Publications by authors named "Mark Zafereo"

117 Publications

Association of Pharyngocutaneous Fistula With Cancer Outcomes in Patients After Laryngectomy: A Multicenter Collaborative Cohort Study.

JAMA Otolaryngol Head Neck Surg 2021 Jul 29. Epub 2021 Jul 29.

Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.

Importance: Pharyngocutaneous fistula (PCF) results in an inflammatory reaction, but its association with the rate of locoregional and distant control, disease-free survival, and overall survival in laryngeal cancer remains uncertain.

Objective: To determine if pharyngocutaneous fistula after salvage laryngectomy is associated with locoregional and distant control, disease-free survival, and/or overall survival.

Design, Setting, And Participants: A multicenter collaborative retrospective cohort study conducted at 5 centers in Canada and the US of 550 patients who underwent salvage laryngectomy for recurrent laryngeal cancer from January 1, 2000, to December 31, 2014. The median follow-up time was 5.7 years (range, 0-18 years).

Main Outcomes And Measures: Outcomes examined included locoregional and distant control, disease-free survival, and overall survival. Fine and Gray competing risk regression and Cox-proportional hazard regression models were used for outcomes. Competing risks and the Kaplan-Meier methods were used to estimate outcomes at 3 years and 5 years.

Results: In all, 550 patients (mean [SD] age, 64 [10.4] years; men, 465 [85%]) met inclusion criteria. Pharyngocutaneous fistula occurred in 127 patients (23%). The difference in locoregional control between the group of patients with PCF (75%) and the non-PCF (72%) group was 3% (95% CI, -6% to 12%). The difference in overall survival between the group with PCF (44%) and the non-PCF group (52%) was 8% (95% CI, -2% to 20%). The difference in disease-free survival between PCF and non-PCF groups was 6% (95% CI, -4% to 16%). In the multivariable model, patients with PCF were at a 2-fold higher rate of distant metastases (hazard ratio, 2.00; 95% CI, 1.22 to 3.27). Distant control was reduced in those with PCF, a 13% (95% CI, 3% to 21%) difference in 5-year distant control.

Conclusions And Relevance: This multicenter retrospective cohort study found that development of PCF after salvage laryngectomy is associated with an increased risk for the development of distant metastases.
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http://dx.doi.org/10.1001/jamaoto.2021.1545DOI Listing
July 2021

Non-functional water clear cell parathyroid carcinoma masquerading as medullary thyroid carcinoma.

Ann Diagn Pathol 2021 Jul 15;54:151791. Epub 2021 Jul 15.

Department of Pathology, The University of Texas MD Anderson Cancer, United States of America; Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer, United States of America. Electronic address:

Parathyroid carcinoma is a rare neuroendocrine tumor. Non-functional parathyroid carcinomas are exceedingly rare neoplasms which generally present at an advanced disease stage, and occasionally can masquerade as medullary thyroid carcinoma.
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http://dx.doi.org/10.1016/j.anndiagpath.2021.151791DOI Listing
July 2021

Decision Making When Cancer Becomes Chronic: Needs Assessment for a Web-Based Medullary Thyroid Carcinoma Patient Decision Aid.

JMIR Form Res 2021 Jul 16;5(7):e27484. Epub 2021 Jul 16.

Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States.

Background: In cancers with a chronic phase, patients and family caregivers face difficult decisions such as whether to start a novel therapy, whether to enroll in a clinical trial, and when to stop treatment. These decisions are complex, require an understanding of uncertainty, and necessitate the consideration of patients' informed preferences. For some cancers, such as medullary thyroid carcinoma, these decisions may also involve significant out-of-pocket costs and effects on family members. Providers have expressed a need for web-based interventions that can be delivered between consultations to provide education and prepare patients and families to discuss these decisions. To ensure that these tools are effective, usable, and understandable, studies are needed to identify patients', families', and providers' decision-making needs and optimal design strategies for a web-based patient decision aid.

Objective: Following the international guidelines for the development of a web-based patient decision aid, the objectives of this study are to engage potential users to guide development; review the existing literature and available tools; assess users' decision-making experiences, needs, and design recommendations; and identify shared decision-making approaches to address each need.

Methods: This study used the decisional needs assessment approach, which included creating a stakeholder advisory panel, mapping decision pathways, conducting an environmental scan of existing materials, and administering a decisional needs assessment questionnaire. Thematic analyses identified current decision-making pathways, unmet decision-making needs, and decision support strategies for meeting each need.

