Archives of Plastic Surgery

Korean Society of Plastic and Reconstructive Surgeons (대한성형외과학회)
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Surgical prevention of terminal neuroma and phantom limb pain: a literature review

  • Bogdasarian, Ronald N. (Division of Plastic and Reconstructive Surgery, Department of Surgery, Rutgers New Jersey Medical School) ;
  • Cai, Steven B. (Division of Plastic and Reconstructive Surgery, Department of Surgery, Rutgers New Jersey Medical School) ;
  • Tran, Bao Ngoc N. (Division of Plastic and Reconstructive Surgery, Department of Surgery, Rutgers New Jersey Medical School) ;
  • Ignatiuk, Ashley (Division of Plastic and Reconstructive Surgery, Department of Surgery, Rutgers New Jersey Medical School) ;
  • Lee, Edward S. (Division of Plastic and Reconstructive Surgery, Department of Surgery, Rutgers New Jersey Medical School)
  • Received : 2020.10.27
  • Accepted : 2021.02.08
  • Published : 2021.05.15
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Abstract

The incidence of extremity amputation is estimated at about 200,000 cases annually. Over 25% of patients suffer from terminal neuroma or phantom limb pain (TNPLP), resulting in pain, inability to wear a prosthetic device, and lost work. Once TNPLP develops, there is no definitive cure. Therefore, there has been an emerging focus on TNPLP prevention. We examined the current literature on TNPLP prevention in patients undergoing extremity amputation. A literature review was performed using Ovid Medline, Cochrane Collaboration Library, and Google Scholar to identify all original studies that addressed surgical prophylaxis against TNPLP. The search was conducted using both Medical Subject Headings and free-text using the terms "phantom limb pain," "amputation neuroma," and "surgical prevention of amputation neuroma." Fifteen studies met the inclusion criteria, including six prospective trials, two comprehensive literature reviews, four retrospective chart reviews, and three case series/technique reviews. Five techniques were identified, and each was incorporated into a targetbased classification system. A small but growing body of literature exists regarding the surgical prevention of TNPLP. Targeted muscle reinnervation (TMR), a form of physiologic target reassignment, has the greatest momentum in the academic surgical community, with multiple recent prospective studies demonstrating superior prevention of TNPLP. Neurorrhaphy and transposition with implantation are supported by less robust evidence, but merit future study as alternatives to TMR.

Keywords

References

  1. Narres M, Kvitkina T, Claessen H, et al. Incidence of lower extremity amputations in the diabetic compared with the non-diabetic population: a systematic review. PLoS One 2017;12:e0182081. https://doi.org/10.1371/journal.pone.0182081
  2. Bosmans JC, Geertzen JH, Post WJ, et al. Factors associated with phantom limb pain: a 31/2-year prospective study. Clin Rehabil 2010;24:444-53. https://doi.org/10.1177/0269215509360645
  3. Hanley MA, Jensen MP, Smith DG, et al. Preamputation pain and acute pain predict chronic pain after lower extremity amputation. J Pain 2007;8:102-9. https://doi.org/10.1016/j.jpain.2006.06.004
  4. Chen MC, Lee SS, Hsieh YL, et al. Influencing factors of outcome after lower-limb amputation: a five-year review in a plastic surgical department. Ann Plast Surg 2008;61:314-8. https://doi.org/10.1097/SAP.0b013e3181571379
  5. Barbera J, Albert-Pamplo R. Centrocentral anastomosis of the proximal nerve stump in the treatment of painful amputation neuromas of major nerves. J Neurosurg 1993;79:331-4. https://doi.org/10.3171/jns.1993.79.3.0331
  6. Bowen JB, Wee CE, Kalik J, et al. Targeted muscle reinnervation to improve pain, prosthetic tolerance, and bioprosthetic outcomes in the amputee. Adv Wound Care (New Rochelle) 2017;6:261-7. https://doi.org/10.1089/wound.2016.0717
  7. Dellon AL, Mackinnon SE, Pestronk A. Implantation of sensory nerve into muscle: preliminary clinical and experimental observations on neuroma formation. Ann Plast Surg 1984;12:30-40. https://doi.org/10.1097/00000637-198401000-00006
