Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P17174 (aspartate aminotransferase)
 14,872 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

High-dose interleukin-2 (IL-2) therapy has a response rate of approximately 20% in patients with metastatic melanoma and renal cell cancer. Animal models have shown that the anti-tumor effects of IL-2 are dose and schedule dependent, and one report has shown that patients with melanoma who responded to IL-2 therapy received more doses of IL-2 than did those who did not respond. The current study evaluated patients' tolerance to IL-2 over multiple courses of therapy and the factors that affected the number of doses delivered. Patients with metastatic melanoma or renal cell cancer who received at least two consecutive courses of high-dose intravenous IL-2 alone from October 1, 1985 through December 31, 1996 were evaluated. Patients served as their own controls in paired analyses. The number of doses tolerated from one course to the next and the reasons for stopping therapy were analyzed. One hundred fifty-nine patients received two or more courses of therapy during the study. The median number of doses of high-dose IL-2 decreased from course 1 (15 doses) to course 2 (12 doses) (p2 = 0.0001). Pretreatment factors were not found to significantly influence the decrease in the number of doses delivered. Only 2 of 33 separate toxic effects resulting in discontinuation of IL-2 dosing were found to be significantly different between courses. After adjusting for multiple tests of statistical significance, serum aspartate aminotransferase elevations were more likely to stop course 1 (p2 = 0.0033) and creatinine elevations were more likely to stop course 2 (p2 = 0.00007). The influence of renal toxicity was further assessed by comparing the median creatinine value at the time IL-2 dosing was discontinued. This difference was found to be significant when cycle 1 of course 1 (1.5 mg/dL) was compared with cycle 1 of course 2 (1.8 mg/dL; p2 = 0.0001). When pretreatment factors were analyzed, male sex (p2 = 0.006), a diagnosis of renal cell cancer (p2 = 0.008), previous nephrectomy (p2 = 0.001), and older age (p2 = 0.0055) were significantly associated with the development of renal toxicity that resulted in discontinuation of IL-2 therapy. Furthermore, the same four patient subsets had higher baseline creatinine values in individual univariate analyses. This study identified subsets of patients who tolerated less IL-2 with repeated courses. The decreasing tolerance to IL-2 was associated primarily with elevations in creatinine. Finding ways to ameliorate the renal toxicity seen during IL-2 therapy in this patient population may allow an increase in the number of IL-2 doses administered and potentially an increase in clinical response.
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PMID:Decreased tolerance to interleukin-2 with repeated courses of therapy in patients with metastatic melanoma or renal cell cancer. 1083 68

About 40% to 60% of melanomas present BRAF mutation. Selective BRAF inhibitors such as vemurafenib and dabrafenib are currently approved for the treatment of advanced melanoma patients with BRAF mutation. The treatment-induced tumor regression occurs in the majority of patients; however, acquired resistance to BRAF inhibitors is observed in most of the patients after 6 to 7 months. After progression of the disease, the patient might be offered treatment with ipilimumab followed by chemotherapy. Subsequent lines of systemic treatment of metastatic melanoma patients do not exist.Here we report a case of a 59-year-old woman with a diagnosis of BRAF-mutant metastatic melanoma that responded to initial treatment with vemurafenib. Subsequently, after disease progression, the patient received chemotherapy. Since no clinical response to dacarbazine was observed, carboplatin with paclitaxel were applied. Transient partial response was obtained, which was followed by further disease progression. Then retreatment with vemurafenib was applied. The patient developed very short-term tumor regression and significant biochemical response (serum lactate dehydrogenase, alanine aminotransferase, and aspartate aminotransferase) to the treatment. However, following 5 weeks of retreatment, the patient developed progression of the disease. Our clinical observation indicates that in melanoma patients who developed resistance to selective BRAF inhibitors, rechallenge after treatment interruption might be beneficial.
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PMID:Resistance to vemurafenib can be reversible after treatment interruption: a case report of a metastatic melanoma patient. 2550 Oct 56

Purpose The clinical activity observed in a phase I dose-escalation study of concurrent therapy with nivolumab (NIVO) and ipilimumab (IPI) in patients with previously treated or untreated advanced melanoma led to subsequent clinical development, including randomized trials. Here, we report long-term follow-up data from study CA209-004, including 3-year overall survival (OS). Patients and Methods Concurrent cohorts 1, 2, 2a, and 3 received escalating doses of NIVO plus IPI once every 3 weeks for four doses, followed by NIVO once every 3 weeks for four doses, then NIVO plus IPI once every 12 weeks for eight doses. An expansion cohort (cohort 8) received concurrent NIVO 1 mg/kg plus IPI 3 mg/kg once every 3 weeks for four doses, followed by NIVO 3 mg/kg once every 2 weeks, which is the dose and schedule used in phase II and III studies and now approved for patients with unresectable or metastatic melanoma. Results Among all concurrent cohorts (N = 94) at a follow-up of 30.3 to 55.0 months, the 3-year OS rate was 63% and median OS had not been reached. Objective response rate by modified WHO criteria was 42%, and median duration of response was 22.3 months. Incidence of grade 3 and 4 treatment-related adverse events was 59%. The most common grade 3 and 4 treatment-related adverse events were increases in lipase (15%), alanine aminotransferase (12%), and aspartate aminotransferase (11%). One treatment-related death (1.1%) occurred in a patient who had multiorgan failure 70 days after the last dose of NIVO plus IPI. Conclusion This is the longest follow-up for NIVO plus IPI combination therapy in patients with advanced melanoma. The 3-year OS rate of 63% is the highest observed for this patient population and provides additional evidence for the durable clinical activity of immune checkpoint inhibitors in the treatment of advanced melanoma.
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PMID:Nivolumab Plus Ipilimumab in Patients With Advanced Melanoma: Updated Survival, Response, and Safety Data in a Phase I Dose-Escalation Study. 3013 77