1932

Abstract

Ultrahigh–dose rate FLASH radiotherapy (FLASH-RT) is a potentially paradigm-shifting treatment modality that holds the promise of expanding the therapeutic index for nearly any cancer. At the heart of this exciting technology comes the capability to ameliorate major normal tissue complications without compromising the efficacy of tumor killing. This combination of benefits has now been termed the FLASH effect and relies on an in vivo validation to rigorously demonstrate the absence of normal tissue toxicity. The FLASH effect occurs when the overall irradiation time is extremely short (<500 ms), and in this review we attempt to understand how FLASH-RT can kill tumors but spare normal tissues—likely the single most pressing question confronting the field today.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-cancerbio-061421-022217
2023-04-11
2024-06-23
Loading full text...

Full text loading...

/deliver/fulltext/cancerbio/7/1/annurev-cancerbio-061421-022217.html?itemId=/content/journals/10.1146/annurev-cancerbio-061421-022217&mimeType=html&fmt=ahah

Literature Cited

  1. Adrian G, Konradsson E, Beyer S, Wittrup A, Butterworth KT et al. 2021. Cancer cells can exhibit a sparing FLASH effect at low doses under normoxic in vitro-conditions. Front. Oncol. 11:686142
    [Google Scholar]
  2. Adrian G, Konradsson E, Lempart M, Back S, Ceberg C, Petersson K. 2020. The FLASH effect depends on oxygen concentration. Br. J. Radiol. 93:20190702
    [Google Scholar]
  3. Alaghband Y, Cheeks SN, Allen BD, Montay-Gruel P, Doan NL et al. 2020. Neuroprotection of radiosensitive juvenile mice by ultra-high dose rate FLASH irradiation. Cancers 12:61671
    [Google Scholar]
  4. Alanazi A, Meesungnoen J, Jay-Gerin JP. 2021. A computer modeling study of water radiolysis at high dose rates. Relevance to FLASH radiotherapy. Radiat. Res. 195:149–62
    [Google Scholar]
  5. Allen BD, Acharya MM, Montay-Gruel P, Jorge PG, Bailat C et al. 2020. Maintenance of tight junction integrity in the absence of vascular dilation in the brain of mice exposed to ultra-high-dose-rate FLASH irradiation. Radiat. Res. 194:625–35
    [Google Scholar]
  6. Allen BD, Limoli CL. 2022. Breaking barriers: neurodegenerative repercussions of radiotherapy induced damage on the blood-brain and blood-tumor barrier. Free Radic. Biol. Med. 178:189–201
    [Google Scholar]
  7. Ameziane-El-Hassani R, Talbot M, de Souza Dos Santos MC, Al Ghuzlan A, Hartl D et al. 2015. NADPH oxidase DUOX1 promotes long-term persistence of oxidative stress after an exposure to irradiation. PNAS 112:5051–56
    [Google Scholar]
  8. Bandiera T, Ponzano S, Piomelli D. 2014. Advances in the discovery of N-acylethanolamine acid amidase inhibitors. Pharmacol. Res. 86:11–17
    [Google Scholar]
  9. Barr RE, Musacchia XJ. 1967. Radiation sensitivity of the hibernating ground squirrel, Citellus tridecemlineatus. Proc. Soc. Exp. Biol. Med. 124:1204–7
    [Google Scholar]
  10. Berthel E, Ferlazzo ML, Devic C, Bourguignon M, Foray N. 2019. What does the history of research on the repair of DNA double-strand breaks tell us? A comprehensive review of human radiosensitivity. Int. J. Mol. Sci 20:215339
    [Google Scholar]
  11. Boscolo D, Scifoni E, Durante M, Kramer M, Fuss MC. 2021. May oxygen depletion explain the FLASH effect? A chemical track structure analysis. Radiother. Oncol. 162:68–75
    [Google Scholar]