Results: The stakeholders reported wide heterogeneity in decision timing and pathways. Relevant existing materials included 2 systematic reviews, 9 additional papers, and multiple educational websites, but none of these met the criteria for a patient decision aid. Patients and family members (n=54) emphasized the need for plain language (46/54, 85%), shared decision making (45/54, 83%), and help with family discussions (39/54, 72%). Additional needs included information about uncertainty, lived experience, and costs. Providers (n=10) reported needing interventions that address misinformation (9/10, 90%), foster realistic expectations (9/10, 90%), and address mistrust in clinical trials (5/10, 50%). Additional needs included provider tools that support shared decision making. Both groups recommended designing a web-based patient decision aid that can be tailored to (64/64, 100%) and delivered on a hospital website (53/64, 83%), focuses on quality of life (45/64, 70%), and provides step-by-step guidance (43/64, 67%). The study team identified best practices to meet each need, which are presented in the proposed decision support design guide.

Conclusions: Patients, families, and providers report multifaceted decision support needs during the chronic phase of cancer. Web-based patient decision aids that provide tailored support over time and explicitly address uncertainty, quality of life, realistic expectations, and effects on families are needed.
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http://dx.doi.org/10.2196/27484DOI Listing
July 2021

Update of Radiofrequency Ablation for Treating Benign and Malignant Thyroid Nodules. The Future Is Now.

Front Endocrinol (Lausanne) 2021 24;12:698689. Epub 2021 Jun 24.

The University of Udine School of Medicine, International Head and Neck Scientific Group, Padua, Italy.

Thermal and chemical ablation are minimally invasive procedures that avoid removal of the thyroid gland and target symptomatic nodules directly. Internationally, Radiofrequency ablation (RFA) is among one of the most widely used thermal ablative techniques, and is gaining traction in North America. Surgery remains the standard of care for most thyroid cancer, and in the right clinical setting, Active Surveillance (AS) can be a reasonable option for low risk disease. Minimally invasive techniques have emerged as an alternative option for patients deemed high risk for surgery, or for those patients who wish to receive a more active treatment approach compared to AS. Herein, we review the literature on the safety and efficacy of RFA for treating benign non-functioning thyroid nodules, autonomously functioning thyroid nodules, primary small low risk thyroid cancer (namely papillary thyroid cancer) as well as recurrent thyroid cancer.
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http://dx.doi.org/10.3389/fendo.2021.698689DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8264548PMC
June 2021

Surgical Considerations in Thyroid Cancer: What the Radiologist Needs to Know.

Neuroimaging Clin N Am 2021 Aug;31(3):327-335

Department of Otolaryngology - Head and Neck Surgery, MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA. Electronic address:

Management of thyroid cancer requires a multidisciplinary approach including head and neck/endocrine surgeons, endocrinologists, oncologists, and radiologists. The radiographic evaluation of thyroid cancer is critical for complete and precise staging and affects the surgical approach to address these cancers. The purpose of this article is to briefly review the common thyroid cancer pathologies and surgical considerations in thyroid cancer, focusing on the extent of surgery and the influence of preoperative imaging on surgical decision-making. This article assumes that a diagnosis of thyroid cancer has been made and does not discuss the workup or surveillance of thyroid nodules.
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http://dx.doi.org/10.1016/j.nic.2021.04.010DOI Listing
August 2021

Novel anaplastic thyroid cancer PDXs and cell lines: Expanding preclinical models of genetic diversity.

J Clin Endocrinol Metab 2021 Jun 19. Epub 2021 Jun 19.

Departments of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX.

Background: Anaplastic thyroid cancer (ATC) is a rare, aggressive, and deadly disease. Robust pre-clinical thyroid cancer models are needed to adequately develop and study novel therapeutic agents. Patient-derived xenograft (PDX) models may resemble patient tumors by recapitulating key genetic alterations and gene expression patterns, making them excellent pre-clinical models for drug response evaluation. We developed distinct ATC PDX models concurrently with cell lines and characterized them in vitro and in vivo.

Materials & Methods: Fresh thyroid tumor from patients with a preoperative diagnosis of ATC was surgically collected and divided for concurrent cell line and PDX model development. Cell lines were created by generating single cells through enzymatic digestion. PDX models were developed following direct subcutaneous implantation of fresh tumor on the flank of immune compromised/athymic mice.

