Harvard Otolaryngology Spring 2022 by HMS Otolaryngology

Spring 2022, vol. 18, no. 1

Fighting HPV Head and Neck Cancer

One Blood Sample At a Time Non-invasive “liquid biopsies” could forever change the way physicians diagnose, monitor and treat the disease.

Department of Otolaryngology Head and Neck Surgery

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CONTENTS News from the Harvard Medical School Department of Otolaryngology– Head and Neck Surgery Spring 2022 | Vol. 18, No. 1 Published twice per year. Please send comments, requests for additional copies and other inquiries regarding this issue to: Michael Kotsopoulos Communications Manager Department of Otolaryngology–Head and Neck Surgery Massachusetts Eye and Ear 243 Charles Street, Boston, MA 02114 617-573-3656 | mkotsopoulos@meei.harvard.edu

1 Letter From the Chair Mark A. Varvares, MD, FACS 2 New Era for the Eaton-Peabody Laboratories 20 Discussion Panel: A Lesson on Diversity, Equity & Inclusion 22 Alumni Giving Society 23 Donor Profile 24 Alumni Profile Edward J. Reardon, MD, ’78

CONTRIBUTORS

26 Highlights

Editor-in-Chief Mark A. Varvares, MD, FACS John W. Merriam and William W. Montgomery Professor and Department Chair of Otolaryngology–Head and Neck Surgery Harvard Medical School

29 Research Advances

Chief of Otolaryngology–Head and Neck Surgery Massachusetts Eye and Ear Massachusetts General Hospital Managing Editor | Writer Michael Kotsopoulos Design | Layout | Photography Garyfallia Pagonis

FEATURES 4 Fighting HPV Head and Neck Cancer One Blood Sample At a Time

8 Correcting Hearing Loss With the Split of a Gene

A novel dual-vector, protein recombination strategy developed at Boston Children’s Hospital has galvanized the field of inner-ear therapeutics.

Cover design: Garyfallia Pagonis

Department of Otolaryngology Head and Neck Surgery Beth Israel Deaconess Medical Center Boston Children’s Hospital Brigham and Women’s Hospital Massachusetts Eye and Ear Massachusetts General Hospital

Non-invasive “liquid biopsies” might be the key to changing the way physicians diagnose, monitor and treat the disease.

Gender-Affirming Care Finds Its Voice

At Mass Eye and Ear, the Division of Laryngology has collaborated with the Voice and Speech Laboratory to care for transgender individuals throughout Greater Boston.

Scouting Surgeries, Healing the Margins

In Nepal, David Shaye, MD, MPH, has turned to a team of surgical scouts to help combat a global surgical crisis.

LETTER FROM THE CHAIR Dear colleagues and friends,

ver the past few decades, otolaryngology has evolved at a remarkable pace. Driven by an innovative spirit, researchers and clinicians have unlocked mechanisms of many of the diseases we treat and have developed therapies and diagnostics once thought unfathomable.

These changes didn’t happen overnight. They took months, years and decades to unfold—each one built upon prior breakthroughs in the lab and clinic; innovations and discoveries that began as a “ripple,” and expanded into a sweeping wave. In this edition of Harvard Otolaryngology, I am proud to report the early ripples of change generated from our laboratories and clinics here in New England. We’ve seen researchers at Mass Eye and Ear develop a “liquid biopsy” that could one day help personalize treatments for HPV-associated head and neck cancers. Across the city, faculty at Boston Children’s Hospital have developed a novel dual-vector gene therapy capable of treating genetic hearing loss and other genes once thought too large to treat. I’m even prouder of the ripples that have surged beyond the region. In Nepal, a surgical scout program developed by David Shaye, MD, MPH, has combatted a global surgical crisis. Our Diversity, Equity & Inclusion Task Force continues to strive for health equity and social justice in multiple areas, and the Transgender Voice and Speech Modification Program at Mass Eye and Ear has encouraged physicians to rethink gender-affirming care as a medical necessity. My hope is that the groundbreaking innovations and discoveries happening here in the Department of Otolaryngology–Head and Neck Surgery at Harvard Medical School will inspire you, and that these breakthroughs will grow into waves of change that transform the next several decades of otolaryngological care, research and education. Thank you for your interest and support of our department’s research, initiatives and activities. Sincerely,

Mark A. Varvares, MD, FACS The John W. Merriam and William W. Montgomery Professor and Chair Department of Otolaryngology– Head and Neck Surgery, Harvard Medical School Chief Departments of Otolaryngology– Head and Neck Surgery, Massachusetts Eye and Ear Massachusetts General Hospital

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NEWS

New Era for the Eaton-Peabody Laboratories As M. Charles Liberman, PhD, steps down from his role as Director of the Eaton-Peabody Laboratories, the future of hearing research at Mass Eye and Ear has never looked brighter.

n February 2022, M. Charles Liberman, PhD, the Harold F. Schuknecht Professor of Otolaryngology–Head and Neck Surgery (OHNS) at Harvard Medical School (HMS), announced his decision to step down from his leadership positions as Director of the Eaton-Peabody Laboratories (EPL) and as Vice Chair of Basic Research in OHNS at Mass Eye and Ear. As a world-renowned leader in inner-ear research, Dr. Liberman had led the EPL, the world’s largest and most productive private research enterprise focused on hearing and deafness, since 1996, and had served as Vice Chair of Basic Research since 2011. The EPL is undergoing a major renovation to its central facilities, much of which has remained as it was built in 1972. The renovations will be funded in large part by a generous gift from the Amelia Peabody Charitable Fund, champions of the EPL since it was founded in 1958 through a partnership between Miss Amelia Peabody and Nelson Kiang, PhD, the EPL’s founding director. “I’ve been planning the transition to a new director for several years,” Dr. Liberman said. “A major factor in my decision to make the change now is that the design for the new EPL research space should be led by the next generation of leadership.” For the past five decades, Dr. Liberman has led cutting-edge research on the pathology of the inner ear and the mechanisms of sound processing in the auditory nerve. He earned his PhD from Harvard University in 1976 before joining Mass Eye and Ear as a research associate. In 1996, Dr. Liberman was appointed Director of the EPL, which has

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M. Charles Liberman, PhD, poses next to his desk in the Eaton-Peabody Laboratories.

undergone immense growth under his leadership. Since his appointment, 12 new HMS faculty have joined the laboratories. Additionally, four researchers from the EPL have been awarded endowed Harvard professorships, five researchers have been appointed endowed Mass Eye and Ear chairs and the EPL’s endowment has grown to $12 million.

Over the span of his research career, Dr. Liberman has authored more than 200 peer-reviewed articles. In 2009, Dr. Liberman and Sharon Kujawa, PhD, the Sheldon and Dorothea Buckler Chair in OHNS at Mass Eye and Ear and a Principal Investigator in the EPL, uncovered a new type of inner-ear damage called cochlear synaptopathy, also known as “hidden

A Future Full of Opportunity

cience has dramatically changed since the EPL first opened more than six decades ago. Today, computer electronics are tinier than ever and molecular

approaches have emerged at the forefront of therapeutics.

M. Charles Liberman, PhD, in the laboratory performing neurophysiological experiments in 1982.

hearing loss.” Their landmark discovery, which has changed the way the scientific community understands hearing loss, showed that there could be permanent damage to auditory nerve fibers from loud noises or age long before there is damage to the sensory cells. Dr. Liberman vacated both roles on February 1, 2022, but has remained a fulltime investigator in the EPL, as well as a full-time HMS faculty member, since. Daniel B. Polley, PhD, the Amelia Peabody Chair of OHNS at Mass Eye and Ear and a Professor of OHNS at HMS, has served as Interim Director of the EPL amid a nationwide search for a permanent director. Future research led by Dr. Liberman will be split between a collaborative P50 grant on hidden hearing loss and an individual NIH R01 grant on the mechanisms and potential treatments of noise-induced hearing loss in animal models. n

[

Starting in 2022, approximately 10,000 square feet of the EPL will undergo renovations to meet the demands of a modern scientific and academic laboratory space. These renovations will likely include state-of-the-art molecular neuroscience laboratories, a new engineering core facility, an academic suite and individual offices. Once completed, these renovations will help Mass Eye and Ear continue its longstanding tradition of international preeminence in hearing science. By expanding its research capabilities and reconfiguring space for cross-discipline collaborations, the EPL will Daniel B. Polley, PhD, is serving as Interim Director of the Eaton-Peabody Laboratories and overseeing the early stages of the lab’s renovations. Dr. Polley is also serving as the Interim Vice Chair of Basic Research.

foster an optimal space for the next generation of groundbreaking hearing advances.

“Dr. Liberman helped transform the Eaton-Peabody Laboratories into the preeminent center

for hearing loss and deafness research. While he has already left an invaluable impact on the EPL, his true impact will be measured by the breakthroughs that emerge years from now and lay the foundation for the next wave of diagnostic tools and therapies.” –Mark A. Varvares, MD, FACS, Chief of the Department of OHNS at Mass Eye and Ear

]

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Fighting

HPV

Head and Neck Cancer One Blood Sample At a Time The incidence of HPV-associated head and neck cancers has become an epidemic in the United States. Recent studies reveal that non-invasive “liquid biopsies” might revolutionize the way surgeons diagnose and treat the disease for years to come.

FEATURE

ead and neck cancer is the sixth most common cancer worldwide. In the United States, human papillomavirus (HPV), a sexually transmitted infection, has fueled the dramatic rise of one head and neck cancer in particular: oropharyngeal squamous cell carcinoma. HPV-associated oropharyngeal squamous cell carcinoma, which is found in the back of the throat, has surpassed cervical cancer as the most common HPV-associated malignancy in the United States. Approximately 75 percent of oropharyngeal squamous cell carcinoma cases are HPV-associated. The disease afflicts younger head and neck cancer patients more than head and neck cancers caused by smoking. Thankfully, if caught in its early stages, HPVassociated oropharyngeal squamous cell carcinoma has a high survival rate. Physicians can use robotic technology, chemotherapy and radiation to treat the disease. However, these treatments can cause severe side effects such as difficulty swallowing, muscle fibrosis of the neck, dry mouth, chronic pain and cranial nerve problems, especially when multiple treatments are combined together. The accumulation of these side effects can impact a patient’s quality of life years later. “It’s no longer enough to ensure a patient is cancerfree,” said Jeremy Richmon, MD, Associate Professor of Otolaryngology–Head and Neck Surgery at Harvard Medical School and Director of Robotic Surgery at Mass Eye and Ear. “These patients should expect to live comfortably for another 20-to-30 years after their treatment. It’s up to us to erase the specter of cancer from patients’ rearview mirrors by tailoring their treatment and optimizing their outcomes.” In recent years, researchers have developed noninvasive “liquid biopsies” that could serve as a tool for detecting cancers earlier, and more accurately, than traditional diagnostic approaches. In a pair of studies published in Clinical Cancer Research and Cancer, a team of researchers at Mass Eye and Ear and Mass General Hospital led by Daniel Faden, MD, FACS, Assistant Professor of Otolaryngology–Head and Neck Surgery at Harvard Medical School and Investigator in the Mike Toth Head and Neck Cancer Center at Mass Eye and Ear, investigated how its own HPV-specific liquid biopsy compared to traditional approaches. Not only did the liquid biopsy prove more accurate, less expensive and potentially faster, but the team

Daniel Faden, MD, FACS, has developed a “liquid biopsy” more accurate, less expensive and potentially faster than conventional methods used for diagnosing HPV-associated head and neck cancers.

became the first to demonstrate how a liquid biopsy could one day help personalize post-operative care for HPV-associated head and neck cancer patients.

