Login Register Cart 0
Review Article

肝放射性栓塞：通过CFD影响基于导管的颗粒输送的参数分析

卷 27, 期 10, 2020

页: [1600 - 1615] 页: 16

弟呕挨: 10.2174/0929867325666180622145647

价格: $65

摘要

放射栓塞（RE）是治疗肝癌的宝贵方法。它包括通过动脉内放置的导管施用放射性微球，目的是将这些由血流驱动的微球放置在肿瘤床中。即使这是一种安全的治疗方法，也可能会引起一些辐射诱发的并发症。在试图检测或解决引起非目标照射的可能事件时，通过计算流体力学（CFD）工具在RE期间模拟肝动脉中的颗粒血液动力学已成为一种有价值的方法。本文回顾了影响RE结果的参数，并已通过数值模拟对其进行了研究。在这种数值方法中，如果颗粒到达供养荷瘤肝段的动脉分支，则RE的结果被认为是成功的。最多审查了10个参数。每个参数的变化实际上改变了导管尖端附近的血液动力学模式，并局部改变了颗粒向血流中的掺入。因此，一般而言，这些参数的局部影响应导致肝动脉分支中颗粒分布的整体差异。然而，已经观察到，在一些（定性描述的）颗粒与血液流线对齐的适当条件下，由给定参数的变化引起的局部影响消失了，没有观察到整体差异。此外，关于RE的CFD研究的数量越来越多，这表明数值模拟已成为RE研究中不可估量的研究工具。

关键词: 放射栓塞，血液动力学，计算流体-颗粒动力学，肝癌，肝动脉，颗粒输送。

« Previous Next »
[1]
Sangro, B.; Iñarrairaegui, M.; Bilbao, J.I. Radioembolization for hepatocellular carcinoma. J. Hepatol., 2012, 56(2), 464-473.
[http://dx.doi.org/10.1016/j.jhep.2011.07.012] [PMID: 21816126]
[2]
Saxena, A.; Bester, L.; Shan, L.; Perera, M.; Gibbs, P.; Meteling, B.; Morris, D.L. A systematic review on the safety and efficacy of yttrium-90 radioembolization for unresectable, chemorefractory colorectal cancer liver metastases. J. Cancer Res. Clin. Oncol., 2014, 140(4), 537-547.
[http://dx.doi.org/10.1007/s00432-013-1564-4] [PMID: 24318568]
[3]
Kennedy, A.; Nag, S.; Salem, R.; Murthy, R.; McEwan, A.J.; Nutting, C.; Benson, A., III; Espat, J.; Bilbao, J.I.; Sharma, R.A.; Thomas, J.P.; Coldwell, D. Recommendations for radioembolization of hepatic malignancies using yttrium-90 microsphere brachytherapy: a consensus panel report from the radioembolization brachytherapy oncology consortium. Int. J. Radiat. Oncol. Biol. Phys., 2007, 68(1), 13-23.
[http://dx.doi.org/10.1016/j.ijrobp.2006.11.060] [PMID: 17448867]
[4]
Bester, L.; Meteling, B.; Boshell, D.; Chua, T.C.; Morris, D.L. Transarterial chemoembolisation and radioembolisation for the treatment of primary liver cancer and secondary liver cancer: a review of the literature. J. Med. Imaging Radiat. Oncol., 2014, 58(3), 341-352.
[http://dx.doi.org/10.1111/1754-9485.12163] [PMID: 24589204]
[5]
Ariel, I.M. Treatment of inoperable primary pancreatic and liver cancer by the intra-arterial administration of radioactive isotopes (Y90 radiating microspheres). Ann. Surg., 1965, 162(2), 267-278.
[http://dx.doi.org/10.1097/00000658-196508000-00018] [PMID: 14327011]
[6]
Gaba, R.C.; Lewandowski, R.J.; Hickey, R.; Baerlocher, M.O.; Cohen, E.I.; Dariushnia, S.R.; Janne d’Othée, B.; Padia, S.A.; Salem, R.; Wang, D.S.; Nikolic, B.; Brown, D.B. Transcatheter therapy for hepatic malignancy: standardization of terminology and reporting criteria. J. Vasc. Interv. Radiol., 2016, 27(4), 457-473.
