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Oh H, Park MK. Assessment and Management of Chemotherapy-Induced Ototoxicity in Children. J Audiol Otol 2025; 29:79-85. [PMID: 40296470 PMCID: PMC12046201 DOI: 10.7874/jao.2025.00073] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2025] [Revised: 04/05/2025] [Accepted: 04/09/2025] [Indexed: 04/30/2025] Open
Abstract
Chemotherapy-induced ototoxicity is a significant concern in pediatric patients with cancer, particularly those treated with platinum-based agents, such as cisplatin and carboplatin. This study reviewed its prevalence, risk factors, early diagnosis, and management strategies. A literature review was conducted to assess the effects of ototoxic chemotherapy, screening methods, and treatment approaches. Various grading scales and rehabilitation strategies were analyzed. Platinum-based chemotherapy causes ototoxic hearing loss in approximately 100% of cases, including high-frequency and delayed-onset losses. Younger age, higher cumulative dose, and cranial irradiation increased the risk. Screening adherence remains suboptimal, despite guidelines recommending early detection through high-frequency audiometry. Sodium thiosulfate may reduce ototoxicity in nonmetastatic cases. If appropriate, hearing aids and cochlear implants can support communication and language development. Ototoxic hearing loss is a prevalent, yet underdiagnosed, complication of pediatric cancer treatment. Standardized screening, otoprotective strategies, and early rehabilitation are essential to minimize their impact on language and quality of life. Greater awareness and national guidelines are required to improve the care of pediatric cancer survivors.
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Affiliation(s)
- Heonjeong Oh
- Department of Medicine, Seoul National University College of Medicine, Seoul, Korea
- Department of Otorhinolaryngology-Head and Neck Surgery, Seoul National University Hospital, Seoul, Korea
- Sensory Organ Research Institute, Seoul National University Medical Research Center, Seoul, Korea
| | - Moo Kyun Park
- Department of Medicine, Seoul National University College of Medicine, Seoul, Korea
- Department of Otorhinolaryngology-Head and Neck Surgery, Seoul National University Hospital, Seoul, Korea
- Sensory Organ Research Institute, Seoul National University Medical Research Center, Seoul, Korea
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Davis ME, Guarini E, O'Connor K, Francis JH, Abramson DH. Hearing Evaluations in Children With Retinoblastoma Treated With Intra-arterial Carboplatin Chemotherapy: A Single Institution Review. J Pediatr Ophthalmol Strabismus 2025; 62:27-32. [PMID: 39254185 PMCID: PMC11757066 DOI: 10.3928/01913913-20240807-02] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 09/11/2024]
Abstract
PURPOSE To determine whether the administration of intra-arterial carboplatin affected the hearing of children with retinoblastoma. METHODS Children with retinoblastoma who were treated with intra-arterial carboplatin chemotherapy were included. Hearing tests before chemotherapy including tympanometry, distortion product otoacoustic emissions, and audiogram (if achievable) were performed and repeated 3 to 9 months after concluding intra-arterial therapy. The study was approved by the institutional review board. Patients were identified from the retinoblastoma clinic when the treatment plan included intra-arterial carboplatin chemotherapy. Children were excluded if they had previous intra-arterial carboplatin or preexisting hearing loss but were included if they had systemic carboplatin and dosing was available. Tympanometry was performed to rule out inner ear fluid. All examinations were performed by a certified audiologist with the same equipment, calibrated regularly by a certified technician. RESULTS Twenty-two children (32 eyes) were evaluable. Because most children are diagnosed at a young age and are unable to participate in an audiogram, distortion product otoacoustic emission measurement was the primary measurement. No child displayed hearing loss. CONCLUSIONS Intra-arterial chemotherapy with carboplatin did not cause ototoxicity in any child by distortion product otoacoustic emission measurement in contrast to systemic chemotherapy where ototoxicity is common. Distortion product otoacoustic emission levels were essentially unchanged from before to after intra-arterial chemotherapy in children with retinoblastoma. These findings suggest that intra-arterial carboplatin does not affect outer hair cell function, and distortion product otoacoustic emission tests can provide useful information when monitoring children at risk of developing carboplatin ototoxicity. [J Pediatr Ophthalmol Strabismus. 2025;62(1):27-32.].
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Abramson DH. What have we learned about intraarterial chemotherapy (Ophthalmic Artery Chemosurgery) for retinoblastoma in the past 18 years? The third A. Linn Murphree Lecture. Ophthalmic Genet 2024; 45:551-557. [PMID: 39232246 DOI: 10.1080/13816810.2024.2388579] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2024] [Revised: 07/18/2024] [Accepted: 07/31/2024] [Indexed: 09/06/2024]
Abstract
Intraarterial chemotherapy (Ophthalmic Artery Chemosurgery/OAC) for retinoblastoma has transformed management of retinoblastoma worldwide since Pierre Gobin MD and I introduced it in 2006. Case reports, institutional series, meta-analyses, and randomized trials have validated its effectiveness and safety. It allows more eyes to be saved (at Memorial Sloan Kettering Cancer Center (MSKCC) as a result, we have gone from removing 96% of retinoblastoma eyes that presented with leukocoria (comparable to modern day International Classification "D" and "E" eyes) to saving 95% of these eyes with primary OAC management allows the majority of advanced intraocular eyes to be salvaged (both "D" and "E" eyes) prior to the chemoreduction era to saving 95% of these eyes with primary OAC management. OAC attains cures faster than intravenous protocols, has fewer systemic side effects, and is overall cheaper than intravenous approaches (because of the absence of side effects which are the main driver of cost in pediatric oncology). Unlike systemic chemotherapy no ports are needed (and no removal of ports for life threatening infections), it does not alter the immune system (so children can be immunized), it does not affect patient growth (and children who had received systemic chemotherapy catch up in growth during OAC), it does not affect hearing (which systemic Carboplatin does-especially in children <6 months of age), it eliminates the second cancers caused by radiation and systemic chemotherapy and does not compromise survival with all series showing patient survival >98%.
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Affiliation(s)
- David H Abramson
- Department of Surgery, Memorial Sloan Kettering Cancer Center Ringgold Standard Institution, New York, New York, USA
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Zhang X, You W, Wang Y, Dejenie R, Wang C, Huang Y, Li J. Prospects of anti-GD2 immunotherapy for retinoblastoma. Front Immunol 2024; 15:1499700. [PMID: 39620227 PMCID: PMC11604707 DOI: 10.3389/fimmu.2024.1499700] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2024] [Accepted: 10/21/2024] [Indexed: 12/11/2024] Open
Abstract
Retinoblastoma is the most common type of eye tumor in infants and children. Current treatments for retinoblastoma include intravenous chemotherapy, intra-arterial chemotherapy, intravitreal chemotherapy, cryotherapy, radiotherapy, and surgery. However, these treatments come accompanied by adverse effects such as the toxic side effects of chemotherapeutic drugs, post-operative complications including blindness after surgery, or other complications caused by radiotherapy. Immunotherapy is more promising for its low toxicity on normal cells and effectively improves the quality of life of patients. Disialoganglioside (GD2), a sphingolipid expressed on the surface of retinoblastoma, is a potential therapeutic target for retinoblastoma. We summarized immunotherapeutic approaches for both preclinical studies and clinical trials of GD2. An anti-GD2 monoclonal antibody (Dinutuximab), which has been approved for the treatment of high-risk neuroblastomas, has shown promising efficacy in improving patients' prognosis. Additionally, chimeric antigen receptors (CAR)-T therapy, GD2 vaccines and nanoparticles are also potential therapeutics. Finally, we discuss the prospects and current limitations of these immunotherapeutic approaches for treating retinoblastoma, as well as how to address these problems.
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Affiliation(s)
- Xinlong Zhang
- Affiliated Hospital of Shandong Second Medical University,School of Clinical Medicine, Shandong Second Medical University, Weifang, Shandong, China
- Jinming Yu Academician Workstation of Oncology, Shandong Second Medical University, Shandong, China
- School of Clinical Medicine, Shandong Second Medical University, Weifang, China
| | - Wulin You
- Department of Orthopedics, Wuxi Hospital Affiliated of Nanjing University of Chinese Medicine, Wuxi, China
- Medical Center, University of Chicago, Chicago, IL, United States
| | - Yuntao Wang
- Affiliated Hospital of Shandong Second Medical University,School of Clinical Medicine, Shandong Second Medical University, Weifang, Shandong, China
- Jinming Yu Academician Workstation of Oncology, Shandong Second Medical University, Shandong, China
- School of Clinical Medicine, Shandong Second Medical University, Weifang, China
| | - Rebeka Dejenie
- Medical Center, University of Chicago, Chicago, IL, United States
- School of Medicine, University of California, Davis, Davis, CA, United States
| | - Chenhao Wang
- Department of Orthopedics, Wuxi Hospital Affiliated of Nanjing University of Chinese Medicine, Wuxi, China
| | - Yan Huang
- Affiliated Hospital of Shandong Second Medical University,School of Clinical Medicine, Shandong Second Medical University, Weifang, Shandong, China
- Jinming Yu Academician Workstation of Oncology, Shandong Second Medical University, Shandong, China
- School of Clinical Medicine, Shandong Second Medical University, Weifang, China
| | - Jingjing Li
- Affiliated Hospital of Shandong Second Medical University,School of Clinical Medicine, Shandong Second Medical University, Weifang, Shandong, China
- Jinming Yu Academician Workstation of Oncology, Shandong Second Medical University, Shandong, China
- School of Clinical Medicine, Shandong Second Medical University, Weifang, China
- Medical Center, University of Chicago, Chicago, IL, United States
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Monterroso PS, Knight K, Roesler MA, Sample JM, Poynter JN. Remote Field Application of Digital Technology for Hearing Assessments in a Cohort of Pediatric Germ Cell Tumor Survivors. Cancer Epidemiol Biomarkers Prev 2024; 33:1177-1184. [PMID: 38869488 PMCID: PMC11371521 DOI: 10.1158/1055-9965.epi-24-0203] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2024] [Revised: 04/23/2024] [Accepted: 06/10/2024] [Indexed: 06/14/2024] Open
Abstract
BACKGROUND Childhood cancer survivors treated with platinum-based chemotherapy are at risk of treatment-induced hearing loss. Accurate evaluation of hearing thresholds has historically been limited to clinical audiometry, which is logistically challenging and expensive to include in epidemiologic studies. We evaluated the feasibility of using a remote, tablet-based hearing assessment in a cohort of pediatric germ cell tumor survivors treated with platinum-based chemotherapy. METHODS Survivors from the GCT Outcomes and Late effects Data (GOLD) study were recruited to the pilot study (n = 100). Study personnel conducted remote hearing assessments of standard and extended high frequency thresholds using validated tablet-based audiometry (SHOEBOX, Inc.). T tests and Wilcoxon rank-sum tests evaluated differences in assessment characteristics between children and adults. Agreement between self-reported and measured hearing loss was calculated using Cohen κ. RESULTS We were able to reach 136/168 (81%) eligible participants, of which 100 (74%) agreed to participate. Successful completion of the remote hearing assessment was high [97%; 20 children (ages 7-17), 77 adults (ages 18-31)]. The mean assessment length was 37.6 minutes, and the mean turnaround time was 8.3 days. We observed hearing loss at standard frequencies in 21% of participants. Agreement between self-reported and measured hearing loss was significant (P value = 1.41 × 10-7), with 83.5% concordance. CONCLUSIONS Hearing loss measured using the remote assessment aligns with self-reporting and rates of hearing loss reported in the literature for this population. IMPACT Remote application of tablet-based audiometry is a feasible and efficacious method for measuring hearing in epidemiologic studies with participants spread across large geographic areas.
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Affiliation(s)
- Pablo S Monterroso
- Division of Epidemiology and Clinical Research, Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota
| | - Kristin Knight
- Department of Pediatrics, Oregon Health and Science University, Portland, Oregon
| | - Michelle A Roesler
- Division of Epidemiology and Clinical Research, Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota
| | - Jeannette M Sample
- Division of Epidemiology and Clinical Research, Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota
| | - Jenny N Poynter
- Division of Epidemiology and Clinical Research, Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota
- Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota
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Rodriguez A, Abruzzo T, Williams JA, Ramasubramanian A. Audiology evaluation following intra-arterial carboplatin for retinoblastoma. CANADIAN JOURNAL OF OPHTHALMOLOGY 2024; 59:e378-e379. [PMID: 38373698 DOI: 10.1016/j.jcjo.2024.01.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/10/2023] [Revised: 12/04/2023] [Accepted: 01/29/2024] [Indexed: 02/21/2024]
Affiliation(s)
| | - Todd Abruzzo
- Creighton University, Phoenix, AZ; Phoenix Children's Hospital, Phoenix, AZ
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Millen GC, Lawford A, Duncan C, Jenkinson H, Veal GJ, Barnett S. Utility of carboplatin therapeutic drug monitoring for the treatment of neonate and infant retinoblastoma patients in the United Kingdom. Br J Cancer 2024; 131:491-497. [PMID: 38871807 PMCID: PMC11300439 DOI: 10.1038/s41416-024-02728-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2024] [Revised: 05/12/2024] [Accepted: 05/16/2024] [Indexed: 06/15/2024] Open
Abstract
BACKGROUND Retinoblastoma is the most common intra-ocular malignancy in children and frequently presents in very young patients who commonly require intravenous carboplatin. Delivering this is challenging due to a lack of uniform dosing recommendations, rapid changes in physiological function and the risk of side-effects. METHODS We conducted a retrospective review of neonates and infants in the UK with retinoblastoma, who have undergone carboplatin therapeutic drug monitoring (TDM). We report on the pharmacokinetic, treatment efficacy and toxicity data. RESULTS In total, 29 patients (median age 5 weeks at treatment onset) underwent a total of 74 TDM guided cycles of chemotherapy, involving real time sampling and dose adjustment. An additional 13 patients underwent TDM sampling to modify doses between cycles. Without the adoption of TDM guided dosing, carboplatin exposures would have been ≥20% outside the target AUC in 38/78 (49%) of treatment cycles. Excellent responses and a reassuringly low incidence of toxicities were observed following dose adjustment, despite the young patient age and the implementation of dose increases in the majority of cases. CONCLUSIONS Real time TDM is safe, effective and deliverable for neonates and infants receiving carboplatin for retinoblastoma and should be considered standard of care up to the age of 6 months.
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Affiliation(s)
- Gerard C Millen
- Department of Paediatric Oncology, Birmingham Children's Hospital, Birmingham, UK.
| | - Alice Lawford
- Department of Paediatric Oncology, Great Ormond Street Hospital, London, UK
| | - Catriona Duncan
- Department of Paediatric Oncology, Great Ormond Street Hospital, London, UK
| | - Helen Jenkinson
- Department of Paediatric Oncology, Birmingham Children's Hospital, Birmingham, UK
| | - Gareth J Veal
- Translational & Clinical Research Institute, Newcastle University Centre for Cancer, Newcastle University, Newcastle upon Tyne, UK
| | - Shelby Barnett
- Translational & Clinical Research Institute, Newcastle University Centre for Cancer, Newcastle University, Newcastle upon Tyne, UK.
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Meijer AJ, Diepstraten FA, Ansari M, Bouffet E, Bleyer A, Fresneau B, Geller JI, Huitema AD, Kogner P, Maibach R, O'Neill AF, Papadakis V, Rajput KM, Veal GJ, Sullivan M, van den Heuvel-Eibrink MM, Brock PR. Use of Sodium Thiosulfate as an Otoprotectant in Patients With Cancer Treated With Platinum Compounds: A Review of the Literature. J Clin Oncol 2024; 42:2219-2232. [PMID: 38648563 PMCID: PMC11191063 DOI: 10.1200/jco.23.02353] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Revised: 01/05/2024] [Accepted: 02/07/2024] [Indexed: 04/25/2024] Open
Abstract
PURPOSE Hearing loss occurs in 50%-70% of children treated with cisplatin. Scientific efforts have led to the recent approval of a pediatric formula of intravenous sodium thiosulfate (STS) for otoprotection by the US Food and Drug Administration, the European Medicines Agency, and the Medicines and Health Regulatory Authority in the United Kingdom. To inform stakeholders regarding the clinical utility of STS, the current review summarizes available literature on the efficacy, pharmacokinetics (PK), and safety of systemic STS to minimize cisplatin-induced hearing loss (CIHL). DESIGN A comprehensive narrative review is presented. RESULTS Thirty-one articles were summarized. Overall, systemic STS effectively reduces CIHL in the preclinical and controlled clinical study settings, in both adults and children with cancer. The extent of CIHL reduction depends on the timing and dosing of STS in relation to cisplatin. Both preclinical and clinical data suggest that systemic STS may affect plasma platinum levels, but studies are inconclusive. Delayed systemic administration of STS, at 6 hours after the cisplatin infusion, does not affect cisplatin-induced inhibition of tumor growth or cellular cytotoxicity in the preclinical setting, nor affect cisplatin efficacy and survival in children with localized disease in the clinical setting. CONCLUSION Systemic administration of STS effectively reduces the development and degree of CIHL in both the preclinical and clinical settings. More studies are needed on the PK of STS and cisplatin drug combinations, the efficacy and safety of STS in patients with disseminated disease, and the ability of STS to prevent further deterioration of pre-established hearing loss.