  8. Ducic I, Mesbahi AN, Attinger CE, et al. The role of peripheral nerve surgery in the treatment of chronic pain associated with amputation stumps. Plast Reconstr Surg 2008;121:908-14. https://doi.org/10.1097/01.prs.0000299281.57480.77
  9. Gorkisch K, Boese-Landgraf J, Vaubel E. Treatment and prevention of amputation neuromas in hand surgery. Plast Reconstr Surg 1984;73:293-9. https://doi.org/10.1097/00006534-198402000-00027
  10. Halbert J, Crotty M, Cameron ID. Evidence for the optimal management of acute and chronic phantom pain: a systematic review. Clin J Pain 2002;18:84-92. https://doi.org/10.1097/00002508-200203000-00003
  11. Ives GC, Kung TA, Nghiem BT, et al. Current state of the surgical treatment of terminal neuromas. Neurosurgery 2018;83:354-64. https://doi.org/10.1093/neuros/nyx500
  12. Martins RS, Siqueira MG, Heise CO, et al. Interdigital direct neurorrhaphy for treatment of painful neuroma due to finger amputation. Acta Neurochir (Wien) 2015;157:667-71. https://doi.org/10.1007/s00701-014-2288-1
  13. Moesker AA, Karl HW, Trescot AM. Treatment of phantom limb pain by cryoneurolysis of the amputated nerve. Pain Pract 2014;14:52-6. https://doi.org/10.1111/papr.12020
  14. Patrick J, Frank W, Theodora M, et al. The pedicled serratus anterior muscle wrap-around flap: a treatment option in the management of posttraumatic axillary neuroma and neuropathic pain. Ann Plast Surg 2010;65:170-3. https://doi.org/10.1097/SAP.0b013e3181c5a81e
  15. Pet MA, Ko JH, Friedly JL, et al. Does targeted nerve implantation reduce neuroma pain in amputees? Clin Orthop Relat Res 2014;472:2991-3001. https://doi.org/10.1007/s11999-014-3602-1
  16. Pet MA, Ko JH, Friedly JL, et al. Traction neurectomy for treatment of painful residual limb neuroma in lower extremity amputees. J Orthop Trauma 2015;29:e321-5. https://doi.org/10.1097/BOT.0000000000000337
  17. Prantl L, Schreml S, Heine N, et al. Surgical treatment of chronic phantom limb sensation and limb pain after lower limb amputation. Plast Reconstr Surg 2006;118:1562-72. https://doi.org/10.1097/01.prs.0000233048.15879.0e
  18. Slooff AC. Microsurgical possibilities in the treatment of peripheral pain. Clin Neurol Neurosurg 1977;80:107-11. https://doi.org/10.1016/S0303-8467(78)80068-7
  19. Souza JM, Cheesborough JE, Ko JH, et al. Targeted muscle reinnervation: a novel approach to postamputation neuroma pain. Clin Orthop Relat Res 2014;472:2984-90. https://doi.org/10.1007/s11999-014-3528-7
  20. Swanson AB, Boeve NR, Lumsden RM. The prevention and treatment of amputation neuromata by silicone capping. J Hand Surg Am 1977;2:70-8. https://doi.org/10.1016/S0363-5023(77)80013-0
  21. Woo SL, Kung TA, Brown DL, et al. Regenerative peripheral nerve interfaces for the treatment of postamputation neuroma pain: a pilot study. Plast Reconstr Surg Glob Open 2016;4:e1038. https://doi.org/10.1097/GOX.0000000000001038
  22. Wood MR, Hunter GA, Millstein SG. The value of revision surgery after initial amputation of an upper or lower limb. Prosthet Orthot Int 1987;11:17-20. https://doi.org/10.3109/03093648709079374
  23. Wood VE, Mudge MK. Treatment of neuromas about a major amputation stump. J Hand Surg Am 1987;12:302-6. https://doi.org/10.1016/S0363-5023(87)80297-6
  24. Goldstein SA, Sturim HS. Intraosseous nerve transposition for treatment of painful neuromas. J Hand Surg Am 1985;10:270-4. https://doi.org/10.1016/S0363-5023(85)80120-9
  25. Jensen TS, Krebs B, Nielsen J, et al. Phantom limb, phantom pain and stump pain in amputees during the first 6 months following limb amputation. Pain 1983;17:243-56. https://doi.org/10.1016/0304-3959(83)90097-0
  26. Jensen TS, Krebs B, Nielsen J, et al. Immediate and longterm phantom limb pain in amputees: incidence, clinical characteristics and relationship to pre-amputation limb pain. Pain 1985;21:267-78. https://doi.org/10.1016/0304-3959(85)90090-9
  27. Nikolajsen L, Ilkjaer S, Jensen TS. Effect of preoperative extradural bupivacaine and morphine on stump sensation in lower limb amputees. Br J Anaesth 1998;81:348-54. https://doi.org/10.1093/bja/81.3.348
