Stemness and Cell Cycle Regulators and Their Modulation by Retinoic Acid in Ewing Sarcoma.

Retinoic acid (RA) regulates stemness and differentiation in human embryonic stem cells (ESCs). Ewing sarcoma (ES) is a pediatric tumor that may arise from the abnormal development of ESCs. Here we show that RA impairs the viability of SK-ES-1 ES cells and affects the cell cycle. Cells treated with RA showed increased levels of p21 and its encoding gene, CDKN1A. RA reduced mRNA and protein levels of SRY-box transcription factor 2 (SOX2) as well as mRNA levels of beta III Tubulin (TUBB3), whereas the levels of CD99 increased. Exposure to RA reduced the capability of SK-ES-1 to form tumorspheres with high expression of SOX2 and Nestin. Gene expression of CD99 and CDKN1A was reduced in ES tumors compared to non-tumoral tissue, whereas transcript levels of SOX2 were significantly higher in tumors. For NES and TUBB3, differences between tumors and control tissue did not reach statistical significance. Low expression of CD99 and NES, and high expression of SOX2, were significantly associated with a poorer patient prognosis indicated by shorter overall survival (OS). Our results indicate that RA may display rather complex modulatory effects on multiple target genes associated with the maintenance of stem cell's features versus their differentiation, cell cycle regulation, and patient prognosis in ES.

Targeting the epigenome of cancer stem cells in pediatric nervous system tumors.

Medulloblastoma, neuroblastoma, and pediatric glioma account for almost 30% of all cases of pediatric cancers. Recent evidence indicates that pediatric nervous system tumors originate from stem or progenitor cells and present a subpopulation of cells with highly tumorigenic and stem cell-like features. These cancer stem cells play a role in initiation, progression, and resistance to treatment of pediatric nervous system tumors. Histone modification, DNA methylation, chromatin remodeling, and microRNA regulation display a range of regulatory activities involved in cancer origin and progression, and cellular identity, especially those associated with stem cell features, such as self-renewal and pluripotent differentiation potential. Here, we review the contribution of different epigenetic mechanisms in pediatric nervous system tumor cancer stem cells. The choice between a differentiated and undifferentiated state can be modulated by alterations in the epigenome through the regulation of stemness genes such as CD133, SOX2, and BMI1 and the activation neuronal of differentiation markers, RBFOX3, GFAP, and S100B. Additionally, we highlighted the stage of development of epigenetic drugs and the clinical benefits and efficacy of epigenetic modulators in pediatric nervous system tumors.

Population Pharmacokinetic Model of Methotrexate in Brazilian Pediatric Patients with Acute Lymphoblastic Leukemia.

OBJECTIVES: Methotrexate (MTX) is subject to therapeutic drug monitoring because of its high pharmacokinetic variability and safety risk outside the therapeutic window. This study aimed to develop a population pharmacokinetic model (popPK) of MTX for Brazilian pediatric acute lymphoblastic leukemia (ALL) patients who attended the Hospital de Clínicas de Porto Alegre, Brazil. METHODS: The model was developed using NONMEM 7.4 (Icon®), ADVAN3 TRANS4, and FOCE-I. To explain inter-individual variability, we evaluated covariates from demographic, biochemical, and genetic data (single nucleotide polymorphisms [SNPs] related to the transport and metabolism of drugs). RESULTS: A two-compartment model was built using 483 data points from 45 patients (0.33-17.83 years of age) treated with MTX (0.25-5 g/m2) in different cycles. Serum creatinine (SCR), height (HT), blood urea nitrogen (BUN) and a low BMI stratification (according to the z-score defined by the World Health Organization [LowBMI]) were added as clearance covariates. The final model described MTX clearance as [Formula: see text]. In the two-compartment structural model, the central and peripheral compartment volumes were 26.8 L and 8.47 L, respectively, and the inter-compartmental clearance was 0.218 L/h. External validation of the model was performed through a visual predictive test and metrics using data from 15 other pediatric ALL patients. CONCLUSION: The first popPK model of MTX was developed for Brazilian pediatric ALL patients, which showed that inter-individual variability was explained by renal function and factors related to body size.

