic rejection, and to obtain a more detailed insight in their effects on the expression of adhesion molecules. Therefore, a rat transplantation model was used. Lewis recipients of renal allografts (with and without CI) from MHC-incompatible Brown Norway rats were inoculated with rat CMV or left uninfected. CMV infection alone resulted in an increased influx of CD4+ cells and macrophages early after infection, and in an increase in glomerular sclerosis and intima proliferation. CI caused an increase in infiltrating NK cells and an effect on intimal proliferation, glomerular sclerosis, and tubular atrophy. When CMV infection and CI were combined, an additive effect could be measured. This was however not the case for the function of the kidney. The creatinin showed a synergistic effect of the two influencing factors. Due to the CMV infection, an increase in CD49d cells was detected. CI resulted in an increase in CD18 cells and an increase in the expression of CD62P on vessels, and CD54 and CD44 on tubules. When CMV infection and CI were combined, all the effects caused by CMV and CI alone were present in an additional way. The results of the present study suggest that special attention should be paid to the recipient of an ischemically injured graft when either the donor or the recipient is CMV-infected. The patterns seen in histology, the infiltration of leukocytes and the expression of adhesion molecules, suggest that CI and CMV infection both have an effect on rejection, but act by different mechanisms.

The thyroid hormone analog DITPA restores I(to) in rats after myocardial infarction.

Previous studies have established that reductions in repolarizing currents occur in heart disease and can contribute to life-threatening arrhythmias in myocardium. In this study, we investigated whether the thyroid hormone analog 3, 5-diiodothyropropionic acid (DITPA) could restore repolarizing transient outward K(+) current (I(to)) density and gene expression in rat myocardium after myocardial infarction (MI). Our findings show that I(to) density was reduced after MI (14.0 +/- 1.0 vs. 10.2 +/- 0.9 pA/pF, sham vs. post-MI at +40 mV). mRNA levels of Kv4.2 and Kv4.3 genes were decreased but Kv1.4 mRNA levels were increased post-MI. Corresponding changes in Kv4.2 and Kv1.4 protein were also observed. Chronic treatment of post-MI rats with 10 mg/kg DITPA restored I(to) density (to 15.2 +/- 1.1 pA/pF at +40 mV) as well as Kv4.2 and Kv1.4 expression to levels observed in sham-operated controls. Other membrane currents (Na(+), L-type Ca(2+), sustained, and inward rectifier K(+) currents) were unaffected by DITPA treatment. Associated with the changes in I(to) expression, action potential durations (current-clamp recordings in isolated single right ventricular myocytes and monophasic action potential recordings from the right free wall in situ) were prolonged after MI and restored with DITPA treatment. Our results demonstrate that DITPA restores I(to) density in the setting of MI, which may be useful in preventing complications associated with I(to) downregulation.

Development of obliterative bronchiolitis after allogeneic rat lung transplantation: implication of acute rejection and the time point of treatment.

BACKGROUND: Chronic allograft failure represents the major cause of late morbidity and mortality after solid organ transplantation. Despite the pathological and clinical changes of this disease being well-described, the etiology and the causative factors are still under discussion. Several clinical, as well experimental studies, emphasize the significance of acute rejection. In rat model of left lung allo-transplantation (F344-to-WKY) the influence of acute rejection (AR) on the development of chronic rejection (CR) was studied. METHODS: In Group I (n = 25) no immunosuppression was used, while methylprednisolone (MP) (10 mg/kg) was applied in Group II (n = 20) in the early phase of AR on postoperative Days 9, 10, 11 and in Group III (n = 20) during AR on Day 14, Day 15, Day 16. The rats were sacrificed on Day 5, Day 15/20, Day 30, Day 60, Day 100 and following HE-staining the extend of AR as well CR was graded according to the working formulation of The International Society of Heart and Lung Transplantation. RESULTS: In Group I, AR was found at Day 15 and Day 30 which resolved spontaneously and resulted in CR on Day 60 and Day 100. In Group II, signs of AR were less evident on Day 20, while mild AR persisted on Day 30 and Day 60. On Day 100, normal lung structure was found in all rats. The recipients of Group III showed decreased signs of AR in the early course, however, severe CR was found on Day 60 and Day 100. Extensive airway inflammation with destruction of the subepithelial layer of the smaller airways resulted in severe early obliterative bronchiolitis. CONCLUSIONS: Untreated severe AR in the early course after lung transplantation results in CR in the F344-to-WKY model. Preventive treatment with MP during the early phase of AR clearly diminishes the degree of AR and the graft recovers completely without any evidence of CR. Late application of steroids during the zenith of AR is successful to control the extent of AR, however, it fails to prevent CR.

Targeted overexpression of elafin protects mice against cardiac dysfunction and mortality following viral myocarditis.