[http://dx.doi.org/10.1016/j.jvir.2015.12.752] [PMID: 26851158]
[7]
Llovet, J.M.; Zucman-Rossi, J.; Pikarsky, E.; Sangro, B.; Schwartz, M.; Sherman, M.; Gores, G. Hepatocellular carcinoma. Nat. Rev. Dis. Primers, 2016, 2(3), 16018.
[http://dx.doi.org/10.1038/nrdp.2016.18] [PMID: 27158749]
[8]
Bilbao, J.I.; Reiser, M.F. Liver Radioembolization with 90Y Microspheres, 2nd ed; Springer Berlin Heidelberg: Berlin, Heidelberg, 2014.
[http://dx.doi.org/10.1007/978-3-642-36473-0]
[9]
Breedis, C.; Young, G. The blood supply of neoplasms in the liver. Am. J. Pathol., 1954, 30(5), 969-977.
[PMID: 13197542]
[10]
Ahmadzadehfar, H.; Biersack, H-J.; Ezziddin, S. Radioembolization of liver tumors with yttrium-90 microspheres. Semin. Nucl. Med., 2010, 40(2), 105-121.
[http://dx.doi.org/10.1053/j.semnuclmed.2009.11.001] [PMID: 20113679]
[11]
Murthy, R.; Kamat, P.; Nuñez, R.; Salem, R. Radioembolization of yttrium-90 microspheres for hepatic malignancy. Semin. Intervent. Radiol., 2008, 25(1), 48-57.
[http://dx.doi.org/10.1055/s-2008-1052306] [PMID: 21326493]
[12]
Vesselle, G.; Petit, I.; Boucebci, S.; Rocher, T.; Velasco, S.; Tasu, J-P. Radioembolization with yttrium-90 microspheres work up: Practical approach and literature review. Diagn. Interv. Imaging, 2015, 96(6), 547-562.
[http://dx.doi.org/10.1016/j.diii.2014.03.014] [PMID: 24776810]
[13]
Denys, A.; Pracht, M.; Duran, R.; Guiu, B.; Adib, S.; Boubaker, A.; Bize, P. How to prepare a patient for transarterial radioembolization? A practical guide. Cardiovasc. Intervent. Radiol., 2015, 38(4), 794-805.
[http://dx.doi.org/10.1007/s00270-015-1071-x] [PMID: 25828724]
[14]
Chiesa, C.; Mira, M.; Maccauro, M.; Spreafico, C.; Romito, R.; Morosi, C.; Camerini, T.; Carrara, M.; Pellizzari, S.; Negri, A.; Aliberti, G.; Sposito, C.; Bhoori, S.; Facciorusso, A.; Civelli, E.; Lanocita, R.; Padovano, B.; Migliorisi, M.; De Nile, M.C.; Seregni, E.; Marchianò, A.; Crippa, F.; Mazzaferro, V. Radioembolization of hepatocarcinoma with (90)Y glass microspheres: development of an individualized treatment planning strategy based on dosimetry and radiobiology. Eur. J. Nucl. Med. Mol. Imaging, 2015, 42(11), 1718-1738.
[http://dx.doi.org/10.1007/s00259-015-3068-8] [PMID: 26112387]
[15]
Kumar, Y.; Sharma, P.; Bhatt, N.; Hooda, K. Transarterial therapies for hepatocellular carcinoma: A comprehensive review with current updates and future directions. Asian Pac. J. Cancer Prev., 2016, 17(2), 473-478.
[http://dx.doi.org/10.7314/APJCP.2016.17.2.473] [PMID: 26925630]
[16]
Riaz, A.; Lewandowski, R.J.; Kulik, L.M.; Mulcahy, M.F.; Sato, K.T.; Ryu, R.K.; Omary, R.A.; Salem, R. Complications following radioembolization with yttrium-90 microspheres: a comprehensive literature review. J. Vasc. Interv. Radiol., 2009, 20(9), 1121-1130.
[http://dx.doi.org/10.1016/j.jvir.2009.05.030] [PMID: 19640737]
[17]
Couinaud, C. [The anatomy of the liver]. Ann. Ital. Chir., 1992, 63(6), 693-697.
