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Laryngoscope Investigative... Aug 2021This study investigates the histopathological changes of the cochlea and vestibular end organs of a patient who received cisplatin for Hodgkin's lymphoma. He experienced...
This study investigates the histopathological changes of the cochlea and vestibular end organs of a patient who received cisplatin for Hodgkin's lymphoma. He experienced acute high-frequency sensorineural hearing loss and tinnitus after receiving treatment. Using histopathological analysis of his temporal bones after he unfortunately succumbed to his disease, we found that the ototoxic effect of cisplatin is primarily within the cochlea, with significant damage located at the organ of Corti at the base-hook region, consistent with findings in animal models. The effects of cisplatin were minimal when reviewing the vestibular end organs.
PubMed: 34401512
DOI: 10.1002/lio2.608 -
Seminars in Hearing May 2019Cisplatin, an effective antineoplastic drug used in the treatment of many cancers, has ototoxic potential, thus placing cancer patients, receiving this treatment, at... (Review)
Review
Cisplatin, an effective antineoplastic drug used in the treatment of many cancers, has ototoxic potential, thus placing cancer patients, receiving this treatment, at risk of hearing loss. It is therefore important for health care professionals managing these patients to be aware of cisplatin's ototoxic properties and its clinical signs to identify patients at risk of developing a hearing impairment. Eighty-five English peer-reviewed articles and two books, from January 1975 to July 2015, were identified from PubMed, ScienceDirect, and EBSCOhost. An overview of cisplatin-associated ototoxicity, namely its clinical features, incidence rates, molecular and cellular mechanisms, and risk factors, is presented in this article. This review further highlights the importance of a team-based approach to complement an audiological monitoring program in reducing any further loss in the quality of life of affected patients, as there is currently no otoprotective agent routinely recommended for the prevention of cisplatin-associated ototoxicity.
PubMed: 31036989
DOI: 10.1055/s-0039-1684041 -
Seminars in Hearing May 2019The purpose of this article is to provide a brief introduction and review regarding basic principles of pharmacology, including terminology and colloquialisms, as well... (Review)
Review
The purpose of this article is to provide a brief introduction and review regarding basic principles of pharmacology, including terminology and colloquialisms, as well as pharmacokinetic and pharmacodynamic principles of ototoxic agents. As an audiology practitioner, it is more important than ever to have a working knowledge regarding the known and proposed mechanisms of action for drugs and chemicals with known ototoxicity potential. Additionally, this article provides a discussion regarding the biochemistry behind distribution, which is a major step in determining ototoxic potential of known and potential ototoxins.
PubMed: 31036986
DOI: 10.1055/s-0039-1684038 -
The Turkish Journal of Pediatrics 2022Hearing is essential in child development. Cisplatin which is a common chemotherapy used in many pediatric solid-tumor protocols cause various degrees of ototoxicity....
BACKGROUND
Hearing is essential in child development. Cisplatin which is a common chemotherapy used in many pediatric solid-tumor protocols cause various degrees of ototoxicity. Several risk factors for cisplatininduced ototoxicity have been reported, including race and age. This study aimed to evaluate the incidence of ototoxicity and its long-term outcome in Thai pediatric solid-tumor patients receiving cisplatin and to determine the risk factors associated with hearing impairment.
METHODS
A retrospective study was conducted in solid-tumor patients < 15 years old from 2007 to 2019 at Siriraj Hospital, Bangkok, Thailand. Hearing was evaluated by an audiogram and/or auditory steady-state response and the impairment was graded according to the Common Terminology Criteria for Adverse Events version 5. Grade 2 and above was considered significant hearing loss.
RESULTS
In total, the hearing of 47 patients was evaluated. At the end of treatment, hearing impairment and significant hearing loss were found in 66% and 48.9% of patients, respectively. A high median cumulative cisplatin dose was significantly associated with worse hearing impairment (p = 0.039) and a more progressive grading of ototoxicity (p = 0.005). A risk factor for significant hearing loss was a cumulative dose ≥400 mg/m2 (p = 0.014). All 9 patients who received a cumulative dose > 600 mg/m2 and 5 patients who received aminoglycoside developed significant hearing loss. One patient had progressive hearing impairment at 8 months after the end of treatment and 1 patient developed grade 3 ototoxicity which required a hearing aid after bone marrow transplantation. The latter patient received a total cisplatin dose of 708.2 mg/m < sup > 2 < /sup > and carboplatin 1400 mg/m < sup > 2 < /sup > .
CONCLUSIONS
The incidence of hearing impairment in pediatric patients receiving cisplatin is high. Regular hearing evaluation is essential for the early detection of ototoxicity. Long-term follow-up is recommended, especially in patients who have a combination of other risk factors for hearing loss.