  28. Mioton LM, Dumanian GA. Targeted muscle reinnervation and prosthetic rehabilitation after limb loss. J Surg Oncol 2018;118:807-14. https://doi.org/10.1002/jso.25256
  29. Andoh J, Milde C, Tsao JW, et al. Cortical plasticity as a basis of phantom limb pain: fact or fiction? Neuroscience 2018;387:85-91. https://doi.org/10.1016/j.neuroscience.2017.11.015
  30. Dettmers C, Adler T, Rzanny R, et al. Increased excitability in the primary motor cortex and supplementary motor area in patients with phantom limb pain after upper limb amputation. Neurosci Lett 2001;307:109-12. https://doi.org/10.1016/S0304-3940(01)01953-X
  31. Flor H. Phantom-limb pain: characteristics, causes, and treatment. Lancet Neurol 2002;1:182-9. https://doi.org/10.1016/S1474-4422(02)00074-1
  32. Flor H. Cortical reorganisation and chronic pain: implications for rehabilitation. J Rehabil Med 2003;(41 Suppl): 66-72.
  33. Flor H. Maladaptive plasticity, memory for pain and phantom limb pain: review and suggestions for new therapies. Expert Rev Neurother 2008;8:809-18. https://doi.org/10.1586/14737175.8.5.809
  34. Flor H, Birbaumer N. Phantom limb pain: cortical plasticity and novel therapeutic approaches. Curr Opin Anaesthesiol 2000;13:561-4. https://doi.org/10.1097/00001503-200010000-00013
  35. Flor H, Diers M, Andoh J. The neural basis of phantom limb pain. Trends Cogn Sci 2013;17:307-8. https://doi.org/10.1016/j.tics.2013.04.007
  36. Flor H, Nikolajsen L, Staehelin Jensen T. Phantom limb pain: a case of maladaptive CNS plasticity? Nat Rev Neurosci 2006;7:873-81. https://doi.org/10.1038/nrn1991
  37. Foell J, Andoh J, Bekrater-Bodmann R, et al. Peripheral origin of phantom limb pain: is it all resolved? Pain 2014;155:2205-6.
  38. Grusser SM, Winter C, Muhlnickel W, et al. The relationship of perceptual phenomena and cortical reorganization in upper extremity amputees. Neuroscience 2001;102:263-72. https://doi.org/10.1016/S0306-4522(00)00491-7
  39. Karl A, Birbaumer N, Lutzenberger W, et al. Reorganization of motor and somatosensory cortex in upper extremity amputees with phantom limb pain. J Neurosci 2001;21:3609-18. https://doi.org/10.1523/JNEUROSCI.21-10-03609.2001
  40. Knecht S, Henningsen H, Elbert T, et al. Cortical reorganization in human amputees and mislocalization of painful stimuli to the phantom limb. Neurosci Lett 1995;201:262-4. https://doi.org/10.1016/0304-3940(95)12186-2
  41. Makin TR, Scholz J, Henderson Slater D, et al. Reassessing cortical reorganization in the primary sensorimotor cortex following arm amputation. Brain 2015;138(Pt 8):2140-6. https://doi.org/10.1093/brain/awv161
  42. Montoya P, Ritter K, Huse E, et al. The cortical somatotopic map and phantom phenomena in subjects with congenital limb atrophy and traumatic amputees with phantom limb pain. Eur J Neurosci 1998;10:1095-102. https://doi.org/10.1046/j.1460-9568.1998.00122.x
  43. Oouchida Y, Sudo T, Inamura T, et al. Maladaptive change of body representation in the brain after damage to central or peripheral nervous system. Neurosci Res 2016;104:38-43. https://doi.org/10.1016/j.neures.2015.12.015
  44. Raffin E, Richard N, Giraux P, et al. Primary motor cortex changes after amputation correlate with phantom limb pain and the ability to move the phantom limb. Neuroimage 2016;130:134-44. https://doi.org/10.1016/j.neuroimage.2016.01.063
  45. Reilly KT, Sirigu A. The motor cortex and its role in phantom limb phenomena. Neuroscientist 2008;14:195-202. https://doi.org/10.1177/1073858407309466
  46. Wu CW, Kaas JH. The effects of long-standing limb loss on anatomical reorganization of the somatosensory afferents in the brainstem and spinal cord. Somatosens Mot Res 2002;19:153-63. https://doi.org/10.1080/08990220220133261
  47. Yanagisawa T, Fukuma R, Seymour B, et al. Induced sensorimotor brain plasticity controls pain in phantom limb patients. Nat Commun 2016;7:13209. https://doi.org/10.1038/ncomms13209
  48. Andreae MH, Andreae DA. Local anaesthetics and regional anaesthesia for preventing chronic pain after surgery. Cochrane Database Syst Rev 2012;10:CD007105.