A non-invasive, liquid biopsy for HPV-associated head and neck cancer According to Dr. Faden, current diagnostic techniques for HPV-associated head and neck cancers have significant limitations. Tissue biopsies are invasive and may require repeat testing before a final diagnosis can be made. Cross-sectional imaging, such as CT scans, and physical exams are only sensitive when a cancer has grown to a size visible to the naked eye. “By the time a tumor appears on a CT scan, that tumor is already millions, or billions, of cells in size,” Dr. Faden said. “We want to detect cancers much earlier, at the cellular level.” Researchers have recently evaluated cell-free DNA as a novel way of tracking and monitoring cancers. Cell-free DNA are fragments of DNA released into the bloodstream from all different types of cells in the body. This includes fragments of DNA from HPV-associated [ continued p. 6 ]

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FIGHTING HPV HEAD AND NECK CANCER UNDER A MICROSCOPE continued cancers, which are referred to as circulating-tumor HPV DNA (ctHPVDNA). In theory, ctHPVDNA should only appear in the bloodstream if a patient has a HPVassociated cancer, which provides an opportunity for dectecting the disease. Unfortunately, these strands become much harder to distinguish in the background of millions of other cell-free DNA fragments. “It’s a needle-in-a-haystack kind of problem,” said Dr. Faden. “But a liquid biopsy that could identify ctHPVDNA from millions of other competing cell-free DNA fragments would allow us to pick needles out of the haystack much quicker and more accurately compared to existing approaches.” In a study published in Clinical Cancer Research, a team led by Dr. Faden conducted a prospective trial where they applied a custom liquid biopsy to 140 patients at Mass Eye and Ear and Mass General Hospital. The liquid biopsy was more than 98 percent accurate for diagnosing HPV-associated head and neck cancer. The team also used modeling to demonstrate that a liquid-biopsy-based approach may cost 38 percent less than standard methods and could arrive at a diagnosis 26 days earlier, on average. Then, after combining the liquid biopsy results with standard

cross-sectional imaging and physical exam findings, the team demonstrated that a fully non-invasive diagnostic approach still had high diagnostic accuracy compared to standard tissue-based approaches.

Personalizing treatment for patients treated with surgery Transoral robotic surgery is a common treatment for early-stage HPV-associated oropharyngeal squamous cell carcinoma. During treatment, a surgeon uses a surgical robot to remove cancer from the back of the throat, along with any affected lymph nodes. After surgery, some patients may require additional treatments, such as radiation therapy or chemoradiotherapy, to treat remaining cancer cells. No perfect method exists for determining how many cancer cells remain after surgery, especially at the microscopic level. Physicians have attempted to tailor treatment by sorting patients into low, intermediate and high-risk categories for residual disease in the post-operative period. Patients categorized as low risk do not require additional treatment, whereas those labeled as intermediate or high risk would require subsequent radiation or chemotherapy. However,

Cell-free HPV DNA provides an accurate, rapid diagnosis of HPV-associated head and neck cancer. The above chart shows the experiemental design of Dr. Faden’s study. His study was published in Clinical Cancer Research.

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physicians often categorize patients according to imperfect pathology reports, which make it more likely for overtreatment or undertreatment to occur. “Our goal is to provide patients with as little treatment as possible to eradicate their cancer, but we also don’t want to undertreat a patient,” Dr. Richmon said. “The margin of error is razor thin.” Without a foolproof way of identifying which patients need more or less treatment after surgery, a giant hurdle stands in the way of personalizing care. To clear this hurdle, Dr. Faden’s team tested if its liquid biopsy could reliably detect the level of ctHPVDNA hours and days after transoral robotic surgery. They believed these levels of ctHPVDNA could predict which patients need to continue post-operative treatments, like radiation therapy, and which do not. In a prospective study at Mass Eye and Ear, Dr. Faden’s team used its HPV liquid biopsy to measure levels of ctHPVDNA in 33 patients undergoing treatment for HPV-associated oropharyngeal squamous cell carcinoma. During the study, the team examined what happens to ctHPVDNA levels in different patients immediately after they undergo surgery. According to results published in Cancer, the team found a correlation between ctHPVDNA blood levels and previously discovered risk factors of residual disease in patients one day after surgery. A sudden drop in ctHPVDNA levels was observed in patients who lack risk factors for residual disease, and levels remained elevated in patients with higher risk factors. “This is the first time a HPV liquid biopsy has been applied to a cohort of patients being treated with surgery,” Dr. Faden said. “Our work demonstrates a proof of principle that physicians could reliably use ctHPVDNA as a personalized biomarker for selecting adjuvant treatments in the future.”

Moving from bench to bedside By 2030, experts predict HPV will account for over 30,000 new HPV-associated oropharyngeal squamous cell carcinoma cases per year in the United States. To combat the wave of cases on the horizon, Drs. Faden and Richmon have proposed testing whether the new liquid biopsy can successfully guide treatment in a prospective interventional trial.

“By the time a tumor appears on a CT scan, that tumor is already millions or billions, of cells in size. We want to detect cancers much earlier, at the cellular level.” —Daniel Faden, MD, FACS, (left) and Jeremy Richmon, MD (right)

According to Dr. Faden, treatments during the trial would be personalized in real time, and the HPV liquid biopsy would serve as a tool to determine the intensity of treatment. For example, if a patient’s ctHPVDNA level is high after surgery, the patient may receive more radiation. Patients with more favorable ctHPVDNA results would receive lower doses of radiation, or none at all. The team has also worked on applying ctHPVDNA as a screening tool for detecting cancers before they become symptomatic in the population. Dr. Faden believes physicians could one day use blood tests to screen individuals for a plethora of cancer types at once. That would mean no more colonoscopies or mammograms. “Liquid biopsies are forever changing the face of cancer diagnosis and monitoring,” he said. “For HPVassociated head and neck cancer, if we can better personalize treatments for patients, and thereby minimize long-term side effects and increase effectiveness, we have the chance to dramatically improve our patients’ lives.” n

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Correcting Hearing Loss With the Split of a Gene A novel dual-vector, protein recombination strategy developed at Boston Children’s Hospital has galvanized the field of inner-ear therapeutics.

Blue: cell nuclei Red: hair bundles Green: stereocilin Images courtesy of Jeffrey R. Holt, PhD, and Olga Shubina-Oleinik, PhD.

Blue is DAPI (4′,6-diamidino-2-phenylindol), which stains DNA and illuminates cell nuclei. Red is phalloidin, which binds and stains actin in hair bundles and cell junctions. Green is an anti-STRC antibody conjugated to AlexaFluor488, which labels the sterocilin protein. 8

FEATURE

ver 430 million people worldwide experience some form of hearing loss, according to the World Health Organization. These cases range from mild to profound, and experts attribute more than half of all cases to genetic mutations. In the past few decades, scientists have developed gene therapies capable of replacing mutated genes for various hereditary conditions. One common practice relies on harmless viruses called adeno-associated viruses (AAVs) to transport healthy copies of genes into cells that lack them. Once delivered to the cell, the healthy genes produce missing proteins that help restore deficits brought on by a mutation. Although viable in some cases, AAV vectors are limited in practice. Genes larger than 4.7 kilobases cannot fit inside standard AAVs. This renders the technique ineffective for correcting larger genes, such as the 6.2 kilobase STRC gene. Humans rely on functional STRC genes to produce stereocilin proteins, which enables the ear to amplify and distinguish sounds. Without a healthy STRC gene, a mild-tomoderate form of hearing loss referred to as DFNB16 occurs. According to Jeffrey R. Holt, PhD, Professor of Otolaryngology–Head and Neck Surgery and Neurology at Harvard Medical School and a Principal Investigator of the Holt/Géléoc Laboratory at Boston Children’s

Olga Shubina-Oleinik, PhD, (left) working alongside Jeffrey R. Holt, PhD, (right) in the Holt/Géléoc Laboratory at Boston Children’s Hospital.

Hospital, there are no biological treatments for DFNB16 patients. Hearing aids and cochlear implants can help amplify sound volume but are less effective in noisy environments. “To fully restore auditory function in these patients, we would need to make a giant leap in replacing genes once deemed too large to fit in single AAVs,” Dr. Holt said. “This problem isn’t exclusive to otolaryngology; it’s a hurdle for many forms of inherited human disease across medical disciplines.” In a study published in Science Advances, a team of scientists led by Dr. Holt tested a novel gene therapy technique capable of overriding the size limitations of standard AAVs. The new technique, developed by Olga Shubina-Oleinik, PhD, a Research Fellow in Dr. Holt’s lab, used two AAV vectors—not just one—to deliver healthy Strc genes into mice, and employed a protein recombination strategy to ensure the successful creation of full-length stereocilin proteins. “If our dual-vector approach can replace full-length stereocilin protein, then perhaps it can also work for other human genetic disorders,” Dr. Holt said. “A new pathway for gene therapy research is being pioneered and it’s hard not to imagine its immense potential.”

A swing set inside the ear Mutations to the STRC gene, which were first discovered in 2008, are the second most common cause of genetic hearing loss in the world. The gene’s role in controlling auditory function begins deep inside the inner ear, where sensory cells, called outer hair cells, control the ear’s internal volume. The microscopic outer hair cells detect the movement of sound waves entering the inner ear. When loud sounds enter, the outer hair cells turn down the volume, sending quieter signals to the brain. The opposite occurs when soft sounds enter the ear; outer hair cells can amplify the softest sounds by a millionfold. This mechanism, referred to as cochlear amplification, can only occur if tiny microvilli on top of outer hair cells stay organized in bundles. Stereocilin proteins, produced by the STRC gene, are what keep the microvilli on top of the outer hair cell glued together. The absence of a functional STRC gene, however, results in a faulty protein and disorganized microvilli. [ continued p. 10 ]

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CORRECTING HEARING LOSS WITH A SPLIT GENE continued Dr. Holt compares the phenomenon to a child swinging their legs on a swing set. “Every child knows that, if they kick their legs together on a swing, they can control how high the swing goes,” Dr. Holt said. “Flailing legs cause them to completely lose control of how high or low the swing goes. If outer hair cells don’t have their microvilli swinging in sync, they can no longer control the sound waves coming into the inner ear, stripping them of their ability to amplify sounds.” To better understand the prevalence of STRC mutations in the global human population, Eliot Shearer, MD, PhD, Assistant Professor of Otolaryngology–Head and Neck Surgery and an Attending Surgeon at Boston Children’s Hospital, examined a large genomic database at Boston Children’s Hospital called the Children’s Rare Disease Cohort Initiative. According to results published in Science Advances, approximately two of every 100 people carry a mutation in the STRC gene, suggesting that an estimated 2.3 million people worldwide suffer from DFNB16 hearing loss. “Having a sense of how widespread the mutation

really is helps underscore the urgency for a treatment,” said Dr. Shearer, a co-author of the study. “A gene therapy solution that could restore cochlear amplification would drastically improve the lives of millions of patients worldwide.”

