Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0019158 (hepatitis)
 30,205 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Conventional interferons including interferon-alpha (IFN-alpha) are cytokines used for years in the treatment of solid tumors and hematological malignancies. Their half-life is short. Pegylated forms of IFN-alpha present an improved pharmacokinetic profile that rendered them the preferred IFNs in hepatitis therapy. In the last decade, pegylated interferons (PegIFNs) have been investigated in melanoma patients. We review the scientific published literature on biology, pharmacokinetics, side effects and clinical applications of PegIFN-alpha in the treatment of stage III and IV melanoma. In the adjuvant setting, PegIFNalpha-2b has significant prolonged distant metastases free survival in patients with microscopic nodal involvement (stage TxN1aM0) and therefore is a promising treatment option in this patient population. In the palliative setting, monotherapy with PegIFNalpha-2alpha can induce complete remissions in a minority of stage IV melanoma patients. The combination of monochemotherapy is feasible and may result in lasting complete remissions. Ongoing research must focus on the identification of patients who mostly benefit, so that unnecessary toxicity would be avoided. Combining PegIFNs and chemotherapy or targeted agents deserves further exploration.
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PMID:Long-term pegylated interferon-alpha and its potential in the treatment of melanoma. 1970 6

Classic interferon-alpha formulations have antitumour activity in a variety of neoplastic diseases, including the adjuvant and palliative setting of metastatic melanoma, as single agents or in combination with chemotherapy and/or interleukin-2. Pegylated interferon, widely used for the treatment of hepatitis, seems to be at least equally efficacious as standard recombinant interferon in the treatment of metastatic melanoma, and the available evidence suggests that equi-efficacious doses have somewhat lower acute toxicity. Moreover, the favourable pharmacokinetic properties of pegylated interferon allow the administration on a weekly basis, with sustained exposure to interferon during that entire period. Several clinical trials have been conducted testing adjuvant and palliative treatment with pegylated interferon-alpha in high-risk melanoma patients with promising results. The role of pegylated interferons in the setting of advanced metastatic melanoma will need further investigation in clinical trials, potentially in combination with targeted or cytotoxic agents with regard to synergistic antiangiogenic and cytotoxic effects. The use of pegylated interferons in earlier stage melanomas will be investigated in upcoming trials.
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PMID:Pegylated interferons: prospects for the use in the adjuvant and palliative therapy of metastatic melanoma. 1985 57

The family of mammalian chitinases includes members both with and without glycohydrolase enzymatic activity against chitin, a polymer of N-acetylglucosamine. Chitin is the structural component of fungi, crustaceans, insects and parasitic nematodes, but is completely absent in mammals. Exposure to antigens containing chitin- or chitin-like structures sometimes induces strong T helper type-I responses in mammals, which may be associated with the induction of mammalian chitinases. Chitinase 3-like-1 (CHI3L1), a member of the mammalian chitinase family, is induced specifically during the course of inflammation in such disorders as inflammatory bowel disease, hepatitis and asthma. In addition, CHI3L1 is expressed and secreted by several types of solid tumors including glioblastoma, colon cancer, breast cancer and malignant melanoma. Although the exact function of CHI3L1 in inflammation and cancer is still largely unknown, CHI3L1 plays a pivotal role in exacerbating the inflammatory processes and in promoting angiogenesis and remodeling of the extracellular matrix. CHI3L1 may be highly involved in the chronic engagement of inflammation which potentiates development of epithelial tumorigenesis presumably by activating the mitogen-activated protein kinase and the protein kinase B signaling pathways. Anti-CHI3L1 antibodies or pan-chitinase inhibitors may have the potential to suppress CHI3L1-mediated chronic inflammation and the subsequent carcinogenic change in epithelial cells.
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PMID:Potential role of chitinase 3-like-1 in inflammation-associated carcinogenic changes of epithelial cells. 1990 31

