An unusual ionic cocrystal of ponatinib hydrochloride: characterization by single-crystal X-ray diffraction and ultra-high field NMR spectroscopy.

This study describes the discovery of a unique ionic cocrystal of the active pharmaceutical ingredient (API) ponatinib hydrochloride (pon·HCl), and characterization using single-crystal X-ray diffraction (SCXRD) and solid-state NMR (SSNMR) spectroscopy. Pon·HCl is a multicomponent crystal that features an unusual stoichiometry, with an asymmetric unit containing both monocations and dications of the ponatinib molecule, three water molecules, and three chloride ions. Structural features include (i) a charged imidazopyridazine moiety that forms a hydrogen bond between the ponatinib monocations and dications and (ii) a chloride ion that does not feature hydrogen bonds involving any organic moiety, instead being situated in a "square" arrangement with three water molecules. Multinuclear SSNMR, featuring high and ultra-high fields up to 35.2 T, provides the groundwork for structural interpretation of complex multicomponent crystals in the absence of diffraction data. A 13C CP/MAS spectrum confirms the presence of two crystallographically distinct ponatinib molecules, whereas 1D 1H and 2D 1H-1H DQ-SQ spectra identify and assign the unusually deshielded imidazopyridazine proton. 1D 35Cl spectra obtained at multiple fields confirm the presence of three distinct chloride ions, with density functional theory calculations providing key relationships between the SSNMR spectra and H⋯Cl- hydrogen bonding arrangements. A 2D 35Cl → 1H D-RINEPT spectrum confirms the spatial proximities between the chloride ions, water molecules, and amine moieties. This all suggests future application of multinuclear SSNMR at high and ultra-high fields to the study of complex API solid forms for which SCXRD data are unavailable, with potential application to heterogeneous mixtures or amorphous solid dispersions.

Carbon-13 chemical shift tensor measurements for nitrogen-dense compounds.

This paper reports the principal values of the 13 C chemical shift tensors for five nitrogen-dense compounds (i.e., cytosine, uracil, imidazole, guanidine hydrochloride, and aminoguanidine hydrochloride). Although these are all fundamentally important compounds, the majority do not have 13 C chemical shift tensors reported in the literature. The chemical shift tensors are obtained from 1 H→13 C cross-polarization magic-angle spinning (CP/MAS) experiments that were conducted at a high field of 18.8 T to suppress the effects of 14 N-13 C residual dipolar coupling. Quantum chemical calculations using density functional theory are used to obtain the 13 C magnetic shielding tensors for these compounds. The best agreement with experiment arises from calculations using the hybrid functional PBE0 or the double-hybrid functional PBE0-DH, along with the triple-zeta basis sets TZ2P or pc-3, respectively, and intermolecular effects modeled using large clusters of molecules with electrostatic embedding through the COSMO approach. These measurements are part of an ongoing effort to expand the catalog of accurate 13 C chemical shift tensor measurements, with the aim of creating a database that may be useful for benchmarking the accuracy of quantum chemical calculations, developing nuclear magnetic resonance (NMR) crystallography protocols, or aiding in applications involving machine learning or data mining. This work was conducted at the National High Magnetic Field Laboratory as part of a 2-week school for introducing undergraduate students to practical laboratory experience that will prepare them for scientific careers or postgraduate studies.

Oval and round window reinforcement surgery leads to improvements in sound tolerance and quality of life for hyperacusis patients.

PURPOSE: Hyperacusis is an audiological disorder in which patients become persistently sensitive and intolerant to everyday environmental sounds. For those patients that fail conservative options, a minimally invasive surgical procedure has been developed. MATERIALS & METHODS: Retrospective case series of 73 adult patients with hyperacusis who underwent oval and round window reinforcement surgery between 1/2017-6/2023. Small pieces of temporalis fascia were used to reinforce the round and oval windows. Patients were separated into two groups based on their preoperative speech Loudness Discomfort Level (LDL). Patients with a preoperative speech LDL ≤ 70 dB were placed in the "low LDL group" whereas patients with a preoperative speech LDL >70 dB were placed in the "high LDL group." Preoperative and one-week postoperative audiogram and speech LDLs were compared. Quality of life was assessed using the Glasgow Benefit Inventory (GBI) survey. RESULTS: 73 patients met inclusion criteria - 21 patients in the low LDL group and 52 in the high LDL group. Patients in the high LDL group significantly improved their LDLs by an average of 3.5 dB (P < 0.0001). 42 patients (80.8 %) in the high LDL group had improvement and would recommend the surgery for hyperacusis. Patients in the low LDL group significantly improved their LDL by an average of 12.9 dB (P = 0.032). Ten patients (47.6 %) from the low LDL group experienced improvement and would recommend hyperacusis surgery. CONCLUSION: Many patients with hyperacusis who undergo oval and round window reinforcement can receive significant improvement in sound tolerance and quality of life. Patients with a pre-op speech LDL > 70 dB have the greatest potential for improvement with surgery (80.8 %), probably because their hyperacusis was less severe. In the high LDL group(>70dB) the improvement in 1-10 scale went from 8.6 pre-op to 2.4 post op. In the low LDL group(<70dB) went from 9.2 pre-op to 6.8 post-op. These findings were consistent with the GBI results.