Correcting the mailing address Ever since the discovery of the STRC gene, scientists have contemplated gene therapies capable of accommodating its large size. Despite their efforts, none of these techniques have succeeded in generating stereocilin in an animal model. Working in collaboration with Dr. Holt, Dr. Shubina-Oleinik innovated her own gene therapy technique. She began by splitting a mouse Strc gene in half and packaging each half into separate AAVs. The dual vector approach would ensure both pieces of the gene arrived at a targeted cell. Once inside the cell, each piece of the gene would create a fragment of the stereocilin protein. Both fragments would then recombine to form a complete protein. Or so she thought.

Gene therapy strategy for restoring hearing with full-length stereocilin. The STRC gene is split in two fragments and packaged into AAV vectors (top line). When introduced into outer hair cells, the split STRC gene is translated into two protein fragments (middle line). The signal sequences direct the protein fragments to the same intracellular site where the inteins mediate protein recombination to yield the full-length sterocilin protein (bottom line).

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“If outer hair cells don’t have their microvilli swinging in sync, they can no longer control the sound waves coming into the inner ear, stripping them of their ability to amplify sounds.” —Jeffrey R. Holt, PhD (left)

“A gene therapy solution that could restore cochlear amplification would drastically improve the lives of millions of patients worldwide.” —Eliot Shearer, MD, PhD (right)

Her hypothesis, she found out, had overlooked a complication in the split Strc gene that had prevented recombination from occurring. According to Dr. Shubina-Oleinik, some genes carry a signal sequence that instructs cells where to deliver a protein. The instructions are transcribed as a signal peptide in a protein made of thousands of other amino acids. Without the signal peptide, the protein floats around the cell without a target destination. When Dr. Shubina-Oleinik first examined her results in Strc-mutant mice, she noticed that only one piece of the split gene contained the necessary signal sequence. The other did not, which meant there was no way for the two protein fragments to arrive at the same location in the cell. “Imagine ordering a computer for work, but you only assign a mailing address for the desktop,” Dr. Shubina-Oleinik said. “Instead of the desktop and monitor both arriving at your home, only the desktop arrives, and the monitor is lost in the mail because there was no delivery address. What good does that do?” Dr. Shubina-Oleinik hypothesized that both protein strands would arrive at the same location if she copied the signal peptide from one strand and added it to the other. After adjusting her methodology and retesting the mice, a drastic change occurred. According to the new study, the mice recovered expression of fulllength stereocilin protein in their outer hair cells, and approximately 60 percent of the hair cell bundles demonstrated proper organization. Perhaps even more encouraging: The mice demonstrated normal cochlear amplification and enhanced auditory sensitivity, sig-

naling the presence of newly generated, functional stereocilin protein.

Limitless possibilities Many other genetic disorders brought on by mutations to large genes could also benefit from Dr. ShubinaOleinik’s novel technique. Several genes responsible for Usher syndrome, a rare disease that causes blindness and deafness, are larger than STRC. Even larger is the gene responsible for Huntington’s disease, a neurodegenerative disorder in the brain. None of these genes could fit inside a single, standard AAV vector. The new gene therapy technique must undergo further testing before it can reach clinics. Dr. Holt’s team will first need to test whether the technique can work on the human STRC gene ex vitro. Human innerear organoids developed in the lab of Karl Koehler, PhD, Assistant Professor of Otolaryngology–Head and Neck Surgery at Harvard Medical School, will provide Dr. Holt and his team with the proper environment needed to test the effectiveness of the technique on human cells. “Our proof-of-concept study is the first step in tackling hereditary conditions across multiple disciplines,” said Dr. Shubina-Oleinik, who, together with Dr. Holt, has filed a patent application for the technique. “I’m confident that, with the world-class resources at our disposal across the Harvard Medical School Department of Otolaryngology–Head and Neck Surgery, our team can turn a treatment that seemed impossible a few years ago into a reality.” n HARVARD Otolaryngology

Gender-Affirming Care Finds Its VOICE At Mass Eye and Ear, the Division of Laryngology has collaborated with the Voice and Speech Laboratory to advocate for, and meet the needs of, the transgender community in Greater Boston.

FEATURE

or members of the transgender community, there has never been a more dangerous time to live in the United States. Human Rights Watch, an international non-government organization, reported 2021 as the nation’s deadliest year for anti-transgender violence. A recent rise in verbal and physical attacks has paralyzed the community into a constant state of fear. Transgender individuals often do their best to change their secondary sex characteristics, which include residual facial hair, voice tones and posture. When any one of these characteristics misaligns with their identified gender in public, the individual feels “outed,” which poses a significant risk for self-harm. Gender dysphoria, the psychological distress from a person’s identified gender not matching their appearance, is associated with an increased risk of depression and suicide. According to results of a 2015 survey produced by the National Center for Transgender Equality1, more than 40 percent of transgender respondents had attempted suicide at one point in their life—nearly nine times higher than the attempted suicide rate of the U.S. population. The recent harm inflicted upon transgender individuals has raised an alarm within the medical community. Those who once doubted the medical necessity of correcting secondary sex characteristics are now beginning to reevaluate their thinking. “Years ago, you could imagine a scenario where a woman might come to her doctor and say, ‘My voice is too low and doesn’t seem right,’ only for the doctor to inform her that nothing can be done,” said Matthew R. Naunheim, MD, MBA, Assistant Professor of Otolaryngology–Head and Neck Surgery at Harvard Medical School and Surgeon in the Division of Laryngology at Mass Eye and Ear. “We now know how risky it is for a transgender individual to be ‘outed’ because their voice sounds too much like that of a man or woman.” In support of this paradigm shift, Dr. Naunheim has collaborated alongside several speech-language pathologists to launch the Transgender Voice and Speech Modification Program at Mass Eye and Ear. The

Matthew R. Naunheim, MD, MBA, (right) and Stefani Kalos, MS, CCCSLP, (left) meet with a patient inside the Transgender Voice and Speech Modification Program. Photo taken prior to COVID-19.

program began in 2019 and has since offered genderaffirming voice care to individuals across Greater Boston looking for a voice they feel safe projecting to the world. Thanks to its multidisciplinary approach, the program has already treated over 100 patients and is now preparing to combat a larger problem looming on the horizon: Convincing insurance providers to consider gender-affirming care a necessity.

More than pitch A natural association exists between gender and a person’s voice. Men typically have lower voices, and women typically have higher voices. Physicians refer to how high or low the voice goes as pitch. Different levels of pitch can depend on the anatomic structure of the vocal cord muscles. Shorter muscles tend to produce higher pitches, whereas longer muscles tend to produce lower pitches. “Think of it like tuning a guitar,” Dr. Naunheim said. “Shorter strings generate higher sounds. On the other hand, a longer string generates a low sound.” While patients can use testosterone to thicken the vocal cords for a deeper-sounding voice, no hormonal therapy exists for heightening the voice. An anatomical change to heighten the voice would require a gender[ continued p. 14 ]

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GENDER-AFFIRMING CARE FINDS ITS VOICE continued affirming procedure called a glottoplasty. During this procedure, a laryngologist de-epithelializes parts of both vocal cords and creates a web to shorten the cords with sutures. Since a limit exists to how short surgeons can make the vocal cord, only so much of a person’s pitch can change from such a procedure. This might discourage patients who assume no other options exist to further modify their voice. However, pitch is just one of several different variables capable of changing how a voice sounds. According to Stefani Kalos, MS, CCC-SLP, a SpeechLanguage Pathologist at Mass Eye and Ear, a person can modify certain variables such as resonance, inflection and articulation to compensate for pitches that sound too high or too low. “Voices are a lot more flexible than people imagine, and pitch is only a small portion of how a voice can be perceived,” said Stefani. “By working with a speech therapist who can explain how these variables are manipulated using scientifically-backed voice techniques, we can try on different techniques until we have tailored a voice that best fits a person’s gender and personality.”

A voice that fits just right After years of feeling underserved or marginalized by the medical community, transgender individuals may feel uncomfortable seeing a licensed professional to alter their voice. They instead might try altering their voice on their own. According to Abigail Garneau, MA, CCC-SLP, a Speech-Language Pathologist at Mass Eye and Ear, individuals who attempt voice-altering techniques without the discretion of a professional can risk harming their voice. Individuals who turn to certain online instructional videos without fully understanding how to apply a specific voice technique, for example, may risk laryngeal hyperfunction, or a strained larynx. If such a condition occurs, a speech-language pathologist can help undo the strain and guide a patient to their target voice. “If a patient explores modifying their voice on their own, we encourage them to practice vigilance for issues like hoarseness, strain or pain in the throat,” she said. “If any of these issues are noted, we then recommend seeking out a medical professional, if possible. The last thing we’d want is for an individual to hurt their voice or throat.”

Members of the Transgender Voice and Speech Modification Program pictured from left to right: Stefani Kalos, MS, CCC-SLP; Abigail Garneau, MA, CCC-SLP; Kara Aries; Matthew R. Naunheim, MD, MBA; Carolyn Hsu, MS, CCC-SLP.

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The Transgender Voice and Speech Modification Program attempts to build strong, trusting relationships between patients and clinicians by employing a shared-decision approach to care. The approach begins with Dr. Naunheim and a speech-language pathologist conducting a thorough evaluation of the patient’s medical history. Several recordings are made of the patient’s voice, after which point Dr. Naunheim can order a laryngoscopy exam to assess the larynx for vocal fold nodules, polyps or any other pre-existing pathologies. The speech-language pathologist can also assign a few initial voice exercises and test how the patient responds. Once the team completes its workup, Dr. Naunheim and a speech-language pathologist meet with the patient to present a complete array of treatment options. Voice therapy sessions, each one 45-to-50 minutes long, are typically recommended first. The number of sessions and techniques taught can be adjusted to the needs of each individual. Permanent treatment options, such as surgical procedures or hormonal therapy, are usually recommended second. Those who choose a permanent treatment option can still modify and adjust their voice with voice therapy sessions, but they must receive the approval of a surgeon weeks after their procedure.

Access for everyone Every year since the Transgender Voice and Speech Modification Program began its operations, patient volume has more than doubled. Its immediate success culminated in a 2021 Pillars of Excellence Award from

Mass General Brigham, which recognized the program’s promotion of diversity, equity and inclusion across the healthcare system. Despite the program’s immediate success, Dr. Naunheim knows that gender-affirming care is still inaccessible to hundreds of thousands of individuals nationwide. He noted that a majority of insurance providers do not cover procedures for correcting secondary sex characteristics. These providers only cover procedures that correct primary sex characteristics, such as genital reconstructive surgery. Providers will often cite published outcomes to justify covering a procedure they deem a medical necessity. With few published outcomes available for transgender voice modification procedures, Dr. Naunheim has begun collecting his own patientreported outcome data. This data includes patient satisfaction scores from before and after voice therapy sessions, changes in the frequency of a patient’s voice and qualitative interviews with patients experiencing gender dysphoria. He believes his research could one day promote equity for a community that continues to move further and further to society’s margins. “Every person should feel comfortable in the way their voice is presented to the world,” Dr. Naunheim said. “If we have the means available to ensure peace of mind among transgender individuals, then we must ensure these techniques are available to all, and not just a fortunate few.” n James, S. E., Herman, J. L., Rankin, S., Keisling, M., Mottet, L., & Anafi, M. (2016). The Report of the 2015 U.S. Transgender Survey. Washington, DC: National Center for Transgender Equality. 1

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Scouting Surgeries, Healing the Margins David Shaye, MD, MPH, partnered with the Cleft and Burn Center in Kathmandu to rethink the way surgical care is distributed in Nepal. The use of surgical scouts might just bring the world a step closer toward solving a global surgical crisis.

