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Limitations include relatively short treatment periods (6 weeks per arm), potential carryover effects despite washout, modest sample size limiting power for subgroup analyses and exclusion of newer agents (e.g., tapentadol) and long-term safety outcomes, which may restrict applicability to broader clinical practice

These microenvironmental constraints can limit iron availability, activating adaptive pathways such as HIF-1, which promotes metabolic adaptation and tumor invasiveness ( Due to their rapid growth and proliferation, tumor cells have an increased demand for iron, disrupting iron metabolism

The Role of MDM2 Amplification and Overexpression in Tumorigenesis

Chen Y, Wang Y, Chen J, Chen X, Cao W, Chen S, et al