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Affiliation(s)
| | | | - Marc Ansari
- Cansearch Research Platform for Pediatric Oncology and Hematology, Faculty of Medicine, Department of Pediatrics, Gynecology and Obstetrics, University of Geneva, Division of Pediatric Oncology and Hematology, Department of Women, Child and Adolescent, University Geneva Hospitals, Geneva, Switzerland
| | - Eric Bouffet
- Division of Pediatric Neuro-Oncology, The Hospital for Sick Children, Toronto, Ontario, Canada
| | - Archie Bleyer
- Department of Radiation Oncology, Knight Cancer Institute, Oregon Health and Science University, Portland, Oregon, Canada
| | - Brice Fresneau
- Department of Children and Adolescents Oncology, Gustave Roussy, University Paris Saclay and Radiation Epidemiology Team, CESO, Inserm U1018, Villejuif, France
| | - James I. Geller
- Division of Oncology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH
| | - Alwin D.R. Huitema
- Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands
- Department of Pharmacy and Pharmacology, Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands
- Department of Clinical Pharmacy, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands
| | - Per Kogner
- Department of Pediatric Oncology and Childhood Cancer Research Unit, Karolinska Institutet, Stockholm, Sweden
| | | | - Allison F. O'Neill
- Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA
| | - Vassilios Papadakis
- Department of Pediatric Hematology-Oncology (TAO), Agia Sofia Children's Hospital, Athens, Greece
| | - Kaukab M. Rajput
- Department of Pediatric Audiology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom
| | - Gareth J. Veal
- Newcastle University Centre for Cancer, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Michael Sullivan
- Children's Cancer Centre and Department of Pediatric Oncology, Royal Children's Hospital, Melbourne, Victoria, Australia
| | - Marry M. van den Heuvel-Eibrink
- Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands
- Wilhelmina Childrens' Hospital, Division of Child Health, Utrecht, the Netherlands
| | - Penelope R. Brock
- Department of Pediatric Oncology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom
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de Bloeme CM, van Elst S, Galluzzi P, Jansen RW, de Haan J, Göricke S, Moll AC, Bot JCJ, Munier FL, Beck-Popovic M, Puccinelli F, Aerts I, Hadjistilianou T, Sirin S, Koob M, Brisse HJ, Cardoen L, Maeder P, de Jong MC, de Graaf P. MR Imaging of Adverse Effects and Ocular Growth Decline after Selective Intra-Arterial Chemotherapy for Retinoblastoma. Cancers (Basel) 2024; 16:1899. [PMID: 38791976 PMCID: PMC11120425 DOI: 10.3390/cancers16101899] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2024] [Revised: 05/10/2024] [Accepted: 05/13/2024] [Indexed: 05/26/2024] Open
Abstract
This retrospective multicenter study examines therapy-induced orbital and ocular MRI findings in retinoblastoma patients following selective intra-arterial chemotherapy (SIAC) and quantifies the impact of SIAC on ocular and optic nerve growth. Patients were selected based on medical chart review, with inclusion criteria requiring the availability of posttreatment MR imaging encompassing T2-weighted and T1-weighted images (pre- and post-intravenous gadolinium administration). Qualitative features and quantitative measurements were independently scored by experienced radiologists, with deep learning segmentation aiding total eye volume assessment. Eyes were categorized into three groups: eyes receiving SIAC (Rb-SIAC), eyes treated with other eye-saving methods (Rb-control), and healthy eyes. The most prevalent adverse effects post-SIAC were inflammatory and vascular features, with therapy-induced contrast enhancement observed in the intraorbital optic nerve segment in 6% of patients. Quantitative analysis revealed significant growth arrest in Rb-SIAC eyes, particularly when treatment commenced ≤ 12 months of age. Optic nerve atrophy was a significant complication in Rb-SIAC eyes. In conclusion, this study highlights the vascular and inflammatory adverse effects observed post-SIAC in retinoblastoma patients and demonstrates a negative impact on eye and optic nerve growth, particularly in children treated ≤ 12 months of age, providing crucial insights for clinical management and future research.
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Affiliation(s)
- Christiaan M. de Bloeme
- Cancer Center Amsterdam, Imaging and Biomarkers, 1081 HV Amsterdam, The Netherlands
- Department of Radiology and Nuclear Medicine, Amsterdam UMC, Vrije Universiteit Amsterdam, 1081 HV Amsterdam, The Netherlands
| | - Sabien van Elst
- Cancer Center Amsterdam, Imaging and Biomarkers, 1081 HV Amsterdam, The Netherlands
- Department of Radiology and Nuclear Medicine, Amsterdam UMC, Vrije Universiteit Amsterdam, 1081 HV Amsterdam, The Netherlands
| | - Paolo Galluzzi
- Department of Neuroimaging Unit, Siena University Hospital, 53100 Siena, Italy
| | - Robin W. Jansen
- Cancer Center Amsterdam, Imaging and Biomarkers, 1081 HV Amsterdam, The Netherlands
- Department of Radiology and Nuclear Medicine, Amsterdam UMC, Vrije Universiteit Amsterdam, 1081 HV Amsterdam, The Netherlands
| | - Joeka de Haan
- Cancer Center Amsterdam, Imaging and Biomarkers, 1081 HV Amsterdam, The Netherlands
| | - Sophia Göricke
- Department of Diagnostic and Interventional Radiology and Neuroradiology, University Hospital Essen, 45147 Essen, Germany
| | - Annette C. Moll
- Cancer Center Amsterdam, Imaging and Biomarkers, 1081 HV Amsterdam, The Netherlands
- Department of Ophthalmology, Amsterdam UMC, Vrije Universiteit Amsterdam, 1081 HV Amsterdam, The Netherlands
| | - Joseph C. J. Bot
- Department of Radiology and Nuclear Medicine, Amsterdam UMC, Vrije Universiteit Amsterdam, 1081 HV Amsterdam, The Netherlands
| | - Francis L. Munier
- Unit of Pediatric Ocular Oncology, Jules-Gonin Eye Hospital, University of Lausanne, 1015 Lausanne, Switzerland
| | - Maja Beck-Popovic
- Department of Pediatrics, Centre Hospitalier Universitaire Vaudois (CHUV), University of Lausanne, 1011 Lausanne, Switzerland
| | - Francesco Puccinelli
- Department of Radiology, Centre Hospitalier Universitaire Vaudois (CHUV), University of Lausanne, 1011 Lausanne, Switzerland
| | - Isabelle Aerts
- Pediatricic Department, Institut Curie, PSL Research University, 75005 Paris, France
| | - Theodora Hadjistilianou
- Unit of Ophthalmology and Referral Center for Retinoblastoma, Department of Surgery, Policlinico “Santa Maria alle Scotte”, 53100 Siena, Italy
| | - Selma Sirin
- Department of Diagnostic Imaging, University Children’s Hospital Zurich, University of Zurich, 8032 Zurich, Switzerland
| | - Mériam Koob
- Department of Pediatrics, Centre Hospitalier Universitaire Vaudois (CHUV), University of Lausanne, 1011 Lausanne, Switzerland
| | - Hervé J. Brisse
- Imaging Department, Institut Curie, Paris University, 75005 Paris, France
| | - Liesbeth Cardoen
- Imaging Department, Institut Curie, Paris University, 75005 Paris, France
| | - Philippe Maeder
- Department of Radiology, Centre Hospitalier Universitaire Vaudois (CHUV), University of Lausanne, 1011 Lausanne, Switzerland
| | - Marcus C. de Jong
- Cancer Center Amsterdam, Imaging and Biomarkers, 1081 HV Amsterdam, The Netherlands
- Department of Radiology and Nuclear Medicine, Amsterdam UMC, Vrije Universiteit Amsterdam, 1081 HV Amsterdam, The Netherlands
| | - Pim de Graaf
- Cancer Center Amsterdam, Imaging and Biomarkers, 1081 HV Amsterdam, The Netherlands
- Department of Radiology and Nuclear Medicine, Amsterdam UMC, Vrije Universiteit Amsterdam, 1081 HV Amsterdam, The Netherlands
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Bass JK, Wang F, Thaxton ME, Warren SE, Srivastava DK, Hudson MM, Ness KK, Brinkman TM. Association of hearing loss with patient-reported functional outcomes in adult survivors of childhood cancer. J Natl Cancer Inst 2024; 116:596-605. [PMID: 38048603 PMCID: PMC10995849 DOI: 10.1093/jnci/djad250] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2023] [Revised: 11/13/2023] [Accepted: 11/27/2023] [Indexed: 12/06/2023] Open
Abstract
BACKGROUND Hearing loss is prevalent following ototoxic therapy for childhood cancer. Associations between hearing loss, self-perceived hearing handicap, and functional outcomes have not been examined in survivors. METHODS Adult survivors treated with platinum or head and neck radiotherapy with hearing loss were recruited. A total of 237 survivors (median age at survey = 37.0 years [range = 30.0-45.0 years]; median = 29.1 years [range = 22.4-35.0 years] since diagnosis; median = 4.0 years [range = 2.9-7.7 years] from last audiogram to survey) completed the Hearing Handicap Inventory for Adults and questionnaires on social and emotional functioning and hearing aid use. Hearing loss severity was defined according to Chang criteria. Multivariable logistic regression models estimated odds ratios (ORs) and 95% confidence intervals (CIs) for associations between hearing loss, hearing handicap, functional outcomes, and hearing aid use with adjustment for sex, race, age at hearing loss diagnosis, and age at survey. RESULTS Two-thirds of survivors had severe hearing loss, which was associated with increased likelihood of hearing handicap (mild-moderate handicap: OR = 2.72, 95% CI = 1.35 to 5.47; severe handicap: OR = 5.99, 95% CI = 2.72 to 13.18). Survivors with severe hearing handicap had an increased likelihood of social isolation (OR = 8.76, 95% CI = 3.62 to 21.20), depression (OR = 9.11, 95% CI = 3.46 to 24.02), anxiety (OR = 17.57, 95% CI = 3.77 to 81.84), reduced personal income (OR = 2.82, 95% CI = 1.46 to 5.43), and less than full-time employment (OR = 2.47, 95% CI = 1.30 to 4.70). Survivors who did not use a recommended hearing aid were twice as likely to have less than full-time employment (OR = 2.26, 95% CI = 1.10 to 4.61) and reduced personal income (OR = 2.24, 95% CI = 1.08 to 4.63) compared with survivors who wore a hearing aid. CONCLUSION Self-perceived hearing handicap beyond measured hearing loss is associated with reduced functional outcomes. Assessment of hearing handicap may facilitate targeted interventions in adult survivors with hearing loss.
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Affiliation(s)
- Johnnie K Bass
- Rehabilitation Services, St. Jude Children’s Research Hospital, Memphis, TN, USA
| | - Fang Wang
- Department of Epidemiology and Cancer Control, St. Jude Children’s Research Hospital, Memphis, TN, USA
| | | | - Sarah E Warren
- School of Communication Sciences and Disorders, University of Memphis, Memphis, TN, USA
| | - Deo Kumar Srivastava
- Department of Biostatistics, St. Jude Children’s Research Hospital, Memphis, TN, USA
| | - Melissa M Hudson
- Department of Epidemiology and Cancer Control, St. Jude Children’s Research Hospital, Memphis, TN, USA
- Department of Oncology, St. Jude Children’s Research Hospital, Memphis, TN, USA
| | - Kirsten K Ness
- Department of Epidemiology and Cancer Control, St. Jude Children’s Research Hospital, Memphis, TN, USA
| | - Tara M Brinkman
- Department of Epidemiology and Cancer Control, St. Jude Children’s Research Hospital, Memphis, TN, USA
- Department of Psychology and Biobehavioral Sciences, St. Jude Children’s Research Hospital, Memphis, TN, USA
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Kodetová M, Švojgr K, Širc J, Vaněček J, Pochop P. Therapy for Vitreous Seeding Caused by Retinoblastoma. A Review. CESKA A SLOVENSKA OFTALMOLOGIE : CASOPIS CESKE OFTALMOLOGICKE SPOLECNOSTI A SLOVENSKE OFTALMOLOGICKE SPOLECNOSTI 2024; 80:123-129. [PMID: 38538290 DOI: 10.31348/2023/35] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/25/2023]
Abstract
Retinoblastoma is the most common primary malignant intraocular tumor in children. Seeding, specifically the dispersion of the tumor into the adjacent compartments, represents a major parameter determining the degree of retinoblastoma according to the International Classification of Retinoblastoma. In this article we focused on vitreous seeding, one of the main limiting factors in the successful "eye preservation treatment" of retinoblastoma. This article presents an overview of the history of vitreous seeding of retinoblastoma, established treatment procedures and new-research modalities. The introduction of systemic chemotherapy in the treatment of retinoblastoma at the end of the 1990s represented a significant breakthrough, which enabled the progressive abandonment of radiotherapy with its attendant side effects. However, the attained concentrations of chemotherapeutics in the vitreous space during systemic chemotherapy are not sufficient for the treatment of vitreous seeding, and the toxic effects of systemic chemotherapy are not negligible. A significant change came with the advent of chemotherapy in situ, with the targeted administration of chemotherapeutic drugs, namely intra-arterial and intravitreal injections, contributing to the definitive eradication of external radiotherapy and a reduction of systemic chemotherapy. Although vitreous seeding remains the most common reason for the failure of intra-arterial chemotherapy, this technique has significantly influenced the original treatment regimen of children with retinoblastoma. However, intravitreal chemotherapy has made the greatest contribution to increasing the probability of preservation of the eyeball and visual functions in patients with advanced findings. Novel local drug delivery modalities, gene therapy, oncolytic viruses and immunotherapy from several ongoing preclinical and clinical trials may represent promising approaches in the treatment of vitreous retinoblastoma seeding, though no clinical trials have yet been completed for routine use.
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12
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Funt SA, Knezevic A, Wilson K, Bromberg M, Budnick A, O’Connor KL, McHugh DJ, Larsen E, Bajorin DF, Motzer RJ, Tonorezos ES, Patil S, Feldman DR. Ototoxicity associated with high-dose carboplatin for patients with previously treated germ cell tumors. Cancer 2023; 129:3952-3961. [PMID: 37715631 PMCID: PMC11305123 DOI: 10.1002/cncr.34991] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Revised: 06/26/2023] [Accepted: 07/18/2023] [Indexed: 09/17/2023]
Abstract
BACKGROUND High-dose carboplatin is an essential part of curative high-dose chemotherapy (HDCT) for patients with previously treated germ cell tumors (GCTs). Although hearing loss (HL) is a known side effect of HDCT, data on its severity and characteristics are limited. METHODS Eligible patients received HDCT for GCTs from 1993 to 2017 and had audiograms before and after HDCT. HL severity was classified by American Speech-Language-Hearing Association criteria, and mean change in hearing threshold at each frequency (0.25-8 kHz) was estimated from pre- to post-HDCT and between HDCT cycles. RESULTS Of 115 patients (median age, 32 years), 102 (89%) received three cycles of HDCT. Of 106 patients with normal hearing to mild HL in the speech frequencies (0.5-4 kHz) before HDCT, 70 (66%) developed moderate to profound HL in the speech frequencies after HDCT. Twenty-five patients (22%) were recommended for hearing aids after HDCT. Patients with moderate to profound HL isolated to the higher frequencies (6-8 kHz) before HDCT were more likely to develop moderate to profound HL in the speech frequencies after HDCT (94% vs. 61%; p = .01) and to be recommended for hearing aids (39% vs. 18%; p = .05). CONCLUSIONS HL was frequent after HDCT for GCTs, with most patients developing at least moderate HL in the speech frequencies and approximately one in five recommended for hearing aids. Moderate to profound HL isolated to high frequencies at baseline was predictive of more clinically significant hearing impairment after HDCT. PLAIN LANGUAGE SUMMARY Some patients with germ cell tumors, the most common malignancy in adolescent and young adult men, are not cured with standard-dose chemotherapy and require high-dose chemotherapy (HDCT). Using detailed hearing assessments of patients receiving HDCT, we found that most patients developed significant hearing loss and that one in five needed hearing aids. Thus, strategies to reduce this side effect are urgently needed, and all patients receiving HDCT should have a hearing test after therapy.
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Affiliation(s)
- Samuel A. Funt
- Genitourinary Oncology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
- Weill Cornell Medical College, New York, NY, USA
| | - Andrea Knezevic
- Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
| | - Kaamilah Wilson
- Genitourinary Oncology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
| | - Maria Bromberg
- Genitourinary Oncology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
| | - Amy Budnick
- Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
| | - Kerri L. O’Connor
- Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
| | - Deaglan J. McHugh
- Genitourinary Oncology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
- Weill Cornell Medical College, New York, NY, USA
| | - Erik Larsen
- Formerly of Decibel Therapeutics, Boston, MA, USA
| | - Dean F. Bajorin
- Genitourinary Oncology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
- Weill Cornell Medical College, New York, NY, USA
| | - Robert J. Motzer
- Genitourinary Oncology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
- Weill Cornell Medical College, New York, NY, USA
| | | | - Sujata Patil
- Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
- Department of Biostatistics, Cleveland Clinic, Cleveland, Ohio, USA
| | - Darren R. Feldman
- Genitourinary Oncology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
- Weill Cornell Medical College, New York, NY, USA
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13
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Zhu X, Li Z, Liu J, Guo J, Xian J, Wu J. MRI features for prediction of the intravenous chemotherapy effect in patients with retinoblastoma. Clin Radiol 2023; 78:e864-e871. [PMID: 37596180 DOI: 10.1016/j.crad.2023.07.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2023] [Revised: 07/07/2023] [Accepted: 07/17/2023] [Indexed: 08/20/2023]
Abstract
AIM To investigate the value of orbital magnetic resonance imaging (MRI) features in predicting the efficacy of intravenous chemotherapy (IVC) for patients with retinoblastoma (RB). MATERIALS AND METHODS The pretreatment clinical and MRI data of 100 eyes from 80 RB patients who underwent IVC were collected retrospectively. There were 59 eyes in the effective group and 41 eyes in the ineffective group, and the baseline data of the two groups were compared statistically. Three radiologists reviewed and evaluated each lesion independently based on 25 MRI features. The predictive values of the MRI features for IVC efficacy were assessed by multi-factor logistic regression analysis, and their odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated. Receiver operating characteristic curves (ROCs) with the area under the curve (AUC) were used to determine the predictive abilities. A predictive model was constructed by integrating all independent predictors visualised by the nomogram. RESULTS There were no statistically significant differences in sex or age between the effective and ineffective groups. The results of multivariate regression analysis showed that laterality, margin, and anterior eye segment enhancement were identified as independent factors that could predict IVC efficacy. The predictive model combining these three features was constructed, and it had an AUC of 0.732 (95% CI: 0.633, 0.831, p<0.01), a sensitivity of 71.2%, and a specificity of 70.7%. CONCLUSION The data demonstrate that the orbital MRI features can be used to predict IVC efficiency before RB patients are treated.