[PMID: 1305370]
[18]
Jiang, M.; Fischman, A.; Nowakowski, F.S.; Heiba, S.; Zhang, Z.; Knesaurek, K.; Weintraub, J.; Machac, J. Segmental perfusion differences on paired Tc-99m macroaggregated albumin (MAA) hepatic perfusion imaging and yttrium-90 (Y-90) bremsstrahlung imaging studies in SIR-sphere radioembolization: Associations with angiography. J. Nucl. Med. Radiat. Ther., 2012, 3(122)
[http://dx.doi.org/10.4172/2155-9619.1000122]
[19]
Wondergem, M.; Smits, M.L.J.; Elschot, M.; de Jong, H.W.A.M.; Verkooijen, H.M.; van den Bosch, M.A.A.J.; Nijsen, J.F.W.; Lam, M.G.E.H. 99mTc-macroaggregated albumin poorly predicts the intrahepatic distribution of 90Y resin microspheres in hepatic radioembolization. J. Nucl. Med., 2013, 54(8), 1294-1301.
[http://dx.doi.org/10.2967/jnumed.112.117614] [PMID: 23749996]
[20]
Kao, Y.H. A clinical dosimetric perspective uncovers new evidence and offers new insight in favor of 99mTc-macroaggregated albumin for predictive dosimetry in 90Y resin microsphere radioembolization. J. Nucl. Med., 2013, 54(12), 2191-2192.
[http://dx.doi.org/10.2967/jnumed.113.128553] [PMID: 24198389]
[21]
Lam, M.G.E.H.; Wondergem, M.; Elschot, M.; Smits, M.L.J. Reply: A clinical dosimetric perspective uncovers new evidence and offers new insight in favor of 99mTc-macroaggregated albumin for predictive dosimetry in 90Y resin microsphere radioembolization. J. Nucl. Med., 2013, 54(12), 2192-2193.
[http://dx.doi.org/10.2967/jnumed.113.132852] [PMID: 24198388]
[22]
Ulrich, G.; Dudeck, O.; Furth, C.; Ruf, J.; Grosser, O.S.; Adolf, D.; Stiebler, M.; Ricke, J.; Amthauer, H. Predictive value of intratumoral 99mTc-macroaggregated albumin uptake in patients with colorectal liver metastases scheduled for radioembolization with 90Y-microspheres. J. Nucl. Med., 2013, 54(4), 516-522.
[http://dx.doi.org/10.2967/jnumed.112.112508] [PMID: 23447653]
[23]
Eisenhauer, E.A.; Therasse, P.; Bogaerts, J.; Schwartz, L.H.; Sargent, D.; Ford, R.; Dancey, J.; Arbuck, S.; Gwyther, S.; Mooney, M.; Rubinstein, L.; Shankar, L.; Dodd, L.; Kaplan, R.; Lacombe, D.; Verweij, J. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur. J. Cancer, 2009, 45(2), 228-247.
[http://dx.doi.org/10.1016/j.ejca.2008.10.026] [PMID: 19097774]
[24]
Dhabuwala, A.; Lamerton, P.; Stubbs, R.S. Relationship of 99mtechnetium labelled macroaggregated albumin (99mTc-MAA) uptake by colorectal liver metastases to response following Selective Internal Radiation Therapy (SIRT). BMC Nucl. Med., 2005, 5(1), 7.
[http://dx.doi.org/10.1186/1471-2385-5-7] [PMID: 16375764]
[25]
Lam, M.G.E.H.; Smits, M.L.J. Value of 99mTc-macroaggregated albumin SPECT for radioembolization treatment planning. J. Nucl. Med., 2013, 54(9), 1681-1682.
[http://dx.doi.org/10.2967/jnumed.113.123281] [PMID: 23781011]
[26]
Ulrich, G.; Dudeck, O.; Grosser, O.S.; Amthauer, H. Reply: Value of 99mTc-macroaggregated albumin SPECT for radioembolization treatment planning. J. Nucl. Med., 2013, 54(9), 1682-1682.
[http://dx.doi.org/10.2967/jnumed.113.123349] [PMID: 23918732]
[27]
Chiesa, C.; Lambert, B.; Maccauro, M.; Ezziddin, S.; Ahmadzadehfar, H.; Dieudonné, A.; Cremonesi, M.; Konijnenberg, M.; Lassmann, M.; Pettinato, C.; Strigari, L.; Vanderlinden, B.; Crippa, F.; Flamen, P.; Garin, E. Pretreatment dosimetry in HCC radioembolization with 90Y glass microspheres cannot Be invalidated with a bare visual evaluation of 99mTc-MAA uptake of colorectal metastases treated with resin microspheres. J. Nucl. Med., 2014, 55(7), 1215-1216.