  49. Borghi B, D'Addabbo M, White PF, et al. The use of prolonged peripheral neural blockade after lower extremity amputation: the effect on symptoms associated with phantom limb syndrome. Anesth Analg 2010;111:1308-15. https://doi.org/10.1213/ANE.0b013e3181f4e848
  50. Enneking FK, Scarborough MT, Radson EA. Local anesthetic infusion through nerve sheath catheters for analgesia following upper extremity amputation. Clinical report. Reg Anesth 1997;22:351-6. https://doi.org/10.1016/S1098-7339(97)80011-9
  51. Finsen V, Persen L, Lovlien M, et al. Transcutaneous electrical nerve stimulation after major amputation. J Bone Joint Surg Br 1988;70:109-12.
  52. Fisher A, Meller Y. Continuous postoperative regional analgesia by nerve sheath block for amputation surgery: a pilot study. Anesth Analg 1991;72:300-3.
  53. Grant AJ, Wood C. The effect of intra-neural local anaesthetic infusion on pain following major lower limb amputation. Scott Med J 2008;53:4-6. https://doi.org/10.1258/RSMSMJ.53.1.4
  54. Hanling SR, Wallace SC, Hollenbeck KJ, et al. Preamputation mirror therapy may prevent development of phantom limb pain: a case series. Anesth Analg 2010;110:611-4. https://doi.org/10.1213/ANE.0b013e3181b845b0
  55. Hayes C, Armstrong-Brown A, Burstal R. Perioperative intravenous ketamine infusion for the prevention of persistent post-amputation pain: a randomized, controlled trial. Anaesth Intensive Care 2004;32:330-8. https://doi.org/10.1177/0310057X0403200305
  56. Jahangiri M, Jayatunga AP, Bradley JW, et al. Prevention of phantom pain after major lower limb amputation by epidural infusion of diamorphine, clonidine and bupivacaine. Ann R Coll Surg Engl 1994;76:324-6.
  57. Lambert Aw, Dashfield Ak, Cosgrove C, et al. Randomized prospective study comparing preoperative epidural and intraoperative perineural analgesia for the prevention of postoperative stump and phantom limb pain following major amputation. Reg Anesth Pain Med 2001;26:316-21. https://doi.org/10.1053/rapm.2001.23934
  58. Madabhushi L, Reuben SS, Steinberg RB, et al. The efficacy of postoperative perineural infusion of bupivacaine and clonidine after lower extremity amputation in preventing phantom limb and stump pain. J Clin Anesth 2007;19:226-9. https://doi.org/10.1016/j.jclinane.2006.07.008
  59. Morey TE, Giannoni J, Duncan E, et al. Nerve sheath catheter analgesia after amputation. Clin Orthop Relat Res 2002;(397):281-9.
  60. Mulvey MR, Bagnall AM, Johnson MI, et al. Transcutaneous electrical nerve stimulation (TENS) for phantom pain and stump pain following amputation in adults. Cochrane Database Syst Rev 2010;(5):CD007264.