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Affiliation(s)
- X Zhu
- Department of Radiology, Beijing Tongren Hospital, Capital Medical University, Beijing, China; Department of Radiology, Affiliated Zhongshan Hospital of Dalian University, Dalian, Liaoning, China
| | - Z Li
- Department of Radiology, Beijing Tongren Hospital, Capital Medical University, Beijing, China
| | - J Liu
- Department of Radiology, Beijing Tongren Hospital, Capital Medical University, Beijing, China
| | - J Guo
- Department of Radiology, Beijing Tongren Hospital, Capital Medical University, Beijing, China
| | - J Xian
- Department of Radiology, Beijing Tongren Hospital, Capital Medical University, Beijing, China.
| | - J Wu
- Department of Radiology, Affiliated Zhongshan Hospital of Dalian University, Dalian, Liaoning, China.
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14
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Barnett S, Makin G, Tweddle DA, Osborne C, Veal GJ. Generation of evidence-based carboplatin dosing guidelines for neonates and infants. Br J Cancer 2023; 129:1773-1779. [PMID: 37816842 PMCID: PMC10667364 DOI: 10.1038/s41416-023-02456-y] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Revised: 09/15/2023] [Accepted: 09/26/2023] [Indexed: 10/12/2023] Open
Abstract
BACKGROUND To optimally dose childhood cancer patients it is essential that we apply evidence-based dosing approaches. Carboplatin is commonly dosed to achieve a cumulative target exposure (AUC) in children, with target AUC values of 5.2-7.8 mg/ml.min defined. To achieve these exposures patients are dosed at 6.6 mg/kg/day or 4.4 mg/kg for patients <5 kg. The current study uses real world clinical pharmacology data to optimise body weight-based doses to effectively target AUCs of 5.2-7.8 mg/ml.min in infants. METHODS Carboplatin exposures were determined across 165 treatment cycles in 82 patients ≤10 kg. AUC and clearance values were determined by Bayesian modelling from samples collected on day 1. These parameters were utilised to assess current dosing variability, determine doses required to achieve target AUC values and predict change in AUC using the modified dose. RESULTS No significant differences in clearance were identified between patients <5 kg and 5-10 kg. Consequently, for patients <5 kg, 4.4 mg/kg dosing was not sufficient to achieve a target AUC of 5.2 mg/ml.min, with <55% of patients within 25% of this target. Optimised daily doses for patients ≤10 kg were 6 mg/kg and 9 mg/kg for cumulative carboplatin target exposures of 5.2 and 7.8 mg/ml.min, respectively. CONCLUSIONS Adoption of these evidence-based carboplatin doses in neonates and infants will reduce drug exposure variability and positively impact treatment.
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Affiliation(s)
- Shelby Barnett
- Translational & Clinical Research Institute, Newcastle University Centre for Cancer, Newcastle University, Newcastle upon Tyne, UK.
| | - Guy Makin
- Division of Cancer Sciences, University of Manchester, Manchester, UK
- Royal Manchester Children's Hospital, Manchester, UK
| | - Deborah A Tweddle
- Translational & Clinical Research Institute, Newcastle University Centre for Cancer, Newcastle University, Newcastle upon Tyne, UK
- Great North Children's Hospital, Newcastle upon Tyne, UK
| | - Caroline Osborne
- Pharmacy Department, Alder Hey Children's NHS Foundation Trust, Liverpool, UK
| | - Gareth J Veal
- Translational & Clinical Research Institute, Newcastle University Centre for Cancer, Newcastle University, Newcastle upon Tyne, UK
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15
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Feng ZX, Zhao J, Zhang N, Jin M, Gallie B. Adjuvant Chemotherapy Improves Survival for Children With Massive Choroidal Invasion of Retinoblastoma. Invest Ophthalmol Vis Sci 2023; 64:27. [PMID: 37603354 PMCID: PMC10445210 DOI: 10.1167/iovs.64.11.27] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2023] [Accepted: 07/30/2023] [Indexed: 08/22/2023] Open
Abstract
Purpose The purpose of this study was to investigate the effect of adjuvant chemotherapy on outcomes of children with massive choroidal invasion (MCI). Methods In this study, we reviewed the 5-year relapse-free survival (RFS) and overall survival (OS) of children diagnosed with MCI, managed with or without adjuvant chemotherapy. Excluded were children with additional other high-risk features (post-laminar optic nerve invasion, scleral invasion, or overt extraocular disease). Results Of 3566 children diagnosed with retinoblastoma, 2023 had enucleation, and 60 eyes of 60 children had pathology showing MCI without concomitant high-risk features. Enucleation was primary (22, 37%), or secondary (38, 63%) after failed eye salvage. Adjuvant systemic chemotherapy (median = 4, range = 1-8 cycles) was given to 48 of 60 (80%) children; 12 of 60 (20%) children had no adjuvant therapy. Five-year RFS was 88.5% (95% confidence interval [CI] = 79.7%-97.3%) and 5-year OS was 90.1% (95% CI = 81.7%-98.5%). Pre-enucleation chemotherapy did not affect RFS (89.7% vs. 75.0%; P = 0.657). Adjuvant chemotherapy improved RFS (97.2% vs. 55.6%; P < 0.001) and OS (97.2% vs. 66.7%; P < 0.001). In subgroup analysis, adjuvant chemotherapy improved RFS for both primarily enucleated (5-year RFS 100% vs. 50.0%; P = 0.002) and secondarily enucleated children (5-year RFS 95.8% vs. 60.0%; P = 0.005). The number of children treated with adjuvant chemotherapy to prevent one post-enucleation systemic relapse or death is three. Conclusions Adjuvant chemotherapy significantly decreased the risk of tumor relapse and death for children with pathological MCI. For every three children treated with adjuvant chemotherapy, one systemic relapse or death could be prevented.
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Affiliation(s)
- Zhao Xun Feng
- Department of Ophthalmology, University of Ottawa, Ottawa, Canada
| | - Junyang Zhao
- Pediatric Oncology Center, Beijing Children's Hospital, Capital Medical University, Beijing, China
- Department of Ophthalmology, Beijing Children's Hospital, Capital Medical University, Beijing, China
| | - Nan Zhang
- Department of Pathology, Beijing Children's Hospital, Capital Medical University, Beijing, China
| | - Mei Jin
- Pediatric Oncology Center, Beijing Children's Hospital, Capital Medical University, Beijing, China
- Department of Medical Oncology, Beijing Children's Hospital, Capital Medical University, Beijing, China
- Beijing Key Laboratory of Pediatric Hematology Oncology, Key Laboratory of Major Diseases in Children, Beijing, China
| | - Brenda Gallie
- Department of Ophthalmology, Hospital for Sick Children, Toronto, Canada
- Krembil Research Institute and Techna Institute, University Health Network, Toronto, Canada
- Departments Ophthalmology, Medical Biophysics and Molecular Genetics, University of Toronto, Toronto, Canada
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16
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Momeni BZ, Abd-El-Aziz AS. Recent advances in the design and applications of platinum-based supramolecular architectures and macromolecules. Coord Chem Rev 2023. [DOI: 10.1016/j.ccr.2023.215113] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/29/2023]
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17
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Freyer DR, Orgel E, Knight K, Krailo M. Special considerations in the design and implementation of pediatric otoprotection trials. J Cancer Surviv 2023; 17:4-16. [PMID: 36637630 DOI: 10.1007/s11764-022-01312-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2022] [Accepted: 12/07/2022] [Indexed: 01/14/2023]
Abstract
PURPOSE Cisplatin-induced hearing loss (CIHL) is a common late effect after childhood cancer treatment having profound, lifelong consequences that lower quality of life. The recent identification of intravenous sodium thiosulfate (STS) as an effective agent for preventing pediatric CIHL represents a paradigm shift that has created new opportunities for expanding STS usage and developing additional otoprotectants. The purpose of this paper is to discuss key considerations and recommendations for the design and implementation of future pediatric otoprotection trials. METHODS An approach synthesizing published data and collective experience was used. RESULTS Key issues were identified in the categories of translational research, trial designs for systemic and intratympanic agents, measurement of ototoxicity, and biostatistical challenges. CONCLUSIONS Future pediatric otoprotection trials should emphasize (1) deep integration of preclinical and early-phase studies; (2) an embedded or free-standing design for systemic agents based on mechanistic considerations; (3) use of suitable audiologic testing batteries for children, SIOP grading criteria, and submission of raw audiologic data for central review; and (4) novel endpoints and innovative study designs that maximize trial efficiency for limited sample sizes. Additional recommendations include routine collection of DNA specimens for assessing modifying effects of genetic susceptibility and meaningful inclusion of patient/family advocates for informing trial development. IMPLICATIONS FOR CANCER SURVIVORS Changing the historical paradigm from acceptance to prevention of pediatric CIHL through expanded research with existing and emerging otoprotectants will dramatically improve quality of life for future childhood cancer survivors exposed to cisplatin.
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Affiliation(s)
- David R Freyer
- Cancer and Blood Disease Institute, Children's Hospital Los Angeles, Los Angeles, CA, USA.
- Departments of Pediatrics, Medicine, and Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
| | - Etan Orgel
- Cancer and Blood Disease Institute, Children's Hospital Los Angeles, Los Angeles, CA, USA
- Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Kristin Knight
- Department of Audiology, Doernbecher Children's Hospital, Portland, OR, USA
- Oregon Health and Science University, Portland, OR, USA
| | - Mark Krailo
- Department of Population and Public Health Sciences, University of Southern California, Los Angeles, CA, USA
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18
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Sun J, Gan L, Ding J, Ma R, Qian J, Xue K. Identification of non-coding RNAs and their functional network associated with optic nerve invasion in retinoblastoma. Heliyon 2023; 9:e13813. [PMID: 36852072 PMCID: PMC9958441 DOI: 10.1016/j.heliyon.2023.e13813] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2022] [Revised: 02/11/2023] [Accepted: 02/13/2023] [Indexed: 02/18/2023] Open
Abstract
Optic nerve invasion (ONI) is an important high-risk feature and prognostic indicator of retinoblastoma (RB). Emerging evidence has revealed that non-coding RNAs (ncRNAs) play important roles in tumor perineural invasion (PNI). Nevertheless, the regulatory role of ncRNAs in the ONI of RB is poorly understood. In the current study, whole-transcriptome sequencing was performed to assess the expression profiles of ncRNAs and mRNAs in RB tissues, with or without ONI. Based on Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses, we predicted the biological functions of differentially expressed (DE) mRNAs. We then constructed competing endogenous RNA (ceRNA) regulatory networks based on bioinformatics analysis. The hsa_circ_0015965/lncRNA MEG3-hsa-miR-378a-5p-NOTCH1 pathway was selected and validated by real-time qPCR, western blotting, and dual luciferase reporter assays. Moreover, we demonstrated that NOTCH1 promotes the malignant progression of RB. Taken together, our results provide novel insights into the mechanism underlying optic nerve invasion in RB.
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Affiliation(s)
- Jie Sun
- Department of Ophthalmology, Eye & ENT Hospital of Fudan University, Shanghai, 200031, China
| | - Lu Gan
- Department of Ophthalmology, Eye & ENT Hospital of Fudan University, Shanghai, 200031, China
| | - Jie Ding
- Department of Ophthalmology, Eye & ENT Hospital of Fudan University, Shanghai, 200031, China
| | - Ruiqi Ma
- Department of Ophthalmology, Eye & ENT Hospital of Fudan University, Shanghai, 200031, China
| | - Jiang Qian
- Department of Ophthalmology, Eye & ENT Hospital of Fudan University, Shanghai, 200031, China
| | - Kang Xue
- Department of Ophthalmology, Eye & ENT Hospital of Fudan University, Shanghai, 200031, China
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19
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Chen Y, Mao J, Xiang Z, Zhang Z, Zhang S, Wu S, Shen L. Retinal microvasculature observations of fellow eyes after intra-arterial chemotherapy for unilateral retinoblastoma using optical coherence tomography angiography. Front Med (Lausanne) 2023; 9:1015301. [PMID: 36703895 PMCID: PMC9871546 DOI: 10.3389/fmed.2022.1015301] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2022] [Accepted: 12/21/2022] [Indexed: 01/12/2023] Open
Abstract
Purpose To investigate the characteristics of the retinal microvasculature of the fellow eyes in patients with unilateral retinoblastoma (RB) after intra-arterial chemotherapy (IAC) through optical coherence tomography angiography. Methods This retrospective study enrolled 11 fellow eyes of patients with unilateral RB receiving IAC (group I), nine fellow eyes of patients with unilateral RB receiving IAC and intravenous chemotherapy (IVC) (group II), and 14 age-matched normal eyes (control group). Optical coherence tomography angiography was performed on all individuals. Vascular density of superficial capillary plexus and deep capillary plexus (DCP), foveal avascular zone related parameters, and retinal thickness were measured and compared among the three groups. Results There was no statistical difference in age and logMAR visual acuity among the three groups. Compared with the control group, the vascular density of the DCP was lower in group I and II. Decreased vascular density of FD-300 and thinner thickness of outer plexus layer to Bruch's membrane were detected in group II compared with the control group. The vascular density and retinal thickness showed no differences between group I and II. Conclusion The decreased vascular density in the DCP without measurable visual impairment was observed in fellow eyes after IAC or IAC + IVC for unilateral RB. Further studies with a larger sample would be necessary to determine the clinical significance of these findings.
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Affiliation(s)
- Yijing Chen
- Department of Ophthalmology, Center for Rehabilitation Medicine, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China,Department of Retina Center, Affiliated Eye Hospital of Wenzhou Medical University, Hangzhou, Zhejiang, China
| | - Jianbo Mao
- Department of Ophthalmology, Center for Rehabilitation Medicine, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China,Department of Retina Center, Affiliated Eye Hospital of Wenzhou Medical University, Hangzhou, Zhejiang, China
| | - Ziyi Xiang
- Department of Ophthalmology, Center for Rehabilitation Medicine, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Zhengxi Zhang
- Department of Ophthalmology, Center for Rehabilitation Medicine, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Shian Zhang
- Department of Retina Center, Affiliated Eye Hospital of Wenzhou Medical University, Hangzhou, Zhejiang, China
| | - Sulan Wu
- Department of Ophthalmology, Center for Rehabilitation Medicine, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Lijun Shen
- Department of Ophthalmology, Center for Rehabilitation Medicine, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China,Department of Retina Center, Affiliated Eye Hospital of Wenzhou Medical University, Hangzhou, Zhejiang, China,*Correspondence: Lijun Shen,
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20
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Hurkmans EGE, Klumpers MJ, Dello Russo C, De Witte W, Guchelaar HJ, Gelderblom H, Cleton-Jansen AM, Vermeulen SH, Kaal S, van der Graaf WTA, Flucke U, Gidding CEM, Schreuder HWB, de Bont ESJM, Caron HN, Gattuso G, Schiavello E, Terenziani M, Massimino M, McCowage G, Nagabushan S, Limaye A, Rose V, Catchpoole D, Jorgensen AL, Barton C, Delaney L, Hawcutt DB, Pirmohamed M, Pizer B, Coenen MJH, te Loo DMWM. Genome-wide analyses of platinum-induced ototoxicity in childhood cancer patients: Results of GO-CAT and United Kingdom MAGIC consortia. Front Pharmacol 2023; 13:980309. [PMID: 36699085 PMCID: PMC9870026 DOI: 10.3389/fphar.2022.980309] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Accepted: 12/14/2022] [Indexed: 01/11/2023] Open
Abstract
Hearing loss (ototoxicity) is a major adverse effect of cisplatin and carboplatin chemotherapy. The aim of this study is to identify novel genetic variants that play a role in platinum-induced ototoxicity. Therefore, a genome-wide association study was performed in the Genetics of Childhood Cancer Treatment (GO-CAT) cohort (n = 261) and the United Kingdom Molecular Genetics of Adverse Drug Reactions in Children Study (United Kingdom MAGIC) cohort (n = 248). Results of both cohorts were combined in a meta-analysis. In primary analysis, patients with SIOP Boston Ototoxicity Scale grade ≥1 were considered cases, and patients with grade 0 were controls. Variants with a p-value <10-5 were replicated in previously published data by the PanCareLIFE cohort (n = 390). No genome-wide significant associations were found, but variants in TSPAN5, RBBP4P5, AC010090.1 and RNU6-38P were suggestively associated with platinum-induced ototoxicity. The lowest p-value was found for rs7671702 in TSPAN5 (odds ratio 2.0 (95% confidence interval 1.5-2.7), p-value 5.0 × 10-7). None of the associations were significant in the replication cohort, although the effect directions were consistent among all cohorts. Validation and functional understanding of these genetic variants could lead to more insights in the development of platinum-induced ototoxicity.