[http://dx.doi.org/10.2967/jnumed.113.129361] [PMID: 24898027]
[28]
Amthauer, H.; Ulrich, G.; Grosser, O.S.; Ricke, J. Reply: pretreatment dosimetry in HCC radioembolization with 90Y glass microspheres cannot be invalidated with a bare visual evaluation of 99mTc-MAA uptake of colorectal metastases treated with resin microspheres. J. Nucl. Med., 2014, 55(7), 1216-1218.
[http://dx.doi.org/10.2967/jnumed.114.138198] [PMID: 24898024]
[29]
Morshedi, M.M.; Bauman, M.; Rose, S.C.; Kikolski, S.G. Yttrium-90 resin microsphere radioembolization using an antireflux catheter: an alternative to traditional coil embolization for nontarget protection. Cardiovasc. Intervent. Radiol., 2015, 38(2), 381-388.
[http://dx.doi.org/10.1007/s00270-014-0941-y] [PMID: 24989143]
[30]
Rose, S.C.; Kikolski, S.G.; Chomas, J.E. Downstream hepatic arterial blood pressure changes caused by deployment of the surefire antireflux expandable tip. Cardiovasc. Intervent. Radiol., 2013, 36(5), 1262-1269.
[http://dx.doi.org/10.1007/s00270-012-0538-2] [PMID: 23250493]
[31]
Arepally, A.; Chomas, J.; Kraitchman, D.; Hong, K. Quantification and reduction of reflux during embolotherapy using an antireflux catheter and tantalum microspheres: ex vivo analysis. J. Vasc. Interv. Radiol., 2013, 24(4), 575-580.
[http://dx.doi.org/10.1016/j.jvir.2012.12.018] [PMID: 23462064]
[32]
van den Hoven, A.F.; Prince, J.F.; Samim, M.; Arepally, A.; Zonnenberg, B.A.; Lam, M.G.E.H.; van den Bosch, M.A.A.J. Posttreatment PET-CT-confirmed intrahepatic radioembolization performed without coil embolization, by using the antireflux Surefire Infusion System. Cardiovasc. Intervent. Radiol., 2014, 37(2), 523-528.
[http://dx.doi.org/10.1007/s00270-013-0674-3] [PMID: 23756882]
[33]
Pasciak, A.S.; McElmurray, J.H.; Bourgeois, A.C.; Heidel, R.E.; Bradley, Y.C. The impact of an antireflux catheter on target volume particulate distribution in liver-directed embolotherapy: a pilot study. J. Vasc. Interv. Radiol., 2015, 26(5), 660-669.
[http://dx.doi.org/10.1016/j.jvir.2015.01.029] [PMID: 25801854]
[34]
van den Hoven, A.F.; Lam, M.G.E.H.; Jernigan, S.; van den Bosch, M.A.A.J.; Buckner, G.D. Innovation in catheter design for intra-arterial liver cancer treatments results in favorable particle-fluid dynamics. J. Exp. Clin. Cancer Res., 2015, 34(1), 74.
[http://dx.doi.org/10.1186/s13046-015-0188-8] [PMID: 26231929]
[35]
Kleinstreuer, C.; Feng, Y.; Childress, E. Drug-targeting methodologies with applications: A review. World J. Clin. Cases, 2014, 2(12), 742-756.
[http://dx.doi.org/10.12998/wjcc.v2.i12.742] [PMID: 25516850]
[36]
Kleinstreuer, C. Methods and devices for targeted injection of microspheres. US 2012/0190976 A1, 2012.
[37]
Aramburu, J.; Antón, R.; Rivas, A.; Ramos, J.C.; Sangro, B.; Bilbao, J.I. Computational particle-haemodynamics analysis of liver radioembolization pretreatment as an actual treatment surrogate. Int. J. Numer. Methods Biomed. Eng., 2017, 33(2), e02791
[http://dx.doi.org/10.1002/cnm.2791] [PMID: 27038438]
[38]
Aramburu, J.; Antón, R.; Rivas, A.; Ramos, J.C.; Sangro, B.; Bilbao, J.I. Computational assessment of the effects of the catheter type on particle-hemodynamics during liver radioembolization. J. Biomech., 2016, 49(15), 3705-3713.
