{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,21]],"date-time":"2025-10-21T15:34:40Z","timestamp":1761060880166,"version":"3.30.1"},"reference-count":42,"publisher":"Medknow","issue":"1","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["smedj"],"published-print":{"date-parts":[[2021,1]]},"abstract":"<jats:p>INTRODUCTION Children with solid organ tumours often present for curative surgery. Even with the best surgical technique, micrometastases can occur. Preclinical studies support the postulation that neuraxial anaesthesia maintains the body\u2019s immune and inflammatory milieu against metastasis. However, human retrospective adult studies showed varying results, and no study has been done in children. We aimed to find out if intraoperative epidural, perioperative opioid and volatile dose are associated with relapse-free survival (RFS) in children with solid organ tumours.  METHODS This is a retrospective cohort study of 126 children from a tertiary paediatric unit who were diagnosed with solid organ tumours (neuroblastoma, hepatoblastoma or sarcoma) over a 16-year period. RFS, stratified by tumour subtypes, was estimated using the Kaplan-Meier method. Adjusted hazard ratios (aHRs) were obtained from multivariable Cox regression models after taking potential covariates into account.  RESULTS Of 126 children with solid organ tumours (51.6% neuroblastoma, 34.9% sarcoma and 13.5% hepatoblastoma), 53.2% received combined general anaesthesia (GA)\/epidural. A total of 21 (31.3%) and 20 (33.9%) patients relapsed during the study period in the combined GA\/epidural group and the GA alone group, respectively. Patients with sarcoma receiving combined GA\/epidural had a clinically meaningful lower risk of relapse compared to patients receiving GA alone (aHR 0.51, 95% confidence interval 0.14\u20131.79), although this was not statistically significant.  CONCLUSION Our study demonstrated some clinically meaningful associations, especially in paediatric sarcoma patients. Overall, however, there was no statistically significant association between epidural use and an improved RFS.<\/jats:p>","DOI":"10.11622\/smedj.2019123","type":"journal-article","created":{"date-parts":[[2019,10,8]],"date-time":"2019-10-08T07:16:57Z","timestamp":1570519017000},"page":"20-28","source":"Crossref","is-referenced-by-count":5,"title":["Anaesthetic modality and post-surgical oncological outcomes for paediatric tumours: is there a link?"],"prefix":"10.4103","volume":"62","author":[{"given":"SY","family":"Lee","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"S","family":"Acharyya","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"AWL","family":"Tan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"AHP","family":"Loh","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"2581","published-online":{"date-parts":[[2021,1]]},"reference":[{"key":"ref0","unstructured":"1. Tan AM, Ha C. Singapore Childhood Cancer Registry 2003-2007. Available at: https:\/\/www.nrdo.gov.sg\/docs\/librariesprovider3\/Publications-Cancer\/sccr-monograph-combined-v1-4.pdf?sfvrsn=0. Accessed October 1, 2019."},{"key":"ref1","doi-asserted-by":"publisher","first-page":"106","DOI":"10.1093\/bja\/aeq164","article-title":"Effect of anaesthetic technique and other perioperative factors on cancer recurrence","volume":"105","author":"GL","year":"2010","unstructured":"2. Snyder GL, Greenberg S. Effect of anaesthetic technique and other perioperative factors on cancer recurrence. Br J Anaesth 2010; 105:106-15.","journal-title":"Br J Anaesth"},{"key":"ref2","doi-asserted-by":"publisher","unstructured":"3. Colvin LA, Fallon MT, Buggy DJ. Cancer biology, analgesics, and anaesthetics: is there a link? Br J Anaesth 2012; 