Results: Six ATC PDX models and four cell lines were developed with distinct genetic profiles. Mutational characterization showed one BRAF/TP53/CDKN2A, one BRAF/CDKN2A, one BRAF/TP53, one TP53 only, one TERT-promoter/HRAS, and one TERT-promoter/KRAS/TP53/NF2/NFE2L2 mutated phenotype. H&E staining comparing the PDX models to the original patient surgical specimens show remarkable resemblance, while immunohistochemistry stains for important biomarkers were in full concordance (Cytokeratin, TTF-1, PAX8, BRAF). Short tandem repeats DNA fingerprinting analysis of all PDX models and cell lines showed strong concordance with the original tumor. PDX successful establishment rate was 32%.

Conclusion: We have developed and characterized six novel ATC PDX models with four matching cell lines. Each PDX model harbors a distinct genetic profile, making them excellent tools for pre-clinical therapeutic trials.
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http://dx.doi.org/10.1210/clinem/dgab453DOI Listing
June 2021

A High-Throughput Approach to Identify Effective Systemic Agents for the Treatment of Anaplastic Thyroid Carcinoma.

J Clin Endocrinol Metab 2021 Jun 12. Epub 2021 Jun 12.

Department of Head and Neck surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Background: Despite the use of aggressive multimodality treatment, most anaplastic thyroid carcinoma (ATC) patients die within a year of diagnosis. Although the combination of BRAF and MEK inhibitors has recently been approved for use in BRAF-mutated ATC, they remain effective in a minority of patients who are likely to develop drug resistance. There remains a critical clinical need for effective systemic agents for ATC with a reasonable toxicity profile to allow for rapid translational development.

Methods & Methods: Twelve human thyroid cancer cell lines with comprehensive genomic characterization were used in a high-throughput screening (HTS) of 257 compounds to select agents with maximal growth inhibition. Cell proliferation, colony formation, orthotopic thyroid models, and patient-derived xenograft models (PDX) were used to validate the selected agents.

Results: Seventeen compounds were effective and docetaxel, LBH-589, and pralatrexate were selected for additional in vitro and in vivo analysis as they have been previously approved by the FDA for other cancers. Significant tumor growth inhibition (TGI) was detected in all tested models treated with LBH-589; pralatrexate demonstrated significant TGI in the orthotopic papillary thyroid carcinoma model and two PDX models; docetaxel demonstrated significant TGI only in the context of mutant TP53.

Conclusions: HTS identified classes of systemic agents which demonstrate preferential effectiveness against aggressive thyroid cancers, particularly those with mutant TP53. Preclinical validation in both orthotopic and PDX models, which are accurate in vivo models mimicking tumor microenvironment, may support initiation of early phase clinical trials in non-BRAF mutated or refractory to BRAF/MEK inhibition ATC.
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http://dx.doi.org/10.1210/clinem/dgab424DOI Listing
June 2021

Afirma Genomic Sequencing Classifier and Xpression Atlas Molecular Findings in Consecutive Bethesda III-VI Thyroid Nodules.

J Clin Endocrinol Metab 2021 Jul;106(8):2198-2207

Department of Medical Affairs, Veracyte, Inc., South San Francisco, CA 94080, USA.

Context: Broad genomic analyses among thyroid histologies have been described from relatively small cohorts.

Objective: Investigate the molecular findings across a large, real-world cohort of thyroid fine-needle aspiration (FNA) samples.

Design: Retrospective analysis of RNA sequencing data files.

Setting: Clinical Laboratory Improvement Amendments laboratory performing Afirma Genomic Sequencing Classifier (GSC) and Xpression Atlas (XA) testing.

Participants: A total of 50 644 consecutive Bethesda III-VI nodules.

Intervention: None.

Main Outcome Measures: Molecular test results.

Results: Of 48 952 Bethesda III/IV FNAs studied, 66% were benign by Afirma GSC. The prevalence of BRAF V600E was 2% among all Bethesda III/IV FNAs and 76% among Bethesda VI FNAs. Fusions involving NTRK, RET, BRAF, and ALK were most prevalent in Bethesda V (10%), and 130 different gene partners were identified. Among small consecutive Bethesda III/IV sample cohorts with one of these fusions and available surgical pathology excision data, the positive predictive value of an NTRK or RET fusion for carcinoma or noninvasive follicular thyroid neoplasm with papillary-like nuclear features was >95%, whereas for BRAF and ALK fusions it was 81% and 67%, respectively. At least 1 genomic alteration was identified by the expanded Afirma XA panel in 70% of medullary thyroid carcinoma classifier-positive FNAs, 44% of Bethesda III or IV Afirma GSC suspicious FNAs, 64% of Bethesda V FNAs, and 87% of Bethesda VI FNAs.