The outskirts of a village in the Nagarkot district of Nepal. Image used with permission from Thomas Kelly.

FEATURE

or most people in the world, surgery has become a privilege, not a basic human right. According to the World Health Organization (WHO), five billion people live without access to safe, timely and affordable surgical care. In low- and middle-income nations, the situation is particularly dire; nine-out-of-10 people are without access to basic surgical services. Doctor shortages, crumbling infrastructure and inconsistent funding often confine surgical services to cities located hundreds of miles away from where care is desperately needed. The crisis looms larger than life in Nepal, where the Himalayas separate millions of people from the nation’s capital, Kathmandu. Without a vehicle or alternative means of transportation, it can take days, or weeks, to reach the capital for even the most basic procedures. “You can’t just cruise to your surgeon’s office on an interstate highway like you would in the United States or Europe,” said David Shaye, MD, MPH, Assistant Professor of Otolaryngology–Head and Neck Surgery at Harvard Medical School and Facial Plastic and Reconstructive Surgeon at Mass Eye and Ear. “The terrain is so challenging that a 50-mile journey can take weeks, with much of it on foot.”

Working in collaboration with Nepalese plastic surgeon Shankar Man Rai, MS, of the Nepal Cleft and Burn Center in Kathmandu, Dr. Shaye investigated how to bring specialized cleft services to rural Nepal. Together, the doctors successfully shifted the screening process for cleft lip and palate repairs away from specialty-trained surgeons in Kathmandu to local scouts. None of these scouts had a formal education, yet knew how to navigate the treacherous Himalayan terrain by foot. As reported in Facial Plastic Surgery & Aesthetic Medicine, the intervention of surgical scouts has led to a significant increase in surgeries for cleft lip and palate patients living in 22 of Nepal’s most-remote districts. The study evaluated a practice called task shifting, or the redistribution of tasks among health care workers, in the context of the surgical screening process. How such tasks are shifted among surgical scouts may provide a novel blueprint for surgeons facing similar problems in areas with equally challenging geography.

Needless morbidity from cleft lip and palates Experts report that cleft lip and palate anomalies occur in approximately one-in-700 births, making them the most common congenital craniofacial anomaly in the world. Children with cleft palates, or a gap between the nasal cavity and the roof of the mouth, often experience air leaks into the nose, which can result in difficulty eating or delayed speech. Those with untreated cleft lips, or a divide in the upper lip, struggle to carry the psychological burden from the social stigma associated with a facial deformity in Nepal. [ continued p. 18 ]

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SCOUTING SURGERIES, HEALING THE MARGINS continued “There’s a cultural belief that facial deformities are a sign of someone having committed a serious wrongdoing in a past life, which can bring immense shame to a family,” said Dr. Rai. “We’ve seen parents abandon children in the jungle or leave them for dead on the side of the road. This has underscored the need for repairing these deformities.” According to Dr. Rai, only three specialty-trained plastic and reconstructive surgeons live outside Kathmandu. Many Nepalese surgeons struggle to live off low wages provided by hospitals, which prompts them to open private practices in large towns with high patient volumes. However, 80 percent of the 31 million people in Nepal live in isolated, rural districts four-tonine days away from the closest tertiary surgical center, which makes cleft lip and palate surgical care extraordinarily inaccessible for the vast majority of the country. In an attempt to decentralize care away from Kathmandu and large towns, Dr. Rai partnered with international aid groups Smile Train and ReSurge International to establish six mobile surgical centers in select districts. Both aid groups would fund the sites, and specialty-trained facial plastic and reconstructive surgeons who practiced in Kathmandu would arrive to perform cleft lip and palate procedures for the local population. However, underdeveloped Nepalese infrastructure often prevented word about the surgical camps from reaching patients in more remote districts. “A bus can take you only so far in Nepal,” Dr. Rai said. “Roads end long before surgeons have a chance to reach many villages, which means villagers might have no idea we even exist. We can’t properly heal the marginalized without actually reaching the margins.”

Blazing a trail to surgical care Task shifting is one common technique employed to relieve severe strains on a surgical workforce. The technique involves training nurses, technicians and residents to perform basic procedures in the absence of a doctor. Although certain procedures, such as caesarean sections, are straightforward enough to shift in high volumes, highly specialized procedures, such as a cleft lip and palate repair, are not. These procedures are too complex and require too much training to shift at a moment’s notice. 18

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Decentralizing the surgical screening process: Mobile surgical scouts assessed patients with cleft lip and palate in remote districts of Nepal. Patients with the condition were then referred to one of six mobile surgical centers. Those with complex comorbidities were referred to the Nepal Cleft and Burn Center in Kathmandu.

“Imagine trying to teach someone a crash course on how to repair a congenital facial defect and then sending them into the mountains?” Dr. Shaye said. “We’d be trying to cram 10 years of reconstructive specialty training into the span of a few days.” Instead of shifting the entirety of cleft lip and palate procedures, surgeons would need to break the procedures into simpler tasks. In partnership with the Nepal Cleft and Burn Center in Kathmandu and with the support of a grant from the Harvard Medical School Center for Global Health Delivery–Dubai, Drs. Shaye and Rai collaborated on an approach that would shift the screening process of these procedures to 44 nonmedical Nepalese surgical scouts. Together, the surgeons collaborated on a five-day course that would train these scouts on how to identify and refer patients for surgery.

The surgical scouts would then rely on their own native, topographical expertise to trek Nepal’s most remote districts and find patients. Otherwise-healthy patients were referred to the six mobile surgical centers set up by Dr. Rai. These sites were located close enough for patients to reach in a matter of a few days, as opposed to the weeks-long trek it might

Bringing scouts, and surgical care, to the world

Throughout his career, Dr. Shaye has traveled to Africa, Asia and Central America to collaborate with surgeons on improving surgical care. His most recent efforts have moved away from the provision of surgery and pivoted towards teaching and investigating creative approaches to distributing care. While surgical scouts are one way of rethinking how patients are screened and identified for surgery, If our educational model can deliver care to the foot of educating more doctors about these Mount Everest, then there’s no reason why it can’t be specialized procedures will ultimately replicated to eliminate barriers elsewhere in the world. decide the trajectory of the global surgical crisis. Trauma, for example, is another enormous disease normally take to reach Kathmandu. Only patients burden left largely untreated in Africa. According to with complex comorbidities, such as airway concerns the WHO, trauma has actually surpassed the combined or cardiopulmonary conditions, were referred to mortality of tuberculosis, HIV and malaria. With Kathmandu for tertiary care. assistance from the Swiss AO Foundation, Dr. Shaye According to the study published in Facial Plastic and a group of international colleagues have developed Surgery & Aesthetic Medicine, the surgical scouts correctly a facial trauma educational program focused on the diagnosed 89 percent of the 139 patients examined, and management of craniomaxillofacial trauma in lowcorrectly referred 82 percent of patients for cleft lip income countries. and palate procedures. As a result, the percentage of Under the Mass Eye and Ear Office of Global patients from remote districts who underwent cleft lip Surgery and Health, Dr. Shaye has also considered and palate repair increased significantly. With scout launching a Global Surgery Academy, where sponsored intervention, the percentage more than doubled, and surgeons from low-income countries could spend time would later quadruple when scouts assisted patients shadowing Mass Eye and Ear surgeons from every with transportation or accompaniment. subspecialty. Surgeons would travel home with expo“As scouts see more and more patients over time, sure to complex subspecialty otolaryngology care we expect their assessment skills to improve,” Dr. Shaye while Mass Eye and Ear surgeons would learn of the said. “This would only increase the percentage of complex challenges surgeons face worldwide. patients on the correct road to a life-altering procedure.” “An education is the greatest gift we can give as surgeons,” Dr. Shaye said. “If our educational model can deliver care to the foot of Mount Everest, then there’s no reason why it can’t be replicated to eliminate barriers elsewhere in the world.” n

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Shankar Man Rai, MS, (pictured far right, standing) teaching a classroom full of lay surgical scouts. For five days, Dr. Rai taught scouts how to identify and refer patients with cleft lip and palates for surgery. Used with permission from Shaye DA et al. Mobile Surgical Scouts Increase Surgical Access for Patients with Cleft Lip and Palate in Nepal. Facial Plastic Surgery & Aesthetic Medicine. September, 2021. Copyright © 2021 the American Academy of Facial Plastic and Reconstructive Surgery.

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PANEL DISCUSSION

A Lesson on Diversity, Equity & Inclusion Boston is a medical paradox.

espite offering some of the best hospitals, universities and treatments in the world, the average life expectancy in Boston can plummet between neighborhoods only a few short blocks apart, and the likelihood of surviving head and neck cancer can vary by skin color.

In the past two years, the Department of Otolaryngology–Head and Neck Surgery at Harvard Medical School has committed itself to confronting healthcare discrepancies within otolaryngology and beyond. Led by Mark A. Varvares, MD, FACS, the Chair of Otolaryngology–Head and Neck Surgery at Harvard Medical School, Gregory W. Randolph, MD, FACS, FACE, the Claire and John Bertucci Endowed Chair in Thyroid Surgical Oncology at Harvard Medical School, and Heidi Nakajima, MD, PhD, Vice Chair of Diversity, Equity and Inclusion for the Department of Otolaryngology–Head and Neck Surgery at Mass Eye and Ear, the department has launched a Diversity, Equity & Inclusion (DE&I) Task Force responsible for infusing diversity, equity and inclusion as core values and imperatives for driving meaningful change. Harvard Otolaryngology spoke with two members of the DE&I Task Force, Ciersten Burks, MD, a PGY-4 Harvard Medical School resident, and Regan Bergmark, MD, Assistant Professor of Otolaryngology–Head and Neck Surgery at Harvard Medical School, for a candid conversation about inequity in healthcare and hope for a brighter future.

How does race affect healthcare in otolaryngology? Ciersten Burks, MD (CB): Research, from our group and others1, has demonstrated significant racial and ethnic disparities existing among patients with head and neck cancer. Black and Hispanic patients, in particular, have a much higher risk of presenting with advanced stage cancer. As a result, these same patients have higher mortality rates than patients belonging to other racial and ethnic groups. Regan Bergmark, MD (RB): When discussing race and ethnicity, it’s important to understand the structural forces preventing individuals from accessing healthcare, especially with respect to head and neck cancer treatments. In America, a deep-rooted legacy of racism has kept Black and Latinx individuals disproportionately stuck in jobs that don’t provide adequate health insurance. These individuals often reside in neighborhoods without access to buses or subway stations, which makes it even harder for them to access research hospitals where, at the very least, they might be able to enter clinical trials for new treatments or access a high enough level of care often necessary for patients who present with advancedstaged disease. CB: It’s important to remember—this isn’t a problem exclusive to Boston. It’s nationwide. For example, inadequate insurance coverage forces millions of people to pay out-of-pocket costs for out-of-network specialists, dentists or primary care providers. If 20

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these costs become too high, many will forgo visits and miss an opportunity to catch a head and neck malignancy in its earliest stages.

