2021 OHNS News

July 14 , 2021

Antihypertension drug may help patients with noncancerous brain tumors affecting hearing

Losartan prevented tumor-induced hearing loss and augmented radiation efficacy in mice.

BOSTON – New research led by investigators at Massachusetts General Hospital (MGH) and Massachusetts Eye and Ear indicates that the blood pressure drug losartan may benefit patients with neurofibromatosis type 2 (NF2), a hereditary condition associated with vestibular schwannomas, or noncancerous tumors along the nerves in the brain that are involved with hearing and balance. The findings, which are published in Science Translational Medicine, are especially important because vestibular schwannomas are currently treated with surgery and radiation therapy (which carry risks of nerve damage), and no drug is approved by the U.S. Food and Drug Administration to treat these tumors or their associated hearing loss.

“Developing effective therapeutics to preserve hearing function in patients with NF2 is an urgent unmet medical need. The greatest barrier to managing NF2-related auditory impairment is our incomplete understanding of how schwannomas cause hearing loss,” says co–senior author Lei Xu, MD, PhD, an investigator in the Steele Laboratories for Tumor Biology within the MGH Department of Radiation Oncology. A previous report showing that scarring, or fibrosis, exists in schwannomas and correlates with hearing loss prompted the team to test whether a drug that blocks fibrosis might be effective.

Losartan blocks a component of the renin-angiotensin system, which is involved not only in regulating blood pressure but also in stimulating fibrosis and inflammation. The entire class of angiotensin-targeting drugs, which includes losartan, has been shown to reduce collagen accumulation in cardiac and kidney fibrotic disease. Using a mouse model of NF2, Xu  and her colleagues found that losartan treatment had several effects on vestibular schwannomas and the brain: It reduced inflammatory signaling and swelling and thus prevented hearing loss, and it increased oxygen delivery to enhance the effectiveness of radiation therapy (which may help lower the radiation dose needed to control tumor growth and limit radiation-associated toxicities). 

In preparation to translate these findings into the clinic, co–senior author Konstantina Stankovic, MD, PhD, former chief of the Division of Otology and Neurotology at Massachusetts Eye and Ear, now Bertarelli Professor and Chair of the Department of Otolaryngology — Head & Neck Surgery at Stanford University School of Medicine, examined patient samples and data. Her team found that vestibular schwannomas associated with poor hearing had more pronounced inflammatory signaling than tumors associated with good hearing. This inflammatory signaling in tumors was capable of directly damaging cochlear cells that are essential for hearing. Also, patients with vestibular schwannoma who took losartan or other drugs in its class experienced no progression in hearing loss, unlike patients on other or no antihypertensive drugs. This study illustrates the advantages offered by an integrated approach and teamwork that spans basic research, translational investigation and clinical care.

The findings support the need for a prospective clinical trial of losartan in patients with NF2 and vestibular schwannomas. “As one of the most commonly prescribed drugs for hypertension, the safety and low cost of losartan warrants rapid translation of our research to patients with vestibular schwannomas to try to prevent tumor-induced sensorineural hearing loss,” Stankovic says.

Xu is an assistant professor at Harvard Medical School. Co-authors included Limeng Wu, Sasa Vasilijic, Yao Sun, Jie Chen, Lukas D. Landegger, Yanling Zhang, Wenjianlong Zhou, Jun Ren, Samuel Early, Zhenzhen Yin, William W. Ho, Na Zhang, Xing Gao, Grace Y. Lee, Meenal Datta, Jessica E. Sagers, Alyssa Brown,Alona Muzikansky, Anat Stemmer-Rachamimov, Luo Zhang, Scott R. Plotkin and Rakesh K. Jain.

This study was supported by the Department of Defense, the Children’s Tumor Foundation Drug
Discovery Initiative, the National Cancer Institute, the Advanced Medical Research Foundation, Jane’s Trust Foundation, the Lustgarten Foundation, the Ludwig Center at Harvard, the National Foundation for Cancer
Research, the Gates Foundation, the Cancer Research Institute, the American Association of Cancer Research, the National Institute on Deafness and Other Communication Disorders, Nancy Sayles Day Foundation, Lauer Tinnitus Research Center, the Barnes Foundation, the Zwanziger Foundation, and Sheldon and Dorothea Buckler.

