S-100 and MATH-1 Protein Expressions Can Be Useful for the Prediction of Clinical Outcome in Neuroblastoma Patients.

Neuroblastoma (NB) is the most frequent extracranial solid tumor of childhood, remarkable for its broad spectrum of clinical behavior. This diversity in behavior correlates closely with defined clinical and biological features and combinations of prognostic variables are used for risk-group assignment. S-100 proteins have roles in differentiation and were shown to be frequently dysregulated in NB. MATH-1 protein plays role in neuronal cell differentiation through development. However, up to date, there are no studies evaluating the relationship between MATH-1 and NB. Grb2-associated binding (Gab) proteins have roles in the regulation of cell growth and differentiation. Gab1 was reported to be related to poor survival of high-risk NB patients. The aim of this study was to investigate the relationship between differentiation-related S-100, MATH-1, and Gab1 proteins and risk group and/or stages of NB. A significant relation was found between S-100 and early stages of NB. This study also revealed a significant association between MATH-1 and low-risk groups. S-100 and MATH-1 were also shown to provide survival advantages among stages and risk groups. The findings of this study support the assumption that S-100 and MATH-1 can be potential prognostic biomarkers for staging and risk-group assignment of NB patients. These proteins can be useful tools for clinicians to guide through treatment options, especially for the evaluation of tumor differentiation.

Pediatric paravertebral tumors: analysis of 96 patients.

PURPOSE: The most important complication of paravertebral tumors is cord compression (CC), which is an oncologic emergency. Early and appropriate intervention is important in terms of reducing morbidity and mortality. Here, we report our clinical experience with paravertebral tumors. METHODS: The files of patients who were followed up for benign/malignant paravertebral tumors between 1988 and 2022 were evaluated retrospectively. RESULTS: There were 96 patients with paravertebral tumors. The median age at diagnosis was 5 years (1 month-17 years). The male/female ratio was 1.13. The median time to diagnosis was 4 weeks (0-28 weeks). The most common presenting complaint was pain (62.5%). The diagnosis distribution was as follows: sympathetic nervous system (SNS) tumors (n: 38), soft tissue sarcomas (STS) (n: 23), Langerhans cell histiocytosis (LCH) (n: 12), central nervous system (CNS) tumors (n: 9), germ cell tumor (n: 6), lymphomas (n: 4), and benign tumors (n: 4). Sixty-five patients (67.7%) had CC, 40% of whom received chemotherapy as first-line treatment. Decompression surgery was performed in 58.5% of the patients. For patients with CC, 26 patients had advanced disease at admission. Serious neurologic sequelae were observed in seventeen (17.7%) patients. CONCLUSION: Pain and neurological findings in childhood are warning signs for paravertebral tumors and CC. A detailed neurologic examination and radiodiagnostic imaging should be performed, and a definitive diagnosis should be made quickly. Anticancer treatment should be planned multidisciplinary. Decompression surgery should be discussed for patients with severe neurological deficits. Childhood cancers are chemosensitive; if possible, treatment should be initiated with chemotherapy to avoid neurological sequelae.

Evaluation of Risk Factors Causing Ototoxicity in Childhood Cancers Located in the Head and Neck Region Treated With Platinum-based Chemotherapy.

The aim of this study is to evaluate risk factors contributing to the development of ototoxicity in children who received platinum-based chemotherapy for malignancies located in the head and neck region. Eighty-four children who received platinum-based chemotherapy were included. Audiologic evaluations were performed before and after each chemotherapy session through pure tone audiometry, distortion product otoacoustic emissions, and auditory brainstem response tests. Ototoxicity was evaluated using Brock, Muenster, and Chang classifications. Factors such as cranial irradiation, cumulative doses of cisplatin, age, sex, cotreatment with aminoglycosides, schedule of platinum, and type of chemotherapeutic agent were analyzed. Using χ2 tests, all risk factors were matched with the 3 ototoxicity classifications, and multivariate analyses were conducted using statistically significant risk factors. In univariate analyses, being between 5 and 12 years of age, cranial irradiation and being treated with both cisplatin and carboplatin were found to be related to ototoxicity in all 3 classifications. Logistic regression modeling analyses with these 3 risk factors showed that being between 5 and 12 years of age and being treated with both cisplatin and carboplatin significantly increased the risk of ototoxicity.