  61. Ong BY, Arneja A, Ong EW. Effects of anesthesia on pain after lower-limb amputation. J Clin Anesth 2006;18:600-4. https://doi.org/10.1016/j.jclinane.2006.03.021
  62. Pavy TJ, Doyle DL. Prevention of phantom limb pain by infusion of local anaesthetic into the sciatic nerve. Anaesth Intensive Care 1996;24:599-600. https://doi.org/10.1177/0310057X9602400517
  63. Pinzur MS, Garla PG, Pluth T, et al. Continuous postoperative infusion of a regional anesthetic after an amputation of the lower extremity. A randomized clinical trial. J Bone Joint Surg Am 1996;78:1501-5. https://doi.org/10.2106/00004623-199610000-00007
  64. Wilson JA, Nimmo AF, Fleetwood-Walker SM, et al. A randomised double blind trial of the effect of pre-emptive epidural ketamine on persistent pain after lower limb amputation. Pain 2008;135:108-18. https://doi.org/10.1016/j.pain.2007.05.011
  65. Wu CL, Tella P, Staats PS, et al. Analgesic effects of intravenous lidocaine and morphine on postamputation pain: a randomized double-blind, active placebo-controlled, crossover trial. Anesthesiology 2002;96:841-8. https://doi.org/10.1097/00000542-200204000-00010
  66. Kubiak CA, Kemp SWP, Cederna PS, et al. Prophylactic regenerative peripheral nerve interfaces to prevent postamputation pain. Plast Reconstr Surg 2019;144:421e-430e. https://doi.org/10.1097/PRS.0000000000005922
  67. Belcher HJ, Pandya AN. Centro-central union for the prevention of neuroma formation after finger amputation. J Hand Surg Br 2000;25:154-9. https://doi.org/10.1054/jhsb.2000.0372
  68. De Smet L. Preventing neuroma formation in finger amputation. Acta Orthop Belg 1996;62:69-70.
  69. St-Laurent JY, Duclos L. Prevention of neuroma in elective digital amputations by utilization of neurovascular island flap. Ann Chir Main Memb Super 1996;15:50-4.
  70. Yuksel F, Kislaoglu E, Durak N, et al. Prevention of painful neuromas by epineural ligatures, flaps and grafts. Br J Plast Surg 1997;50:182-5. https://doi.org/10.1016/S0007-1226(97)91367-9
  71. Economides JM, DeFazio MV, Attinger CE, et al. Prevention of painful neuroma and phantom limb pain after transfemoral amputations through concomitant nerve coaptation and collagen nerve wrapping. Neurosurgery 2016;79:508-13. https://doi.org/10.1227/NEU.0000000000001313
  72. Kuiken TA, Barlow AK, Hargrove L, et al. Targeted muscle reinnervation for the upper and lower extremity. Tech Orthop 2017;32:109-16. https://doi.org/10.1097/BTO.0000000000000194
  73. Alexander JH, Jordan SW, West JM, et al. Targeted muscle reinnervation in oncologic amputees: early experience of a novel institutional protocol. J Surg Oncol 2019;120:348-58. https://doi.org/10.1002/jso.25586
  74. Bowen JB, Ruter D, Wee C, et al. Targeted muscle reinnervation technique in below-knee amputation. Plast Reconstr Surg 2019;143:309-12. https://doi.org/10.1097/PRS.0000000000005133
  75. Valerio IL, Dumanian GA, Jordan SW, et al. Preemptive treatment of phantom and residual limb pain with targeted muscle reinnervation at the time of major limb amputation. J Am Coll Surg 2019;228:217-26. https://doi.org/10.1016/j.jamcollsurg.2018.12.015
  76. Agnew SP, Schultz AE, Dumanian GA, et al. Targeted reinnervation in the transfemoral amputee: a preliminary study of surgical technique. Plast Reconstr Surg 2012;129:187-94. https://doi.org/10.1097/PRS.0b013e3182268d0d
  77. Gart MS, Souza JM, Dumanian GA. Targeted muscle reinnervation in the upper extremity amputee: a technical roadmap. J Hand Surg Am 2015;40:1877-88. https://doi.org/10.1016/j.jhsa.2015.06.119
  78. Morgan EN, Kyle Potter B, Souza JM, et al. Targeted muscle reinnervation for transradial amputation: description of operative technique. Tech Hand Up Extrem Surg 2016;20:166-71. https://doi.org/10.1097/BTH.0000000000000141
  79. Prasetyono TO, Permatasari E, Soetrisno E. Implantation of nerve stump inside a vein and a muscle: comparing neuroma formation in rat. Int Surg 2014;99:807-11. https://doi.org/10.9738/INTSURG-D-13-00184.1
  80. Lewin-Kowalik J, Marcol W, Kotulska K, et al. Prevention and management of painful neuroma. Neurol Med Chir (Tokyo) 2006;46:62-7. https://doi.org/10.2176/nmc.46.62
