Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0025202 (melanoma)
 69,561 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Axitinib is an oral inhibitor of the VEGF, PDGF and colony stimulating factor-1 receptor tyrosine kinases and is currently in development by Pfizer Inc for the potential treatment of various solid tumors. Phase II trials with this agent alone or in combination with chemotherapeutic drugs were reported in several types of malignancy, with activity observed in thyroid, pancreatic, lung, renal, breast and colorectal cancers, melanoma and other carcinomas. Although frequent side effects have included fatigue, hypertension, diarrhea, hand-foot syndrome and proteinuria, axitinib was well tolerated overall. Larger, randomized phase II/III studies were ongoing at the time of publication.
 ...
PMID:Axitinib, a novel anti-angiogenic drug with promising activity in various solid tumors. 1851 65

Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) blockade therapies have been evaluated in clinical trials and have shown promise as possible options for treating patients with cancer. One agent under investigation is tremelimumab (CP-675,206), a monoclonal antibody that has been demonstrated to be a safe and efficacious treatment in patients with malignant melanoma. Results of a phase I clinical trial suggested that a dose of 15 mg/kg of tremelimumab would be the maximum-tolerated dose, with the most common grade 3-4 toxicities being diarrhea and rash. Pharmacokinetic studies showed that the postinfusion plasma concentration and area under the plasma disposition curve both increased in an approximately proportional manner with dose. Studies also showed that tremelimumab has a low clearance (0.132 ml/h x kg), a small volume of distribution (81.2 ml/kg), and a long terminal-phase half-life (22.1 days). A pivotal phase II clinical trial assessing single-agent tremelimumab as second-line therapy in metastatic melanoma has completed accrual, with response rate as the primary endpoint. A pivotal phase III trial has also completed accrual; that study compared the overall survival of previously untreated patients receiving single-agent tremelimumab versus dacarbazine or temozolomide.
 ...
PMID:Overcoming immunologic tolerance to melanoma: targeting CTLA-4 with tremelimumab (CP-675,206). 1900 Nov 46

Thirty patients with various solid tumors were treated with 5-azacytidine. Total doses ranged from 1.0 to 24.0 mg/kg and were given over a minimal period of 8 days. The major toxic effect was hematologic with significant leukopenia and thrombocytopenia usually occurring 20-30 days after the start of therapy, especially at higher dose levels. The marrow depression lasted 1-5 weeks and was fully reversible. Nausea and mild diarrhea were common following injection of the drug. Serum glutamic oxaloacetic transaminase levels rose in several patients. No other evidence of hepatic toxicity was seen. Objective remissions were noted in seven of 11 patients with cancer of the breast, two of five with melanoma, and two of six with cancer of the colon.
 ...
PMID:Phase I study of 5-azacytidine (NSC-102816) . 1905 3

We present a case report of a 59-year-old man with a history of arterial hypertension and excision of malignant melanoma. He was admitted to the hospital because of two months history of diarrhoea, weight loss and circulatory collapse. In addition, the patient suffered from marked vegetative instability with symptomatic hypotension, polyneuropathy and progression of renal insufficiency, without proteinuria. Complex examination did not reveal neoplasms, endocrine, autoimmune, infectious or neurodegenerative disorders. A serial biopsy of colon failed to provide a clue to the diagnosis. However, AA amyloidosis was found on the kidney biopsy. Neither chronic inflammation nor malignancy was revealed and, hence, no causal treatment could have been established. The patient died from multiple organ failure. The autopsy confirmed systemic AA amyloidosis. The triad consisting ofdiarrhoea, polyneuropathy and hypotension should rise the suspicion on amyloidosis.
 ...
PMID:[Persistent diarrhoea, hypotension, polyneuropathy]. 1906 86

Pathogens localized extracellularly or incorporated into endosomes are recognized mainly by Toll-like receptors, whereas pathogens and pathogen-derived molecules that invade into the cytoplasm of host cells typically are recognized by intracellular pattern recognition receptors (PRRs), such as retinoic acid-inducible gene (RIG)-like helicases (RLHs) and nucleotide-binding oligmerization domain (NOD)-like receptors (NLRs). RIG-I and melanoma differentiation-associated gene 5 (MDA5), which belong to the RLH family, recognize viral genomic RNA, whereas NOD2, a member of the NLR family, responds to microbial peptidoglycans. These receptors may play an important role in pig opportunistic infectious diseases, such as pneumonia and diarrhea, which markedly impair livestock productivity, such that polymorphisms of these receptor genes are potential targets of pig breeding to increase disease resistance. Here, we report single nucleotide polymorphisms (SNPs) in porcine DDX58, IFIH1, and NOD2, which encode RIG-I, MDA5, and NOD2, respectively. Interestingly, compared with DDX58 and IFIH1, NOD2 abounded in nonsynonymous SNPs both throughout the coding sequence and in sequences encoding domains important for ligand recognition, such as helicase domains for RIG-I and MDA5 and leucine-rich repeats in NOD2. These differences in the distribution of SNPs in intracellular PRRs may parallel the diversity of their ligands, which include nucleic acids and peptidoglycans.
 ...
PMID:Differences in distribution of single nucleotide polymorphisms among intracellular pattern recognition receptors in pigs. 1909 99