Histone Methyltransferases G9a/Ehmt2 and GLP/Ehmt1 Are Associated with Cell Viability and Poorer Prognosis in Neuroblastoma and Ewing Sarcoma.

Changes in epigenetic programming have been proposed as being key events in the initiation and progression of childhood cancers. HMT euchromatic histone lysine methyltransferase 2 (G9a, EHMT2), which is encoded by the G9a (Ehmt2) gene, as well as its related protein GLP, which is encoded by the GLP/Ehmt1 gene, participate in epigenetic regulation by contributing to a transcriptionally repressed chromatin state. G9a/GLP activation has been reported in several cancer types. Herein, we evaluated the role of G9a in two solid pediatric tumors: neuroblastoma (NB) and Ewing sarcoma (ES). Our results show that G9a/Ehmt2 and GLP/Ehmt1 expression is higher in tumors with poorer prognosis, including St4 International Neuroblastoma Staging System (INSS) stage, MYCN amplified NB, and metastatic ES. Importantly, higher G9a and GLP levels were associated with shorter patient overall survival (OS) in both NB and ES. Moreover, pharmacological inhibition of G9a/GLP reduced cell viability in NB and ES cells. These findings suggest that G9a and GLP are associated with more aggressive NB and ES tumors and should be further investigated as being epigenetic targets in pediatric solid cancers.

Risk factors associated with the development of oral mucositis in pediatric oncology patients: Systematic review and meta-analysis.

OBJECTIVES: Oral mucositis (OM) is an acute toxicity related to cancer treatment. This systematic review aimed to identify potential risk factors associated with the development of OM in pediatric cancer patients. METHODS: A search was performed in four electronic databases to identify studies that analyzed risk factors for OM in pediatric cancer patients. RESULTS: Nineteen articles were included. The incidence of OM ranged from 20% to 80.4%. Chemotherapeutic agents were potential risk factors for OM in eight (42%) studies. Hematological, hepatic, and renal parameters were also considered in eight (42%) studies, while specific individual factors were reported in five (26.3%) studies. Baseline disease, oral microbiota, genetic profile, and biomarkers were reported in four (21.5%) studies each. Meta-analysis showed that groups submitted to high-risk chemotherapy for OM had a 2.79-fold increased risk of OM. CONCLUSIONS: Identifying risk factors for OM is essential in order to allow individualized and early prevention treatment.

The effect of hospital care volume on overall survival of children with cancer in Southern Brazil.

PURPOSE: The purpose of this study was to analyze the effect of hospital care volume on the overall survival of children with cancer in Southern Brazil. PATIENTS AND METHODS: We performed a retrospective cohort study of 1378 cancer patients aged 0-19 years, diagnosed with cancer between August 1, 2009 and December 31, 2015 in Rio Grande do Sul, who received hospital treatment in institutions affiliated with the Universal Health Care System (Sistema Único de Saúde [SUS]). RESULTS: Most children and adolescents were male (56.9%) and White (75.8%). The most common types of cancer in our cohort were acute leukemia (40.7%), followed by lymphoma (15.9%) and central nervous system tumors (8.8%). Ninety-five percent of the patients were treated in specialized pediatric oncology centers. The cumulative probability of survival at 5 years for all patients was 73.8% (95% confidence interval [CI] 71.4-76.0%). Survival was significantly higher for patients younger than 4 years of age (P = .012) compared to all other age groups. Patients treated in institutions with a pediatric oncology patient volume of less than 15 patients/year were 41% more likely to die than patients treated in institutions with a volume of 60 patients/year or more (P = .029). CONCLUSION: Cancer is the leading cause of death by natural causes in all age groups in Brazil, but, even so, childhood tumors are rare. This complexity makes childhood cancer care a challenge. In this study, we reiterate that pediatric cancer patients demonstrate better overall survival when treated in high-volume hospitals.

Incidence and risk factors for oral mucositis in pediatric patients receiving chemotherapy.

