Chromosome (cytogenetic) analysis is widely used for the detection of chromosome instability. When followed by G-banding and molecular techniques such as fluorescence in situ hybridization (FISH), this assay has the powerful ability to analyze individual cells for aberrations that involve gains or losses of portions of the genome and rearrangements involving one or more chromosomes. In humans, chromosome abnormalities occur in approximately 1 per 160 live births 1,2 , 60-80% of all miscarriages 3,4

Objective To conduct a scoping review on etiologic investigation of prelingual hearing loss among children <2 years of age in the era of universal newborn hearing screening (UNHS). Data Sources PubMed, Embase, PsycInfo, CINAHL, and Cochrane Library databases. Review Methods We searched for articles published from January 1, 1998, to February 19, 2020. We reviewed studies that (1) included children identified with either congenital or delayed-onset hearing loss before 2 years of age among cohorts who had undergone UNHS and (2) investigated ≥1 etiologies of hearing loss. We defined hearing loss as congenital when confirmed after UNHS failure and as delayed onset when diagnosed after ≥1 assessments with normal hearing. Results Among 2069 unique citations, 115 studies met criteria for full-text assessment, and 20 met our inclusion criteria. Six studies tested children diagnosed with hearing loss for genetic etiology, 9 for congenital cytomegalovirus (CMV) infection, and 5 for both. Among 1787 children with congenital hearing loss and etiologic investigation, 933 (52.2%) were tested for genetic mutations and 1021 (57.1%) for congenital CMV infection. The proportion of congenital hearing loss cases attributable to genetic etiology ranged between 7.7% and 83.3% and to congenital CMV infection between 0.0% and 32.0%. Conclusion Data are lacking on the identification and etiology of delayed-onset hearing loss in children <2 years of age in the UNHS era. The proportion of congenital hearing loss cases attributable to genetic etiologies and congenital CMV infection appears to vary widely.

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Advances in sequencing technologies and increased understanding of the contribution of genetics to congenital sensorineural hearing loss have led to vastly improved outcomes for patients and their families. Next-generation sequencing and diagnostic panels have become increasingly reliable and less expensive for clinical use. Despite these developments, the diagnosis of genetic sensorineural hearing loss still presents challenges for healthcare providers. Inherited sensorineural hearing loss has high levels of genetic heterogeneity and variable expressivity. Additionally, syndromic hearing loss (hearing loss and additional clinical abnormalities) should be distinguished from non-syndromic (hearing loss is the only clinical symptom). Although the diagnosis of genetic sensorineural hearing loss can be challenging, the patient’s family history and ethnicity may provide critical information, as certain genetic mutations are more common in specific ethnic populations. The early identification of the cause of deafness can benefit patients and their families by estimating recurrence risks for future family planning and offering the proper interventions to improve their quality of life. Collaboration between pediatricians, audiologists, otolaryngologists, geneticists, and other specialists are essential in the diagnosis and management of patients with hearing disorders. An early diagnosis is vital for proper management and care, as some clinical manifestations of syndromic sensorineural hearing loss are not apparent at birth and have a delayed age of onset. We present a case of Usher syndrome (congenital deafness and childhood-onset blindness) illustrating the challenges encountered in the diagnosis and management of children presenting with congenital genetic sensorineural hearing loss, along with helpful resources for clinicians and families.

Purpose: Pediatric cancer survivors often experience long-term adverse health conditions or late effects, including hearing loss, that are attributable to cancer therapy. Ototoxic late effects have been documented in patients with cancer treated with cisplatin-based chemotherapy and/or radiation. This study evaluated the late effects of methotrexate as compared to cisplatin and other cancer therapy agents on pediatric cancer survivors at the Children's Hospital of New Orleans in Louisiana (CHNOLA) and patients currently undergoing cancer treatment at Our Lady of the Lake (OLOL) Hospital in Baton Rouge, Louisiana. Method: A retrospective chart review was conducted of medical records from the CHNOLA Audiology Clinic and the Treatment After Cancer Late Effects clinic, which followed patients 2–19 years after cancer treatment completion and current patients with pediatric cancer at OLOL. This study identified pediatric cancer survivors between 2 and 24 years of age with treatment protocol information and audiological evaluations. Association studies were performed to calculate p values using an exact chi-square test. Results: More than 44% of late-effects patients had significant hearing loss; mild-to-profound hearing loss was observed in 37.5% of patients who received methotrexate treatment without cisplatin or irradiation. Eighty-three percent of the patients who received cisplatin had late-effect hearing loss. In patients currently receiving cancer treatment, 12% had significant hearing loss. Conclusions: The results from this study suggest that children who receive therapies not clinically established as ototoxic (i.e., methotrexate) may still be at a high risk of developing long-term hearing loss as a late effect. Due to the high incidence rate of hearing loss among patients with pediatric cancer, we recommend that audiologists be part of the late-effects care team. This study also demonstrates that patients with pediatric cancer treated with methotrexate should receive routine long-term auditory monitoring as part of their standard of care to detect and manage hearing loss early, minimizing adverse outcomes.