Serine elastases degrade elastin, stimulate vascular smooth muscle cell migration and proliferation, and are associated with myocardial damage. To evaluate the impact of elastase inhibition on cardiovascular development and disease, transgenic mice were created in which the mouse preproendothelin-1 promoter was used to target elafin overexpression to the cardiovascular system. To distinguish the transgene from endogenous elafin, constructs were made incorporating a FLAG sequence; the COOH-terminus FLAG-tagged elafin construct produced a stable, functionally active gene product and was used to create transgenic mice. Consistent with endothelin expression, abundant elafin mRNA was observed in transgenic F1 embryos (embryonic day 13.5) and in adult transgenic mice heart, trachea, aorta, kidney, lung, and skin, but not in liver, spleen, and intestine. Functional activity of the transgene was confirmed by heightened myocardial elastase inhibitory activity. No tissue abnormalities were detected by light microscopy or elastin content. However, injection of 10 plaque-forming units (PFU) of encephalomyocarditis virus resulted in death within 11 days in 10 out of 12 nontransgenic mice compared with one out of nine transgenic littermates. This reduced mortality was associated with better cardiac function and less myocardial inflammatory damage. Thus, elafin expression may confer a protective advantage in myocarditis and other inflammatory diseases.

Analysis of leukocyte activation during acute rejection of pulmonary allografts in noninfected and cytomegalovirus-infected rats.

After human lung transplantation acute rejection and cytomegalovirus (CMV) infections may occur, probably contributing to the development of chronic rejection. We established a model of subacute allograft rejection in rats to analyze leukocyte activation and effects of a CMV infection. Histoincompatible lung transplants (BN/LEW) without immunosuppression (group A) and lungs of initially immunosuppressed animals (group B) were analyzed. The production of inflammatory mediators (interleukin-6, tumor necrosis factor alpha, nitric oxides) and the expression of MHC class II antigens by alveolar and lung tissue macrophages were significantly enhanced during the alloresponse. In recipients without immunosuppression (group A) allograft necrosis was detected by day 6, whereas group B allografts were fully rejected by day 25. In allografts of immunosuppressed, CMV-infected animals (group C) the CMV infection was clearly aggravated and the number of activated lung tissue macrophages was increased when compared with noninfected allografts or isografts. The subacute model provides the advantage of allowing us to study mechanisms of acute rejection without the effects of reperfusion injury. Furthermore these findings underline the role of inflammatory mediators produced by macrophages during rejection.

Enhancement of cytomegalovirus infection and acute rejection after allogeneic lung transplantation in the rat: virus-induced expression of major histocompatibility complex class II antigens.

BACKGROUND: Cytomegalovirus infection is considered a major complication after lung and heart-lung transplantation because it can trigger acute and chronic rejection. The potential mechanisms of lung transplant rejection induced by viral infection include the upregulation of expression of major histocompatibility complex antigens. To address this question, a model of rat cytomegalovirus infection and acute lung transplant rejection was established. METHODS: Lewis inbred strain rats received syngeneic (n = 25) or allogeneic (Brown-Norway inbred rat strain, n = 38) orthotopic left-side lung transplants. Triple-drug immunosuppression with cyclosporin A, methylprednisolone, and azathioprine was given from postoperative days 1 through 10. Rat cytomegalovirus was inoculated intraperitoneally on postoperative day 3. Two control groups, those infected with cytomegalovirus (n = 15) and those without rat cytomegalovirus infection (n = 6) were treated with identical immunosuppressive regimens. Animals were sacrificed on postoperative days 11, 15, 18, 20, and 25. The salivary glands and both lungs were removed for pathologic and immunohistochemical investigations. RESULTS: All animals inoculated with rat cytomegalovirus developed systemic viral infection on or after postoperative day 11, as confirmed by an assay of plaque-forming units and immunohistologic examination. Cytomegalovirus-induced expression of major histocompatibility complex class II antigens on vascular endothelial cells was seen in the nontransplanted lungs of rats, but no major histocompatibility complex class II antigens were detected on noninfected, nontransplanted lungs. Cytomegalovirus infection also was found to enhance major histocompatibility complex class II antigen expression on pneumocytes and leukocytes in rats. Acute rejection occurred in allogeneic transplants from postoperative days 15 through 25. The expression of class II antigens on endothelial cells, pneumocytes, and leukocytes was further enhanced during the course of allograft rejection in the cytomegalovirus-infected rats compared with the noninfected controls. In cytomegalovirus-positive rats, the rejection grade was higher than that in cytomegalovirus-negative rats on postoperative days 15 through 18. CONCLUSIONS: Our results indicate that cytomegalovirus induces and enhances the expression of major histocompatibility complex class II antigens on endothelial cells, pneumocytes and leukocytes. Upregulation by cytomegalovirus infection may trigger or promote acute rejection by alloantigenic T-lymphocyte stimulation after lung transplantation. By this mechanism it may strongly influence the long-term course of lung transplant rejection.