[http://dx.doi.org/10.1016/j.jbiomech.2016.09.035] [PMID: 27751570]
[39]
Anderson, J.D. Computational Fluid Dynamics: The Basics with Applications; McGraw-Hill: Singapore, 1995.
[40]
Batchelor, G.K. An introduction to fluid dynamics; Cambridge University Press: Cambridge, 2000.
[http://dx.doi.org/10.1017/CBO9780511800955]
[41]
Kenner, T. The measurement of blood density and its meaning. Basic Res. Cardiol., 1989, 84(2), 111-124.
[http://dx.doi.org/10.1007/BF01907921] [PMID: 2658951]
[42]
Buchanan, J.R.; Kleinstreuer, C.; Comer, J.K. Rheological effects on pulsatile hemodynamics in a stenosed tube. Comput. Fluids, 2000, 29(6), 695-724.
[http://dx.doi.org/10.1016/S0045-7930(99)00019-5]
[43]
Basciano, C.A.; Kleinstreuer, C.; Kennedy, A.S.; Dezarn, W.A.; Childress, E. Computer modeling of controlled microsphere release and targeting in a representative hepatic artery system. Ann. Biomed. Eng., 2010, 38(5), 1862-1879.
[http://dx.doi.org/10.1007/s10439-010-9955-z] [PMID: 20162358]
[44]
Richards, A.L.; Kleinstreuer, C.; Kennedy, A.S.; Childress, E.; Buckner, G.D. Experimental microsphere targeting in a representative hepatic artery system. IEEE Trans. Biomed. Eng., 2012, 59(1), 198-204.
[http://dx.doi.org/10.1109/TBME.2011.2170195] [PMID: 21965193]
[45]
Grinberg, L.; Karniadakis, G.E. Outflow boundary conditions for arterial networks with multiple outlets. Ann. Biomed. Eng., 2008, 36(9), 1496-1514.
[http://dx.doi.org/10.1007/s10439-008-9527-7] [PMID: 18612828]
[46]
Basciano, C.A. PhD Thesis: Computational particlehemodynamics analysis applied to an abdominal aortic aneurysm with thrombus and microsphere-targeting of liver tumors, North Carolina State University, Raleigh, North Carolina. 2010.
[47]
Aramburu, J.; Antón, R.; Bernal, N.; Rivas, A.; Ramos, J.C.; Sangro, B.; Bilbao, J.I. Physiological outflow boundary conditions methodology for small arteries with multiple outlets: a patient-specific hepatic artery haemodynamics case study. Proc. Inst. Mech. Eng. H, 2015, 229(4), 291-306.
[http://dx.doi.org/10.1177/0954411915578549] [PMID: 25934258]
[48]
Aramburu, J.; Antón, R.; Rivas, A.; Ramos, J.C.; Sangro, B.; Bilbao, J.I. Liver cancer arterial perfusion modelling and CFD boundary conditions methodology: a case study of the haemodynamics of a patient-specific hepatic artery in literature-based healthy and tumour-bearing liver scenarios. Int. J. Numer. Methods Biomed. Eng., 2016, 32(11), e02764
[http://dx.doi.org/10.1002/cnm.2764] [PMID: 26727946]
[49]
Childress, E.M.; Kleinstreuer, C.; Kennedy, A.S. A new catheter for tumor-targeting with radioactive microspheres in representative hepatic artery systems--part II: solid tumor-targeting in a patient-inspired hepatic artery system. J. Biomech. Eng., 2012, 134(5), 051005
[http://dx.doi.org/10.1115/1.4006685] [PMID: 22757493]
[50]
Van de Wiele, C.; Maes, A.; Brugman, E.; D’Asseler, Y.; De Spiegeleer, B.; Mees, G.; Stellamans, K. SIRT of liver metastases: physiological and pathophysiological considerations. Eur. J. Nucl. Med. Mol. Imaging, 2012, 39(10), 1646-1655.