Conclusions: This large study demonstrates that almost one-half of Bethesda III/IV Afirma GSC suspicious and most Bethesda V/VI nodules had at least 1 genomic variant or fusion identified, which may optimize personalized treatment decisions.
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http://dx.doi.org/10.1210/clinem/dgab304DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8277199PMC
July 2021

Transoral endoscopic vestibular approach for thyroidectomy and parathyroidectomy - From promise to practice.

Am J Otolaryngol 2021 Mar 31;42(5):103022. Epub 2021 Mar 31.

A.R.M. Center of Otolaryngology Head and Neck Surgery, Assuta Medical Center, Tel Aviv, Israel.

Objectives: To describe the evolution and recent series on transoral endoscopic vestibular approach thyroidectomy and parathyroidectomy (TOET/PVA).

Data Sources: PubMed, Google Scholar.

Review Methods: Review of the available English literature.

Results: TOET/PVA may offer several advantages over other remote access thyroidectomy approaches and has been adopted by many centers worldwide with excellent success rates. Indications include benign disease and early thyroid cancer patients. Complication rate is comparable to the trans-cervical approach. The suggested framework has been validated in recent studies and its feasibility confirmed.

Conclusion: TOET/PVA has now been used to treat thousands of patients worldwide due to low cost, short learning curve and excellent cosmetic outcomes. Further studies will be necessary to demonstrate oncologic non-inferiority and also the true value that is added by the approach.
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http://dx.doi.org/10.1016/j.amjoto.2021.103022DOI Listing
March 2021

Occlusion of the internal jugular vein in differentiated thyroid carcinoma: Causes and diagnosis.

Eur J Surg Oncol 2021 Jul 22;47(7):1552-1557. Epub 2021 Feb 22.

International Head and Neck Scientific Group, Padua, Italy.

Occlusion of the internal jugular vein (IJV) can be observed in thyroid cancer either on preoperative imaging with ultrasound or cross-sectional imaging, particularly contrast-enhanced CT-scan, and can be detected during follow-up when using these same imaging modalities. For thyroid cancer, four different causes of occlusion of the IJV can be identified: venous thrombosis associated with a hypercoagulable state, tumor thrombus in the vein, compression or invasion of the IJV by thyroid disease or lymph node metastases, and fibrotic collapse of the IJV following lateral neck dissection. Clinicians managing patients with thyroid cancer need to be aware of and able to diagnose each of these conditions. The overall patient impact and appropriate management of each will be discussed.
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http://dx.doi.org/10.1016/j.ejso.2021.02.021DOI Listing
July 2021

Lateral Neck Dissection for Papillary Thyroid Cancer.

VideoEndocrinology 2020 28;7(4). Epub 2020 Dec 28.

Department of Head and Neck Surgery, MD Anderson Cancer Center, Houston, Texas, USA.

Lateral neck metastases occur in ~15% of papillary thyroid cancer and in ~40% of medullary thyroid cancer. We present herein a systematic approach to a standard comprehensive lateral neck dissection, with attention to specific areas where thyroid cancer lymph node metastases may be missed during surgery. Video demonstration of a comprehensive levels 2a, 3, 4, and 5b lateral neck dissection for thyroid cancer. A systematic step-wise approach to a standard comprehensive lateral neck dissection for thyroid cancer, inclusive of levels 2a, 3, 4, and 5b, is demonstrated. Areas where thyroid cancer lateral neck lymph nodes can be missed are noted, including low level 4 nodes and carotid-vertebral nodes, level 5B nodes, and subdigastric level 2 nodes medial to the carotid artery. A step-wise systematic approach to a comprehensive lateral neck dissection for thyroid cancer may lower the risk for missed thyroid cancer lateral neck lymph node metastases. No competing financial interests exist. Runtime of video: 8 mins 35 secs.
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http://dx.doi.org/10.1089/ve.2020.0199DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7888291PMC
December 2020

Clinical Utility of Circulating Cell-Free DNA Mutations in Anaplastic Thyroid Carcinoma.

Thyroid 2021 Apr 19. Epub 2021 Apr 19.

Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

Anaplastic thyroid carcinoma (ATC) is an aggressive thyroid cancer that requires a rapid diagnosis and treatment to achieve disease control. Gene mutation profiling of circulating cell-free DNA (cfDNA) in peripheral blood may help to facilitate early diagnosis and treatment selection. The relatively rapid turnaround time compared with conventional tumor mutation testing is a major advantage. The objectives of this study were to examine the concordance of ATC-related mutations detected in cfDNA with those detected in the corresponding tumor tissue, and to determine the prognostic significance of cfDNA mutations in ATC patients. The ATC patients who were diagnosed and treated at The University of Texas MD Anderson Cancer Center between January 2015 and February 2018 and who had cfDNA testing were included in this study. cfDNA was collected by blood draw and was analyzed by next-generation sequencing (NGS) using the Guardant360-73 gene platform. A total of 87 patients were included in the study. The most frequently mutated genes detected in cfDNA were , and . In 28 treatment naive ATC patients, the concordance rate of detected mutations in , and between cfDNA and matched tissue NGS was 82.1%, 92.9%, and 92.9%, respectively. Patients with a mutation detected on cfDNA had worse overall survival (OS) ( = 0.03). This association was observed across various treatment modalities, including surgery, cytotoxic chemotherapy, radiation, and BRAF inhibitor (BRAFi) therapy. With regard to treatment, BRAFi therapy significantly improved ATC OS ( = 0.003). cfDNA is a valuable tool to evaluate a tumor's molecular profile in ATC patients. We identified high concordance rates between the gene mutations identified via cfDNA analysis and those identified from the NGS of the corresponding tumor tissue sequencing. Identified mutations in cfDNA can potentially provide timely information to guide treatment selection and evaluate the prognosis in patients with ATC.
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http://dx.doi.org/10.1089/thy.2020.0296DOI Listing
April 2021

Head and neck surgery global outreach: Ethics, planning, and impact.

Head Neck 2021 06 14;43(6):1780-1787. Epub 2021 Feb 14.

Department of Head and Neck Surgery, Division of Surgery, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

Background: Head and neck surgical oncology and reconstruction are uniquely suited to address burdens of disease in underserved areas. Since these efforts are not well known in our specialty, we sought to understand global outreach throughout our society of surgeons.

Methods: Survey distributed to members of the American Head and Neck Surgery involved in international humanitarian head and neck surgical outreach trips.

Results: Thirty surgeons reported an average of seven trips to over 70 destinations. Identification of candidates, finances, on-site patient care, complications, long-term post-surgical care, ethics, and educational goals are reported. We report a success rate of 90% on 125 free flaps performed in these settings.

Conclusions: The effort to answer the call for alleviating the global burden of surgical disease is strong within our specialty. There is a shared focus on humanitarian effort and teaching. Ethics of high resource surgeries such as free flap reconstruction remains controversial.
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http://dx.doi.org/10.1002/hed.26643DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248027PMC
June 2021

Distant Metastases From Childhood Differentiated Thyroid Carcinoma: Clinical Course and Mutational Landscape.

J Clin Endocrinol Metab 2021 Mar;106(4):e1683-e1697

Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

Context: Distant metastases (DM) from childhood differentiated thyroid carcinoma (DTC) are uncommon and published studies are limited.

Objective: This work aimed to describe the outcomes of patients with DM from childhood DTC and to evaluate the molecular landscape of these tumors.

Methods: A retrospective study was conducted at a tertiary cancer center including patients with pediatric DTC (diagnosed at age ≤ 18 years from 1946 to 2019) and DM.

Results: We identified 148 patients; 144 (97%) had papillary thyroid carcinoma (PTC) and 104 (70%) were female. Median age at DTC diagnosis was 13.4 years (interquartile range [IQR], 9.9-15.9 years). Evaluable individuals received a median of 2 (IQR, 1-3) radioactive iodine (RAI) treatments at a median cumulative administered activity of 238.0 mCi (IQR, 147.5-351.0 mCi). The oncogenic driver was determined in 64 of 69 PTC samples: RET fusion (38/64; 59%), NTRK1/3 fusions (18/64; 28%), and the BRAF V600E mutation (8/64; 13%). At last evaluation, 93% had persistent disease. The median overall and disease-specific survival after DTC diagnosis were 50.7 and 52.8 years, respectively. Eight (5%) PTC patients died of disease after a median of 30.7 years (IQR, 20.6-37.6 years).