Topics: Adolescent; Antineoplastic Agents; Child; Cisplatin; Hearing; Hearing Loss; Humans; Neoplasms; Ototoxicity; Retrospective Studies; Thailand
PubMed: 35899566
DOI: 10.24953/turkjped.2021.5012 -
Pharmaceuticals (Basel, Switzerland) May 2022Nitrative stress is increasingly recognized as a critical mediator of apoptotic cell death in many pathological conditions. The accumulation of nitric oxide along with... (Review)
Review
Nitrative stress is increasingly recognized as a critical mediator of apoptotic cell death in many pathological conditions. The accumulation of nitric oxide along with superoxide radicals leads to the generation of peroxynitrite that can eventually result in the nitration of susceptible proteins. Nitrotyrosine is widely used as a biomarker of nitrative stress and indicates oxidative damage to proteins. Ototoxic insults, such as exposure to noise and ototoxic drugs, enhance the generation of 3-nitrotyrosine in different cell types in the cochlea. Nitrated proteins can disrupt critical signaling pathways and eventually lead to apoptosis and loss of sensory receptor cells in the cochlea. Accumulating evidence shows that selective targeting of nitrative stress attenuates cellular damage. Anti-nitrative compounds, such as peroxynitrite decomposition catalysts and inducible nitric oxide synthase inhibitors, prevent nitrative stress-mediated auditory damage. However, the role of nitrative stress in acquired hearing loss and its potential significance as a promising interventional target is yet to be fully characterized. This review provides an overview of nitrative stress mechanisms, the induction of nitrative stress in the auditory tissue after ototoxic insults, and the therapeutic value of targeting nitrative stress for mitigating auditory dysfunction.
PubMed: 35745568
DOI: 10.3390/ph15060649 -
Antioxidants & Redox Signaling Jun 2022Transient receptor potential (TRP) channels are cation-gated channels that serve as detectors of various sensory modalities, such as pain, heat, cold, and taste. These... (Review)
Review
Transient receptor potential (TRP) channels are cation-gated channels that serve as detectors of various sensory modalities, such as pain, heat, cold, and taste. These channels are expressed in the inner ear, suggesting that they could also contribute to the perception of sound. This review provides more details on the different types of TRP channels that have been identified in the cochlea to date, focusing on their cochlear distribution, regulation, and potential contributions to auditory functions. To date, the effect of TRP channels on normal cochlear physiology in mammals is still unclear. These channels contribute, to a limited extent, to normal cochlear physiology such as the hair cell mechanoelectrical transduction channel and strial functions. More detailed information on a number of these channels in the cochlea awaits future studies. Several laboratories focusing on TRPV1 channels have shown that they are responsive to cochlear stressors, such as ototoxic drugs and noise, and regulate cytoprotective and/or cell death pathways. TRPV1 expression in the cochlea is under control of oxidative stress (produced primarily by NOX3 NADPH oxidase) as well as STAT1 and STAT3 transcription factors, which differentially modulate inflammatory and apoptotic signals in the cochlea. Inhibition of oxidative stress or inflammation reduces the expression of TRPV1 channels and protects against cochlear damage and hearing loss. TRPV1 channels are activated by both capsaicin and cisplatin, which produce differential effects on the inner ear. How these differential actions are produced is yet to be determined. It is clear that TRPV1 is an essential component of cisplatin ototoxicity as knockdown of these channels protects against hearing loss. In contrast, activation of TRPV1 by capsaicin protected against subsequent hearing loss induced by cisplatin. The cellular targets that are influenced by these two drugs to account for their differential profiles need to be fully elucidated. Furthermore, the potential involvement of different TRP channels present in the cochlea in regulating cisplatin ototoxicity needs to be determined. TRPV1 has been shown to mediate the entry of aminoglycosides into the hair cells. Thus, novel otoprotective strategies could involve designing drugs to inhibit entry of aminoglycosides and possibly other ototoxins into cochlear hair cells. TRP channels, including TRPV1, are expressed on circulating and resident immune cells. These receptors modulate immune cell functions. However, whether they are activated by cochlear stressors to initiate cochlear inflammation and ototoxicity needs to be determined. A better understanding of the function and regulation of these TRP channels in the cochlea could enable development of novel treatments for treating hearing loss. . 36, 1158-1170.
Topics: Aminoglycosides; Animals; Capsaicin; Cisplatin; Hearing Loss; Inflammation; Mammals; Ototoxicity; Transient Receptor Potential Channels
PubMed: 34465184
DOI: 10.1089/ars.2021.0191 -
The Journal of Neuroscience : the... Apr 2019Ototoxic side effects of cisplatin and aminoglycosides have been extensively studied, but no therapy is available to date. Sensory hair cells, upon exposure to cisplatin...
Ototoxic side effects of cisplatin and aminoglycosides have been extensively studied, but no therapy is available to date. Sensory hair cells, upon exposure to cisplatin or aminoglycosides, undergo apoptotic and necrotic cell death. Blocking these cell death pathways has therapeutic potential in theory, but incomplete protection and lack of therapeutic targets in the case of necrosis, has hampered the development of clinically applicable drugs. Over the past decade, a novel form of necrosis, termed necroptosis, was established as an alternative cell death pathway. Necroptosis is distinguished from passive necrotic cell death, in that it follows a cellular program, involving the receptor-interacting protein kinase (RIPK) 1 and RIPK3. In this study, we used pharmacological and genetic interventions in the mouse to test the relative contributions of necroptosis and caspase-8-mediated apoptosis toward cisplatin and aminoglycoside ototoxicity. We find that , only apoptosis contributes to cisplatin and aminoglycoside ototoxicity, while , necroptosis as well as apoptosis are involved in both sexes. Inhibition of necroptosis and apoptosis using pharmacological compounds is thus a viable strategy to ameliorate aminoglycoside and cisplatin ototoxicity. The clinical application of cisplatin and aminoglycosides is limited due to ototoxic side effects. Here, using pharmaceutical and genetic intervention, we present evidence that two types of programmed cell death, apoptosis and necroptosis, contribute to aminoglycoside and cisplatin ototoxicity. Key molecular factors mediating necroptosis are well characterized and druggable, presenting new avenues for pharmaceutical intervention.
