Harvard Otolaryngology Fall 2025

News from the Harvard Medical School

Department of Otolaryngology–Head and Neck Surgery

Fall 2025 | Vol. 21, No. 2

Published twice per year.

For any inquiries or comments regarding this issue, please contact:

Nicole Feldman

Communications Manager nfeldman1@meei.harvard.edu

Department of Otolaryngology–Head and Neck Surgery Mass Eye and Ear 243 Charles Street, Boston, MA 02114

CONTRIBUTORS

Editor-in-Chief

Mark A. Varvares, MD, FACS

William W. Montgomery and John W. Merriam Professor and Department Chair of Otolaryngology–Head and Neck Surgery

Harvard Medical School

Chair, Otolaryngology–Head and Neck Surgery Mass General Brigham

Managing Editor | Writer

Nicole Feldman

Design | Layout | Photography

Garyfallia Pagonis

Surgical cover photo courtesy of: Conchita Getgano, RN, Brigham and Women's Hospital.

CONTENTS

Department of Otolaryngolog y Head and Neck Surger y

Beth Israel Deaconess Medical Center

Boston Children’s Hospital

Brigham and Women’s Hospital

Mass Eye and Ear

Massachusetts General Hospital

1 Letter From the Chair

Mark A. Varvares, MD, FACS

2 News: Jeffrey R. Holt, PhD

Elected to the National Academy of Sciences

16 Graduation

19 New Trainees

20 Alumni Profile

Aaron Tward, MD, PhD, 2012

22 In Memoriam

Joseph B. Nadol, Jr., MD

FEATURES

4 Moving Immunotherapy to the Surgical Setting: Earlier Intervention, Better Outcomes

A groundbreaking phase 3 trial shows that pembrolizumab administered before and after surgery significantly improves event-free survival, the first major advancement for resectable head and neck cancer patients in more than two decades.

8 Transforming Our Understanding of Ménière’s Disease

Researchers at Mass Eye and Ear outline a new way of thinking about Ménière’s disease, reveal genetic underpinnings in a subset of patients and show how these insights are already improving diagnosis and care—while opening paths to future therapies.

12 From Implants to Editing: A New Era in Hearing Restoration

Comparisons between gene therapy and cochlear implants in children with DFNB9 reveal equivalent or enhanced outcomes, and research in P2rx2 mouse models suggests new avenues for treating late-onset genetic deafness.

Dear colleagues and friends,

For decades, the Department of Otolaryngology–Head and Neck Surgery at Harvard Medical School has been a hub of education and training, innovation, discovery and extraordinary patient care. From groundbreaking research to advanced clinical therapies, our work continually pushes the boundaries of what’s possible. At the center of it all are our people, whose vision and dedication drive progress in the treatment of patients who come to us seeking care.

Through new scientific challenges, evolving patient needs and a constantly changing medical landscape, our department members have continued to adapt, innovate and persevere. By embracing change while upholding excellence, we advance care, expand knowledge and meet the needs of every patient we serve.

In this edition of Harvard Otolaryngology, our cover story features a phase 3 clinical trial led by Ravindra Uppaluri, MD, PhD, demonstrating that pembrolizumab given before and after surgery significantly improves event-free survival—the first meaningful advance for resectable head and neck cancer patients in more than two decades.

I am also excited to report on research led by Andreas H. Eckhard, MD, at Mass Eye and Ear, which offers a new perspective on Ménière’s disease, identifies genetic factors in a subset of patients and demonstrates how these insights are already enhancing diagnosis and care while paving the way for future therapies.

Additionally, I am proud to share studies led by Zheng-Yi Chen, DPhil, comparing gene therapy and cochlear implants in children with DFNB9, which show equivalent or superior outcomes, as well as research in P2rx2 mouse models that points to promising new approaches for treating late-onset genetic deafness.

Throughout this edition, you’ll also find several highlights, including the election of Jeffrey R. Holt, PhD, to the National Academy of Sciences; an alumni spotlight on Aaron Tward, MD, PhD; Beth Israel Deaconess Medical Center’s first-ever graduating resident class; and more.

As we enter the new year, I remain committed to guiding our department through evolving challenges and opportunities, fostering innovation, supporting our talented teams, and advancing excellence in patient care and discovery in otolaryngology–head and neck surgery.

As the new Chair of the Department of Otolaryngology–Head and Neck Surgery at Mass General Brigham, I am inspired to lead through change and unite the exceptional teams at Mass Eye and Ear, Massachusetts General Hospital and Brigham and Women’s Hospital—building on the collaborative approach that has guided my leadership at Harvard Medical School. Together, we will continue to strengthen a cohesive department focused on patient-centered care, cutting-edge research, training future medical professionals and advancing community well-being.

As always, thank you for your interest and support of our department’s research, initiatives and activities.

Sincerely,

Mark A. Varvares, MD, FACS

William W. Montgomery and John W. Merriam

Professor and Chair Department of Otolaryngology–Head and Neck Surgery, Harvard Medical School

Chair, Otolaryngology–Head and Neck Surgery, Mass General Brigham

Dr. Jeffrey R. Holt Elected to the National Academy of Sciences

Jeffrey R. Holt, PhD, Professor of Otolaryngology–Head and Neck Surgery and Neurology at Harvard Medical School and Neuro–Otology Research Chair at Boston Children’s Hospital, was elected this year to the National Academy of Sciences (NAS).

The NAS, established by President Abraham Lincoln in 1863, is a private, nonprofit institution that provides independent, objective advice to the nation on matters related to science and technology. Election to the NAS is considered one of the highest honors in science. Dr. Holt is one of 120 scientists nationwide elected this year in recognition of their distinguished achievements in original research.

Dr. Holt is the first member of the Harvard Medical School Department of Otolaryngology–Head and Neck Surgery (OHNS) ever elected to this prestigious society, which currently includes 2,662 active United States members. “It’s an honor to contribute to the NAS. Since my election, I’ve become aware of numerous ways to advise and engage in service, and I plan to actively participate. I’m committed to using this position to

promote science and advocate for research funding in the U.S.,” said Dr. Holt.

Dr. Holt serves as one of two principal investigators of the Holt/Géléoc Lab at Boston Children’s Hospital. His research focuses on the function and dysfunction of the inner ear, with the goal of understanding how external stimuli, such as sound, gravity, and head movements, are converted into electrical signals, how this information is encoded, and how it is transmitted to the brain.

His lab is renowned for uncovering the molecules and mechanisms of sensory transduction in inner ear

hair cells. Most notably, they identified TMC1 as the ion channel that converts sound into electrical signals— a discovery fundamental to hearing in humans and all mammals. This breakthrough was the result of more than a decade of work, with the hypothesis originating in 2002. He published initial evidence in 2011, followed by two landmark papers published in 2013 and 2018 in Neuron.

Beyond basic science, Dr. Holt has pioneered translational efforts to develop gene therapies for genetic hearing loss, including TMC1-related hearing loss. While not yet in clinical trials, the lab aims to advance TMC1 gene therapies within the next few years. The lab’s work also includes contributions to gene therapy vectors, like Anc80, which is now being used in otoferlin clinical trials, and ongoing research targeting stereocilin and Usher syndrome (USH2A), the latter potentially addressing both hearing and vision loss.

Since joining the Department of Otolaryngology and Communication Enhancement at Boston Children’s Hospital, led by Michael J. Cunningham, MD, FACS, Professor of Otolaryngology–Head and Neck Surgery at Harvard Medical School, Dr. Holt has received two of the most prestigious awards in auditory neuroscience, including the 2019 Scientific Grand Prize from the Foundation Pour l’Audition and the 2021

Pioneer Award from the Association for Research in Otolaryngology. He is also the recipient of the 2024 Boston Children’s Hospital Investment Conference Award.

“Dr. Holt has been a key contributor to developing a vibrant research component within our pediatric otolaryngology department at Boston Children’s Hospital. He is not only a remarkable scientist but also an exceptional leader and colleague. I know he is well positioned, and well deserved, to take on such an important role for our nation in science,” said Dr. Cunningham.

Dr. Holt views his NAS election not just as personal recognition but as acknowledgment of the entire auditory research community. “This isn’t just about me, it’s about the lab, their dedication and the field as a whole,” he said. In addition to being the first faculty member from the Department of OHNS at Harvard Medical School, Dr. Holt is only the second member of an otolaryngology department nationwide to be elected to the NAS. “The lab’s work is being recognized, but so is our broader community,” Dr. Holt shared. “With gene therapy trials making headlines, it feels like there’s a rising tide of interest and support for our field. It’s gratifying to see our efforts advancing both the science and the prospects for patients with hearing loss.” n

Moving Immunotherapy to the Surgical Setting: Earlier

Intervention, Better Outcomes

A groundbreaking phase 3 trial shows that pembrolizumab administered before and after surgery significantly improves event-free survival, the first major advancement for resectable head and neck cancer patients in more than two decades.

Over the past 20 years, outcomes for many locally advanced head and neck squamous cell carcinomas (HNSCCs) have remained largely unchanged. The standard approach of surgery followed by radiation with or without chemotherapy remains suboptimal, with roughly one-third of patients experiencing disease recurrence within a year and fewer than half surviving beyond five years.

Ravindra Uppaluri, MD, PhD, Professor of Otolaryngology–Head and Neck Surgery at Harvard Medical School and physician leader and surgeonscientist at Brigham and Women’s Hospital, has spent years exploring how immunotherapy could transform the treatment of head and neck cancer. Immune checkpoint inhibitors—a type of immunotherapy that blocks “brakes,” or checkpoints, that prevent the immune system from attacking cancer cells—had been approved, but only for patients with recurrent or metastatic disease. To address this limitation, he asked a critical question about earlier use of these drugs for locally advanced HNSCC.

“I wanted to explore how we could bring these novel therapies into the upfront surgical setting,” Dr. Uppaluri explained. “By activating the immune system before surgery, we might shrink tumors and stimulate a longer-lasting response, potentially changing the entire treatment paradigm.”

Introduction to pembrolizumab

Around 2013, Dr. Uppaluri’s idea aligned with an exciting opportunity. Merck, the American pharmaceutical company that developed the immune checkpoint inhibitor pembrolizumab, invited national investigators to conduct investigator-initiated trials (IITs) testing the drug in a clinical setting.

At the time, Dr. Uppaluri was a faculty member at the Department of Otolaryngology–Head and Neck Surgery at Washington University School of Medicine.

He and his colleague, Douglas R. Adkins, MD, Professor of Medicine and Director, Section of Head and Neck and Thyroid Medical Oncology at Washington University School of Medicine, designed a clinical trial using this drug before patients underwent surgical treatment. “The timing was fortuitous. The company was interested, and we were already considering this approach,” Dr. Uppaluri explained.

The duo conducted an initial phase 2 trial of pembrolizumab in head and neck cancer patients who had not received any prior therapy and were scheduled for surgery. The goal was to determine whether a neoadjuvant dose of pembrolizumab before surgery could activate the immune system and begin attacking tumor cells.

Early in the trial, Dr. Uppaluri received a surprise phone call from the pathologist examining surgically resected tumors. After just one dose of pembrolizumab, some tumors showed dramatic changes, including dying tumor cells consistent with immune activation. Additionally, patients had encouraging clinical outcomes

consistent with a “vaccination effect” of neoadjuvant pembrolizumab activating the immune system. Reassuringly for patients and surgeons, there was no detrimental impact on planned surgery.

These promising findings from the phase 2 study were presented at the 2017 American Society of Clinical Oncology meeting and were key data that Merck relied on to move forward with a randomized phase 3 study.

Phase 3 clinical trial, KEYNOTE-689

Unlike the earlier phase 2 single arm clinical trial, this international phase 3 trial, KEYNOTE-689, compared patients with locally advanced HNSCC receiving pembrolizumab before and after surgery with those receiving standard of care: surgery followed by radiation, with or without chemotherapy. Patients in the experimental arm received two cycles of pembrolizumab before surgery (neoadjuvant) and 15 cycles after surgery (adjuvant), given every three weeks. The study also assessed tumor PD-L1 combined positive score (CPS), a biomarker that can indicate how well a patient’s cancer might respond, with higher levels generally associated with better responses.

The trial included 192 sites worldwide and enrolled

more than 700 patients. The primary endpoint was event-free survival (EFS), measuring the time from randomization until disease recurrence or death. The study was carefully designed to balance patient characteristics between the two arms, ensuring valid comparisons. It began in 2018 and completed enrollment in 2023, and Dr. Uppaluri served as the global principal investigator, contributing particularly to the design of the study’s surgical components.

