Phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) plays a crucial role in the control of cellular growth, proliferation, survival, metabolism, angiogenesis, transcription, and translation. In most human cancers, alterations to this pathway are common and cause activation of other downstream signaling pathways linked with oncogenesis. The mTOR pathway modulates the interactions between the stroma and the tumor, thereby affecting both tumor immunity and angiogenesis. Inflammation is a hallmark of cancer, playing a central role in the tumor dynamics, and immune cells can exert antitumor functions or promote the growth of cancer cells. In this context, mTOR may regulate the activity of macrophages and T cells by regulating the expression of cytokines/chemokines, such as interleukin (IL)-10 and transforming growth factor (TGF-β), and/or membrane receptors, such as cytotoxic T-Lymphocyte protein 4 (CTLA-4) and Programmed Death 1 (PD-1). Furthermore, inhibitors of mammalian target of rapamycin are demonstrated to actively modulate osteoclastogenesis, exert antiapoptotic and pro-differentiative activities in osteoclasts, and reduce the number of lytic bone metastases, increasing bone mass in tumor-bearing mice. With regard to the many actions in which mTOR is involved, the aim of this review is to describe its role in the immune system and bone metabolism in an attempt to identify the best strategy for therapeutic opportunities in the metastatic phase of solid tumors.

Background This study aimed to assess the characteristics of breakthrough cancer pain (BTcP) in patients receiving low doses of opioids for background pain in comparison with patients receiving at least 60 mg of oral morphine equivalents (OME). Materials and Methods Patients with advanced cancer receiving less than 60 mg/day of OME with episodes of BTcP were included in the analysis (group L). Data were compared with patients receiving doses of opioids ≥60 mg of OME (group H). Pain intensity, current analgesic therapy, number of BTcP episodes, intensity of BTcP, its predictability and triggers, onset duration, interference with daily activities, BTcP medications, and time to meaningful pain relief were collected. Adverse effects imputable to a BTcP medication were recorded. Results A total of 1,418 and 2,474 patients were included in groups L and H, respectively. A lower number of BTcP episodes (p = .005), a lower BTcP intensity (p = .0001), a faster BTcP onset (p = .024), and a longer time to meaningful pain relief after taking a BTcP medication (p = .009) were found in group L as compared with group H. In group L, BTcP interference on daily activity was less than in group H (p = .009). Patients in group L were less likely to be prescribed an opioid as BTcP medication in comparison with patients in group H (p = .0001). Opioid doses used for BTcP were significantly higher in group H. Patients in group L were more likely to be less satisfied (p = .003) than patients in group H. No adverse effects of severe intensity were reported in both groups. Conclusion Patients receiving lower doses of opioids exhibit some differences in BTcP presentation: fewer episodes with lower intensity and a faster onset, a longer time to meaningful pain relief, and less satisfaction with BTcP medication. A relevant percentage of patients was receiving fentanyl preparations normally reserved for patients receiving higher doses of opioids. Implications for Practice Breakthrough pain is present in patients receiving low doses of opioids. It has its own peculiarities: less frequent, lower intensity, faster onset, longer time to meaningful pain relief, and less satisfaction with medication. Many patients were prescribed fentanyl preparations, which are normally reserved for patients receiving higher doses of opioids.

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