Publications by authors named "Carol R Bradford"

233 Publications

Long-term neck and shoulder function among survivors of oropharyngeal squamous cell carcinoma treated with chemoradiation as assessed with the neck dissection impairment index.

Head Neck 2021 Feb 12. Epub 2021 Feb 12.

Department of Otolaryngology - Head and Neck Surgery, University of Michigan Health System, Ann Arbor, Michigan, USA.

Background: Of interest is the long-term neck and shoulder impairment of patients treated with primary chemoradiotherapy (CRT). This is important for counseling patients regarding treatment decisions when discussing primary CRT.

Methods: A cross-sectional study to identify factors that contribute to neck and shoulder dysfunction in patients treated with primary CRT. We utilized the neck dissection impairment index (NDII). Eighty-seven patients treated between 2003 and 2010, who were free of disease, responded; 24 of these 87 underwent post-CRT neck dissection. Mean interval since completion of CRT was over 5 years (62.7 months). Mean age, 63.5 years, male:female 75:12.

Results: Mean NDII score was 87.4 (SD 22.1, range 5-100). Multiple linear regression revealed worse NDII scores for patients with larger pre-CRT gross tumor nodal volume (GTVnodal), controlled for age, sex, body mass index (BMI), and the presence of neck dissection (p = 0.02). There were significant associations with increasing GTVnodal and "low" scores for components of the NDII that assessed neck pain (p = 0.02), neck stiffness (p = 0.01), lifting heavy objects (p = 0.02), reaching overhead (p = 0.02), and ability to do work (p = 0.02). Physical therapy (PT) was evaluated as an "anchor" but it was prescribed "as needed." Regression revealed participation in PT was associated with higher GTVnodal, lower BMI, presence of neck dissection, and female sex (p = 0.00007).

Conclusion: GTVnodal was an independent predictor of neck and shoulder impairment. High GTVnodal was associated with increased pain and stiffness, and increased difficulty lifting heavy objects, reaching overhead, overall ability to perform work-related tasks and was associated with participation in post-treatment PT.
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http://dx.doi.org/10.1002/hed.26636DOI Listing
February 2021

New Age Mentoring and Disruptive Innovation-Navigating the Uncharted With Vision, Purpose, and Equity.

JAMA Otolaryngol Head Neck Surg 2021 Feb 4. Epub 2021 Feb 4.

Department of Head and Neck Surgery & Communication Sciences, Duke University, Durham, North Carolina.

For individuals aspiring to a career in otolaryngology-head and neck surgery, mentorship can shape destiny. Mentorship helps assure safe passage into the specialty, and it influences the arc of professional development across the career continuum. Even before the novel coronavirus disease 2019 (COVID-19) pandemic, technology and social networking were transforming mentorship in otolaryngology. Now, in an increasingly virtual world, where in-person interactions are the exception, mentorship plays an even more pivotal role. Mentors serve as trusted guides, helping learners navigate accelerating trends toward early specialization, competency-based assessments, and key milestones. However, several structural barriers render the playing field unlevel. For medical students, cancellation of visiting clerkships, in-person rotations, and other face-to-face interactions may limit access to mentors. The pandemic and virtual landscape particularly threaten the already-leaky pipeline for underrepresented medical students. These challenges may persist into residency and later career stages, where structural inequities continue to subtly influence opportunities and pairings of mentors and mentees. Hence, overreliance on serendipitous encounters can exacerbate disparities, even amid societal mandates for equity. The decision to take deliberate steps toward mentoring outreach and engagement has profound implications for what otolaryngology will look like in years to come. This article introduces the concept of new age mentoring, shining a light on how to modernize practices. The key shifts are from passive to active engagement; from amorphous to structured relationships; and from hierarchical dynamics to bidirectional mentoring. Success is predicated on intentional outreach and purposefulness in championing diversity, equity, and inclusion in the progressively technology-driven landscape.
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http://dx.doi.org/10.1001/jamaoto.2020.5448DOI Listing
February 2021

Identification of cisplatin-resistant factor by integration of transcriptomic and proteomic data using head and neck carcinoma cell lines.

Nagoya J Med Sci 2020 Aug;82(3):519-531

Department of Otorhinolaryngology, Aichi Medical University School of Medicine, Nagakute, Japan.

Cisplatin is an important drug for the treatment of head and neck squamous cell carcinoma (HNSCC). Determining chemoresistant factors prior to treatment will lead to great benefits for clinicians and patients. Here, we evaluated chemoresistant factors by integrating proteomic and transcriptomic data using HNSCC cell lines to identify a more precise chemoresistant factor in HNSCC. We used four HNSCC cell lines: cisplatin-sensitive, acquired cisplatin resistance, naturally cisplatin-resistant, and acquired 5-FU resistance. Proteomic analysis was performed using iTRAQ, tandem mass spectrometry, and liquid chromatography-electrospray ionization-tandem mass spectrometry. Transcriptomic analysis was performed using microarrays. By integrating these independent data, common factors were addressed and functional analysis was performed using small interfering RNAs (siRNAs) to change the chemosensitivity. Using iTRAQ analysis, 7 proteins were identified as specific for cisplatin chemoresistance factors. Transcriptomic analysis revealed hundreds of potential candidate factors. By combining and integrating these data, S100A2 was identified as a potential cisplatin-specific chemoresistance factor. Functional analysis with siRNA revealed that the expression of S100A2 was reduced and cisplatin sensitivity recovered in the acquired and naturally cisplatin-resistant cell lines, but not in the cisplatin-sensitive cell lines. S100A2 was identified as a cisplatin-specific chemoresistance factor by integrating the transcriptomic and proteomic results obtained using HNSCC cell lines. This is a novel technique that allows for a precise identification, also known as a comprehensive analysis. Our findings indicate that these proteins could be used as biomarkers of HNSCC treatments, providing physicians with new treatment strategies for patients with HNSCC, showing chemoresistance.
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http://dx.doi.org/10.18999/nagjms.82.3.519DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7548249PMC
August 2020

Prioritizing Diversity in Otolaryngology-Head and Neck Surgery: Starting a Conversation.

