Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0019204 (hepatocellular carcinoma)
 71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

At detection or over time, hepatocellular carcinoma(HCC) is multicentric in origin, against a background of chronic hepatic disease at different stages. Orthotopic liver transplantation (OLT) is the only therapy able to definitely cure both diseases. When OLT is not feasible, all other options can be only palliative. Owing to the multicentricity, surgical resection may be one possible option at the initial detection in selected patients, whereas percutaneous interventional techniques (percutaneous ethanol injection [PEI], radiofrequency ablation [RFA], selected transcatheter arterial chemoembolization [TACE]) are the options more of tenused. The range of their indications is becoming wider. Although it is understood that partial resection assures the greatest local control, the survival rates after surgery are roughly comparable with those obtained with PEI. The explanation for this result reflects a balance among the advantages and disadvantages of the two therapies. PEI survival curves are better than curves of resected patients who present with adverse prognostic factors, and this means that a better selection of the patients for surgery is needed. An open question remains the choice among percutaneous techniques. In our department we currently use RFA in most patients but consider PEI and selected TACE complementary, and use them according to the features of the disease and the response.
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PMID:Radiofrequency ablation, PEIT, and TACE for hepatocellular carcinoma. 1291 60

Surface-shielded DNA delivery systems have been synthesized with virus-like characteristics that target gene expression into distant tumor tissues. Polyethylenimine (PEI)/DNA complexes ('polyplexes') conjugated with the cell-binding ligand transferrin (Tf) or epidermal growth factor (EGF) were used to achieve receptor-mediated endocytosis. The surface charge of the complexes was masked by covalently linking PEI to polyethylene glycol (PEG). Three alternatives for generating these surface-shielded formulations were utilized, attaching ligand and PEG molecules to PEI either before or after DNA complex formation. The stabilized formulations could be ultra-concentrated, stored frozen, and applied systemically after thawing. Intravenous injection of Tf-PEG-coated polyplexes resulted in gene transfer to subcutaneous Neuro2a neuroblastoma tumors of syngeneic A/J mice; EGF-PEG-coated polyplexes were intravenously applied for targeting human hepatocellular carcinoma xenografts in SCID mice. In these models, luciferase marker gene expression levels in tumor tissues were 10- to 100-fold higher than in other organ tissues. Repeated systemic application of Tf-PEG-PEI/DNA complexes encoding tumor necrosis factor alpha (TNF-alpha) into tumor-bearing mice induced tumor necrosis and inhibition of tumor growth in three murine tumor models of different tissue origin (Neuro2a, M-3 or B16 melanoma).
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PMID:Tumor-targeted gene therapy: strategies for the preparation of ligand-polyethylene glycol-polyethylenimine/DNA complexes. 1293 49

A 54-year-old male with hepatocellular carcinoma (HCC) underwent transcatheter arterial embolization (TAE) at a nearby hospital. He was then referred to our hospital for the purpose of additional treatment of HCC. Because TAE was not a complete therapy and HCC was growing and protruding from the left lobe of the liver, laparoscopic radio-frequency ablation (RFA) was chosen for the treatment of HCC. After inserting a laparoscope into the abdominal cavity, it was observed that HCC unexpectedly adhered to the mesentery as a result of TAE performed previously. After cutting off the adhered mesentery and removing it from the tumor, the combination therapy of percutaneous ethanol injection and RFA (PEI-RFA), developed at our department, was performed on the tumor. The tumor was successfully abrogated by PEI-RFA and the sufficient safety margin was confirmed by computed tomography after the treatment.
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PMID:Successful laparoscopic radiofrequency ablation of hepatocellular carcinoma adhered to the mesentery after transcatheter arterial embolization. 1558 3

A novel pH-sensitive and targetable antisense ODN delivery system based on multimolecular assembly into polyion complex (PIC) micelles of poly(L-lysine) (PLL) and a lactosylated poly(ethylene glycol)-antisense ODN conjugate (Lac-PEG-ODN) containing an acid-labile linkage (beta-propionate) between the PEG and ODN segments has been developed. The PIC micelles thus prepared had clustered lactose moieties on their peripheries and achieved a significant antisense effect against luciferase gene expression in HuH-7 cells (hepatoma cells), far more efficiently than that produced by the nonmicelle systems (ODN and Lac-PEG-ODN) alone, as well as by the lactose-free PIC micelle. In line with this pronounced antisense effect, the lactosylated PIC micelles showed better uptake than the lactose-free PIC micelles into HuH-7 cells; this suggested the involvement of an asialoglycoprotein (ASGP) receptor-mediated endocytosis process. Furthermore, a significant decrease in the antisense effect (27 % inhibition) was observed for a lactosylated PIC micelle without an acid-labile linkage (thiomaleimide linkage); this suggested the release of the active (free) antisense ODN molecules into the cellular interior in response to the pH decrease in the endosomal compartment is a key process in the antisense effect. Use of branched poly(ethylenimine) (B-PEI) instead of the PLL for PIC micellization led to a substantial decrease in the antisense effect, probably due to the buffer effect of the B-PEI in the endosome compartment, preventing the cleavage of the acid-labile linkage in the conjugate. The approach reported here is expected to be useful for the construction of smart intracellular delivery systems for antisense ODNs with therapeutic value.
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PMID:Smart polyion complex micelles for targeted intracellular delivery of PEGylated antisense oligonucleotides containing acid-labile linkages. 1575 96