How can we address this problem now? RB: The idea that we can just ignore these disparities is over. Quite frankly, it should have been over a long time ago. As a department of Harvard Medical School, we have an ethical obligation to structure healthcare around the needs of every person in our community, not just a privileged few. CB: We’re seeing a significant gap in the types of patients receiving care at our affiliate hospitals. From 2015 to 2020, more than 87 percent of the patient population at Mass Eye and Ear, Mass General Hospital and Brigham and Women’s identified as White. Less than 10 percent identified as Black and Hispanic, which is shocking considering that more than 45 percent of the city population belongs to both the Black and Hispanic communities. RB: The good news is that this discrepancy is solvable. We can expand access to insurance, which would help us get more patients into our clinics earlier. Mass General Brigham has launched a United Against Racism initiative that will commit Gadkaree SK, McCarty JC, Feng AL, et al. “Role of physician density in predicting stage and survival for head and neck squamous cell carcinoma.” Head & Neck. 2021; 43: 438– 448. Doi: 10.1002/hed.26495 1

scholarships to underrepresented trainees and additional financial support to underrepresented faculty. We have also launched webinars at a number of medical schools across the country— from historically Black colleges and universities to medical schools without home otolaryngology departments—in an effort to provide exposure to the field, as well as mentorship, networking and research opportunities.

RB: We are excited to see a consistent trend towards more of our otolaryngology trainees coming from underrepresented groups. This is key to achieving our long-term goal of equity in the provision of health care.

What recent work has excited you most? CB: In October 2021, Mass Eye and Ear hosted an “Eye, Ear, Eat” clinic at its 800 Huntington Avenue location. This was a free clinic held on a Saturday in Mission Hill, one of the most diverse neighborhoods in Boston. Specialists based at Mass Eye and Ear from an array of disciplines—not just otolaryngology—arrived to offer eye, hearing and head and neck cancer screening exams. Patients with concerning findings were connected with faculty at Mass Eye and Ear to follow up and address these concerns. Financial counselors were also provided to help navigate the insurance process.

millions of dollars toward promoting diversity on leadership boards, establish a culture of health equity across its hospitals and improve outreach efforts in marginalized communities, to name just a handful of its programs.

RB: Through a United Against Racism grant, Dr. Burks and I are spearheading a campaign to improve patient access to head and neck cancer resources across Mass General Brigham. This includes the translation of head and neck cancer surgical resources into multiple languages. The initiative will facilitate access to care, as well as safe recoveries for our surgical patients. Together, our efforts remind people from diverse communities that not only are our doors open to them, but that we’re more than willing to meet them where they are.

What steps toward change have been discussed by the DE&I Task Force?

What gives you hope for the future success of the DE&I Task Force?

RB: Right now, we see this as a unique opportunity to rethink patient care and create a welcoming environment. That starts with asking some hard questions, like, ‘Are our hospitals offering enough multilingual services?’ or, ‘What audiences are our marketing teams catering to?’ It’s humbling, really, because you need to identify blind spots, reevaluate conventional approaches and weed out communication practices that might be preventing patients from receiving care that could save their lives.

RB: The sky is the limit when you have leaders as deeply committed to equity as Dr. Varvares and Stacey T. Gray, MD, Program Director of the Harvard Combined Residency Program in Otolaryngology–Head and Neck Surgery. Their enthusiasm for discussing these issues makes every person in the room more comfortable speaking up so that they can voice their opinion. That’s the kind of environment that fosters change with respect to the patients we serve, the research we do and the trainees we foster.

CB: We’ve also put a lot of thought into who is coming into our surgical workforce—representation matters. We want members of underrepresented communities to feel comfortable trusting their care providers, which means staffing more surgeons who share common backgrounds with their patients. The task force has started the Rebecca Crumpler Fund to provide academic

CB: Actions speak louder than words, and it says a lot when the chair of your department, your program director, senior faculty and junior faculty are joining these task forces and volunteering at these free clinics. This isn’t just a siloed group of people talking about change; it’s buy-in from the entire department, from the top-down, actually trying to make change happen. n

Regan Bergmark, MD, (left) and Ciersten Burks, MD (right).

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ALUMNI GIVING SOCIETY

Current Alumni Giving Society members for fiscal year 2021, from October 1, 2020, to September 30, 2021, are listed below. With your gift of $1,000 or more, you will be included in the 2022 Alumni Giving Society.

he 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 make gifts of $1,000 or more during the fiscal year (October 1–September 30). Participation is a way to stay connected and to help deliver the finest teaching experience for today’s otolaryngology trainees. Our alumni know from firsthand experience that support of the vital work of our students and faculty in the Department of Otolaryngology– Head and Neck Surgery helps drive continued achievement across all areas of education, research and patient care. In the 2021 fiscal year, we had 50 members who we thanked for their generosity and partnership. Their collective support helped us achieve our department goals and institutional mission. If you are not a member, please consider joining your colleagues today by making a gift with the enclosed envelope. As a member, you may designate your gift in the way that is most meaningful to you. To learn more, please contact Julie Dutcher in the Development Office at 617-573-3350.

Department of Otolaryngology Head and Neck Surgery

The Alumni Giving Society of the Department of Otolaryngology– Head and Neck Surgery at Harvard Medical School

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CHAMPION

FRIEND

Gifts of $25,000 or higher

Gifts of $1,000 to $2,499

Jessica L. Fewkes, MD

Blake C. Alkire, MD Nicolas Y. Bu-Saba, MD Adam P. Campbell, MD Daryl G. Colden, MD, FACS Ruth Anne Eatock, PhD Bruce A. Feldman, MD Ramon A. Franco, Jr., MD Robert A. Gryboski, MD Paul E. Hammerschlag, MD, FACS Jeffrey P. Harris, MD, PhD Qasim Husain, MD Man-Kit Leung, MD Giant C. Lin, MD Jamie R. Litvack, MD William W. McClerkin, MD Cliff A. Megerian, MD Eugene N. Myers, MD Joseph B. Nadol, Jr., MD Adrian James Priesol, MD Edward J. Reardon, MD Jeremy D. Richmon, MD Mark F. Rounds, MD Felipe Santos, MD George A. Scangas, MD Ahmad R. Sedaghat, MD, PhD, FACS Herbert Silverstein, MD, FACS Theodoros N. Teknos, MD

VISIONARY Gifts of $10,000 to $24,999 Michael S. Cohen, MD Gregory W. Randolph, MD, FACS

INNOVATOR Gifts of $5,000 to $9,999 Neil Bhattacharyya, MD John B. Lazor, MD, MBA, FACS Daniel J. Lee, MD, FACS Steven Pletcher, MD Michael B. Rho, MD, FACS Raj Sindwani, MD Jonathan Y. M. Ting, MD

PIONEER Gifts of $2,500 to $4,999 Barry J. Benjamin, MD Christen L. Caloway, MD Nipun Chhabra, MD Richard E. Gliklich, MD Wade W. Han, MD David Healy, MD Kasey K. Li, MD, DDS Ralph B. Metson, MD David E. Nash, MD H. Gregory Ota, MD Harry Dennis Snyder, MD Zachary M. Soler, MD Mark A. Varvares, MD, FACS

DONOR PROFILE

“We were immediately impressed by Dr. Bleier’s novel approaches to research aimed at developing less invasive and more effective therapies for CRS,” said Anna. “He is an extraordinarily skilled and compassionate clinician and a truly visionary researcher. The prospect of partnering with him was an inspiration and an honor.” Unlike acute rhinosinusitis, which is a temporary infection of the sinuses that often occurs after colds, CRS is a persistent problem that causes symptoms such as nasal congestion, post-nasal drip, facial pain and reduced sense of smell. With CRS, symptoms last for 12 weeks or more and can significantly reduce quality of life. For Dr. Bleier, caring for CRS patients in the Sinus Center is a constant reminder of the urgent need for better treatments. With this explicit goal, his laboratory studies the role of the body’s immune system in triggering inflammation of the nasal

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passages in CRS and has identified biological indicators of

“We were immediately impressed by

Anna and Neil Rasmussen A passion for innovation fuels bold new research.

nna and Neil Rasmussen believe in the power of innovation to solve the toughest medical problems. Chronic rhinosinusitis (CRS), a persistent, currently incurable inflam-

matory disease of the sinuses, is one such challenge the

Dr. Bleier’s novel approaches to research aimed at developing less invasive and more effective therapies for CRS.” –Anna Rasmussen

disease as potential targets for new treatment. He is currently screening candidate drugs in his lab to test their ability to treat and reverse inflammation caused by CRS, and he will begin testing the most promising of these drugs in specialized animal models of CRS in the near future. Ultimately, he aims to develop multiple treatment approaches that can be evaluated in human trials.

Rasmussens have taken on as enthusiastic champions. In 2015,

Anna and Neil are invaluable partners in Dr. Bleier’s quest,

Anna and Neil met Benjamin Bleier, MD, FACS, an Associate

making multiple generous gifts to expedite his research. There is

Professor of Otolaryngology–Head and Neck Surgery at Harvard

no doubt their tremendous investment in his laboratory has and

Medical School and a Clinician-Investigator in the Mass Eye and

will continue to make a transformational impact—ultimately,

Ear Sinus Center.

bettering the lives of many thousands of patients. n

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ALUMNI PROFILE

Edward J. Reardon, MD, ’78

Bringing teamwork – and world-class care – into the community.

dward J. Reardon, MD, likes to joke that his fellowship at Mass Eye and Ear was longer than any other in the world.

The fellowship, he said behind a grin, was called the Mass Eye and Ear Teaching Service. How long did it run for, exactly? Two-and-a-half months. Every year, that is, for 20 years—under the mentorship of world-renowned otolaryngologist William Montgomery, MD, no less. “Back in the 1970s and 1980s, medical fellowships were not as popular as they are today,” explained Dr. Reardon, a 1978 graduate of the Harvard Medical School Otolaryngology Residency Program. “The teaching service was our version of a fellowship. It gave me the once-in-alifetime opportunity to learn from someone who was widely considered a giant in our field.” After completing residency training, all new otolaryngologists at Mass Eye and Ear were required to join one of five teams on the teaching service. These otolaryngologists were junior attendings responsible for leading a cohort of residents alongside a senior faculty member. In the winter of 1978, Dr. Reardon began his time in the service; he would meet the residents every day at 7 AM, guide them through their rounds and spend one day a week tackling different surgical cases in the operating room (OR). “One day it might have been a general otolaryngology case, the next it might have been a more complex head and neck procedure,” said Dr. Reardon, the former Chief of the Department of Surgery at Milton Hospital. “You never knew what you

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Edward J. Reardon, MD, standing outside the office of his Milton practice.

were going to get, which meant we were learning something new almost every day.” Forty-four years later, Dr. Reardon plans to retire from his current practice at Mass Eye and Ear, Milton, in the summer of 2022. He will leave behind a legacy unmatched by

his founding of the first-ever Mass Eye and Ear suburban practice south of Boston. This feat, he believed, would not have been accomplished if not for a lesson he learned from Dr. Montgomery in the teaching service.

“There’s work that I can do on my own, and then there’s work that I need a team for,” said Dr. Reardon. “Dr. Montgomery taught me how to discern between the two, which built my confidence and reinforced my long-held belief in working with colleagues.”