The management of unresectable metastatic melanoma is a major clinical challenge because of the lack of reliably effective systemic therapies. Blocking cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) has recently been proposed as a strategy to enhance cell-mediated immune responses to cancer, and clinical trials have demonstrated that anti-CTLA-4 therapy can produce durable outcomes with different response patterns than cytotoxic chemotherapy. We enrolled eight out of 155 patients with advanced melanoma in a multicentre phase II trial that evaluated the activity and tolerability of ipilimumab, a fully human, anti-CTLA-4 monoclonal antibody ( www.clinicaltrials.gov ; NCT00289627; CA184-008). Here we report our experience with three of these patients, who experienced progressive disease after a variety of previous therapies, including prior immunotherapies, and who achieved good outcomes with ipilimumab. One patient had a partial response ongoing at 17+ months on ipilimumab despite failure with four prior therapies, and the other two patients showed durable stable disease, both still ongoing at 17+ and 20+ months, respectively. The patient achieving a partial response experienced no side effects while receiving ipilimumab. The other two patients developed immune-related adverse events (irAEs) including rash (one case; grade 2) and diarrhoea (both cases; grades 1 and 2, respectively); the histopathology of colon biopsy samples from both was suggestive of colitis, with an abundant CD8+ T-cell infiltrate. Nausea, vomiting and acute pancreatitis were also observed in one patient. In addition, immunohistochemical findings of a dense CD8+, TIA1+ and granzyme B+ lymphoid infiltrate within a biopsied lesion provide indirect evidence of functional T-cell activation induced by treatment. These case reports highlight the potential for anti-CTLA-4-based therapy in previously treated patients with advanced melanoma. Moreover, because the patterns of response to ipilimumab differ from chemotherapy, we need to understand how and when patients may respond to treatment so that appropriate clinical decisions can be made.
 ...
PMID:Therapeutic efficacy of ipilimumab, an anti-CTLA-4 monoclonal antibody, in patients with metastatic melanoma unresponsive to prior systemic treatments: clinical and immunological evidence from three patient cases. 1913 84

Docosahexaenoic acid (DHA)-paclitaxel has a unique pharmacokinetic profile that allows high concentrations of paclitaxel to be delivered to melanoma cells for prolonged periods compared with paclitaxel. We investigated the response rate and safety of weekly DHA-paclitaxel in metastatic melanoma patients. We enrolled chemotherapy-naive patients with metastatic nonchoroidal melanoma using the two-stage Fleming design. At least one response was needed in the first stage to proceed to the second stage. DHA-paclitaxel (500 mg/m/week by 1-h intravenous infusion) was administered for 5 weeks every 6-week cycle until disease progression, intolerable toxicity, or treatment refusal. Response and toxicity were assessed every 6 weeks and weekly, respectively. Thirty patients were enrolled. The patients' median age was 67 years (range: 29-86 years). The median number of treatment cycles was 2 (range: 1-6 cycles). Three patients (10%) had partial responses; one lasted 4 months, and two lasted 5.6 months. Fifteen patients (50%) had stable disease with a median duration of 2.8 months (range: 2.6-8.9 months). The median survival was 14.8 months. Neutropenia (10%) and musculoskeletal pain (10%) were the most common grade 3 and 4 toxicities, and fatigue (73%), skin rash (70%), and diarrhea (60%) were the most common side effects. As a single-agent therapy, DHA-paclitaxel was well tolerated in metastatic melanoma patients. Its efficacy as a first-line therapy for metastatic melanoma does not exceed that seen with other single-agent chemotherapies such as dacarbazine. Further evaluation of DHA-paclitaxel in combination with other chemotherapy or targeted agents could be considered.
Melanoma Res 2009 Aug
PMID:Phase 2 open-label study of weekly docosahexaenoic acid-paclitaxel in cutaneous and mucosal metastatic melanoma patients. 1952 Dec 62

