A Phase 1B open-label study of gedatolisib (PF-05212384) in combination with other anti-tumour agents for patients with advanced solid tumours and triple-negative breast cancer.

BACKGROUND: This Phase 1b study (B2151002) evaluated the PI3K/mTOR inhibitor gedatolisib (PF-05212384) in combination with other anti-tumour agents in advanced solid tumours. METHODS: Patients with various malignancies were administered gedatolisib (90‒310 mg intravenously every week [QW]) plus docetaxel (arm A) or cisplatin (arm B) (each 75 mg/m2 intravenously Q3W) or dacomitinib (30 or 45 mg/day orally). The safety and tolerability of combination therapies were assessed during dose escalation; objective response (OR) and safety were assessed during dose expansion. RESULTS: Of 110 patients enrolled, 107 received gedatolisib combination treatment. Seven of 70 (10.0%) evaluable patients had dose-limiting toxicities; the most common was grade 3 oral mucositis (n = 3). Based upon reprioritisation of the sponsor's portfolio, dose expansion focused on arm B, gedatolisib (180 mg QW) plus cisplatin in patients (N = 22) with triple-negative breast cancer (TNBC). OR (95% CI) was achieved in four of ten patients in first-line (overall response rate 40.0% [12.2-73.8%]) and four of 12 in second/third-line (33.3% [9.9-65.1%]) settings. One patient in each TNBC arm (10%, first-line; 8.3%, second/third-line) achieved a complete response. CONCLUSIONS: Gedatolisib combination therapy showed an acceptable tolerability profile, with clinical activity at the recommended Phase 2 dose in patients with TNBC. CLINICAL TRIAL: ClinicalTrial.gov: NCT01920061.

Adrenergic CaV1.2 Activation via Rad Phosphorylation Converges at α1C I-II Loop.

RATIONALE: Changing activity of cardiac CaV1.2 channels under basal conditions, during sympathetic activation, and in heart failure is a major determinant of cardiac physiology and pathophysiology. Although cardiac CaV1.2 channels are prominently upregulated via activation of PKA (protein kinase A), essential molecular details remained stubbornly enigmatic. OBJECTIVE: The primary goal of this study was to determine how various factors converging at the CaV1.2 I-II loop interact to regulate channel activity under basal conditions, during ß-adrenergic stimulation, and in heart failure. METHODS AND RESULTS: We generated transgenic mice with expression of CaV1.2 α1C subunits with (1) mutations ablating interaction between α1C and ß-subunits, (2) flexibility-inducing polyglycine substitutions in the I-II loop (GGG-α1C), or (3) introduction of the alternatively spliced 25-amino acid exon 9* mimicking a splice variant of α1C upregulated in the hypertrophied heart. Introducing 3 glycine residues that disrupt a rigid IS6-α-interaction domain helix markedly reduced basal open probability despite intact binding of CaVß to α1C I-II loop and eliminated ß-adrenergic agonist stimulation of CaV1.2 current. In contrast, introduction of the exon 9* splice variant in the α1C I-II loop, which is increased in ventricles of patients with end-stage heart failure, increased basal open probability but did not attenuate stimulatory response to ß-adrenergic agonists when reconstituted heterologously with ß2B and Rad or transgenically expressed in cardiomyocytes. CONCLUSIONS: Ca2+ channel activity is dynamically modulated under basal conditions, during ß-adrenergic stimulation, and in heart failure by mechanisms converging at the α1C I-II loop. CaVß binding to α1C stabilizes an increased channel open probability gating mode by a mechanism that requires an intact rigid linker between the ß-subunit binding site in the I-II loop and the channel pore. Release of Rad-mediated inhibition of Ca2+ channel activity by ß-adrenergic agonists/PKA also requires this rigid linker and ß-binding to α1C.

Characterization of otologic symptoms appearing after COVID-19 vaccination.