The results, presented by Dr. Uppaluri in the Clinical Trials Plenary Session of the 2025 American Association of Cancer Research Annual Meeting and

[“To see a small idea grow into a global phase 3 trial that has now changed the standard of care for the first time in 20 years is remarkable. It's truly the highlight of my career.”

—Ravindra

Uppaluri, MD, PhD

published in The New England Journal of Medicine, were groundbreaking. Patients who received pembrolizumab and had a PD-L1 CPS≥1 experienced a nearly two-fold

longer event-free survival with a median of 59.7 months in the pembrolizumab arm versus 29.6 months in the control arm. The study also found higher rates of major pathologic response in the surgical specimens, consistent with results from the phase 2 trial in patients receiving pembrolizumab. Another key finding was that patients given pembrolizumab required less radiation and chemotherapy than those in the standard of care arm.

The treatment was found to be safe with no newly observed side effects. “A primary concern for surgeons is whether giving a drug before surgery makes tumors harder to remove. What we saw here was that patients were still able to undergo surgery on time, and that’s very reassuring,” said Dr. Uppaluri.

Based on the results, the U.S. Food and Drug Administration (FDA) approved pembrolizumab in this setting for patients with locally advanced HNSCC. The approval specifies use in patients with a CPS of at least one, a biomarker present in more than 95 percent of cases, making the regimen widely applicable.

For Dr. Uppaluri, the impact of the study is profound. “To see a small idea grow into a global phase 3 trial that has now changed the standard of care for the first time in 20 years is remarkable. It’s truly the highlight of my career,” he said. “Additionally, this trial demonstrates the power of multidisciplinary care. Treating head and neck cancer requires surgeons, medical oncologists and radiation oncologists working in close coordination. This study reinforces that collaborative model and shows how combining expertise across specialties can directly improve patient outcomes on a global scale.”

Looking ahead

Dr. Uppaluri says these positive trial results highlight priorities in surgically treatable head and neck cancer. The first is increasing awareness and adoption of these approaches among surgeons worldwide, as it requires changes to current workflows. The second is further studies to determine whether immunotherapy should be given before surgery, after surgery, or both and how to safely de-intensify treatment.

He credits the mentorship and support of department leadership, particularly Mark A. Varvares, MD,

FACS, the William W. Montgomery/John W. Merriam Professor and Chair of Otolaryngology–Head and Neck Surgery at Harvard Medical School. “It’s a long process, and I’m incredibly grateful for the support of Dr. Varvares and our Harvard team,” said Dr. Uppaluri. “Having leaders and colleagues who truly believe in this work has made all the difference, and seeing the department embrace and push it forward has been especially meaningful.”

Additionally, Dr. Uppaluri has a focused laboratory effort on understanding why some patients do not respond to immunotherapy, which was recently funded with a National Institutes of Health R01 grant titled “Dissecting CCL5 contribution to antigen specific T cell responses in head and neck cancers.” As co-principal investigator, Dr. Uppaluri and team aim to investigate how the chemokine signals CCL5 and CXCL9 in head and neck cancers guide the development and activity of T cells—critical components in the immune system—and to use this knowledge to design therapies that reshape the tumor environment to help the immune system attack cancers resistant to anti-PD1 immunotherapy.

“Head and neck cancer is a challenging disease, and treatments can be grueling.

But with clinical trial results like Dr. Uppaluri's, we can improve outcomes, refine our treatment approaches and offer patients new hope.”

—Mark A. Varvares, MD, FACS

“Head and neck cancer is a challenging disease, and treatments can be grueling. But with clinical trial results like Dr. Uppaluri’s, and with his future studies supported by this new grant, we can improve outcomes, refine our treatment approaches and offer patients new hope,” said Dr. Varvares, who also serves as Chair of Otolaryngology–Head and Neck Surgery at Mass General Brigham. “These results are a powerful reminder of why we do this work.” n

Disclosures: Dr. Uppaluri has served on scientific advisory boards for Merck, Regeneron, Daiichi-Sankyo and Johnson & Johnson and has received research funding from Merck.

Transforming Our Understanding of Ménière’s Disease

Researchers at Mass Eye and Ear outline a new way of thinking about Ménière’s disease, reveal genetic underpinnings in a subset of patients and show how these insights are already improving diagnosis and care—while opening paths to future therapies.

Before 1861, sudden spells of vertigo, ringing in the ears and fluctuating hearing loss were blamed exclusively on brain disorders. French physician Prosper Ménière overturned that view by showing that, in some patients, these symptoms arise from disease in the inner ear—home to the organs of hearing and, newly recognized at the time, balance. In his early autopsies of individuals with combined hearing and vertigo symptoms, Ménière described “swollen inner ear membranes,” later interpreted as a sign of excess inner ear fluid pressure, or endolymphatic hydrops. Ménière’s finding came to be regarded as the defining feature of the disorder that would bear his name.

Following Ménière’s early descriptions, the field largely adopted a “pressure-based model,” viewing the disease for decades as a local fluid problem and earning it the nickname “glaucoma of the inner ear.” The analogy seemed natural because in both conditions, elevated fluid pressure was thought to trigger attacks and cause long-term damage.

“Many diagnostic tests, both past and present, try to detect excess fluid, and first-line therapies—like low-salt diets and diuretics—aim to lower that alleged pressure,” said Andreas H. Eckhard, MD, Assistant Professor of Otolaryngology–Head and Neck Surgery at Harvard Medical School and Co-Director of the Otopathology Laboratory at Mass Eye and Ear. “Some surgical approaches even attempt to create an opening in the inner ear to let excess fluid out.”

Despite these efforts, no therapy stops disease progression, and even their benefits for acute symptom attacks remain inconsistent. “The pressure-centric model has not delivered effective, durable therapies for patients,” Dr. Eckhard noted. The unpredictability and relentlessness of symptoms is often devastating, affecting every aspect of a patient’s life, including mental well-being and day-to-day safety. For approximately 30 percent of patients who develop the disease in both ears, the impact is especially profound.

“It’s not just an ear disease,” Dr. Eckhard added. “It touches every part of life, from the ability to work, to socialize, to feeling safe. And because symptoms flare without warning, patients find themselves needing care and adjustment of therapy again and again. That’s why finding treatments that truly help with lasting effect is so urgent.”

Revisiting the foundations

With that in mind, Dr. Eckhard’s team returned to the original human tissue evidence to test whether the basic story of pressure-driven hydrops still holds up under modern scrutiny.

Mass Eye and Ear’s Otopathology Laboratory, a basic and translational human temporal bone pathology center, houses one of the world’s most extraordinary resources for this work: approximately 5,000 human temporal bones, including more than 100 from patients with Ménière’s disease. Prepared over decades for microscopic analysis into more than two million tissue sections and recently largely digitized at cell-level resolution, these precious specimens allow today’s researchers to re-examine long-standing ideas using cutting-edge, machinelearning–supported approaches.

“More than half a century ago, researchers looked at these very same specimens with the best microscopes, guided by the prevailing mechanistic hypotheses,” Dr. Eckhard explained. “What they saw seemed to support the idea of increased fluid pressure. But microscope techniques weren’t as sophisticated then, and there was no artificial intelligence to enhance the analysis of these tissues at different levels and scales.”

Using advanced laser microscopy, 3D reconstruction techniques and machine-learning–assisted image analysis, the team reanalyzed classic sections alongside newly prepared material. The results challenged the traditional pressure theory. Instead of [ continued p. 10 ]

TRANSFORMING OUR UNDERSTANDING OF MÉNIÈRE’S DISEASE

the thinned or stretched membranes expected if high pressure were the cause, hydropic regions consistently showed a striking increase in epithelial cell number: hyperplasia. These changes appeared in both early and advanced specimens, pointing to an active, celldriven process. Molecular profiling reinforced that the expanded epithelial layers overexpress proteins involved in fluid and ion regulation, demonstrating a biological “rescue response” that adds cells and transport capacity to compensate for lost function, rather than simply ballooning under pressure. As in other organs, a protective response can become maladaptive if it overshoots or persists.

“Our new data suggest hydrops isn’t primarily a pressure problem,” said Dr. Eckhard. “It’s an organ-level rescue response that can tip from helpful to harmful when it runs unchecked.”

The roots of disease

This finding naturally led to the next question: if hydrops is the inner ear’s rescue response, what injury is it responding to?

The team focused on the endolymphatic sac, a small but crucial structure that keeps the inner ear’s fluid and chemistry in balance. Previous studies from Dr. Eckhard's group showed that the sac is injured in nearly all Ménière’s patients. In about 30 percent of cases, the sac and its bony channel—the vestibular aqueduct—never fully develop, leaving an underdeveloped sac from birth. In the remaining roughly 70 percent, a sac that formed normally later degenerates, likely from inflammation or reduced blood supply. In both cases, much of the sac’s epithelial lining—the cells that move salts and fluid—is lost, weakening the system’s “pump.” By combining earlier observations with new imaging and analysis, the team found that other inner-ear membranes grow extra cells, or undergo hyperplasia, to compensate for the sac’s lost function. This added tissue creates the swollen appearance recognized clinically as hydrops.

This new framework, detailed in the team’s recently published Scientific Reports work, knits the

pathology data into a clear sequence: an upstream problem in the endolymphatic sac; a downstream hyperplastic “rescue” response by other inner-ear, fluid-facing membranes; and, when that compensation is partial or misdirected, a vicious cycle of injury and imperfect repair that continues to cause symptoms and over time, can damage or destroy the inner ear. Ongoing animal studies aim to separate the “good” aspects of this compensation, which stabilize the system, from the “bad,” which drive chronic disease, with the goal of enhancing the former and reducing the latter.

From tissue clues to patient care

Building on these tissue insights, the team asked whether the two sac patterns can be identified in living Ménière’s patients and whether they correspond to different causes, clinical profiles or therapy needs.

To bridge pathology and clinical application, the team—which included Divya A. Chari, MD, Lecturer of Otolaryngology–Head and Neck Surgery at Harvard Medical School and neurotologist and investigator at Mass Eye and Ear, and Amy Juliano, MD, Associate

Professor of Radiology at Harvard Medical School and staff radiologist at Mass Eye and Ear—developed and clinically standardized a simple, reproducible CT/ MRI marker: the angular trajectory of the vestibular aqueduct (ATVA), which measures the bend of the bony channel that encases the endolymphatic duct and sac. On high-resolution CT, an angle of 140 degrees or greater indicates the underdeveloped, or hypoplastic, type, while an angle of 120 degrees or less points to a degenerative type. The ATVA marker, for the first time, enables grouping Ménière’s patients by underlying disease mechanism rather than symptoms alone—a diagnostic refinement known as endotyping.

In retrospective and prospective patient studies, the team showed that ATVA reliably distinguishes Ménière’s patients by sac pathology. It also helps anticipate the clinical course—for example, earlier onset and a higher likelihood of bilateral involvement in the underdeveloped type—and guides counseling and follow-up. In further work, ATVA patterns have correlated with later interventions such as cochlear implantation, improving long-term planning for patients with severe hearing loss.

“Our new data suggest hydrops isn't primarily a pressure problem. It's an organ-level rescue response that can tip from helpful to harmful when it runs unchecked.”

—Andreas H. Eckhard, MD

Endotyping also opened the door to in-depth genetic analyses aimed at understanding why the disease develops in the first place. Using the ATVA marker to identify the underdeveloped type, the team found a strong link within this patient subgroup to X-linked hypophosphatemia (XLH), a rare condition caused by variants in the PHEX gene. In their medRxiv preprint, the association between the hypoplastic form of Ménière’s disease and XLH was far stronger than expected by chance. Detailed genetic analyses revealed a clear gene-dosage effect: males with fully inactivating PHEX variants were most likely to develop early, bilateral disease of the underdeveloped

type; mosaic or milder variants showed attenuated involvement; and female carriers often experienced fluctuating hearing loss with variable expressivity. “This was the breakthrough we were looking for,” said Dr. Chari. “It explains why some patients develop severe, bilateral disease early and points to a concrete biological pathway we can target.”

What’s next

With a novel disease mechanism mapped out, an imaging tool for the clinic and a genetic foothold in a defined subgroup, the team’s next step is to connect these discoveries to improve personalized patient care.

