Special considerations in the design and implementation of pediatric otoprotection trials

Freyer, David R.; Orgel, Etan; Knight, Keith; Krailo, Mark

doi:10.1007/s11764-022-01312-x

Cited by 13 publications

(15 citation statements)

References 82 publications

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“…But, in a subsequent comparison of expected outcomes, taken from historic published outcomes for a mixed disseminated tumor group, the control group with disseminated disease was found to have an unexpectedly favorable outcome, whereas the STS group with disseminated disease had the expected outcome. 14,15 Following the initial publication of ACCL0431, a misinterpretation about STS became widely spread; namely, that it was safe in localized disease but not safe in patients with metastatic disease. The more obvious conclusion is that the two arms of the ACCL0431 trial were not matched for tumor type or any prognostic factor.…”

Section: Randomized Clinical Trials With Sts and The Misconception Th...mentioning

confidence: 99%

“…No difference in EFS/OS was noted among patients retrospectively classified as having localized disease but among those retrospectively classified as having disseminated disease, a significantly lower OS was noted. But, in a subsequent comparison of expected outcomes, taken from historic published outcomes for a mixed disseminated tumor group, the control group with disseminated disease was found to have an unexpectedly favorable outcome, whereas the STS group with disseminated disease had the expected outcome 14,15 . Following the initial publication of ACCL0431, a misinterpretation about STS became widely spread; namely, that it was safe in localized disease but not safe in patients with metastatic disease.…”

Section: Randomized Clinical Trials With Sts and The Misconception Th...mentioning

confidence: 99%

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Sodium thiosulfate as cisplatin otoprotectant in children: The challenge of when to use it

Brock

Meijer

Kogner

et al. 2023

Pediatric Blood & Cancer

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Section: Randomized Clinical Trials With Sts and The Misconception Th...mentioning

confidence: 99%

Section: Randomized Clinical Trials With Sts and The Misconception Th...mentioning

confidence: 99%

Sodium thiosulfate as cisplatin otoprotectant in children: The challenge of when to use it

Brock

Meijer

Kogner

et al. 2023

Pediatric Blood & Cancer

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“…Oto‐toxicty is another important treatment‐related adverse event (AE). Cisplatin is the treatment backbone for many newly diagnosed nonhematologic tumors in children and AYAs, including neuroblastoma, hepatoblastoma, medulloblastoma, osteosarcoma, and malignant germ cell tumors 50 . While cisplatin is effective, it also damages the cochlea, leading to progressive and permanent hearing loss in most children who receive platinum‐intensive therapy 51 .…”

Section: Cancer Control and Supportive Care: Areas Of Focusmentioning

confidence: 99%

“…Cisplatin is the treatment backbone for many newly diagnosed nonhematologic tumors in children and AYAs, including neuroblastoma, hepatoblastoma, medulloblastoma, osteosarcoma, and malignant germ cell tumors. 50 While cisplatin is effective, it also damages the cochlea, leading to progressive and permanent hearing loss in most children who receive platinum-intensive therapy. 51 Hearing loss, in turn, leads to cognitive deficits, difficulties with socialization, and reduced academic and work functioning.…”

Section: Neuro-and Oto-toxictymentioning

confidence: 99%

Children's Oncology Group's 2023 blueprint for research: Cancer control and supportive care

Esbenshade,

Sung,

Brackett

et al. 2023

Pediatric Blood & Cancer

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The objective of the Cancer Control and Supportive Care (CCL) Committee in the Children's Oncology Group (COG) is to reduce the overall morbidity and mortality of therapy‐related toxicities in children, adolescents, and young adults with cancer. We have targeted five major domains that cause clinically important toxicity: (i) infections and inflammation; (ii) malnutrition and metabolic dysfunction; (iii) chemotherapy‐induced nausea and vomiting; (iv) neuro‐ and oto‐toxicty; and (v) patient‐reported outcomes and health‐related quality of life. Subcommittees for each domain prioritize randomized controlled trials and biology aims to determine which strategies best mitigate the toxicities. The findings of these trials are impactful, informing clinical practice guidelines (CPGs) and directly leading to changes in the standard of care for oncology practice. With the development of new therapies, there will be new toxicities, and the COG CCL Committee is dedicated to developing interventions to minimize acute and delayed toxicities, lessen morbidity and mortality, and improve quality of life in pediatric and young adult patients with cancer.