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Affiliation(s)
| | - Marije J. Klumpers
- Department of Pediatrics, Radboud University Medical Center, Nijmegen, Netherlands
| | - Cinzia Dello Russo
- Department of Pharmacology and Therapeutics, Institute of Systems, Molecular and Integrative Biology (ISMIB), University of Liverpool, Liverpool, United Kingdom,Department of Healthcare Surveillance and Bioethics, Section of Pharmacology, Università Cattolica del Sacro Cuore-Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
| | - Ward De Witte
- Department of Human Genetics, Radboud University Medical Center, Nijmegen, Netherlands
| | - Henk-Jan Guchelaar
- Department of Clinical Pharmacy & Toxicology, Leiden University Medical Center, Leiden, Netherlands
| | - Hans Gelderblom
- Department of Medical Oncology, Leiden University Medical Center, Leiden, Netherlands
| | | | - Sita H. Vermeulen
- Department for Health Evidence, Radboud University Medical Center, Nijmegen, Netherlands
| | - Suzanne Kaal
- Department of Medical Oncology, Radboud University Medical Center, Nijmegen, Netherlands
| | - Winette T. A. van der Graaf
- Department of Medical Oncology, Radboud University Medical Center, Nijmegen, Netherlands,Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, Netherlands
| | - Uta Flucke
- Department of Pathology, Radboud University Medical Center, Nijmegen, Netherlands
| | | | | | - Eveline S. J. M. de Bont
- Department of Pediatrics, Beatrix Children’s Hospital, University Medical Center Groningen, Groningen, Netherlands
| | - Huib N. Caron
- Department of Pediatrics, Amsterdam University Medical Centers, Emma Children’s Hospital, Amsterdam, Netherlands
| | - Giovanna Gattuso
- Pediatric Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Elisabetta Schiavello
- Pediatric Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Monica Terenziani
- Pediatric Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Maura Massimino
- Pediatric Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Geoff McCowage
- Cancer Centre for Children, The Children’s Hospital at Westmead, Sydney, NSW, Australia
| | - Sumanth Nagabushan
- Cancer Centre for Children, The Children’s Hospital at Westmead, Sydney, NSW, Australia,Discipline of Child and Adolescent Health, University of Sydney, Sydney, NSW, Australia
| | - Anuja Limaye
- Department of Audiology, The Children’s Hospital at Westmead, Sydney, NSW, Australia
| | - Victoria Rose
- Department of Neuro-Otology, Royal Prince Alfred Hospital, University of Sydney, Sydney, NSW, Australia
| | - Daniel Catchpoole
- Children’s Cancer Research Unit, The Children’s Hospital at Westmead, Sydney, NSW, Australia
| | - Andrea L. Jorgensen
- Department of Health Data Science, University of Liverpool, Liverpool, United Kingdom
| | - Christopher Barton
- Department of Women’s and Children’s Health, University of Liverpool, Liverpool, United Kingdom
| | - Lucy Delaney
- Department of Women’s and Children’s Health, University of Liverpool, Liverpool, United Kingdom
| | - Daniel B. Hawcutt
- Department of Women’s and Children’s Health, University of Liverpool, Liverpool, United Kingdom,NIHR Alder Hey Clinical Research Facility, Alder Hey Children’s Hospital, Liverpool, United Kingdom
| | - Munir Pirmohamed
- Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool, United Kingdom
| | - Barry Pizer
- Department of Pediatric Oncology, Alder Hey Children’s Hospital, Liverpool, United Kingdom
| | - Marieke J. H. Coenen
- Department of Human Genetics, Radboud University Medical Center, Nijmegen, Netherlands
| | - D. Maroeska W. M. te Loo
- Department of Pediatrics, Radboud University Medical Center, Nijmegen, Netherlands,*Correspondence: D. Maroeska W. M. te Loo,
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21
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Sherief LM, Rifky E, Attia M, Ahmed R, Kamal NM, Oshi MAM, Hanna D. Platinum-induced ototoxicity in pediatric cancer survivors: GSTP1 c.313A>G variant association. Medicine (Baltimore) 2022; 101:e31627. [PMID: 36397425 PMCID: PMC9666226 DOI: 10.1097/md.0000000000031627] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2022] [Accepted: 10/11/2022] [Indexed: 11/19/2022] Open
Abstract
Hearing damage is one of the main toxic effects of platinum compounds, it derives from the irreversible degeneration of hair cells of the ear. Genetic association studies have suggested an association between GSTP1 c.313A>G variant and platinum-induced ototoxicity in childhood cancer survivors. We aimed to detect the frequency of ototoxicity and associated risk factors in survivors of childhood cancer receiving platinum-based chemotherapy and to detect the relation between GSTP1 c.313A>G (rs1695) polymorphisms and ototoxicity. We conducted a cross-sectional study on 64 cancer survivors who received platinum agents (cisplatin and/or carboplatin) at least 2 years after the end of chemotherapy. The patients underwent comprehensive audiological evaluations and genotyping to detect the presence of the GSTP1 c.313A>G polymorphisms. Hearing loss (HL) was identified in 16/64 patients (25%), including 62.5% treated with cisplatin and 37.5% treated with carboplatin. The greater incidence of ototoxicity was found in children treated for osteosarcoma (28.1%) followed by patients with germ cell tumors (25%) and neuroblastoma (21.9%). The AA, AG, and GG types of GSTP1 c.313A>G variant were detected in 84.4%, 9.4%, and 6.3%, respectively, of patients with HL with a significant association between mutant genotype of GSTP1 rs1695 and platinum-induced ototoxicity (P = .035). HL was not significantly associated with the total cumulative dose of cisplatin and carboplatin. GSTP1 c.313A>G variant may increase the risk of HL in pediatric oncology patients treated with cisplatin or carboplatin chemotherapy.
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Affiliation(s)
- Laila M. Sherief
- Department of Pediatrics and Pediatric Hematology/Oncology, Faculty of Medicine, Zagazig University, Zagazig, Egypt
| | - Elhamy Rifky
- Department of Pediatrics and Pediatric Hematology/Oncology, Faculty of Medicine, Zagazig University, Zagazig, Egypt
| | - Mohamed Attia
- Department of Clinical Pathology, Faculty of Medicine, Tanta University, Tanta, Egypt
| | | | - Naglaa M. Kamal
- Department of Pediatrics and Pediatric Hepatology, Faculty of Medicine Cairo University, Cairo, Egypt
| | - Mohammed A. M. Oshi
- Department of Pediatrics and Pediatric Neurology, Alhada Armed Forces Hospital, Taif, Saudi Arabia
| | - Diana Hanna
- Department of Pediatrics, Faculty of Medicine, Zagazig University, Zagazig, Egypt
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22
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Zhu HD, Li X, Ji JS, Huang M, Shao GL, Lu J, Zhao XY, Li HL, Yang ZQ, Tu JF, Zhou JM, Zeng CH, Teng GJ. TACE with dicycloplatin in patients with unresectable hepatocellular carcinoma: a multicenter randomized phase II trial. Eur Radiol 2022; 32:7335-7343. [PMID: 35776182 DOI: 10.1007/s00330-022-08848-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Revised: 04/14/2022] [Accepted: 04/26/2022] [Indexed: 01/03/2023]
Abstract
OBJECTIVES To investigate the efficacy and safety of dicycloplatin as chemotherapeutic regimen in transcatheter arterial chemoembolization (TACE) for hepatocellular carcinoma (HCC). METHODS In this randomized, open-label, phase II trial, patients with unresectable HCC who were TACE treatment-naïve or experienced recurrence after surgical resection or ablation were enrolled at 7 centers in China from March 2019 to November 2019. Participants were randomly assigned (1:1:1) to receive TACE with chemotherapeutic regimen of dicycloplatin alone (group A1), dicycloplatin plus epirubicin (group A2), or epirubicin alone (group B). The primary endpoint was objective response rate (ORR). The secondary endpoints included disease control rate (DCR), duration of response (DOR), progression-free survival (PFS), and safety. RESULTS The ORR at 6 months in group A1 (n = 22) was significantly better than that in group B (p = 0.093; 90% confidence interval [CI], 1.03-9.45). The DCR in group A1 was significantly higher than that in group B (p = 0.045; 90% CI, 1.29-12.88). There was no significant difference in DOR among the groups (p = 0.271). The median PFS were 6.00 and 3.05 months in groups A2 (n = 25) and B (n = 24), respectively (p = 0.061). Grade 3 or worse adverse events were similar among groups in the safety population (p = 0.173). CONCLUSION TACE with dicycloplatin was comparably safe and well tolerable as epirubicin alone in patients with unresectable HCC. Compared with epirubicin alone, significant improvement in ORR and DCR when dicycloplatin was applied, as well as prolonged PFS when dicycloplatin plus epirubicin was applied, was generated. KEY POINTS • To our knowledge, this is the first multicenter randomized trial to assess the efficacy and safety of TACE with dicycloplatin in patients with unresectable HCC. • This phase II trial showed that TACE with dicycloplatin alone or plus epirubicin was comparably safe and well tolerable as epirubicin alone. • Significant improvements in ORR, DCR when dicycloplatin was applied, and prolonged PFS when dicycloplatin plus epirubicin was applied were recorded compared with epirubicin alone.
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Affiliation(s)
- Hai-Dong Zhu
- Center of Interventional Radiology & Vascular Surgery, Department of Radiology, Zhongda Hospital, Medical School, Southeast University, 87 Dingjiaqiao Road, Nanjing, 210009, China
| | - Xiao Li
- Department of Interventional Therapy, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Jian-Song Ji
- Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Lishui Hospital of Zhejiang University, Lishui, 323000, China
| | - Ming Huang
- Department of Minimally Invasive Interventional Radiology, Yunnan Tumor Hospital, the Third Affiliated Hospital of Kunming Medical University, Kunming, 650106, China
| | - Guo-Liang Shao
- Department of Radiology, Cancer Hospital Affiliated to University of Chinese Academy of Sciences, Hangzhou, 310022, China
| | - Jian Lu
- Center of Interventional Radiology & Vascular Surgery, Department of Radiology, Zhongda Hospital, Medical School, Southeast University, 87 Dingjiaqiao Road, Nanjing, 210009, China
| | - Xu-Ya Zhao
- Department of Interventional Radiology, Guizhou Cancer Hospital, Cancer Hospital of Guizhou Medical University, Guiyang, 550000, China
| | - Hai-Liang Li
- Department of Intervention Radiology, Henan Cancer Hospital, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, 450008, China
| | - Zheng-Qiang Yang
- Department of Interventional Therapy, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Jian-Fei Tu
- Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Lishui Hospital of Zhejiang University, Lishui, 323000, China
| | - Jin-Mei Zhou
- Department of Minimally Invasive Interventional Radiology, Yunnan Tumor Hospital, the Third Affiliated Hospital of Kunming Medical University, Kunming, 650106, China
| | - Chu-Hui Zeng
- Center of Interventional Radiology & Vascular Surgery, Department of Radiology, Zhongda Hospital, Medical School, Southeast University, 87 Dingjiaqiao Road, Nanjing, 210009, China
| | - Gao-Jun Teng
- Center of Interventional Radiology & Vascular Surgery, Department of Radiology, Zhongda Hospital, Medical School, Southeast University, 87 Dingjiaqiao Road, Nanjing, 210009, China.
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23
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Strebel S, Mader L, Sláma T, Waespe N, Weiss A, Parfitt R, Am Zehnhoff-Dinnesen A, Kompis M, von der Weid NX, Ansari M, Kuehni CE. Severity of hearing loss after platinum chemotherapy in childhood cancer survivors. Pediatr Blood Cancer 2022; 69:e29755. [PMID: 35723448 DOI: 10.1002/pbc.29755] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Revised: 03/25/2022] [Accepted: 04/15/2022] [Indexed: 11/11/2022]
Abstract
BACKGROUND Hearing loss is a potential side effect from childhood cancer treatment. We described the severity of hearing loss assessed by audiometry in a representative national cohort of childhood cancer survivors (CCS) and identified clinical risk factors. PROCEDURE We included all CCS from the Swiss Childhood Cancer Registry who were diagnosed ≤18 age and treated with platinum-based chemotherapy between 1990 and 2014. We extracted audiograms, treatment-related information, and demographic data from medical records. Two reviewers independently assessed the severity of hearing loss at latest follow-up using the Münster Ototoxicity Scale. We used ordered logistic regression to identify clinical risk factors for severity of hearing loss. RESULTS We analyzed data from 270 CCS. Median time from cancer diagnosis to last audiogram was 5 years (interquartile range 2.5-8.1 years). We found 53 (20%) CCS with mild, 78 (29%) with moderate, and 75 (28%) with severe hearing loss. Higher severity grades were associated with (a) younger age at cancer diagnosis (odds ratio [OR] 5.4, 95% confidence interval [CI]: 2.5-12.0 for <5 years); (b) treatment in earlier years (OR 4.8, 95% CI: 2.1-11.0 for 1990-1995); (c) higher cumulative cisplatin doses (OR 13.5, 95% CI: 4.7-38.8 for >450 mg/m2 ); (d) concomitant cranial radiation therapy (CRT) (OR 4.4, 95% CI: 2.5-7.8); and (e) hematopoietic stem cell transplantation (HSCT) (OR 2.7, 95% CI: 1.0-7.2). CONCLUSION Three of four CCS treated with platinum-based chemotherapy experienced some degree of hearing loss. We recommend closely monitoring patient's hearing function if treated at a young age with high cumulative cisplatin doses, and concomitant CRT as part of long-term care.
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Affiliation(s)
- Sven Strebel
- Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland.,CANSEARCH research platform in pediatric oncology and hematology, Department of Pediatrics, Gynecology and Obstetrics, University of Geneva, Geneva, Switzerland.,Graduate School for Health Sciences, University of Bern, Bern, Switzerland
| | - Luzius Mader
- Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland
| | - Tomáš Sláma
- Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland.,Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland
| | - Nicolas Waespe
- Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland.,CANSEARCH research platform in pediatric oncology and hematology, Department of Pediatrics, Gynecology and Obstetrics, University of Geneva, Geneva, Switzerland.,Division of Pediatric Hematology/Oncology, Department of Pediatrics, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Annette Weiss
- Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland.,Bavarian Care and Nursing Authority, Amberg, Germany
| | - Ross Parfitt
- Department for Phoniatrics and Pedaudiology, University Hospital Münster, University of Münster, Münster, Germany
| | | | - Martin Kompis
- Department of ENT, Head and Neck Surgery, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Nicolas X von der Weid
- Department of Pediatric Oncology and Hematology, University Children's Hospital Basel (UKBB), University of Basel, Basel, Switzerland
| | - Marc Ansari
- CANSEARCH research platform in pediatric oncology and hematology, Department of Pediatrics, Gynecology and Obstetrics, University of Geneva, Geneva, Switzerland.,Department of Women, Child and Adolescent, Division of Pediatric Oncology and Hematology, Geneva University Hospital, University of Geneva, Geneva, Switzerland
| | - Claudia E Kuehni
- Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland.,Division of Pediatric Hematology/Oncology, Department of Pediatrics, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
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24
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Nanotechnology for Pediatric Retinoblastoma Therapy. Pharmaceuticals (Basel) 2022; 15:ph15091087. [PMID: 36145308 PMCID: PMC9504930 DOI: 10.3390/ph15091087] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2022] [Revised: 08/26/2022] [Accepted: 08/27/2022] [Indexed: 12/11/2022] Open
Abstract
Retinoblastoma is a rare, sometimes hereditary, pediatric cancer. In high-income countries this disease has a survival rate approaching 100%, while in low- and middle-income countries the prognosis is fatal for about 80% of cases. Depending on the stage of the disease, different therapeutic protocols are applied. In more advanced forms of the disease, surgical removal of the entire globe and its intraocular contents (enucleation) is, unfortunately, necessary, whereas in other cases, conventional chemotherapy is normally used. To overcome the side-effects and reduced efficacy of traditional chemotherapic drugs, nanodelivery systems that ensure a sustained drug release and manage to reach the target site have more recently been developed. This review takes into account the current use and advances of nanomedicine in the treatment of retinoblastoma and discusses nanoparticulate formulations that contain conventional drugs and natural products. In addition, future developments in retinoblastoma treatment are discussed.
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25
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Dillard LK, Lopez-Perez L, Martinez RX, Fullerton AM, Chadha S, McMahon CM. Global burden of ototoxic hearing loss associated with platinum-based cancer treatment: A systematic review and meta-analysis. Cancer Epidemiol 2022; 79:102203. [PMID: 35724557 PMCID: PMC9339659 DOI: 10.1016/j.canep.2022.102203] [Citation(s) in RCA: 48] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2022] [Revised: 06/10/2022] [Accepted: 06/12/2022] [Indexed: 11/06/2022]
Abstract
Platinum-based chemotherapeutic agents cisplatin and carboplatin are widely used in cancer treatment worldwide and may result in ototoxic hearing loss. The high incidence of cancer and salient ototoxic effects of platinum-based compounds pose a global public health threat. The purpose of this study was twofold. First, to estimate the prevalence of ototoxic hearing loss associated with treatment with cisplatin and/or carboplatin via a systematic review and meta-analysis. Second, to estimate the annual global burden of ototoxic hearing loss associated with exposure to cisplatin and/or carboplatin. For the systematic review, three databases were searched (Ovid Medline, Ovid Embase, and Web of Science Core Collection) and studies that reported prevalence of objectively measured ototoxic hearing loss in cancer patients were included. A random effects meta-analysis determined pooled prevalence (95% confidence intervals [CI]) of ototoxic hearing loss overall, and estimates were stratified by treatment and patient attributes. Estimates of ototoxic hearing loss burden were created with published global estimates of incident cancers often treated with platinum-based compounds and cancer-specific treatment rates. Eighty-seven records (n = 5077 individuals) were included in the meta-analysis. Pooled prevalence of ototoxic hearing loss associated with cisplatin and/or carboplatin exposure was 43.17% [CI 37.93-48.56%]. Prevalence estimates were higher for regimens involving cisplatin (cisplatin only: 49.21% [CI 42.62-55.82%]; cisplatin & carboplatin: 56.05% [CI 45.12-66.43%]) versus carboplatin only (13.47% [CI 8.68-20.32%]). Our crude estimates of burden indicated approximately one million individuals worldwide are likely exposed to cisplatin and/or carboplatin, which would result in almost half a million cases of hearing loss per year, globally. There is an urgent need to reduce impacts of ototoxicity in cancer patients. This can be partially achieved by implementing existing strategies focused on primary, secondary, and tertiary hearing loss prevention. Primary ototoxicity prevention via otoprotectants should be a research and policy priority.
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Affiliation(s)
- Lauren K Dillard
- Department of Population Health Sciences, University of Wisconsin-Madison, Madison, WI, United States.
| | - Lucero Lopez-Perez
- Cluster of Healthier Populations, World Health Organization, Geneva, Switzerland
| | - Ricardo X Martinez
- Cluster of Healthier Populations, World Health Organization, Geneva, Switzerland
| | - Amanda M Fullerton
- Department of Linguistics, Macquarie University, Sydney, New South Wales, Australia
| | - Shelly Chadha
- Department on Noncommunicable Diseases, World Health Organization, Geneva, Switzerland
| | - Catherine M McMahon
- Department of Linguistics, Macquarie University, Sydney, New South Wales, Australia
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26
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Surgical Antimicrobial Prophylaxis in Patients of Neonatal and Pediatric Age Subjected to Eye Surgery: A RAND/UCLA Appropriateness Method Consensus Study. Antibiotics (Basel) 2022; 11:antibiotics11050561. [PMID: 35625205 PMCID: PMC9137626 DOI: 10.3390/antibiotics11050561] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2022] [Revised: 04/14/2022] [Accepted: 04/19/2022] [Indexed: 01/25/2023] Open
Abstract
Ocular surgery encompasses a wide range of procedures, including surgery of the tear ducts, eyelid, cornea and conjunctiva, lens, ocular muscle, and vitreoretinal and iris surgery. Operations are also performed for the removal of tumors, repairs of ocular trauma and, finally, corneal transplantation. Antibiotic prophylaxis for the prevention of surgical site infections (SSIs) in ocular surgery is a complex field in which shared lines of action are absent. In light of the scarcity of shared evidence in the use of ocular antimicrobial prophylaxis for the pediatric population, this consensus document aims to provide clinicians with a series of recommendations on antimicrobial prophylaxis for patients of neonatal and pediatric age undergoing eye surgery. The following scenarios are considered: (1) intraocular surgery; (2) extraocular surgery; (3) ocular trauma; (4) ocular neoplasm; (5) ocular surface transplantations; (6) corneal grafts. This work has been made possible by the multidisciplinary contribution of experts belonging to the most important Italian scientific societies and represents, in our opinion, the most complete and up-to-date collection of recommendations regarding clinical actions in the peri-operative environment in eye surgery. The application of uniform and shared protocols aims to improve surgical practice, through the standardization of procedures, with a consequent reduction of SSIs, also limiting the phenomenon of antimicrobial resistance.