Topics: Aminoglycosides; Animals; Anti-Bacterial Agents; Antineoplastic Agents; Apoptosis; Caspase 8; Cell Death; Cisplatin; Ear, Inner; Evoked Potentials, Auditory, Brain Stem; Female; Hair Cells, Auditory; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Necroptosis; Ototoxicity; Receptor-Interacting Protein Serine-Threonine Kinases
PubMed: 30733218
DOI: 10.1523/JNEUROSCI.1384-18.2019 -
Seminars in Hearing May 2019The need for monitoring hearing and auditory function during drug therapy and other treatments that have the potential to cause hearing loss is well documented. Besides... (Review)
Review
The need for monitoring hearing and auditory function during drug therapy and other treatments that have the potential to cause hearing loss is well documented. Besides the main purpose of ototoxic monitoring, which is to provide feedback to the attending physician about the effects the treatment is having on the auditory system, it is also helpful in setting expectations for the patient and his/her family about the communication issues that may result from the drug therapy. This article will review tests available to an audiologist, both subjective and objective, that can be used to effectively monitor hearing levels and auditory function during treatment. Published guidelines and various ototoxic monitoring protocols are reviewed regarding tests administered, what constitutes a significant change in test results and how these findings are reported, and the impact significant changes may have on the course of treatment. Test protocols from different institutions are compared for both similarities and contrasts. Effective scheduling and test location are key to a successful monitoring program. Finally, the need to streamline ototoxic monitoring of hearing and auditory function to reduce test time and make it less stressful and tiresome on the patient will be considered.
PubMed: 31036990
DOI: 10.1055/s-0039-1684042 -
JCO Oncology Practice May 2023Cisplatin is a bedrock of cancer management and one of the most used chemotherapeutic agents in the treatment of germ cell, lung, bladder, ovarian, and head and neck... (Review)
Review
Cisplatin is a bedrock of cancer management and one of the most used chemotherapeutic agents in the treatment of germ cell, lung, bladder, ovarian, and head and neck cancers. Approximately 500,000 patients diagnosed annually with these cancer types in the United States could be candidates for treatment with cisplatin. There is a 5-fold increase in the risk of hearing impairment or ototoxicity with cisplatin, which can manifest as ringing in the ear (tinnitus), high-frequency hearing loss, and at late stages, a decreased ability to hear normal conversation. More than half of adult and pediatric patients with cancer treated with cisplatin developed hearing impairment with major impact on patients' health-related quality of life. A considerable evidence gap persists regarding the burden and effective prevention and interception strategies for cisplatin-induced ototoxicity, especially in adult patients with cancer. We conducted a review of the published literature to provide an update on the status of this important clinical challenge. We also surveyed practicing oncologists within our network of academic and community practices to gain a better understanding of how the published literature compares with real-world practice. Our review of the literature showed a lack of standardized guidelines for monitoring and treatment of cisplatin-induced ototoxicity, especially in the adult cancer patient population. Our survey of practicing oncologists mirrored the findings from the published literature with a heterogeneity of practice, which highlights the need for standardization.
Topics: Adult; Humans; Child; United States; Cisplatin; Antineoplastic Agents; Ototoxicity; Quality of Life; Hearing Loss; Head and Neck Neoplasms
PubMed: 36921239
DOI: 10.1200/OP.22.00710 -
Toxicology Letters Sep 2015Cisplatin is one of the most widely-used drugs to treat cancers. However, its nephrotoxic and ototoxic side-effects remain major clinical limitations. Recent studies... (Review)
Review
Cisplatin is one of the most widely-used drugs to treat cancers. However, its nephrotoxic and ototoxic side-effects remain major clinical limitations. Recent studies have improved our understanding of the molecular mechanisms of cisplatin-induced nephrotoxicity and ototoxicity. While cisplatin binding to DNA is the major cytotoxic mechanism in proliferating (cancer) cells, nephrotoxicity and ototoxicity appear to result from toxic levels of reactive oxygen species and protein dysregulation within various cellular compartments. In this review, we discuss molecular mechanisms of cisplatin-induced nephrotoxicity and ototoxicity. We also discuss potential clinical strategies to prevent nephrotoxicity and ototoxicity and their current limitations.
Topics: Antineoplastic Agents; Cisplatin; Humans; Kidney Diseases; Reactive Oxygen Species; Vestibular Diseases
PubMed: 26101797
DOI: 10.1016/j.toxlet.2015.06.012