June 18, 2021

Congratulations to our amazing graduating chief residents, Michael Chang, Brian Nuyen and Jared Shenson — all fellowship bound!

Dr. Chang will be staying on with us for rhinology, Dr. Nuyen will be headed for Oregon to pursue voice with Dr. James Thomas, and Dr. Shenson will be relocating to Texas for a head and neck fellowship at MD Anderson.

Michael Chang, MD

Brian Nuyen, MD

Jared Shenson, MD

May 25, 2021

Congrats to Chief Jared for being a winner at the 7th (2021) annual Resident QI Patient Safety Symposium for his work on “Prevention of tracheostomy-related pressure ulcers.” All abstracts and posters presented can be found at the GME website.

May 14, 2021

Pediatric Otolaryngology Fellow Match 2022-23: we are so proud to announce the Match of Dr Grace Kim MD, PGY4 to Stanford Pediatric Otolaryngology.

Also, on Friday, May 14, 2021, Dr. Grace Kim was awarded first-place at BARRS on Friday for her presentation “Fate-Mapping Reveals Features of Surviving Hair Cells During Recovery of the Damaged Mouse Balance Organs.” She’s a rising star in the field!

May 13, 2021

Dr. Koltai is being named the recipient of the 2021 Distinguished Award for Humanitarian Service by the American Academy of Otolaryngology — Head & Neck Surgery.

“…Each year this award is conferred on a member who is widely recognized for a consistent, stable character distinguished by honesty, zeal for truth, integrity, love and devotion to humanity and a self-giving spirit. You were selected because you encompass these attributes and are to be lauded for your significant contribution to the advancement of otolaryngology care both domestically and internationally. You embody all the credentials outlined pursuant to this award and are commended for your dedication to the advancement of pediatric otolaryngology care in Harare, Zimbabwe, and your lifelong commitment to the advancement of global health…”

Letter PDF

May 8, 2021

2021 Microtia Webinar

On May 8, 2021 Dr. Truong, MD and Dr. Chang, MD gave a presentation for the California Academy of Audiology at the 2021 Microtia Webinar. They discussed  the current concepts and controversies in management of microtia and atresia.

Melissa Tribble, AuD spoke about considerations of audiologic management of pediatric patients with microtia and aural atresia. 

May 3-5, 2021

"Endoscopic Surgery of the Sinuses, Eustachian Tube and Ear" Course

During the “Endoscopic Surgery of the Sinuses, Eustachian Tube and Ear” held May 3-5, 2021, Dr. Jennifer Lee lectured,  presented, and served as a panelist for ET dilatory dysfunction and patulous ET. This highly interactive course focused on rhinologic topics, including surgery of the skull base, frontal sinus and orbit; treatment of Eustachian tube dysfunction, including balloon dilation techniques; and innovative technologies for endoscopic and exoscopic ear surgery.

All presentations and course materials are available on-demand to watch and review for 90 days.

 

 

April 14, 2021

Grillet lab’s new high impact paper makes the cover of Journal of Neuroscience!

Vol. 41, Issue 15, 14 Apr 2021

Trouillet, Alix, Katharine K. Miller, Shefin Sam George, Pei Wang, Noor-E.-Seher Ali, Anthony Ricci, and Nicolas Grillet. “Loxhd1 Mutations Cause Mechanotransduction Defects in Cochlear Hair Cells.” The Journal of Neuroscience: The Official Journal of the Society for Neuroscience 41, no. 15 (April 14, 2021): 3331–43. https://doi.org/10.1523/JNEUROSCI.0975-20.2021.

Hearing loss occurs frequently due to the dysfunction of the auditory sensory cells in the inner ear, which transform mechanical stimulations into electric signals. Trouillet et al. demonstrate that the molecule LOXHD1 is required for this mechanotransduction process, but surprisingly, only in mature auditory cells. When LOXHD1 is mutated, some of the known molecules required for mechanotransduction are still correctly positioned in the sensory cells, suggesting that the mechanotransduction machinery is still present, but not activatable. Their research identified a new step in the auditory cell development. It will be critical to further understand them as they are responsible for congenital and age-related forms of hearing loss in humans.