Conclusion: Childhood DTC with DM persists in most patients despite multiple courses of RAI, but disease-specific death is uncommon, typically occurring decades after diagnosis. Fusion genes are highly prevalent in PTC, and all identified molecular alterations have appropriate targeted therapies. Future studies should focus on expanding genotype-phenotype correlations, determining how to integrate molecularly targeted therapy into treatment paradigms, and relying less on repeated courses of RAI to achieve cure in patients with DM from childhood DTC.
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http://dx.doi.org/10.1210/clinem/dgaa935DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7993569PMC
March 2021

Frozen section in thyroid gland follicular neoplasms: It's high time to abandon it!

Surg Oncol 2021 Mar 8;36:76-81. Epub 2020 Dec 8.

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

Thyroid nodules are a very common clinical condition. The 2015 American Thyroid Association (ATA) guidelines recommend surgical excision for Bethesda IV nodules. The use of intraoperative frozen section (FS) has been recommended as a strategy to tailor the extent of the initial surgery. We critically evaluated the literature that discusses the utility and cost-effectiveness of FS to make an intraoperative decision in patients with thyroid nodules classified as follicular neoplasm. FS should not be recommended as a routine intraoperative test to assess for malignancy in thyroid follicular patterned lesions due to its low performance; the high number of deferred results; the inability to adequately assess histologically defining features; the improvements in risk stratification guiding total thyroidectomy; and the low cost-effectiveness of FS.
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http://dx.doi.org/10.1016/j.suronc.2020.12.005DOI Listing
March 2021

Management of the Neck in Well-Differentiated Thyroid Cancer.

Curr Oncol Rep 2020 11 14;23(1). Epub 2020 Nov 14.

International Head and Neck Scientific Group, Padua, Italy.

Purpose Of Review: In this narrative review, we discuss the indications for elective and therapeutic neck dissections and the postoperative surveillance and treatment options for recurrent nodal disease in patients with well-differentiated thyroid cancer.

Recent Findings: Increased availability of advanced imaging modalities has led to an increased detection rate of previously occult nodal disease in thyroid cancer. Nodal metastases are more common in young patients, large primary tumors, specific genotypes, and certain histological types. While clinically evident nodal disease in the lateral neck compartments has a significant oncological impact, particularly in the older age group, microscopic metastases to the central or the lateral neck in well-differentiated thyroid cancer do not significantly affect outcome. As patients with clinically evident nodal disease are associated with worse outcomes, they should be treated surgically in order to reduce rates of regional recurrence and improve survival. The benefit of elective neck dissection remains unverified as the impact of microscopic disease on outcomes is not significant.
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http://dx.doi.org/10.1007/s11912-020-00997-6DOI Listing
November 2020

Neoadjuvant selpercatinib for advanced medullary thyroid cancer.

Head Neck 2021 01 9;43(1):E7-E12. Epub 2020 Nov 9.

Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA.

Background: Targeted kinase inhibitors have been increasingly utilized in the treatment of advanced medullary thyroid cancer (MTC) over the last decade. Recently, highly potent next generation selective RET inhibitors have been clinically validated, and selpercatinib was recently Food and Drug Administration (FDA)-approved for advanced MTC. The advent of highly selective, potent RET inhibitors is broadening the treatment options for patients with RET-mutated cancers.

Methods: We report the first published case of neoadjuvant selpercatinib followed by surgery for a patient with initially unresectable, widely metastatic, RET-mutated MTC who was treated on a single patient protocol.

Results: After greater than 50% RECIST response, the patient underwent complete surgical resection followed by selpercatinib resumption. He remains locoregionally disease-free 21 months after starting therapy with stable metastatic disease (after initial partial response); and calcitonin/CEA continue to decline.

Conclusion: This novel treatment strategy for locoregionally advanced RET-mutated MTC warrants further study in clinical trials.
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http://dx.doi.org/10.1002/hed.26527DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7756223PMC
January 2021

Immediate Intraoperative Repair of the Recurrent Laryngeal Nerve in Thyroid Surgery.

Laryngoscope 2021 06 29;131(6):1429-1435. Epub 2020 Oct 29.

Department of Otorhinolaryngology Head and Neck Surgery, University of Udine School of Medicine, Udine, Italy.

Objectives: Recurrent laryngeal nerve (RLN) injury is a recognized risk during thyroid and parathyroid surgery and can result in significant morbidity. The aim of this review paper is to consider the optimal approach to the immediate intraoperative repair of the RLN during thyroid surgery.