OBJECTIVES: Anecdotal reports of sudden sensorineural hearing loss (SSNHL) following COVID-19 vaccination have emerged in the otolaryngology community. Studies have demonstrated no association between COVID-19 vaccination and SSNHL. We aim to characterize the spectrum of otologic symptoms following COVID-19 vaccination. METHODS: A cross-sectional study of patients seen in the otology clinic at an academic center was performed. Patients completed a questionnaire on the development of new otologic symptoms within 4 weeks of COVID-19 vaccination. Diagnostic and audiometric data was collected retrospectively for patients reporting otologic symptoms. RESULTS: Between May and July 2021, 500 patients were screened. Median age was 56.6 years old, with 59.4 % female and 40.2 % male. 420 patients (84.0 %) were vaccinated, with 58.4 % receiving Pfizer, 29.1 % receiving Moderna, and 3.8 % receiving Johnson & Johnson. 61 patients (14.5 %) reported one or more otologic symptoms within 4 weeks of vaccination, including 21 (5.0 %) with hearing loss, 26 (6.2 %) with tinnitus, 33 (7.9 %) with dizziness, and 19 (4.5 %) with vertigo. Of the 16 patients (3.2 %) reporting tinnitus with no associated hearing loss, 8 were diagnosed with subjective tinnitus and 4 were diagnosed with temporomandibular joint syndrome. Of the 18 patients reporting hearing loss, 11 had exacerbations of underlying pathologies (e.g. Meniere's disease, presbycusis) and 7 were newly diagnosed with SSNHL (1.4 %). CONCLUSIONS: Patients reporting otologic symptoms following COVID-19 vaccination received various diagnoses of uncertain etiology. The incidence of SSNHL in these patients is comparable to the general otology patient population. Additional studies are required to determine the incidence of specific diagnoses following vaccination.

Induction Chemotherapy Plus Neoadjuvant Chemoradiation for Esophageal and Gastroesophageal Junction Adenocarcinoma.

BACKGROUND: Neoadjuvant chemotherapy with concurrent radiotherapy (nCRT) is an accepted treatment regimen for patients with potentially curable esophageal and gastroesophageal junction (GEJ) adenocarcinoma. The purpose of this study is to evaluate whether induction chemotherapy (IC) before nCRT is associated with improved pathologic complete response (pCR) and overall survival (OS) when compared with patients who received nCRT alone for esophageal and GEJ adenocarcinoma. METHODS: Using the National Cancer Database (NCDB), patients who received nCRT and curative-intent esophagectomy for esophageal or GEJ adenocarcinoma from 2006 to 2015 were included. Chemotherapy and radiation therapy start dates were used to define cohorts who received IC before nCRT (IC + nCRT) versus those who only received concurrent nCRT before surgery. Propensity weighting was conducted to balance patient, disease, and facility covariates between groups. RESULTS: 12,460 patients met inclusion criteria, of whom 11,880 (95%) received nCRT and 580 (5%) received IC + nCRT. Following propensity weighting, OS was significantly improved among patients who received IC + nCRT versus nCRT (HR 0.82; 95% CI 0.74-0.92; p < 0.001) with median OS for the IC + nCRT cohort of 3.38 years versus 2.45 years for nCRT. For patients diagnosed from 2013 to 2015, IC + nCRT was also associated with higher odds of pCR compared with nCRT (OR 1.59; 95% CI 1.14-2.21; p = 0.007). CONCLUSION: IC + nCRT was associated with a significant OS benefit as well as higher pCR rate in the more modern patient cohort. These results merit consideration of a sufficiently powered prospective multiinstitutional trial to further evaluate these observed differences.

A bidirectional relationship between sleep and oxidative stress in Drosophila.

Although sleep appears to be broadly conserved in animals, the physiological functions of sleep remain unclear. In this study, we sought to identify a physiological defect common to a diverse group of short-sleeping Drosophila mutants, which might provide insight into the function and regulation of sleep. We found that these short-sleeping mutants share a common phenotype of sensitivity to acute oxidative stress, exhibiting shorter survival times than controls. We further showed that increasing sleep in wild-type flies using genetic or pharmacological approaches increases survival after oxidative challenge. Moreover, reducing oxidative stress in the neurons of wild-type flies by overexpression of antioxidant genes reduces the amount of sleep. Together, these results support the hypothesis that a key function of sleep is to defend against oxidative stress and also point to a reciprocal role for reactive oxygen species (ROS) in neurons in the regulation of sleep.

Phase II Multicenter, Open-Label Study of Oral ENMD-2076 for the Treatment of Patients with Advanced Fibrolamellar Carcinoma.