[http://dx.doi.org/10.1007/s00259-012-2189-6] [PMID: 22801733]
[51]
Caine, M.; McCafferty, M.S.; McGhee, S.; Garcia, P.; Mullett, W.M.; Zhang, X.; Hill, M.; Dreher, M.R.; Lewis, A.L. Impact of yttrium-90 microsphere density, flow dynamics, and administration technique on spatial pistribution: analysis using an in vitro model. J. Vasc. Interv. Radiol., 2017, 28(2), 260-268.e2.
[http://dx.doi.org/10.1016/j.jvir.2016.07.001] [PMID: 27641675]
[52]
Kleinstreuer, C.; Basciano, C.A.; Childress, E.M.; Kennedy, A.S. A new catheter for tumor targeting with radioactive microspheres in representative hepatic artery systems. Part I: impact of catheter presence on local blood flow and microsphere delivery. J. Biomech. Eng., 2012, 134(5), 051004
[http://dx.doi.org/10.1115/1.4006684] [PMID: 22757492]
[53]
Aramburu, J.; Antón, R.; Rivas, A.; Ramos, J.C.; Sangro, B.; Bilbao, J.I. Numerical investigation of liver radioembolization via computational particle-hemodynamics: The role of the microcatheter distal direction and microsphere injection point and velocity. J. Biomech., 2016, 49(15), 3714-3721.
[http://dx.doi.org/10.1016/j.jbiomech.2016.09.034] [PMID: 27751569]
[54]
Aramburu, J.; Antón, R.; Rivas, A.; Ramos, J.C.; Sangro, B.; Bilbao, J.I. The role of angled-tip microcatheter and microsphere injection velocity in liver radioembolization: A computational particle-hemodynamics study. Int. J. Numer. Methods Biomed. Eng., 2017, 33(12), e2895
[http://dx.doi.org/10.1002/cnm.2895] [PMID: 28474382]
[55]
Basciano, C.A.; Kleinstreuer, C.; Kennedy, A.S. Computational fluid dynamics modeling of 90Y microspheres in human hepatic tumors. J. Nucl. Med. Radiat. Ther., 2011, 1(1)
[http://dx.doi.org/10.4172/2155-9619.1000112]
[56]
Childress, E.M.; Kleinstreuer, C. Computationally efficient particle release map determination for direct tumor-targeting in a representative hepatic artery system. J. Biomech. Eng., 2014, 136(1), 011012
[http://dx.doi.org/10.1115/1.4025881] [PMID: 24190601]
[57]
Childress, E.M.; Kleinstreuer, C. Impact of fluid-structure interaction on direct tumor-targeting in a representative hepatic artery system. Ann. Biomed. Eng., 2014, 42(3), 461-474.
[http://dx.doi.org/10.1007/s10439-013-0910-7] [PMID: 24048712]
[58]
Michels, N.A. Newer anatomy of the liver and its variant blood supply and collateral circulation. Am. J. Surg., 1966, 112(3), 337-347.
[http://dx.doi.org/10.1016/0002-9610(66)90201-7] [PMID: 5917302]
[59]
Hiatt, J.R.; Gabbay, J.; Busuttil, R.W. Surgical anatomy of the hepatic arteries in 1000 cases. Ann. Surg., 1994, 220(1), 50-52.
[http://dx.doi.org/10.1097/00000658-199407000-00008] [PMID: 8024358]
[60]
Kennedy, A.S.; Kleinstreuer, C.; Basciano, C.A.; Dezarn, W.A. Computer modeling of yttrium-90-microsphere transport in the hepatic arterial tree to improve clinical outcomes. Int. J. Radiat. Oncol. Biol. Phys., 2010, 76(2), 631-637.
[http://dx.doi.org/10.1016/j.ijrobp.2009.06.069] [PMID: 19910131]
[61]
Sznitman, J.; Steinman, D.A. Relevance and challenges of computational fluid dynamics in the biomedical sciences. J. Biomech., 2016, 49(11), 2101.
[http://dx.doi.org/10.1016/j.jbiomech.2016.07.017] [PMID: 27481635]
[62]
Ballyk, P.D. Numerical/experimental synergy: more than just a reality check. J. Vasc. Interv. Radiol., 2015, 26(2), 259-261.
[http://dx.doi.org/10.1016/j.jvir.2014.12.003] [PMID: 25645415]

Rights & Permissions Print Cite
Article Metrics
28
1
© 2024 Bentham Science Publishers | Privacy Policy