Successful treatment of congenital systemic juvenile xanthogranulomatosis with pulmonary involvement.

Juvenile xanthogranuloma (JXG) is a common form of non-Langerhans cell histiocytosis, which usually presents with spontaneously regressing skin lesions. Systemic involvement is rare and mostly seen in patients with multiple skin nodules. It can spontaneously regress, but sometimes systemic involvement can cause life-threatening symptoms and can be fatal. Herein, we report a case of congenital systemic JXG with multiple skin nodules, soft tissue and pulmonary involvement. She was successfully treated with chemotherapy according to Langerhans cell histiocytosis treatment protocol IV of the Histiocyte Society (LCH-IV).

Low Expression of CASP8 Could be a Prognostic Biomarker in Neuroblastoma Patients.

The aim of study was to investigate whether CASP8 (CASPASE8) could be a biomarker for prognosis in neuroblastoma. The prognostic value of CASP8 was determined by analyzing CASP8 methylation status and gene expressions in the tumor tissues of 37 neuroblastoma patients. Bisulfite and quantitative multiplex-methylation-specific polymerase chain reaction (PCR) were used to identify the methylation status. CASP8 messenger ribonucleic acid (RNA) expression levels were determined using reverse transcriptase-quantitative PCR. CASP8 expression levels associated with prognostic value were also analyzed using the TARGET NBL (141 cases) database through PDX for Childhood Cancer Therapeutics (PCAT) and SEQC (498 cases) via the R2 platform. CASP8 methylation status was associated with risk groups, MYCN amplification, and 17q gain status. CASP8 expression was found to be statistically different between high- and low-risk neuroblastoma groups. Low expression of CASP8 was associated with MYCN amplification status. Low expression of CASP8 has shown statistically significant prognostic value through TARGET NBL and SEQC-498 data sets. CASP8 messenger RNA expressions and methylation status were associated with the MYCN amplified high-risk group in neuroblastoma. CASP8 messenger RNA expressions may be considered as a clinical prognostic marker in neuroblastoma.

Infantile Hemangiomas of the Head and Neck: A Single-Center Experience.

Background: Infantile hemangiomas (IHs) are the most common benign vascular tumors of infancy. Methods: We report our experiences with 248 patients with head and neck IHs. Results: The median admission age was 4 months, and the female/male ratio was 2.18. Among the cases, 45% were followed by no treatment. No local complications were observed in any of these patients. Propranolol was provided to all patients who received medical treatment. The median duration of treatment was 12 months (1-30 months), and the median follow-up period of all patients was 14 months (0-118 months). The treatment response was 98%. The complication rate was 17%, and children aged between 3 and 9 months accounted for 60% of the patients who developed complications. Most of the complications were local complications, such as ulceration and bleeding. Conclusions: Although most IHs regress spontaneously, complications may occur. Propranolol alone is an effective treatment option, and early treatment initiation increases the success rate.

Investigation of YAP-1, OTX-2, and nestin protein expressions in neuroblastoma: a preliminary study.

OBJECTIVES: Neuroblastoma is the most common extracranial solid tumor in childhood. YAP (Yes-associated protein) is a highly expressed protein in NB. Nestin is an important marker of neuronal differentiation in NB. Orthodenticle homeobox (OTX) is a transcription factor and is overexpressed in blastoma-derived tumors. The aim of this study was to examine the potential roles of YAP-1, Nestin, and OTX-2 proteins in prognosis and risk stratification in neuroblastoma METHODS: Tumor sections of 56 patients with different NB risk groups were analyzed. YAP-1, Nestin, and OTX-2 protein expression levels were evaluated by immunohistochemical staining in NB patient tissue samples. RESULTS: YAP-1, Nestin, and OTX-2 protein expression levels were evaluated together with the clinical findings of NB patients. YAP-1 was expressed in 18% of all tissues, while Nestin was expressed in 20.4%. OTX-2 protein expression was found in 41.1% of the NB patients. YAP-1 was expressed in 26.9% of high-risk and 11.5% of low-risk patients. Nestin was expressed in 24.4% high-risk and 33.3% low-risk patients. OTX-2 was expressed in 68.2% high-risk and 60% low-risk patients.YAP-1 was shown to provide survival advantages among risk groups. INTERPRETATION: The findings of this study support that YAP-1 may be a potential prognostic biomarker for staging and risk-group assignment of NB patients. YAP-1 expression in neuroblastoma is associated with significantly poorer survival probabilities and should be considered as a potential therapeutic target. OTX-2 is a promising predictive biomarker candidate, but its mechanisms need further investigation in neuroblastoma, as nestin expression is not significantly linked to patient survival.