PURPOSE: To investigate the incidence and risk factors for oral mucositis (OM) in patients with childhood cancer undergoing chemotherapy. METHODS: Eight hundred and twenty-nine cycles of chemotherapy were evaluated in 112 patients with childhood cancer undergoing chemotherapy. Chemotherapy protocol, hematological, hepatic, and renal function parameters were collected and compared to presence and severity of OM, as graded by the World Health Organization (WHO) scale. Patients received counseling on oral hygiene and those who presented with OM (grade ≥1) received photobiomodulation therapy (PBMT). RESULTS: Age ranged from 0 to 17 years (mean/SD, 8.58 ± 5.05) and fifty-one patients (45.54%) were females. The most common baseline diseases were leukemia (51%) followed by sarcomas (23%) and lymphomas (18%). Eight hundred and twenty-nine cycles of chemotherapy were evaluated, and OM was diagnosed in 527 cycles (63.57%). Higher incidence and severity of OM was observed in protocols using high-dose methotrexate (MTX-HD), MTX-HD cyclophosphamide/doxorubicin combination, and MTX-HD combined with cyclophosphamide (p <0.001). Patients with severe OM had lower levels of leukocytes (p = 0.003), hemoglobin (p = 0.005), platelets (p = 0.034), and higher levels of total bilirubin (p = 0.027), alanine aminotransferase (ALT) (p = 0.001), and creatinine (p = 0.007). CONCLUSION: The study contributes to the elucidation of the risk factors for OM in pediatric cancer patients. Chemotherapy protocols using MTX-HD, MTX-HD associated with doxorubicin and cyclophosphamide, and MTX-HD and cyclophosphamide a have higher incidence of severe grades of OM. Other toxicities such as hematological, hepatic, and renal also developed in patients with OM.

Assessing the Relationship between PTSS in Childhood Cancer Survivors and Their Caregivers and Their Quality of Life.

Childhood cancer is a traumatic experience for survivors and their families. The experience of this disease affects survivors' and families' quality of life, even years after it occurs. The purpose of the present study was to assess if the caregivers' posttraumatic stress symptoms mediated the associations between survivors' posttraumatic stress symptoms and caregivers' quality of life, in a sample of 46 dyads of caregivers and childhood cancer survivors. Survivors and caregivers completed the PCL-5, and caregivers completed the WHOQOL-bref. Results showed that survivors' and caregivers' posttraumatic stress symptoms scores and caregivers' quality of life were associated. The caregivers' posttraumatic stress symptoms mediated the relationship between survivors' posttraumatic stress symptoms and caregivers' quality of life. Knowing posttraumatic stress symptoms direct and indirect effects on caregivers' quality of life contributes to understand their experience and to develop intervention strategies with this population.

Oral mucositis in childhood cancer patients receiving high-dose methotrexate: Prevalence, relationship with other toxicities and methotrexate elimination.

BACKGROUND: Oral mucositis (OM) is one of the main adverse effects of the chemotherapeutic agent methotrexate (MTX). AIM: To evaluate the relationship of OM with MTX metabolism time and other toxicities in childhood, cancer patients receiving high-dose of methotrexate (HD-MTX). DESIGN: Seventy-seven childhood patients receiving HD-MTX for treatment of leukaemia, osteosarcoma or lymphoma were evaluated. MTX serum level, hepatic and renal function parameters, and presence and intensity of OM were analysed. RESULTS: The patients were submitted to 255 cycles of chemotherapy. OM was diagnosed in 191 (74.9%) cycles. Of these, 119 (46.6%) presented ulcerative lesions. Lymphoma was associated with severe OM (P = .01). OM was associated with higher serum levels of aspartate aminotransferase (P = .006), alanine aminotransferase (P = .04) and creatinine (P = .008). Increase of one unit of total bilirubin and indirect bilirubin associated, respectively, with 11% and 39% higher prevalence of OM. For each increase of one unit of creatinine serum level, it was observed a 37% higher prevalence of OM in patients with lymphoma. No association was found between delayed excretion of MTX and OM development. CONCLUSIONS: OM is a prevalent complication of childhood cancer patients receiving HD-MTX. Renal and hepatic toxicity could be considered risk factors for OM, especially in patients with lymphoma.