LESSONS LEARNED: The fibrolamellar carcinoma-associated DNAJB1-PRKACA gene fusion transcript RNA codes for the catalytic domain of protein kinase A and, thus, overexpression of Aurora kinase A. ENMD-2076 showed a favorable toxicity profile. The limited results, one patient (3%) with a partial response and 57% of patients with stable disease, do not support further evaluation of ENMD-2076 as single agent. Future studies will depend on the simultaneous targeting approach of DNAJB1-PRKACA and the critical downstream components. BACKGROUND: Fibrolamellar carcinoma (FLC) represents approximately 0.85% of liver cancers. The associated DNAJB1-PRKACA gene fusion transcript RNA codes for the catalytic domain of protein kinase A and overexpression of Aurora kinase A (AURKA). ENMD-2076 is a selective anti-AURKA inhibitor. METHODS: Patients aged >12 years with pathologically confirmed incurable FLC, with measurable disease, Eastern Cooperative Oncology Group performance status 0-2 or Lansky 70-100, and adequate organ function were eligible. Patients were prescribed ENMD-2076 based on body surface area. The primary endpoint was overall objective response rate by RECIST v1.1, with a null hypothesis of true response rate of 2% versus one-sided alternative of 15%. Secondary endpoints included 6-month progression-free survival (PFS) rate (Fig. 1), median PFS, time to progression (TTP), and overall survival (OS). Safety was evaluated throughout the study. RESULTS: Of 35 patients who enrolled and received treatment, 1 (3%) had a partial response (PR) and 20 (57%) had stable disease (SD). Median TTP, PFS, and OS were 5, 3.9, and 19 months, respectively. The most frequently reported drug-related serious adverse event was hypertension in three patients. Three deaths were reported on-study-two due to disease progression and one due to pulmonary embolism not related to ENMD-2076. CONCLUSION: The study provided no rationale for further studying ENMD-2076 as a single agent in FLC.

Esophageal and Esophagogastric Junction Cancers, Version 2.2019, NCCN Clinical Practice Guidelines in Oncology.

Esophageal cancer is the sixth leading cause of cancer-related deaths worldwide. Squamous cell carcinoma is the most common histology in Eastern Europe and Asia, and adenocarcinoma is most common in North America and Western Europe. Surgery is a major component of treatment of locally advanced resectable esophageal and esophagogastric junction (EGJ) cancer, and randomized trials have shown that the addition of preoperative chemoradiation or perioperative chemotherapy to surgery significantly improves survival. Targeted therapies including trastuzumab, ramucirumab, and pembrolizumab have produced encouraging results in the treatment of patients with advanced or metastatic disease. Multidisciplinary team management is essential for all patients with esophageal and EGJ cancers. This selection from the NCCN Guidelines for Esophageal and Esophagogastric Junction Cancers focuses on recommendations for the management of locally advanced and metastatic adenocarcinoma of the esophagus and EGJ.

Pilot Prehabilitation Program for Patients With Esophageal Cancer During Neoadjuvant Therapy and Surgery.

BACKGROUND: Locally advanced esophageal cancer is often treated with neoadjuvant therapy followed by surgery. Many patients present with or experience clinical deconditioning during neoadjuvant therapy. Prehabilitation programs in other areas of surgery have demonstrated improved postoperative outcomes. The aims of this study were to evaluate the feasibility of a pilot prehabilitation program and determine preliminary effects on surgical and cancer-related outcomes. METHODS: A retrospective review of patients treated at a single institution with resectable esophageal cancer was performed (n = 22). Patients in the prehabilitation group received protocol-structured intervention in several clinical domains including nutrition, psychosocial support, and physical exercise. RESULTS: Clinical stage and comorbidities were well matched between groups. The structured prehabilitation program was feasible and well received by participants. Fewer patients required admission during neoadjuvant therapy in the prehabilitation group (27.3% versus 54.5%). Percentage weight loss during treatment was 3.0% in the prehabilitation group versus 4.3% in the control group. Compared with the control group, the prehabilitation group demonstrated 0.0% versus 18.2% 30-d postoperative readmission rate and 18.2% versus 27.3% 90-d postoperative readmission rate. There were no statistically significant differences between groups in regard to complications or mortality. CONCLUSIONS: The pilot prehabilitation program demonstrated feasibility of implementing a structured program for patients receiving neoadjuvant therapy for esophageal cancer. Although the small population limits evaluation of statistical significance, trends in the data suggest a potential benefit of the prehabilitation program on neoadjuvant hospital admission rates, postsurgical readmission rates, and nutritional status.