Methods: A PubMed literature search was performed from inception to June 2020 using the following search strategy: immediate repair or repair recurrent laryngeal nerve, repair or reinnervation recurrent laryngeal nerve and immediate neurorraphy or neurorraphy recurrent laryngeal nerve.

Results: Methods of immediate intraoperative repair of the RLN include direct end-to-end anastomosis, free nerve graft anastomosis, ansa cervicalis to RLN anastomosis, vagus to RLN anastomosis, and primary interposition graft. Techniques of nerve repair include micro-suturing, use of fibrin glue, and nerve grafting. Direct micro-suture is preferable when the defect can be repaired without tension. Fibrin glue has also been proposed for nerve repair but has been criticized for its toxicity, excessive slow reabsorption, and the risk of inflammatory reaction in the peripheral tissues. When the proximal stump of the RLN cannot be used, grafting could be done using transverse cervical nerve, supraclavicular nerve, vagus nerve, or ansa cervicalis.

Conclusions: Current evidence is low-level; however, it suggests that when the RLN has been severed, avulsed, or sacrificed during thyroid surgery it should be repaired intraoperatively. The immediate repair has on balance more advantages than disadvantages and should be considered whenever possible. This should enable the maintenance of vocal cord tone, better and prompter voice recovery and avoidance of aspiration. Laryngoscope, 131:1429-1435, 2021.
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http://dx.doi.org/10.1002/lary.29204DOI Listing
June 2021

The synergy of germline C634Y and V292M RET mutations in a northern Chinese family with multiple endocrine neoplasia type 2A.

J Cell Mol Med 2020 11 29;24(22):13163-13170. Epub 2020 Sep 29.

Department of Otolaryngology Head and Neck Surgery, Key Laboratory of Otolaryngology Head and Neck Surgery (Capital Medical University), Ministry of Education, Beijing Tongren Hospital, Capital Medical University, Beijing, China.

Genetic analysis for germline mutations of RET proto-oncogene has provided a basis for individual management of medullary thyroid carcinoma (MTC) and pheochromocytoma. Most of compound mutations have more aggressive phenotypes than single point mutations, but the compound C634Y/V292M variant in MTC has never been reported. Thus, we retrospectively investigated synergistic effect of C634Y and V292M RET germline mutations in family members with multiple endocrine neoplasia type 2A. Nine of 14 family members in a northern Chinese family underwent RET mutation screening using next-generation sequencing and PCR followed by direct bidirectional DNA sequencing. Clinical features of nine individuals were retrospectively carefully reviewed. In vitro, the scratch-wound assay was used to investigate the difference between the cells carrying different mutations. We find no patients died of MTC. All 3 carriers of the V292M variant were asymptomatic and did not have biochemical or structural evidence of disease (age: 82, 62 and 58). Among 4 C634Y mutation carriers, 2 patients had elevated calcitonin with the highest (156 pg/mL) in an 87-year-old male. Two carriers of compound C634Y/V292M trans variant had bilateral MTC with pheochromocytoma or lymph node metastasis (age: 54 and 41 years, respectively). Further, the compound C634Y/V292M variant had a faster migration rate than either single point mutation in vitro (P < .05). In conclusion, the V292M RET variant could be classified as 'likely benign' according to ACMG (2015). The compound variant V292M/C634Y was associated with both more aggressive clinical phenotype and faster cell growth in vitro than was either single mutation.
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http://dx.doi.org/10.1111/jcmm.15922DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7701567PMC
November 2020

Association between postoperative complications and long-term oncologic outcomes following total laryngectomy: 10-year experience at MD Anderson Cancer Center.

Cancer 2020 11 15;126(22):4905-4916. Epub 2020 Sep 15.

Department of Plastic and Reconstructive Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Background: Postoperative complications are an independent predictor of poor survival across several tumors. However, there is limited literature on the association between postoperative morbidity and long-term survival following total laryngectomy (TL) for cancer.

Methods: We conducted a retrospective review of all TL patients at a single institution from 2008 to 2013. Demographic and clinical data were collected and analyzed, including postsurgical outcomes, which were classified using the Clavien-Dindo system. Multivariable Cox regression analyses were performed to identify factors associated with overall survival (OS) and disease-free survival (DFS).