About the Cover:

This scanning electron micrograph shows the hair bundle of a inner hair cell from a wild-type mouse cochlea. Sound-induced forces displace these mechanosensitive organelles, which comprise stereocilia organized into rows of increasing height. Hair bundle deflection tenses external filaments (called tip links) that connect stereocilia rows, and this gates mechanotransduction channels, initiating the auditory signal. A critical maturation step for hair bundle mechanotransduction that occurs between postnatal days 7 and 11 requires the integrity of the deafness gene LOXHD1. For more information, see the article by Trouillet et al. (pages 3331–3343). Cover image: Nicolas Grillet.

April 14, 2021

Dr. Santa Maria’s team publishes “Treatment with a Neutrophil Elastase Inhibitor and Ofloxacin Reduces P. Aeruginosa Burden in a Mouse Model of Chronic Suppurative Otitis Media,” in Open Access on April 6, 2021.

Dr. Santa Maria’s team publishes “Treatment with a Neutrophil Elastase Inhibitor and Ofloxacin Reduces P. Aeruginosa Burden in a Mouse Model of Chronic Suppurative Otitis Media,” in Open Access on April 6, 2021.

Abstract:
Chronic suppurative otitis media (CSOM) is a widespread, debilitating problem with poorly understood immunology. Here, we assess the host response to middle ear infection over the course of a month post-infection in a mouse model of CSOM and in human subjects with the disease. Using multiparameter flow cytometry and a binomial generalized linear machine learning model, we identified Ly6G, a surface marker of mature neutrophils, as the most informative factor of host response driving disease in the CSOM mouse model. Consistent with this, neutrophils were the most abundant cell type in infected mice and Ly6G expression tracked with the course of infection. Moreover, neutrophil-specific immunomodulatory treatment using the neutrophil elastase inhibitor GW 311616A significantly reduces bacterial burden relative to ofloxacin-only treated animals in this model. The levels of dsDNA in middle ear effusion samples are elevated in both humans and mice with CSOM and decreased during treatment, suggesting that dsDNA may serve as a molecular biomarker of treatment response. Together these data strongly implicate neutrophils in the ineffective immune response to P. aeruginosa infection in CSOM and suggest that immunomodulatory strategies may benefit drug-tolerant infections for chronic biofilm-mediated disease.

Khomtchouk, K. M., L. I. Joseph, B. B. Khomtchouk, A. Kouhi, S. Massa, A. Xia, I. Koliesnik, D. Pletzer, P. L. Bollyky, and P. L. Santa Maria. “Treatment with a Neutrophil Elastase Inhibitor and Ofloxacin Reduces P. Aeruginosa Burden in a Mouse Model of Chronic Suppurative Otitis Media.” Npj Biofilms and Microbiomes 7, no. 1 (December 2021): 31. https://bit.ly/3mKIaks

March 29, 2021

Thyroid, Parathyroid & Neck Ultrasound Course, Apr 24, 2021

After being forced to cancel last year's event due to the COVID-19 pandemic, Dr. Lisa Orloff, MD, FACS, FACE, will be hosting the American College of Surgeons Thyroid, Parathyroid, and Neck Ultrasound Course in conjunction with the Otolaryngology Programs at UCSF, UC Irvine and UCSD.

While the didactic portion will be held virtually, the hands-on portion will be held in-person at each respective institution.

We are so excited to be able to introduce this topic to residents, fellows and physicians in this setting as we all make the transition from a world of completely remote learning into one that offers opportunities to share knowledge in new, creative ways!

Dr. Lisa Orloff, MD, FACS, FACE is Director of the Endocrine Head and Neck Surgery Program (Stanford Cancer Center), a Professor of Otolaryngology — Head & Neck Surgery, and Clinical Instructorship Director of the Endocrine Surgery

March 23, 2021

Chickens are an important animal model for hearing restoration research because they are naturally capable of regenerating cochlear hair cells. This fact is known for many years, but the mechanisms that initiate and control this regenerative ability are unknown. Likewise, the cochlea of neonatal mice bears the capacity to form new cells, including new hair cells. However, this feature disappears between the second and third week, around the onset of hearing in mice.

In a series of three high-profile publications in the journal Cell Reports, Dr. Stefan Heller’s laboratory led by postdoctoral fellows Marie Kubota, Amanda Janesick, and Nesrine Benkafadar reported several novel findings that lay the foundation for in-depth characterization of the cellular signaling that initiates cochlear hair cell regeneration in birds. The researchers identified a transiently existing cell group in the mammalian cochlea that is the source of the regenerative capacity that is observed in neonates. The later research is related to a project conducted by Dr. Alan Cheng’s laboratory, which will report more details on this cell population later this year.