Activation of BDNF/TrkB/Akt pathway is associated with aggressiveness and unfavorable survival in oral squamous cell carcinoma.

OBJECTIVES: To evaluate the expression of brain-derived neurotrophic factor (BDNF), its tyrosine kinase receptor B (TrkB), and two downstream targets of this pathway, Akt and ribosomal protein S6 (RPS6), in normal oral mucosa (NOM), oral leukoplakia (OL), and oral squamous cell carcinoma (OSCC) and correlate this expression with OSCC patients' outcomes, cell senescence, and "stemness" profile. MATERIALS AND METHODS: Ten cases of NOM, 32 OL, and 72 primary OSCC were included. Immunohistochemical analysis for BDNF, TrkB, p-TrkB, p-Akt, and p-RPS6 was performed. Cell senescence and stemness profile of OSCC were evaluated through p16 and BMI-1 immunohistochemical expression, respectively. The slides were scanned into high-resolution images and quantified through digital analysis. RESULTS: Oral squamous cell carcinoma presented increased expression of BDNF/TrkB/Akt pathway compared to NOM and OL. OSCC diagnosed in advanced clinical stages presented an upregulation of BDNF and p-TrkB. BDNF and p-Akt were identified as predictors of poor disease-specific survival. The increase in stemness profile was correlated with a decrease in p-TrkB and p-Akt expression. CONCLUSIONS: BDNF/TrkB/Akt pathway is significantly increased in malignant cells from OSCC. Moreover, BDNF and Akt represent biomarkers capable to predict a poor prognosis of OSCC patients.

Epidermal Growth Factor Receptor Regulation of Ewing Sarcoma Cell Function.

OBJECTIVE: Ewing sarcoma (ES) is a type of childhood cancer probably arising from stem mesenchymal or neural crest cells. The epidermal growth factor receptor (EGFR) acts as a driver oncogene in many types of solid tumors. However, its involvement in ES remains poorly understood. METHODS: Human SK-ES-1 and RD-ES ES cells were treated with EGF, the EGFR inhibitor tyrphostin (AG1478), or phosphoinositide 3-kinase (PI3K) or extracellular-regulated kinase (ERK)/mitogen-activated kinase (MAPK) inhibitors. Cell proliferation survival, cycle, and senescence were analyzed. The protein content of possible targets of EGFR manipulation was measured by Western blot. RESULTS: Cell proliferation and survival were increased by EGF and inhibited by AG1478. The EGFR inhibitor also altered the cell cycle, inducing arrest in G1 and increasing the sub-G1 population, reduced polyploidy and increased the population of senescent cells. In addition, AG1478 reduced the levels of phosphorylated AKT (p-AKT), ERK, p-ERK, cyclin D1, and brain-derived neurotrophic factor (BDNF), while enhancing p53 levels. Cell proliferation was also impaired by inhibitors of PI3K or ERK, alone or combined with AG1478. CONCLUSIONS: Our findings reveal novel aspects of EGFR regulation of ES cells and provide early evidence for antitumor activities of EGFR inhibitors in ES.

Microbiological profile and nutritional quality of a regular diet compared to a neutropenic diet in a pediatric oncology unit.

It has been hypothesized that a neutropenic diet has lower microbe content. Here, the microbiological and nutritional contents of regular and neutropenic diets offered to pediatric patients were analyzed. Microbiological contamination was detected in five of 36 of the food samples analyzed, yet there was no statistical differences between the diets (P = 1.00) or in their odds ratio (0.62) (95% CI = 0.05-6.35; P = 0.63). The strict neutropenic diet did have less fiber (P = 0.05) and vitamin C (P = 0.01). Thus, the regular diet appears safe, and possibly provides greater benefits, for pediatric patients with neutropenia.

What is the impact of local control in Ewing sarcoma: analysis of the first Brazilian collaborative study group - EWING1.