Comparing Tribbles Homolog 3 (TRIB3) Protein Expression Levels with Clinicopathological Characteristics and Survival Among Neuroblastoma Patients.

Background: Tribbles Homolog 3 (TRIB3) is a member of the pseudokinase family of tribbles and acts as an adaptor protein to regulate different cellular processes. Upregulation of TRIB3 expression was shown either as a favorable or an adverse prognostic factor in various adult malignancies. However, TRIB3 expression has not been examined in pediatric cancers. Neuroblastoma is the most common malignant solid tumor of childhood, which affects mostly children under 5 years old. Risk stratification of patients defined by International Neuroblastoma Risk Group was used to determine prognosis and treatment of the disease. This study aimed to examine the relationship between TRIB3 protein expression levels and clinicopathological features and survival of patients. Methods: TRIB3 protein expression was analyzed using immunohistochemical staining on formalin-fixed paraffin-embedded tissue samples of neuroblastoma patients (n = 56). Survival analyses were performed with Kaplan-Meier method and log-rank tests. Association between TRIB3 expression and clinicopathological characteristics were analyzed with Spearman's correlation. Results: Of the patients, 32.1% were in the low-risk group, 21.4% in the medium-risk group, and 46.4% in the high-risk group. Survival analysis was performed in the entire neuroblastoma patient group and sub-risk groups of neuroblastoma patients. In the entire patient group, there was no significant difference in overall survival (P = .202) and event-free survival (P = .172) between TRIB3-positive and -negative patients. However, when survival analyses were performed in each risk group, TRIB3 expression was significantly associated with higher overall survival (P = .034) and event-free survival (P = .032) in low-risk group neuroblastoma patients. Nevertheless, no association was found between TRIB3 expression and overall survival (P = .799) and event-free survival (P = .448) in high-risk neuroblastoma patients. Furthermore, a significant correlation was identified between 1p36 loss-of-heterozygosity and TRIB3 expression (P = .030). However, TRIB3 expression did not correlate with other clinicopathological features. Conclusion: TRIB3 expression is a potential predictive biomarker for low-risk neuroblastoma patients.

Identification of ALK Mutation in Neuroblastoma on the Point of Molecular Heterogeneity.

BACKGROUND AND AIM: In neuroblastoma, anaplastic lymphoma kinase mutations have recently received attention as molecular targets for the treatment of neuroblastoma, as 6% to 10% of patients with neuroblastoma have anaplastic lymphoma kinase mutations. There are little data from the cases in Turkey. We aimed to detect anaplastic lymphoma kinase mutations and molecular heterogeneity in neuroblastoma using next-generation sequencing. This study is the first one with this many cases in Turkey. METHODS: Next-generation sequencing analysis was performed using an Illumina MiniSeq custom gene panel. Clinically important mutations were selected for the analysis. We also gathered clinical data of the patients from Turkish Pediatric Oncology Group cohorts to associate them with anaplastic lymphoma kinase mutations. This study is a retrospective cross-sectional study. We followed STROBE guideline (https://www.equator-network.org/reporting-guidelines/strobe/) on this study. RESULTS: We analyzed anaplastic lymphoma kinase in 108 patients with neuroblastoma, with a mean age of 43.76 months. Pathogenic anaplastic lymphoma kinase mutations were detected in 13 patients (12.04%). We noted that anaplastic lymphoma kinase mutations were primarily observed in intermediate- and high-risk patients (P = .028). R1275Q and F1174-related mutations were predominant; I1171T, L1226F, S1189F, V1135A, and G1125S mutations were rare. Duplicate samples did not exhibit any heterogeneity. CONCLUSIONS: We found that F1174 and R1275Q-related anaplastic lymphoma kinase mutations are the most common pathogenic mutations in neuroblastoma. Anaplastic lymphoma kinase mutation status did not show any heterogeneity, and the mutations were correlated with intermediate- or high-risk groups.