Otolaryngol Head Neck Surg 2021 Feb 13;164(2):229-233. Epub 2020 Oct 13.

America Academy of Otolaryngology-Head and Neck Surgery, Alexandria, Virginia, USA.

Academic centers embody the ideals of otolaryngology and are the specialty's port of entry. Building a diverse otolaryngology workforce-one that mirrors society-is critical. Otolaryngology continues to have an underrepresentation of racial and ethnic minorities. The specialty must therefore redouble efforts, becoming more purposeful in mentoring, recruiting, and retaining underrepresented minorities. Many programs have never had residents who are Black, Indigenous, or people of color. Improving narrow, leaky, or absent pipelines is a moral imperative, both to mitigate health care disparities and to help build a more just health care system. Diversity supports the tripartite mission of patient care, education, and research. This commentary explores diversity in otolaryngology with attention to the salient role of academic medical centers. Leadership matters deeply in such efforts, from culture to finances. Improving outreach, taking a holistic approach to resident selection, and improving mentorship and sponsorship complement advances in racial disparities to foster diversity.
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http://dx.doi.org/10.1177/0194599820960722DOI Listing
February 2021

Controversies in the Workup and Surgical Management of Parotid Neoplasms.

Otolaryngol Head Neck Surg 2021 Jan 23;164(1):27-36. Epub 2020 Jun 23.

The University of Minnesota School of Medicine, Minneapolis, Minnesota, USA.

Objective: Parotid neoplasms are a rare heterogeneous group of tumors with varied clinical presentation and behavior. Here we provide an evidence-based review of the contemporary approach to evaluation and surgical management of parotid tumors.

Data Source: PubMed and Web of Science Databases.

Review Methods: Searches of the PubMed and Web of Science databases were performed on subjects related to the diagnosis and surgical management of parotid neoplasms. Particular emphasis was placed on the following areas: evaluation of parotid tumors, including imaging workup and the utility of fine-needle aspiration; extent of surgery of the primary lesion, including the extent of parotidectomy as well as oncologic management of the facial nerve; the extent of surgery of involved and at-risk cervical lymphatics; and parotid bed reconstruction. Articles published from 2014 to the present were prioritized, supplementing with information from prior studies in areas where data are lacking.

Conclusion: A summary of the literature in these areas is outlined to provide an evidence-based approach to evaluation and management of parotid neoplasms.

Implications For Practice: While data are available to help guide many aspects of workup and management of parotid neoplasms, further research is needed to refine protocols for this heterogeneous group of diseases.
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http://dx.doi.org/10.1177/0194599820932512DOI Listing
January 2021

Upholding the Tripartite Mission in Times of Crisis: Purpose and Perseverance in the COVID-19 Pandemic.

Otolaryngol Head Neck Surg 2020 07 5;163(1):54-59. Epub 2020 May 5.

Department of Otolaryngology-Head and Neck Surgery, University of Michigan Medical School, Ann Arbor, Michigan, USA.

Academic otolaryngology has historically comprised a tripartite mission of research, education, and clinical care. This mission is greatly strained by the COVID-19 pandemic. Research laboratories are fallow, surgical cases are deferred, and clerkships are canceled. Otolaryngologists are adapting to new circumstances ranging from virtual patient care to urgent procedures in protective gear to deployment to provisional field hospitals. Amid these operational challenges, the specialty is demonstrating extraordinary resilience and grit, discovering new ways to serve learners, colleagues, and communities. Statements from leaders in otolaryngology reveal selfless acts and purposefulness. Necessity has spurred innovation in education, science, and novel models of care. Paragons strike notes of hope, inspiring us to persevere and serve. This commentary explores the present challenges and offers a vision for upholding the academic mission.
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http://dx.doi.org/10.1177/0194599820922986DOI Listing
July 2020

COVID-19 pandemic: Effects and evidence-based recommendations for otolaryngology and head and neck surgery practice.

Head Neck 2020 06 15;42(6):1259-1267. Epub 2020 Apr 15.

International Head and Neck Scientific Group, Udine, Italy.

The 2019 novel coronavirus disease (COVID-19) is a highly contagious zoonosis produced by SARS-CoV-2 that is spread human-to-human by respiratory secretions. It was declared by the WHO as a public health emergency. The most susceptible populations, needing mechanical ventilation, are the elderly and people with associated comorbidities. There is an important risk of contagion for anesthetists, dentists, head and neck surgeons, maxillofacial surgeons, ophthalmologists, and otolaryngologists. Health workers represent between 3.8% and 20% of the infected population; some 15% will develop severe complaints and among them, many will lose their lives. A large number of patients do not have overt signs and symptoms (fever/respiratory), yet pose a real risk to surgeons (who should know this fact and must therefore apply respiratory protective strategies for all patients they encounter). All interventions that have the potential to aerosolize aerodigestive secretions should be avoided or used only when mandatory. Health workers who are: pregnant, over 55 to 65 years of age, with a history of chronic diseases (uncontrolled hypertension, diabetes mellitus, chronic obstructive pulmonary diseases, and all clinical scenarios where immunosuppression is feasible, including that induced to treat chronic inflammatory conditions and organ transplants) should avoid the clinical attention of a potentially infected patient. Health care facilities should prioritize urgent and emergency visits and procedures until the present condition stabilizes; truly elective care should cease and discussed on a case-by-case basis for patients with cancer. For those who are working with COVID-19 infected patients' isolation is compulsory in the following settings: (a) unprotected close contact with COVID-19 pneumonia patients; (b) onset of fever, cough, shortness of breath, and other symptoms (gastrointestinal complaints, anosmia, and dysgeusia have been reported in a minority of cases). For any care or intervention in the upper aerodigestive tract region, irrespective of the setting and a confirmed diagnosis (eg, rhinoscopy or flexible laryngoscopy in the outpatient setting and tracheostomy or rigid endoscopy under anesthesia), it is strongly recommended that all health care personnel wear personal protective equipment such as N95, gown, cap, eye protection, and gloves. The procedures described are essential in trying to maintain safety of health care workers during COVID-19 pandemic. In particular, otolaryngologists, head and neck, and maxillofacial surgeons are per se exposed to the greatest risk of infection while caring for COVID-19 positive subjects, and their protection should be considered a priority in the present circumstances.
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http://dx.doi.org/10.1002/hed.26164DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7262203PMC
June 2020

Parathyroid cancer: An update.