The murine coronavirus mouse hepatitis virus (MHV) induced the expression of type I interferon (alpha/beta interferon [IFN-alpha/beta]) in mouse oligodendrocytic N20.1 cells. This induction is completely dependent on virus replication, since infection with UV light-inactivated virus could no longer induce IFN-alpha/beta. We show that MHV infection activated both transcription factors, the IFN regulatory factor 3 (IRF-3) and nuclear factor kappaB (NF-kappaB), as evidenced by phosphorylation and nuclear translocation of IRF-3 and an increased promoter binding activity for IRF-3 and NF-kappaB. Furthermore, the cytoplasmic pattern recognition receptor retinoic acid-inducible gene I (RIG-I) was induced by MHV infection. Knockdown of RIG-I by small interfering RNAs blocked the activation of IRF-3 and subsequent IFN-alpha/beta production induced by MHV infection. Knockdown of another cytoplasmic receptor, the melanoma-differentiation-associated gene 5 (MDA5), by small interfering RNAs also blocked IFN-beta induction. These results demonstrate that MHV is recognized by both RIG-I and MDA5 and induces IFN-alpha/beta through the activation of the IRF-3 signaling pathway. However, knockdown of RIG-I only partially blocked NF-kappaB activity induced by MHV infection and inhibition of NF-kappaB activity by a decoy peptide inhibitor had little effect on IFN-alpha/beta production. These data suggest that activation of the NF-kappaB pathway might not play a critical role in IFN-alpha/beta induction by MHV infection in oligodendrocytes.
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PMID:Murine coronavirus induces type I interferon in oligodendrocytes through recognition by RIG-I and MDA5. 2042 26

The liver is the primary site of metastases for many malignancies. Gastrointestinal cancers are especially prone to spread to the liver and other tumours, as breast cancer and melanoma often spread to the liver. On the other hand, hepatocellular cancer (HCC) is the fifth most common malignancy in the world due to its common etiology from chronic liver damage caused by hepatitis or cirrhosis. Treatments of liver tumours vary according to histology and liver invasion and until now trans-arterial chemoembolization (TACE) has represented a main approach in the therapy of liver tumours. This review takes into consideration: (i) the background to utilizing TACE in liver tumours; (ii) TACE methods and the biological rationale for utilizing chemotherapeutic agents coated to a new micro-particle such as DC-Beads and HepaSphere; (iii) clinical experiences employing TACE in different liver tumours; (iv) the pivotal role of angiogenesis and hypoxia-induced angiogenesis following TACE with special references to HCC. Finally, the rationale for the combination of TACE with angiogenesis inhibitors is also discussed.
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PMID:Trans-arterial chemoembolization as a therapy for liver tumours: New clinical developments and suggestions for combination with angiogenesis inhibitors. 2106 40

Malignant melanoma is rising faster in incidence than any other malignancy. Long-term remission or "cure" is rare and is almost exclusively limited to therapies that stimulate an immune antitumor response. Ipilimumab is a novel targeted human immunostimulatory monoclonal antibody that blocks cytotoxic T-lymphocyte antigen4 (CTLA-4), an immune-inhibitory site expressed on activated T cells. Ipilimumab is well tolerated as an outpatient infusion therapy. Multiple studies have confirmed significant antimelanoma activity. A randomized trial has documented a survival benefit when ipilimumab was compared to a gp-100 vaccine only arm. The unique mechanism of action of ipilimumab makes assessment of response by conventional criteria difficult. Benefit from ipilimumab can occur after what would be considered progression with World Health Oganization (WHO) or Response Evaluation Criteria in Solid Tumors (RECIST) criteria. New immune response criteria have been proposed. Therapeutic responses peak between 12 and 24 weeks, with slow responses continuing up to and beyond 12 months. The major drug- related adverse side effects (10%-15% grade 3 or above) are immune-related and consist most commonly of rash, colitis, hypophysitis, thyroiditis, and hepatitis. Colonic perforation can occur and patients with diarrhea have to be monitored carefully with strict adherence to treatment algorithms. Algorithms for the treatment of other adverse side effects have been developed. The treatment of immune-related side effects with immunosuppressive agents, such as corticosteroids, does not appear to impair antitumor response. With proper monitoring and management of side effects, ipilimumab is an extremely safe drug to administer. The benefits of ipilimumab will most certainly extend to other malignancies in the near future.
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PMID:Ipilimumab: unleashing the power of the immune system through CTLA-4 blockade. 2107 58