Unraveling the Mystery: Next Generation Sequencing Sheds Light on Neuroblastoma Pathogenesis and Targeted Therapies.

BACKGROUND: There is considerable interest in the molecular evaluation of solid tumors in pediatric cases. Although clinical trials are in progress for targeted therapies against neuroblastoma (NB), novel therapeutic strategies are needed for high-risk cases that are resistant to therapy. The aim of the present study was to document the specific gene mutations related to targeted therapy in relapsed or refractory NB patients by using next generation sequencing (NGS). METHODS: The study included 57 NB patients from amongst 1965 neuroblastic cases in Turkey who experienced a recurrence after multi-model therapy. The cases were diagnosed, risk-stratified, and treated according to the classification system from the International Neuroblastoma Risk Group. Single nucleotide variations in 60 genes were investigated using the Pillar Onco/Reveal Multicancer v4 panel and Pillar RNA fusion panel on the Illumina Miniseq platform. RESULTS: ERBB2 I655V was the most frequent mutation and was found in 39.65% of cases. Anaplastic Lymphoma Kinase (ALK) mutations (F1174L, R1275Q, and rare mutations in the tyrosine kinase domain) were detected in 29.3% of cases. Fusion mutations in NTRK1, NTRK3, ROS1, RET, FGFR3, ALK and BRAF were observed in 19.6% of cases. CONCLUSIONS: This study presents valuable mutation data for relapsed and refractory NB patients. The high frequency of the ERBB2 I655V mutation may allow further exploration of this mutation as a potential therapeutic target. Rare BRAF mutations may also provide opportunities for targeted therapy. The role of ABL1 mutations in NB should also be explored further.

Atypical Presentation and Course of ACTH-independent Cushing's Syndrome in Two Families.

Primary pigmented nodular adrenocortical disease (PPNAD) is a rare genetic disease mainly associated with Carney complex (CNC), which is caused by germline mutations of the regulatory subunit type 1A (RIα) of the cAMP-dependent protein kinase (PRKAR1A) gene. We report three cases suffering from CNC with unique features in diagnosis and follow-up. All cases had obesity and a cushingoid appearance and exhibited laboratory characteristics of hypercortisolism. However biochemical and radiological examinations initially suggested Cushing's disease in one case . All of the cases were treated surgically; two of them underwent bilateral adrenalectomy at once, one of them had unilateral adrenalectomy at first but required contralateral adrenalectomy after nine months. Contrary to what is usually known regarding PPNAD, the adrenal glands of two cases (case 2 and 3) had a macronodular morphology. Genetic analyses revealed pathogenic variants in PRKAR1A (case 1: c.440+5 G>A, not reported in the literature; cases 2 and 3: c.349G>T, p.V117F). One case developed Hodgkin lymphoma five year after adrenalectomy, this association was not previously reported with CNC. The findings of these families provide important information for a better understanding of the genetic pathogenesis, diagnosis, and clinical management of CNC. Hodgkin lymphoma may be a component of CNC.

Dinutuximab beta plus conventional chemotherapy for relapsed/refractory high-risk neuroblastoma: A single-center experience.