Nutraceuticals in Bulk and Dosage Forms: Analysis by 35Cl and 14N Solid-State NMR and DFT Calculations.

This study uses 35Cl and 14N solid-state NMR (SSNMR) spectroscopy and dispersion-corrected plane-wave density functional theory (DFT) calculations for the structural characterization of chloride salts of nutraceuticals in their bulk and dosage forms. For eight nutraceuticals, we measure the 35Cl EFG tensor parameters of the chloride ions and use plane-wave DFT calculations to elucidate relationships between NMR parameters and molecular-level structure, which provide rapid NMR crystallographic assessments of structural features. We employ both 35Cl direct excitation and 1H→35Cl cross-polarization methods to characterize a dosage form containing α-d-glucosamine HCl, observe possible impurity and/or adulterant phases, and quantify the weight percent of the active ingredient. To complement this, we also investigate 14N SSNMR spectroscopy and DFT calculations to characterize nitrogen atoms in the nutraceuticals. This includes a discussion of targeted acquisition experimental protocols (i.e., acquiring a select region of the overall pattern that features key discontinuities) that allow ultrawideline spectra to be acquired rapidly, even for unreceptive samples (i.e., those with long values of T1(14N), short values of T2eff(14N), or very broad patterns). It is hoped that these experimental and computational protocols will be useful for the characterization of various solid forms of nutraceuticals (i.e., salts, polymorphs, hydrates, solvates, cocrystals, amorphous solid dispersions, etc.), help detect impurity and counterfeit solid phases in dosage forms, and serve as a foundation for future NMR crystallographic studies of nutraceutical solid forms, including studies using ab initio crystal structure prediction algorithms.

Hydrates of active pharmaceutical ingredients: A 35Cl and 2H solid-state NMR and DFT study.

This study uses 35Cl and 2H solid-state NMR (SSNMR) spectroscopy and dispersion-corrected plane-wave density functional theory (DFT) calculations to characterize the molecular-level structures and dynamics of hydrates of active pharmaceutical ingredients (APIs). We use 35Cl SSNMR to measure the EFG tensors of the chloride ions to characterize hydrated forms of hydrochloride salts of APIs, along with two corresponding anhydrous forms. DFT calculations are used to refine the crystal structures of the APIs and determine relationships between the 35Cl EFG tensors and the spatial arrangements of proximate hydrogen bonds, which are particularly influenced by interactions with water molecules. We find that the relationship between 35Cl EFG tensors and local hydrogen bonding geometries is complex, but meaningful structure/property relationships can be garnered through use of DFT calculations. Specifically, for every case in which such a comparison could be made, we find that the hydrate has a smaller magnitude of CQ than the corresponding anhydrous form, indicating a chloride ion environment with a ground-state electron density of higher spherical symmetry in the former. Finally, variable-temperature 35Cl and 2H SSNMR experiments on a deuterium-exchanged sample of the API cimetidine hydrochloride monohydrate are used to monitor temperature-dependent influences on the spectra that may arise from motional influences on the 35Cl and 2H EFG tensors. From the 2H SSNMR spectra, we determine that the motions of water molecules are characterized by jump-like motions about their C2 rotational axes that occur on timescales that are unlikely to influence the 35Cl central-transition (+1/2 ↔︎ -1/2) powder patterns (this is confirmed by 35Cl SSNMR). Together, these methods show great promise for the future study of APIs in their bulk and dosage forms, especially variable hydrates in which crystallographic water content varies with external conditions such as humidity.

Dispersion-Corrected DFT Methods for Applications in Nuclear Magnetic Resonance Crystallography.