109:140-3.","DOI":"10.1093\/bja\/aes255"},{"key":"ref3","doi-asserted-by":"publisher","first-page":"159","DOI":"10.1007\/s10555-016-9647-8","article-title":"Anaesthetic technique and cancer recurrence in oncologic surgery: unraveling the puzzle","volume":"36","author":"Kim","year":"2017","unstructured":"4. Kim R. Anaesthetic technique and cancer recurrence in oncologic surgery: unraveling the puzzle. Cancer Metastasis Rev 2017; 36:159-77.","journal-title":"Cancer Metastasis Rev"},{"key":"ref4","doi-asserted-by":"publisher","unstructured":"5. Shakhar G, Ben-Eliyahu S. Potential prophylactic measures against postoperative immunosuppression: could they reduce recurrence rates in oncological patients? Ann Surg Oncol 2003; 10:972-92.","DOI":"10.1245\/ASO.2003.02.007"},{"key":"ref5","doi-asserted-by":"publisher","first-page":"1668","DOI":"10.1378\/chest.114.6.1668","article-title":"Vascular endothelial growth factor increased by pulmonary surgery accelerates the growth of micrometastases in metastatic lung cancer","volume":"114","author":"Maniwa","year":"1998","unstructured":"6. Maniwa Y, Okada M, Ishii N, Kiyooka K. Vascular endothelial growth factor increased by pulmonary surgery accelerates the growth of micrometastases in metastatic lung cancer. Chest 1998; 114:1668-75.","journal-title":"Chest"},{"key":"ref6","doi-asserted-by":"publisher","first-page":"149","DOI":"10.1038\/nm0295-149","article-title":"Dormancy of micrometastases: balanced proliferation and apoptosis in the presence of angiogenesis suppression","volume":"1","author":"Holmgren","year":"1995","unstructured":"7. Holmgren L, O'Reilly MS, Folkman J. Dormancy of micrometastases: balanced proliferation and apoptosis in the presence of angiogenesis suppression. Nat Med 1995; 1:149-53.","journal-title":"Nat Med"},{"key":"ref7","doi-asserted-by":"publisher","first-page":"90","DOI":"10.1007\/BF03014331","article-title":"Halothane and isoflurane enhance melanoma tumour metastasis in mice","volume":"44","author":"GC","year":"1997","unstructured":"8. Moudgil GC, Singal DP. Halothane and isoflurane enhance melanoma tumour metastasis in mice. Can J Anaesth 1997; 44:90-4.","journal-title":"Can J Anaesth"},{"key":"ref8","doi-asserted-by":"publisher","first-page":"220","DOI":"10.1177\/0310057X1404200209","article-title":"Effects of different general anaesthetic techniques on immune responses in patients undergoing surgery for tongue cancer","volume":"42","author":"Zhang","year":"2014","unstructured":"9. Zhang T, Fan Y, Liu K, Wang Y. Effects of different general anaesthetic techniques on immune responses in patients undergoing surgery for tongue cancer. Anaesth Intensive Care 2014; 42:220-7.","journal-title":"Anaesth Intensive Care"},{"key":"ref9","doi-asserted-by":"publisher","first-page":"354","DOI":"10.1097\/01.mjt.0000132250.95650.85","article-title":"Opioid therapy and immunosuppression: a review","volume":"11","author":"Vallejo","year":"2004","unstructured":"10. Vallejo R, de Leon-Casasola O, Benyamin R. Opioid therapy and immunosuppression: a review. Am J Ther 2004; 11:354-65.","journal-title":"Am J Ther"},{"key":"ref10","unstructured":"11. Gupta K, Kshirsagar S, Chang L, et al. Morphine stimulates angiogenesis by activating proangiogenic and survival-promoting signaling and promotes breast tumor growth. Cancer Res 2002; 62:4491-8."