Background: Ovarian tissue cryopreservation and transplantation are the only available fertility techniques for prepubertal girls with cancer. Though autotransplantation carries a risk of ...reintroducing malignant cells, it can be avoided by identifying minimal infiltrative disease (MID) within ovarian tissue. Methods: A broad search for peer-reviewed articles in the PubMed database was conducted in accordance with PRISMA guidelines up to March 2023. Search terms included ‘minimal residual disease’, ‘cryopreservation’, ‘ovarian’, ‘cancer’ and synonyms. Results: Out of 542 identified records, 17 were included. Ovarian tissues of at least 115 girls were evaluated and categorized as: hematological malignancies (n = 56; 48.7%), solid tumors (n = 42; 36.5%) and tumors of the central nervous system (n = 17; 14.8%). In ovarian tissue of 25 patients (21.7%), MID was detected using RT-qPCR, FISH or multicolor flow cytometry: 16 of them (64%) being ALL (IgH rearrangements with/without TRG, BCL-ABL1, EA2-PBX1, TEL-AML1 fusion transcripts), 3 (12%) Ewing sarcoma (EWS-FLI1 fusion transcript, EWSR1 rearrangements), 3 (12%) CML (BCR-ABL1 fusion transcript, FLT3) and 3 (12%) AML (leukemia-associated immunophenotypes, BCR-ABL1 fusion transcript) patients. Conclusion: While the majority of malignancies were found to have a low risk of containing malignant cells in ovarian tissue, further studies are needed to ensure safe implementation of future fertility restoration in clinical practice.
Cisplatin, widely used in the treatment of solid tumors, causes permanent hearing loss in more than 60% of treated children. Previous studies have implicated several clinical factors in the ...development of ototoxicity, including cumulative cisplatin dose. However, the role of cisplatin dose intensity in the development of hearing loss in children remains unclear. Pharmacogenetic studies have also identified genetic variants in TPMT that increase the risk of cisplatin-induced hearing loss. This study aims to determine whether cisplatin dose intensity contributes to the risk of hearing loss in children and whether genetic variations in TPMT further modifies the risk of cisplatin-induced hearing loss.
The authors genotyped 371 cisplatin-treated children for the presence of any 3 TPMT -risk variants. Patients were categorized into high-, moderate-, and low-intensity cisplatin dosing groups according to the cisplatin dose administered per unit time. Kaplan-Meier curves were plotted to compare the cumulative incidence of hearing loss between the genotype and dose intensity groups.
Patients receiving cisplatin at high dose intensity experienced significantly higher incidences of ototoxicity than those receiving cisplatin at low dose intensity ( P = 9 × 10 -7 ). Further stratification by TPMT genotype revealed that carriers of ≥1 TPMT variants receiving high-intensity cisplatin developed ototoxicity sooner and more often than their wild-type counterparts (93.8% vs. 56.6% at 12 months; P = 5 × 10 -5 ) and noncarriers receiving low-intensity cisplatin (21.2% at 12 months).
Cisplatin dose intensity is strongly associated with ototoxicity development in children, and this risk is further increased by the presence of TPMT -risk alleles.
Ototoxicity is a devastating direct, irreversible side effect of platinum use in children with cancer, with its consequent effect on speech, language and social development, quality of life and adult ...productivity. Cisplatin, an essential chemotherapeutic agent for the treatment of solid tumors in children, is a DNA cross-linking agent. Which causes hearing loss in 50-70% of cisplatin treated children. Fortunately, to prevent hearing loss, sodium thiosulfate (STS), which binds to cisplatin, and reduces the superoxides in both tumor and outer hair cells of the cochlea has now been discovered to be an effective and safe otoprotectant if administered correctly. The aim of this perspective paper is to explore the key safety issues and challenges important for pediatric oncologists and pharmacists when considering the clinical use of STS as an otoprotectant for children and adolescents receiving cisplatin. These include: the choice of the formulation; the timing, both that of the STS in relation to cisplatin as well as the timing of the cisplatin infusion itself; the dosing; the challenge left by the definition of localized versus disseminated disease and the difference in indication for STS, between cisplatin treated patients and those receiving another platinum chemotherapeutic agent, carboplatin.
Background
Ototoxicity is a common adverse event of cisplatin treatment. The authors investigated the development of cisplatin‐induced hearing loss (CIHL) over time in children with cancer by age and ...examined the influence of other clinical characteristics on the course of CIHL.
Methods
Data from Canadian patients with childhood cancer were retrospectively reviewed. Hearing loss was graded according to International Society of Pediatric Oncology criteria. The Kaplan‐Meier method was applied to estimate the cumulative incidence of CIHL for the total cohort and according to age. Cox regression models were used to explore the effects of independent variables on CIHL development up to 3 years after the start of therapy.