Cancer Treat Rev 2020 Jun 19;86:102012. Epub 2020 Mar 19.

Coordinator of the International Head and Neck Scientific Group, Padua, Italy.

Parathyroid cancer (PC) is a rare malignant tumor which comprises 0.5-5% of patients with primary hyperparathyroidism (PHPT). Most of these cancers are sporadic, although it may also occur as a feature of various genetic syndromes including hyperparathyroidism-jaw tumor syndrome (HPT-JT) and multiple endocrine neoplasia (MEN) types 1 and 2A. Although PC is characterized by high levels of serum ionized calcium (Ca) and parathyroid hormone (PTH), the challenge to the clinician is to distinguish PC from the far more common entities of parathyroid adenoma (PA) or hyperplasia, as there are no specific clinical, biochemical, or radiological characteristic of PC. Complete surgical resection is the only known curative treatment for PC with the surgical approach during initial surgery strongly influencing the outcome. In order to avoid local recurrence, the lesion must be removed en-bloc with clear margins. PC has high recurrence rates of up to 50% but with favorable long-term survival rates (10-year overall survival of 60-70%) due to its slow-growing nature. Most patients die not from tumor burden directly but from uncontrolled severe hypercalcemia. In this article we have updated the information on PC by reviewing the literature over the past 10 years and summarizing the findings of the largest series published in this period.
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http://dx.doi.org/10.1016/j.ctrv.2020.102012DOI Listing
June 2020

Predictors of survival in patients undergoing oropharyngeal surgery for cancer recurrence after radiation therapy.

Eur Arch Otorhinolaryngol 2020 Jul 19;277(7):2085-2093. Epub 2020 Mar 19.

Department of Otolaryngology Head and Neck Surgery, University of Michigan, 1500 East Medical Center Dr., Ann Arbor, MI, 48109-5312, USA.

Purpose: The incidence of oropharyngeal squamous cell carcinoma continues to rise with the majority of patients receiving definitive or adjunctive radiation. For patients with locoregional recurrence after radiation, optimal treatment involves salvage surgery. The aim of this study is to identify factors that predict survival to ultimately improve patient selection for salvage surgery.

Methods: Retrospective cohort study at an NCI-designated cancer center. We analyzed patients with a history of head and neck radiation who presented with persistent/recurrent or second primary disease requiring salvage oropharyngeal resection from 1998-2017 (n = 120). Patients were stratified into three classes based on time to recurrence and presence of laryngopharyngeal dysfunction. Primary outcomes were 5-year overall survival (OS) and disease specific survival (DSS).

Results: Median OS was 27 months (median follow-up 20 months). Five-year OS was 47% for class I (recurrence > 2 years), 26% for class II (recurrence ≤ 2 years), and 0% for class III (recurrence ≤ 2 years and laryngopharyngeal dysfunction), (p < 0.0001). Five-year DSS showed significant differences between classes (p < 0.0001). On multivariate analysis, class remained predictive of OS (p = 0.04- < 0.001) and DSS (p = 0.04-0.001). Adjuvant radiation after salvage surgery with negative margins showed superior OS (71% vs. 28%, p = 0.01) and DSS (83% vs 37%, p = 0.02) compared to surgery alone and was a significant predictor of improved survival on multivariate analysis (HR 0.1, p = 0.04).

Conclusion: This study identified a subset of patients with oropharyngeal cancer recurrence within two years of initial treatment and with laryngopharyngeal dysfunction who have poor outcomes for salvage surgery.
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http://dx.doi.org/10.1007/s00405-020-05913-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7292755PMC
July 2020

"My Research Is Their Business, but I'm Not Their Business": Patient and Clinician Perspectives on Commercialization of Precision Oncology Data.

Oncologist 2020 07 13;25(7):620-626. Epub 2020 Mar 13.

Center for Bioethics & Social Sciences in Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA.

Background: Genetic sequencing and precision oncology have supported clinical breakthroughs but depend upon access to vast arrays of research specimens and data. One way for academic medical centers to fund such infrastructure and research is "commercialization" of access to specimens and data to industry. Here we explore patient and clinician perspectives regarding cancer specimen and data commercialization with the goal of improving such processes in the future.

Materials And Methods: This qualitative analysis was embedded within a prospective precision oncology sequencing study of adults with head and neck cancer. Via semistructured dyadic interviews with patients with cancer and their doctors, we assessed understanding and concerns regarding potential commercialization, opinions regarding investment of profits, and perspectives regarding the return of information directly to participants from industry.

Results: Several patient- and clinician-participants did not understand that the consent form already permitted commercialization of patient genetic data and expressed concerns regarding who would profit from the data, how profits would be used, and privacy and access. Patients were generally more comfortable with commercialization than clinicians. Many patients and clinicians were comfortable with investing profits back into research, but clinicians were more interested in investment in head and neck cancer research specifically. Patients generally supported potential return-of-results from a private entity, but their clinicians were more skeptical.

Conclusion: Our results illustrate the limitations of mandatory disclosures in the informed consent process. The voices of both patients and their doctors are critical to mitigate violations of privacy and a degradation of trust as stakeholders negotiate the terms of academic and commercial engagement.

Implications For Practice: Further education is needed regarding how and why specimens and data in precision oncology research may be commercialized for both patients and providers alike. This process will require increased transparency, comprehension, and engagement of involved stakeholders.
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http://dx.doi.org/10.1634/theoncologist.2019-0863DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7356718PMC
July 2020

Prognostic factors in laryngeal squamous cell carcinoma.