BACKGROUND: Relapse in localized Ewing sarcoma patients has been a matter of concern regarding poor prognosis. Therefore, we investigated the impact of local control modality (surgery, surgery plus radiotherapy, and radiotherapy) on clinical outcomes such as survival and recurrence in patients with non-metastatic Ewing sarcoma treated on the first Brazilian Collaborative Group Trial of the Ewing Family of Tumors (EWING1). METHODS: Seventy-three patients with localized Ewing sarcoma of bone aged < 30 years were included. The treating physicians defined the modality of local control based on the recommendations of the coordinating center and the patient and tumor characteristics. Possible associations of local control modality with local failure (LF), disease-free survival (DFS), event-free survival (EFS), overall survival (OS), and clinical characteristics were analyzed. RESULTS: Mean patient age was 12.8 years (range, 2 to 25 years) and median follow-up time was 4.5 years (range, 2.3 to 6.7 years). Forty-seven patients underwent surgery, 13 received radiotherapy, and 13 received both. The 5-year EFS, OS, and DFS for all patients was 62.1%, 63.3%, and 73.1%, respectively. The 5-year cumulative incidence (CI) of LF was 7.6% for surgery, 11.1% for radiotherapy, and 0% for postoperative radiotherapy (PORT) (p = 0.61). The 5-year EFS was 71.7% for surgery, 30.8% for radiotherapy, and 64.1% for PORT (p = 0.009). CONCLUSIONS: There was a significant effect of local control modality on EFS and OS in the study. Surgery and PORT modalities yielded very close results. The group treated with radiotherapy alone had considerably worse outcomes. This may be confounded by greater risk factors in these patients. There was no significant effect of local control modality on the CI of LF and DFS.

New photobiomodulation protocol prevents oral mucositis in hematopoietic stem cell transplantation recipients-a retrospective study.

Oral mucositis (OM) is an adverse side effect among hematopoietic stem cell transplantation (HSCT) recipients. The objective of this retrospective study was to evaluate the preventive effect of photobiomodulation (PBM) applied three times per week versus seven times per week in patients undergoing HSCT. The risk factors related to the incidence and severity of OM were also assessed. This was a retrospective study that evaluated 99 HSCT recipients who received different PBM protocols. Group I received three sessions per week, and group II received daily treatment. PBM was applied using a continuous-wave diode laser (InGaAlP; MM Optics, São Carlos, SP, Brazil) at a wavelength of 660 nm (visible-red) and a total radiant energy of 0.24 J per point. The baseline disease, type of transplant, type of conditioning, prophylaxis against graft-versus-host disease, OM grade, absolute leukocyte and platelet counts, and levels of liver and renal function markers were collected from medical records. The patients' age ranged from 13 to 71 years (mean/SD, 40.54 ± 16.45). No significant difference was observed between groups I and II regarding sex, age, ethnic, diagnosis, donor type, and conditioning treatment. Both PBM protocols were equally efficient in preventing OM (p = 0.34, ANOVA). Independent of the PBM protocol used, patients who received allogeneic transplant (p < 0.01-Fischer's exact test), total body irradiation (TBI-12Gy) (p = 0.01-chi-square test), busulfan + cyclophosphamide (p < 0.01-chi-square test), or methotrexate-containing regimens (p < 0.01-Fischer's exact test) demonstrated higher OM incidence and severity. Myelosuppression (p < 0.01-Mann-Whitney test) and impaired renal function (p = 0.02-Mann-Whitney test) were also considered risk factors for OM. Based on this retrospective data, PBM was effective in preventing OM in patients undergoing HSCT even when it was applied three times a week. A prospective study might be necessary to confirm these findings.

Viability of D283 medulloblastoma cells treated with a histone deacetylase inhibitor combined with bombesin receptor antagonists.