The work uses single-cell RNA-sequencing. This technology provides insight into changes in the activity of all genes as cochlear cells respond to hair cell damage and death.

The research created a comprehensive “inventory” of more than 15,000 individual genes expressed in the different cell types of the chicken and the mouse inner ear. Moreover, it led to identifying new cell types and many new marker genes for virtually every cell group of the cochlea.

The next steps of this research are already progressing. Dr. Heller’s team is now focusing on changes in gene expression that happen when the inner ear is damaged by drugs that cause sensory hair cell death. Their goal is to identify the mechanisms that birds utilize to repair their inner ears and figure out why mice and humans cannot do the same thing. 

The majority of funding of this work came through SICHL and the Hearing Health Foundation.

Benkafadar, Nesrine, Amanda Janesick, Mirko Scheibinger, Angela H. Ling, Taha A. Jan, and Stefan Heller. “Transcriptomic Characterization of Dying Hair Cells in the Avian Cochlea.” Cell Reports 34, no. 12 (March 23, 2021). https://doi.org/10.1016/j.celrep.2021.108902.

Janesick, Amanda, Mirko Scheibinger, Nesrine Benkafadar, Sakin Kirti, Daniel C. Ellwanger, and Stefan Heller. “Cell-Type Identity of the Avian Cochlea.” Cell Reports 34, no. 12 (March 23, 2021). https://doi.org/10.1016/j.celrep.2021.108900.

Kubota, Marie, Mirko Scheibinger, Taha A. Jan, and Stefan Heller. “Greater Epithelial Ridge Cells Are the Principal Organoid-Forming Progenitors of the Mouse Cochlea.” Cell Reports 34, no. 3 (January 19, 2021). https://doi.org/10.1016/j.celrep.2020.108646.

March 18, 2021

Stanford OHNS Welcomes Its Incoming Intern Class!

Michael Belsky, MD, MS

Medical School: University of Pittsburgh
Undergraduate: Schreyer Honors College, The Pennsylvania State University

Hobbies: Music - piano and singing; currently learning guitar and music production to record cover album with roommate; Musical theater - favorite shows are "The Last 5 Years," "Dear Evan Hansen," and "Next To Normal"; Running; Reading - currently "Why We're Polarized" by Ezra Klein; Mentoring junior medical students.

Rami Ezzibdeh, MD, MS

Medical School: Stanford
Undergraduate: University of Pennsylvania

Hobbies: Urban design and architectural preservation, education, biomaterials, surgical oncology, premier league soccer, drumming and percussion.

Patrick Kiessling, MD (Clinical Scientist Research Track)

Medical School: Mayo Clinic Alix School of Medicine
Undergraduate: University of Michigan

Hobbies: Music performance: solo classical singing, opera, musical theatre, choir, and classical piano; Baking, cooking, and teaching myself new recipes; Running, hiking, reading, and yoga.

Steven Losorelli, MD, MS

Medical School: Stanford
Undergraduate: Stanford

Hobbies: Scientific Scuba Diving, Great Highland Bagpiper (Grade III; 2011–present), Coffee roasting and farming, Long-distance trail running, Surfski ocean kayaking, Backpacking, Tennis, and Creative writing.

Arifeen Rahman, MD

Medical School: Stanford
Undergraduate: Harvard College

Hobbies: Creative writing, theater (plays, musicals, live magazines), crafting travel itineraries, and baking.

March 1, 2021

NIH awards $2.4M to Dr. Nayak's research, March 1, 2021

Dr. Nayak's R-01 independent investigator grant application to the NIH was funded this morning (3/1/2021) by the National Heart, Lung and Blood Institute (NHLBI). This is a 5-year award (3/1/2021 - 1/31/2026) totaling $2.4M, to support his laboratory group's pre-clinical in vitro and in vivo animal model work to optimize the transplantation of CRISPR gene-corrected human stem cells into the airway epithelium, as a candidate treatment for cystic fibrosis sinusitis. Co-Investigators on this award, all within Stanford University, include Drs. Matthew Porteus (Pediatrics and Biochemistry), Tushar Desai (Pulmonary Critical Care Medicine), Y. Peter Yang (Orthopedics), and Jeffrey Wine (Psychology, CF Biology).