Nuclear electric field gradient (EFG) tensor parameters depend strongly on electronic structures, making their calculation from first principles an excellent metric for the prediction, refinement, and optimization of crystal structures. Here, we use plane-wave density functional theory (DFT) calculations of EFG tensors in organic solids to optimize the Grimme (D2) and Tkatchenko-Scheffler (TS) atomic-pairwise force field dispersion corrections. Refinements using these new force field correction methods result in better representations of true crystal structures, as gauged by calculations of 177 14N, 17O, and 35Cl EFG tensors from 95 materials. The most striking result is the degree by which calculations of 35Cl EFG tensors of chloride ions match with experiment, due to the ability of these new methods to properly locate the positions of hydrogen atoms participating in H···Cl- hydrogen bonds. These refined structures also feature atomic coordinates that are more similar to those of neutron diffraction structures than those obtained from calculations that do not employ the optimized force fields. Additionally, we assess the quality of these new energy-minimization protocols for the prediction of 15N magnetic shielding tensors and unit cell volumes, which complement the larger analysis using EFG tensors, since these quantities have different physical origins. It is hoped that these results will be useful in future nuclear magnetic resonance (NMR) crystallographic studies and will be of great interest to a wide variety of researchers, in fields including NMR spectroscopy, computational chemistry, crystallography, pharmaceutical sciences, and crystal engineering.

Chemical Shift Tensors of Cimetidine Form A Modeled with Density Functional Theory Calculations: Implications for NMR Crystallography.

The principal components of the 13C chemical shift tensors for the ten crystallographically distinct carbon atoms of the active pharmaceutical ingredient cimetidine Form A have been measured using the FIREMAT technique. Density functional theory (DFT) calculations of 13C and 15N magnetic shielding tensors are used to assign the 13C and 15N peaks. DFT calculations were performed on cimetidine and a training set of organic crystals using both plane-wave and cluster-based approaches. The former set of calculations allowed several structural refinement strategies to be employed, including calculations utilizing a dispersion-corrected force field that was parametrized using 13C and 15N magnetic shielding tensors. The latter set of calculations featured the use of resource-intensive hybrid-DFT methods for the calculation of magnetic shielding tensors. Calculations on structures refined using the new force-field correction result in improved values of 15N magnetic shielding tensors (as gauged by agreement with experimental chemical shift tensors), although little improvement is seen in the prediction of 13C shielding tensors. Calculations of 13C and 15N magnetic shielding tensors using hybrid functionals show better agreement with experimental values in comparison to those using GGA functionals, independent of the method of structural refinement; the shielding of carbon atoms bonded to nitrogen are especially improved using hybrid DFT methods.

High-resolution 13 C and 43 Ca solid-state NMR and computational studies of the ethylene glycol solvate of atorvastatin calcium.

We report 43 Ca and 13 C solid-state nuclear magnetic resonance (NMR) spectroscopic studies of the ethylene glycol solvate of atorvastatin calcium. The 13 C and 43 Ca chemical shift and 43 Ca quadrupolar coupling tensor parameters are reported. The results are interpreted in terms of the reported X-ray diffraction crystal structure of the solvate and are compared with the NMR parameters of atorvastatin calcium trihydrate, the active pharmaceutical ingredient in Lipitor®. Hartree-Fock and density functional theory calculations of the NMR parameters based on a cluster model derived from the optimized X-ray diffraction crystal structure of the ethylene glycol solvate of atorvastatin calcium are in reasonable agreement with the experimental 43 Ca and 13 C NMR measurables.

A new NMR crystallographic approach to reveal the calcium local structure of atorvastatin calcium.

We combine experimental and computational determination of 43Ca solid-state NMR parameters (chemical shift tensors, quadrupolar coupling tensors, and Euler angles) to constrain the structure of the local calcium-ligand coordination environment. A new 43Ca NMR crystallographic approach which includes an extensive survey of the Cambridge Structural Database and a new symmetry benchmark is developed to enhance the selectivity of structural screening. The application of this method to quadrupolar NMR crystallographic investigations is demonstrated by unearthing the calcium local structure of the active pharmaceutical ingredient atorvastatin calcium trihydrate, the active ingredient in Lipitor®, in the absence of diffraction data. This method has been tested by applying it to calcium acetate monohydrate which has a known structure.

Calculations of solid-state 43 Ca NMR parameters: A comparison of periodic and cluster approaches and an evaluation of DFT functionals.