The anti-CTLA4 antibody, ipilimumab, has shown clinical activity against melanoma. Diarrhea due to immune-related colitis is the most frequent serious toxicity and, if untreated, may lead to intestinal perforation. Diarrhea treatment guidelines were developed based on clinical experience in over 2000 patients treated with ipilimumab, and these safety guidelines recommend systemic steroids as the first choice for the treatment of severe diarrhea. In this article, we present an alternative approach to the control of immune-related colitis by using the antitumor necrosis factor antibody, infliximab. Patients with metastatic melanoma received ipilimumab 10 mg/kg every 3 weeks for 4 doses, then every 3 months. Those who developed grade 2 diarrhea were treated with infliximab 5 mg/kg weeks 0 and 2 with mesalamine and loperamide. Steroids were given only for refractory cases requiring hospitalization. Of the first 3 cases of ipilimumab-induced diarrhea, 2 proved refractory and required hospitalization, but 1 recovered quickly without systemic steroids. We then added hydrocortisone enemas daily to the above regimen, and the next 3 patients recovered from grade 2 ipilimumab-induced colitis without difficulty. Treatment with infliximab, mesalamine, and hydrocortisone enemas may produce a rapid improvement in ipilimumab-induced colitis and avoid the administration of systemic steroids.
 ...
PMID:Infliximab in the treatment of anti-CTLA4 antibody (ipilimumab) induced immune-related colitis. 1953 54

Abstract The use of immunotherapeutics in melanoma has received much attention, and recent advances to further characterize the regulatory components of the immune system and the importance of co-stimulatory molecules have opened a new area for clinical investigation. Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) serves as a negative regulator of immunity. Recent trials administering fully human anti-CTLA-4 monoclonal antibodies to melanoma patients have demonstrated clinically meaningful responses. Treatment with CTLA-4 blocking antibodies, however, is not without potential toxicities. Autoimmune side-effects, the most common being colitis-associated diarrhea, are frequently associated with clinical responses. In efforts to build upon prior vaccination efforts as well as attempt to offer patients clinically meaningful immune responses with a CTLA-4 blockade but without significant toxicities, we conducted a clinical trial in patients who previously received autologous tumor cells engineered to secrete granulocyte-macrophage colony stimulating factor (GVAX; Cell Genesys, South San Francisco, CA, USA) with periodic infusions of CTLA-4 blocking antibodies. This sequential treatment resulted in clinically significant anti-tumor immunity without grade 3 or 4 toxicity in most patients. Pathological analyses following treatment of pre-existing tumors revealed a linear correlation between tumor necrosis and the ratio of intra-tumoral CD8+ effector cells to FoxP3+ regulatory cells (T(regs)). Effective anti-tumor immunity and serious autoimmunity can be disassociated. Further targeting of anti-tumor T(regs)in combinatorial therapy approaches may be a rich avenue of future investigation.
 ...
PMID:Overcoming immunological tolerance to melanoma: Targeting CTLA-4. 2048 28

Gastrointestinal malignant melanomas, either primary or metastatic, are rare and overlooked tumors. There is also controversy regarding the actual existence of primary melanoma in the gastrointestinal tract apart from the esophagus and anorectal regions, where melanocytes normally exist. A case of malignant melanoma in the cecum is presented. The patient was a 30- year-old male who presented to the hospital for abdominal pain and diarrhea. The tumor was located mainly in the submucosa and measured 14x11x4.5 cm. The cut surface was solid, gray-white and fleshy. Histologically, tumor cells were arranged in compact nests or wide cords surrounded by fibrous stroma. The tumor cells had pleomorphic nuclei and quite rich cytoplasm; multinucleated, giant tumor cells were intermingled. Although no tumor cells contained apparent brown pigment, most were found to be positive for S-100 protein, HMB-45, Melan-A, and vimentin. The possibility of a metastatic lesion was considered. While the patient had a history of a pathologically examined dorsal nevus excision two years before, there was no evidence of either cutaneous or ocular primary melanoma at the time of diagnosis. Moreover, a thorough postoperative investigation did not reveal any other lesion in any other site favoring a metastatic spread. There was also no evidence of recurrent disease or metastasis one year after the surgery. This case is presented in view of its rare occurrence in the cecum. The difficulties in the diagnostic course are discussed, together with a literature review on distinguishing a primary mucosal melanoma from a metastatic one from an unknown or regressed cutaneous primary tumor.
 ...
PMID:Colonic malignant melanoma, primary or metastatic? Case report. 2053 13


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>