},{"key":"ref11","doi-asserted-by":"publisher","unstructured":"12. Le-Wendling L, Nin O, Capdevila X. Cancer recurrence and regional anaesthesia: the theories, the data, and the future in outcomes. Pain Med 2016; 17:756-75.","DOI":"10.1111\/pme.12893"},{"key":"ref12","doi-asserted-by":"publisher","first-page":"1066","DOI":"10.1097\/00000542-200106000-00022","article-title":"Attenuation of the tumor-promoting effect of surgery by spinal blockade in rats","volume":"94","author":"Bar-Yosef","year":"2001","unstructured":"13. Bar-Yosef S, Melamed R, Page GG, et al. Attenuation of the tumor-promoting effect of surgery by spinal blockade in rats. Anesthesiology 2001; 94:1066-73.","journal-title":"Anesthesiology"},{"key":"ref13","doi-asserted-by":"publisher","first-page":"499","DOI":"10.1097\/00000542-200703000-00014","article-title":"Combined spinal and general anaesthesia attenuates liver metastasis by preserving TH1\/TH2 cytokine balance","volume":"106","author":"Wada","year":"2007","unstructured":"14. Wada H, Seki S, Takahashi T, et al. Combined spinal and general anaesthesia attenuates liver metastasis by preserving TH1\/TH2 cytokine balance. Anesthesiology 2007; 106:499-506.","journal-title":"Anesthesiology"},{"key":"ref14","doi-asserted-by":"publisher","first-page":"164","DOI":"10.1093\/bja\/aer100","article-title":"Reduction in mortality after epidural anaesthesia and analgesia in patients undergoing rectal but not colonic cancer surgery: a retrospective analysis of data from 655 patients in central Sweden","volume":"107","author":"Gupta","year":"2011","unstructured":"15. Gupta A, Bj\u00f6rnsson A, Fredriksson M, Hallb\u00f6\u00f6k O, Eintrei C. Reduction in mortality after epidural anaesthesia and analgesia in patients undergoing rectal but not colonic cancer surgery: a retrospective analysis of data from 655 patients in central Sweden. Br J Anaesth 2011; 107:164-70.","journal-title":"Br J Anaesth"},{"key":"ref15","doi-asserted-by":"publisher","unstructured":"16. Exadaktylos AK, Buggy DJ, Moriarty DC, Mascha E, Sessler DI. Can anesthetic technique for primary breast cancer surgery affect recurrence or metastasis? Anaesthesiology 2006; 105:660-4.","DOI":"10.1097\/00000542-200610000-00008"},{"key":"ref16","doi-asserted-by":"publisher","first-page":"325","DOI":"10.1213\/ane.0b013e3181770f55","article-title":"Long-term survival after colon cancer surgery: a variation associated with choice of anaesthesia","volume":"107","author":"Christopherson","year":"2008","unstructured":"17. Christopherson R, James KE, Tableman M, Marshall P, Johnson FE. Long-term survival after colon cancer surgery: a variation associated with choice of anaesthesia. Anesth Analg 2008; 107:325-32.","journal-title":"Anesth Analg"},{"key":"ref17","doi-asserted-by":"publisher","unstructured":"18. Cakmakkaya OS, Kolodzie K, Apfel CC, Pace NL. Anaesthetic techniques for risk of malignant tumor recurrence. Cochrane Database Syst Rev 2014; (11):CD008877.","DOI":"10.1002\/14651858.CD008877.pub2"},{"key":"ref18","doi-asserted-by":"publisher","first-page":"1464","DOI":"10.1213\/ANE.0b013e3181bab1bd","article-title":"The effect of perioperative intravenous lidocaine on postoperative pain and immune function","volume":"109","author":"Yardeni","year":"2009","unstructured":"19. Yardeni IZ, Beilin B, Mayburd E, Levinson Y, Bessler H. The effect of perioperative intravenous lidocaine on postoperative pain and immune function. Anesth Analg 2009; 109:1464-9.","journal-title":"Anesth Analg"},{"key":"ref19","doi-asserted-by":"publisher","first-page":"685","DOI":"10.1093\/bja\/aep261","article-title":"Effect of anaesthetic technique on oestrogen receptor-negative breast cancer cell function in vitro","volume":"103","author":"Deegan","year":"2009","unstructured":"20. Deegan CA, Murray D, Doran P, et al. Effect of anaesthetic technique on oestrogen receptor-negative breast cancer cell function in vitro. Br J Anaesth 2009; 103:685-90.","journal-title":"Br J Anaesth"},{"key":"ref20","doi-asserted-by":"publisher","first-page":"191","DOI":"10.1016\/S0304-3959(00)00403-6","article-title":"Evidence that postoperative pain is a mediator of the tumor-promoting effects of surgery in