Background: Relapsed/refractory high-risk neuroblastoma has a dismal prognosis. Anti-GD2-mediated chemo-immunotherapy has a notable anti-tumor activity in patients with relapsed/refractory high-risk neuroblastoma. The purpose of this study was to analyze the efficacy and safety of the combination of immunotherapy with dinutuximab beta (DB) and chemotherapy in patients with relapsed/refractory high-risk neuroblastoma. Methods: All patients received the Turkish Pediatric Oncology Group NB 2009 national protocol for HR-NB treatment at the time of diagnosis. Salvage treatments were administered after progression or relapse. The patients who could not achieve remission in primary or metastatic sites were included in the study. The most common chemotherapy scheme was irinotecan and temozolomide. DB was administered intravenously for 10 days through continuous infusion with 10 mg/m2 per day. The patients received 2 to 14 successive cycles with duration of 28 days each. Disease assessment was performed after cycles 2, 4, and 6 and every 2 to 3 cycles thereafter. Results: Between January 2020 and March 2022, nineteen patients received a total of 125 cycles of DB and chemotherapy. Objective responses were achieved in 12/19 (63%) patients, including complete remission in 6/19 and partial response in 6/19. Stable disease was observed in two patients. The remaining five patients developed bone/bone marrow and soft tissue progression after 2-4 cycles of treatment. The most common Grade ≥3 toxicities were leukopenia, thrombocytopenia, hypertransaminasemia, fever, rash/itching and capillary leak syndrome, respectively. Conclusion: Our study results suggest that DB-based chemo-immunotherapy seems to be suitable with encouraging response rates in patients with relapsed/refractory high-risk neuroblastoma.

Investigation of the Relationship Between Fok1 and Col1A1 Gene Polymorphisms and Development of Treatment-Related Bone Complications in Children with Acute Lymphoblastic Leukemia

Objective: In acute lymphoblastic leukemia (ALL), various clinical risk factors and genetic predispositions contribute to the development of bone complications during and after chemotherapy. In this study, we aimed to investigate whether vitamin D receptor (VDR) Fok1 and collagen protein Col1A1 Sp1-binding site gene polymorphisms, which are important in bone mineral and matrix formation, have effects on the development of bone abnormalities in childhood ALL survivors. Materials and Methods: Fifty children with ALL who were treated with the ALL Berlin-Frankfurt-Muenster-95 protocol between 1998 and 2008 and were followed for at least 7 years were enrolled. The control group consisted of 96 healthy children. VDR Fok1 and Col1A1 Sp1-binding site gene polymorphisms were analyzed by polymerase chain reaction and restriction fragment length polymorphism. Bone mineral density (BMD) and markers of bone metabolism were all noted. All patients who presented with pain in the joints were examined for bone pathologies while on chemotherapy or during long-term follow-up. Results: Low BMD (16%), osteoporosis (12%), and osteonecrosis (8%) were present in a total of 18 patients (36%). The frequency of osteonecrosis and total bone abnormalities was significantly higher in children aged ≥10 years (p=0.001). The risk of low BMD and osteonecrosis was higher in those with vitamin D deficiency. Only the Col1A1 Sp1-binding site gene polymorphism showed a significant association in ALL patients with osteonecrosis. Conclusion: The development of therapy-induced bone mineral loss and osteonecrosis in children with ALL is frequent and the risk is especially higher in children aged ≥10 years and with vitamin D deficiency. The association between Col1A1 Sp1-binding site gene polymorphisms and osteonecrosis has to be assessed in a larger group of ALL survivors.

Analysis of apoptotic, platelet-derived, endothelial-derived, and tissue factor-positive microparticles of children with acute lymphoblastic leukemia during induction therapy.

OBJECTIVES: Thromboembolism is one of the most common complications during induction therapy of pediatric acute lymphoblastic leukemia (ALL). Procoagulant microparticles in the circulation may cause thromboembolic events. The aim of our study was to determine the levels of apoptotic, platelet-derived, endothelial-derived, and tissue factor-positive microparticles of children with ALL at diagnosis and during induction therapy. METHODS: Sixteen precursor B-cell ALL cases and 30 healthy children between 1 and 18 years of age were included. Microparticle levels were analyzed from peripheral blood samples at initial diagnosis, on days 12 and 13 (before and after the first L-asparaginase administration), and on day 33 of ALL-BFM 2000 treatment protocol. Microparticle levels were analyzed by using flow cytometry. RESULTS: At initial diagnosis, platelet, endothelial-derived, and tissue factor-positive microparticle levels were significantly high in children with ALL. They increased significantly after prednisone and L-asparaginase administration. Apoptotic microparticle levels were not elevated at diagnosis, but remained high during all induction therapy period. None of the patients had evidence of thromboembolism during induction therapy. CONCLUSION: Our study demonstrated that children with ALL have increased levels of apoptotic, platelet-derived, endothelial-derived, and tissue factor-positive microprticles during induction therapy. Further studies are needed in larger groups of patients in order to evaluate the risk of elevated microprticles for development of thromboembolism during induction therapy period in children with ALL.