  12. Bourhis J, Sozzi WJ, Jorge PG, Gaide O, Bailat C et al. 2019. Treatment of a first patient with FLASH-radiotherapy. Radiother. Oncol. 139:18–22
    [Google Scholar]
  13. Buonanno M, Grilj V, Brenner DJ. 2019. Biological effects in normal cells exposed to FLASH dose rate protons. Radiother. Oncol. 139:51–55
    [Google Scholar]
  14. Cao X, Zhang R, Esipova TV, Allu SR, Ashraf R et al. 2021. Quantification of oxygen depletion during FLASH irradiation in vitro and in vivo. Int. J. Radiat. Oncol. Biol. Phys. 111:1240–248
    [Google Scholar]
  15. Chabi S, To THV, Leavitt R, Poglio S, Jorge PG et al. 2021. Ultra-high-dose-rate FLASH and conventional-dose-rate irradiation differentially affect human acute lymphoblastic leukemia and normal hematopoiesis. Int. J. Radiat. Oncol. Biol. Phys. 109:819–29
    [Google Scholar]
  16. Chaudhuri AA, Binkley MS, Osmundson EC, Alizadeh AA, Diehn M. 2015. Predicting radiotherapy responses and treatment outcomes through analysis of circulating tumor DNA. Semin. Radiat. Oncol. 25:305–12
    [Google Scholar]
  17. Collins-Underwood JR, Zhao W, Sharpe JG, Robbins ME. 2008. NADPH oxidase mediates radiation-induced oxidative stress in rat brain microvascular endothelial cells. Free Radic. Biol. Med. 45:929–38
    [Google Scholar]
  18. Coyle CH, Martinez LJ, Coleman MC, Spitz DR, Weintraub NL, Kader KN. 2006. Mechanisms of H2O2-induced oxidative stress in endothelial cells. Free Radic. Biol. Med. 40:2206–13
    [Google Scholar]
  19. Cunningham S, McCauley S, Vairamani K, Speth J, Girdhani S et al. 2021. FLASH proton pencil beam scanning irradiation minimizes radiation-induced leg contracture and skin toxicity in mice. Cancers 13:51012
    [Google Scholar]
  20. Dayal D, Martin SM, Limoli CL, Spitz DR. 2008. Hydrogen peroxide mediates the radiation-induced mutator phenotype in mammalian cells. Biochem. J. 413:185–91
    [Google Scholar]
  21. Dayal D, Martin SM, Owens KM, Aykin-Burns N, Zhu Y et al. 2009. Mitochondrial complex II dysfunction can contribute significantly to genomic instability after exposure to ionizing radiation. Radiat. Res. 172:737–45
    [Google Scholar]
  22. Diffenderfer ES, Verginadis, II, Kim MM, Shoniyozov K, Velalopoulou A et al. 2020. Design, implementation, and in vivo validation of a novel proton FLASH radiation therapy system. Int. J. Radiat. Oncol. Biol. Phys. 106:440–48
    [Google Scholar]
  23. Dokic I, Meister S, Bojcevski J, Tessonnier T, Walsh D et al. 2022. Neuroprotective effects of ultra-high dose rate FLASH Bragg peak proton irradiation. Int. J. Radiat. Oncol. Biol. Phys. 113:614–23
    [Google Scholar]
  24. Eggold JT, Chow S, Melemenidis S, Wang J, Natarajan S et al. 2022. Abdominopelvic FLASH irradiation improves PD-1 immune checkpoint inhibition in preclinical models of ovarian cancer. Mol. Cancer Ther. 21:371–81
    [Google Scholar]
  25. Epperly MW, Sikora CA, DeFilippi SJ, Gretton JA, Zhan Q et al. 2002. Manganese superoxide dismutase (SOD2) inhibits radiation-induced apoptosis by stabilization of the mitochondrial membrane. Radiat. Res. 157:568–77
    [Google Scholar]
  26. Farr JV, Parodi K, Carlson DJ. 2022. FLASH: current status and the transition to clinical use. Med. Phys. 49:31972–73
    [Google Scholar]
  27. Fath MA, Diers AR, Aykin-Burns N, Simons AL, Hua L, Spitz DR. 2009. Mitochondrial electron transport chain blockers enhance 2-deoxy-D-glucose induced oxidative stress and cell killing in human colon carcinoma cells. Cancer Biol. Ther. 8:1228–36