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27
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Schaiquevich P, Francis JH, Cancela MB, Carcaboso AM, Chantada GL, Abramson DH. Treatment of Retinoblastoma: What Is the Latest and What Is the Future. Front Oncol 2022; 12:822330. [PMID: 35433448 PMCID: PMC9010858 DOI: 10.3389/fonc.2022.822330] [Citation(s) in RCA: 48] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2021] [Accepted: 02/24/2022] [Indexed: 01/09/2023] Open
Abstract
The management of retinoblastoma, the most common intraocular malignancy in children, has changed drastically over the last decade. Landmark developments in local drug delivery, namely, safer techniques for intravitreal chemotherapy injection and ophthalmic artery chemosurgery, have resulted in eye globe salvages that were not previously attainable using systemic chemotherapy or external beam irradiation. Novel drugs, oncolytic viruses, and immunotherapy are promising approaches in the treatment of intraocular retinoblastoma. Importantly, emerging studies of the pattern of tumor dissemination and local drug delivery may provide the first steps toward new treatments for metastatic disease. Here, we review recent advances in retinoblastoma treatment, especially with regard to local drug delivery, that have enabled successful conservative management of intraocular retinoblastoma. We also review emerging data from preclinical and clinical studies on innovative approaches that promise to lead to further improvement in outcomes, namely, the mechanisms and potential uses of new and repurposed drugs and non-chemotherapy treatments, and discuss future directions for therapeutic development.
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Affiliation(s)
- Paula Schaiquevich
- Unit of Innovative Treatments, Hospital de Pediatría JP Garrahan, Buenos Aires, Argentina,National Scientific and Technological Research Council (CONICET), Buenos Aires, Argentina
| | - Jasmine H. Francis
- Ophthalmic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY, United States,Department of Ophthalmology, Weill/Cornell Medical School, New York, NY, United States
| | - María Belén Cancela
- Unit of Innovative Treatments, Hospital de Pediatría JP Garrahan, Buenos Aires, Argentina,National Scientific and Technological Research Council (CONICET), Buenos Aires, Argentina
| | - Angel Montero Carcaboso
- Hemato-Oncology, Hospital Sant Joan de Déu, Barcelona, Spain,Institut de Recerca Sant Joan de Déu, Barcelona, Spain
| | - Guillermo L. Chantada
- National Scientific and Technological Research Council (CONICET), Buenos Aires, Argentina,Hemato-Oncology, Hospital Sant Joan de Déu, Barcelona, Spain,Institute for Translational Research, Universidad Austral, Buenos Aires, Argentina,Research Department, Fundacion Perez-Scremini, Montevideo, Uruguay
| | - David H. Abramson
- Ophthalmic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY, United States,Department of Ophthalmology, Weill/Cornell Medical School, New York, NY, United States,*Correspondence: David H. Abramson,
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28
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Nijstad AL, Barnett S, Lalmohamed A, Bérénos IM, Parke E, Carruthers V, Tweddle DA, Kong J, Zwaan CM, Huitema ADR, Veal GJ. Clinical pharmacology of cytotoxic drugs in neonates and infants: Providing evidence-based dosing guidance. Eur J Cancer 2022; 164:137-154. [PMID: 34865945 PMCID: PMC8914347 DOI: 10.1016/j.ejca.2021.11.001] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2021] [Revised: 10/11/2021] [Accepted: 11/01/2021] [Indexed: 01/29/2023]
Abstract
Cancer in neonates and infants is a rare but challenging entity. Treatment is complicated by marked physiological changes during the first year of life, excess rates of toxicity, mortality, and late effects. Dose optimisation of chemotherapeutics may be an important step to improving outcomes. Body size-based dosing is used for most anticancer drugs used in infants. However, dose regimens are generally not evidence based, and dosing strategies are frequently inconsistent between tumour types and treatment protocols. In this review, we collate available pharmacological evidence supporting dosing regimens in infants for a wide range of cytotoxic drugs. A systematic review was conducted, and available data ranked by a level of evidence (1-5) and a grade of recommendation (A-D) provided on a consensus basis, with recommended dosing approaches indicated as appropriate. For 9 of 29 drugs (busulfan, carboplatin, cyclophosphamide, daunorubicin, etoposide, fludarabine, isotretinoin, melphalan and vincristine), grade A was scored, indicating sufficient pharmacological evidence to recommend a dosing algorithm for infants. For busulfan and carboplatin, sufficient data were available to recommend therapeutic drug monitoring in infants. For eight drugs (actinomycin D, blinatumomab, dinutuximab, doxorubicin, mercaptopurine, pegaspargase, thioguanine and topotecan), some pharmacological evidence was available to guide dosing (graded as B). For the remaining drugs, including commonly used agents such as cisplatin, cytarabine, ifosfamide, and methotrexate, pharmacological evidence for dosing in infants was limited or non-existent: grades C and D were scored for 10 and 2 drugs, respectively. The review provides clinically relevant evidence-based dosing guidance for cytotoxic drugs in neonates and infants.
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Affiliation(s)
- A Laura Nijstad
- Department of Clinical Pharmacy, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, the Netherlands; Department of Pharmacology, Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, 3584 CS Utrecht, the Netherlands.
| | - Shelby Barnett
- Newcastle University Centre for Cancer, Newcastle University, NE2 4HH Newcastle Upon Tyne, UK
| | - Arief Lalmohamed
- Department of Clinical Pharmacy, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, the Netherlands; Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Universiteitsweg 99, 3584 CG Utrecht, the Netherlands
| | - Inez M Bérénos
- Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Universiteitsweg 99, 3584 CG Utrecht, the Netherlands
| | - Elizabeth Parke
- Newcastle University Centre for Cancer, Newcastle University, NE2 4HH Newcastle Upon Tyne, UK
| | - Vickyanne Carruthers
- Newcastle University Centre for Cancer, Newcastle University, NE2 4HH Newcastle Upon Tyne, UK
| | - Deborah A Tweddle
- Newcastle University Centre for Cancer, Newcastle University, NE2 4HH Newcastle Upon Tyne, UK; Great North Children's Hospital, NE1 4LP Newcastle Upon Tyne, UK
| | - Jordon Kong
- Division of Cancer Sciences, University of Manchester, Manchester, UK
| | - C Michel Zwaan
- Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, 3584 CS Utrecht, the Netherlands; Department of Pediatric Oncology, Erasmus MC-Sophia Children's Hospital, Dr. Molewaterplein 40, 3015 GD Rotterdam, the Netherlands
| | - Alwin D R Huitema
- Department of Clinical Pharmacy, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, the Netherlands; Department of Pharmacology, Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, 3584 CS Utrecht, the Netherlands; Department of Pharmacy & Pharmacology, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands
| | - Gareth J Veal
- Newcastle University Centre for Cancer, Newcastle University, NE2 4HH Newcastle Upon Tyne, UK.
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29
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Grümme L, Biewald E, Reschke M, Fischhuber K, Hanbücken A, Schlüter S, Müller B, Kiefer T, Göricke S, Geismar D, Ryl T, Sirin S, Wieland R, Timmermann B, Lohmann D, Ebinger M, Brecht IB, Schönberger S, Schwab C, Eggert A, Süsskind D, Ritter-Sovinz P, Bechrakis NE, Ketteler P. Comparing efficacy and side effects of two systemic chemotherapy regimens for eye-preserving therapy in children with retinoblastoma. Pediatr Blood Cancer 2022; 69:e29362. [PMID: 34606174 DOI: 10.1002/pbc.29362] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Revised: 08/28/2021] [Accepted: 08/28/2021] [Indexed: 11/06/2022]
Abstract
BACKGROUND Eye-preserving therapy in retinoblastoma comprises systemic chemotherapy, but studies analyzing the efficacy of different chemotherapy regimens are scarce. METHODS The efficacy and side effects of two different eye-preserving chemotherapy regimens containing either vincristine, etoposide, and carboplatin (VEC) or cyclophosphamide, vincristine, etoposide, and carboplatin (CyVEC) were compared in a prospective non-interventional observational study including children diagnosed with retinoblastoma between 2013 and 2019 in Germany and Austria. Event-free eye survival (EFES) and overall eye survival (OES) of all 164 eyes treated with both regimens and risk factors were investigated. RESULTS The EFES after VEC (2-year EFES 72.3%) was higher than after CyVEC (2-year EFES 50.4%) (plogrank < .001). The OES did not differ significantly between the two treatment groups (plogrank = .77; 2-year OES VEC: 82.1% vs. CyVEC: 84.8%). Advanced International Classification of Retinoblastoma (ICRB) group was prognostic for a lower EFES (plogrank < .0001; 2-year EFES ICRB A/B/C 71.3% vs. ICRB D/E 43.0%) and OES (plogrank < .0001; 2-year OES ICRB A/B/C 93.1% vs. ICRB D/E 61.5%). The multivariate analysis showed that age at diagnosis older than 12 months and ICRB A/B/C were associated with better EFES. No second malignancies or ototoxicities were reported after a follow-up of median 3.1 years after diagnosis of retinoblastoma (range 0.1-6.9 years). CONCLUSIONS Despite omitting cyclophosphamide, the EFES was higher after VEC chemotherapy that contains higher doses of carboplatin compared to CyVEC. The major risk factor for enucleation was advanced ICRB tumor grouping. Randomized clinical trials on efficacy and side effects of eye-preserving chemotherapy are required to tailor treatment protocols for retinoblastoma patients.
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Affiliation(s)
- Lea Grümme
- Department of Pediatric Hematology and Oncology, University Hospital Essen, Essen, Germany
| | - Eva Biewald
- Department of Ophthalmology, University Hospital Essen, Essen, Germany
| | - Madlen Reschke
- Department of Pediatric Hematology and Oncology, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Karen Fischhuber
- Institute of Biostatistics and Clinical Research, University of Münster, Münster, Germany
| | - Anna Hanbücken
- Department of Pediatric Hematology and Oncology, University Hospital Essen, Essen, Germany
| | - Sabrina Schlüter
- Department of Ophthalmology, University Hospital Essen, Essen, Germany
| | - Bert Müller
- Department of Ophthalmology, Charité Berlin, Berlin, Germany
| | - Tobias Kiefer
- Department of Ophthalmology, University Hospital Essen, Essen, Germany
| | - Sophia Göricke
- Department of Diagnostic and Interventional Radiology and Neuroradiology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Dirk Geismar
- West German Proton Centre, University Duisburg-Essen, University Hospital Essen, Essen, Germany
| | - Tatsiana Ryl
- Department of Pediatric Hematology and Oncology, University Hospital Essen, Essen, Germany
| | - Selma Sirin
- Department of Diagnostic and Interventional Radiology and Neuroradiology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Regina Wieland
- Department of Pediatric Hematology and Oncology, University Hospital Essen, Essen, Germany
| | - Beate Timmermann
- West German Proton Centre, University Duisburg-Essen, University Hospital Essen, Essen, Germany
| | - Dietmar Lohmann
- Institute of Human Genetics, University Hospital Essen, University Duisburg Essen, Essen, Germany
| | - Martin Ebinger
- Institute of Human Genetics, University Hospital Essen, University Duisburg Essen, Essen, Germany
| | - Ines B Brecht
- Pediatric Oncology and Hematology, Children's Hospital, Eberhard Karls Universität, Tübingen, Germany
| | - Stefan Schönberger
- Department of Pediatric Hematology and Oncology, University Hospital Essen, Essen, Germany
| | | | - Angelika Eggert
- Department of Pediatric Hematology and Oncology, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Daniela Süsskind
- Department of Ophthalmology, Eberhard Karls Universität, Tübingen, Germany
| | | | | | - Petra Ketteler
- Department of Pediatric Hematology and Oncology, University Hospital Essen, Essen, Germany
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Patatt FSA, Gonçalves LF, Paiva KMD, Haas P. Ototoxic effects of antineoplastic drugs: a systematic review. Braz J Otorhinolaryngol 2022; 88:130-140. [PMID: 33757754 PMCID: PMC9422719 DOI: 10.1016/j.bjorl.2021.02.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Revised: 01/11/2021] [Accepted: 02/06/2021] [Indexed: 02/08/2023] Open
Abstract
INTRODUCTION Platinum-based chemotherapeutics play an important role in the treatment of cancer at different levels and are the most cited ototoxic agents when scientific evidence is analyzed. OBJECTIVE To present scientific evidence based on a systematic literature review, PRISMA, in order to systematize information on the ototoxic effects of using antineoplastic drugs. METHODS For the selection of studies, the combination based on the Medical Subject Heading Terms (MeSH) was used. The Medline (Pubmed), LILACS, SciELO, SCOPUS, WEB OF SCIENCE and BIREME databases were used, without restriction of language, period, and location. Evaluation of the quality of the articles was carried out, which included articles with a minimum score of 6 in the modified scale of the literature. The designs of the selected studies were descriptive, cohort, and cross-sectional, which were related to the research objective. RESULTS Three articles were included in this systematic review. The ototoxicity caused by cisplatin alone varied from 45% to 83.3%, while that caused by the use associated with carboplatin varied from 16.6% to 75%. There was a significant variation in the cumulative doses of these antineoplastic agents, both in isolated and in combination. Auditory changes, especially at high frequencies, were evident after completion of treatment. CONCLUSION Auditory changes after the use of platinum-based antineoplastic drugs were found, however, there was an important heterogeneity regarding the frequency of ototoxicity and the cumulative dose of the drugs used.
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Affiliation(s)
| | | | | | - Patrícia Haas
- Universidade Federal de Santa Catarina (UFSC), Florianópolis, SC, Brazil
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Diepstraten FA, Hoetink AE, van Grotel M, Huitema ADR, Stokroos RJ, van den Heuvel-Eibrink MM, Meijer AJM. Aminoglycoside- and glycopeptide-induced ototoxicity in children: a systematic review. JAC Antimicrob Resist 2021; 3:dlab184. [PMID: 34917943 PMCID: PMC8669239 DOI: 10.1093/jacamr/dlab184] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Accepted: 11/16/2021] [Indexed: 11/25/2022] Open
Abstract
Background Ototoxicity has been reported after administration of aminoglycosides and glycopeptides. Objectives To identify available evidence for the occurrence and determinants of aminoglycoside- and glycopeptide-related ototoxicity in children. Materials and methods Systematic electronic literature searches that combined ototoxicity (hearing loss, tinnitus and/or vertigo) with intravenous aminoglycoside and/or glycopeptide administration in children were performed in PubMed, EMBASE and Cochrane Library databases. Studies with sample sizes of ≥50 children were included. The QUIPS tool and Cochrane criteria were used to assess the quality and risk of bias of included studies. Results Twenty-nine aminoglycoside-ototoxicity studies met the selection criteria (including 7 randomized controlled trials). Overall study quality was medium/low. The frequency of hearing loss within these studies ranged from 0%–57%, whereas the frequency of tinnitus and vertigo ranged between 0%–53% and 0%–79%, respectively. Two studies met the criteria on glycopeptide-induced ototoxicity and reported hearing loss frequencies of 54% and 55%. Hearing loss frequencies were higher in gentamicin-treated children compared to those treated with other aminoglycosides. In available studies aminoglycosides had most often been administered concomitantly with platinum agents, diuretics and other co-medication. Conclusions In children the reported occurrence of aminoglycoside/glycopeptide ototoxicity highly varies and seems to depend on the diagnosis, aminoglycoside subtype and use of co-administered medication. More research is needed to investigate the prevalence and determinants of aminoglycoside/glycopeptide ototoxicity. Our results indicate that age-dependent audiological examination may be considered for children frequently treated with aminoglycosides/glycopeptides especially if combined with other ototoxic medication.
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Affiliation(s)
- F A Diepstraten
- Princess Máxima Center for pediatric oncology, Utrecht, The Netherlands
| | - A E Hoetink
- Department of Otorhinolaryngology-Head and Neck Surgery, University Medical Centre Utrecht, UMC Brain Centre, Utrecht, The Netherlands
| | - M van Grotel
- Princess Máxima Center for pediatric oncology, Utrecht, The Netherlands
| | - A D R Huitema
- Princess Máxima Center for pediatric oncology, Utrecht, The Netherlands.,Department of Pharmacy and Pharmacology, Netherlands Cancer Institute, Amsterdam, The Netherlands.,Department of Clinical Pharmacy, University Medical Centre Utrecht, Utrecht University, Utrecht, The Netherlands
| | - R J Stokroos
- Department of Otorhinolaryngology-Head and Neck Surgery, University Medical Centre Utrecht, UMC Brain Centre, Utrecht, The Netherlands
| | - M M van den Heuvel-Eibrink
- Princess Máxima Center for pediatric oncology, Utrecht, The Netherlands.,Wilhelmina Children's Hospital, University Medical Centre Utrecht, Utrecht, The Netherlands
| | - A J M Meijer
- Princess Máxima Center for pediatric oncology, Utrecht, The Netherlands
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Quantitative evaluation of retinal microvasculature and retrobulbar vessels after intravenous chemotherapy for retinoblastoma. BMC Ophthalmol 2021; 21:405. [PMID: 34836533 PMCID: PMC8620235 DOI: 10.1186/s12886-021-02170-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Accepted: 11/10/2021] [Indexed: 11/10/2022] Open
Abstract
Backgroud To evaluate the changes in retinal microvasculature and retrobulbar blood flow, using optical coherence tomography angiography (OCTA) and Color Doppler imaging (CDI) after intravenous chemotherapy (IVC) in patients with retinoblastoma (RB). Methods This was a retrospective comparative case control series involving 30 patients. Ten bilateral RB patients that had a preserved eye with extramacular tumours (group I), 10 unilateral RB treated with IVC that had a normal fellow study eye (group II), and 10 age-matched healthy controls. The macular retinal thickness, foveal avascular zone (FAZ) area, and the macular and peripapillary retinal vessel densities (RVD) were measured. The peak systolic and end diastolic velocities of the ophthalmic, central retinal and posterior ciliary arteries were determined. A comparison among the three groups was conducted. Results Between the three cohorts, OCTA revealed no significant difference in FAZ area, superficial foveal and parafoveal RVD, deep parafoveal RVD and peripapillary RVD, (P > 0.05). By contrast, the mean deep foveal RVD, the full, inner and outer foveal and the parafoveal retinal thickness were significantly lower in group I compared with the controls, (P = 0.0329, 0.0153, 0.0311 0.0352, 0.0215). No significant difference in the blood flow velocities occurred in the retrobulbar circulation (P > 0.05). Conclusions In patients with retinoblastoma, OCTA did not detect significant changes of retinal thickness and vessel density in the eyes treated with IVC, but a slight reduction in retinal thickness and the deep foveal RVD seemed to occur in bilateral RB eyes. The retrobulbar blood flow parameters showed no measurable changes.