Recognizing Ménière’s disease as a family of biologically distinct endotypes reframes diagnosis, monitoring and treatment. Building on their pathology–imaging–genetics framework, the Mass Eye and Ear team is mapping the molecular signals that drive protective epithelial growth versus maladaptive remodeling, aiming to strengthen the former and temper the latter. They are also translating these insights to the clinic by integrating the angular trajectory of the ATVA into routine imaging to guide counseling, follow-up, research enrollment, and link patterns with longitudinal hearing and balance outcomes. For patients with the hypoplastic endotype, the PHEX pathway provides a concrete target for therapeutic and preventive interventions.

“We’re not just rethinking the disease; we’re redefining it from its cellular roots to patient care. Ménière’s is no longer a single mysterious disorder but a set of biologically distinct conditions, each with its own path to prevention or treatment,” said Dr. Eckhard.

As efforts progress, the team’s recent review in Frontiers in Neurology presents a practical framework— endotype-based diagnosis, imaging-guided monitoring and pathway-targeted research—to guide care today while accelerating studies needed for lasting treatments and, potentially, cures. They envision endotypespecific pathways and trials that align interventions with each patient’s biology, shifting from reactive symptom control to proactive, mechanism-guided prevention and treatment to preserve hearing and balance over the long term. n

From Implants to Editing: A

New Era in Hearing Restoration

by

Comparisons between gene therapy and cochlear implants in children with DFNB9 reveal equivalent or enhanced outcomes, and research in P2rx2 mouse models suggests new avenues for treating late-onset genetic deafness.

An estimated 26 million people worldwide live with congenital hearing loss, up to 60 percent of which is caused by genetic factors. Cochlear implants have transformed the lives of more than a million people over the past six decades, but access remains limited, with fewer than one in 10 eligible patients receiving them. Outcomes also vary, with some patients gaining only modest benefits, and challenges such as music perception and speech recognition in noisy environments persist despite technological advances.

Gene therapy offers a new approach by addressing the underlying genetic causes of hearing loss. Zheng-Yi Chen, DPhil, Associate Professor of Otolaryngology–Head and Neck Surgery at Harvard Medical School and Principal Investigator and Ines and Fredrick Yeatts Chair in Otolaryngology at Mass Eye and Ear, has been at the forefront of this research. His team, in collaboration with colleagues at the Eye & ENT Hospital of Fudan University in Shanghai, first reported in The Lancet that adeno-associated virus (AAV)–based delivery of OTOF successfully restored hearing in children born with DFNB9, a severe form of autosomal recessive deafness.

Building on this milestone, the group later published in Nature Medicine the first trial to restore hearing in both ears of affected children. Treated patients not only regained auditory sensitivity but also demonstrated sound localization and improved speech recognition in noisy environments—capabilities that standard cochlear implants often struggle to deliver.

“At this time, the gene therapy trial is available only for individuals with OTOF variants, but my lab is actively developing approaches for other genetic forms of deafness, with promising results in mouse models,” [ continued p. 14 ]

Dr. Chen said. “One of the biggest questions from families has been how gene therapy compares with cochlear implants. Until recently, we had no evidence to guide those decisions.”

Gene therapy vs cochlear implants

To address the gap, Dr. Chen and his collaborators designed a study to directly compare outcomes among children who received gene therapy, those who received cochlear implants, and those who received both—gene therapy in one ear and a cochlear implant in the other. Participants ranged in age from one to 18 years and had severe to complete congenital hearing loss. To ensure a rigorous comparison, children were matched on duration of deafness, hearing thresholds and baseline speech ability before treatment. Of the 1,568 children screened, 72 were ultimately enrolled.

The study carefully aligned the groups so that children receiving gene therapy and cochlear implants were treated at similar ages, followed for the same periods and assessed for unilateral or bilateral interventions. This detailed matching allowed the team to attribute any differences in outcomes directly to the treatments themselves rather than external factors.

Results showed that gene therapy performed equivalently to cochlear implants in detecting sound and supporting speech recognition. “This was extremely reassuring, as it demonstrates that gene therapy can

achieve the same level of effectiveness as the current standard of care,” Dr. Chen emphasized.

Beyond basic hearing, the study, published in JAMA Neurology, revealed distinct advantages of gene therapy in complex auditory tasks. Within six to 12 months, children who received gene therapy showed greater improvements in auditory and speech perception scores, faster auditory processing on electrophysiologic tests and better performance in challenging listening conditions, such as understanding speech in noisy environments. Music perception also showed notable improvement. While cochlear implants often limit pitch recognition and produce a mechanical auditory experience, children treated with gene therapy—and particularly those who received gene therapy in one ear and a cochlear implant in the other—showed significantly better accuracy in reproducing melodies and perceiving pitch. These results suggest that gene therapy more closely restores natural hearing.

Gene therapy also accelerated brain adaptation. Typically, cochlear implant recipients require one to two years of rehabilitation to develop fluent speech. However, gene therapy patients exhibited faster activation of brain regions associated with hearing and speech. Speech outcomes were evaluated through clinical assessments and electrophysiological measurements.

Dr. Chen noted that cochlear implants remain broadly effective across different types of hearing loss, while gene therapy is currently targeted to specific genetic mutations, such as those affecting the OTOF gene. The success of this targeted approach, however, demonstrates the potential for gene therapy to exceed conventional outcomes in patients with certain genetic hearing loss.

“Cochlear implants have transformed countless lives and remain exceptionally effective, but with the majority of congenital deafness rooted in genetics, these findings remind us that we must keep pushing forward to develop gene therapies that can restore hearing for all,” said Dr. Chen.

New findings and future directions

While OTOF therapy targets children born deaf, Dr. Chen’s lab is also pursuing strategies for patients who lose hearing later in life. The team has expanded its focus to progressive, late-onset deafness caused by dominant mutations such as P2RX2, which leads to autosomal dominant deafness-41 (DFNA41). Unlike children with congenital deafness, these patients begin life with normal or near-normal hearing that gradually deteriorates. “We were excited to focus on these patients because their inner ear cells are still healthy when they are born, which makes them more likely to respond to treatment,” explained co-senior author

Xue Zhong Liu, MD, PhD, Leonard M. Miller Professor of Otolaryngology at the University of Miami Miller School of Medicine. “This gives us a wider window for intervention, from childhood through adulthood.”

In collaboration with multiple institutions, Dr. Chen’s team developed a one-time CRISPR-Cas9–based therapy delivered through an AAV2 vector directly into the inner ear of a mouse model. The therapy was designed to selectively disable the harmful mutation in the P2rx2 gene while leaving the healthy copy intact.

To accomplish this, the researchers designed a highly specific editing system (SaCas9 paired with a mutation-targeting guide RNA) and delivered it through a minimally invasive injection at the round window of the ear, a delivery approach already successfully used

injection restored long-term hearing and balance in adult mice with DFNA41, offering proof that gene editing can rescue auditory function even in fully mature ears. Treated mice were also protected from hypersensitivity to loud noise, a known risk factor for patients with DFNA41, and early intervention produced even stronger benefits. The team further validated the strategy in human stem cells carrying the same P2RX2 mutation, underscoring its potential for clinical translation.

“Our study demonstrated how gene editing can be a one-time, lasting treatment for adults with genetic inner ear disorders, something previously thought to be possible only during early development,” Dr. Chen mentioned. Beyond restoring hearing, the dual benefit of protecting balance and protecting against noiseinduced loss points to a therapy that could address multiple challenges faced by patients with progressive genetic deafness.

Looking ahead, Dr. Chen’s lab is advancing this work toward clinical application with support from the National Institutes of Health (NIH) Somatic Cell Genome Editing (SCGE) program. Investigational New Drug (IND)-enabling studies are underway to evaluate safety, biodistribution and toxicity in preparation for first-in-human trials. The NIH grant, under Dr. Chen’s leadership as principal investigator, supports parallel development of editing therapies for both DFNA41, caused by P2RX2 mutations, and autosomal dominant deafness-2A (DFNA2A), caused by KCNQ4 mutations.

“Our study demonstrated how gene editing can be a one-time, lasting treatment for adults with genetic inner ear disorders, something previously thought to be possible only during early development.”

—Zheng-Yi Chen, DPhil

in humans. Genetic sequencing and tissue analysis confirmed that the therapy precisely removed the harmful mutation without introducing off-target effects or viral DNA integration.

The results, published in The Journal of Clinical Investigation (JCI), were groundbreaking. A single

In partnership with the Mass General Brigham Gene and Cell Therapy Institute, the team is also building platforms and delivery systems designed to accelerate testing of new gene therapy strategies across a range of deafness-causing mutations.

By studying both congenital and lateonset forms of deafness, Dr. Chen and his collaborators are building a framework for genetic therapies that span all ages. The ultimate goal, he emphasizes, is not to replace cochlear implants but to complement them and gather robust alternatives, restoring natural hearing for patients of all ages and genetic backgrounds. n

FAREWELL CLASS OF 2025

Harvard Medical School Celebrates Residents and Fellows Graduating From Combined Otolaryngology Training Program.

Faculty and staff from the Department of Otolaryngology–Head and Neck Surgery (OHNS) at Harvard Medical School (HMS) celebrated the 2025 graduating class of residents from the Harvard Combined Residency Program in OHNS and fellows on Friday, June 20. The ceremony took place in the Meltzer Auditorium at Mass Eye and Ear, where current and former trainees, along with immediate family members, gathered to honor the graduates.

Five chief residents graduated from the program, which is led by HMS Otolaryngology Residency Director Stacey T. Gray, MD; Associate Residency Directors Kevin S. Emerick, MD, Alice Z. Maxfield, MD, and David Jung, MD, PhD, FACS; and Chair of OHNS Mark A. Varvares, MD, FACS. In addition to the chief residents, seven clinical fellows graduated from the Mass Eye and Ear program. Boston Children’s Hospital celebrated the graduation of three clinical fellows at a separate event.

Derrick T. Lin, MD, FACS, Associate Chair of OHNS at Mass Eye and Ear, opened the ceremony, followed by a meaningful presentation from Dr. Gray, emphasizing the deep impact that mentorship and a sense of connection can have on both personal and professional fulfillment in medicine. Drawing from personal experience, Dr. Gray shared that while residencies and fellowships can be demanding and unpredictable, one thing trainees can actively build is strong, intentional relationships.

“If you have a best friend at work, you’re more committed, more engaged and you encourage each other,” said Dr. Gray. “These people often become the closest part of your life. As you grow older, those you once saw as mentors often become your friends, too. It’s a truly special aspect of our field.”

Following Dr. Gray’s presentation, Konstantina Stankovic, MD, PhD, FACS, a 2006 graduate of the Harvard Combined Residency Program in Otolaryngology–Head and Neck Surgery, and now Bertarelli Foundation Professor and Chair of the Department of Otolaryngology–Head and Neck Surgery at Stanford University School of Medicine, was introduced to deliver the annual Joseph B. Nadol, Jr., MD, Graduation Lectureship.

Dr. Stankovic was welcomed by Dr. Emerick, a colleague and friend she trained with during residency and worked alongside for nearly 20 years at Mass Eye and Ear. Their live Q&A offered a glimpse into her journey, reflecting on mentorship and shared experiences—fitting for the day’s theme—before she took the podium.

Honored to deliver the lecture, Dr. Stankovic reflected on how training in otolaryngology–head and neck surgery prepares physicians for both clinical excellence and life’s broader journey. Using a painting that hung for many years in Dr. Nadol’s office as a metaphor, she explored five elements: the ship (self), the crew (community), the storm (world), the waves (surgeon’s calling), and the compass (purpose). Through these symbols, she encouraged graduates to embrace their strengths, honor their support systems, find resilience, seek fulfilling work and pursue a meaningful path ahead.

“Remember the words of Mark Twain, who said, ‘Twenty years from now, you will be more disappointed by the things you didn't do than those you did. So throw off the bowlines. Sail away from the safe harbor. Catch the wind in your sails. Explore. Dream. Discover,’” said Dr. Stankovic in conclusion. “Graduating residents and fellows, congratulations, and may your sailing continue to be adventurous and lead to breakthrough discoveries.”