rats","volume":"90","author":"Page","year":"2001","unstructured":"21. Page GG, Blakely WP, Ben-Eliyahu S. Evidence that postoperative pain is a mediator of the tumor-promoting effects of surgery in rats. Pain 2001; 90:191-9.","journal-title":"Pain"},{"key":"ref21","doi-asserted-by":"publisher","first-page":"180","DOI":"10.1097\/ALN.0b013e31817f5b73","article-title":"Anesthetic technique for radical prostatectomy surgery affects cancer recurrence: a retrospective analysis","volume":"109","author":"Biki","year":"2008","unstructured":"22. Biki B, Mascha E, Moriarty DC, et al. Anesthetic technique for radical prostatectomy surgery affects cancer recurrence: a retrospective analysis. Anesthesiology 2008; 109:180-7.","journal-title":"Anesthesiology"},{"key":"ref22","doi-asserted-by":"publisher","first-page":"989","DOI":"10.1097\/SLA.0b013e3182915f61","article-title":"Peridural analgesia may affect long-term survival in patients with colorectal cancer after surgery (PACO-RAS-Study): an analysis of a cancer registry","volume":"258","author":"Holler","year":"2013","unstructured":"23. Holler JP, Ahlbrandt J, Burkhardt E, et al. Peridural analgesia may affect long-term survival in patients with colorectal cancer after surgery (PACO-RAS-Study): an analysis of a cancer registry. Ann Surg 2013; 258:989-93.","journal-title":"Ann Surg"},{"key":"ref23","doi-asserted-by":"publisher","first-page":"317","DOI":"10.1097\/ALN.0000000000000489","article-title":"Factors associated with improved survival after resection of pancreatic adenocarcinoma: a multivariable model","volume":"122","author":"Call","year":"2015","unstructured":"24. Call TR, Pace NL, Thorup DB, et al. Factors associated with improved survival after resection of pancreatic adenocarcinoma: a multivariable model. Anesthesiology 2015; 122:317-24.","journal-title":"Anesthesiology"},{"key":"ref24","doi-asserted-by":"publisher","unstructured":"25. Myles PS, Peyton P, Silbert B, et al; ANZCA Trials Group Investigators. Perioperative epidural analgesia for major abdominal surgery for cancer and recurrence-free survival: randomised trial. BMJ 2011; 342:d1491.","DOI":"10.1136\/bmj.d1491"},{"key":"ref25","doi-asserted-by":"publisher","first-page":"15262","DOI":"10.18632\/oncotarget.7683","article-title":"The effect of neuraxial anaesthesia on cancer recurrence and survival after cancer surgery: an updated meta-analysis","volume":"7","author":"Weng","year":"2016","unstructured":"26. Weng M, Chen W, Hou W, et al. The effect of neuraxial anaesthesia on cancer recurrence and survival after cancer surgery: an updated meta-analysis. Oncotarget 2016; 7:15262-73.","journal-title":"Oncotarget"},{"key":"ref26","doi-asserted-by":"publisher","first-page":"2022","DOI":"10.1111\/j.1742-4658.2009.06938.x","article-title":"Chronic high-dose morphine treatment promotes SH-SY5Y cell apoptosis via c-Jun N-terminal kinase-mediated activation of mitochondria-dependent pathway","volume":"276","author":"Lin","year":"2009","unstructured":"27. Lin X, Wang YJ, Li Q, et al. Chronic high-dose morphine treatment promotes SH-SY5Y cell apoptosis via c-Jun N-terminal kinase-mediated activation of mitochondria-dependent pathway. FEBS J 2009; 276:2022-36.","journal-title":"FEBS J"},{"key":"ref27","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1097\/SPC.0000000000000056","article-title":"Opioids and cancer recurrence","volume":"8","author":"Juneja","year":"2014","unstructured":"28. Juneja R. Opioids and cancer recurrence. Curr Opin Support Palliat Care 2014; 8:91-101.","journal-title":"Curr Opin Support Palliat Care"},{"key":"ref28","unstructured":"29. Olbrecht V, Siekerman M, Pinkard O, et al. Effect of common opioids and methylnaltrexone on pediatric tumor growth: differential expression of mu-opioid receptors in tumor lines. Available at: http:\/\/www5.pedsanesthesia.org\/meetings\/2014winter\/syllabus\/submissions\/aandp\/walkarounds\/PR2-123.pdf. Accessed October 1, 2019."