Jemma Castle, Gary Shaw, Dominic Weller, E. Fielder, T. Egnuni, Mankaran Singh, Roderick Skinner, T. von Zglinicki, Steven C. Clifford, Susan C Short, Satomi Miwa, Debbie Hicks
{"title":"体内建模再现儿童髓母细胞瘤的放疗给药和后期疗效特征","authors":"Jemma Castle, Gary Shaw, Dominic Weller, E. Fielder, T. Egnuni, Mankaran Singh, Roderick Skinner, T. von Zglinicki, Steven C. Clifford, Susan C Short, Satomi Miwa, Debbie Hicks","doi":"10.1093/noajnl/vdae091","DOIUrl":null,"url":null,"abstract":"\n \n \n Medulloblastoma (MB) is the most common malignant paediatric brain tumour, with 5-year survival rates >70%. Cranial radiotherapy (CRT) to the whole-brain, with posterior fossa boost (PFB), underpins treatment for non-infants, however, radiotherapeutic insult to normal brain has deleterious consequences to neurocognitive and physical functioning, and causes accelerated ageing/frailty. Approaches to ameliorate radiotherapy-induced late-effects are lacking and a paucity of appropriate model systems hinders their development.\n \n \n \n We have developed a clinically-relevant in vivo model system that recapitulates the radiotherapy dose, targeting and developmental stage of childhood medulloblastoma. Consistent with human regimens, age-equivalent (postnatal days 35-37) male C57Bl/6J mice received CT image-guided CRT (human-equivalent 37.5 Gy EQD2, n=12) ± PFB (human-equivalent 48.7 Gy EQD2, n=12), via the small animal radiation research platform (SARRP) and were longitudinally assessed for >12 months.\n \n \n \n CRT was well tolerated, independent of PFB receipt. Compared to a sham-irradiated group (n=12), irradiated mice were significantly frailer following irradiation (frailty index; p=0.0002) and had reduced physical functioning; time to fall from a rotating rod (rotarod; p=0.026) and grip strength (p=0.006) were significantly lower. Neurocognitive deficits were consistent with childhood MB survivors; irradiated mice displayed significantly worse working memory (Y-maze; p=0.009) and exhibited spatial memory deficits (Barnes maze; p=0.029). Receipt of PFB did not induce a more severe late-effect profile.\n \n \n \n Our in vivo model mirrored childhood MB radiotherapy and recapitulated features observed in the late-effect profile of MB survivors. Our clinically-relevant model will facilitate both the elucidation of novel/target mechanisms underpinning MB late-effects and the development of novel interventions for their amelioration.\n","PeriodicalId":3,"journal":{"name":"ACS Applied Electronic Materials","volume":"110 S1","pages":""},"PeriodicalIF":4.3000,"publicationDate":"2024-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"In vivo modelling recapitulates radiotherapy delivery and late-effect profile for childhood medulloblastoma\",\"authors\":\"Jemma Castle, Gary Shaw, Dominic Weller, E. Fielder, T. Egnuni, Mankaran Singh, Roderick Skinner, T. von Zglinicki, Steven C. Clifford, Susan C Short, Satomi Miwa, Debbie Hicks\",\"doi\":\"10.1093/noajnl/vdae091\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"\\n \\n \\n Medulloblastoma (MB) is the most common malignant paediatric brain tumour, with 5-year survival rates >70%. Cranial radiotherapy (CRT) to the whole-brain, with posterior fossa boost (PFB), underpins treatment for non-infants, however, radiotherapeutic insult to normal brain has deleterious consequences to neurocognitive and physical functioning, and causes accelerated ageing/frailty. Approaches to ameliorate radiotherapy-induced late-effects are lacking and a paucity of appropriate model systems hinders their development.\\n \\n \\n \\n We have developed a clinically-relevant in vivo model system that recapitulates the radiotherapy dose, targeting and developmental stage of childhood medulloblastoma. Consistent with human regimens, age-equivalent (postnatal days 35-37) male C57Bl/6J mice received CT image-guided CRT (human-equivalent 37.5 Gy EQD2, n=12) ± PFB (human-equivalent 48.7 Gy EQD2, n=12), via the small animal radiation research platform (SARRP) and were longitudinally assessed for >12 months.\\n \\n \\n \\n CRT was well tolerated, independent of PFB receipt. Compared to a sham-irradiated group (n=12), irradiated mice were significantly frailer following irradiation (frailty index; p=0.0002) and had reduced physical functioning; time to fall from a rotating rod (rotarod; p=0.026) and grip strength (p=0.006) were significantly lower. Neurocognitive deficits were consistent with childhood MB survivors; irradiated mice displayed significantly worse working memory (Y-maze; p=0.009) and exhibited spatial memory deficits (Barnes maze; p=0.029). Receipt of PFB did not induce a more severe late-effect profile.\\n \\n \\n \\n Our in vivo model mirrored childhood MB radiotherapy and recapitulated features observed in the late-effect profile of MB survivors. 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In vivo modelling recapitulates radiotherapy delivery and late-effect profile for childhood medulloblastoma
Medulloblastoma (MB) is the most common malignant paediatric brain tumour, with 5-year survival rates >70%. Cranial radiotherapy (CRT) to the whole-brain, with posterior fossa boost (PFB), underpins treatment for non-infants, however, radiotherapeutic insult to normal brain has deleterious consequences to neurocognitive and physical functioning, and causes accelerated ageing/frailty. Approaches to ameliorate radiotherapy-induced late-effects are lacking and a paucity of appropriate model systems hinders their development.
We have developed a clinically-relevant in vivo model system that recapitulates the radiotherapy dose, targeting and developmental stage of childhood medulloblastoma. Consistent with human regimens, age-equivalent (postnatal days 35-37) male C57Bl/6J mice received CT image-guided CRT (human-equivalent 37.5 Gy EQD2, n=12) ± PFB (human-equivalent 48.7 Gy EQD2, n=12), via the small animal radiation research platform (SARRP) and were longitudinally assessed for >12 months.
CRT was well tolerated, independent of PFB receipt. Compared to a sham-irradiated group (n=12), irradiated mice were significantly frailer following irradiation (frailty index; p=0.0002) and had reduced physical functioning; time to fall from a rotating rod (rotarod; p=0.026) and grip strength (p=0.006) were significantly lower. Neurocognitive deficits were consistent with childhood MB survivors; irradiated mice displayed significantly worse working memory (Y-maze; p=0.009) and exhibited spatial memory deficits (Barnes maze; p=0.029). Receipt of PFB did not induce a more severe late-effect profile.
Our in vivo model mirrored childhood MB radiotherapy and recapitulated features observed in the late-effect profile of MB survivors. Our clinically-relevant model will facilitate both the elucidation of novel/target mechanisms underpinning MB late-effects and the development of novel interventions for their amelioration.
期刊介绍:
ACS Applied Electronic Materials is an interdisciplinary journal publishing original research covering all aspects of electronic materials. The journal is devoted to reports of new and original experimental and theoretical research of an applied nature that integrate knowledge in the areas of materials science, engineering, optics, physics, and chemistry into important applications of electronic materials. Sample research topics that span the journal's scope are inorganic, organic, ionic and polymeric materials with properties that include conducting, semiconducting, superconducting, insulating, dielectric, magnetic, optoelectronic, piezoelectric, ferroelectric and thermoelectric.
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