A Phase I Dose-Escalation Study of Linsitinib (OSI-906), a Small-Molecule Dual Insulin-Like Growth Factor-1 Receptor/Insulin Receptor Kinase Inhibitor, in Combination with Irinotecan in Patients with Advanced Cancer.

LESSONS LEARNED: The maximum tolerated dose of the combination of linsitinib and irinotecan is linsitinib 450 mg daily on days 1-3 every 7 days and irinotecan 125 mg/m2 days 1 and 8 of a 21-day cycle.The adverse effects associated with the combination are not significantly increased beyond what is expected of each drug as a single agent.Multiple negative trials of insulin-like growth factor-1 receptor inhibitors performed in unselected patient populations led to the early discontinuation of linistinib development and this trial.Earlier integration of assessment of potential predictive biomarkers into clinical trials, as was planned in this study, is vital to the development of targeted therapies in oncology. BACKGROUND: This phase I dose-escalation study was designed to evaluate the safety and tolerability of the combination of irinotecan and insulin-like growth factor-1 receptor (IGF-1R) inhibitor linsitinib in patients with advanced cancer refractory to standard therapy. METHODS: Dose escalation in three specified dose levels was performed according to a standard 3 + 3 design. Dose levels were as follows: (a) linsitinib 400 mg and irinotecan 100 mg/m2, (b) linsitinib 450 mg and irinotecan 100 mg/m2, and (c) linsitinib 450 mg and irinotecan 125 mg/m2. Linisitinib was administered once daily on days 1-3, 8-10, and 15-17, and irinotecan on days 1 and 8. Assessment of a candidate predictive biomarker was planned in all patients, with further evaluation in an expansion cohort of advanced colorectal cancer. RESULTS: A total of 17 patients were treated, with 1 patient in both cohort 2 and 3 experiencing dose-limiting toxicity. Linsitinib 450 mg and irinotecan 125 mg/m2 was the maximum tolerated dose. Sixteen (94%) patients experienced at least one treatment-related adverse event. Neutropenia was the only grade >3 toxicity (4%). No significant hyperglycemia or QT interval prolongation was noted. No objective responses were observed; 47% (n = 8) had stable disease with median duration of 5.25 months. CONCLUSION: Although the combination was determined safe, the study was halted due to termination of linsitinib development, and biomarker testing was not performed.

Dual compartmental targeting of cell cycle and angiogenic kinases in colorectal cancer models.

Cancer is a disease caused by several factors characterized by uncontrolled cell division, growth, and survival. ENMD-2076, is a novel orally active small molecule multikinase inhibitor targeting angiogenesis, proliferation, and the cell cycle. It is selectively active against the mitotic kinases aurora A and B, and kinases responsible for angiogenesis including VEGFR2/KDR and FGFR1 and 2. ENMD-2076 has been shown to inhibit tumor growth and prevent angiogenesis in vitro and in vivo in preclinical cancer models. Moreover, in a phase I trial, ENMD-2076 was well tolerated, exhibited a linear pharmacokinetic profile, and showed a promising antitumor activity in a number of solid tumors. In this study, we show that ENMD-2076 has antiproliferative effects, causes cell cycle arrest, and has activity in preclinical models of colorectal cancer (CRC), including patient-derived xenograft (PDX) models. Forty-seven human CRC cell lines were exposed in vitro to ENMD-2076 and analyzed for effects on cell cycle, apoptosis, and downstream effector proteins. The drug was then tested against 20 human CRC PDX models to further evaluate in-vivo antitumor activity. We show that ENMD-2076 exhibits a broad range of activity against a large panel of CRC cell lines with varying molecular characteristics. Mechanistically, ENMD-2076 exposure resulted in a G2/M cell cycle arrest, an increase in aneuploidy, and cell death in responsive cell lines. In addition, ENMD-2076 treatment resulted in a promising antitumor activity in CRC PDX models. These results support the continued development of ENMD-2076 in CRC including further exploration of rational combinations.

A Phase I Dose-Escalation Study of the Safety and Pharmacokinetics of Pictilisib in Combination with Erlotinib in Patients with Advanced Solid Tumors.

