High FiO2 and Cancer

Meyhoff CS, et al.: Increased long-term mortality after a high perioperative inspiratory oxygen fraction during abdominal surgery: follow-up of a randomized clinical trial. Anesth Analg. 2012 Oct;115(4):849-54. Epub 2012 Jul 13.

  • High perioperative inspiratory oxygen fraction (80%) may prevent postoperative wound infections.
  • PROXI trial, found no reduction in surgical site infection, and 30-day mortality was higher in patients given 80% oxygen
  • 1386 patients underwent laparotomy
  • randomization to receive either 80% or 30% oxygen during and for 2 hours after surgery
  • Median follow-up of 2.3 years (range 1.3 to 3.4 years)
  • 159 of 685 patients (23.2%) died in the 80% oxygen group compared to 128 of 701 patients (18.3%) assigned to 30% oxygen (HR, 1.30 [95% confidence interval, 1.03 to 1.64], P = 0.03)
  • CANCER SURGERY: HR was 1.45; 95% confidence interval, 1.10 to 1.90; P = 0.009
  • NON-CANCER SURGERY: HR was 1.06; 95% confidence interval, 0.69 to 1.65; P = 0.79
  • Administration of 80% oxygen significantly increased long-term mortality in patients undergoing cancer surgery but not in non-cancer patients

Hatfield SM, et al.: Immunological mechanisms of the antitumor effects of supplemental oxygenation. Sci Transl Med. 2015 Mar 4;7(277):277ra30

  • Antitumor T cells either avoid or are inhibited in hypoxic and extracellular adenosine-rich tumor microenvironments (TMEs) by A2A adenosine receptors
  • Respiratory hyperoxia decreases intratumoral hypoxia and concentrations of extracellular adenosine.
  • Respiratory hyperoxia reverses the hypoxia-adenosinergic immunosuppression in the TME.
  • Respiratory hyperoxia stimulates enhanced intratumoral infiltration and reduced inhibition of endogenously developed or adoptively transfered tumor-reactive CD8 T cells
  • Respiratory hyperoxia increases proinflammatory cytokines and decreased immunosuppressive molecules, such as transforming growth factor-β (TGF-β)
  • Respiratory hyperoxia weakens immunosuppression by regulatory T cells, and improves lung tumor regression and long-term survival in mice
  • Respiratory hyperoxia promotes the regression of spontaneous metastasis from orthotopically grown breast tumors => T cell- and natural killer cell-dependent processes
  • Supplemental oxygen as an immunological coadjuvant to combine with existing immunotherapies for cancer should be tested.

Lee D, et al.: Hyperoxia resensitizes chemoresistant glioblastoma cells to temozolomide through unfolded protein response. Anticancer Res. 2014 Jun;34(6):2957-6

  • Intratumoural hypoxia is associated with chemoresistance in glioblastoma multiforme (GBM)
  • This study test whether hyperoxia resensitizes temozolomide-resistant GBM cells to temozolomide by abrogating the hypoxia-induced, unfolded protein response (UPR)-related protective mechanisms.
  • They looked at changes to key UPR modulators in temozolomide-sensitive and -resistant human GBM cells (D54 and U87) treated with/without temozolomide at different oxygen concentrations using western blotting, and cytotoxic benefits of overexpressing key chaperone, P4HB, in GBM cells (U87 and U251) under normoxia and hyperoxia.
  • Hyperoxia, alone or synergistically with temozolomide, activated the UPR in sensitive and resistant D54 and U87 cell lines.
  • Hyperoxia also reduced survival benefit of U87 and U251 cells with P4HB overexpression through the UPR.
  • Hyperoxia enhanced GBM cell sensitivity to temozolomide, likely through UPR, highlighting an important treatment modality targeting chemosensitive and -resistant GBM.

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