  81. Low CK, Chew SH, Song IC, et al. Implantation of a nerve ending into a vein. Clin Orthop Relat Res 2000;(379):242-6.
  82. Otfinowski J, Pawelec A, Kaluza J. Implantation of peripheral neural stump into muscle and its effect on the development of posttraumatic neuroma. Pol J Pathol 1994;45:195-202.
  83. Zhang B, Guo Y, Liang Y. Experimental study on prevention and treatment of neuroma by implanting nerve stump into muscle. Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi 1997;11:325-7.
  84. Kim PS, Ko JH, O'Shaughnessy KK, et al. The effects of targeted muscle reinnervation on neuromas in a rabbit rectus abdominis flap model. J Hand Surg Am 2012;37:1609-16. https://doi.org/10.1016/j.jhsa.2012.04.044
  85. Ko JH, Kim PS, Smith DG. Targeted muscle reinnervation as a strategy for neuroma prevention. In: Kuiken TA, Schultz Feuser AE, Barlow AK, editors. Targeted muscle reinnervation: a neural interface for artificial limbs (Series in Medical Physics and Biomedical Engineering). Boca Raton: Taylor & Francis; 2013. p. 45-66.
  86. Chen A, Yao J, Kuiken T, et al. Cortical motor activity and reorganization following upper-limb amputation and subsequent targeted reinnervation. Neuroimage Clin 2013;3:498-506. https://doi.org/10.1016/j.nicl.2013.10.001
  87. Gradl G, Postl LK, Lenze U, et al. Long-term functional outcome and quality of life following rotationplasty for treatment of malignant tumors. BMC Musculoskelet Disord 2015;16:262. https://doi.org/10.1186/s12891-015-0721-0
  88. Forni C, Gaudenzi N, Zoli M, et al. Living with rotationplasty: quality of life in rotationplasty patients from childhood to adulthood. J Surg Oncol 2012;105:331-6. https://doi.org/10.1002/jso.22088
  89. Fuchs B, Kotajarvi BR, Kaufman KR, et al. Functional outcome of patients with rotationplasty about the knee. Clin Orthop Relat Res 2003;(415):52-8.
  90. Furtado S, Grimer RJ, Cool P, et al. Physical functioning, pain and quality of life after amputation for musculoskeletal tumours: a national survey. Bone Joint J 2015;97-B:1284-90. https://doi.org/10.1302/0301-620X.97B9.35192
  91. Hanlon M, Krajbich JI. Rotationplasty in skeletally immature patients: long-term followup results. Clin Orthop Relat Res 1999;(358):75-82.
  92. Mayerson JL. Living with rotationplasty: quality of life in rotationplasty patients from childhood to adulthood. J Surg Oncol 2012;105:743-4. https://doi.org/10.1002/jso.22126
  93. Rodl RW, Pohlmann U, Gosheger G, et al. Rotationplasty: quality of life after 10 years in 22 patients. Acta Orthop Scand 2002;73:85-8. https://doi.org/10.1080/000164702317281468
  94. Veenstra KM, Sprangers MA, van der Eyken JW, et al. Quality of life in survivors with a Van Ness-Borggreve rotationplasty after bone tumour resection. J Surg Oncol 2000;73:192-7. https://doi.org/10.1002/(SICI)1096-9098(200004)73:4<192::AID-JSO2>3.0.CO;2-H
  95. Ackman J, Altiok H, Flanagan A, et al. Long-term follow-up of Van Nes rotationplasty in patients with congenital proximal focal femoral deficiency. Bone Joint J 2013;95-B:192-8. https://doi.org/10.1302/0301-620X.95B2.30853

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