    [Google Scholar]
  28. Favaudon V, Caplier L, Monceau V, Pouzoulet F, Sayarath M et al. 2014. Ultrahigh dose-rate FLASH irradiation increases the differential response between normal and tumor tissue in mice. Sci. Transl. Med. 6:245ra93
    [Google Scholar]
  29. Favaudon V, Labarbe R, Limoli CL. 2022. Model studies of the role of oxygen in the FLASH effect. Med. Phys. 49:2068–81
    [Google Scholar]
  30. Field SB, Bewley DK. 1974. Effects of dose-rate on the radiation response of rat skin. Int. J. Radiat. Biol. Relat. Stud. Phys. Chem. Med. 26:259–67
    [Google Scholar]
  31. Fouillade C, Curras-Alonso S, Giuranno L, Quelennec E, Heinrich S et al. 2020. FLASH irradiation spares lung progenitor cells and limits the incidence of radio-induced senescence. Clin. Cancer Res. 26:1497–506
    [Google Scholar]
  32. Froidevaux P, Grilj V, Bailat C, Geyer WR, Bochud F, Vozenin M-C 2023. FLASH irradiation does not induce lipid peroxidation in lipids micelles and liposomes. Radiat. Phys. Chem. 205:110733
    [Google Scholar]
  33. Gaide O, Herrera F, Sozzi WJ, Gonçalves Jorge P, Kinj R et al. 2022. Comparison of ultra-high versus conventional dose rate radiotherapy in a patient with cutaneous lymphoma. Radiother. Oncol. 174:87–91
    [Google Scholar]
  34. Gao F, Yang Y, Zhu H, Wang J, Xiao D et al. 2022. First demonstration of the FLASH effect with ultrahigh dose rate high-energy X-rays. Radiother. Oncol. 166:44–50
    [Google Scholar]
  35. Hall EJ, Giaccia AJ. 2019. Radiobiology for the Radiologist Philadelphia: Wolters Kluwer
    [Google Scholar]
  36. Hendry JH, Moore JV, Hodgson BW, Keene JP. 1982. The constant low oxygen concentration in all the target cells for mouse tail radionecrosis. Radiat. Res. 92:172–81
    [Google Scholar]
  37. Hill MA, Herdman MT, Stevens DL, Jones NJ, Thacker J, Goodhead DT. 2004. Relative sensitivities of repair-deficient mammalian cells for clonogenic survival after α-particle irradiation. Radiat. Res. 162:667–76
    [Google Scholar]
  38. Hornsey S. 1956. Protection from whole-body X-irradiation afforded to adult mice by reducing the body temperature. Nature 178:87
    [Google Scholar]
  39. Hornsey S, Alper T. 1966. Unexpected dose-rate effect in the killing of mice by radiation. Nature 210:212–13
    [Google Scholar]
  40. Houten SM, Violante S, Ventura FV, Wanders RJ. 2016. The biochemistry and physiology of mitochondrial fatty acid β-oxidation and its genetic disorders. Annu. Rev. Physiol. 78:23–44
    [Google Scholar]
  41. Inada T, Nishio H, Amino S, Abe K, Saito K 1980. High dose-rate dependence of early skin reaction in mouse. Int. J. Radiat. Biol. Relat. Stud. Phys. Chem. Med. 38:139–45
    [Google Scholar]
  42. Jansen J, Knoll J, Beyreuther E, Pawelke J, Skuza R et al. 2021. Does FLASH deplete oxygen? Experimental evaluation for photons, protons, and carbon ions. Med. Phys. 48:73982–90
    [Google Scholar]
  43. Jin JY, Gu A, Wang W, Oleinick NL, Machtay M, Spring Kong FM 2020. Ultra-high dose rate effect on circulating immune cells: a potential mechanism for FLASH effect?. Radiother. Oncol. 149:55–62
    [Google Scholar]
  44. Joyce JA, Fearon DT. 2015. T cell exclusion, immune privilege, and the tumor microenvironment. Science 348:74–80
    [Google Scholar]
  45. Kacem H, Psoroulas S, Boivin G, Folkerts M, Grilj V et al. 2022. Comparing radiolytic production of H2O2 and development of Zebrafish embryos after ultra high dose rate exposure with electron and transmission proton beams. Radiother. Oncol. 175:197–202