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van de Velde ME, den Bakker E, Blufpand HN, Kaspers GL, Abbink FCH, Kors AWA, Wilhelm AJ, Honeywell RJ, Peters GJ, Stoffel-Wagner B, Buffart LM, Bökenkamp A. Carboplatin Dosing in Children Using Estimated Glomerular Filtration Rate: Equation Matters. Cancers (Basel) 2021; 13:5963. [PMID: 34885072 PMCID: PMC8656997 DOI: 10.3390/cancers13235963] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Revised: 11/17/2021] [Accepted: 11/19/2021] [Indexed: 11/16/2022] Open
Abstract
Renal function-based carboplatin dosing using measured glomerular filtration rate (GFR) results in more consistent drug exposure than anthropometric dosing. We aimed to validate the Newell dosing equation using estimated GFR (eGFR) and study which equation most accurately predicts carboplatin clearance in children with retinoblastoma. In 13 children with retinoblastoma 38 carboplatin clearance values were obtained from individual fits using MWPharm++. Carboplatin exposure (AUC) was calculated from administered dose and observed carboplatin clearance and compared to predicted AUC calculated with a carboplatin dosing equation (Newell) using different GFR estimates. Different dosing regimens were compared in terms of accuracy, bias and precision. All patients had normal eGFR. Carboplatin exposure using cystatin C-based eGFR equations tended to be more accurate compared to creatinine-based eGFR (30% accuracy 76.3-89.5% versus 76.3-78.9%, respectively), which led to significant overexposure, especially in younger (aged ≤ 2 years) children. Of all equations, the Schwartz cystatin C-based equation had the highest accuracy and lowest bias. Although anthropometric dosing performed comparably to many of the eGFR equations overall, we observed a weight-dependent change in bias leading to underdosing in the smallest patients. Using cystatin C-based eGFR equations for carboplatin dosing in children leads to more accurate carboplatin-exposure in patients with normal renal function compared to anthropometric dosing. In children with impaired kidney function, this trend might be more pronounced. Anthropometric dosing is hampered by a weight-dependent bias.
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Affiliation(s)
- Mirjam E. van de Velde
- Emma Children’s Hospital, Amsterdam UMC, Vrije Universiteit Amsterdam, Pediatric Oncology, 1081 HV Amsterdam, The Netherlands; (H.N.B.); (A.W.A.K.); (G.L.K.)
- Department of Pediatric Oncology/Hematology, Amsterdam UMC, 1081 HV Amsterdam, The Netherlands
| | - Emil den Bakker
- Emma Children’s Hospital, Amsterdam UMC, Vrije Universiteit Amsterdam, Pediatric Nephrology, 1081 HV Amsterdam, The Netherlands; (E.d.B.); (A.B.)
| | - Hester N. Blufpand
- Emma Children’s Hospital, Amsterdam UMC, Vrije Universiteit Amsterdam, Pediatric Oncology, 1081 HV Amsterdam, The Netherlands; (H.N.B.); (A.W.A.K.); (G.L.K.)
| | - Gertjan L. Kaspers
- Emma Children’s Hospital, Amsterdam UMC, Vrije Universiteit Amsterdam, Pediatric Oncology, 1081 HV Amsterdam, The Netherlands; (H.N.B.); (A.W.A.K.); (G.L.K.)
- Princess Máxima Center for Pediatric Oncology, 3584 CS Utrecht, The Netherlands
| | - Floor C. H. Abbink
- Emma Children’s Hospital, Amsterdam UMC, Amsterdam Medical Center, Pediatric Oncology, 1081 HV Amsterdam, The Netherlands;
| | - Arjenne W. A. Kors
- Emma Children’s Hospital, Amsterdam UMC, Vrije Universiteit Amsterdam, Pediatric Oncology, 1081 HV Amsterdam, The Netherlands; (H.N.B.); (A.W.A.K.); (G.L.K.)
- Princess Máxima Center for Pediatric Oncology, 3584 CS Utrecht, The Netherlands
| | - Abraham J. Wilhelm
- Amsterdam UMC, Vrije Universiteit Amsterdam, Clinical Pharmacology and Pharmacy, 1081 HV Amsterdam, The Netherlands;
| | - Richard J. Honeywell
- Laboratory of Medical Oncology, Amsterdam University Medical Center, VUMC, 1081 HV Amsterdam, The Netherlands; (R.J.H.); (G.J.P.)
| | - Godefridus J. Peters
- Laboratory of Medical Oncology, Amsterdam University Medical Center, VUMC, 1081 HV Amsterdam, The Netherlands; (R.J.H.); (G.J.P.)
- Department of Biochemistry, Medical University of Gdansk, 80-210 Gdansk, Poland
| | - Birgit Stoffel-Wagner
- Institute for Clinical Chemistry and Clinical Pharmacology, University of Bonn-Medical Center, 53127 Bonn, Germany;
| | - Laurien M. Buffart
- Department of Epidemiology and Biostatistics, Amsterdam UMC, Vrije Universiteit Amsterdam, 1081 HV Amsterdam, The Netherlands;
| | - Arend Bökenkamp
- Emma Children’s Hospital, Amsterdam UMC, Vrije Universiteit Amsterdam, Pediatric Nephrology, 1081 HV Amsterdam, The Netherlands; (E.d.B.); (A.B.)
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Sánchez-Canteli M, Núñez-Batalla F, Martínez-González P, de Lucio-Delgado A, Antonio Villegas-Rubio J, Gómez-Martínez JR, Luis Llorente-Pendás J. Ototoxicity in cancer survivors: Experience and proposal of a surveillance protocol. An Pediatr (Barc) 2021; 95:290-297. [PMID: 34702687 DOI: 10.1016/j.anpede.2020.08.014] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Accepted: 08/26/2020] [Indexed: 11/18/2022] Open
Abstract
INTRODUCTION Ototoxicity occurs in different percentages in patients after treatment with platinum-based chemotherapy or cranial radiation therapy. The aim of this study was to present our experience in ototoxicity monitoring. MATERIAL AND METHODS A review was made of the registry of paediatric cancer patients referred to the Children's Hearing Loss Unit from 1999 to 2019. RESULTS Of the 46 patients referred to this unit, 41 had received platinum as part of their treatment, 17 patients underwent neurosurgery, and 18 patients received cranial radiation therapy. An anamnesis and otoscopy were performed on all of them, and the monitoring was carried out with tone-verbal audiometry and/or distortion products. Hearing loss was observed in eight patients (21.05% of patients referred for audiological follow-up) as a consequence of the treatment. It was impossible to determine the audiological situation in eight patients at the end of treatment. Hearing aid adaption was necessary in two patients. In coordination with Paediatric Oncology, a change from cisplatin to carboplatin due to bilateral grade two ototoxicity was considered appropriate during treatment in one patient. CONCLUSION Adequate coordination with Paediatric Oncology is essential to carry out active surveillance for ototoxicity and to modify, if possible, the dosage or type of chemotherapy in case hearing is affected. In our experience, and following current recommendations, a pre-treatment assessment is usually performed, as well as monitoring during treatment, at the end of treatment, and annually thereafter due to the risk of a later development of hearing loss.
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Affiliation(s)
- Mario Sánchez-Canteli
- Unidad de Hipoacusia Infantil, Servicio de Otorrinolaringología, Hospital Universitario Central de Asturias, Oviedo, Spain; Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, Spain.
| | - Faustino Núñez-Batalla
- Unidad de Hipoacusia Infantil, Servicio de Otorrinolaringología, Hospital Universitario Central de Asturias, Oviedo, Spain; Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, Spain; Universidad de Oviedo, Oviedo, Spain
| | - Patricia Martínez-González
- Unidad de Hipoacusia Infantil, Servicio de Otorrinolaringología, Hospital Universitario Central de Asturias, Oviedo, Spain
| | - Ana de Lucio-Delgado
- Oncología Pediátrica, Servicio de Pediatría, Hospital Universitario Central de Asturias, Oviedo, Spain
| | | | - Justo Ramón Gómez-Martínez
- Unidad de Hipoacusia Infantil, Servicio de Otorrinolaringología, Hospital Universitario Central de Asturias, Oviedo, Spain; Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, Spain; Universidad de Oviedo, Oviedo, Spain
| | - José Luis Llorente-Pendás
- Unidad de Hipoacusia Infantil, Servicio de Otorrinolaringología, Hospital Universitario Central de Asturias, Oviedo, Spain; Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, Spain; Universidad de Oviedo, Oviedo, Spain
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Long-Term Variability of Distortion-Product Otoacoustic Emissions in Infants and Children and Its Relation to Pediatric Ototoxicity Monitoring. Ear Hear 2021; 41:239-253. [PMID: 29280917 DOI: 10.1097/aud.0000000000000536] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
OBJECTIVE Distortion-product otoacoustic emissions (DPOAEs) provide a rapid, noninvasive measure of outer hair cell damage associated with chemotherapy and are a key component of pediatric ototoxicity monitoring. Serial monitoring of DPOAE levels in reference to baseline measures is one method for detecting ototoxic damage. Interpreting DPOAE findings in this context requires that test-retest differences be considered in relation to normal variability, data which are lacking in children. This study sought to (1) characterize normal test-retest variability in DPOAE level over the long time periods reflective of pediatric chemotherapy regimens for a variety of childhood ages and f2 primary frequencies using common clinical instrumentation and stimulus parameters; (2) develop level-shift reference intervals; and (3) account for any age-related change in DPOAE level or measurement error that may occur as the auditory system undergoes maturational change early in life. DESIGN Serial DPOAE measurements were obtained in 38 healthy children (25 females and 13 males) with normal hearing and ranging in age from one month to 10 years at the initial (baseline) visit. On average, children were tested 5.2 times over an observation period of 6.5 months. Data were collected in the form of DP grams, in which DPOAE level was measured for f2 ranging from 1.4 to 10 kHz, using a fixed f2/f1 ratio of 1.22 and stimulus level of 65/55 dB SPL for L1/L2. Age effects on DPOAE level and measurement error were estimated using Bayesian regression of the longitudinal data. The raw and model-based distribution of DPOAE test-retest differences were characterized using means and standard error of the measurement for several ages and f2's. RESULTS DPOAE test-retest differences for the children in this study are at the high end of those previously observed in adults, as reflected in the associated shift reference intervals. Further, although we observe substantial child-specific variation in DPOAE level, the pattern of age-related changes is highly consistent across children. Across a wide range of f2's, DPOAE level decreases by 3 to 4 dB from 1 to 13 months of age followed by a more gradual decline of <1 dB/year. An f2 of 6 kHz shows the smallest decrease during the early rapid maturation period. DPOAE measurement error is fairly constant with age. It is 3 to 4 dB at most f2's and is greater (indicating poorer reliability) at 1.5, 8, and 10 kHz. CONCLUSIONS DPOAE level decreases with childhood age, with the greatest changes observed in the first year of life. Maturational effects during infancy and greater measurement error at very low and high f2's affect test-retest variability in children. An f2 of 6 kHz shows minimal maturation and measurement error, suggesting it may be an optimal sentinel frequency for ototoxicity monitoring in pediatric patients. Once validated with locally developed normative data, reference intervals provided herein could be used to determine screen fail criteria for serial monitoring using DPOAEs. Employing state-of-the-art calibration techniques might reduce variability, allowing for more sensitive screen fail criteria.
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Dittner-Moormann S, Reschke M, Abbink FCH, Aerts I, Atalay HT, Fedorovna Bobrova N, Biewald E, Brecht IB, Caspi S, Cassoux N, Castela G, Diarra Y, Duncan C, Ebinger M, Garcia Aldana D, Hadjistilianou D, Kepák T, Klett A, Kiratli H, Maka E, Opocher E, Pawinska-Wasikowska K, Rascon J, Russo I, Rutynowska-Pronicka O, Sábado Álvarez C, Pacheco SSR, Svojgr K, Timmermann B, Vishnevskia-Dai V, Eggert A, Ritter-Sovinz P, Bechrakis NE, Jenkinson H, Moll A, Munier FL, Popovic MB, Chantada G, Doz F, Ketteler P. Adjuvant therapy of histopathological risk factors of retinoblastoma in Europe: A survey by the European Retinoblastoma Group (EURbG). Pediatr Blood Cancer 2021; 68:e28963. [PMID: 33720495 DOI: 10.1002/pbc.28963] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Revised: 01/17/2021] [Accepted: 02/01/2021] [Indexed: 11/11/2022]
Abstract
INTRODUCTION Advanced intraocular retinoblastoma can be cured by enucleation, but spread of retinoblastoma cells beyond the natural limits of the eye is related to a high mortality. Adjuvant therapy after enucleation has been shown to prevent metastasis in children with risk factors for extraocular retinoblastoma. However, histological criteria and adjuvant treatment regimens vary and there is no unifying consensus on the optimal choice of treatment. METHOD Data on guidelines for adjuvant treatment in European retinoblastoma referral centres were collected in an online survey among all members of the European Retinoblastoma Group (EURbG) network. Extended information was gathered via personal email communication. RESULTS Data were collected from 26 centres in 17 countries. Guidelines for adjuvant treatment were in place at 92.3% of retinoblastoma centres. There was a consensus on indication for and intensity of adjuvant treatment among more than 80% of all centres. The majority of centres use no adjuvant treatment for isolated focal choroidal invasion or prelaminar optic nerve invasion. Patients with massive choroidal invasion or postlaminar optic nerve invasion receive adjuvant chemotherapy, while microscopic invasion of the resection margin of the optic nerve or extension through the sclera are treated with combined chemo- and radiotherapy. CONCLUSION Indications and adjuvant treatment regimens in European retinoblastoma referral centres are similar but not uniform. Further biomarkers in addition to histopathological risk factors could improve treatment stratification. The high consensus in European centres is an excellent foundation for a common European study with prospective validation of new biomarkers.
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Affiliation(s)
- Sabine Dittner-Moormann
- Department of Pediatric Hematology and Oncology, University Duisburg-Essen, University Hospital Essen, Essen, Germany
| | - Madlen Reschke
- Department of Pediatric Oncology and Hematology, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Floor C H Abbink
- Amsterdam UMC, Location VU University Medical Centre, Amsterdam, The Netherlands
| | - Isabelle Aerts
- Institut Curie, PSL Research University and University of Paris, Paris, France
| | | | | | - Eva Biewald
- Department of Ophthalmology, University Duisburg-Essen, University Hospital Essen, Essen, Germany
| | - Ines B Brecht
- Children's Hospital, University of Tuebingen, Tuebingen, Germany
| | - Shani Caspi
- Pediatric Oncology, Sheba Medical Center, Tel Aviv University, Tel Aviv, Israel
| | - Nathalie Cassoux
- Institut Curie, PSL Research University and University of Paris, Paris, France
| | - Guilherme Castela
- Centro Hospitalar e Universitário de Coimbra, University of Coimbra, Coimbra, Portugal
| | - Yelena Diarra
- Department of Pediatric Hematology and Oncology, University Duisburg-Essen, University Hospital Essen, Essen, Germany
| | - Catriona Duncan
- Royal London Hospital and Great Ormond Street Hospital, London, England
| | - Martin Ebinger
- Children's Hospital, University of Tuebingen, Tuebingen, Germany
| | | | | | - Tomáš Kepák
- University Hospital Brno and St. Anna University Hospital/ICRC, Masaryk University, Brno, Czech Republic
| | - Artur Klett
- East-Tallinn Central Hospital, Tallinn, Estonia
| | | | - Erika Maka
- Department of Ophthalmology, Semmelweis University, Budapest, Hungary
| | - Enrico Opocher
- Royal London Hospital and Great Ormond Street Hospital, London, England.,Pediatric Hematology, Oncology and Stem Cell Transplant Division, Padua University Hospital, Padua, Italy
| | | | - Jelena Rascon
- Centre for Pediatric Oncology and Hematology, Vilnius University, Vilnius, Lithuania
| | - Ida Russo
- Department of Pediatric Hematology/Oncology, IRCCS, Ospedale Pediatrico Bambino Gesù, Rome, Italy
| | | | | | | | - Karel Svojgr
- Charles University in Prague, 2nd Faculty of Medicine and University Hospital Motol, Prague, Czech Republic
| | - Beate Timmermann
- Department of Particle Therapy, University Hospital Essen, West German Proton Therapy Centre Essen (WPE), West German Cancer Center (WTZ), Essen, Germany.,German Consortium for Translational Cancer Research (DKTK), Essen, Germany German Cancer Research Center (DKFZ), Heidelberg, Germany
| | | | - Angelika Eggert
- Department of Pediatric Oncology and Hematology, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Petra Ritter-Sovinz
- Division of Pediatric Hematology/Oncology, Medical University of Graz, Graz, Austria
| | - Nikolaos E Bechrakis
- Department of Ophthalmology, University Duisburg-Essen, University Hospital Essen, Essen, Germany
| | | | - Annette Moll
- Department of Ophthalmology, Amsterdam UMC, Vrije Universiteit Amsterdam, Cancer Center Amsterdam, Amsterdam, The Netherlands
| | - Francis L Munier
- Jules-Gonin Eye Hospital, Fondation Asile des Aveugles, University of Lausanne, Lausanne, Switzerland
| | - Maja Beck Popovic
- Department of Pediatric Hematology and Oncology, University Hospital CHUV, University of Lausanne, Lausanne, Switzerland
| | | | - François Doz
- Institut Curie, PSL Research University and University of Paris, Paris, France
| | - Petra Ketteler
- Department of Pediatric Hematology and Oncology, University Duisburg-Essen, University Hospital Essen, Essen, Germany.,German Consortium for Translational Cancer Research (DKTK), Essen, Germany German Cancer Research Center (DKFZ), Heidelberg, Germany
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Palmer JD, Tsang DS, Tinkle CL, Olch AJ, Kremer LCM, Ronckers CM, Gibbs IC, Constine LS. Late effects of radiation therapy in pediatric patients and survivorship. Pediatr Blood Cancer 2021; 68 Suppl 2:e28349. [PMID: 33818893 DOI: 10.1002/pbc.28349] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2020] [Revised: 03/19/2020] [Accepted: 03/20/2020] [Indexed: 11/08/2022]
Abstract
Advances in multimodality therapy have led to childhood cancer cure rates over 80%. However, surgery, chemotherapy, and radiotherapy may lead to debilitating or even fatal long-term effects among childhood survivors beyond those inflicted by the primary disease process. It is critical to understand, mitigate, and prevent these late effects of cancer therapy to improve the quality of life of childhood cancer survivors. This review summarizes the various late effects of radiotherapy and acknowledges the Pediatric Normal Tissue Effects in the Clinic (PENTEC), an international collaboration that is systematically analyzing the association between radiation treatment dose/volume and consequential organ toxicities, in developing children as a basis to formulate recommendations for clinical practice of pediatric radiation oncology. We also summarize initiatives for survivorship and surveillance of late normal tissue effects related to radiation therapy among long-term survivors of childhood cancer treated in the past.