PURPOSE: Medulloblastoma (MB) comprises four distinct molecular subgroups, and survival remains particularly poor in patients with Group 3 tumors. Mutations and copy number variations result in altered epigenetic regulation of gene expression in Group 3 MB. Histone deacetylase inhibitors (HDACi) reduce proliferation, promote cell death and neuronal differentiation, and increase sensitivity to radiation and chemotherapy in experimental MB. Bombesin receptor antagonists potentiate the antiproliferative effects of HDACi in lung cancer cells and show promise as experimental therapies for several human cancers. Here, we examined the viability of D283 cells, which belong to Group 3 MB, treated with an HDACi alone or combined with bombesin receptor antagonists. METHODS: D283 MB cells were treated with different doses of the HDACi sodium butyrate (NaB), the neuromedin B receptor (NMBR) antagonist BIM-23127, the gastrin releasing peptide receptor (GRPR) antagonist RC-3095, or combinations of NaB with each receptor antagonist. Cell viability was examined by cell counting. RESULTS: NaB alone or combined with receptor antagonists reduced cell viability at all doses tested. BIM-23127 alone did not affect cell viability, whereas RC-3095 at an intermediate dose significantly increased cell number. CONCLUSION: Although HDACi are promising agents to inhibit MB growth, the present results provide preliminary evidence that combining HDACi with bombesin receptor antagonists is not an effective strategy to improve the effects of HDACi against MB cells.

Carboplatin in the treatment of Ewing sarcoma: Results of the first Brazilian collaborative study group for Ewing sarcoma family tumors-EWING1.

BACKGROUND: Large cooperative group studies have shown the efficacy of risk-adapted treatment for Ewing sarcoma. However, validation and local adaptation by National cooperative groups is needed. A multicenter protocol to determine the efficacy and safety of a risk-adapted intensive regimen was developed by the Brazilian cooperative group. PROCEDURE: Patients <30 years old with Ewing sarcoma were eligible. Induction chemotherapy consisted of two cycles of ICE (ifosfamide, carboplatin, and etoposide) followed by two cycles of VDC (vincristine, doxorubicin, and cyclophosphamide), followed by local control. Patients with low risk (LR) disease (localized resectable with normal LDH) received 10 additional alternating courses of IE with VDC. For patients with high-risk (HR) disease (unresectable, pelvic, metastatic, or high LDH), two additional cycles of ICE were given. RESULTS: One-hundred seventy five patients (39% metastatic) were enrolled. Fifty-two patients (29.7%) were LR and 123 (70.3%) were HR. Overall response rate at end of induction was 27.4%. Five-year event-free survival (EFS) and overall survival (OS) estimates were 51.4% and 54.4%, respectively. Patients with localized disease had better outcomes than patients with metastases (5-year EFS 67.9% vs. 25.5%, and 5-year OS 70.3% vs. 29.1%, respectively). On multivariate analysis, the presence of metastatic disease was the only prognostic factor (P < 0.01). CONCLUSION: The VDC/ICE protocol was feasible, and considering the high tumor burden in our population, resulted in comparable results to those reported by cooperative groups in high-income countries. Further adaptation to maximize efficacy and minimize toxicity will be required.

Beyond Clinical Trials: Understanding Neurotrophic Tropomyosin Receptor Kinase Inhibitor Challenges and Efficacy in Real-World Pediatric Oncology.

PURPOSE: Our study aimed to explore real-world treatment scenarios for children and adolescents with neurotrophic tropomyosin receptor kinase (NTRK)-fused tumors, emphasizing access, responses, side effects, and outcomes. PATIENTS AND METHODS: Pooled clinical data from 17 pediatric cases (11 soft-tissue sarcomas, five brain tumors, and one neuroblastoma) treated with larotrectinib and radiologic images for 14 patients were centrally reviewed. Testing for gene fusions was prompted by poor response to treatment, tumor progression, or aggressiveness. RESULTS: Six different NTRK fusion subtypes were detected, and various payment sources for testing and medication were reported. Radiologic review revealed objective tumor responses (OR) in 11 of 14 patients: Complete responses: two; partial responses: nine; and stable disease: three cases. Grades 1 or 2 Common Terminology Criteria for Adverse Events adverse effects were reported in five patients. Regarding the entire cohort's clinical information, 15 of 17 patients remain alive (median observation time: 25 months): four with no evidence of disease and 11 alive with disease (10 without progression). One patient developed resistance to the NTRK inhibitor and died from disease progression while another patient died due to an unrelated cause. CONCLUSION: This real-world study confirms favorable agnostic tumor OR rates to larotrectinib in children with NTRK-fused tumors. Better coordination to facilitate access to medication remains a challenge, particularly in middle-income countries like Brazil.