Many highly effective therapies used to treat cancer have been associated with irreversible development of detrimental neurological sequelae following the survival of childhood and adolescent cancer. While cancer treatment-induced late effects vary due to patient-related risk factors, cancer survivors who received chemotherapy or radiation may develop conductive or sensorineural hearing loss (SNHL). The purpose of this project is to determine which neuroinflammation-associated genes and biological pathways are affected by pediatric cancer treatments, and which treatment protocols are associated with increased ototoxicity. We hypothesize that cancer treatment causes abnormal gene expression of neuroinflammation and deafness-associated genes. The hypothesis will be tested with two specific aims. Aim I is to perform a retrospective review of diagnostic audiograms from pediatric cancer survivors enrolled in the Treatment After Cancer and Late Effects Center at Children’s Hospital New Orleans, Louisiana (CHNOLA). Aim II is to perform Nanostring neuroinflammation gene expression analysis followed by Ingenuity Pathway Analysis (IPA) of brain autopsy specimens from deceased pediatric patients who have previously undergone cancer treatment (Pathology Department, CHNOLA). Preliminary results revealed abnormal upregulation or downregulation of key genes, some of which are related to hearing loss and cochlear neuron degeneration when compared to age-matched controls (e.g., GJA1 and CASP3). The present study may provide information regarding which cancer treatment agents are ototoxic and reveal the candidate risk genes and pathways that contribute to auditory late effects. The long term goal of this project is to identify the needs of cancer survivors who are affected by treatment-induced hearing loss and provide them and their families with access to educational materials, medical resources, and social support to increase their health-related quality of life. Citation Format: Brittney T. Moore, Fern Tsien, Gabrielle Sheets, Ayesha Umrigar, Jordan Doss, Michael Norman, Matthew Stark, Pinki Prasad, Amanda Musso, Chindo Hicks, David Otohinoyi, Jovanny Zabaleta, Li Li. Ototoxicity of chemotherapy and radiation agents used in pediatric cancer treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3658.

Alveolar rhabdomyosarcoma (ARMS) is characterized by one of three translocation states: t(2;13) (q35;q14) producing PAX3-FOXO1, t(1;13) (p36;q14) producing PAX7-FOXO1, or translocation-negative. Tumors with t(2;13) are associated with greater disease severity and mortality than t(1;13) positive or translocation negative patients. Consistent with this fact, previous work concluded that a molecular analysis of RMS translocation status is essential for the accurate determination of prognosis and diagnosis. However, despite this knowledge, most diagnoses rely on histology and in some cases utilize fluorescence in situ hybridization (FISH) probes unable to differentiate between translocation products. Along these same lines, diagnostic RT-PCR analysis, which can differentiate translocation status, is unable to determine intratumoral translocation heterogeneity, making it difficult to determine if heterogeneity exists and whether correlations exist between this heterogeneity and patient outcomes. Using newly developed FISH probes, we demonstrate that intratumoral heterogeneity exists in ARMS tumors with respect to the presence or absence of the translocation product. We found between 3 and 98% of cells within individual tumor samples contained a translocation event with a significant inverse correlation (R 2 = 0.66, p = 0.001) between the extent of intratumoral translocation heterogeneity and failurefree survival of patients. Taken together, these results provide additional support for the inclusion of the molecular analysis of these tumors and expand on this idea to support determining the extent of intratumoral translocation heterogeneity in the diagnosis of ARMS to improve diagnostic and prognostic indicators for patients with these tumors.

The Southeast Partnership for Improving Research and Training in Cancer Health Disparities (SPIRIT-CHD) unites Louisiana State University Health Sciences Center (LSUHSC) and Moffitt Cancer Center (MCC) to advance translational research on cancer health disparities and to establish a Cancer Research Education Program (CREP). The CREP addresses a national priority to develop an educational training pipeline for one-on-one mentoring of undergraduates and medical students by a diverse group of LSUHSC and MCC faculty with unique expertise to conduct cancer health disparities research and outreach in underserved communities. The CREP supports 8-week internships providing: (1) hands-on summer research experiences; (2) a curriculum focusing on biobanking, precision medicine, and cancer health disparities; and (3) community outreach experiences in underserved communities. The curriculum includes web-based training modules, immersion experiences (e.g., biobank tour), professional development workshops, and learning activities (e.g., book and journal clubs). Data from the students' pre/post summative (impact/outcome) evaluations determine the acceptability and impact of these research and educational activities, students' knowledge, career aspirations, goal attainment, and their satisfaction based on nationally normed scales. Baseline and post-training data will be analyzed in August, at training completion, to assess program impact. Long-term yearly follow-up data will focus on the impact of CREP on student career trajectories. These data will help modify the CREP for years 2-4 of the SPIRIT-CHD. Seventy-five percent of the student participants in the first cohort were female. Students self-identified as Black/African American non-Hispanic (62.5%), White Hispanic (25%), and Asian non-Hispanic (12.5%). Student projects included genomic, immunologic, and cellular wet-lab research (analyzing proliferation of renal cell carcinoma, RNA sequencing and bioinformatics of Luminal B breast carcinomas, expression differences of polyamine enzymes in prostate cancer) and clinical studies (detection, prevention, and treatment of anal cancer in HIV-positive populations). Dry-lab projects focused on the analysis of Behavioral Risk Factor Surveillance System to assess policy-related trends in colorectal cancer screenings, studying the effectiveness of barbers as lay health educators for skin cancer prevention, and smoking cessation among Hispanics. CREP students also participated in cancer education outreach events to explain their projects to the communities at an elevated risk for certain types of cancer. This program has applicability to undergraduate and medical students nationwide on best practices for efficacious training in cancer health disparities, precision medicine, and biobanking. Ultimately, these efforts will enhance the diversity of the cancer research workforce, while contributing to the reduction of cancer health disparities. Citation Format: Fern Tsien, Paula Gregory, Gwendolyn Quinn, Vani N. Simmons, Z'Kera Sims, Megan E. Sutter, Ayesha Umrigar, Arnold H. Zea, Cathy Meade, Clement K. Gwede. The Cancer Research Education Program (CREP): Training the next generation of cancer health disparities researchers through the Southeast Partnership for Improving Research and Training in Cancer Health Disparities (SPIRIT-CHD) [abstract]. In: Proceedings of the Eleventh AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2018 Nov 2-5; New Orleans, LA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl):Abstract nr A065.