The use of chitosan for gene delivery is limited due to the low transfection efficiency and difficulty in transfecting into a variety of cell types, especially the hepatoma cells. In order to solve this problem, lactobionic acid (LA) bearing galactose group was coupled with water-soluble chitosan (WSC) for liver specificity and poly(ethylenimine) (PEI) was combined to galactosylated chitosan (GC)/DNA complexes to enhance the transfection efficiency. For initial study, the effect of PEI on the transfection efficiency of WSC/DNA complex was studied in HeLa, A549 and 293 T cells, and bafilomycin A1 was used to ascertain the mechanism of synergistic effect. Transfection efficiency, cytotoxicity, and physicochemical properties of GC/DNA complex combined with PEI were investigated to determine the potential for the hepatocyte-targeting. The combination of PEI with WSC/DNA and GC/DNA complex dramatically increased the luciferase expression 10- to 1000-fold in various cell lines, and the synergistic effect was proved to be induced by proton sponge effect of PEI. The transfection of GC/DNA complex in HepG2 was much higher than that of WSC/DNA even after combination with PEI, and was highly inhibited in the presence of galactose. Cytotoxicity of PEI was much decreased by combination with GC/DNA complex. And PEI was proved to be coated on the surface of GC/DNA complex through the ionic interaction.
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PMID:Synergistic effect of poly(ethylenimine) on the transfection efficiency of galactosylated chitosan/DNA complexes. 1594 61

The asialoglycoprotein receptor (ASGP-R) on the hepatocyte membrane is a specific targeting marker for gene and drug delivery. Polyethylenimine (PEI) is a polycationic nonviral vector that is used for gene transfer. We have synthesized galactosylated polyethylenimine-graft-poly(ethylene glycol) (GPP) for performing gene delivery to the hepatocytes. The present study reports on the in vitro and in vivo data that was achieved in hepatoma bearing transgenic mice. The cytotoxicity was decreased with the increasing PEG content. The particle size of the complex was increased with the increasing PEG at an N/P ratio of 3.0, while the zeta potentials were decreased. The (99m)Tc labeled complexes were transfected into HepG2 and HeLa cells, while the GFP reporter genes were mainly expressed in the HepG2 cells. The in vivo data was achieved in ALB/c-Ha-ras transgenic mice. (99m)Tc labeled GPP(50)/DNA was injected into the mice via the tail vein, and the gamma images were acquired at 5, 15 and 30 min. The (99m)Tc labeled complexes were mainly localized in the heart and liver, and they were excreted through the kidneys. The GFP gene was mainly expressed in the proliferating cells at the tumor periphery. This result was confirmed by PCNA staining. The GPP(50)/DNA complexes were bound to ASGP-R of the proliferating hepatocytes in vitro and in vivo. The present results demonstrate the feasibility of nonviral gene transfer using galactosylated PEI-PEG in vivo.
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PMID:Asialoglycoprotein receptor targeted gene delivery using galactosylated polyethylenimine-graft-poly(ethylene glycol): in vitro and in vivo studies. 1625 76