Laryngoscope Investig Otolaryngol 2020 Feb 27;5(1):74-81. Epub 2020 Jan 27.

Former Department of Otolaryngology-Head and Neck Surgery, University of Udine School of Medicine Udine Italy.

Background: The current treatment results of laryngeal squamous cell carcinoma still remain modest. Various prognostic factors have been investigated and need to be included in the management decision making.

Methods: We reviewed the pertinent literature regarding host, tumor, and treatment factors as prognostic indicators that influence outcome in patients diagnosed with laryngeal squamous cell carcinoma.

Results: Host, tumor, and treatment factors all have an important impact upon an individual patient's prognosis with laryngeal squamous cell carcinoma, whereas staging systems only take into account tumor factors. There is much work yet to be done to establish reliable, independent biomarkers that predict survival and response to treatment.

Conclusions: Optimal outcomes for an individual patient can be achieved when taking into account tumor, host, and treatment factors.
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http://dx.doi.org/10.1002/lio2.353DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7042656PMC
February 2020

Sentinel Lymph Node Biopsy in Head and Neck Melanoma: Long-term Outcomes, Prognostic Value, Accuracy, and Safety.

Otolaryngol Head Neck Surg 2020 04 11;162(4):520-529. Epub 2020 Feb 11.

Department of Otolaryngology-Head and Neck Surgery, Michigan Medicine, Ann Arbor, Michigan, USA.

Objective: To evaluate the long-term outcomes of sentinel lymph node biopsy (SLNB) for head and neck cutaneous melanoma (HNCM).

Study Design: Retrospective cohort study.

Setting: Tertiary academic medical center.

Subjects And Methods: Longitudinal review of a 356-patient cohort with HNCM undergoing SLNB from 1997 to 2007.

Results: Descriptive characteristics included the following: age, 53.5 ± 19 years (mean ± SD); sex, 26.8% female; median follow-up, 4.9 years; and Breslow depth, 2.52 ± 1.87 mm. Overall, 75 (21.1%) patients had a positive SLNB. Among patients undergoing completion lymph node dissection following positive SLNB, 20 (27.4%) had at least 1 additional positive nonsentinel lymph node. Eighteen patients with local control and negative SLNB developed regional disease, indicating a false omission rate of 6.4%, including 10 recurrences in previously unsampled basins. Ten-year overall survival (OS) and melanoma-specific survival (MSS) were significantly greater in the negative sentinel lymph node (SLN) cohort (OS, 61% [95% CI, 0.549-0.677]; MSS, 81.9% [95% CI, 0.769-0.873]) than the positive SLN cohort (OS, 31% [95% CI, 0.162-0.677]; MSS, 60.3% [95% CI, 0.464-0.785]) and positive SLN/positive nonsentinel lymph node cohort (OS, 8.4% [95% CI, 0.015-0.474]; MSS, 9.6% [95% CI, 0.017-0.536]). OS was significantly associated with SLN positivity (hazard ratio [HR], 2.39; < .01), immunosuppression (HR, 2.37; < .01), angiolymphatic invasion (HR, 1.91; < .01), and ulceration (HR, 1.86; < .01). SLN positivity (HR, 3.13; < .01), angiolymphatic invasion (HR, 3.19; < .01), and number of mitoses ( = .0002) were significantly associated with MSS. Immunosuppression (HR, 3.01; < .01) and SLN status (HR, 2.84; < .01) were associated with recurrence-free survival, and immunosuppression was the only factor significantly associated with regional recurrence (HR, 6.59; < .01).

Conclusions: Long-term follow up indicates that SLNB showcases durable accuracy, safety, and prognostic importance for cutaneous HNCM.
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http://dx.doi.org/10.1177/0194599819899934DOI Listing
April 2020

Speech and swallowing outcomes after laryngectomy for the dysfunctional irradiated larynx.

Eur Arch Otorhinolaryngol 2020 May 27;277(5):1459-1465. Epub 2020 Jan 27.

Department of Otolaryngology, Head and Neck Surgery, University of Michigan, 1500 E. Medical Center Dr., Ann Arbor, MI, 48109-5312, USA.

Purpose: To characterize outcomes of total laryngectomy for the dysfunctional larynx after radiation.

Methods: Retrospective case series of all subjects who underwent total laryngectomy for the irradiated dysfunctional larynx between 2000 and 2018 at an NCI-designated comprehensive cancer center at a single tertiary care academic medical center. Main outcomes included enteral tube feeding dependency, functional tracheoesophageal speech, and number and timing of postoperative pharyngeal dilations.

Results: Median time from radiation to laryngectomy was 2.8 years (range 0.5-27 years). Functional outcomes were analyzed for the 32 patients with 1-year follow-up. Preoperatively, 81% required at least partial enteral tube feeding, as compared to 34% 1-year postoperatively (p = 0.0003). At 1 year, 81% had achieved functional tracheoesophageal speech, which was associated with cricopharyngeal myotomy (p = 0.04, HR 0.04, 95% CI 0.002-0.949). There were 34% of subjects who required at least one pharyngeal dilation for stricture by 1 year postoperatively. Over half (60%) of the cohort were dilated over the study period.

Conclusions: Laryngectomy for the dysfunctional larynx improves speech and swallowing outcomes in many patients. Cricopharyngeal myotomy is associated with improved postoperative voice. While the need for enteral feeding is decreased, persistent postoperative swallowing dysfunction is common. Careful patient selection and education regarding functional expectations are paramount.
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http://dx.doi.org/10.1007/s00405-020-05809-yDOI Listing
May 2020

Patient-reported financial toxicity and adverse medical consequences in head and neck cancer.

Oral Oncol 2020 02 23;101:104521. Epub 2019 Dec 23.