We present a computational study of magnetic-shielding and quadrupolar-coupling tensors of 43 Ca sites in crystalline solids. A comparison between periodic and cluster-based approaches for modeling solid-state interactions demonstrates that cluster-based approaches are suitable for predicting 43 Ca NMR parameters. Several model chemistries, including Hartree-Fock theory and 17 DFT approximations (SVWN, CA-PZ, PBE, PBE0, PW91, B3PW91, rPBE, PBEsol, WC, PKZB, BMK, M06-L, M06, M06-2X, M06-HF, TPSS, and TPSSh), are evaluated for the prediction of 43 Ca NMR parameters. Convergence of NMR parameters with respect to basis sets of the form cc-pVXZ (X = D, T, Q) is also evaluated. All DFT methods lead to substantial, and frequently systematic, overestimations of experimental chemical shifts. Hartree-Fock calculations outperform all DFT methods for the prediction of 43 Ca chemical-shift tensors. © 2017 Wiley Periodicals, Inc.

Semi-empirical refinements of crystal structures using 17O quadrupolar-coupling tensors.

We demonstrate a modification of Grimme's two-parameter empirical dispersion force field (referred to as the PW91-D2* method), in which the damping function has been optimized to yield geometries that result in predictions of the principal values of 17O quadrupolar-coupling tensors that are systematically in close agreement with experiment. The predictions of 17O quadrupolar-coupling tensors using PW91-D2*-refined structures yield a root-mean-square deviation (RMSD) (0.28 MHz) for twenty-two crystalline systems that is smaller than the RMSD for predictions based on X-ray diffraction structures (0.58 MHz) or on structures refined with PW91 (0.53 MHz). In addition, 13C, 15N, and 17O chemical-shift tensors and 35Cl quadrupolar-coupling tensors determined with PW91-D2*-refined structures are compared to the experiment. Errors in the prediction of chemical-shift tensors and quadrupolar-coupling tensors are, in these cases, substantially lowered, as compared to predictions based on PW91-refined structures. With this PW91-D2*-based method, analysis of 42 17O chemical-shift-tensor principal components gives a RMSD of only 18.3 ppm, whereas calculations on unrefined X-ray structures give a RMSD of 39.6 ppm and calculations of PW91-refined structures give an RMSD of 24.3 ppm. A similar analysis of 35Cl quadrupolar-coupling tensor principal components gives a RMSD of 1.45 MHz for the unrefined X-ray structures, 1.62 MHz for PW91-refined structures, and 0.59 MHz for the PW91-D2*-refined structures.

Knowledge of HPV-Related Oropharyngeal Cancer and Use of Human Papillomavirus Vaccines by Pediatricians in Louisiana.

OBJECTIVES: To determine the level of knowledge of HPV related oropharyngeal cancer and practice patterns of HPV vaccine use by pediatricians. STUDY DESIGN, SUBJECTS, METHODS: IRB approved 18-question survey was administered to members of the Louisiana Chapter of the American Academy of Pediatrics. RESULTS: We received 116 responses (response rate: 15.9 percent );. 104 respondents (89.66 percent ); routinely recommend/offer HPV vaccine, 6 (5.17 percent ); occasionally or only at caregiver request, and 6 (5.17 percent ); do not offer the vaccine. 17 (15.5 percent ); reported having no awareness of the link between oropharyngeal cancer and HPV, and only 50 (45.9 percent ); had knowledge that HPV-related oropharyngeal cancer incidence was increasing. Strength of recommendation for males and knowledge of HPV-related oropharyngeal cancer were not associated with years in practice, practice type or patient population served. CONCLUSIONS: Increased awareness regarding HPV-related oropharyngeal cancers among primary care providers may increase HPV immunization rates, especially in males.

Analysis of the bond-valence method for calculating (29) Si and (31) P magnetic shielding in covalent network solids.

(29) Si and (31) P magnetic-shielding tensors in covalent network solids have been evaluated using periodic and cluster-based calculations. The cluster-based computational methodology employs pseudoatoms to reduce the net charge (resulting from missing co-ordination on the terminal atoms) through valence modification of terminal atoms using bond-valence theory (VMTA/BV). The magnetic-shielding tensors computed with the VMTA/BV method are compared to magnetic-shielding tensors determined with the periodic GIPAW approach. The cluster-based all-electron calculations agree with experiment better than the GIPAW calculations, particularly for predicting absolute magnetic shielding and for predicting chemical shifts. The performance of the DFT functionals CA-PZ, PW91, PBE, rPBE, PBEsol, WC, and PBE0 are assessed for the prediction of (29) Si and (31) P magnetic-shielding constants. Calculations using the hybrid functional PBE0, in combination with the VMTA/BV approach, result in excellent agreement with experiment. © 2016 Wiley Periodicals, Inc.