    [Google Scholar]
  46. Karsch L, Pawelke J, Brand M, Hans S, Hideghéty K et al. 2022. Beam pulse structure and dose rate as determinants for the flash effect observed in zebrafish embryo. Radiother. Oncol. 175:49–54
    [Google Scholar]
  47. Kim MM, Verginadis, II, Goia D, Haertter A, Shoniyozov K et al. 2021. Comparison of FLASH proton entrance and the spread-out Bragg peak dose regions in the sparing of mouse intestinal crypts and in a pancreatic tumor model. Cancers 13:164244
    [Google Scholar]
  48. Kim YE, Gwak SH, Hong BJ, Oh JM, Choi HS et al. 2021. Effects of ultra-high doserate FLASH irradiation on the tumor microenvironment in Lewis lung carcinoma: role of myosin light chain. Int. J. Radiat. Oncol. Biol. Phys. 109:1440–53
    [Google Scholar]
  49. Konradsson E, Arendt ML, Bastholm Jensen K, Borresen B, Hansen AE et al. 2021. Establishment and initial experience of clinical FLASH radiotherapy in canine cancer patients. Front. Oncol. 11:658004
    [Google Scholar]
  50. Labarbe R, Hotoiu L, Barbier J, Favaudon V. 2020. A physicochemical model of reaction kinetics supports peroxyl radical recombination as the main determinant of the FLASH effect. Radiother. Oncol. 153:303–10
    [Google Scholar]
  51. Leach JK, Van Tuyle G, Lin PS, Schmidt-Ullrich R, Mikkelsen RB. 2001. Ionizing radiation-induced, mitochondria-dependent generation of reactive oxygen/nitrogen. Cancer Res 61:3894–901
    [Google Scholar]
  52. Leavitt RJ, Limoli CL, Baulch JE. 2019. miRNA-based therapeutic potential of stem cell-derived extracellular vesicles: a safe cell-free treatment to ameliorate radiation-induced brain injury. Int. J. Radiat. Biol. 95:427–35
    [Google Scholar]
  53. Lee SH, Dudok B, Parihar VK, Jung KM, Zoldi M et al. 2016. Neurophysiology of space travel: energetic solar particles cause cell type-specific plasticity of neurotransmission. Brain Struct. Funct. 222:2345–57
    [Google Scholar]
  54. Levy K, Natarajan S, Wang J, Chow S, Eggold JT et al. 2020. Abdominal FLASH irradiation reduces radiation-induced gastrointestinal toxicity for the treatment of ovarian cancer in mice. Sci. Rep. 10:21600
    [Google Scholar]
  55. Liljedahl E, Konradsson E, Gustafsson E, Jonsson KF, Olofsson JK et al. 2022. Long-term anti-tumor effects following both conventional radiotherapy and FLASH in fully immuocompetent animals with glioblastoma. Sci. Rep. 12:12285
    [Google Scholar]
  56. Limoli C, Giedzinski E. 2003. Induction of chromosomal instability by chronic oxidative stress. Neoplasia 5:339–46
    [Google Scholar]
  57. Limoli C, Giedzinski E, Morgan W, Swarts S, Jones G, Hyun W 2003. Persistent oxidative stress in chromosomally unstable cells. Cancer Res 63:3107–11
    [Google Scholar]
  58. Limoli CL, Hartmann A, Shephard L, Yang CR, Boothman DA et al. 1998. Apoptosis, reproductive failure, and oxidative stress in Chinese hamster ovary cells with compromised genomic integrity. Cancer Res 58:3712–18
    [Google Scholar]
  59. Marples B, Welford SM. 2018. Radiation biology and circulating tumor cells. Int. J. Radiat. Oncol. Biol. Phys. 100:813–15
    [Google Scholar]
  60. Maxim PG, Loo BW, Bailat C, Montay-Gruel P, Limoli CL, Vozenin M-C 2020. FLASH radiation therapy: a new treatment modality. The Modern Technology of Radiation Oncology: A Compendium for Medical Physicists and Radiation Oncologists JV Dyk 488–500. Madison, WI: Med. Phys. Publ.