Awards and Honors

Jeffrey P. Harris, MD, PhD, Research Award

Presented to the graduating chief resident with the most outstanding FOCUS research project. Christopher I. McHugh, MD, PhD Elucidating the anatomy and motion of the human cochlear partition

Clinical Fellow Teaching Award: Abel P. David, MD

Mark A. Varvares, MD, FACS, Chief Resident Teaching Award: Margaret B. Mitchell, MD, MS-HPEd

William W. Montgomery, MD, Faculty Teaching Award: Caroline A. Banks, MD

Harvard Otolaryngology Resident Life Award: Donald Fabiano, RN

Graduating Residents, Mass Eye and Ear

Danielle R. Larrow, MD

Future Plans: Pediatric Otolaryngology Fellowship, Mass Eye and Ear

Rui Han Liu, MD

Future Plans: Facial Plastics Fellowship, FACE Toronto

Christopher I. McHugh, MD, PhD

Future Plans: Comprehensive Otolaryngologist, Arlington, Virginia

Margaret B. Mitchell, MD, MS-HPEd

Future Plans: Rhinology and Skull Base Surgery Fellowship, University of Pennsylvania

Isaac Wasserman, MD, MPH

Future Plans: Advanced Thyroid and Parathyroid Surgery Fellowship, Mass Eye and Ear

From left to right: Graduating Mass Eye and Ear residents

Margaret B. Mitchell, MD, MS-HPEd; Isaac Wasserman, MD, MPH; Danielle R. Larrow, MD; Rui Han Liu, MD; and Christopher I. McHugh, MD, PhD.

Sathish Paramasivan, MBBS(Hons), MPH, PhD

Rhinology

Future Plans: Skull Base Fellowship, Cambridge University, United Kingdom 2025-2026 Attending Surgeon at The Queen Elizabeth Hospital/The University of Adelaide 2026

E’ Ching Shih, MD

Pediatric Otolaryngology

Future Plans: Attending in Pediatric Otolaryngology, National University Hospital, Singapore

Roy Xiao, MD, MS

Facial Plastic and Reconstructive Surgery

Future Plans: Assistant Professor, University of Pennsylvania

From left to right:

Graduating Mass Eye and Ear fellows

Roy Xiao, MD, MS; E' Ching Shih, MD; Sathish Paramasivan, MBBS(Hons), MPH, PhD; Sarah C. Nyirjesy, MD; Abel P. David, MD; Katherine A. Larrabee, MD; and Sean P. McKee, MD.

Graduating Fellows, Mass Eye and Ear

Abel P. David, MD Neurotology

Future Plans: Practicing Academic Neurotologist

Katherine A. Larrabee, MD

Thyroid and Parathyroid Surgery

Future Plans: Otolaryngologist with Endocrine Focus, Geisinger Health System

Sean P. McKee, MD Rhinology

Future Plans: Private Practice, The Oregon Clinic, Portland, Oregon

Sarah C. Nyirjesy, MD

Head and Neck Oncology

Future Plans: Head and Neck Surgeon, Boston University

Graduating Fellows, Pediatric Otolaryngology, Boston Children's Hospital

Isobel O’Riordan, MD

Future plans: Head and Neck Surgical Oncology Fellowship at MD Anderson Cancer Center in Houston, Texas

Ross O’Shea, MD

Future plans: Otology Neurotology Fellowship at the University of Toronto

Jakob Pugi, MD

Future plans: Faculty member, Department of Otolaryngology and Communication Enhancement at Boston Children's Hospital

NEW TRAINEES s

Meet our PGY-1 Residents

Harvard

Combined Residency

Program in Otolaryngology–Head and Neck Surgery

Ryan J. Carlson, MD, PhD, grew up in Puyallup, Washington, and graduated cum laude from the University of Washington (UW) with degrees in neurobiology and biochemistry. He completed an IRTA post-baccalaureate research fellowship at the National Institute of Allergy and Infectious Diseases in Bethesda, Maryland, before returning to UW to join its MD-PhD program, earning his PhD in Genome Sciences in the laboratory of Mary-Claire King, PhD. His research focused on identifying novel genes and variants linked to hearing loss, exploring genetic and phenotypic heterogeneity in childhood hearing loss, and examining how specific variants affect cochlear implant outcomes. During his training, he received multiple awards, including a Ruth L. Kirschstein NRSA F30 fellowship, the Achievement Reward for College Scientists, and two Virginia Merrill Bloedel Hearing Research Center mini-grants for innovation in hearing research. His interests include gene discovery in hearing loss, development of inner ear gene therapies and the utilization of genomic technologies to improve hearing outcomes.

Maya Cara Fleseriu, MD, was raised in in Lake Oswego, Oregon, and attended the University of Pittsburgh Honors College as part of the eight-year BS/MD program. She graduated summa cum laude with degrees in neuroscience and Spanish before matriculating at the University of Pittsburgh School of Medicine. During medical school, Dr. Fleseriu contributed to several clinical research projects, including studies within a nationwide multi-institutional consortium examining quality of life in patients with sinonasal malignancies and a prospective analysis of infant feeding modalities and their impact on sleep-disordered breathing in toddlers. In 2025, she received the University of Pittsburgh School of Medicine Frank I. Marlowe Award for Excellence in Otolaryngology. Dr. Fleseriu’s interests include patient-reported outcomes such as quality

of life, clinical outcomes and treatment decision-making, and the intersection of medical education and mentorship.

Julia Telischi, MD, is originally from Miami, Florida, and graduated magna cum laude from Cornell University with a degree in biomedical engineering. Before attending medical school, she worked in research and design at Stryker, contributing to the redesign of their microdebrider. She went on to attend the University of Miami Miller School of Medicine, where she pursued a scholarly concentration in biomedical engineering and was selected for the National Institutes of Health Medical Research Scholars Program. At the National Institute on Deafness and Other Communication Disorders, she conducted research under the mentorship of Michael Hoa, MD, focusing on identifying biomarkers of hearing instability through inner ear fluid quantification and longitudinal audiovestibular data analysis. Dr. Telischi also co-founded Miami Med Reentry Care Coordination, a program that provides patient navigation services to individuals returning from incarceration. Her research interests include auditory and vestibular disorders, medical device innovation and health equity.

Maryann Zhao, MD, is originally from San Diego, California, and graduated Phi Beta Kappa from Pomona College with a degree in molecular biology. Prior to medical school, she conducted research in cancer genomics and immunology at the Broad Institute in the laboratory of Aviv Regev, PhD. She then matriculated at Harvard Medical School, graduating cum laude from the Harvard–MIT Health Sciences and Technology program and receiving the Janee and Paul Friedmann, MD, ’59 Surgery Prize. During medical school, Dr. Zhao led research with Ravindra Uppaluri, MD, PhD, at the Dana-Farber Cancer Institute to develop 3D organoid models of HPV-negative head and neck tumors and to characterize their immune response to neoadjuvant immunotherapy using genomic approaches. She also investigated patient-reported outcomes in otolaryngology with Matthew Naunheim, MD, MBA, and

explored socioeconomic barriers to cochlear implantation with James Naples, MD. Her interests include cancer genomics, immunology and healthcare access.

Hasan Abdulbaki, MD, is originally from Hama, Syria, and graduated summa cum laude from the University of California, Los Angeles, with a degree in Arabic studies and a concentration in music. He then matriculated at the University of California, San Francisco (UCSF) School of Medicine, where he engaged in clinical, health systems and global health research. Dr. Abdulbaki studied the impact of musical rehabilitation on cochlear implant sound perception under the mentorship of Charles Limb, MD, and investigated global disparities in otolaryngology workforce resources and access to non-operative treatment strategies through the Global Otolaryngology–Head and Neck Surgery (OHNS) Initiative, aiming to identify widely implementable approaches to address deficits in OHNS care in resourcelimited settings. His interests include global health, health system capacity building, scalable alternative treatment strategies and hearing care outcomes research.

New Clinical Fellows

Mass Eye and Ear

James Alrassi, MD, Laryngology

Liliya Benchetrit, MD, Neurotology

Alice Huang, MD, Rhinology

Danielle Larrow, MD, Pediatric Otolaryngology

Tina Munjal, MD, Neurotology

Kush Panara, MD, Rhinology

Justine Philteos, MD, Head and Neck

Catherine Roy, MDMC, Facial Plastic

Isaac Wasserman, MD, MPH, Thyroid

Boston Children’s Hospital

Mary Ghrayeb Haddad, MD

Elias Saba, MD

Eve Sedillot-Daniel, MD

OHNS Residency Program at Beth Israel Deaconess Medical Center/ Harvard Medical School Celebrates First Graduation

On June 14, 2025, the Harvard Medical School Residency Program in OHNS at Beth Israel Deaconess Medical Center (BIDMC) celebrated a milestone—its first graduating class—at the BraeBurn Country Club. The evening honored two exceptional residents: Peter Nagy, MD, who will be pursuing a fellowship in facial plastic and reconstructive surgery at the University of Texas at San Antonio and Victoria Huang, MD, who will begin her fellowship training in neurotology at Case Western Reserve University.

Kenneth Grundfast, MD, FACS, Professor of Otolaryngology at Boston University and physician and surgeon at Mass Eye and Ear, served as Guest of Honor for the event, which was held in conjunction with the Combined Harvard Otolaryngology Grand Rounds. The program featured special lectures by Steven J. Wang, MD, Professor and Chair of the Department of Otolaryngology–Head and Neck Surgery at the University of Arizona College of Medicine, Tucson, on HPV-related head and neck cancers and leadership in otolaryngology.

Established in July 2020, the BIDMC residency is a fully accredited ACGME program created through a collaboration between Beth Israel Deaconess Medical Center and Boston Children’s Hospital. The graduation ceremony marked a proud milestone, celebrating the hard work, growth and excellence of the program’s inaugural residents.

Please join us in welcoming the newest class of trainees to the OHNS Residency Program at Beth Israel Deaconess Medical Center/Harvard Medical School

Residents

Originally from Glastonbury, Connecticut, Matthew Holdaway, MD, graduated summa cum laude from Union College in Schenectady, New York, where he received his undergraduate degree in neuroscience. After graduation, he conducted research in the laboratory of Sally Temple, PhD, investigating miRNA expression in iPSC derived microglia organoids and microglia subtype differentiation following spinal cord injury. He then graduated summa cum laude from Albany Medical College, earning awards for both academic excellence and clinical compassion. There, he published manuscripts on a variety of topics including outcomes for skull base surgery and disparities in healthcare leadership. He was an active member of the Albany Medical College Skull Base Cadaveric Otolaryngology Laboratory, where he helped develop novel endoscopic approaches to the skull base and infratemporal fossa. Dr. Holdaway's interests include innovations in surgical technology and how that drives patient outcomes, as well as medical education research.

Summer Xu, MD, is originally from Glastonbury, Connecticut, and graduated from the University of Virginia with a degree in chemical engineering. She matriculated at the University of Connecticut School of Medicine, where she conducted research on metopic craniosynostosis and pediatric sleep apnea. In medical school she received awards for excellence in clinical skills and overall academic achievement. Dr. Xu chose otolaryngology for the opportunity to help patients connect with the world through speech, hearing, facial expression and even the enjoyment of food. Her clinical and research interests include medical education, public health initiatives and technology.

ALUMNI PROFILE s

Aaron Tward, MD, PhD, 2012

When Aaron Tward, MD, PhD, recently rediscovered a paper he had written in seventh grade about gene therapy, it struck him as more than just a childhood assignment. It was a reminder of how early his fascination with science began and offered a glimpse into the path his career would follow.

At first, Dr. Tward imagined a future in internal medicine or perhaps a career spent entirely in the lab. While completing his combined MD and PhD at the University of California, San Francisco (UCSF), surgery was not on his radar. That changed during a short elective in otolaryngology, when he witnessed a cochlear implant procedure for the first time.

“I asked my mentor how the device worked, and when he told me these children, diagnosed as deaf, would have nearnormal hearing afterward, I was in awe,” he recalled. “It was unbelievable that a neural prosthesis could restore hearing. It was the most amazing thing I had seen in medicine.”

That single case inspired him to not only shift his focus toward surgery but also seek out the most rigorous training, which he found in the Harvard Combined Residency Program in Otolaryngology–Head and Neck Surgery at Harvard Medical School.

“I was grateful to be accepted into such a prestigious program, one that was both clinically intensive and surrounded by strong science,” said Dr. Tward. “Because I had always planned to devote much of my career to research, I worried about not getting enough surgical training. I didn’t want to be only half-way trained. I wanted an intensive, dense clinical experience. I knew Mass Eye and Ear would provide that, and it did.”

Even before his surgical training, Dr. Tward’s scientific curiosity had been shaped by his PhD research in cancer biology. He sought to understand how normal cells transform into precancerous and cancerous states. “Mutations drive these transitions,” he explained. “During my PhD, I studied liver cancer in mice and human tissue, but the technology

“Dr. McKenna shaped my development as a surgeon, and now we're working together to move discoveries from the lab bench to the bedside. It reflects what Mass Eye and Ear has always stood for: uniting science and patient care.”