The promising new class of immunomodulating antibodies directed against cytotoxic T-lymphocyte antigen-4 (CTLA-4) has been extensively tested in clinical trials and found to be active against cutaneous melanoma and other tumor histotypes. Inhibition of CTLA-4 characteristically induces well-identified side effects for which the definition "immune-related adverse events" (irAEs) has been proposed. IrAEs mainly include colitis/diarrhea, dermatitis, hepatitis, and endocrinopathies; uveitis, nephritis, and inflammatory myopathy also have been reported occasionally. These unique side effects are likely a direct result of breaking immune tolerance upon CTLA-4 blockade and are generally mild, reversible, and manageable, following specific treatment guidelines that include symptomatic therapies or systemic corticosteroids. However, patient-physician communication and early treatment are also emerging as critical issues to successfully manage irAEs, thus avoiding major complications. The major experience in identifying and managing CTLA-4 treatment-related side effects has derived from studies in melanoma patients; nevertheless, accumulating clinical experiences are clearly demonstrating that irAEs are class-specific events, and that they are fully overlapping in patients with tumors of different histotypes. This review provides an overview of current safety data on CTLA-4 antagonists and of available strategies to optimize their clinical use in cancer patients.
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PMID:The emerging toxicity profiles of anti-CTLA-4 antibodies across clinical indications. 2107 65

Immune-modifying monoclonal antibodies may induce or enhance the natural immune response against tumor cells. The complex interaction between antigen-presenting cells and T lymphocytes as an immune response is strongly affected by anti-CD152 (CTLA-4)-antibodies. The cytotoxic T-lymphocyte (CTLA-4) receptor binds molecules of the B7-family which leads to a suppression of T cells. Specific CTLA-4 antibodies induce an unrestrained T-cell activation. Treatment with the CTLA-4 antibodies ipilimumab and tremelimumab has been investigated in metastatic melanoma only within clinical trials. Currently, the critical phase III trial on ipilimumab is in the final analysis process and expected to lead to approval. CTLA-4 antibodies belong to the most promising new molecules for the treatment of advanced melanoma. During treatment with CTLA-4 antibodies, distinct adverse events may occur. Treating physicians must be familiar with their appropriate treatment and prophylaxis. The most frequently observed side effects are diseases such as an autoimmune colitis which is typically characterized by a mild to moderate, but occasionally also severe and persistent diarrhea. Other autoimmune-mediated side effects like hypophysitis, hepatitis, iridocyclitis or an exacerbation of lupus nephritis have been reported in the literature. Their early recognition and treatment are mandatory to reduce the risk of sequelae for CTLA-4-antibod-treated patients. Autoimmune-mediated side effects are reported to correlate positively with treatment response. We review the mechanisms of action, provide an update on clinical trials with the two CTLA-4-antibodies for metastatic melanoma, and present detailed recommendations for managing the side effects of these new agents.
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PMID:Treatment and side effect management of CTLA-4 antibody therapy in metastatic melanoma. 2108 48

A 61-year-old man, who had medical history of hepatitis type C, surgery for malignant melanoma of the lower limb, endoscopic mucosal resection for esophageal cancer, was pointed out a pulmonary nodule in the right middle lobe by surveillance computed tomography after 5 years of surgery for melanoma. Pathology of esophageal cancer was squamous cell carcinoma limited in mucosa without lymphatic nor venous invasion. The nodule gradually enlarged and respiratory endoscopic examination could not establish pathological diagnosis. Thoracoscopy-assisted pulmonary biopsy revealed squamous cell carcinoma, and right middle lobectomy with mediastinal node dissection was performed. Histological examination showed moderately differentiated squamous cell carcinoma without lymph node involvement. The stage of lung cancer was T1N0M0, stage IA. Although 9 months have passed since surgery for lung cancer, recurrence of each malignancy has not been detected.
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PMID:[Three primary cancers of pulmonary cancer, malignant melanoma and esophageal cancer; report of a case]. 2159 48

Arden Syntax is a widely recognized standard for representing clinical and scientific knowledge in an executable format. It has a history that reaches back until 1989 and is currently maintained by the Health Level 7 (HL7) organization. We created a production-ready development environment, compiler, rule engine and application server for Arden Syntax. Over the course of several years, we have applied this Arden - Syntax - based CDS system in a wide variety of clinical problem domains, such as hepatitis serology interpretation, monitoring of nosocomial infections or the prediction of metastatic events in melanoma patients. We found the Arden Syntax standard to be very suitable for the practical implementation of CDS systems. Among the advantages of Arden Syntax are its status as an actively developed HL7 standard, the readability of the syntax, and various syntactic features such as flexible list handling. A major challenge we encountered was the technical integration of our CDS systems in existing, heterogeneous health information systems. To address this issue, we are currently working on incorporating the HL7 standard GELLO, which provides a standardized interface and query language for accessing data in health information systems. We hope that these planned extensions of the Arden Syntax might eventually help in realizing the vision of a global, interoperable and shared library of clinical decision support knowledge.
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PMID:The Arden Syntax standard for clinical decision support: experiences and directions. 2234 33


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