    [Google Scholar]
  61. McMillan TJ, Cassoni AM, Edwards S, Holmes A, Peacock JH. 1990. The relationship of DNA double-strand break induction to radiosensitivity in human tumour cell lines. Int. J. Radiat. Biol. 58:427–38
    [Google Scholar]
  62. Michaels HB. 1986. Oxygen depletion in irradiated aqueous solutions containing electron affinic hypoxic cell radiosensitizers. Int. J. Radiat. Oncol. Biol. Phys. 12:1055–58
    [Google Scholar]
  63. Montay-Gruel P, Acharya MM, Gonçalves Jorge P, Petit B, Petridis IG et al. 2021. Hypofractionated FLASH-RT as an effective treatment against glioblastoma that reduces neurocognitive side effects in mice. Clin. Cancer Res. 27:775–84
    [Google Scholar]
  64. Montay-Gruel P, Acharya MM, Petersson K, Alikhani L, Yakkala C et al. 2019. Long-term neurocognitive benefits of FLASH radiotherapy driven by reduced reactive oxygen species. PNAS 116:10943–51
    [Google Scholar]
  65. Montay-Gruel P, Bouchet A, Jaccard M, Patin D, Serduc R et al. 2018. X-rays can trigger the FLASH effect: Ultra-high dose-rate synchrotron light source prevents normal brain injury after whole brain irradiation in mice. Radiother. Oncol. 129:3582–88
    [Google Scholar]
  66. Montay-Gruel P, Markarian M, Allen BD, Baddour JD, Giedzinski E et al. 2020. Ultra-high-dose-rate FLASH irradiation limits reactive gliosis in the brain. Radiat. Res. 194:636–45
    [Google Scholar]
  67. Montay-Gruel P, Petersson K, Jaccard M, Boivin G, Germond JF et al. 2017. Irradiation in a flash: unique sparing of memory in mice after whole brain irradiation with dose rates above 100 Gy/s. Radiother. Oncol. 124:365–69
    [Google Scholar]
  68. Musacchia XJ, Barr RE. 1968. Survival of whole-body-irradiated hibernating and active ground squirrels; Citellus tridecemlineatus. Radiat. Res. 33:348–56
    [Google Scholar]
  69. Pratx G, Kapp DS. 2019. A computational model of radiolytic oxygen depletion during FLASH irradiation and its effect on the oxygen enhancement ratio. Phys. Med. Biol. 64:185005
    [Google Scholar]
  70. Rohrer Bley C, Wolf F, Gonçalves Jorge P, Grilj V, Petridis I et al. 2022. Dose- and volume-limiting late toxicity of FLASH radiotherapy in cats with squamous cell carcinoma of the nasal planum and in mini pigs. Clin. Cancer Res. 28:173814–23
    [Google Scholar]
  71. Schonfeld P, Reiser G. 2017. Brain energy metabolism spurns fatty acids as fuel due to their inherent mitotoxicity and potential capacity to unleash neurodegeneration. Neurochem. Int. 109:68–77
    [Google Scholar]
  72. Schuler E, Acharya M, Montay-Gruel P, Loo BW Jr., Vozenin MC, Maxim PG. 2022. Ultra-high dose rate electron beams and the FLASH effect: from preclinical evidence to a new radiotherapy paradigm. Med. Phys. 49:2082–95
    [Google Scholar]
  73. Simmons DA, Lartey FM, Schuler E, Rafat M, King G et al. 2019. Reduced cognitive deficits after FLASH irradiation of whole mouse brain are associated with less hippocampal dendritic spine loss and neuroinflammation. Radiother. Oncol. 139:4–10
    [Google Scholar]
  74. Slane BG, Aykin-Burns N, Smith BJ, Kalen AL, Goswami PC et al. 2006. Mutation of succinate dehydrogenase subunit C results in increased O2·−, oxidative stress, and genomic instability. Cancer Res 66:7615–20
    [Google Scholar]
  75. Smith F, Grenan MM. 1951. Effect of hibernation upon survival time following whole-body irradiation in the marmot (Marmota monax). Science 113:686–88
    [Google Scholar]
  76. Solorzano C, Zhu C, Battista N, Astarita G, Lodola A et al. 2009. Selective N-acylethanolamine-hydrolyzing acid amidase inhibition reveals a key role for endogenous palmitoylethanolamide in inflammation. PNAS 106:20966–71
    [Google Scholar]