},{"key":"ref29","doi-asserted-by":"publisher","unstructured":"30. Yeager MP, Procopio MA, Deleo JA, et al. Intravenous fentanyl increases natural killer cell cytotoxicity and circulating CD16(+) lymphocytes in humans. Anesth Analg 2002; 94:94-9.","DOI":"10.1097\/00000539-200201000-00018"},{"key":"ref30","doi-asserted-by":"publisher","first-page":"805","DOI":"10.1093\/bja\/aeg273","article-title":"Low-dose remifentanil infusion does not impair natural killer cell function in healthy volunteers","volume":"91","author":"Cronin","year":"2003","unstructured":"31. Cronin AJ, Aucutt-Walter NM, Budinetz T, et al. Low-dose remifentanil infusion does not impair natural killer cell function in healthy volunteers. Br J Anaesth 2003; 91:805-9.","journal-title":"Br J Anaesth"},{"key":"ref31","doi-asserted-by":"publisher","first-page":"648","DOI":"10.1111\/pan.13146","article-title":"Assessing the survival impact of perioperative opioid consumption in children and adolescents undergoing cytoreductive surgery with hyperthermic intraperitoneal chemotherapy","volume":"27","author":"Owusu-Agyemang","year":"2017","unstructured":"32. Owusu-Agyemang P, Hayes-Jordan A, Van Meter A, et al. Assessing the survival impact of perioperative opioid consumption in children and adolescents undergoing cytoreductive surgery with hyperthermic intraperitoneal chemotherapy. Paediatr Anaesth 2017; 27:648-56.","journal-title":"Paediatr Anaesth"},{"key":"ref32","doi-asserted-by":"publisher","first-page":"200","DOI":"10.1093\/bja\/aes128","article-title":"Lidocaine time- and dose-dependently demethylates deoxyribonucleic acid in breast cancer cell lines in vitro","volume":"109","author":"Lirk","year":"2012","unstructured":"33. Lirk P, Berger R, Hollmann MW, Fiegl H. Lidocaine time- and dose-dependently demethylates deoxyribonucleic acid in breast cancer cell lines in vitro. Br J Anaesth 2012; 109:200-7.","journal-title":"Br J Anaesth"},{"key":"ref33","doi-asserted-by":"publisher","first-page":"548","DOI":"10.1097\/ALN.0b013e3182661977","article-title":"Antimetastatic potential of amide-linked local anesthetics: inhibition of lung adenocarcinoma cell migration and inflammatory Src signaling independent of sodium channel blockade","volume":"117","author":"Piegeler","year":"2012","unstructured":"34. Piegeler T, Votta-Velis EG, Liu G, et al. Antimetastatic potential of amide-linked local anesthetics: inhibition of lung adenocarcinoma cell migration and inflammatory Src signaling independent of sodium channel blockade. Anesthesiology 2012; 117:548-59.","journal-title":"Anesthesiology"},{"key":"ref34","doi-asserted-by":"publisher","first-page":"841","DOI":"10.1097\/ALN.0b013e31824babfe","article-title":"Antiproliferative effects of local anesthetics on mesenchymal stem cells: potential implications for tumor spreading and wound healing","volume":"116","author":"Lucchinetti","year":"2012","unstructured":"35. Lucchinetti E, Awad AE, Rahman M, et al. Antiproliferative effects of local anesthetics on mesenchymal stem cells: potential implications for tumor spreading and wound healing. Anesthesiology 2012; 116:841-56.","journal-title":"Anesthesiology"},{"key":"ref35","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1097\/EJA.0b013e32834cd6c4","article-title":"Lipophilicity but not stereospecificity is a major determinant of local anaesthetic-induced cytotoxicity in human T-lymphoma cells","volume":"29","author":"Werdehausen","year":"2012","unstructured":"36. Werdehausen R, Braun S, Fazeli S, et al. Lipophilicity but not stereospecificity is a major determinant of local anaesthetic-induced cytotoxicity