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“…Irreversible hearing loss afflicts more than 10% of the world population; however, there is only one Food and Drug Administration (FDA) approved drug to prevent any type of hearing loss 1,2 . Sodium Thiosulfate (brand name PEDMARK) was recently approved by the FDA for the prevention of cisplatin-induced hearing loss in pediatric patients with non-metastatic tumors [3][4][5] . No other patient population or type of hearing loss has a drug that can protect from this very common disability; therefore, there is a dire need to find compounds that protect from different types of hearing loss.…”

Section: Introductionmentioning

confidence: 99%

KSR1 knockout mouse model demonstrates MAPK pathway’s key role in cisplatin- and noise-induced hearing loss

Ingersoll,

Lutze,

Kelmann

et al. 2023

Preprint

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Hearing loss is a major disability in everyday life and therapeutic interventions to protect hearing would benefit a large portion of the world population. Here we found that mice devoid of the protein kinase suppressor of RAS 1 (KSR1) in their tissues (germline KO mice) exhibit resistance to both cisplatin- and noise- induced permanent hearing loss compared to their wild-type KSR1 littermates. KSR1 is expressed in the cochlea and is a scaffold protein that brings in proximity the mitogen-activated protein kinase (MAPK) proteins BRAF, MEK and ERK and assists in their activation through a phosphorylation cascade induced by both cisplatin and noise insults in the cochlear cells. Deleting the KSR1 protein tempered down the MAPK phosphorylation cascade in the cochlear cells following both cisplatin and noise insults and conferred hearing protection of up to 30 dB SPL in three tested frequencies in mice. Treatment with dabrafenib, an FDA- approved oral BRAF inhibitor, downregulated the MAPK kinase cascade and protected the KSR1 wild-type mice from both cisplatin- and noise-induced hearing loss. Dabrafenib treatment did not enhance the protection of KO KSR1 mice, as excepted, providing evidence dabrafenib works primarily through the MAPK pathway. Thus, either elimination of the KSR1 gene expression or drug inhibition of the MAPK cellular pathway in mice resulted in profound protection from both cisplatin- and noise-induce hearing loss. Inhibition of the MAPK pathway, a cellular pathway that responds to damage in the cochlear cells, can prove a valuable strategy to protect and treat hearing loss.Significance StatementTen percent of the world population suffers from hearing loss but this impairment may be preventable. We show that mice devoid of the KSR1 protein (KO) exhibit resistance to cisplatin- and noise-induced permanent hearing loss compared to wild-type littermates that harbor the protein. Removing KSR1 tempers down the MAPK phosphorylation cascade of BRAF-MEK-ERK induced in the cochlea following cisplatin and noise insults. Treatment of KSR1 wild-type mice following cisplatin or noise with an FDA-approved BRAF inhibitor, dabrafenib, protected the hearing and, importantly, did not confer additional protection to the KO KSR1 mice. Hence, the MAPK pathway has a unique role in responding to cochlear damage, and removing KSR1 gene expression or drug inhibition of the pathway results in hearing protection.

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Special considerations in the design and implementation of pediatric otoprotection trials

Cited by 13 publications

References 82 publications

Sodium thiosulfate as cisplatin otoprotectant in children: The challenge of when to use it

Sodium thiosulfate as cisplatin otoprotectant in children: The challenge of when to use it

Children's Oncology Group's 2023 blueprint for research: Cancer control and supportive care

KSR1 knockout mouse model demonstrates MAPK pathway’s key role in cisplatin- and noise-induced hearing loss

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