BACKGROUND: Epidermal growth factor receptor (EGFR) and phosphatidylinositol 3-kinase (PI3K) are involved in the proliferation and survival of many cancer types. Enhanced antitumor activity may be achieved through combined inhibition of these pathways. We report results for pictilisib (GDC-0941, a class I pan-PI3K inhibitor) plus erlotinib (an EGFR tyrosine kinase inhibitor) in patients with advanced solid tumors. MATERIALS AND METHODS: A 3 + 3 dose-escalation study was carried out at a starting daily dose of 60 mg pictilisib on days 1-21 of a 28-day cycle and 150 mg erlotinib from day 2 of cycle 1. The primary objectives of the study were to assess safety and tolerability, identify dose-limiting toxicities (DLTs), estimate the maximum tolerated dose, and identify the recommended phase II dose (RP2D). Evaluation of a dose-expansion cohort at the RP2D was performed. RESULTS: Fifty-seven patients were treated in the study. All patients experienced at least one adverse event (AE). Grade ≥3 AEs, serious AEs, and deaths were reported in 38 (66.7%), 19 (33.3%), and 4 (7.0%) patients, respectively. DLTs occurred in nine patients across eight cohorts and the RP2D was determined to be 340 mg pictilisib on a "5 days on, 2 days off" schedule plus 100 mg erlotinib. Two patients (3.5%) experienced partial response and 19 (33.3%) had stable disease. CONCLUSION: Combining pictilisib with erlotinib in patients with advanced solid tumors is feasible; however, antitumor activity is limited. Additional studies may identify patients likely to benefit from combined inhibition of EGFR and PI3K pathways. IMPLICATIONS FOR PRACTICE: Combining drugs targeting different signaling pathways in cancer growth and survival could overcome drug resistance and improve antitumor activity. In this first-in-human study for the combination, addition of the PI3K inhibitor pictilisib to the EGFR tyrosine kinase inhibitor erlotinib resulted in toxicity that led to dose and schedule modifications to identify a tolerable recommended phase II dose of 340 mg pictilisib on a "5 days on, 2 days off" schedule plus 100 mg erlotinib daily. The limited antitumor activity observed, however, suggests that additional studies are needed to identify patients most likely to benefit from combined EGFR and PI3K inhibition.

Phase I trial of vandetanib in combination with gemcitabine and capecitabine in patients with advanced solid tumors with an expanded cohort in pancreatic and biliary cancers.

BACKGROUND: Vandetanib is a multitargeted tyrosine kinase inhibitor that affects vascular endothelial growth factor receptor (VEGF), epidermal growth factor (EGF), and rearranged during transfection (RET) mediated receptors which are important for growth and invasion of biliary and pancreatic cancers. This phase I study evaluated the safety profile of vandetanib in combination with standard doses of gemcitabine and capecitabine in order to determine the maximum tolerated dose (MTD). METHODS: In this single center phase I trial, patients received gemcitabine intravenously (i.v.) at 1000 mg/m2 days 1, 8, 15 in a 28 day cycle, capecitabine orally at 850 mg/m2 twice daily on days 1-21, and escalating doses of vandetanib (200 or 300 mg orally daily). Once the MTD was defined, an expansion cohort of patients with advanced biliary cancers and locally advanced or metastatic pancreatic cancer was enrolled. Blood samples were also collected at predetermined time points for biomarker analysis. RESULTS: Twenty-three patients were enrolled: 9 in the dose escalation and 14 in the dose expansion cohort. One dose limiting toxicity (DLT), of grade 4 neutropenia, occurred in the 200 mg vandetanib cohort. The most common adverse effects were diarrhea (39 %), nausea and vomiting (34%), and rash (33%). There were 3 partial responses and stable disease of >2 months (range 2-45, median 5) was observed in 15/23 patients. There was no association between changes in biomarker analytes and disease response. CONCLUSION: The combination of gemcitabine, capecitabine and vandetanib is well tolerated at the recommended phase II dose of gemcitabine 1000 mg/m2 weekly for three consecutive weeks, capecitabine 850 mg/m2 BID days 1-21, and vandetanib 300 mg daily, every 28 days. This combination demonstrated promising activity in pancreaticobiliary cancers and further evaluation is warranted in these diseases. NCT00551096.