in human T-lymphoma cells. Eur J Anaesthesiol 2012; 29:35-41.","journal-title":"Eur J Anaesthesiol"},{"key":"ref36","doi-asserted-by":"publisher","unstructured":"37. L\u00fcthy IA, Bruzzone A, Pi\u00f1ero CP, et al. Adrenoceptors: non-conventional target for breast cancer? Curr Med Chem 2009; 16:1850-62.","DOI":"10.2174\/092986709788186048"},{"key":"ref37","doi-asserted-by":"publisher","first-page":"233","DOI":"10.1097\/EJA.0b013e32832d540e","article-title":"Does analgesia and condition influence immunity after surgery? Effects of fentanyl, ketamine and clonidine on natural killer activity at different ages","volume":"27","author":"Forget","year":"2010","unstructured":"38. Forget P, Collet V, Lavand'homme P, De Kock M. Does analgesia and condition influence immunity after surgery? Effects of fentanyl, ketamine and clonidine on natural killer activity at different ages. Eur J Anaesthesiol 2010; 27:233-40.","journal-title":"Eur J Anaesthesiol"},{"key":"ref38","doi-asserted-by":"publisher","first-page":"981","DOI":"10.1097\/00000539-200110000-00036","article-title":"Oxidative stress status during exposure to propofol, sevoflurane and desflurane","volume":"93","author":"Allaouchiche","year":"2001","unstructured":"39. Allaouchiche B, Debon R, Goudable J, Chassard D, Duflo F. Oxidative stress status during exposure to propofol, sevoflurane and desflurane. Anesth Analg 2001; 93:981-5.","journal-title":"Anesth Analg"},{"key":"ref39","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1111\/j.1460-9592.2011.03691.x","article-title":"Benefits of regional anaesthesia in children","volume":"22","author":"Bosenberg","year":"2012","unstructured":"40. Bosenberg AT. Benefits of regional anaesthesia in children. Pediatr Anesth 2012; 22:10-8.","journal-title":"Pediatr Anesth"},{"key":"ref40","doi-asserted-by":"publisher","first-page":"1061","DOI":"10.1111\/j.1460-9592.2010.03448.x","article-title":"Epidemiology and morbidity of regional anaesthesia in children: a follow-up one-year prospective survey of the French- Language Society of Paediatric Anaesthesiologists (ADARPEF)","volume":"20","author":"Ecoffey","year":"2010","unstructured":"41. Ecoffey C, Lacroix F, Giaufr\u00e9 E, Orliaguet G, Courr\u00e8ges P. Epidemiology and morbidity of regional anaesthesia in children: a follow-up one-year prospective survey of the French- Language Society of Paediatric Anaesthesiologists (ADARPEF). Paediatr Anaesth 2010; 20:1061-9.","journal-title":"Paediatr Anaesth"},{"key":"ref41","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1097\/AIA.0000000000000117","article-title":"Making the case for the subspecialty of onco-anaesthesia","volume":"54","author":"Wigmore","year":"2016","unstructured":"42. Wigmore T, Gottumukkala V, Riedel B. Making the case for the subspecialty of onco-anaesthesia. Int Anesthesiol Clin 2016; 54:19-28.","journal-title":"Int Anesthesiol Clin"}],"container-title":["Singapore Medical Journal"],"original-title":[],"link":[{"URL":"http:\/\/www.smj.org.sg\/article\/anaesthetic-modality-and-post-surgical-oncological-outcomes-paediatric-tumours-there-link","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,8,9]],"date-time":"2022-08-09T10:52:15Z","timestamp":1660042335000},"score":1,"resource":{"primary":{"URL":"http:\/\/www.smj.org.sg\/article\/anaesthetic-modality-and-post-surgical-oncological-outcomes-paediatric-tumours-there-link"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,1]]},"references-count":42,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2021,1]]},"published-print":{"date-parts":[[2021,1]]}},"URL":"https:\/\/doi.org\/10.11622\/smedj.2019123","relation":{},"ISSN":["0037-5675"],"issn-type":[{"type":"print","value":"0037-5675"}],"subject":[],"published":{"date-parts":[[2021,1]]}}}