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In 1995, Dr. Reardon partnered with Joseph B. Nadol, Jr., MD, then Chief of the Department of Otolaryngology–Head and Neck Surgery at Mass Eye and Ear, to integrate his Quincy practice into the Mass Eye and Ear practice network. The Quincy location became the first Mass Eye and

“There’s work that I can do on my own, and then there’s

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work that I need a team for. Dr. Montgomery taught me how to discern between the two, which built my confidence and reinforced my long-held belief in working with colleagues.”

Long before he joined the service, Dr. Reardon was born and raised outside of Worcester, MA, and studied biology at Boston College. He earned his medical degree from Tufts University, where he decided to specialize in otolaryngology during his third year of medical school. The collaborative working environment he experienced on a head and neck surgery rotation forever galvanized his interest in the field. That summer, he was awarded a National Institutes of Health education stipend to study neuro-otologic anatomy at the University of Chicago alongside worldrenowned researcher César Fernández, MD. Dr. Reardon served in the Air Force for three years before entering the Harvard Medical School Otolaryngology Residency Program. After completing his residency training and joining the Mass Eye and Ear Teaching Service, he kept the advice of his mentor, Dr. Montgomery, close to heart. The advice played a crucial role in him launching his own South Shore head and neck surgery practice at Carney Hospital, Milton Hospital and Quincy City Hospital. He recruited Paul Konowitz, MD, FACS, and Peter N. Friedensohn, MD, to expand the practice, knowing he couldn’t run the practice at all three sites on his own.

Ear otolaryngology site south of Boston and, with the recruitment of John Lazor, MD, another mentee of Dr. Montgomery, the practice would only grow bigger. To this day, the site has expanded to 12 otolaryngologists across five clinical locations.

“Mass Eye and Ear was way ahead of the curve of healthcare providers delivering world-class medicine into the suburbs,” Dr. Reardon said. “People from as far away as Rhode Island and Connecticut were arriving at clinics with conditions routinely treated in Boston. Even better: They were leaving without needing another referral for an appointment in the city.”

and skull base surgeries. To this day, these systems are used in operating rooms worldwide. In 2012, Dr. Reardon began his mostrecent leadership position as Chief of Surgery at Milton Hospital, just as the hospital joined the Beth Israel Lahey Health network. His role allowed him to oversee the expansion of the hospital’s surgical services, which included the creation of world-class bariatrics, orthopedics and robotics programs. Dr. Reardon believes his passion for healthcare development will continue long after his retirement. He will reside in Biddeford Pool, a small coastal community in Maine, where he will explore community outreach programs, always keeping the advice of his former mentor front-of-mind. “While I’m excited to spend more time with friends and family, I know I can still have quite an impact on my new community in Maine,” he said. “Remembering what I can do on my own, and who I might need to call on for help, will determine how big that impact is.” n William Montgomery, MD, (below) a mentor to Edward J. Reardon, MD.

Motivated to grow his suburban practices even further, Dr. Reardon enrolled in a management program at Harvard Business School that opened the door to countless leadership opportunities. In addition to serving as President of the Medical Staff at Mass Eye and Ear and Carney Hospital, he was a founding member of the Massachusetts Society of Otolaryngology. Meanwhile, his unique interest in technology from his time in the Air Force led him to collaborate on a multi-center study on the accuracy of electromagnetic navigation systems for endoscopic sinus HARVARD Otolaryngology

HIGHLIGHTS

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 (OHNS). Giovanni Battistella, PhD, is an investigator at Mass Eye and Ear. He earned his PhD in neuroscience from the Lemanic Neuroscience Doctoral School at the University of Lausanne in Switzerland and completed two postdoctoral neurology fellowships: one at the Icahn School of Medicine at Mount Sinai and a second at the Memory and Aging Center at the University of California, San Francisco. Dr. Battistella’s research focuses on decoding the neural mechanisms underlying neurological language and voice disorders, with a particular interest in addressing the relationship between neurotransmission, abnormal brain function and brain structure. Andreas Eckhard, MD, is an investigator at Mass Eye and Ear. He trained as a postdoctoral fellow in the Otopathology Laboratory at Mass Eye and Ear and completed his clinical training in otolaryngology at the University Hospital Zurich in Switzerland. In both his research and clinical work, Dr. Eckhard has pursued a strong focus on vestibular disorders. His research interests are the cellular and molecular pathomechanisms of inner-ear diseases, foremost Meniere’s disease, with a special interest in the pathogenic roles of non-sensory supporting cells. Jeffrey Hoffman, MD, FACS, is a boardcertified ear, nose and throat surgeon who also serves as Chief Medical Officer for Cambridge Health Alliance and President of the Cambridge Health Alliance Physician Organization. Dr. Hoffman

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completed his surgical residency at Beth Israel Medical Center in New York and his residency training at the Harvard Combined Residency Program in OHNS. With more than 25 years of clinical and leadership experience, Dr. Hoffman has been invited to speak at regional and national meetings on both OHNS and health care management and delivery. His clinical practice specializes in thyroid and parathyroid surgery. Karen Lee, MD, is a neurologist at Mass Eye and Ear who is board-certified in both neurology and sleep medicine. Upon earning her medical degree from the Drexel University College of Medicine, Dr. Lee completed residency training in neurology at the University of California, Los Angeles, and fellowship training in sleep medicine at the Stanford University School of Medicine. Her clinical interests include narcolepsy, REM sleep behavior disorder, restless leg syndrome, obstructive sleep apnea and chronic migraines.

Recent Promotions [ 1 ] Regan Bergmark, MD, Assistant Professor of Otolaryngology–Head and Neck Surgery [ 2 ] Scharukh Jalisi, MD, MA, Associate Professor of Otolaryngology– Head and Neck Surgery

Awards, Grants and Honors Ryan Bartholomew, MD, a T32 OHNS resident in the Harvard Combined Residency Program, was awarded an American Hearing Research Foundation Discovery Grant for his research evaluating whether magnetic stimulation can improve cochlear implant outcomes compared to traditional electric stimulation. A few months later, he was awarded a 2022 New England Otolaryngological Society Resident Research Grant for his research developing a lateral skull base surgical navigation system using stereoscopic surface reconstruction. Regan Bergmark, MD, received a 2021 Pillars of Excellence Award from Mass General Brigham, which recognized her exceptional commitment toward promoting the integration of diversity, equity and inclusion across the health care system. The American Academy of Otolaryngic Allergy awarded Christopher D. Brook, MD, its national Golden Apple Award for his outstanding dedication and effort in otolaryngic allergy education. Jeffrey T. Cheng, PhD, renewed a R01 grant from the National Institutes of Health that will support his research on the transmission of loud sounds from the middle ear into the inner ear. Dr. Cheng’s research, which will receive more than $2 million in funding over a five-year span, will examine how well normal and reconstructed middle ears function when exposed to loud sounds. According to Dr. Cheng, his research could help better predict noiseinduced hearing damage, develop new strategies for ear protection and improve the surgical repair of damaged middle ears.

The National Institutes of Health awarded Daniel Faden, MD, FACS, a R03 grant for his research on a non-invasive “liquid biopsy” tool for detecting head and neck cancers. The grant, which is worth $336,000 over two years, will fund a study that evaluates how the detection or absence of cell-free DNA in blood using a liquid biopsy relates to current methods of diagnosing head and neck cancer and monitoring it after surgery. Dr. Faden was also awarded best oral presentation at the International Papillomavirus Conference in Toronto, Canada, for his talk entitled “Cell free HPV DNA for the diagnosis of HPV+ oropharynx cancer.” Gwenaelle S. Géléoc, PhD, was named co-recipient of an Usher Syndrome Society Translational Research Grant, which will fund the development of new experimental treatments for Usher syndrome type 2A. The treatments are headlined by a promising class of drugs that can alter patterns of gene splicing and assembly. Victoria Huang, MD, a PGY-2 OHNS resident in the Beth Israel Deaconess Medical Center/Harvard Residency Program, earned third-place honors for her presentation on insights about the endolymphatic sac at the New England Otolaryngological Society. The lab of Artur A. Indzhykulian, MD, PhD, received a share of a $1 million Blavatnik Therapeutics Challenge Award for its collaborative research on a treatment for Usher syndrome 1F, a rare—albeit debilitating—form of Usher syndrome. Nate Jowett, MD, PhD, FRCSC, was named a sub-site investigator on a two-year Gilbert Family Foundation Grant led by Casey Maguire, PhD. The grant is valued at more than $750,000, which will help fund gene therapy research at Mass General Hospital and Mass Eye and Ear. Dr. Jowett was also awarded the 2021 John F. and Evangeline Davis Award from the McGill University Department of Biomedical Engineering. The award recognizes Dr. Jowett’s significant contributions to diagnostic and treatment procedures for neurological disorders.

Margaret A. Kenna, MD, MPH, FACS, was named the 2022 Alumnus of the Year by Children’s Hospital of Pittsburgh. She also delivered the annual James S. Reilly, MD, Lecture in Pediatric Otolaryngology at Thomas Jefferson University in March. The topic of her lecture was “Pediatric Hearing Loss: CMV, Genetics and Funky Anatomy.” The Department of Defense awarded Karl Koehler, PhD, a research grant through its Hearing Restoration Program, which promotes research for the treatment of burdensome and prevalent auditory system injuries. The grant will fund Dr. Koehler’s research on organ-on-chip platforms inside the human inner ear that could lead to the discovery of hearing-loss drugs. Leila Mankarious, MD, was awarded a grant from the Ellen Abbott Gilman Trust to help support the Pediatric Hearing Loss Mentorship Program (PHLMP) she cofounded at Mass Eye and Ear. The PHLMP connects children who wear a hearing device with older mentors who have led successful lives while wearing a device. The Mass Eye and Ear Sleep Surgery Team implanted its 200th adult hypoglossal nerve stimulator. The hospital performs the most implants in New England and was recog-

New Leadership Gwenaelle S. Géléoc, PhD, has been named Director of the Speech and Hearing Bioscience and Technology Harvard Graduate Program. Sharon Kujawa, PhD, was named a Board Member of the Hearing Health Foundation. Gregory W. Randolph, MD, FACS, FACE, was re-elected to another fiveyear term as President of the World Congress Thyroid Cancer. Felipe Santos, MD, has been named Division Chief of Otology, Neurotology and Skull Base Surgery at Mass Eye and Ear.

nized last year by Inspire Medical Systems, manufacturer of the only FDA-approved hypoglossal nerve stimulation device, as one of nine programs with a “Physician of Excellence.” The Harvard Catalyst Translational Innovator Program awarded funding to James G. Naples, MD, for his research on balance biomarkers for the diagnosis of dizziness. Dr. Naples hopes to build off his prior line of vestibular research and work towards identifying a serum biomarker that has the potential to differentiate between central and peripheral dizziness.

Mark A. Varvares, MD, FACS, presenting The Sandy and Herb Pollack Young Investigator Award to Alicia Quesnel, MD.