Gastric Cancer, Version 3.2016, NCCN Clinical Practice Guidelines in Oncology.

Gastric cancer is the fifth most frequently diagnosed cancer and the third leading cause of death from cancer in the world. Several advances have been made in the staging procedures, imaging techniques, and treatment approaches. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Gastric Cancer provide an evidence- and consensus-based treatment approach for the management of patients with gastric cancer. This manuscript discusses the recommendations outlined in the NCCN Guidelines for staging, assessment of HER2 overexpression, systemic therapy for locally advanced or metastatic disease, and best supportive care for the prevention and management of symptoms due to advanced disease.

Esophageal and esophagogastric junction cancers, version 1.2015.

Esophageal cancer is the sixth most common cause of cancer deaths worldwide. Adenocarcinoma is more common in North America and Western European countries, originating mostly in the lower third of the esophagus, which often involves the esophagogastric junction (EGJ). Recent randomized trials have shown that the addition of preoperative chemoradiation or perioperative chemotherapy to surgery significantly improves survival in patients with resectable cancer. Targeted therapies with trastuzumab and ramucirumab have produced encouraging results in the treatment of advanced or metastatic EGJ adenocarcinomas. Multidisciplinary team management is essential for patients with esophageal and EGJ cancers. This portion of the NCCN Guidelines for Esophageal and EGJ Cancers discusses management of locally advanced adenocarcinoma of the esophagus and EGJ.

A phase 1, open-label, dose-escalation study of BIIB022 (anti-IGF-1R monoclonal antibody) in subjects with relapsed or refractory solid tumors.

PURPOSE: The IGF-1R signaling pathway has been implicated in multiple cancers as important for cell survival, proliferation, invasion and metastasis. BIIB022 is a non-glycosylated human IgG4 monoclonal antibody (mAb) with specificity for IGF-1R. Unlike other anti-IGF1R antibodies, BIIB022 has no effector functions. Additionally, inhibition is via an allosteric rather than competitive mechanism, which further differentiates this antibody from others. We sought to determine the safety and tolerability of BIIB022 and determine the pharmacokinetic (PK) and pharmacodynamic (PD) profile of this antibody. METHODS: A multi-institutional phase I study evaluated the safety of escalating doses of BIIB022 given IV q3wk until progression or unacceptable toxicity in patients with advanced solid tumors. Five sequential BIIB022 dose cohorts were evaluated using a standard 3 + 3 dose-escalation design (1.5, 5. 10, 20, 30 mg/kg); 10 additional patients were treated at the recommended phase 2 dose. RESULTS: 34 patients were treated. Toxicities were manageable and mostly low grade; grade 3-4 hyperglycemia was not observed. No RECIST responses were observed, although three patients had metabolic responses associated with prolonged stable disease. The PK of BIIB022 was nearly linear in the dose range from 10 to 30 mg/kg, with some nonlinearity at lower doses (1.5-5.0 mg/kg), likely due to target-mediated drug disposition of BIIB022 at low serum concentrations. PD analyses showed decrease in IGF-1R levels on leucocytes, with stable serum values of IGF-1 and IGF-2. CONCLUSIONS: BIIB022 can be safely given at 30 mg/kg IV every 3 weeks with preliminary evidence of biological activity in selected patients.

Physiologic Effects of Microneedle-Mediated Intracochlear Dexamethasone Injection in the Guinea Pig.

OBJECTIVES: Oral or intratympanic corticosteroids are commonly used to treat sudden sensorineural hearing loss (SSHL), tinnitus, and Meniere disease. Direct intracochlear delivery has been proposed to overcome the variability in bioavailability and efficacy of systemic or middle ear delivery. In this study, we aim to characterize the physiologic consequences of microneedle-mediated direct intracochlear injection of dexamethasone through the round window membrane (RWM). METHODS: In Hartley guinea pigs (n = 5), a post-auricular incision followed by bullostomy was made to access the round window membrane. Using 100 µm diameter hollow microneedles, 1.0 µl of 10 mg/ml dexamethasone was injected through the RWM over 1 min. Compound action potential (CAP) and distortion product otoacoustic action emissions (DPOAE) were measured before perforation, at 1 h, and at 5 h following injection. CAP hearing thresholds were measured from 0.5 to 40 kHz, and DPOAE f2 frequencies ranged from 1.0 and 32 kHz. Repeated measures ANOVA followed by pairwise t-tests were used for statistical analysis. RESULTS: ANOVA identified significant CAP threshold shifts at four frequencies (4, 16, 36, and 40 kHz) and differences in DPOAE at 1 frequency (6 kHz). Paired t-tests revealed differences between the pre-perforation and 1 h time point. By 5 h post injection, both CAP hearing thresholds and DPOAE recover and are not significantly different from baseline thresholds. CONCLUSION: Direct intracochlear delivery of dexamethasone via microneedles results in temporary shifts in hearing thresholds that resolve by 5 hours, thus supporting microneedle technology for the treatment of inner ear disorders. LEVEL OF EVIDENCE: NA Laryngoscope, 134:388-392, 2024.