Results
In total, 368 patients with 2052 audiological assessments were included. Three years after initiating therapy, the cumulative incidence of CIHL was highest in patients aged ≤5 years (75%; 95% confidence interval CI, 66%‐84%), with a rapid increase observed to 27% (95% CI, 21%‐35%) at 3 months and to 61% (95% CI, 53%‐69%) at 1 year, compared with patients aged >5 years (48%; 95% CI, 37%‐62%; P < .001). The total cumulative dose of cisplatin at 3 months (per 100 mg/m2 increase: hazard ratio HR, 1.20; 95% CI, 1.01‐1.41) vincristine (HR, 2.87; 95% CI, 1.89‐4.36) and the total duration of concomitantly administered antibiotics (>30 days: HR, 1.85; 95% CI, 1.17‐2.95) further influenced CIHL development over time.
Conclusions
In young children, the cumulative incidence of CIHL is higher compared with that in older children and develops early during therapy. The course of CIHL is further influenced by the total cumulative dose of cisplatin and other ototoxic (co‐)medication. These results highlight the need for audiological monitoring at each cisplatin cycle.
In young children, the cumulative incidence of cisplatin‐induced hearing loss is higher compared with that in older children and develops early during therapy. The course of cisplatin‐induced hearing loss development over time is further influenced by the total cumulative dose of cisplatin, vincristine treatment, and total duration of concomitantly administered antibiotics.
•Childhood cancer patients and survivors seem at higher risk for tinnitus development compared to siblings.•Platinum agents, high dose cranial radiation and central nervous system tumors are risk ...factors for tinnitus development.•Regular screening for tinnitus and information providing before, during and after childhood cancer therapy is recommended.
Tinnitus can occur during and after treatment for childhood cancer. Studies on the occurrence of, and risk factors for tinnitus during and after childhood cancer treatment are scarce. The aim of this study is to get insight into the frequency and risk factors of tinnitus during and after childhood cancer therapy, based on a review of all previously reported literature.
Systematic electronic literature searches that combined childhood cancer with different treatments and tinnitus terms were performed in the databases EMBASE, Medline, Cochrane, Web of Science, and Google Scholar. Studies were included based on reporting the frequency of tinnitus during and/or after childhood cancer, with 75% of participants being under the age of 25 at time of diagnosis, diagnosed with any type of childhood malignancy and treated with any type of chemotherapy and/or radiotherapy. A risk of bias assessment per research question was performed.
Tinnitus incidence rates were reported up to 15.9 (95% CI 11.8–21.4) during therapy and up to 5.4 (95% CI 4.3–6.9) more than 5 years after diagnosis. The relative risk of developing tinnitus as compared to siblings during and after childhood cancer therapy were reported up to 17.2 (95% CI 11.8–25.0) during therapy and up to 3.7 (95% CI 2.7–5.1) more than 5 years after diagnosis. Independent risk factors for tinnitus development included high dose cranial radiation and platinum based chemotherapy.
The frequency of and risk to develop tinnitus seems to be higher in childhood cancer patients and survivors as compared to the normal population. Regular tinnitus screening before, during and after therapy with standardized questionnaires for early detection seems therefore reasonable in order to identify high-risk patients and eventually develop successful clinical preventive, supportive and management strategies.
The frequency and patterns of HL in a HNRMS survivor cohort were investigated. A dose-effect relationship between the dose to the cochlea and HL was explored.
Dutch survivors treated for HNRMS ...between 1993 and 2017 with no relapse and at least two years after the end of treatment were eligible for inclusion. The survivors were evaluated for HL with pure-tone audiometry. HL was graded according to the Muenster, Common Terminology Criteria for Adverse Events (CTCAE) v4.03 and International Society for Paediatric Oncology (SIOP) classification. We defined deleterious HL as Muenster ≥ 2b, CTCAE ≥ 2, and SIOP ≥ 2. Mixed-effects logistic regression was used to search for the dose-effect relationship between the irradiation dose to the cochlea and the occurrence of HL.
Forty-two HNRMS survivors underwent pure-tone audiometry. The Muenster, CTCAE and SIOP classification showed that 19.0% (
= 8), 14.2% (
= 6) and 11.9% (
= 5) of survivors suffered from HL, respectively. A low-frequency HL pattern with normal hearing or milder hearing loss in the higher frequencies was seen in four survivors. The maximum cochlear irradiation dose was significantly associated with HL (≥Muenster 2b) (
= 0.047). In our series, HL (≥Muenster 2b) was especially observed when the maximum dose to the cochlea exceeded 19 Gy.