  77. Sorensen BS, Sitarz MK, Ankjaergaard C, Johansen JG, Andersen CE et al. 2022. Pencil beam scanning proton FLASH maintains tumor control while normal tissue damage is reduced in a mouse model. Radiother. Oncol. 175:178–84
    [Google Scholar]
  78. Soto LA, Casey KM, Wang J, Blaney A, Manjappa R et al. 2020. FLASH irradiation results in reduced severe skin toxicity compared to conventional-dose-rate irradiation. Radiat. Res. 194:6618–24
    [Google Scholar]
  79. Spinelli JB, Rosen PC, Sprenger HG, Puszynska AM, Mann JL et al. 2021. Fumarate is a terminal electron acceptor in the mammalian electron transport chain. Science 374:1227–37
    [Google Scholar]
  80. Spitz DR. 2011. Metabolic oxidative stress and low dose radiation responses: Are mitochondria involved?. Health Phys 100:295
    [Google Scholar]
  81. Spitz DR, Buettner GR, Petronek MS, St-Aubin JJ, Flynn RT et al. 2019. An integrated physico-chemical approach for explaining the differential impact of FLASH versus conventional dose rate irradiation on cancer and normal tissue responses. Radiother. Oncol. 139:23–27
    [Google Scholar]
  82. Steel GG, Down JD, Peacock JH, Stephens TC. 1986. Dose-rate effects and the repair of radiation damage. Radiother. Oncol. 5:321–31
    [Google Scholar]
  83. Storer JB, Hempelmann LH. 1952. Hypothermia and increased survival rate of infant mice irradiated with X-rays. Am. J. Physiol. 171:341–48
    [Google Scholar]
  84. Tinganelli W, Weber U, Puspitasari A, Simoniello P, Abdollahi A et al. 2022. FLASH with carbon ions: tumor control, normal tissue sparing, and distal metastasis in a mouse osteosarcoma model. Radiother. Oncol. 175:185–90
    [Google Scholar]
  85. Velalopoulou A, Karagounis IV, Cramer GM, Kim MM, Skoufos G et al. 2021. FLASH proton radiotherapy spares normal epithelial and mesenchymal tissues while preserving sarcoma response. Cancer Res 81:4808–21
    [Google Scholar]
  86. Vilalta M, Rafat M, Graves EE. 2016. Effects of radiation on metastasis and tumor cell migration. Cell. Mol. Life Sci. 73:2999–3007
    [Google Scholar]
  87. Vozenin MC, De Fornel P, Petersson K, Favaudon V, Jaccard M et al. 2019a. The advantage of FLASH radiotherapy confirmed in mini-pig and cat-cancer patients. Clin. Cancer Res. 25:35–42
    [Google Scholar]
  88. Vozenin MC, Hendry JH, Limoli CL. 2019b. Biological benefits of ultra-high dose rate FLASH radiotherapy: sleeping beauty awoken. Clin. Oncol. 31:7407–15
    [Google Scholar]
  89. Warburg O. 1956. On the origin of cancer cells. Science 132:309–14
    [Google Scholar]
  90. Wardman P. 2020. Radiotherapy using high-intensity pulsed radiation beams (FLASH): a radiation-chemical perspective. Radiat. Res. 194:607–17
    [Google Scholar]
  91. Wardman P, Candeias LP. 1996. Fenton chemistry: an introduction. Radiat. Res. 145:523–31
    [Google Scholar]
  92. Weiss H, Epp ER, Heslin JM, Ling CC, Santomasso A. 1974. Oxygen depletion in cells irradiated at ultra-high dose-rates and at conventional dose-rates. Int. J. Radiat. Biol. Relat. Stud. Phys. Chem. Med. 26:17–29
    [Google Scholar]
  93. Wilson JD, Hammond EM, Higgins GS, Petersson K. 2019. Ultra-high dose rate (FLASH) radiotherapy: silver bullet or fool's gold?. Front. Oncol. 9:1563
    [Google Scholar]
  94. Zhang Y, Ding Z, Perentesis JP, Khuntia D, Pfister SX, Sharma RA. 2021. Can rational combination of ultra-high dose rate FLASH radiotherapy with immunotherapy provide a novel approach to cancer treatment?. Clin. Oncol. 33:713–22
    [Google Scholar]
  95. Zhu Y, Dean AE, Horikoshi N, Heer C, Spitz DR, Gius D. 2018. Emerging evidence for targeting mitochondrial metabolic dysfunction in cancer therapy. J. Clin. Investig. 128:3682–91
    [Google Scholar]
/content/journals/10.1146/annurev-cancerbio-061421-022217
Loading
/content/journals/10.1146/annurev-cancerbio-061421-022217
Loading

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error