c-Abl and Arg are activated in human primary melanomas, promote melanoma cell invasion via distinct pathways, and drive metastatic progression.

Despite 35 years of clinical trials, there is little improvement in 1-year survival rates for patients with metastatic melanoma, and the disease is essentially untreatable if not cured surgically. The paucity of chemotherapeutic agents that are effective for treating metastatic melanoma indicates a dire need to develop new therapies. Here, we found a previously unrecognized role for c-Abl and Arg in melanoma progression. We demonstrate that the kinase activities of c-Abl and Arg are elevated in primary melanomas (60%), in a subset of benign nevi (33%) and in some human melanoma cell lines. Using siRNA and pharmacological approaches, we show that c-Abl/Arg activation is functionally relevant because it is requiredfor melanoma cell proliferation, survival and invasion. Significantly, we identify the mechanism by which activated c-Abl promotes melanoma invasion by showing that it transcriptionally upregulates matrix metalloproteinase-1 (MMP-1), and using rescue approaches we demonstrate that c-Abl promotes invasion through a STAT3 → MMP-1 pathway. Additionally, we show that c-Abl and Arg are not merely redundant, as active Arg drives invasion in a STAT3-independent manner, and upregulates MMP-3 and MT1-MMP, in addition to MMP-1. Most importantly, c-Abl and Arg not only promote in vitro processes important for melanoma progression, but also promote metastasis in vivo, as inhibition of c-Abl/Arg kinase activity with the c-Abl/Arg inhibitor, nilotinib, dramatically inhibits metastasis in a mouse model. Taken together, these data identify c-Abl and Arg as critical, novel, drug targets in metastatic melanoma, and indicate that nilotinib may be useful in preventing metastasis in patients with melanomas harboring active c-Abl and Arg.

Subsequent general anaesthesia in patients with a history of previous anaphylactoid/anaphylactic reaction to muscle relaxant.

Of 151 patients with a possible anaphylactoid/anaphylactic reaction to a muscle relaxant investigated over a 20-year period, follow-up for any subsequent general anaesthesia was complete in 145 (96%). One hundred and twenty-two anaesthetics in 72 patients were documented. There were no anaesthetic-related deaths. No subsequent reactions were seen if muscle relaxants were not used in the subsequent anaesthetic, nor were they in patients with severe reactions if the original intradermal test had been equivocal or negative. In the patients with a severe reaction and a positive intradermal test to one or more muscle relaxants, six out of 40 later anaesthetics using muscle relaxants were associated with clinical problems, three being probable anaphylactic reactions, whilst three were minor. Intradermal testing should be performed prior to surgery in this group of patients for the muscle relaxant(s) planned, or an anaesthetic technique which avoids relaxants should be used. This review should encourage other centres to undertake similar follow-up.

A hypersensitivity screening clinic following untoward reactions to anaesthesia.

Anaphylactoid or anaphylactic reactions to drugs used during general anaesthesia are potentially life threatening. It is important that they be differentiated from other types of cardio-respiratory collapse. At present a detailed history of the time sequence of events in relation to drug administration is of a greatest importance. Retrospective skin testing may then indicate which agent was involved, although false positives and false negatives may occur. Forty-nine patients who presented with a history of collapse during anaesthesia over a five year period were skin tested. Positive results were obtained in 22, ten gave inconclusive test results but a strongly suggestive history. The remainder were considered to have other causes for their clinical presentation. The incidence of severe reactions confirmed by history and by skin testing in this community is approximately 1:4000.