Spin-orbit effects on the (119)Sn magnetic-shielding tensor in solids: a ZORA/DFT investigation.

Periodic-boundary and cluster calculations of the magnetic-shielding tensors of (119)Sn sites in various co-ordination and stereochemical environments are reported. The results indicate a significant difference between the predicted NMR chemical shifts for tin(ii) sites that exhibit stereochemically-active lone pairs and tin(iv) sites that do not have stereochemically-active lone pairs. The predicted magnetic shieldings determined either with the cluster model treated with the ZORA/Scalar Hamiltonian or with the GIPAW formalism are dependent on the oxidation state and the co-ordination geometry of the tin atom. The inclusion of relativistic effects at the spin-orbit level removes systematic differences in computed magnetic-shielding parameters between tin sites of differing stereochemistries, and brings computed NMR shielding parameters into significant agreement with experimentally-determined chemical-shift principal values. Slight improvement in agreement with experiment is noted in calculations using hybrid exchange-correlation functionals.

Carbon-13 chemical-shift tensors in indigo: A two-dimensional NMR-ROCSA and DFT Study.

The principal components of the (13)C NMR chemical-shift tensors for the eight unique carbon sites of crystalline indigo have been measured using the ROCSA pulse sequence. The chemical shifts have been assigned unambiguously to their respective nuclear sites through comparison of the experimental data to the results of density-functional calculations employing a refined X-ray diffraction structure. These measurements expand the database of measured aromatic (13)C chemical-shift tensors to the indole ring. Magnetic shielding calculations for hypoxanthine and adenosine are also reported. Comparisons of calculations that include the effect of the crystalline lattice with calculations that model indigo as an isolated molecule give an estimate of the intermolecular contribution to the magnetic shielding.

Density functional investigation of intermolecular effects on 13C NMR chemical-shielding tensors modeled with molecular clusters.

A quantum-chemical method for modeling solid-state nuclear magnetic resonance chemical-shift tensors by calculations on large symmetry-adapted clusters of molecules is demonstrated. Four hundred sixty five principal components of the (13)C chemical-shielding tensors of 24 organic materials are analyzed. The comparison of calculations on isolated molecules with molecules in clusters demonstrates that intermolecular effects can be successfully modeled using a cluster that represents a local portion of the lattice structure, without the need to use periodic-boundary conditions (PBCs). The accuracy of calculations which model the solid state using a cluster rivals the accuracy of calculations which model the solid state using PBCs, provided the cluster preserves the symmetry properties of the crystalline space group. The size and symmetry conditions that the model cluster must satisfy to obtain significant agreement with experimental chemical-shift values are discussed. The symmetry constraints described in the paper provide a systematic approach for incorporating intermolecular effects into chemical-shielding calculations performed at a level of theory that is more advanced than the generalized gradient approximation. Specifically, NMR parameters are calculated using the hybrid exchange-correlation functional B3PW91, which is not available in periodic codes. Calculations on structures of four molecules refined with density plane waves yield chemical-shielding values that are essentially in agreement with calculations on clusters where only the hydrogen sites are optimized and are used to provide insight into the inherent sensitivity of chemical shielding to lattice structure, including the role of rovibrational effects.

Structure and bonding in rhodium coordination compounds: a 103Rh solid-state NMR and relativistic DFT study.

This study demonstrates the application of 103Rh solid-state NMR (SSNMR) spectroscopy to inorganic and organometallic coordination compounds, in combination with relativistic density functional theory (DFT) calculations of 103Rh chemical shift tensors and their analysis with natural bond orbital (NBO) and natural localized molecular orbital (NLMO) protocols, to develop correlations between 103Rh chemical shift tensors, molecular structure, and Rh-ligand bonding. 103Rh is one of the least receptive NMR nuclides, and consequently, there are very few reports in the literature. We introduce robust 103Rh SSNMR protocols for stationary samples, which use the broadband adiabatic inversion-cross polarization (BRAIN-CP) pulse sequence and wideband uniform-rate smooth-truncation (WURST) pulses for excitation, refocusing, and polarization transfer, and demonstrate the acquisition of 103Rh SSNMR spectra of unprecedented signal-to-noise and uniformity. The 103Rh chemical shift tensors determined from these spectra are complemented by NBO/NLMO analyses of contributions of individual orbitals to the 103Rh magnetic shielding tensors to understand their relationship to structure and bonding. Finally, we discuss the potential for these experimental and theoretical protocols for investigating a wide range of materials containing the platinum group elements.