—Aaron Tward, MD, PhD

limited us to the mutations we already knew, leaving many questions unanswered.”

At Mass Eye and Ear, he arrived just as high-throughput sequencing was transforming the field, making it possible to record every mutation in a tumor sample. Through institutional connections, Dr. Tward joined a lab at the Broad Institute and helped pioneer the use of these techniques in head and neck squamous cell carcinoma. His work generated one of the first comprehensive maps

of mutations in head and neck cancer, laying the groundwork for the lab he would later establish at UCSF.

After completing residency, he pursued a fellowship in neurotology at Mass Eye and Ear under the mentorship of Michael J. McKenna, MD, before returning to California to begin his faculty career. “At Mass Eye and Ear, working closely with Dr. McKenna, I learned how science directly informed patient care, and how patient care inspired new scientific questions. That connection has stayed with me,” he reflected.

When he joined UCSF, Dr. Tward divided his time between patient care and research, spending about 40 percent in the clinic and 60 percent leading his laboratory. In the clinic, he focused on skull base surgery, cochlear implants, middle ear disease and meningiomas. In the lab, he balanced teaching graduate students and postdocs with running a research program that built on his computational skills in high-throughput sequencing. These skills had wide applications, but it wasn’t until a new technology arrived that his research took an unexpected turn.

Coincidentally, his wife Julie Sneddon, PhD, Associate Professor of Cell and Tissue Biology and a stem cell biologist at UCSF, gained early access to an emerging technology known as the 10x Genomics machine. The instrument enabled single-cell RNA sequencing, a method capable of identifying previously unknown cell types. While she was applying the technique to study the pancreas, Dr. Tward proposed using it to study the inner ear. That idea launched an entirely new research trajectory.

His team created one of the first comprehensive census of inner ear cell types, discovering populations that had never before been identified. The findings were highly relevant for gene therapy, providing details of which genes are expressed in which cell types, data critical to delivering genetic material where it is most needed.

Soon after, new opportunities began to emerge. At a conference, his former mentor, Dr. McKenna, then preparing to launch a company focused on gene therapy for hearing loss, invited Dr. Tward to join the scientific advisory board. That company, Akouos, aimed to restore hearing by delivering therapeutic genes directly to malfunctioning hair cells in the inner ear.

Through his involvement with Akouos, Dr. Tward met Luk Vandenberghe, PhD, Grousbeck Family Chair in Gene Therapy at Mass Eye and Ear, a leader in the field. Their collaboration led to the founding of Affinia Therapeutics, a company developing next-generation viral vectors for gene delivery. These engineered vectors are designed to precisely target specific cells, reduce immune responses and improve overall efficiency. Affinia continues to advance its pipeline, including a therapy currently in pre-Investigational New Drug (IND) studies for cardiomyopathy.

Meanwhile, Dr. Tward’s UCSF lab was rapidly growing. National Institutes of Health (NIH) funding supported his team’s expansion from cancer genetics into ear biology, where they discovered stem cells in the eardrum—an important finding for understanding regeneration and potential therapeutic targets. By 2021, Manny Simons, PhD, MBA, the CEO of Akouos, asked if he could dedicate more time to the company. After reviewing promising preclinical data, he recognized that the work was not just compelling science but potentially transformative for patients. With his department’s support at UCSF, he deepened his involvement, bridging his academic research with clinical translation.

Today, Dr. Tward serves as Associate Vice President of Gene Therapy at Eli Lilly (which acquired Akouos in 2022), working alongside Dr. McKenna, now Co-Founder and Chief Surgical Officer. For him, the collaboration represents a milestone moment. Reconnecting with Dr. McKenna—the surgeon who trained him in fellowship— opened an incredible new chapter for Dr. Tward, uniting former teacher and trainee as colleagues working together to advance gene therapies for hearing loss.

“Having this opportunity brings everything together,” said Dr. Tward. “Dr. McKenna shaped my development as a surgeon, and now we’re working together to move discoveries from the lab bench to the bedside. It reflects what Mass Eye and Ear has always stood for: uniting science and patient care.”

What started as a seventh-grade paper on gene therapy has come full circle. Today, Dr. Tward channels that early curiosity into advancing treatments to restore hearing and transform lives. n

OIN MEMORIAM:

JOSEPH B. NADOL, JR., MD

n August 2, Joseph B. Nadol, Jr., MD, Professor of Otolaryngology–Head and Neck Surgery Emeritus at Harvard Medical School and Director Emeritus, Otopathology Laboratory at Mass Eye and Ear, passed away. For those who knew renowned otologist Dr. Nadol, his influence ran deep, both professionally and personally. For many, he began as a mentor and became one of their closest friends. Everyone who worked with him felt the impact of his extraordinary kindness, integrity and unwavering dedication to the field.

In 1984, Dr. Nadol became Interim Chief of the Department of Otolaryngology–Head and Neck Surgery at Mass Eye and Ear, and on June 5, 1985, he was officially named the department’s fifth chief. At the time, there were only five full-time physicians in the department. Under his remarkable leadership over nearly three decades, the department grew to 49 full-time physicians across the Boston campus and 21 full-time physicians across a dozen clinical sites. In recognition of his academic and clinical excellence, he was promoted to Professor of Otology and Laryngology at Harvard Medical School in 1985, and in 1987 became an incumbent of the Walter Augustus Lecompte Professorship of Otolaryngology–Head and Neck Surgery.

Dr. Nadol was more than a leader. He was a coach, a mentor and a steadfast source of support. He cultivated a culture that celebrated curiosity, creativity and excellence. The values he championed—compassion, generosity, collegiality and humility—continue to define the department to this day. He cared greatly about his faculty and trainees. He provided advice that was well thought out and always aimed to facilitate the academic growth of his mentees. As a result, he helped to develop many of the most influential leaders of the specialty.

Dr. Nadol also loved the staff who worked closely with him, and they loyally stayed by his side, becoming like family to him and his wife, Ruth. Many of these staff members spent over 40 years working for Dr. Nadol and the department, a testament to the devotion he inspired through his interactions with those around him. A pioneer

in the surgery of the ear and temporal bone, Dr. Nadol performed the first-ever cochlear implant surgery in New England. He was an exceptionally skilled surgeon and often was called upon to assist with the most complex ear cases, a responsibility he embraced without hesitation.

Dr. Nadol was a career-long student of the pathology of the ear and temporal bone. His scholarly impact across the course of his career was profound. Throughout his career, he published extensively, with 267 research articles. In 2012, the year before he stepped down as Chair, Mass Eye and Ear received more National Institutes of Health (NIH) research funding than any other otolaryngology program in the country. Throughout his tenure, the department was consistently ranked in the top five nationwide, often number one.

Dr. Nadol’s research passion was human otopathology. He was the first to apply transmission electron microscopy to the study of pathologic human temporal bones. This led to a complete change in our understanding of Ménière’s disease, where he demonstrated the loss of terminal dendrites which could not be seen on the light microscopic level. Later in his career, he focused on the histopathology of cochlear implant recipients, reshaping how we understand what happens following implantation.

Dr. Nadol served as the Director of the Otopathology Laboratory at Mass Eye and Ear, where he and his team reviewed all available pathological temporal bones, aiming to improve the diagnosis and treatment of disorders causing hearing loss, balance dysfunction and facial paralysis. These findings were shared regularly at otopathology conferences and shaped the education of countless trainees.

One of his lasting contributions was the creation of The Joseph B. Nadol, Jr., MD, Otolaryngology Surgical Training Laboratory, which is a state-of-the-art facility offering advanced instruction capabilities for a variety of subspecialties of otolaryngology. Dr. Nadol brought this project to life from the ground up, and his dedication helped shape many young surgeons who trained under his guidance.

Over the course of his career, Dr. Nadol mentored more than 100 research fellows and trained over 100 residents. His dedication to excellence, his generosity of spirit and his unwavering commitment to the people around him have left a legacy that will continue to shape the field for generations to come.

Many of those who worked at Mass Eye and Ear knew him well and came to understand the personality of this incredible man. He freely shared his opinion, regardless of whether you agreed with him or not. He could be intimidating based on his incredible intellect, but he always treated others as equals. His broad knowledge of the field was impressive; he could speak to any aspect at any Morbidity and Mortality conference—or at any other conference, for that matter. He was famous for his absolute love for the operating room, which served as his refuge and escape from the challenges of leading the department. He liked to laugh and have fun, and he had incredible wit—he could train his dogs to growl at the mention of his current political nemesis.

Dr. Nadol was generous. He and Ruth would open their home for faculty parties, lobster bakes and the annual skating party each winter when their pond froze. He loved being outside, and gardening was one of his favorite pastimes.

The Department of Otolaryngology–Head and Neck Surgery will deeply feel the loss of Dr. Nadol, who played a foundational role in shaping who we are today. As Jeffery P. Harris, MD, PhD, a Harvard Medical School Department of Otolaryngology–Head and Neck Surgery alumni and a close friend of Dr. Nadol’s for 46 years, so aptly said, “My brother in otolaryngology has passed away. It is a truly sad day for all of us who knew him, and for me personally it leaves a huge, empty hole in my heart.”

Dr. Nadol's remarkable legacy will live on—carried by the many he trained, mentored and influenced over the years. He will be profoundly missed. n

ALUMNI GIVING SOCIETY

The Alumni Giving Society of the Department of Otolaryngology–Head and Neck Surgery

at Harvard Medical School

The Department of Otolaryngology–Head and Neck Surgery at Mass Eye and Ear/Harvard Medical School established the Alumni Giving Society in 2015 to recognize faculty and alumni who contribute $1,000 or more during the fiscal year (October 1–September 30). Participation not only strengthens your connection to the department but also provides critical resources, training tools and mentorship for the next generation of physicians, ensuring they are well-prepared to become future leaders in otolaryngology–head and neck surgery.

Our alumni understand firsthand how essential philanthropic support is in driving excellence and innovation in education, research and patient care. In fiscal year 2025, we proudly recognized 51 dedicated members whose generosity helped advance our department’s goals and institutional mission.

We are thrilled to share that exciting changes are coming to the Alumni Giving Society! As we look ahead, we want to ensure that this community is as meaningful and impactful as possible—and we need your help to make it great. Your input and support will shape the future of the society, strengthening its role in advancing our field.

If you’re not already a member, now is the perfect time to join. Your gift can be designated in a way that is most meaningful to you. Together, we can continue to build a vibrant, engaged alumni community that supports the next generation of physicians, researchers and patients.

Stay tuned for more details and thank you for being a valued part of our alumni network!

To learn more, please contact Elizabeth Vitello in the Development Office at evitello@meei.harvard.edu.

Department of Otolaryngolog y Head and Neck Surger y

sCurrent Alumni Giving Society members for fiscal year 2025, from October 1, 2024, to September 30, 2025, are listed below. With your gift of $1,000 or more, you will be included in the 2026 Alumni Giving Society.

CHAMPION

(Gifts of $25,000 and more)

Anonymous

Michael S. Cohen, MD

Eugene N. Myers, MD, FACS, FRCS Edin (Hon)

VISIONARY

(Gifts of $10,000 - $24,999)

Joseph B. Nadol, Jr., MD*

Richard D. Salerno, MD

Mark A. Varvares, MD, FACS

INNOVATOR

(Gifts of $5,000 - $9,999)

Trevor J. McGill, MD

Michael G. Moore, MD

Jay T. Rubinstein, MD, PhD

Josef Shargorodsky, MD

Noah S. Siegel, MD

William M. White, MD

PIONEER

(Gifts of $2,500 - $4,999)

Fred G. Arrigg, Jr., MD

Neil Bhattacharyya, MD

Nicolas Y. Busaba, MD

Daniel G. Deschler, MD, FACS

Jordan T. Glicksman, MD, MPH

Richard E. Gliklich, MD

Paul E. Hammerschlag, MD

Wade W. Han, MD

John B. Lazor, MD, MBA, FACS

Kasey K. Li, MD, DDS

Leila A. Mankarious, MD

Sunil Puria, PhD

Dukhee Rhee, MD

Michael B. Rho, MD, FACS

FRIEND

(Gifts of $1,000 - $2,499)

Anonymous (2)

Barry J. Benjamin, MD

David S. Caradonna, MD

Andreas Eckhard, MD

Stacey T. Gray, MD

Warren L. Griffin, Jr., MD

Ken E. Hancock, PhD

Eric H. Holbrook, MD

Jennifer C. Kim, MD

Ely A. Kirschner, MD

Paul M. Konowitz, MD, FACS

Elliott D. Kozin, MD

Daniel J. Lee, MD, FACS

Derrick T. Lin, MD, FACS

William W. McClerkin, MD

Cliff A. Megerian, MD

David E. Nash, MD

Didier L. Peron, MD

Edward J. Reardon, MD

Jeremy D. Richmon, MD

Felipe Santos, MD

George A. Scangas, MD

Prerak D. Shah, MD

Phillip C. Song, MD

Feodor Ung, MD

*Deceased

HIGHLIGHTS s

News from every corner of the Department of Otolaryngology–Head and Neck Surgery at Harvard Medical School.