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Affiliation(s)
- Joshua D Palmer
- Department of Radiation Oncology, The James Cancer Hospital at the Ohio State University Wexner Medical Center and Nationwide Children's Hospital, Ohio, Columbus
| | - Derek S Tsang
- Radiation Medicine Program, Princess Margaret Cancer Centre, Division of Haematology/Oncology, Hospital for Sick Children, University Health Network, Toronto, Canada
| | - Christopher L Tinkle
- Department of Radiation Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee
| | - Arthur J Olch
- Department of Radiation Oncology, Keck School of Medicine of USC and Children's' Hospital Los Angeles, Los Angeles, California
| | - Leontien C M Kremer
- Department of Pediatrics, Amsterdam UMC, Emma Children's Hospital, Amsterdam, the Netherlands.,Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands
| | - Cecile M Ronckers
- Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands.,Brandenburg Medical School, Institute for Biostatistics and Registry Research, Neuruppin, Germany
| | - Iris C Gibbs
- Department of Radiation Oncology, Stanford Cancer Institute, Stanford University, Stanford, California
| | - Louis S Constine
- Department of Radiation Oncology, University of Rochester, Rochester, New York
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King BA, Sahr N, Sykes A, Wilson MW, Brennan RC. Chemoreduction with topotecan and vincristine: Quantifying tumor response in bilateral retinoblastoma patients. Pediatr Blood Cancer 2021; 68:e28882. [PMID: 33507604 DOI: 10.1002/pbc.28882] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2020] [Revised: 12/03/2020] [Accepted: 12/10/2020] [Indexed: 11/08/2022]
Abstract
BACKGROUND Evaluate the efficacy of two courses of vincristine and topotecan (VT) neoadjuvant intravenous chemotherapy in reducing retinoblastoma tumor volumes. METHODS Twenty-seven patients with previously untreated, bilateral advanced retinoblastoma who were enrolled on a prospective treatment protocol (NCT00186888). Patients underwent high-resolution ophthalmic imaging at diagnosis and were reimaged following treatment with two cycles of VT. Tumor height and diameter were measured before and after treatment, and tumor volumes were calculated. Statistical methods for dependent samples were used. RESULTS Imaging was completed for 75 tumors in 23 patients (43 eyes). After two cycles of VT, median decrease in tumor height was 47% and median decrease in tumor diameter was 22%. Median decrease in estimated tumor volume was 74%. Sixty-one of 75 tumors demonstrated >50% reduction in tumor volume. Distance from the optic nerve (=0 vs >0), age (<4 vs >4 months), macular location (within vs outside), and time (pre- and posttreatment) were found significantly associated with log-transformed tumor volume adjusting for the repeated effect of patient eye using generalized estimating equations to estimate the parameters of a generalized linear model (P < .0001 [ β : 1.95, CI: 1.53-2.36], P = .0031 [ β : 1.49, CI: 0.57-2.41], P < .0001 [ β : .94, CI: 0.54-1.35], and P < .0001 [ β : 1.43, CI: 1.15-1.71]). CONCLUSION Chemoreduction was achieved in all patients and most retinoblastoma tumors following two cycles of VT. Reduction in tumor dimensions was comparable to that reported with platinum-based chemotherapy. Tumor location, distance from the optic nerve, and age at diagnosis were significant predictors of treatment response.
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Affiliation(s)
- Benjamin A King
- Department of Ophthalmology, Hamilton Eye Institute, University of Tennessee Health Science Center, College of Medicine, Memphis, Tennessee.,Department of Surgery, St. Jude Children's Research Hospital, Memphis, Tennessee
| | - Natasha Sahr
- Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, Tennessee
| | - April Sykes
- Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, Tennessee
| | - Matthew W Wilson
- Department of Ophthalmology, Hamilton Eye Institute, University of Tennessee Health Science Center, College of Medicine, Memphis, Tennessee.,Department of Surgery, St. Jude Children's Research Hospital, Memphis, Tennessee
| | - Rachel C Brennan
- Department of Ophthalmology, Hamilton Eye Institute, University of Tennessee Health Science Center, College of Medicine, Memphis, Tennessee.,Department of Oncology, Solid Tumor Division, St. Jude Children's Research Hospital, Memphis, Tennessee
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Abstract
Retinoblastoma is the most common ocular malignancy of childhood. With an estimated 300 cases annually in the United States, retinoblastoma is nevertheless considered a rare tumor. Although retinoblastoma primarily affects younger children, diagnosis during the neonatal age range is less common. However, an understanding of patients at risk is critical for appropriate screening. Early detection and treatment by a multidisciplinary specialty team maximizes the chance for survival and ocular/vision salvage while minimizing treatment-related toxicity. Testing for alterations in the RB1 gene has become standard practice, and informs screening and genetic counseling recommendations for patients and their families.
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Maillard M, Le Louedec F, Thomas F, Chatelut E. Diversity of dose-individualization and therapeutic drug monitoring practices of platinum compounds: a review. Expert Opin Drug Metab Toxicol 2020; 16:907-925. [PMID: 33016786 DOI: 10.1080/17425255.2020.1789590] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Introduction: Platinum-derived drugs are commonly used for the treatment of solid tumors. The differences in chemical structures of these molecules lead to different pharmacological properties, in terms of indication, efficacy, and toxicity. Their pharmacokinetics (PK) differ according to their respective renal elimination and have led to many studies investigating their dose optimization. Area covered: This review attempts to summarize and compare PK and pharmacodynamics of cisplatin, carboplatin, and oxaliplatin, with an emphasis on differences of dose calculations and opportunities for therapeutic drug monitoring (TDM) in various patient populations. Expert opinion: Although cisplatin and carboplatin can be considered as analogs since they share the same DNA interacting properties, the slower hydrolysis of the latter results in a better safety profile. Carboplatin is the only drug in oncology to be administrated according to a target area under the curve of concentration versus time, considering that its PK variability is almost fully explained by renal function, not by body size. This enables individual dosing based on predicted carboplatin clearance (along with patients renal characteristics) or on actual clearance with TDM, especially in a high-dose protocol.
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Affiliation(s)
- Maud Maillard
- Laboratoire De Pharmacologie, Institut Claudius-Regaud, IUCT-Oncopole , Toulouse Cedex 9, France.,Cancer Research Center of Toulouse, INSERM UMR1037, Team 14 DIAD (Dose Individualization of Anticancer Drug) , Toulouse, France.,Faculté de Pharmacie, Université Paul Sabatier Toulouse III , Toulouse, France
| | - Félicien Le Louedec
- Laboratoire De Pharmacologie, Institut Claudius-Regaud, IUCT-Oncopole , Toulouse Cedex 9, France.,Cancer Research Center of Toulouse, INSERM UMR1037, Team 14 DIAD (Dose Individualization of Anticancer Drug) , Toulouse, France.,Faculté de Pharmacie, Université Paul Sabatier Toulouse III , Toulouse, France
| | - Fabienne Thomas
- Laboratoire De Pharmacologie, Institut Claudius-Regaud, IUCT-Oncopole , Toulouse Cedex 9, France.,Cancer Research Center of Toulouse, INSERM UMR1037, Team 14 DIAD (Dose Individualization of Anticancer Drug) , Toulouse, France.,Faculté de Pharmacie, Université Paul Sabatier Toulouse III , Toulouse, France
| | - Etienne Chatelut
- Laboratoire De Pharmacologie, Institut Claudius-Regaud, IUCT-Oncopole , Toulouse Cedex 9, France.,Cancer Research Center of Toulouse, INSERM UMR1037, Team 14 DIAD (Dose Individualization of Anticancer Drug) , Toulouse, France.,Faculté de Pharmacie, Université Paul Sabatier Toulouse III , Toulouse, France
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Sánchez-Canteli M, Núñez-Batalla F, Martínez-González P, de Lucio-Delgado A, Villegas-Rubio JA, Gómez-Martínez JR, Llorente-Pendás JL. [Ototoxicity in cancer survivors: experience and proposal of a surveillance protocol]. An Pediatr (Barc) 2020; 95:S1695-4033(20)30296-4. [PMID: 32998843 DOI: 10.1016/j.anpedi.2020.08.008] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Revised: 08/25/2020] [Accepted: 08/26/2020] [Indexed: 01/18/2023] Open
Abstract
INTRODUCTION Ototoxicity occurs in different percentages in patients after treatment with platinum-based chemotherapy or cranial radiation therapy. The aim of this study was to present experience in ototoxicity monitoring. MATERIAL AND METHODS A review was made of the registry of paediatric cancer patients referred to the Children's Hearing Loss Unit from 1999 to 2019. RESULTS Of the 46 patients referred to this unit, 41 had received platinum as part of their treatment, 17 patients underwent neurosurgery, and 18 patients received cranial radiation therapy. An anamnesis and otoscopy were performed on all of them, and the monitoring was carried out with tone-verbal audiometry and/or distortion products. Hearing loss was observed in eight patients (21.05% of patients referred for audiological follow-up) as a consequence of the treatment. It was impossible to determine the audiological situation in eight patients at the end of treatment. Hearing aid adaption was necessary in two patients. In coordination with Paediatric Oncology, a change from cisplatin to carboplatin due to bilateral grade two ototoxicity was considered appropriate during treatment in one patient. CONCLUSION Adequate coordination with Paediatric Oncology is essential to carry out active surveillance for ototoxicity and to modify, if possible, the dosage or type of chemotherapy in case hearing is affected. In our experience, and following current recommendations, a pre-treatment assessment is usually performed, as well as monitoring during treatment, at the end of treatment, and annually thereafter due to the risk of a later development of hearing loss.
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Affiliation(s)
- Mario Sánchez-Canteli
- Unidad de Hipoacusia Infantil, Servicio de Otorrinolaringología, Hospital Universitario Central de Asturias, Oviedo, España; Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, España.
| | - Faustino Núñez-Batalla
- Unidad de Hipoacusia Infantil, Servicio de Otorrinolaringología, Hospital Universitario Central de Asturias, Oviedo, España; Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, España; Universidad de Oviedo, Oviedo, España
| | - Patricia Martínez-González
- Unidad de Hipoacusia Infantil, Servicio de Otorrinolaringología, Hospital Universitario Central de Asturias, Oviedo, España
| | - Ana de Lucio-Delgado
- Oncología Pediátrica, Servicio de Pediatría, Hospital Universitario Central de Asturias, Oviedo, España
| | | | - Justo Ramón Gómez-Martínez
- Unidad de Hipoacusia Infantil, Servicio de Otorrinolaringología, Hospital Universitario Central de Asturias, Oviedo, España; Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, España; Universidad de Oviedo, Oviedo, España
| | - José Luis Llorente-Pendás
- Unidad de Hipoacusia Infantil, Servicio de Otorrinolaringología, Hospital Universitario Central de Asturias, Oviedo, España; Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, España; Universidad de Oviedo, Oviedo, España
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Bass JK, Liu W, Banerjee P, Brinkman TM, Mulrooney DA, Gajjar A, Pappo AS, Merchant TE, Armstrong GT, Srivastava D, Robison LL, Hudson MM, Krull KR. Association of Hearing Impairment With Neurocognition in Survivors of Childhood Cancer. JAMA Oncol 2020; 6:1363-1371. [PMID: 32729886 PMCID: PMC7393588 DOI: 10.1001/jamaoncol.2020.2822] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2020] [Accepted: 05/19/2020] [Indexed: 11/14/2022]
Abstract
Importance Despite advancements in cancer therapy and supportive care, childhood cancer survivors remain at risk for chronic morbidities associated with disease and treatment, such as hearing impairment (HI) and neurocognitive deficits. This study, to our knowledge, is the first to objectively measure hearing and neurocognitive function in a large cohort of long-term survivors of childhood cancer stratified by treatment exposures. Objective To assess the association of HI with neurocognitive function and the factors in HI that mediate neurocognitive outcomes in survivors of childhood cancer. Design, Setting, and Participants Data analyzed in this cross-sectional study were collected for the period April 25, 2007, to June 30, 2017, from participants in the St. Jude Lifetime Cohort Study (SJLIFE), an ongoing study that quantifies the long-term health outcomes of survivors of childhood cancer. Participants included those treated at St. Jude Children's Research Hospital (Memphis, Tennessee) for childhood cancer who survived 5 or more years after their original diagnosis and who were eligible for audiologic and neurocognitive testing. Hearing outcomes were coded using the Chang Ototoxicity Grading Scale. Data analysis was performed from March 22, 2019, to March 5, 2020. Main Outcomes and Measures Hearing and neurocognitive function. Survivors were grouped by hearing sensitivity (normal hearing [Chang grade 0], mild HI [Chang grades 1a, 1b, and 2a], or severe HI [Chang grade ≥2b]) and stratified by treatment exposure (platinum-only exposure group [treated with cisplatin and/or carboplatin chemotherapy], cochlear radiotherapy [RT] exposure group [treated with cochlear RT with or without platinum-based chemotherapy], or no exposure group [no platinum-based chemotherapy or cochlear RT]). Multivariable log-binomial models were adjusted for age at diagnosis, time since diagnosis, sex, and relevant treatment exposures. Results A total of 1520 survivors of childhood cancer were analyzed, among whom 814 were male survivors (53.6%), the median (interquartile range [IQR]) age was 29.4 (7.4-64.7) years, and the median (IQR) time since diagnosis was 20.4 (6.1-53.8) years. Prevalence and risk of severe HI among survivors were higher in survivors in the platinum-only (n = 107 [34.9%]; relative risk [RR], 1.68 [95% CI, 1.20-2.37]) or cochlear RT (n = 181 [38.3%]; RR, 2.69 [95% CI, 2.02-3.57) exposure group compared with those in the no exposure group (n = 65 [8.8%]). Severe HI was associated with deficits in verbal reasoning skills (no exposure group RR, 1.11 [95% CI, 0.50-2.43]; platinum-only exposure group RR, 1.93 [95% CI, 1.21-3.08]; cochlear RT exposure group RR, 2.00 [95% CI, 1.46-2.75]), verbal fluency (no exposure group RR, 1.86 [95% CI, 1.19-2.91]; platinum-only exposure group RR, 1.83 [95% CI, 1.24-2.71]; cochlear RT exposure group RR, 1.45 [95% CI, 1.09-1.94]), visuomotor speed (no exposure group RR, 1.87 [95% CI, 1.07-3.25]; platinum-only exposure group RR, 3.10 [95% CI, 1.92-4.99]; cochlear RT exposure group RR, 1.40 [95% CI, 1.11-1.78]), and mathematics skills (no exposure group RR, 1.90 [95% CI, 1.18-3.04]; platinum-only exposure group RR, 1.63 [95% CI, 1.05-2.53]; cochlear RT exposure group RR, 1.58 [95% CI, 1.15-2.18]), compared with survivors with normal hearing or with mild HI. Conclusions and Relevance Results of this study suggest that severe HI in childhood cancer survivors is associated with neurocognitive deficits independent of the neurotoxic treatment received. Early screening and intervention for HI may facilitate the development and maintenance of neurocognitive function and identify individuals at risk for impairment.