The Sandy and Herb Pollack Young Investigator Award was awarded to Alicia Quesnel, MD, at the 2021 Mass Eye and Ear Annual Meeting of Trustees and Medical Staff. The award, which is endowed by the late Herb Pollack, a former Mass Eye and Ear Board member and trustee, will help expand an initiative by Dr. Quesnel to analyze the genetic makeup of human temporal bone specimens inside the Otopathology Laboratory at Mass Eye and Ear. Gregory W. Randolph, MD, FACS, FACE, was nominated by Women in Otolaryngology for its inaugural He for She Award. The award celebrates male colleagues who support and empower women otolaryngologists in achieving their professional goals. [ continued p. 28 ]

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HIGHLIGHTS

A cohort of OHNS residents in the Harvard Combined Residency Program competed in a Spartan Race at Fenway Park. Led by Harvard Medical School faculty members Jeremy D. Richmon, MD, and Jeremy W. Goldfarb, MD, the group of residents included Ciersten Burks, MD; Adeeb Derakhshan, MD; Rui Liu, MD; Christopher McHugh, MD, PhD; Margaret Mitchell, MD; Suresh Mohan, MD; and Krish Suresh, MD. Residents and faculty members participated in a Spartan Race at Fenway Park.

Mass Eye and Ear Announces Endowment Of Jessica Fewkes Center in Dermatology and Facial Plastic Fund

or more than 40 years, Jessica L. Fewkes, MD, Director of Mohs and Cutaneous Surgery at Mass Eye, has cared for thousands of patients with skin cancer. In 2021, the Jessica Fewkes Center in Dermatology and Facial Plastic Fund was endowed in perpetuity at Mass Eye and Ear. The fund celebrates Dr. Fewkes’ lifelong dedication to her patients and the treatment and prevention of skin cancer worldwide.

The Department of Defense awarded Srinivas V. Saladi, PhD, an Idea Award grant for his research on tumorigenesis and immune evasion. With the support of the grant, Dr. Saladi and his team will combine novel therapies—including epigenetic factors, DNA repair machinery and immune checkpoint inhibitors—in an attempt to control tumor growth. Additionally, Dr. Saladi gave a visiting professor lecture at the University of Wisconsin, Madison, during which he talked about his work targeting the Hippo epigenetic pathway in squamous and skin cancers. The Voice Foundation invited Kristina Simonyan, MD, PhD, Dr med, to deliver the keynote address at its 51st Anniversary Symposium in Philadelphia. Krish Suresh, MD; Tiffany Wang, MD; and Phoebe Yu, MD, MPH, won the 14th Annual American Academy of Otolaryngology–Head and Neck Surgery (AAO-HNS) Academic Bowl at the AAO-HNS Annual Meetings. All three doctors are OHNS residents in the Harvard Combined Residency Program.

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Congratulations on Your Retirement, Dr. Terrell Clark!

fter 45 years of practice, Terrell Clark, PhD, Founding Director of the Deaf and Hard of Hearing Program at Boston Children’s Hospital, will retire this spring.

Krish Suresh, MD; Tiffany Wang, MD; and Phoebe Yu, MD, MPH, posing with their trophy after winning the Annual AAO-HNS Academic Bowl.

Alan D. Workman, MD, MTR, a PGY-4 OHNS resident in the Harvard Combined Residency Program, and Benjamin Bleier, MD, FACS, won the Best Basic Science Research Presentation Award at the Annual Meeting of the American Rhinologic Society for their presentation on the potential role of the protein Cystatin-SN in the development of nasal polyp disease.

RESEARCH ADVANCES

The following are select research advances from the Harvard Medical School Department of Otolaryngology–Head and Neck Surgery. Analyzing age-related immunohistological changes in the human olfactory epithelium and the olfactory bulb Olfactory epithelium (OE) along the inside of the nose plays a crucial role in detecting odors. Neurons carrying signals from the OE to the olfactory bulb are what allow the brain to perceive smell. When damaged, parts of the OE, including its neuronal projections, can regenerate thanks to the presence of nearby basal progenitor cells. However, progenitor cells can lose its regenerative function as humans age. To better understand how age-related changes occur within the olfactory system, a team of researchers led by Eric H. Holbrook, MD, of Mass Eye and Ear, conducted an in-depth study of the OE and its neuronal projections to the olfactory bulb (OB). Human olfactory tissues from 36 subjects, which were an average age of 74.1 years, were analyzed, and results of the study were published in The Journal of Comparative Neurology. The researchers commonly identified respiratory metaplasia, submucosal cysts and neuromata in aged OE, which suggest a progression of progenitor cell inactivity as an underlying pathophysiology of age-related smell loss in humans. Fitzek M, Patel PK, Solomon PD, et al. “Integrated agerelated immunohistological changes occur in human olfactory epithelium and olfactory bulb.” The Journal of Comparative Neurology. 2022. 1-22. Doi: 10.1002/cne.25325

Association between pediatric hearing quality and sports participation During childhood, a sports-related injury can result in considerable morbidity and a range of developmental consequences. Concussions, for example, are generally recognized as one possible cause of auditory dysfunction. However, few epidemiologic studies have quantified an association

between hearing quality and sports-related activity in the pediatric population. Using data from the 2015-2016 National Health and Nutrition Examination Survey, Mass Eye and Ear researchers Elliott D. Kozin, MD; Renata M. Knoll, MD; and Neil Bhattacharyya, MD, FACS, completed a population-based study on whether an association existed between the practice of a sport with a high risk of concussions and hearing quality among children.

Published in Otolaryngology–Head and Neck Surgery, results from the study indicated that subjective abnormal hearing quality was more frequent among children who played football than those who did not. In fact, the authors of the study concluded that children practicing football are 1.56 times more likely to report abnormal hearing quality. Kozin ED, Knoll RM, Bhattacharyya N. “Association of Pediatric Hearing Quality and Sports Participation: A Population-Based Study.” Otolaryngology–Head and Neck Surgery. 2022. Online ahead of print Doi: 10.1177/01945998211064578

Correlation discovered between imbalance and dizziness caused by vestibular schwannomas and vestibular-mediated eye movement Many patients with vestibular schwannomas (VS), or benign tumors on the vestibular nerve, experience debilitating imbalance and dizziness. Standard clinical tests do not assess how severely these tumors damage the vestibular nerve, nor do they provide information on imbalance and dizziness symptoms caused by the tumor. In a recent study published in the Journal of Neurophysiology, Richard Lewis, MD, and

Faisal Karmali, PhD, of Mass Eye and Ear, found that the “imprecision,” or variability, of vestibular-mediated eye movements, rather than the size of those movements, captures clinically relevant information about the severity of nerve damage and the effect of this damage on patient disability. The work of Drs. Lewis and Karmali is part of a larger, inter-institutional research collaboration supported by two R01 grants from the National Institutes of Health. The collaboration is attempting to predict how two groups of patients―one with sporadic VS and another with neurofibromatosis type 2, a genetic disorder characterized by bilateral VS―respond to different treatment interventions. King S, Dahlem K, Karmali F, Stankovic KM, Welling DB, Lewis RF. “Imbalance and dizziness caused by unilateral vestibular schwannomas correlate with vestibulo-ocular reflex precision and bias.” Journal of Neurophysiology. 2022; Vol. 127, Issue 2; p. 596-606 Doi: 10.1152/jn.00725.2020

Detailing the generation and characterization of hair-bearing skin organoids from human pluripotent stem cells Human skin serves a variety of vital functions: The organ acts as an external barrier, a thermoregulator and a sensor for the entire body. Millions of appendages inside the skin, including hair follicles, sweat glands, nerves and fats, are responsible for this array of function. Once damaged, appendages cannot regenerate on their own, which makes it difficult for plastic reconstructive surgeons to repair skin severely damaged by burns, infections, head and neck cancers or alopecia. While researchers have had success engineering the different layers of human skin, many have struggled to recreate full layers of skin that contain these appendages. This changed in 2020 when Karl Koehler, PhD, and Jiyoon Lee, PhD, of

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RESEARCH ADVANCES

Boston Children’s Hospital, used pluripotent stem cells to successfully engineer the firstever appendaged human skin organoid. In Nature Protocols, Drs. Koehler and Lee published a follow-up protocol detailing how to generate and preserve hair-bearing skin tissue from a homogenous population of human pluripotent stem cells in a threedimensional culture system. According to the authors, the final organoid can be maintained in culture for up to 150 days, which, in theory, might give researchers enough time to adapt future organoids for disease modelling, functional skin grafts or investigative research on the biology of skin. Lee J, van der Valk WH, Serdy SA, et al. “Generation and characterization of hair-bearing skin organoids from human pluripotent stem cells.” Nature Protocols. 2022. Doi: 10.1038/s41596-022-00681-y

Establishing safer singing practices during the SARS-CoV-2 pandemic In September 2020, more than a year and a half into the COVID-19 pandemic, scientific research had yet to determine the safety of singing practices in relation to the transmission of COVID-19. Amid lay media reports that “super-spreader” gatherings could occur at choral events in the United States and abroad, not enough evidence was available to determine when or how singers could gather again for in-person performances. Matthew R. Naunheim, MD, MBA, of Mass Eye and Ear, led an inter-institutional study that evaluated existing information about singing and COVID-19, and suggested best practices for how singers could properly gather in ways that would lower the risk of transmission. Published in Journal of Voice, the study concluded that, while the risk of transmission can be mitigated with certain practices, the risk could not be entirely eliminated. Therefore, each community of singers and performers needed to take into consideration a wide range of factors when deciding to resume singing activities in groups.

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The best practices suggested by the paper included outside rehearsals, shortened rehearsal times, proper personal protective equipment and meticulous hygiene, among several others. Editors of Journal of Voice voted the published study its Best Clinical Medicine Paper of 2021. Naunheim MR, Bock J, Doucette PA, et al. “Safer Singing During the SARS-CoV-2 Pandemic: What We Know and What We Don’t.” Journal of Voice. Published online in 2020. Published in print in 2021; Vol. 35, Issue 5; p. 765-771 Doi: 10.1016/j.jvoice.2020.06.028.

Hearing outcomes of cochlear implant patients with Meniere’s disease analyzed in retrospective study Meniere’s disease is a debilitating balance and hearing disorder characterized by sudden bouts of vertigo, tinnitus and progressive hearing loss in one or both ears. Although researchers have had success preventing vertigo symptoms in patients, no treatments have been found to prevent hearing loss in either ear. Approximately one-in-20 patients with Meniere’s disease will experience deafness profound enough to consider cochlear implant surgery. In a retrospective study published in Otolaryngology– Head and Neck Surgery, lead author Steven D. Rauch, MD, of Mass Eye and Ear, and colleagues examined hearing outcomes of patients with Meniere’s disease who underwent cochlear implantation. Dr. Rauch’s team examined the medical and audiologic records of every cochlear implant case at Mass Eye and Ear from 1984 to 2014—more than 1,400 patients—and analyzed the pre- and post-operative speech recognition scores of 29 patients with the disease. Research from Dr. Rauch’s study was featured in the March 2022 edition of the American Academy of Otolaryngology–Head and Neck Surgery Foundation’s OTO podcast. The study concluded that cochlear implants significantly improved word recognition scores among patients. Word score improvement occurred regardless of whether the patient underwent

medical or surgical vertigo treatment prior to implantation, and the potential improvement in scores decreased in patients over age 70, but was still significant. Chien C, Kulthaveesup A, Herrmann B, Rauch SD. “Cochlear Implantation Hearing Outcome in Ménière’s Disease.” Otolaryngology–Head and Neck Surgery. 2022; Vol. 166, Issue 3; p. 523-529 Doi: 10.1177/01945998211012298