HL occurred in up to 19% of survivors of HNRMS. More research is needed on HL patterns in HNRMS survivors and on radiotherapy dose-effect relationships.
Invasive fungal infections (IFIs) are an important cause of morbidity and mortality in children with cancer. Studies on the clinical characteristics of IFI in children with solid tumors are limited. ...This Dutch retrospective cohort study reviewed the medical records of 61 children with solid tumors to analyze the clinical characteristics during their full treatment period. Seven IFI episodes were reported in 6/61 patients (10%), all diagnosed with intermediate-risk or high-risk Wilms tumor or neuroblastoma. Larger studies are necessary to reveal the determinants of IFI in this group of patients and the value of fungal prophylaxis.
Ototoxicity is an irreversible direct and late effect of certain childhood cancer treatments. Audiologic surveillance during therapy as part of the supportive care pathway enables early detection of ...hearing loss, decision-making about ongoing cancer treatment, and, when applicable, the timely use of audiologic interventions. Pediatric oncologic clinical practice and treatment trials have tended to be driven by tumor type and tumor-specific working groups. Internationally accepted standardized recommendations for monitoring hearing during treatment have not previously been agreed on.
To provide standard recommendations on hearing loss monitoring during childhood cancer therapy for clinical practice.
An Ototoxicity Task Force was formed under the umbrella of the International Society of Paediatric Oncology, consisting of international audiologists, otolaryngologists, and leaders in the field of relevant pediatric oncology tumor groups. Consensus meetings conducted by experts were organized, aimed at providing standardized recommendations on age-directed testing, timing, and frequency of monitoring during cancer treatment based on literature and consensus. Consensus statements were prepared by the core group, adapted following several videoconferences, and finally agreed on by the expert panel.
The consensus reached was that children who receive ototoxic cancer treatment (platinum agents, cranial irradiation, and/or brain surgery) require a baseline case history, monitoring of their middle ear and inner ear function, and assessment of tinnitus at each audiologic follow-up. As a minimum, age-appropriate testing should be performed before and at the end of treatment. Ideally, audiometry with counseling before each cisplatin cycle should be considered in the context of the individual patient, specific disease, feasibility, and available resources.
This is an international multidisciplinary consensus report providing standardized supportive care recommendations on hearing monitoring in children undergoing potentially ototoxic cancer treatment. The recommendations are intended to improve the care of children with cancer and facilitate comparative research on the timing and development of hearing loss caused by different cancer treatment regimens.
Some children with central nervous system (CNS) and solid tumors are at risk to develop ototoxicity during treatment. Up to now, several risk factors have been identified that may contribute to ...ototoxicity, such as platinum derivates, cranial irradiation, and brain surgery. Comedication, like antibiotics and diuretics, is known to enhance ototoxicity, but their independent influence has not been investigated in childhood cancer patients. Recommendations for hearing loss screening are missing or vary highly across treatment protocols. Additionally, adherence to existing screening guidelines is not always optimal. Currently, knowledge is lacking on the prevalence of ototoxicity.
The aim of the Study on Prevalence and Determinants of Ototoxicity During Treatment of Childhood Cancer (SOUND) is to determine the feasibility of audiological testing and to determine the prevalence and determinants of ototoxicity during treatment for childhood cancer in a national cohort of patients with solid and CNS tumors.
The SOUND study is a prospective cohort study in the national childhood cancer center in the Netherlands. The study aims to include all children aged 0 to 19 years with a newly diagnosed CNS or solid tumor. Part of these patients will get audiological examination as part of their standard of care (stratum 1). Patients in which audiological examination is not the standard of care will be invited for inclusion in stratum 2. Age-dependent audiological assessments will be pursued before the start of treatment and within 3 months after the end of treatment. Apart from hearing loss, we will investigate the feasibility to screen patients for tinnitus and vertigo prevalence after cancer treatment. This study will also determine the independent contribution of antibiotics and diuretics on ototoxicity.
This study was approved by the Medical Research Ethics Committee Utrecht (Identifier 20-417/M). Currently, we are in the process of recruitment for this study.
The SOUND study will raise awareness about the presence of ototoxicity during the treatment of children with CNS or solid tumors. It will give insight into the prevalence and independent clinical and cotreatment-related determinants of ototoxicity. This is important for the identification of future high-risk patients. Thereby, the study will provide a basis for the selection of patients who will benefit from innovative otoprotective intervention trials during childhood cancer treatment that are currently being prepared.
Netherlands Trial Register NL8881; https://www.trialregister.nl/trial/8881.
DERR1-10.2196/34297.
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