New Faculty

Introducing the newest clinicians, clinician-scientists, researchers and educators in the Department of Otolaryngology–Head and Neck Surgery.

Nicholas Abt, MD, is an otolaryngologist who treats both pediatric and adult patients with disorders of the ears, nose and throat at Mass Eye and Ear’s Mashpee and Harwich offices on Cape Cod. He obtained his medical degree from The Johns Hopkins University School of Medicine and subsequently completed his residency training through the Harvard Combined Program in Otolaryngology–Head and Neck Surgery. Following his residency, Dr. Abt pursued an advanced fellowship in head and neck surgical oncology, skull base, and reconstructive surgery at the University of Miami’s Sylvester Comprehensive Cancer Center. Dr. Abt’s clinical interests include thyroid and parathyroid disorders and surgery; head and neck cancer; sinus and sleep apnea surgery; and minimally invasive endoscopic techniques for treating sinus disease.

Eye and Ear Emergency Department. He obtained his medical degree from the Washington University School of Medicine and subsequently completed his residency in otolaryngology–head and neck surgery at the University of Colorado Health Sciences Center. His clinical interests include both adult and pediatric general otolaryngology as well as emergency ear, nose and throat care.

sensory cues to orient themselves in the wider world.

Jakob Pugi, MD, is a fellowshiptrained pediatric otolaryngologist who practices at Boston Children's Hospital. He received his medical degree and completed his residency in otolaryngology–head and neck surgery at McMaster University in Hamilton, Ontario. Following his residency, Dr. Pugi completed a fellowship in pediatric otolaryngology from Boston Children's Hospital prior to joining the faculty. His clinical interests include pediatric airway management, pediatric rhinology and general pediatric otolaryngology.

Gregory E. Krause, MD, is a boardcertified otolaryngologist working in the Division of Comprehensive Otolaryngology at Mass Eye and Ear’s Boston Main Campus and in the Mass

Recent Promotions

[2] Andrew R. Scott, MD, Associate Professor of Otolaryngology–Head and Neck Surgery, Part-time

[3] Giovanni Battistella, PhD, Assistant Professor of Otolaryngology–Head and Neck Surgery

Heather Panic, MD, PhD, is a neurologist with subspecialty fellowship training in neuro-vestibular and balance disorders at Mass Eye and Ear. She specializes in treating patients with dizziness, vertigo and imbalance. Upon earning her medical degree from the University of Miami Miller School of Medicine, Dr. Panic completed residency training in neurology at the University of Florida, and fellowship training in neuro-visual and vestibular neurology at The Johns Hopkins Hospital. Her clinical interests include vestibular migraine, persistent postural-perceptual dizziness, benign paroxysmal positional vertigo and vestibular neuritis. Her research interests center broadly on understanding how people combine vestibular and other

Kimberly Reinhold, PhD, is an investigator in the Eaton-Peabody Laboratories at Mass Eye and Ear. She earned her PhD in neuroscience from the University of California, San Diego, and completed postdoctoral training in neurobiology at Harvard Medical School. Dr. Reinhold’s lab focuses on how sensory cues shape behavior and mental health by tracing how the brain links sensory experiences to adaptive or maladaptive responses. Using an innovative approach that trains mice to respond to a synthetic cue—optogenetic activation of neurons in the sensory cortex—her team maps activity through defined neural pathways to reveal how circuits and synapses change during learning. Dr. Reinhold’s long-term goal is to harness the brain’s learning mechanisms to accelerate learning and reverse the pathological changes underlying auditory disorders.

HIGHLIGHTS

Phoebe Yu, MD, MPH, is a fellowshiptrained sleep surgeon with expertise in obstructive sleep apnea and sleep performance at Mass Eye and Ear. She obtained her medical degree from Yale School of Medicine prior to completing her residency training through the Harvard Combined Program in Otolaryngology–Head and Neck Surgery. She then completed a fellowship at the University of Pennsylvania in sleep medicine and surgery. Dr. Yu specializes in surgical interventions for sleep-disordered breathing, including nasal and soft palate surgery, maxillary expansion, genioglossus advancement and hypoglossal nerve stimulation.

Awards, Grants and Honors

Thomas L. Carroll, MD, was appointed as Treasurer of The Voice Foundation. In this leadership role, Dr. Carroll will help guide the organization’s financial strategy and support its mission to advance voice research, education and clinical care.

New Leadership

Kevin S. Emerick, MD, Vice Chair for Faculty Development and Mentorship, Mass Eye and Ear

Paul M. Konowitz, MD, FACS, Associate Chief of Suburban Sites and Network Development, Mass Eye and Ear

Richard F. Lewis, MD, Director of the Vestibular Division, Mass Eye and Ear

Artur A. Indzhykulian, PhD, has received National Institutes of Health (NIH) R21 funding for a collaborative project with Ruben Stepanyan, PhD, of Case Western Reserve University, to develop treatments for noiseinduced hearing loss. This project aims to repurpose FDA-approved drugs to reversibly block the Mitochondrial Calcium Uniporter (MCU) complex, preventing mitochondrial calcium overload to reduce cochlear cell damage. Using an integrated pipeline of computational modeling, in vitro assays and in vivo testing in mouse models, the team will identify and validate drug candidates capable of preserving hearing after acoustic trauma. This drug repurposing approach offers a rapid, cost-effective alternative to traditional drug discovery.

Stella Lee, MD, has been awarded funding from the Massachusetts Institute of Technology (MIT)-Mass General Brigham (MGB) Seed Program for the “Bionic Nose Initiative.” In collaboration with Timothy Swager, PhD, of MIT, Dr. Lee will use this funding to develop and validate miniaturized chemical sensors that can detect volatile biomarkers of airway inflammation directly in vivo. The project will generate translational data to support creation of the first wearable and, ultimately, implantable “bionic nose” for objective smell diagnostics and neural restoration. The long-term goal is to transform care for patients with smell loss, bringing olfactory diagnostics and prosthetic therapy into clinical reality, much like cochlear implants revolutionized the restoration of hearing.

Anand T. N. Kumar, PhD, is the Principal Investigator on a R01 grant from the National Institute of Biomedical Imaging and Bioengineering to develop a novel surgical guidance system for intraoperative imaging of sarcomas. The system will be based on fluorescence lifetime imaging, the first of its kind, and will be validated for sarcoma surgeries in collaboration with Santiago Lozano-Calderon, MD, PhD, orthopedic oncology surgeon at Massachusetts General Hospital. Dr. Kumar's group is already involved in another R01 project from the National Institute of Dental and Craniofacial Research, applying fluorescence lifetime imaging to guide head and neck cancer surgeries at Mass Eye and Ear.

Claire Lawlor, MD, and Gregory W. Randolph, MD, FACS, FACE, received the 2025 Distinguished Service Award from the American Academy of OtolaryngologyHead and Neck Surgery Foundation. This prestigious honor recognizes Academy members who have completed the highest level of volunteer service.

Alan D. Workman, MD, MTR, was named the recipient of the Norman Knight Leadership Development Award at Mass Eye and Ear’s Spring Meeting of the Trustees and Medical Staff. The award is endowed by the late Norman Knight, a self-made broadcast pioneer and media mogul who was a passionate champion of Mass Eye and Ear for more than 25 years. Additionally, Dr. Workman was named the recipient of the American Rhinologic Society New Investigator Grant. Established to support basic, translational or clinical research in rhinology, the grant serves as a career-development award for promising investigators. Dr. Workman will lead a two-year project (2025–2027) titled “Inflammatory and disruptive effects of micro/nanoplastics in nasal epithelium” to study the impact of microplastics and nanoplastics on nasal tissue.

Matthew G. Crowson, MD, was selected as a 2025 American Academy of Otolaryngology Cochrane Scholar. As part of the program, he will conduct a systematic review examining how artificial intelligence can advance evidence in otolaryngology–head and neck surgery, from rigorous study design and bias appraisal to realworld clinical impact.

Robin W. Lindsay, MD, has been appointed as a Current Procedural Terminology (CPT) advisor (trainee) for the American Academy of Otolaryngology–Head and Neck Surgery (AAO-HNS). She has also joined the AAO-HNS Physician Payment Policy (3P) /Relative Value Update Committee (RUC).

Rahul Pal, PhD, was named Principal Investigator on a K01 Mentored Research Scientist Development Award from the National Institute of Biomedical Imaging and Bioengineering titled “Developing a library of near-infrared fluorophores for multiplexed in vivo fluorescence lifetime imaging of disease biomarkers.” The goal of this project is to create a set of fluorescent probes that can help noninvasively measure multiple cancer biomarkers in real time, directly in living tissue. Dr. Pal will work in close collaboration with Mark A. Varvares, MD, FACS, and Anand T.N. Kumar, PhD, at the Mike Toth Head and Neck Cancer Research Center.

and Neck Reconstruction: A Colorimetric and Aesthetic Analysis,” was selected from among all 2024 publications in the prestigious PRS journal, following a rigorous editorial and citation-based review conducted by the journal’s leadership.

Matthew R. Naunheim, MD, MBA, delivered a talk titled “Voice, Video, and Voxels: Artificial Intelligence in Laryngology” at the Eastern Virginia Medical School/Old Dominion University within the Department of Otolaryngology.

For the first time, Beth Israel Deaconess Medical Center Department of Otolaryngology–Head and Neck Surgery has been ranked among the Top 50 programs in the nation by U.S. News & World Report—a major milestone for their department. The team is thrilled to receive this recognition marking a significant step forward in their growth and visibility, positioning them among the leading OHNS programs in the country.

induced hearing loss. Dr. Bui-Nguyen, under the guidance of Derrick T. Lin, MD, FACS, will study the role of non-coding RNAs as prognostic biomarkers and therapeutic targets in head and neck squamous cell carcinoma (HNSCC).

Dr. Sim, mentored by Ravindra Uppaluri, MD, PhD, will use highdimensional genomic analysis of HNSCC tumor samples from a phase 2 clinical trial of perioperative pembrolizumab to explore how tumor-associated myeloid cells contribute to immunotherapy resistance.

Gregory W. Randolph, MD, FACS, FACE, has been inducted into The Royal College of Surgeons of Edinburgh (RCSEd, ad hominem), one of the oldest surgical colleges in the world. Founded in 1505, RCSEd is dedicated to promoting excellence in surgical education, training and clinical practice.

BIDMC resident Brett Campbell, MD, received the Best Oral Presentation award in the Education and Technology session at the American Head and Neck Society meeting for his research on Transoral Robotic Surgery (TORS) simulation.

Allen L. Feng, MD, received the 2025 Plastic and Reconstructive Surgery (PRS) Award for Best Head and Neck Reconstruction Paper. His study, titled “Color Match Following Free Flap Surgery in Head

Richard F. Lewis, MD, was named Principal Investigator of a four-year grant from the National Institutes of Health titled “Vestibular implant tested in patients with peripheral vestibular damage: effects on spatial orientation, navigation, and neuropsychologic function." His research team will study how vestibular damage in the inner ear impacts cognitive function in patients. They will also evaluate how effectively a vestibular implant that simulates the three semicircular canals restores function.

Residents Zachary A. Kons, MD, Hoang Bui-Nguyen, MD, PhD, and Edward Sim, MD, were recently awarded Centralized Otolaryngology Research Effort grants by the American Academy of Otolaryngology–Head and Neck Surgery Foundation. Dr. Kons, mentored by Aaron Remenschneider, MD, MPH, FACS, will investigate a self-administered otic drop method for delivering sodium thiosulfate (STS) to prevent cisplatin-

Sophia Z. Shalhout, PhD, Mark A. Varvares, MD, FACS, and Tessa Goldsmith, MA, CCC-SLP, Program Director of Head and Neck Cancer Survivorship at Mass Eye and Ear, were awarded the Design Impact Award through Mass General Brigham’s Springboard Studio for their project titled "Artificial Intelligence Powered Survivorship Care Plans for Patients with Head and Neck Cancer." The team is creating AI-powered Survivorship Care Plans (SCPs) tailored for head and neck cancer survivors, addressing treatment summaries and challenges such as swallowing, speech, dental and psychosocial issues. Using machine learning, the SCPs educate patients, identify concerns and prioritize care. Accessible to caregivers, primary care providers and oncology teams, this approach supports personalized survivorship care and improves quality of life.