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Affiliation(s)
- Johnnie K. Bass
- Rehabilitation Services, St. Jude Children’s Research Hospital, Memphis, Tennessee
| | - Wei Liu
- Department of Biostatistics, St. Jude Children’s Research Hospital, Memphis, Tennessee
| | - Pia Banerjee
- Department of Epidemiology and Cancer Control, St. Jude Children’s Research Hospital, Memphis, Tennessee
| | - Tara M. Brinkman
- Department of Epidemiology and Cancer Control, St. Jude Children’s Research Hospital, Memphis, Tennessee
- Department of Psychology, St. Jude Children’s Research Hospital, Memphis, Tennessee
| | - Daniel A. Mulrooney
- Department of Epidemiology and Cancer Control, St. Jude Children’s Research Hospital, Memphis, Tennessee
- Department of Oncology, St. Jude Children’s Research Hospital, Memphis, Tennessee
| | - Amar Gajjar
- Department of Oncology, St. Jude Children’s Research Hospital, Memphis, Tennessee
- Department of Pediatric Medicine, St. Jude Children’s Research Hospital, Memphis, Tennessee
| | - Alberto S. Pappo
- Department of Oncology, St. Jude Children’s Research Hospital, Memphis, Tennessee
| | - Thomas E. Merchant
- Department of Radiological Sciences, St. Jude Children’s Research Hospital, Memphis, Tennessee
| | - Gregory T. Armstrong
- Department of Epidemiology and Cancer Control, St. Jude Children’s Research Hospital, Memphis, Tennessee
- Department of Oncology, St. Jude Children’s Research Hospital, Memphis, Tennessee
| | - Deokumar Srivastava
- Department of Biostatistics, St. Jude Children’s Research Hospital, Memphis, Tennessee
| | - Leslie L. Robison
- Department of Epidemiology and Cancer Control, St. Jude Children’s Research Hospital, Memphis, Tennessee
| | - Melissa M. Hudson
- Department of Epidemiology and Cancer Control, St. Jude Children’s Research Hospital, Memphis, Tennessee
- Department of Oncology, St. Jude Children’s Research Hospital, Memphis, Tennessee
| | - Kevin R. Krull
- Department of Epidemiology and Cancer Control, St. Jude Children’s Research Hospital, Memphis, Tennessee
- Department of Psychology, St. Jude Children’s Research Hospital, Memphis, Tennessee
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Barnett S, Kong J, Makin G, Veal GJ. Over a decade of experience with carboplatin therapeutic drug monitoring in a childhood cancer setting in the United Kingdom. Br J Clin Pharmacol 2020; 87:256-262. [PMID: 32519769 DOI: 10.1111/bcp.14419] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2020] [Revised: 04/27/2020] [Accepted: 04/30/2020] [Indexed: 11/30/2022] Open
Abstract
The widely used platinum agent carboplatin represents a good example of an anticancer drug where clear relationships between pharmacological exposure and clinical response and toxicity have previously been shown. Within the setting of childhood cancer, there are defined groups of patients who present a particular challenge when dosing with carboplatin, including neonates and infants, those who are anephric, and poor prognosis patients receiving high-dose chemotherapy. For these groups, nonstandard chemotherapy dosing regimens are currently utilised, often with different approaches between clinical study protocols and between treatment centres. For the treatment of these patient populations in the UK, there is now significant experience in carrying out therapeutic drug monitoring, aiming to consistently achieve target drug exposures, maximise drug efficacy and minimise treatment-related side effects. An ongoing clinical trial is currently providing information on drug exposure for a wide range of anticancer agents in these hard to treat patient populations. In addition to supporting dosing decisions for individual patients, the collection and analysis of these data may allow the development of future dosing regimens. For example, current reduced dosing approaches for neonates and infants based on age or body weight, may well be better replaced by regimens based on a sound pharmacological rationale. The successful use of adaptive carboplatin dosing in childhood cancer should encourage the development of therapeutic drug monitoring approaches more widely in an oncology setting.
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Affiliation(s)
- Shelby Barnett
- Newcastle University Centre for Cancer, Newcastle University, Newcastle upon Tyne, UK
| | - Jordon Kong
- Division of Cancer Sciences, University of Manchester, Manchester, UK
| | - Guy Makin
- Division of Cancer Sciences, University of Manchester, Manchester, UK.,Royal Manchester Children's Hospital, Manchester, UK
| | - Gareth J Veal
- Newcastle University Centre for Cancer, Newcastle University, Newcastle upon Tyne, UK
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Gersten BK, Fitzgerald TS, Fernandez KA, Cunningham LL. Ototoxicity and Platinum Uptake Following Cyclic Administration of Platinum-Based Chemotherapeutic Agents. J Assoc Res Otolaryngol 2020; 21:303-321. [PMID: 32583132 PMCID: PMC7445222 DOI: 10.1007/s10162-020-00759-y] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2020] [Accepted: 05/22/2020] [Indexed: 01/04/2023] Open
Abstract
Cisplatin is a widely used anti-cancer drug used to treat a variety of cancer types. One of the side effects of this life-saving drug is irreversible ototoxicity, resulting in permanent hearing loss in many patients. In order to understand why cisplatin is particularly toxic to the inner ear, we compared the hearing loss and cochlear uptake of cisplatin to that of two related drugs, carboplatin and oxaliplatin. These three drugs are similar in that each contains a core platinum atom; however, carboplatin and oxaliplatin are considered less ototoxic than cisplatin. We delivered these three drugs to mice using a 6-week cyclic drug administration protocol. We performed the experiment twice, once using equimolar concentrations of the drugs and once using concentrations of the drugs more proportional to those used in the clinic. For both concentrations, we detected a significant hearing loss caused by cisplatin and no hearing loss caused by carboplatin or oxaliplatin. Cochlear uptake of each drug was measured using inductively coupled plasma mass spectrometry (ICP-MS) to detect platinum. Cochlear platinum levels were highest in mice treated with cisplatin followed by oxaliplatin, while carboplatin was largely excluded from the cochlea. Even when the drug doses were increased, cochlear platinum remained low in mice treated with oxaliplatin or carboplatin. We also examined drug clearance from the inner ear by measuring platinum levels at 1 h and 24 h after drug administration. Our findings suggest that the reduced cochlear platinum we observed with oxaliplatin and carboplatin were not due to increased clearance of these drugs relative to cisplatin. Taken together, our data indicate that the differential ototoxicity among cisplatin, carboplatin, and oxaliplatin is attributable to differences in cochlear uptake of these three drugs.
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Affiliation(s)
- Benjamin K Gersten
- Section on Sensory Cell Biology, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD, 20814, USA
| | - Tracy S Fitzgerald
- Mouse Auditory Testing Core, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD, 20814, USA
| | - Katharine A Fernandez
- Section on Sensory Cell Biology, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD, 20814, USA. .,Porter Neuroscience Research Center, 35A Convent Drive, Room 1D-955, Bethesda, MD, 20892, USA.
| | - Lisa L Cunningham
- Section on Sensory Cell Biology, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD, 20814, USA
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Mao Y, Nie Q, Yang Y, Mao G. Identification of co‑expression modules and hub genes of retinoblastoma via co‑expression analysis and protein‑protein interaction networks. Mol Med Rep 2020; 22:1155-1168. [PMID: 32468072 PMCID: PMC7339782 DOI: 10.3892/mmr.2020.11189] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2019] [Accepted: 04/01/2020] [Indexed: 12/14/2022] Open
Abstract
Retinoblastoma is a common intraocular malignant tumor in children. However, the molecular and genetic mechanisms of retinoblastoma remain unclear. The gene expression dataset GSE110811 was retrieved from Gene Expression Omnibus. After preprocessing, coexpression modules were constructed by weighted gene coexpression network analysis (WGCNA), and modules associated with clinical traits were identified. In addition, functional enrichment analysis was performed for genes in the indicated modules, and protein-protein interaction (PPI) networks and subnetworks were constructed based on these genes. Eight coexpression modules were constructed through WGCNA. Of these, the yellow module had the highest association with severity and age (r=0.82 and P=3e-07; r=0.72 and P=3e-05). The turquoise module had the highest association with months (r=−0.63 and P=5e-04). The genes in the two modules participate in multiple pathways of retinoblastoma, and by combining the PPI network and subnetworks; 10 hub genes were identified in the two modules. The present study identified coexpression modules and hub genes associated with clinical traits of retinoblastoma, providing novel insight into retinoblastoma progression.
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Affiliation(s)
- Yukun Mao
- Department of Orthopedics, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, P.R. China
| | - Qingbin Nie
- Department of Neurovascular Surgery, The Third Medical Centre, Chinese PLA (People's Liberation Army) General Hospital, Beijing 100039, P.R. China
| | - Yang Yang
- Department of Neurovascular Surgery, The Third Medical Centre, Chinese PLA (People's Liberation Army) General Hospital, Beijing 100039, P.R. China
| | - Gengsheng Mao
- Department of Neurovascular Surgery, The Third Medical Centre, Chinese PLA (People's Liberation Army) General Hospital, Beijing 100039, P.R. China
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Tanner L, Keppner K, Lesmeister D, Lyons K, Rock K, Sparrow J. Cancer Rehabilitation in the Pediatric and Adolescent/Young Adult Population. Semin Oncol Nurs 2020; 36:150984. [DOI: 10.1016/j.soncn.2019.150984] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
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van As JW, van den Berg H, van Dalen EC, Cochrane Childhood Cancer Group. Different infusion durations for preventing platinum-induced hearing loss in children with cancer. Cochrane Database Syst Rev 2020; 1:CD010885. [PMID: 31961948 PMCID: PMC6984653 DOI: 10.1002/14651858.cd010885.pub5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
BACKGROUND Platinum-based therapy, including cisplatin, carboplatin or oxaliplatin, or a combination of these, is used to treat a variety of paediatric malignancies. Unfortunately, one of the most important adverse effects is the occurrence of hearing loss or ototoxicity. In an effort to prevent this ototoxicity, different platinum infusion durations have been studied. This review is the third update of a previously published Cochrane Review. OBJECTIVES To assess the effects of different durations of platinum infusion to prevent hearing loss or tinnitus, or both, in children with cancer. Secondary objectives were to assess possible effects of these infusion durations on: a) anti-tumour efficacy of platinum-based therapy, b) adverse effects other than hearing loss or tinnitus, and c) quality of life. SEARCH METHODS We searched the electronic databases Cochrane Central Register of Controlled Trials (CENTRAL; the Cochrane Library 14 November 2019), MEDLINE (PubMed) (1945 to 14 November 2019) and Embase (Ovid) (1980 to 14 November 2019). In addition, we handsearched reference lists of relevant articles and we assessed the conference proceedings of the International Society for Paediatric Oncology (2009 up to and including 2019) and the American Society of Pediatric Hematology/Oncology (2014 up to and including 2019). We scanned ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP; apps.who.int/trialsearch) for ongoing trials (both searched on 4 November 2019). SELECTION CRITERIA Randomised controlled trials (RCTs) or controlled clinical trials (CCTs) comparing different platinum infusion durations in children with cancer. Only the platinum infusion duration could differ between the treatment groups. DATA COLLECTION AND ANALYSIS Two review authors independently performed the study selection, 'Risk of bias' assessment and GRADE assessment of included studies, and data extraction including adverse effects. Analyses were performed according to the guidelines of the Cochrane Handbook for Systematic Reviews of Interventions. MAIN RESULTS We identified one RCT and no CCTs; in this update no additional eligible studies were identified. The RCT (total number of children = 91) evaluated the use of a continuous cisplatin infusion (N = 43) versus a one-hour bolus cisplatin infusion (N = 48) in children with neuroblastoma. For the continuous infusion, cisplatin was administered on days one to five of the cycle, but it is unclear if the infusion duration was a total of five days. Risk of bias was present. Only results from shortly after induction therapy were provided. No clear evidence of a difference in hearing loss (defined as asymptomatic and symptomatic disease combined) between the different infusion durations was identified as results were imprecise (risk ratio (RR) 1.39, 95% confidence interval (CI) 0.47 to 4.13, low-quality evidence). Although the numbers of children were not provided, it was stated that tumour response was equivalent in both treatment arms. With regard to adverse effects other than ototoxicity, we were only able to assess toxic deaths. Again, the confidence interval of the estimated effect was too wide to exclude differences between the treatment groups (RR 1.12, 95% CI 0.07 to 17.31, low-quality evidence). No data were available for the other outcomes of interest (i.e. tinnitus, overall survival, event-free survival and quality of life) or for other (combinations of) infusion durations or other platinum analogues. AUTHORS' CONCLUSIONS Since only one eligible RCT evaluating the use of a continuous cisplatin infusion versus a one-hour bolus cisplatin infusion was found, and that had methodological limitations, no definitive conclusions can be made. It should be noted that 'no evidence of effect', as identified in this review, is not the same as 'evidence of no effect'. For other (combinations of) infusion durations and other platinum analogues no eligible studies were identified. More high-quality research is needed.
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Affiliation(s)
- Jorrit W van As
- Princess Máxima Center for Pediatric Oncologyc/o Cochrane Childhood CancerHeidelberglaan 25UtrechtNetherlands3584 CS
| | - Henk van den Berg
- Emma Children's Hospital, Amsterdam UMC, University of AmsterdamDepartment of Paediatric OncologyPO Box 22660AmsterdamNetherlands1100 DD
| | - Elvira C van Dalen
- Princess Máxima Center for Pediatric OncologyHeidelberglaan 25UtrechtNetherlands3584 CS
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Abstract
PURPOSE Platinum-derived chemotherapy is one of the cornerstones in the treatment of central nervous system tumors in children. We aimed to assess the incidence of hearing loss in children after the exposure to platinum drugs. MATERIAL AND METHODS Retrospective study of prospectively collected data on children consecutively diagnosed with brain tumors and treated with platinum derivatives at a tertiary referral hospital between January 2006 and December 2015. We analyzed multiples variables, such as: age at diagnosis, tumor location, hydrocephalus, platinum drug type, radiotherapy, and follow-up time. The final sample size was 51 patients. RESULTS The median age at diagnosis was 6 years. The median overall follow-up time was 75 months. The incidence of ototoxicity was 23.5%. Rates of hearing loss with carboplatinum were lower than with cisplatinum. A statistically significant association occurred between the presence of hydrocephalus, radiotherapy exposure, infratentorial tumor location, and ototoxicity after treatment with platinum derivatives. CONCLUSIONS Childhood central nervous system tumors nowadays exhibit improved cure and survival rates. However, the ototoxicity resulting from the chemotherapy treatment may accompany patients for the rest of their lives. This study reveals that this occurrence is not negligible, and the association of radiotherapy and the presence of hydrocephalus can be potentiating factors.
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Turan C, Kantar M, Aktan Ç, Kosova B, Orman M, Bilgen C, Kirazlı T. Cisplatin ototoxicity in children: risk factors and its relationship with polymorphisms of DNA repair genes ERCC1, ERCC2, and XRCC1. Cancer Chemother Pharmacol 2019; 84:1333-1338. [PMID: 31586226 DOI: 10.1007/s00280-019-03968-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2019] [Accepted: 09/25/2019] [Indexed: 12/19/2022]
Abstract
PURPOSE We aimed to investigate the cisplatin-related hearing toxicity and its possible relationship with polymorphic variants in DNA repair genes, ERCC1, ERCC2, and XRCC1. METHODS Fifty patients treated with cisplatin in the past were included in the study. There were 29 females and 21 males; mean age 13.4 ± 6.0 years). The polymorphism in DNA repair genes was studied using primer and probes in Light Cycler device after DNA isolation was carried out with PCR technique. The polymorphisms and clinical risk factors were evaluated using Chi square test and logistic regression modelling. RESULTS The patients had hearing loss in 44%. For ERCC1 gene, the patients with hearing loss had 50% of GG (wild type), 40.9% of AG and 9.1% of AA genotypes, while the patients without hearing loss had 28.6% of GG, 53.5% of AG, and 17.9% of AA genotypes. For ERCC2 gene, the patients with hearing loss had 18.2% of GG (wild type), 40.9% of TG, and 40.9% of TT genotypes, while the patients without hearing loss had 10.7% of GG 39.3% of TG, and 50% of TT genotypes. For XRCC1 gene, the patients with hearing loss had 18.2% of CC (wild type), 59.1% of CT, and 22.7% of TT genotypes, while the patients without hearing loss had 35.7% of CC, 50% of CT, and 14.3% of TT genotypes. There was no statistically significant association among the groups (p = 0.24). CONCLUSION We did not find a relationship between DNA repair gene polymorphisms and hearing toxicity of cisplatin.
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Affiliation(s)
- Caner Turan
- Department of Pediatrics, Ege University School of Medicine, Izmir, Turkey
| | - Mehmet Kantar
- Department of Pediatrics, Division of Pediatric Oncology, Ege University School of Medicine, Izmir, Turkey.
| | - Çağdaş Aktan
- Department of Medical Biology, Beykent University School of Medicine, Istanbul, Turkey
| | - Buket Kosova
- Department of Medical Biology, Beykent University School of Medicine, Istanbul, Turkey
| | - Mehmet Orman
- Department of Biostatistics and Medical Informatics, Ege University School of Medicine, Izmir, Turkey
| | - Cem Bilgen
- Department of Otorhinolaryngology, Ege University School of Medicine, Izmir, Turkey
| | - Tayfun Kirazlı
- Department of Otorhinolaryngology, Ege University School of Medicine, Izmir, Turkey
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50
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Guo J, Chai R, Li H, Sun S. Protection of Hair Cells from Ototoxic Drug-Induced Hearing Loss. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1130:17-36. [PMID: 30915699 DOI: 10.1007/978-981-13-6123-4_2] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
Hair cells are specialized sensory epithelia cells that receive mechanical sound waves and convert them into neural signals for hearing, and these cells can be killed or damaged by ototoxic drugs, including many aminoglycoside antibiotics, platinum-based anticancer agents, and loop diuretics, leading to drug-induced hearing loss. Studies of therapeutic approaches to drug-induced hearing loss have been hampered by the limited understanding of the biological mechanisms that protect and regenerate hair cells. This review briefly discusses some of the most common ototoxic drugs and describes recent research concerning the mechanisms of ototoxic drug-induced hearing loss. It also highlights current developments in potential therapies and explores current clinical treatments for patients with hearing impairments.
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Affiliation(s)
- Jin Guo
- Key Laboratory of Hearing Medicine of NHFPC, ENT Institute and Otorhinolaryngology Department, Shanghai Engineering Research Centre of Cochlear Implant, Affiliated Eye and ENT Hospital, State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, China
| | - Renjie Chai
- Key Laboratory of Hearing Medicine of NHFPC, ENT Institute and Otorhinolaryngology Department, Shanghai Engineering Research Centre of Cochlear Implant, Affiliated Eye and ENT Hospital, State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, China.,MOE Key Laboratory for Developmental Genes and Human Disease, Institute of Life Sciences, Jiangsu Province High-Tech Key Laboratory for Bio-Medical Research, Southeast University, Nanjing, China
| | - Huawei Li
- Key Laboratory of Hearing Medicine of NHFPC, ENT Institute and Otorhinolaryngology Department, Shanghai Engineering Research Centre of Cochlear Implant, Affiliated Eye and ENT Hospital, State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, China
| | - Shan Sun
- Key Laboratory of Hearing Medicine of NHFPC, ENT Institute and Otorhinolaryngology Department, Shanghai Engineering Research Centre of Cochlear Implant, Affiliated Eye and ENT Hospital, State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, China.
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