Community Health Worker Intervention for Newborns Not Passing Initial Universal Hearing Screening.

BACKGROUND: Universal newborn hearing screening (UNHS) is effective in identifying newborns with possible hearing loss (HL). Outpatient follow-up for newborns referred after hospital-based screening remains a potential area of improvement. In this study, we evaluate the efficacy of a community health worker (CHW) intervention in promoting adherence to outpatient rescreening for newborns referred after initial UNHS. METHODS: A mixed prospective-retrospective cohort study was performed to evaluate a CHW intervention at an academic medical center. Caregivers of referred newborns were contacted by CHWs prior to discharge and educated about HL and the importance of follow-up screening. The CHW outreach intervention was performed for 297 referred newborns between May 2020 and June 2021 and compared to a cohort of 238 newborns without the CHW intervention between March 2019 and June 2021. Statistical analyses were conducted using 2 × 2 Chi-square tests, two-tailed unpaired t-tests, multinomial logistic regression, and multiple linear regression. RESULTS: In the intervention group, 236 of 297 newborns (79.5%) completed their outpatient follow-up rescreening; in the comparison group, 170 of 238 newborns (71.4%) completed their follow-up rescreening (P = .031, OR = 1.55 with regression P = .04). In the intervention group, the average time to follow-up was 13.4 days versus 12.5 days for the comparison group (P = .449, multiple R2 = .02 with P = .78). CONCLUSIONS: CHW outreach intervention may increase adherence to outpatient follow-up rescreening for newborns referred after initial, hospital-based UNHS. Expansion of nursery teams to include CHWs may thus improve completion of recommended follow-up hearing screens.

Microneedle-Mediated Delivery of siRNA via Liposomal-Based Transfection for Inner Ear Gene Therapy.

HYPOTHESIS: Microneedle-mediated intracochlear injection of siRNA-Lipofectamine through the round window membrane (RWM) can be used to transfect cells within the cochlea. BACKGROUND: Our laboratory has developed 100-µm diameter hollow microneedles for intracochlear injection through the guinea pig RWM. In this study, we test the feasibility of microneedle-mediated injection of siRNA and Lipofectamine, a commonly used reagent with known cellular toxicity, through the RWM for cochlear transfection. METHODS: Fluorescently labeled scramble siRNA was diluted into Lipofectamine RNAiMax and OptiMEM. One microliter of 5 µM siRNA was injected through the RWM of Hartley guinea pigs at a rate of 1 µl/min (n = 22). In a control group, 1.0 µl of Lipofectamine, with no siRNA, was diluted into OptiMEM and injected in a similar fashion (n = 5). Hearing tests were performed before and either at 24 hours, 48 hours, or 5 days after injection. Afterward, animals were euthanized, and cochleae were harvested for imaging. Control cochleae were processed in parallel to untreated guinea pigs. RESULTS: Fluorescence, indicating successful transfection, was observed within the basal and middle turns of the cochlea with limited distribution in the apex at 24 and 48 hours. Signal was most intense in the organ of Corti, spiral ligament, and spiral ganglion. Little to no fluorescence was observed at 5 days post-injection. No significant changes in auditory brainstem response (ABR) were noted post-perforation at 5 days, suggesting that siRNA-Lipofectamine at low doses does not cause cochlear toxicity. CONCLUSIONS: Small volumes of siRNA and Lipofectamine can be effectively delivered to cochlear structures using microneedles, paving the way for atraumatic cochlear gene therapy.