Department of Internal Medicine, University of Michigan, Ann Arbor, MI, United States; Department of Internal Medicine, Ann Arbor Veterans Affairs Hospital, Ann Arbor, MI, United States. Electronic address:

Objectives: Financial toxicity (FT) is a significant barrier to high-quality cancer care, and patients with head and neck cancer (HNCA) are particularly vulnerable given their need for intensive support, daily radiotherapy (RT), and management of long-term physical, functional, and psychosocial morbidities following treatment. We aim to identify predictors of FT and adverse consequences in HNCA following RT.

Materials And Methods: We performed a prospective survey study of patients with HNCA seen in follow-up at an academic comprehensive cancer center (CCC) or Veterans Affairs hospital between 05/2016 and 06/2018. Surveys included validated patient-reported functional outcomes and the COST measure, a validated instrument for measuring FT.

Results: The response rate was 86% (n = 63). Younger age and lower median household income by county were associated with lower COST scores (i.e., worse FT) on multivariable analysis (p = .045 and p = .016, respectively). Patients with worse FT were more likely to skip clinic visits (RR (95% CI) 2.13 (1.23-3.67), p = .007), be noncompliant with recommended supplements or medications (1.24 (1.03-1.48), p = .02), and require supportive infusions (1.10 (1.02-1.20), p = .02). At the CCC, patients with worse FT were more likely to require feeding tubes (1.62 (1.14-2.31), p = .007). Overall, 36% reported that costs were higher than expected, 48% were worried about paying for treatment, and 33% reported at least a moderate financial burden from treatment.

Conclusion: HNCA patients experience substantial FT from their diagnosis and/or therapy, with potential implications for medical compliance, QOL, and survivorship care.
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http://dx.doi.org/10.1016/j.oraloncology.2019.104521DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7008081PMC
February 2020

Patient and Provider Perspectives Regarding Enrollment in Head and Neck Cancer Research.

Otolaryngol Head Neck Surg 2020 01 10;162(1):73-78. Epub 2019 Dec 10.

Department of Otolaryngology-Head and Neck Surgery, Medical School, University of Michigan, Ann Arbor, Michigan, USA.

Objective: The advent of precision oncology complicates how clinicians and participants understand how clinical care and research interface. Here we examine how key stakeholders perceive the utility of, and evaluate the decision to participate in, genomic sequencing head and neck cancer research. The goal of this study was to highlight unique considerations for our community as this type of research proliferates across the country.

Study Design: Prospective multimethod qualitative and quantitative embedded ethics protocol.

Setting: Single-institution National Cancer Institute-designated academic cancer center.

Subjects And Methods: Multimethod study using paired surveys and semistructured interviews among patients and providers involved in a prospective precision head and neck oncology sequencing protocol (116 survey patient-participants, response rate 82%) with 18 interviewees.

Results: Participants were generally enthusiastic about enrollment in research, both to help future patients and as a way of giving back to the community. They described reliance on information from and trust in their cancer doctor regarding the decision to participate in research, but paradoxically there was discordance in how doctors and patients reported their respective influence in the decision-making process. Clinicians also stressed the importance in separating clinical and research-informed consent processes, although patients did not describe this tension.

Conclusion: As we enter an era of increasing personalized medicine and targeted therapies, the relationship between clinicians, scientists, and patients plays a larger role in how we individualize and contextualize cancer research. Our data are another step toward the ultimate goal of respecting and protecting patients as participants in head and neck translational oncology.
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http://dx.doi.org/10.1177/0194599819889976DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6946860PMC
January 2020

The risk of second primary tumors in head and neck cancer: A systematic review.

Head Neck 2020 03 21;42(3):456-466. Epub 2019 Nov 21.

Coordinator of the International Head and Neck Scientific Group, Padua, Italy.

Background: Second primary tumors (SPTs) are a common cause of reduced life expectancy in patients treated for head and neck cancer (HNC). This phenomenon forms an area to be addressed during posttreatment follow-up.

Methods: We conducted a systematic review of literature following PRISMA guidelines, from 1979 to 2019, to investigate incidence of SPTs, synchronous, and metachronous, in HNC population.

Results: Our review includes data of 456 130 patients from 61 articles. With a minimum follow-up of 22 months, mean incidence of SPTs was 13.2% (95% CI: 11.56-14.84): 5.3% (95% CI: 4.24-6.36) for synchronous SPTs and 9.4% (95% CI: 7.9-10.9) for metachronous SPTs. The most frequent site for SPTs was head and neck area, followed by the lungs and esophagus.

Conclusion: Although with wide variations between studies, the rate of SPTs in HNC patients is high. Given the impact in the prognosis, we must develop strategies for the early diagnosis of SPTs.
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http://dx.doi.org/10.1002/hed.26016DOI Listing
March 2020

Cranial nerve outcomes in regionally recurrent head & neck melanoma after sentinel lymph node biopsy.

Laryngoscope 2020 07 23;130(7):1707-1714. Epub 2019 Aug 23.

Department of Dermatology, Michigan Medicine, University of Michigan, Ann Arbor, Michigan, U.S.A.

Objective: Characterize long-term cranial nerve (CN) outcomes following sentinel lymph node biopsy (SLNB) based management for head and neck cutaneous melanoma (HNCM).

Methods: Longitudinal review of HNCM patients undergoing SLNB from 1997-2007.

Results: Three hundred fifty-six patients were identified, with mean age 53.5 ± 19.0 years, mean Breslow depth 2.52 ± 1.87 mm, and 4.9 years median follow-up. One hundred five (29.4%) patients had SLNB mapping to the parotid basin. Eighteen patients had positive parotid SLNs and underwent immediate parotidectomy / immediate completion lymph node dissection (iCLND), with six possessing positive parotid non-sentinel lymph nodes (NSLNs). Fifty-two of 356 (14.6%) patients developed delayed regional recurrences, including 20 total intraparotid recurrences: five following false negative (FN) parotid SLNB, three following prior immediate superficial parotidectomy, two following iCLND without parotidectomy, and the remaining 12 parotid recurrences had negative extraparotid SLNBs. Parotid recurrences were multiple (4.9 mean recurrent nodes) and advanced (n = 4 extracapsular extension), and all required salvage dissection including parotidectomy. Immediate parotidectomy/iCLND led to no permanent CN injuries. Delayed regional HNCM macrometastasis precipitated 16 total permanent CN injuries in 13 patients: 10 CN VII, five CN XI, and one CN XII deficits. Fifty percent (n = 10) of parotid recurrences caused ≥1 permanent CN deficits.

