Background Obesity has been linked to increased mortality in several cancer types; however, the relationship between obesity and survival in metastatic melanoma is unknown. The aim of this study was to examine the association between BMI, progression-free survival (PFS), and overall survival (OS) in metastatic melanoma. Methods This study included 6 independent cohorts for a total of 1918 metastatic melanoma patients. These included two targeted therapy cohorts [randomized control trials (RCTs) of dabrafenib and trametinib (n=599) and vemurafenib and cobimetinib (n=240)], two immunotherapy cohorts [RCT of ipilimumab + dacarbazine (DTIC) (n=207) and a retrospective cohort treated with anti-PD-1/PDL-1 (n=331)], and two chemotherapy cohorts [RCT DTIC cohorts (n=320 and n=221)]. BMI was classified as normal (BMI 18 to <25; n=694 of 1918, 36.1%) overweight (BMI 25-29.9; n=711, 37.1%) or obese (BMI≥30; n=513, 26.7%). The primary outcomes were the association between BMI, PFS, and OS, stratified by treatment type and sex. These exploratory analyses were based on previously reported intention-to-treat data from the RCTs. The effect of BMI on PFS and OS was assessed by multivariable-adjusted Cox models in independent cohorts. In order to provide a more precise estimate of the association between BMI and outcomes, as well as the interaction between BMI, sex, and therapy type, adjusted hazard ratios were combined in mixed-effects meta-analyses and heterogeneity was explored with meta-regression analyses. Findings In the pooled analysis, obesity, as compared to normal BMI, was associated with improved survival in patients with metastatic melanoma [average adjusted hazard ratio (HR) and 95% CI: 0.77 (0.66-0.90) and 0.74 (0.58-0.95) for PFS and OS, respectively]. The survival benefit associated with obesity was restricted to patients treated with targeted therapy [0.72 (0.57-0.91) and 0.60 (0.45-0.79) for PFS and OS, respectively] and immunotherapy [0.75 (0.56-1.00) and 0.64 (0.47-0.86)]. No associations were observed with chemotherapy [0.87 (0.65-1.17) and 1.03 (0.80-1.34); treatment p for interaction = 0.61 and 0.01, for PFS and OS, respectively]. The prognostic effect of BMI with targeted and immune therapies differed by sex with pronounced inverse associations in males [PFS 0.67 (0.53-0.84) and OS 0.53 (0.40-0.70)], but not females [PFS 0.92 (0.70-1.23) and OS 0.85 (0.61-1.18), sex p for interaction= 0.08 and 0.03, for PFS and OS, respectively] Interpretation Obesity is associated with improved PFS and OS in metastatic melanoma, driven by strong associations observed in males treated with targeted or immune therapy. The magnitude of the benefit detected supports the need for investigation into the underlying mechanism of these unexpected observations Funding ASCO/CCF Young Investigator Award and ASCO/CCF Career Development Award to JLM
Sublethal insults can induce tolerance to subsequent stressors in neurons. As cell death activators such as ROS generation and decreased ATP can initiate tolerance, we tested whether other cellular elements normally associated with neuronal injury could add to this process. In an in vivo model of ischemic tolerance, we were surprised to observe widespread caspase 3 cleavage, without cell death, in preconditioned tissue. To dissect the preconditioning pathways activating caspases, and the mechanisms by which these proteases are held in check, we developed an in vitro model of excitotoxic tolerance. In this model, antioxidants and caspase inhibitors blocked ischemia-induced protection against N-methyl-D-aspartate toxicity. Moreover, agents that blocked preconditioning also attenuated induction of HSP 70; transient overexpression of a constitutive form of this protein prevented HSP 70 upregulation and blocked tolerance. We outline a neuroprotective pathway where events normally associated with apoptotic cell death are critical for cell survival. P rior exposure to sublethal challenges can render neuronal tissue less vulnerable to severe insults (1). Preconditioning models share several key features, including limited window of efficacy, requirement for protein synthesis, involvement of ATP sensitive K ϩ (K ATP ) channels, and heat-shock protein (HSP) induction (2, 3). However, the underlying mechanisms mediating neuroprotection remain undefined. The up-regulation of prosurvival elements within preconditioned cells seems to depend upon activation of pathways typically associated with degeneration. For example, generation of reactive oxygen species (ROS) is critical for induction of tolerance in cardomyocytes (4, 5) and neurons (6-9). Metabolic dysfunction also contributes to preconditioning, as decline in ATP͞ADP ratios leads to mitochondrial K ATP channel opening (8) and ROS production (10). In fact, neuronal preconditioning is attenuated with K ATP antagonists (2), and K ATP activators are neuroprotective (11).Although ROS and energetic dysfunction contribute to preconditioning, little is known about how far these pathways progress before being halted, or the mechanism by which they are blocked. Here, we investigated the extent of activation of cell death pathways during ischemic preconditioning (IP) in vivo as well as the mechanism by which activation of these pathways results in tolerance in vitro. We propose a new model of IP in which neuroprotection depends upon activation of factors typically associated with neurodegeneration. Materials and MethodsFocal IP, Immunohistochemistry, and Immunoblotting. Transient MCAO was performed on spontaneously hypertensive rats (12). Immunohistochemistry for activated caspase 3 was performed as described (12). At various times after preconditioning, tissue was harvested, and proteins were run by SDS͞PAGE (13). For details, see Supporting Materials and Methods, which is published as supporting information on the PNAS web site, www.pnas.org.Tissue Culture and in Vitro Precondit...
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