RESEARCH ADVANCES s

The following are select research advances from the Harvard Medical School Department of Otolaryngology–Head and Neck Surgery.

Basic Research

AAV-delivered exon skipping approach for Usher syndrome 2A

Usher syndrome (USH) is a genetic disorder that can lead to combined loss of vision, hearing and balance. It is classified into four clinical subtypes (USH1–4), each associated with mutations in genes essential for the structure, function and survival of photoreceptor cells in the retina and sensory hair cells in the inner ear. Among these, mutations in the USH2A gene, which encodes the usherin protein, are the most common cause worldwide. The c.2299delG (p.Glu767Serfs*21) variant is the most frequent pathogenic mutation in USH2A.

Therapies targeting USH2A face unique challenges due to the gene’s large size, which exceeds the capacity of traditional AAV gene replacement vectors. Antisense oligonucleotides (ASOs), such as QR-421a, have been developed to bypass the c.2299delG mutation by inducing exon skipping, and it has already shown promise in phase 1/2 clinical trials. However, ASOs typically require repeated injections for sustained efficacy, even with newer chemistries that extend half-life. To address this limitation, a research team led by Gwenaëlle S.G. Géléoc, PhD, Jeffrey R. Holt, PhD, and Karl R. Koehler, PhD, all of Boston Children’s Hospital, screened novel exon 13 skippers and 20 AAV capsids to create a vectorized ASO delivery system capable of long-term exon skipping. Optimized constructs were tested in human inner ear and retinal organoids harboring the c.2299delG mutation.

The results, published in Molecular Therapy, demonstrated enhanced skipping of the pathogenic exon, suggesting a potential single local injection approach to slow

or prevent progression of vision and hearing loss in USH2A patients.

Mauriac SA, Lee J, Zhang J, et al. AAV-mediated exon skipping therapy for Usher syndrome, type 2A. Molecular Therapy. 2025:S1525-0016(25)00767-1. doi: 10.1016/j. ymthe.2025.09.038.

Slow neural synchronization is most affected by auditory distraction

Listening in noisy environments requires focusing on a target sound while filtering out competing sounds. Some background noise can be ignored, but other sounds capture attention and interfere with perception. During active listening, the auditory system separates target and distracting sounds using temporal cues that occur across multiple timescales, from rapid fluctuations in acoustic fine structure to slower grouping patterns that unfold over seconds. Understanding how the brain maintains focus in the presence of distraction offers insight into why some individuals struggle to hear in noisy settings despite normal hearing.

In a study led by Daniel B. Polley, PhD, of Mass Eye and Ear, researchers developed an approach to directly measure how the brain encodes multiple layers of sound features under different levels of distraction. Target sounds contained nested temporal features across four timescales, from fine structure (~500 Hz) to slower pattern changes (~0.5 Hz), and were presented with either a highly distracting melody or a less distracting noise. Neural synchronization to these features was recorded using electroencephalogram (EEG) to determine how distraction affects auditory encoding.

The study, published in Frontiers in Human Neuroscience, found that synchronization to relatively slow changes in the envelope of target sounds deteriorated with increasing distraction, while synchronization to

faster fluctuations in the fine structure or envelope remained stable. For error trials, reduced synchronization to the target sound occurred alongside enhanced entrainment to slower temporal features of the distractor sound. By using a novel stimulus paradigm, the team was able to measure multiple target and distractor sound features in the EEG simultaneously. This approach may provide a valuable tool for studying listening difficulties in noisy environments and clinical populations who struggle to suppress distracting sounds.

Sorensen DO, Sugai JA, Parthasarathy A, et al. The slowest timescales of neural synchronization reveal the strongest influence of auditory distraction. Frontiers in Human Neuroscience. 2025;19:1623431. doi: 10.3389/ fnhum.2025.1623431.

Translational Research

High-frequency hearing restoration in partial ossicular discontinuity

Ossicular discontinuity refers to an abnormal separation of the three middle ear bones, or ossicles. It can be complete, where the ossicles lose all contact and cause a large 40–60 dB air-bone gap, or partial, where abnormal bony or soft tissue connections replace normal joints. Partial discontinuity often produces high-frequency conductive hearing loss because low-frequency sounds still transmit through fibrous tissue. While previous studies have examined surgical repair of ossicular discontinuity, most have grouped partial and complete cases together and reported only frequency averaged hearing improvements. As a result, the specific effects of partial discontinuity and its repair on highfrequency hearing (≥4 kHz) remain poorly understood.

To address this gap, researchers in the Eaton-Peabody Laboratories (EPL) at Mass Eye and Ear conducted a study

led by Aaron K. Remenschneider, MD, MPH, of Boston Children’s Hospital, with contributions from EPL principal investigators Jeffrey T. Cheng, PhD, and John J. Rosowski, PhD. The study aimed to evaluate how partial ossicular discontinuity and its repair affect sound transmission in the middle ear using human cadaveric temporal bones, and to correlate these mechanical findings with pre- and post-operative patient audiometric outcomes. The researchers hypothesized that repairing partial discontinuity with bone cement would restore stapes velocity to baseline in temporal bones and improve highfrequency hearing in patients. Six human temporal bones were tested before and after creating and repairing partial discontinuity using dual laser Doppler vibrometers to measure stapes and umbo motion. Audiometric thresholds were also analyzed from two patients who underwent endoscopic bonecement repair of surgically confirmed partial ossicular discontinuity

Results, published in Otology & Neurotology, showed that partial discontinuity decreased stapes velocity by 20 dB between 4–14 kHz and increased umbo velocity at low frequencies, consistent with a ‘loose’ ossicular system. Repair of the ossicles with bone cement restored sound-induced motion of both structures to normal levels. Clinically, the team reported on a series of patients with high frequency hearing loss and an air-bone gap at 4kHz. Exploratory middle ear surgery demonstrated partial ossicular discontinuity that was repaired with bone cement. Post-operatively high-frequency conductive hearing losses were significantly improved—closing or nearly closing their 4 kHz air-bone gaps, improving hearing at higher frequencies and normalizing tympanometry. These findings indicate that bone cement repair can restore high-frequency sound trans-

mission in the middle ear and that certain types of high-frequency hearing loss are surgically correctable.

Fallon K, Inuzuka Y, Cheng JT, et al. Restoration of HighFrequency Middle Ear Function in Partial Ossicular Discontinuity: A Basic Science and Clinical Correlation. Otology & Neurotology. 2025 Oct 10. doi: 10.1097/ MAO.0000000000004657.

HPV-related oropharyngeal cancer detected early with ctHPVDNA

Early detection of human papillomavirus (HPV)-associated oropharyngeal cancer (HPV+OPSCC), the most common HPVrelated cancer in the United States, could dramatically reduce disease-related morbidity and mortality. Unlike cervical cancer, HPV+OPSCC currently has no recommended screening test, and most cases are diagnosed after metastasis to cervical lymph nodes. HPV+OPSCC develops over many years, and infected cells release fragments of the viral genome, known as circulating tumor HPV DNA (ctHPVDNA), into the bloodstream. While ctHPVDNA is detectable at diagnosis, it has been unclear whether it can be reliably detected in asymptomatic patients years before clinical onset.

These findings, published in the Journal of the National Cancer Institute (JNCI), demonstrate that ctHPVDNA can be reliably detected in blood years before clinical diagnosis, with high specificity. Detection of ctHPVDNA alone or alongside serological biomarkers may provide a feasible approach for early detection and intervention in HPV+OPSCC. Recent work also published in JNCI from Anil Chaturvedi, PhD, cancer epidemiologist at the NCI, found that early detection of HPV+OPSCC could reduce the number of cancers diagnosed at advanced stages, treated by multiple modalities and mortality, using traditional treatment approaches. However, identifying cancer up to a decade before it becomes clinically apparent raises important ethical and clinical questions regarding patient counseling, surveillance and the potential harms of overdiagnosis. Future work must define not only when and how to act upon early detection, but also explore potential interventions—whether immunologic, antiviral or local/topical— that could alter the natural history of the disease.

A study led by Daniel L. Faden, MD, FACS, of Mass Eye and Ear, used plasma samples collected 1–11 years before diagnosis from 28 HPV+OPSCC patients and 28 matched controls. Researchers applied HPV-DeepSeek, a newly developed multi-feature HPV wholegenome sequencing liquid biopsy assay developed by the Faden Lab, along with a HPV antibody test. ctHPVDNA was detected in 22 of 28 pre-diagnostic cases, achieving a sensitivity of 79 percent, and was not detected in any of the controls, giving 100 percent specificity. The assay was most accurate within four years of diagnosis and outperformed HPV antibody detection. Incorporating a machine learning model further increased sensitivity to 27 of 28 cases, or 96 percent, and extended the maximum lead time to 10.3 years.

Das D, Hirayama S, Aye L, et al. Circulating tumor human papillomavirus DNA whole genome sequencing enables human papillomavirus-associated oropharynx cancer early detection. Journal of the National Cancer Institute. 2025:djaf249. doi: 10.1093/jnci/djaf249.

Landy R, Haber GW, Graubard BI, et al. Impact of screening for human papillomavirus-positive oropharyngeal cancers: a microsimulation-based modeling study. Journal of the National Cancer Institute. 2025 Jun 1;117(6):1209-1217. doi: 10.1093/jnci/djaf033

Understanding per-and polyfluoroalkyl substances exposure and effects on sinonasal health

Environmental exposure to pollutants, including particulate matter and toxic gases, poses risks to respiratory health and olfaction. With the increasing production and use of synthetic chemicals, chronic exposure to potentially harmful substances has become a major public health concern. Among these, perand polyfluoroalkyl substances (PFAS)— a class of over 4,000 highly stable,

RESEARCH ADVANCES s

fluorinated compounds—have garnered attention due to their widespread use in firefighting foams, nonstick coatings, and other industrial and consumer applications. PFAS resist degradation and accumulate in the environment, wildlife, and humans, primarily entering the body through contaminated food and water, with additional exposure from air, household dust, and consumer products. Known health effects include metabolic, kidney, liver, and thyroid dysfunction, as well as immunosuppression. The respiratory effects of PFAS, particularly in the upper airways, remain poorly understood, with limited and inconsistent evidence regarding pulmonary function and infection risk.

contaminants, may be linked to olfactory dysfunction and sinonasal disease. Some effects appear to depend on the specific composition of the mixture. Further mechanistic and longitudinal studies are needed to clarify how PFAS mixtures interact and impact the nose and sinuses.

Chiang S, Jung YS, Thorley W, et al. Forever Chemicals: An Exploratory, Population-Based Analysis of Per- and Polyfluoroalkyl Substances Exposure and Effects on Sinonasal Health. Allergy. 2025. doi: 10.1111/all.70092.

Real-time vocal fold motion during laryngoscopy

Using 2011–2014 National Health and Nutrition Examination Survey (NHANES) data, this study led by Stella E. Lee, MD, of Brigham and Women’s Hospital, utilized a cross-sectional design to investigate possible asso-ciations between PFAS exposure and sinonasal symptoms, aiming to provide population-based epidemiological evidence on their toxicological effects. The team of researchers analyzed associations between serum PFAS concentrations and self-reported sinonasal symptoms in 1,911 adults 40 years of age or older.

Multivariable logistic regression showed that one of the more bioactive chemicals in the PFAS family, Me-PFOSA-AcOH, was associated with an increased likelihood of sinonasal symptoms such as nasal congestion. Bayesian kernel machine regression (BKMR) indicated that Me-PFOSA-AcOH and PFHxS had exposure–response effects on olfaction that became more pronounced at higher concentrations of PFNA within the mixture.