The use of high-frequency audiometry increases the diagnosis of asymptomatic hearing loss in pediatric patients treated with cisplatin-based chemotherapy.

BACKGROUND: Cisplatin may cause permanent cochlear damage by changing cochlear frequency selectivity and can lead to irreversible sensorineural hearing loss. High-frequency audiometry (HFA) is able to assess hearing frequencies above 8,000 Hz; hence, it has been considered a high-quality method to monitor and diagnose early and asymptomatic signs of ototoxicity in patients receiving cisplatin. PROCEDURE: Forty-two pediatric patients were evaluated for hearing loss induced by cisplatin utilizing HFA, and its diagnostic efficacy was compared to that of standard pure-tone audiometry and distortion-product otoacoustic emissions (DPOAEs). The patient population consisted of those who signed an informed consent form and had received cisplatin chemotherapy between 1991 and 2008 at the Hospital de Clínicas de Porto Alegre Pediatric Unit, Brazil. RESULTS: Forty-two patients were evaluated. The median age at study assessment was 14.5 years (range 4-37 years). Hearing loss was detected in 24 patients (57%) at conventional frequencies. Alterations of DPOAEs were found in 64% of evaluated patients and hearing loss was observed in 36 patients (86%) when high-frequency test was added. The mean cisplatin dose was significantly higher (P = 0.046) for patients with hearing impairment at conventional frequencies. CONCLUSION: The results suggest that HFA is more effective than pure-tone audiometry and DPOAEs in detecting hearing loss, particularly at higher frequencies. It may be a useful tool for testing new otoprotective agents, beside serving as an early diagnostic method for detecting hearing impairment.

Cancer Stem Cells and Chemoresistance in Ewing Sarcoma.

Resistance to chemotherapy poses a major challenge for cancer treatment. Reactivating a stem cell program resembling that seen in embryonic development can lead cancer cells to acquire a stem-cell phenotype characterized by expression of stemness genes, pluripotency, high self-renewal ability, and tumor-initiating capability. These cancer stem cells (CSCs) are usually resistant to anticancer drugs and are likely involved in treatment failure in many cancer types. Ewing sarcoma (ES) is a pediatric cancer type typically resulting from a typical genetic alteration affecting bone or soft tissues. Despite advances in treatment, survival prognostic remains poor for patients with refractory or recurrent disease. Here, we review the increasing evidence indicating that ES tumors contain a CSC subpopulation expressing stem cell genes, including BM1, OCT3/4, NANOG, and SOX2, that plays a role in resistance to drug treatment, and current experimental strategies that successfully counteract chemoresistance mediated by CSCs in ES.

Illness perceptions in childhood cancer survivor and caregivers' dyads.

Surviving childhood cancer is a difficult experience for children and their caregivers, it can produce long-term emotional distress. Illness perceptions refer to the way people understand the different aspects related to illness from their individual and collective experiences. OBJECTIVE: to compare the illness perceptions of adolescent childhood cancer survivors and their caregivers and examine the relationship between illness perception of childhood cancer survivors, their caregivers, and sociodemographic, illness, and treatment variables. Forty-three survivor-caregiver dyads (the mean age of a survivor 17.05 years old; the mean age of caregivers 47.53 years old) participated in the study and answered the Brief Illness Perception Questionnaire (Brief IPQ) and Demographics data. RESULTS: Results showed significant differences in the illness perceptions of survivors and caregivers. Caregivers presented more negative cognitive perceptions than survivors (t = -6.701, p < 0.001), especially in the identity dimension (t = -4.327, p < 0.001), and more negative emotional perceptions than survivors (t = -4.132, p < 0.001), both in concern (t = -3.695, p < 0.001) and emotional representation (t = -3.466, p < 0.001). No significant correlations were found between survivors' and caregivers' illness perceptions and sociodemographic illness variables. CONCLUSION: These findings showed that even though dyads went through cancer together, survivors' and caregivers' perceptions of childhood cancer are different, indicating the need to better understand how children growing up with a chronic disease develop such illness perceptions and their experience.