Conclusions: Regional HNCM macrometastases and salvage dissection confer marked CN injury risk, whereas early surgical intervention via SLNB ± iCLND ± immediate parotidectomy yielded no CN injuries. Further, superficial parotidectomy performed in parotid-mapping HNCM does not obviate delayed intraparotid recurrences, which increase risk of CN VII injury. Despite lack of a published disease-specific survival advantage in melanoma, early disease control in cervical and parotid basins is paramount to minimize CN complications.

Level Of Evidence: 4 (retrospective case series) Laryngoscope, 130:1707-1714, 2020.
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http://dx.doi.org/10.1002/lary.28243DOI Listing
July 2020

Assessment of Intraoperative Nerve Monitoring Parameters Associated With Facial Nerve Outcome in Parotidectomy for Benign Disease.

JAMA Otolaryngol Head Neck Surg 2019 May 2. Epub 2019 May 2.

Department of Otolaryngology-Head and Neck Surgery, Michigan Medicine, Ann Arbor.

Importance: Prior studies suggest that the use of facial nerve monitoring decreases the rate of immediate postoperative facial nerve weakness in parotid surgery, but published data are lacking on normative values for these parameters or cutoff values to prognosticate facial nerve outcomes.

Objective: To identify intraoperative facial nerve monitoring parameters associated with postoperative weakness and to evaluate cutoff values for these parameters under which normal nerve function is more likely.

Design, Setting, And Participants: This retrospective case series of 222 adult patients undergoing parotid surgery for benign disease performed with intraoperative nerve monitoring was conducted at an academic medical institution from September 13, 2004, to October 30, 2014. The data analysis was conducted from May 2018 to January 2019.

Main Outcomes And Measures: The main outcome measure was facial nerve weakness. Receiver operating characteristic curves were generated to define optimal cut point to maximize the sensitivity and specificity of the stimulation threshold, mechanical events, and spasm events associated with facial nerve weakness.

Results: Of 222 participants, 121 were women and 101 were men, with a mean (SD) age of 51 (16) years. The rate of temporary facial nerve paresis of any nerve branch was 45%, and the rate of permanent paralysis was 1.3%. The mean predissection threshold was 0.22 milliamperes (mA) (range, 0.1-0.6 mA) and the mean postdissection threshold was 0.24 mA (range, 0.08-1.0 mA). The average number of mechanical events was 9 (range, 0-66), and mean number of spontaneous spasm events was 1 (range, 0-12). Both the postdissection threshold (area under the curve [AUC], 0.69; 95% CI, 0.62-0.77) and the number of mechanical events (AUC, 0.58; 95% CI, 0.50-0.66) were associated with early postoperative facial nerve outcome. The number of spasm events was not associated with facial nerve outcome. The optimal cutoff value for the threshold was 0.25 mA, and the optimal cutoff for number of mechanical events was 8. If a threshold of greater than 0.25 mA was paired with more than 8 mechanical events, there was a 77% chance of postoperative nerve weakness. Conversely, if a threshold was 0.25 mA or less and there were 8 mechanical events or less, there was 69% chance of normal postoperative nerve function. No parameters were associated with permanent facial nerve injury.

Conclusions And Relevance: Postdissection threshold and the number of mechanical events are associated with immediate postoperative facial nerve function. Accurate prediction of facial nerve function may provide anticipatory guidance to patients and may provide surgeons with intraoperative feedback allowing adjustment in operative techniques and perioperative management.
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http://dx.doi.org/10.1001/jamaoto.2019.1041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6499124PMC
May 2019

T4 Laryngeal Cancer With Good Function: Should We Be Reluctant to Treat Without Surgery?

Int J Radiat Oncol Biol Phys 2018 12;102(5):1400-1403

International Head and Neck Scientific Group, Padua, Italy.

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http://dx.doi.org/10.1016/j.ijrobp.2018.03.007DOI Listing
December 2018

Work-Life Balance Among Head and Neck Surgeons-Seeking Visionary Leadership From Everywhere.

JAMA Otolaryngol Head Neck Surg 2019 05;145(5):458-459

Department of Otolaryngology-Head and Neck Surgery, University of Michigan, Ann Arbor.

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http://dx.doi.org/10.1001/jamaoto.2019.0103DOI Listing
May 2019

The current practice of open neck mass biopsy in the diagnosis of head and neck cancer: A retrospective cohort study.

Laryngoscope Investig Otolaryngol 2019 Feb 15;4(1):57-61. Epub 2019 Jan 15.

Department of Surgery; and the Department of Otolaryngology-Head and Neck Surgery University of Michigan Health System Ann Arbor Michigan.

Objective: To characterize current use of open neck mass biopsy for diagnosis of squamous cell carcinoma in patients presenting with a neck mass.

Methods: Using the University of Michigan Specialized Program of Research Excellence in Head and Neck Cancer patient database (2008-2014), we reviewed patients' referral documentation to identify those who received open neck mass biopsies as part of their squamous cell carcinoma diagnosis. We compared subsequent treatment between patients who did and did not receive an open neck mass biopsy.

Results: Of 940 patients, 50 patients had received open neck mass biopsy leading to squamous cell carcinoma diagnosis. Only 19 of 50 patients (38%) had undergone fine-needle aspiration prior to open neck mass biopsy. There were no statistically significant differences in treatment or outcomes between patients who did and those who did not receive open neck mass biopsy.