Laryngeal function and survival outcomes in recurrent laryngeal nerves invaded by thyroid cancers Invasion of the recurrent laryngeal nerves (RLNs) by thyroid cancer is believed to be a sign of extensive disease with significant co-morbidity. An improved understanding of both the initial presentation and longterm behavior of invaded RLNs could help optimize surgical decision-making as well as oncological outcomes in patients with thyroid cancers. In one of the largest single-center studies ever conducted on invaded RLNs, a team of researchers led by Gregory W. Randolph, MD, FACS, FACE, of Mass Eye and Ear, examined the outcomes of 65 patients who underwent treatment for thyroid cancers. Published in The Laryngoscope, results from the study revealed no association between surgically resecting invaded RLNs and better five-year survival rates. The use of radioactive iodine after surgery, instead, was associated with an improvement in the five-year survival rate. Furthermore, preoperative vocal cord paralysis as a result of RLN invasion was documented in 44 percent of cases, which suggested a need for preoperative laryngeal examination in patients with thyroid cancers. Brooks JA, Abdelhamid Ahmed AHA, Al-Qurayshi Z, et al. “Recurrent Laryngeal Nerve Invasion by Thyroid Cancer: Laryngeal Function and Survival Outcomes.” The Laryngoscope. 2022. Doi: 10.1002/lary.30115

Measuring immune checkpoint inhibitor responses in head and neck cutaneous squamous cell carcinoma When detecting cancer in the body, the immune system uses immune checkpoints

to tag cells as either healthy or cancerous. These checkpoints prevent the body from destroying healthy cells in its immune response to the cancer; cells engaged with the checkpoint are spared by T-cells, while those without the checkpoint are killed. Unfortunately, checkpoints can engage with cancerous cells by mistake, and an immune checkpoint inhibitor (ICI) is required to kill the cancerous cells. In recent years, researchers have looked at ICIs as a new, exciting treatment option for head and neck cancer. A team of researchers led by Kevin S. Emerick, MD, of Mass Eye and Ear, tested a new grading system for the effectiveness of ICIs in a retrospective study of 11 patients with advanced head and neck squamous cell carcinoma (cSCC) with clinical perineural invasion (cPNI). The grading system weighed responses to ICI treatment using radiographic and clinical evidence as it appeared on retrospective chart reviews. Results from the study were published in The Laryngoscope and confirmed that ICI is a viable treatment option for head and neck cSCC with cPNI. It also confirmed that a combination of radiographic and clinical evidence correlates well with ICI treatment response outcomes. Wu MP, Reinshagen KL, Cunnane MB, et al. “Clinical Perineural Invasion and Immunotherapy for Head and Neck Cutaneous Squamous Cell Carcinoma.” The Laryngoscope. 2021. Epub ahead of print Doi: 10.1002/lary.29953

Measuring tympanic membrane impulse responses with highspeed holography The eardrum, or tympanic membrane, plays an essential role in sound transmission. When sounds enter the ear, the membrane responds by transforming acoustic energy into ossicular vibrations inside the middle ear. How the membrane moves and changes shape in response to sounds across a broad frequency range is believed to

affect the fidelity of acousto-mechanical transformation. To better understand how sounds trigger vibrations across the tympanic membrane, a team of researchers at Mass Eye and Ear led by Jeffrey T. Cheng, PhD, developed a High-speed Digital Holography (HDH) system capable of measuring the shape and transient displacements of the membrane within just a few milliseconds. In a study published in Hearing Research, the research team used the HDH system to record frequency and impulse responses at more than 100,000 points along the tympanic membrane surface, which were then built into a two-dimensional map of the tympanic membrane’s response. Results from the study revealed that a majority of the tympanic membrane surface has a tuning frequency of about 1.5 kHz. The results also showed that much of the membrane is set in motion within 50 µs by an impulsive sound. Tang H, Psota P, Rosowski JJ, Furlong C, Cheng JT. “Analyses of the Tympanic Membrane Impulse Response Measured with High-Speed Holography.” Hearing Research. 2021. Vol. 410, 108335; Doi: 10.1016/j.heares.2021.108335

Optical coherence tomography captures new images of the spaces and structures within the cochlea Direct observation of a living cochlea is considered a major challenge in otology and neurotology research. Nearly all knowledge of cochlear morphology has been derived from postmortem tissue, which is typically fixed and processed in a way that could distort the structures and fluid spaces of the organ of Corti. Using optical coherence tomography, Sunil Puria, PhD, of Mass Eye and Ear, worked with a team of researchers to obtain new volumetric images of the high-frequency hook region of the gerbil cochlea. The region was viewed through the round window with far better resolution than had ever been recorded before.

In a study published in the Journal of the Association for Research in Otolaryngology, Dr. Puria and his team reported that the outer tunnel of the cochlea was nearly twice as big as the tunnel of Corti or the space of Nuel, suggesting that the outer tunnel could have a more substantial effect on cochlear micro-mechanics than previously thought. From their study, the researchers speculate that the outer tunnel forms a resonant structure that may affect reticular-lamina motion. Cho NH, Wang H, Puria S. “Cochlear Fluid Spaces and Structures of the Gerbil High-Frequency Region Measured Using Optical Coherence Tomography.” Journal of the Association for Research in Otolaryngology. 2022. 23, 195211. Doi: 10.1007/s10162-022-00836-4

Researchers use geographic data and artificial intelligence to predict mortality rates for falling In the United States, falling is the leading cause of fatal and nonfatal injuries among adults over 65 years old. The mortality rate for falling among these older adults has rapidly increased in recent years. To better understand the sudden rise in mortality, researchers have attempted to look beyond known risk factors—such as balance disorders, medical co-morbidities and environmental hazards—and deploy stateof-the-art machine learning techniques to enhance the risk prediction of falls. In a recent study published in BMC Public Health, a research team comprising members from four different institutions and led by Matthew G. Crowson, MD, of Mass Eye and Ear, used machine learning to examine whether trends in state-level healthcare utilization could predict the mortality from falls. Upon analyzing data collected by the Centers for Disease Control and Prevention, the researchers found that older adults carried the highest death rate from unintentional falls in the United States and that the rate is predicted to accelerate in future years. The machine learning analysis found that there is considerable state-level variability in death rates with healthcare resource

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RESEARCH ADVANCES

utilization intensity being predictive of mortality. Ultimately, the researchers concluded that further study of the relationship between health resource utilization and mortality from unintentional falls may inform enhanced public health policy efforts to mitigate the growing risk of death from unintentional falls in older adults. Crowson MG, Beyea JA, Cottrell J, et al. “The predictive power of geographic health care utilization for unintentional fatal fall rates.” BMC Public Health. 2022; 22 (328) Doi: 10.1186/s12889-022-12731-x

Review of insurance coverage policies for gender-affirming procedures in otolaryngology Gender dysphoria can lead to significant distress, substance abuse, depression and even suicide among members of the transgender community. While genderaffirming surgery may ameliorate these problems, insurance coverage for these procedures remains inconsistent. Elliana DeVore, MD, and David Shaye, MD, MPH, led a team of colleagues from Mass Eye and Ear in a systematic review of state-by-state insurance coverage policies for gender-affirming otolaryngology treatments. In a study published in Facial Plastic Surgery & Aesthetic Medicine, the researchers found that, among the top three commercial health plans per state, only 18 percent held policies they deemed favorable for gender-affirming facial reconstructive surgery. Furthermore, payors in states with less overall legal support for the transgender community were more restrictive in coverage of gender-affirming surgeries. In a follow-up study published in The Laryngoscope, the researchers demonstrated that only 2.7 percent of payors supported voice-related interventions, while 75.8 percent provided no coverage. From both studies, the authors concluded that gender-affirming interventions within the otolaryngology specialty have yet to

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be fully considered by third-party payors. They also determined that further research would be needed to better understand how state advocacy and insurance coverage impact health outcomes for transgender individuals. Gadkaree SK, DeVore EK, Richburg K, Lee LN, Derakhshan A, McCarty JC, Seth R, Shaye DA. “National Variation of Insurance Coverage for Gender-Affirming Facial Feminization Surgery.” Facial Plastic Surgery & Aesthetic Medicine. 2021; Vol. 23, No. 4. Doi: 10.1089/fpsam.2020.0226 DeVore EK, Gadkaree SK, Richburg K, Banaszak EM, Wang TV, Naunheim MR, Shaye DA. “Coverage for GenderAffirming Voice Surgery and Therapy for Transgender Individuals.” The Laryngoscope. 2020; Vol. 131, Issue 3; p. E896-E902 Doi: 10.1002/lary.28986

Tailored multidisciplinary approach helps prevent feeding tube use after transoral robotic surgery HPV-associated oropharyngeal squamous cell carcinoma (OPSCC) is one of the most common head and neck cancers in the world. Treatment for this disease with transoral robotic surgery (TORS) has excellent survival outcomes. As a result, clinicians have heightened their focus on optimizing patient quality of life. While some centers place up-front feeding tubes in patients, careful patient selection can help initiate an early oral diet while avoiding feeding tube placement. In a study led by Allen L. Feng, MD, and Jeremy D. Richmon, MD, both of Mass Eye and Ear, the vast majority of patients undergoing TORS procedures did not require feeding tube placement. Thanks to the close interaction between the surgical, nursing and Speech-Language Pathology teams, a unique multidisciplinary protocol was developed to allow these patients to initiate safe early oral intake. This study was published in Otolaryngology– Head and Neck Surgery. Feng A, Holcomb A, Abt N, et al. “Feeding Tube Placement Following Transoral Robotic Surgery for Oropharyngeal Squamous Cell Carcinoma.” Otolaryngology–Head and Neck Surgery. 2022; Vol. 166, Issue 4; p. 696-703 Doi: 10.1177/01945998211020302

Transmission rate of COVID-19 among patients following otolaryngology outpatient encounters Amid the COVID-19 pandemic, many experts believed routine outpatient otolaryngology visits posed a particularly high risk of spreading SARS-CoV-2, the virus responsible for causing COVID-19. Since patients are unable to wear masks during comprehensive otolaryngology examinations, and many upper-airway procedures have a high propensity for aerosolization, providers insisted that such visits put themselves and their patients at a higher risk of viral transmission.

Mass Eye and Ear researchers Neil Bhattacharyya, MD, FACS; Alan D. Workman, MD, MTR; and Mark A. Varvares, MD, FACS, put this idea to the test by investigating the rate of COVID-19 infection among patients following otolaryngology outpatient encounters, and comparing it to the infection rate among patients following non-otolaryngology outpatient encounters. In a study published in Otolaryngology– Head and Neck Surgery, the researchers evaluated a matched-cohort sampling of more than 20,000 patients seen between April 2020 and January 2021. When comparing their results to other non-otolaryngology outpatient encounters, researchers found no increased rate of post-visit COVID-19 positivity following an in-office otolaryngology encounter. Results from the study suggest that the perceived risk of provider-to-patient and patient-topatient transmission during outpatient otolaryngologic care may have been unfounded. Workman AD, Varvares MA, Bhattacharyya N. “Rate of COVID-19 Infection in Patients Following Otolaryngology vs Non-otolaryngology Outpatient Encounters.” Otolaryngology–Head and Neck Surgery. 2021. 131; E896– E902 Doi: 10.1177/01945998211049702

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

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Upcoming Events oto.hms.harvard.edu/event-calendar Please visit our online calendar for information about upcoming events in the Harvard Medical School Department of Otolaryngology– Head and Neck Surgery.

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