Hepatocellular carcinoma (HCC) is one of the most common solid cancers worldwide with surgery being considered the treatment of choice. However, it is limited in view of the hepatic dysfunction and high recurrence rates associated with the disease. Liver transplantation offers the advantage of both, eradicating the tumor and treating the underlying liver disease and is the only chance for cure in patients suffering from HCC. Survival is known to reach 70% after 5 years and recurrent tumor can be found in less than 20% provided transplantation is restricted to patients with single tumors < or =5 cm or three nodules <3 cm (Milan criteria). However, donor organs are limited and the time on the transplant waiting list is up to 6 or 12 months in Europe and the United States with up to 30-40% dropouts per year. It has been demonstrated that patients with untreated HCC while on the waiting list longer than 6-10 months do not have any benefit in survival after liver transplantation. Interventional treatment options such as transarterial chemoembolization and percutaneous ablation techniques documented promising results concerning the reduction of dropouts from the waiting list and the potential risk for recurrent tumor. Mortality and morbidity were considerably low when radiological interventions had been considered as bridging therapies for liver transplantation. Percutaneous therapies come along with tumoral seeding of 0.1% to 0.6%. Adjuvant treatment with TACE, PEI, and/ or RFA in T1- and T2-staged HCC resulted in tumor-free survival after transplantation of 95.2% after 4 years and intention-to-treat survival of 94%, 85%, and 79% at 1, 2, and 3 years, respectively. Aggressive ablation therapy with a short transplant waiting time has the potential to optimize the use of liver transplantation for curative intent in selected cirrhotic HCC patients. Especially combined treatments seemed to play a key role in achieving complete tumor necrosis associated with improved disease-free survival after liver transplantation. In conclusion, no evidence based data exist in the literature supporting the efficacy of adjuvant interventional treatment modalities for HCC in patients awaiting liver transplantation. However, it has been shown that adjuvant (multimodal) interventional treatments seem a promising option for safe and effective bridging.
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PMID:Hepatocellular carcinoma: interventional bridging to liver transplantation. 1628 87

We have previously reported that the combination therapy of percutaneous ethanol injection and radiofrequency ablation (PEI-RFA) was more effective than RFA alone to induce wider coagulated necrosis for the treatment of hepatocellular carcinoma (HCC). In the present study, the effect of time-lag performance of RFA after PEI was evaluated under the same ablation condition as PEI-RFA by analyzing the volume of coagulated necrosis, the energy requirement for ablation and the amount of ethanol injected into HCC. The comparative study between time-lag PEI-RFA and no time-lag PEI-RFA showed that the total energy requirement and the energy requirement per unit volume for whole and marginal coagulated necrosis were significantly smaller in the time-lag group than in the no time-lag PEI-RFA group. In time-lag PEI-RFA, the volume of coagulated necrosis induced positively correlated with the amount of ethanol injected into HCC as previously observed in PEI-RFA treatment. These results suggest that time-lag PEI-RFA can induce comparable coagulated necrosis with a smaller energy requirement than no time-lag PEI-RFA, and that time-lag PEI-RFA is likely to be less invasive than no time-lag PEI-RFA for inducing comparable coagulated necrosis. Thus, time-lag performance of RFA after PEI may make RFA treatment more effective and less invasive for the treatment of patients with HCC.
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PMID:Time-lag performance of radiofrequency ablation after percutaneous ethanol injection for the treatment of hepatocellular carcinoma. 1652 48

We previously reported that the combination therapy of percutaneous ethanol injection and radiofrequency ablation (PEI-RFA) was more effective than RFA alone in inducing wider coagulated necrosis for the treatment of hepatocellular carcinoma (HCC). In the present study, we thoracoscopically applied the combination therapy to the treatment of HCC located immediately under the diaphragm. RFA electrode and ethanol injection needle were inserted into the tumor through the right side of the diaphragm in 6 patients with HCC close to the diaphragm. In all cases, the tumor was completely ablated with enough safety margin around the tumor. No local tumor recurrence has been observed in a relatively short-time follow-up period. The volume of coagulated necrosis and the energy requirement for coagulation in thoracoscopic ethanol injection and RFA (T-EI-RFA) were comparable to those of PEI-RFA. Although HCC located immediately under the diaphragm is difficult to treat with a percutaneous approach due to the poor visualization by ultrasonography, T-EI-RFA is considered to be an effective treatment modality.
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PMID:Thoracoscopic ethanol injection and radiofrequency ablation for the treatment of hepatocellular carcinoma located immediately under the diaphragm. 1682 Aug 79

Despite considerable efforts no ideal treatment exists for HCC. The disease is usually detected late and few patients are candidates for potentially curative treatment options such as surgical resection or liver transplantation. Surgical resection is limited mostly by the impaired liver function in cirrhotic livers, whereas liver transplantation is limited by tumor size, multi-localized disease and, most important, by shortage of donor organs. TACE as a local ablative treatment is able to induce local disease control and to prolong survival and might even achieve survival similar to surgical resection. The high rates of recurrence of HCC after successful control of local tumor spread is the reason to consider that procedure as a non-curative treatment option. PEI and RFA are able to control local tumor growth, but cannot influence tumor recurrence or de novo tumor growth. Systemic therapies need to be investigated in large randomized trials, especially to evaluate the use of somatostain analogues, HMGCoA reductase inhibitors, or other drugs such as rapamycin or inhibitors of vascular endothelial growth factor (VEGF).
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PMID:Hepatocellular carcinoma--rising incidence, changing therapeutic strategies. 1693 43


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