Assessment of Health-Related Quality of Life in Pediatric Acute Lymphoblastic Leukemia Survivors: Perceptions of Children, Siblings, and Parents

Objective: We investigated the health-related quality of life (HRQL) in survivors of pediatric acute lymphoblastic leukemia (ALL) and evaluated the perceptions of the children, their siblings, and their parents. Materials and Methods: Seventy ALL survivors, who were between 7 and 17 years of age and had completed therapy ≥2 years, were included. The control group consisted of their healthy siblings. HRQL was assessed by the age-specific KINDLR questionnaire. Results: No significant differences could be found among HRQL scores of ALL survivors with respect to variables such as sex, risk group, and having chronic illness. HRQL scores for physical well-being, emotional well-being, family, and social functioning of the patient and sibling self-reports and parent proxy reports were lower than the expected values for healthy and chronically ill children. Conclusion: These results demonstrate that both ALL survivors and their families need help via psychological counseling programs to improve their HRQL even after completion of therapy.

FLAG Regimen with or without Idarubicin in Children with Relapsed/Refractory Acute Leukemia: Experience from a Turkish Pediatric Hematology Center.

INTRODUCTION: The optimal therapy to achieve higher rates of survival in pediatric relapsed/refractory acute leukemia (AL) is still unknown. In developing countries, it is difficult to obtain some of the recent drugs for optimal therapy and mostly well-known drugs proven to be effective are used. We assessed the efficacy of the combination of fludarabine, high-dose cytarabine, and granulocyte colony-stimulating factor (FLAG regimen) with or without idarubicin (IDA) in children with relapsed/refractory acute lymphoblastic leukemia and acute myeloid leukemia. METHODS: Between September 2007 and May 2015, 18 children with refractory/relapsed AL attending our center, treated with a FLAG regimen with or without IDA, were included. The primary end point was the remission status of the bone marrow sampled after the first/second course of chemotherapy. The second end point was the duration of survival after hematopoietic stem cell transplantation (HSCT). RESULTS: Complete remission (CR) was achieved in 7 patients (38.8%) after the first cycle, and at the end of the second cycle the total number of patients in CR was 8 (42.1%). All patients in CR underwent HSCT. The CR rate in patients who had IDA in combination therapy was 28.6%, and it was 50% in patients treated without IDA (p=0.36). Mean survival duration in transplanted patients was 24.7±20.8 months (minimum-maximum: 2-70, median: 25 months), and it was 2.7±1.64 months (minimum-maximum: 0-5, median: 3 months) in nontransplanted patients. Five of them (27.7%) were still alive at the end of the study and in CR. The median time of follow-up for these patients was 33 months (minimum-maximum: 25-70 months). CONCLUSION: FLAG regimens with or without IDA produced a CR of >24 months in 27.7% of children with relapsed/refractory AL and can be recommended as therapeutic options prior to HSCT in developing countries.

Analysis of genetic and non genetic risk factors for cisplatin ototoxicity in pediatric patients.