Hearing Rehabilitation in Vestibular Schwannoma.

The most common complaint among patients with vestibular schwannoma (VS) is hearing loss. This significantly affects the quality of life before, during, and after treatment for patients with VS. Untreated hearing loss in VS patients may even lead to depression and feelings of social isolation. A variety of devices are available for hearing rehabilitation for patients with vestibular schwannoma. These include contralateral routing of hearing signals (CROSs), bone-anchored hearing devices, auditory brainstem implants (ABI), and cochlear implants. In the United States, ABI is approved for patients 12 years of age and older with neurofibromatosis type 2. In the past few years, cochlear implantation has been offered simultaneously or sequentially with tumor resection or irradiation, or even to patients whose VS have been monitored with serial imaging. However, determining the functional integrity of the auditory nerve in patients with vestibular schwannoma is a challenge. This review article consists of (1) the pathophysiology of vestibular schwannoma (VS), (2) hearing loss in VS, (3) treatment of VS and associated hearing loss, (4) options for auditory rehabilitation in patients with VS with their individual benefits and limitations, and (5) challenges in hearing rehabilitation in this cohort of patients to determine auditory nerve functionality. (6) Future directions.

Helping Patients Understand Their Dizziness: Assessment of a Three-Dimensional Printed Vestibular Model.

To assess the improvement in patient understanding with use of a three-dimensional printed vestibular model as a teaching tool and to evaluate the effects of educational approach on dizziness-related disabilities. Single center randomized controlled trial set in the Otolaryngology ambulatory care clinic located at a tertiary care, teaching institution in Shreveport, Louisiana. Patients with a current or suspected diagnosis of benign paroxysmal positional vertigo who met inclusion criteria were randomized to either the three-dimensional model group or the control group. Each group received the same education session about dizziness, with the three-dimensional model being used as a visual aid in the experimental group. The control group received only verbal education. Outcome measures included patient understanding of benign paroxysmal positional vertigo etiology, comfort level with symptom prevention, anxiety related to vertigo symptoms, and how likely the patient was to recommend the teaching session to another individual suffering from vertigo. Pre-session and post-session surveys were administered to all patients to assess outcome measures. Eight patients were enrolled in the experimental group, and eight patients were enrolled in the control group. On post-survey data, the experimental group reported increased understanding of symptom etiology (p = 0.0289), increased comfort level with preventing symptoms (p = 0.2999), a larger decrease in symptom related anxiety (p = 0.0453) and were more likely to recommend the education session (p = 0.2807) compared to the control group. Three-dimensional printed vestibular model demonstrates promise for patient education and reducing related anxiety. Supplementary Information: The online version contains supplementary material available at 10.1007/s12070-022-03325-5.

Ototoxicity Review: A Growing Number of Non-Platinum-Based Chemo- and Immunotherapies.

OBJECTIVE: To raise awareness of the growing list of non-platinum-based chemo- and immunotherapeutic agents that have been associated with ototoxicity and to introduce the possible mechanism of ototoxicity of these agents. DATA SOURCES: PubMed, Embase, and Web of Science. REVIEW METHODS: A systematic review was performed following the PRISMA guidelines (Preferred Reporting Items for Systematic Reviews and Meta-analyses). PubMed, Embase, and Web of Science databases were searched for published reports of ototoxicity from non-platinum-based chemo- and immunotherapeutic agents in adult and pediatric patients. Therapies that utilized any platinum-based agent were excluded. CONCLUSIONS: Ototoxicity from non-platinum-based chemo- and immunotherapies is an evolving problem. There were 54 reports-39 case reports and 15 cohort studies-documenting ototoxicity from 7 agents/combination therapies. Of these reports, 37 (69%) were published within the last 15 years (after 2005). No recovery of hearing was documented in 21 of 56 cases (38%). Pretreatment audiograms were uncommon (19/54 studies, 35%), despite documented ototoxic associations. IMPLICATIONS FOR PRACTICE: There is a growing number of novel, ototoxic, non-platinum-based chemo- and immunotherapeutic agents with various potential mechanisms of action. Otolaryngologists will need to prioritize awareness of these agents. This growing list of agents, many of which have reversible effects, suggest a need for standardized ototoxicity monitor protocols so that appropriate and timely management options can be implemented.