These findings, published in Allergy, indicate that exposure to Me-PFOSAAcOH may contribute to upper airway symptoms such as nasal congestion, while other PFAS, often present in complex mixtures with additional

Laryngoscopy is widely used to diagnose voice, swallowing and breathing disorders by identifying anatomical or functional abnormalities. However, assessments currently rely heavily on clinician experience and subjective interpretation, with limited support from automated or quantitative tools. Recent advances in artificial intelligence (AI) and computer vision (CV) have shown promise in automating laryngoscopic image analysis. Applications include keypoint tracking for glottal opening angle estimation, vocal fold image segmentation, pose estimation and glottal closure estimation. AI models have achieved high accuracy in detecting anatomical structures and motion, even in challenging clinical videos. However, most current AI tools are designed for specific offline analyses, limiting their utility for real-time clinical use. Integrating AI and CV into real-time videolaryngoscopy could improve diagnostic accuracy, reduce subjectivity and provide immediate feedback during procedures.

A study led by Matthew R. Naunheim, MD, MBA, and Kristina Simonyan, MD, PhD, DrMed, both of Mass Eye and Ear, assessed the feasibility of a real-time solution for automated vocal fold tracking during in-office laryngoscopy.

The team, with first author Aki Koivu, PhD, research fellow at Mass Eye and Ear, at the helm of training the keypoint detection model, identified 39 individual keypoints of the larynx using over 1,200 annotated video frames from 57 laryngoscopy videos. Model performance was evaluated using a validation set of 140 images and an independent test set of 50 images. Accuracy was measured by comparing predicted keypoints to manually annotated keypoints using mean keypoint accuracy (mKA), and temporal stability was assessed using mean temporal consistency (mTC) from a calibration video. For real-time testing, a live laryngoscope feed was routed through a video capture card to a laptop running the model, allowing evaluation of its performance during in-office laryngoscopy.

The results, published in The Laryngoscope, showed that the model achieved mKA of 85 percent on validation data and 75 percent on an independent test set, with strong mTC. When connected to a live laryngoscope feed, it operated smoothly at 30 frames per second with minimal latency. These findings demonstrate that AI-based tracking of laryngeal motion is accurate, stable, and compatible with standard hardware, supporting future real-time diagnostic applications in clinical settings.

Clinical Research

Completeness of surgery index predicts CRSwNP-asthma outcomes by SNOT-22 and ACT

Chronic rhinosinusitis with nasal polyps (CRSwNP) and asthma share Type 2 inflammatory mediators. CRSwNP with comorbid asthma, including aspirinexacerbated respiratory disease (AERD), represents a more severe and difficult-tocontrol subtype. Endoscopic sinus surgery (ESS) improves sinonasal and asthma

outcomes, though patients with asthma often have higher revision rates. More extensive procedures, including adequate frontal sinus opening, often offer better long-term control, particularly in AERD. The Completion of Surgery Index (CoSI) was developed to assess surgical completeness, and patients who had previously incomplete surgeries (CoSI <70) had greater improvement after revision ESS.

More extensive ESS has been shown to correlate with better disease control in CRSwNP. A study, led by Alan D. Workman, MD, MTR, of Mass Eye and Ear, evaluated the impact of CoSI on sinonasal quality of life (SNOT-22) and asthma control (ACT) in CRSwNP patients with asthma. Seventy patients who underwent revision ESS between 2018 and 2023 were included; 49 (70 percent) had CoSI <70 on preoperative CT. The CoSI <70 group demonstrated significantly greater improvements in SNOT-22 and ACT scores over two years compared to the CoSI ≥70 group.

The findings, published in International Forum of Allergy & Rhinology, revealed that preoperative CoSI <70 was associated with significantly greater long-term improvements in sinonasal and asthma outcomes after revision ESS, supporting the importance of complete surgery in managing CRSwNP with asthma.

Yu AJ, Phung C, Kuppusamy K, et al. The Completeness of Surgery Index Predicts Success in CRSwNP With Asthma by SNOT-22 and Asthma Control Test. International Forum of Allergy & Rhinology. 2025. doi: 10.1002/alr.70043.

Social and financial barriers to timely head and neck cancer

care in the United States

An estimated 67,000 new cases of head and neck cancer (HNC) and 15,000 deaths in 2023 highlighted the significant health burden of this disease in the United States. Despite advancements in care, timely diagnosis and treatment remain critical for patient outcomes. Delays in care and the financial strain

of treatment are often linked to social determinants of health (SDOH), including socioeconomic status, insurance coverage and transportation access. Low income and lack of insurance are associated with more advanced disease at diagnosis and poorer survival, and rural patients face additional challenges due to the costs and logistics of traveling for specialized care. High out-of-pocket costs and lost income from treatment-related work absences amplify financial strain, disproportionately affecting socioeconomically disadvantaged patients. Despite recognition of these challenges, their precise impact on access to care remains poorly understood.

Hypoglossal nerve stimulation for treating obstructive sleep apnea in children with Down syndrome under 13

A qualitative study, led by Regan W. Bergmark, MD, MPH, of Brigham and Women’s Hospital, aimed to explore how SDOH facilitate or hinder HNC care in the United States, using insights from patients and healthcare workers to identify potential targets for intervention. Semi-structured interviews were conducted between June 2022 and July 2023 with patients newly diagnosed with HNC and the healthcare workers who care for them at two large cancer centers, including a safety net center. A total of 72 participants were interviewed, including 42 patients and 30 healthcare workers. Analysis revealed three key mechanisms affecting care: socioeconomic instability that forces patients to make critical choices, the burden of navigating health insurance gaps, and transportation-related financial and logistical barriers that disrupt care processes.

Published in Oral Oncology, the team concluded that financial instability, insurance gaps and transportation challenges create barriers to HNC care for disadvantaged patients. Addressing these factors can enhance the timeliness of care and has the potential to improve patient outcomes.

Batool S, Hansen EE, Sethi RKV, et al. Financial instability, insurance, and transportation influence timely head and neck cancer care in the United States: Patient and healthcare worker perspectives. Oral Oncology. 2025;169:107607. doi: 10.1016/j. oraloncology.2025.107607.

Obstructive Sleep Apnea (OSA) is highly prevalent among children with Down syndrome, affecting up to 80 percent, compared with just 5 percent of the general pediatric population. Adenotonsillectomy is the standard treatment, but it is often less effective in children with Down syndrome due to anatomical differences, including a larger tongue that can obstruct the airway during sleep. The hypoglossal nerve stimulator (HGNS)—an implant that functions like a “tongue pacemaker” by moving the tongue forward to open the airway during apnea—has been shown to be safe and effective in patients with Down syndrome between the ages of 13 to 21 and is approved by the U.S. Food and Drug Administration for this use. However, there remains an unmet need for HGNS implantation in children under 13 with severe OSA.

Christopher J. Hartnick, MD, MS, of Mass Eye and Ear, led a study with an objective to determine the safety and efficacy of HGNS placement in children under 13 years of age with Down syndrome and severe OSA. This was a retrospective review of 29 children between the ages of four and 12 who underwent HGNS implant surgeries at two hospitals: Mass Eye and Ear and Phoenix Children’s Hospital. All children received sleep studies prior to surgery, with follow-up assessments conducted between a few months and three years postoperatively.

The findings, published in International Journal of Pediatric Otorhinolaryngology, demonstrated that HGNS surgery was safe in all 29 children, with no serious adverse events reported. One child experienced a minor surgical wound healing issue, which was resolved without complication. Importantly, no adverse events were attributed to the device itself. The study also found substantial

RESEARCH ADVANCES s

improvements in sleep apnea severity. At six months post-surgery, over 95 percent of children experienced a reduction of 50 percent or more in the obstructive apnea–hypopnea index (OAHI). Prior to surgery, the median OAHI was over 18 events per hour, which decreased to nearly four events per hour after surgery, representing a marked improvement in respiratory outcomes. The team concluded that HGNS implantation in children with Down syndrome and severe OSA can be safely performed in children ages between four and 13, and initial efficacy studies demonstrate outcomes similar to children over 13. Work is underway for a future project to evaluate the effects upon neurocognition and expressive language by treating the underlying sleep apnea in this age group population.

Kim M, Xu LJ, Shih E, et al. Hypoglossal nerve stimulator for obstructive sleep apnea in children with Down syndrome younger than 13. International Journal of Pediatric Otorhinolaryngology. 2025;196:112497. doi: 10.1016/j.ijporl.2025.112497.

United States thyroid disorder healthcare expenditures

Thyroid disorders, including hypo- and hyperthyroidism as well as benign and malignant nodules, are increasingly common in the United States. Diagnosis typically involves laboratory testing and imaging, while management ranges from medication to surgery depending on disease severity and malignancy risk. These conditions impose substantial healthcare costs, with thyroid cancer projected to exceed $3.5 billion annually and hypothyroidism costing up to $2,500 per patient per year. However, no national study had previously quantified total expenditures across all thyroid disorders.

Neil Bhattacharyya, MD, FACS, and Gregory W. Randolph, MD, FACS, FACE, both of Mass Eye and Ear, led a national cross-sectional study using the Medical Expenditure Panel Survey (MEPS). The team estimated that nearly 20 million

adults—8.1 percent of the U.S. adult population—are affected by thyroid disorders. Patients with these conditions had significantly higher healthcare utilization, including an average of three additional office visits and nine additional prescription fills per year compared to individuals without a thyroid disorder diagnosis. Emergency department visits did not differ between groups.

The findings, published in Head & Neck, revealed that thyroid disorders are associated with an incremental $3,110 in annual healthcare costs per patient, translating to an estimated $61.5 billion in national expenditures (2018 U.S. dollars). These increased costs stem primarily from office-based care and prescription medications. This work represents the first and most comprehensive U.S. estimate to date of healthcare expenditures associated with both benign and malignant thyroid conditions.

Feng AY, Soffer JM, Mitchell MB, et al. Estimating the Annual Healthcare Expenditure Costs and Utilization of Thyroid Disorders in the United States. Head Neck. 2025. doi: 10.1002/hed.28223.

Assessing voice impairment with a patient-centered, lower burden approach

Characterizing and quantifying voice impairments is complex, as patients’ experiences of dysphonia differ widely depending on factors such as the demands of their voice use and the onset and duration of symptoms. New or shortterm problems may feel more disruptive than long-standing ones, emphasizing the importance of patient-centered assessments. The Voice Handicap Index (VHI) and its 10-item variant (VHI-10) are widely used tools for quantifying patients’ perceptions of their voicerelated handicap. However, less is known about how patients themselves view and prioritize the items included in the VHI-10, or whether all items carry equal relevance to their lived experience, such that a shorter version may be sufficient.

To explore this practical clinical question as it relates to daily practice, Jennifer Shin, MD, MPH and Thomas L. Carroll, MD, both of Brigham and Women’s Hospital, performed a prospective, psychometric and patientcentered study which was conducted across tertiary and community-based laryngology practices. The study included 6,048 adult respondents who completed VHI-10 prior to visits for laryngology evaluations. Factor analysis confirmed the VHI-10 reliably measures a single concept of voice handicap and item response theory analyses identified the questions most sensitive to differences in voice impairment. In addition, 461 patients ranked the VHI-10 items by importance, and 521 assessed three proposed sixitem subsets informed by these analyses.

Published in JAMA Otolaryngology–Head & Neck Surgery, the results demonstrated that the most effective items at distinguishing between different levels of impairment were those addressing difficulty being heard, being understood in noisy settings, vocal strain and the effort required to produce voice. Patients most often prioritized items related to vocal strain, unpredictable voice clarity and difficulty being heard. Income-related impact was also deemed important. Based on these discoveries, a six-item subset was determined to encompass a patientcentered, lower burden, new approach for assessing patients in daily clinical care. These findings suggest that a shorter, patient-informed version of the VHI-10 may enhance patientcenteredness, improve measurement efficiency and reduce response burden while maintaining clinical and psychometric integrity.

Willard EG, Carroll TL, Kim M, et al. Patient-Centered Approach to Assessing Voice Impairment. JAMA Otolaryngology Head & Neck Surgery. 2025:e252691. doi: 10.1001/jamaoto.2025.2691.

Connect with us on LinkedIn: All former residents and fellows are invited to join the Harvard Otolaryngology–Head and Neck Surgery Alumni Group.

U.S. News & World Report "Best Hospitals"

In its 2025–2026 "Best Hospitals" issue, U.S. News & World Report recognized Mass Eye and Ear, Brigham and Women's Hospital, and Beth Israel Deaconess Medical Center as top hospitals for ear, nose, and throat care. Mass Eye and Ear ranked #5 nationally. Brigham and Women's and Beth Israel ranked among the nation’s Top 50. Mass Eye and Ear remained #1 in New England, a distinction the hospital has held since the inception of the rankings in 1990.

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