OBJECTIVE: The aim of this study was to analyse the genetic and non genetic risk factors for cisplatin ototoxicity. METHODS: This study was conducted on 72 children who received cisplatin based chemotherapy. Brock and Muenster classifications were used to evaluate ototoxicity seen in these children. 6 single nucleotide polymorphisms (SNP); ERCC1 rs 11615, GSTP1 rs1138272, GSTP1 rs1695, LRP2 rs 2075252, TPMT rs 12201199, COMT rs 9332377, were evaluated as genetic factors by real time PCR. Non genetic factors such as cranial irradiation, cumulative doses of cisplatin, age, gender, administration of other ototoxic drugs were analysed as well. By using Chi-square test, risk factors were matched with the ototoxicity classifications. Significant risk factors were reevaluated using logistic regression modelling. RESULTS: According to univariate analyses, male gender, co-treatment with aminoglycosides and mutant genotype of GSTP1 rs1695 were significantly related with cisplatin ototoxicity. Logistic regression modelling analyses also showed that male gender, co-treatment with aminoglycosides were found to be significantly related with cisplatin ototoxicity. Mutant genotype of GSTP1 rs1695 was not found to be significant, but close to the level of statistical significance. CONCLUSION: Male gender, co-treatment with aminoglycosides are significant risk factors for cisplatin ototoxicity in pediatric patients. Mutant genotype of GSTP1 rs1695 seems to be a genetic risk factor in univariate analyses, although not confirmed by multivariate analyses. Therefore, GSTP1 rs1695 SNP needs to be studied in larger series.

Protective Effect of Korean Red Ginseng on Cisplatin Ototoxicity: Is It Effective Enough?

OBJECTIVE: The aim of our study was to investigate the effects Korean Red Ginseng (KRG) on cisplatin (CDDP) ototoxicity in vivo and in vitro. MATERIALS AND METHODS: The first part of the study was conducted on the House Ear Institute-Organ of Corti 1 (HEI-OC1) cell line. Cells were treated with CDDP, KRG, and their combination for 24 h. Cell viability, apoptosis, and the expression of 84 apoptosis-related genes were analyzed. In the second part of the study, 30 Wistar albino rats were divided into five groups. Baseline distortion product otoacoustic emissions (DPOAEs) and auditory brainstem response (ABR) measurements were obtained. In groups I, II, and III, only saline, KRG, and CDDP, respectively, were given. In group IV, 500 mg/kg KRG and in group V, 150 mg/kg of KRG were administered for 10 days. In groups III, IV, and V, 16 mg/kg CDDP injections were administered on day 11. On day 14, final DPOAEs and ABR measurements were completed. The rats were then sacrificed, and their inner ear structures were evaluated by transmission electron microscopy. RESULTS: In the first part of the study, pretreatment with 1 mg/mL KRG protected cells from CDDP ototoxicity. This protection was mainly due to a decline in apoptotic gene expression and an increase in antiapoptotic gene expression. In the in vivo part of the study, we found that both KRG doses had otoprotective effects. This protection was more prominent at the lower dose, especially on the spiral ganglion and the brainstem. CONCLUSION: KRG was shown to be an otoprotective agent against CDDP-induced ototoxicity both in vivo and in vitro.

Friend or foe? Effect of oral resveratrol on cisplatin ototoxicity.

OBJECTIVES/HYPOTHESIS: Our objectives were to study effects of orally administered resveratrol (RV) against cisplatin (CDDP) ototoxicity in different doses and to investigate ultrastructural changes in the cochlea and brainstem. STUDY DESIGN: In vivo study using an animal model. METHODS: Thirty-two male Wistar albino rats were divided into six groups. Baseline distortion product otoacoustic emissions (DPOAEs) and auditory brainstem response (ABR) measurements were made. In groups I, II, and III, only saline, RV, and CDDP were given, respectively. Group IV, V, and VI animals were administered 10 mg/kg/day, 1 mg/kg/day, and 0.1 mg/kg/day of RV for 10 days, respectively, before 16 mg/kg CDDP injections were administered on day 11. All animals were sacrificed after repeated DPOAEs and ABR measurements were made on day 14. Cochleas of animals were investigated with transmission electron microscopy. Apoptosis were investigated with caspase-3 activity and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) method in the brainstem. RESULTS: In groups IV and V, DPOAEs and ABR findings revealed that oral administration of RV 10 mg/kg/day and 1 mg/kg/day doses before CDDP injection enhanced ototoxicity. In group VI, electomicroscopy revealed better ultrastructural findings than in the cisplatin group; however, these changes were not reflected in the audiological findings accordingly. CONCLUSIONS: Our results implied that there were noticeable differences between different oral RV doses used for cisplatin ototoxicity. Especially in higher doses, RV was observed to enhance cisplatin ototoxicity.