Conclusion: Optimal care for patients who present with a neck mass is fine-needle aspiration. Unfortunately, these data show that many patients undergo open neck mass biopsy for diagnosis, often without prior fine-needle aspirate. Compared to fine-needle aspiration, open biopsy incurs additional risks of general anesthesia and greater surgical risks. While our data did not find statistically significant differences between treatment offered and outcomes, this small study was not expected to demonstrate a difference in outcomes. Further work is needed to promote the utility of fine-needle aspiration for diagnosis of neck mass and to discourage use of open neck mass biopsy as a primary diagnostic intervention.

Level Of Evidence: 2c (Outcomes Research).
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http://dx.doi.org/10.1002/lio2.240DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6383295PMC
February 2019

Elective Paratracheal Lymph Node Dissection in Salvage Laryngectomy.

Ann Surg Oncol 2019 Aug 4;26(8):2542-2548. Epub 2019 Mar 4.

Department of Otolaryngology - Head and Neck Surgery, University of Michigan, Ann Arbor, MI, USA.

Background: Indications for and efficacy of paratracheal nodal dissection (PTND) in patients undergoing laryngectomy (salvage) for persistent or recurrent laryngeal squamous cell carcinoma are not well-defined.

Methods: A retrospective cohort study was performed for patients undergoing salvage laryngectomy with clinically and radiographically negative neck disease between 1998 and 2015 (n = 210). Univariate and multivariate Cox regression analyses were performed.

Results: PTND was performed on 77/210 patients (36%). The PTND cohort had a greater proportion of advanced T classification (rT3/rT4) tumors (78%) than subjects without PTND (55%; p = 0.001). There was a 14% rate of occult nodal metastases in the paratracheal basin; of these, 55% did not have pathologic lateral neck disease. Multivariate analysis controlling for tumor site, tumor stage, and pathologic lateral neck disease demonstrated that PTND was associated with improved overall survival [OS] (p = 0.03; hazard ratio [HR] 0.60, 95% confidence interval [CI] 0.38-0.96), disease-free survival [DFS] (p = 0.03; HR 0.55, 95% CI 0.31-0.96), and distant DFS survival (p = 0.01; HR 0.29, 95% CI 0.11-0.77). The rate of hypocalcemia did not differ between subjects who underwent bilateral PTND, unilateral PTND, or no PTND (p = 0.19 at discharge, p = 0.17 at last follow-up).

Conclusions: PTND at the time of salvage laryngectomy was more common in patients with rT3/rT4 tumors and was associated with improved OS and DFS, with no effect on hypocalcemia. In patients undergoing PTND, the finding of occult paratracheal metastases was often independent of lateral neck metastases.
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http://dx.doi.org/10.1245/s10434-019-07270-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6612310PMC
August 2019

Impact of American Joint Committee on Cancer Eighth Edition clinical stage and smoking history on oncologic outcomes in human papillomavirus-associated oropharyngeal squamous cell carcinoma.

Head Neck 2019 04 18;41(4):857-864. Epub 2019 Feb 18.

Department of Otolaryngology - Head and Neck Surgery, University of Michigan, Ann Arbor, Michigan.

Background: The purpose of this study was to evaluate the AJCC eighth edition clinical staging system for human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma and to further understand how clinical stage and smoking history affect oncologic outcomes. The purpose of this study was to present the understanding of how clinical stage and smoking history affect oncologic outcomes in human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (SCC) is critical for selecting patients for treatment deintensification.

Methods: Kaplan-Meier and Cox regression were used to evaluate overall survival (OS), locoregional recurrence-free survival (LRFS), and distant recurrence-free survival (DRFS). Concordance statistics (C-indices) were used to compare discriminating ability.

Results: The OS and DRFS but not LRFS were significantly distributed using the American Joint Committee on Cancer (AJCC) seventh and eighth editions criteria. The C-indices for OS, LRFS, and DRFS were 0.57, 0.54, and 0.60, respectively, using the AJCC seventh edition, and 0.63, 0.53, and 0.65, respectively, using the AJCC eighth edition. On multivariate analysis, 1 + pack-year smoking history correlated with OS (hazard ratio [HR] 1.96; 95% confidence interval [CI] 1.2-3.1; P < .01) but not LRFS or DRFS.

Conclusion: These results support implementation of the AJCC eighth edition for HPV-associated oropharyngeal SCC. Clinical stage may be more important than smoking history in selection for deintensification.
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http://dx.doi.org/10.1002/hed.25336DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6420360PMC
April 2019

The role of age in treatment-related adverse events in patients with head and neck cancer: A systematic review.

Head Neck 2019 07 9;41(7):2410-2429. Epub 2019 Feb 9.

International Head and Neck Scientific Group, Padua, Italy.

Head and neck squamous cell carcinoma (HNSCC) is often diagnosed in advanced stage and therefore requires aggressive, multimodal treatment. Elderly patients are often excluded from standard therapy regimens purely based on age. This clinical review aims to collect all published data in the literature on treatment modality selection in elderly patients and on age-related adverse events following treatment of HNSCC. We performed a literature search for articles on the treatment of HNSCC in elderly patients. Most of the articles were retrospective studies with the consequent limitations. It can be concluded that age is not an absolute contraindication for intensive treatment and comorbidity is an important predictor of outcome, but not the only one. Despite the existence of multiple tools for pretreatment evaluation, there are not consistent data on their use.
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http://dx.doi.org/10.1002/hed.25696DOI Listing
July 2019

Contemporary management of primary parapharyngeal space tumors.

Head Neck 2019 02 14;41(2):522-535. Epub 2018 Dec 14.

Coordinator of the International Head and Neck Scientific Group.

The parapharyngeal space is a complex anatomical area. Primary parapharyngeal tumors are rare tumors and 80% of them are benign. A variety of tumor types can develop in this location; most common are salivary gland neoplasm and neurogenic tumors. The management of these tumors has improved greatly owing to the developments in imaging techniques, surgery, and radiotherapy. Most tumors can be removed with a low rate of complications and recurrence. The transcervical approach is the most frequently used. In some cases, minimally invasive approaches may be used alone or in combination with a limited transcervical route, allowing large tumors to be removed by reducing morbidity of expanded approaches. An adequate knowledge of the anatomy and a careful surgical plan is essential to tailor management according to the patient and the tumor. The purpose of the present review was to update current aspects of knowledge related to this more challenging area of tumor occurrence.
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http://dx.doi.org/10.1002/hed.25439DOI Listing
February 2019

Mutational profiles of persistent/recurrent laryngeal squamous cell carcinoma.

Head Neck 2019 02 12;41(2):423-428. Epub 2018 Dec 12.

Department of Otolaryngology - Head and Neck Surgery, University of Michigan Medical School, Ann Arbor, Michigan.

Background: We sought to describe targeted DNA sequencing data of persistent/recurrent laryngeal squamous cell carcinoma (LSCC) and to compare gene-specific alteration frequencies with that of primary, untreated LSCC specimens from The Cancer Genome Atlas (TCGA).

Methods: The tumors of 21 patients with persistent/recurrent LSCC were subjected to targeted DNA sequencing using the Ion AmpliSeq Comprehensive Cancer Panel. Gene-specific alteration frequencies were compared (Chi-Square test) to primary, untreated LSCC sequencing data from TCGA using the cBioPortal platform.

Results: Persistent/recurrent LSCC was characterized by a high rate of inactivating alterations in TP53 (38.1%) and CDKN2A (33%), amplification events of CCND1 (19.1%), and ERBB2 (14.3%), and NOTCH1 (19.1%) mutations. Comparison of primary vs persistent/recurrent LSCC revealed significant differences in alteration frequencies of eight critical genes: BAP1, CDKN2A, DCUN1D1, MSH2, MTOR, PIK3CA, TET2, and TP53.

Conclusions: Our results provide preliminary support for a distinct mutational profile of persistent/recurrent LSCC that requires validation in larger cohorts.
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http://dx.doi.org/10.1002/hed.25444DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6431792PMC
February 2019

Analysis of tumor-infiltrating CD103 resident memory T-cell content in recurrent laryngeal squamous cell carcinoma.

Cancer Immunol Immunother 2019 Feb 25;68(2):213-220. Epub 2018 Oct 25.

Department of Otolaryngology - Head and Neck Surgery, University of Michigan, 1150 E. Medical Center Dr., 9301B MSRB3, Ann Arbor, 48109-0602, MI, USA.

Background: Recurrent laryngeal squamous cell carcinomas (LSCCs) are associated with poor outcomes, without reliable biomarkers to identify patients who may benefit from adjuvant therapies. Given the emergence of tumor-infiltrating lymphocytes (TIL) as a biomarker in head and neck squamous cell carcinoma, we generated predictive models to understand the utility of CD4, CD8 and/or CD103 TIL status in patients with advanced LSCC.

Methods: Tissue microarrays were constructed from salvage laryngectomy specimens of 183 patients with recurrent/persistent LSCC and independently stained for CD4, CD8, and CD103 TIL content. Cox proportional hazards regression analysis was employed to assess combinations of CD4, CD8, and CD103 TIL levels for prediction of overall survival (OS), disease-specific survival (DSS), and disease-free survival (DFS) in patients with recurrent/persistent LSCC.

Results: High tumor CD103 TIL content was associated with significantly improved OS, DSS, and DFS and was a stronger predictor of survival in recurrent/persistent LSCC than either high CD8 or CD4 TIL content. On multivariate analysis, an "immune-rich" phenotype, in which tumors were enriched for both CD103 and CD4 TILs, conferred a survival benefit (OS hazard ratio: 0.28, p = 0.0014; DSS hazard ratio: 0.09, p = 0.0015; DFS hazard ratio: 0.18, p = 0.0018) in recurrent/persistent LSCC.

Conclusions: An immune profile driven by CD103 TIL content, alone and in combination with CD4 TIL content, is a prognostic biomarker of survival in patients with recurrent/persistent LSCC. Predictive models described herein may thus prove valuable in prognostic stratification and lead to personalized treatment paradigms for this patient population.
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http://dx.doi.org/10.1007/s00262-018-2256-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6375747PMC
February 2019

Management of the facial nerve in parotid cancer: preservation or resection and reconstruction.

Eur Arch Otorhinolaryngol 2018 Nov 28;275(11):2615-2626. Epub 2018 Sep 28.

Coordinator of the International Head and Neck Scientific Group, Padua, Italy.

Purpose: Management of the facial nerve is instrumental in the surgical treatment of parotid cancer.

Methods: A literature search was conducted using PubMed and ScienceDirect database. A total of 195 articles were finally included into the analysis, based on relevance, scientific evidence and actuality.

Results: In the majority of cases the facial nerve is not involved by tumor. In these cases, identification and preservation of the nerve, in addition to complete tumor removal, are essential for successful surgery. When the nerve is infiltrated by tumor, the affected portion of the nerve must be resected as part of radical parotidectomy. Primary nerve reconstruction or other reanimation techniques give the best long-term functional and cosmetic results. A comprehensive diagnostic evaluation with current imaging and electrophysiological studies will provide the surgeon with the best knowledge of the relationship of the facial nerve to the tumor. Several standardized methods are helpful in finding, dissecting and preserving the nerve during parotid cancer surgery. When radical parotidectomy is indicated, the initial diagnostic work-up can assist in defining the need for adjuvant postoperative therapy and facial reanimation. The aim of rehabilitation is to restore tone, symmetry, and movement to the paralyzed face.

Conclusions: The surgical management of facial paralysis has undergone many improvements in recent years. This review gives an overview of recent advances in the diagnostic work-up, surgical techniques and any necessary rehabilitation of the facial nerve in parotid cancer surgery.
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http://dx.doi.org/10.1007/s00405-018-5154-6DOI Listing
November 2018