Results: A total of 362 patients were identified. The mean age was 64 years, and the majority of patients were male (81%). The median follow-up interval was 21 months. Fifty-seven percent of patients had received preoperative radiation, and 40% had received preoperative chemotherapy. Fifty-seven percent of patients underwent salvage TL, and 60% underwent advanced reconstruction (45% free flap and 15% pedicled flap). A total of 136 patients (37.6%) developed postoperative complications, 92 (25.4%) of which were major. Multivariable modeling demonstrated that postoperative complications independently predicted shorter OS (hazard ratio [HR], 1.50; 95% CI, 1.16-1.96; P = .002) and DFS (HR, 1.36; 95% CI, 1.05-1.76; P = .021). Other independent negative predictors of OS and DFS included positive lymph node status, preoperative chemotherapy, comorbidity grade, and delayed adjuvant therapy. Severity of complication and reason for TL (salvage vs primary) were not shown to be predictive of OS or DFS.

Conclusion: Postoperative complications are associated with worse long-term OS and DFS relative to uncomplicated cases. Patient optimization and timely management of postoperative complications may play a critical role in long-term survival.
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http://dx.doi.org/10.1002/cncr.33185DOI Listing
November 2020

Case for staged thyroidectomy.

Head Neck 2020 10 6;42(10):3061-3071. Epub 2020 Aug 6.

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

Recent modifications in the management of well-differentiated thyroid cancer have resulted in significant alterations in clinical approach. Utilizing a series of preoperative and postoperative risk factors involving both the patient and the disease pathology, we offer the term "staged thyroidectomy" to help organize these risk factors for patients and the endocrine team to optimize management. This approach is intended to incorporate our latest nuanced understanding of certain endocrine pathology and may serve to optimize patient outcomes.
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http://dx.doi.org/10.1002/hed.26393DOI Listing
October 2020

Evaluation of Overall Survival in Patients With Anaplastic Thyroid Carcinoma, 2000-2019.

JAMA Oncol 2020 09;6(9):1397-1404

Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston.

Importance: Anaplastic thyroid carcinoma (ATC) historically has a 4-month median overall survival (OS) from time of diagnosis, with disease-specific mortality approaching 100%. The association between recent major advancements in treatment and OS has yet to be evaluated.

Objective: To evaluate rates of OS in patients with ATC over the last 2 decades.

Design, Setting, And Participants: Retrospective cohort study in a single tertiary care institution. Patients with histopathological confirmation of ATC from January 2000 to October 2019 were included and divided into 3 groups according to date of presentation: 2000-2013, 2014-2016, and 2017-2019.

Main Outcomes And Measures: Overall survival compared among different treatment eras and differing therapies, including targeted therapy, immunotherapy, and surgery.

Results: Of 479 patients (246 men [51%]; median age, 65.0 [range, 21.1-92.6] years) with ATC evaluated, 52 (11%) were stage IVA, 172 (36%) stage IVB, and 255 (53%) stage IVC at presentation. The median OS of the entire cohort was 0.79 years (9.5 months), ranging from 0.01 to 16.63. The OS at 1 and 2 years was 35% (95% CI, 29%-42%) and 18% (95% CI, 13%-23%) in the 2000-2013 group (n = 227), 47% (95% CI, 36%-56%) and 25% (95% CI, 17%-34%) in the 2014-2016 group (n = 100), and 59% (95% CI, 49%-67%) and 42% (95% CI, 30%-53%) in the 2017-2019 group (n = 152), respectively (P < .001). The hazard ratio was 0.50 (95% CI, 0.38-0.67) for the 2017-2019 group compared with the 2000-2013 patients (P < .001). Factors associated with improved OS included targeted therapy (hazard ratio, 0.49; 95% CI, 0.39-0.63; P < .001), the addition of immunotherapy to targeted therapy (hazard ratio, 0.58; 95% CI, 0.36-0.94; P = .03), and surgery following neoadjuvant BRAF-directed therapy (hazard ratio, 0.29; 95% CI, 0.10-0.78; P = .02). Patients undergoing surgery following neoadjuvant BRAF-directed therapy (n = 20) had a 94% 1-year survival with a median follow-up of 1.21 years.

Conclusion And Relevance: In this large single-institution cohort study spanning nearly 20 years, changes in patient management appear to be associated with significant increase in survival. The era of untreatable ATC is progressively being replaced by molecular-based personalized therapies, with integration of multidisciplinary therapies including surgery and radiation therapy.
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http://dx.doi.org/10.1001/jamaoncol.2020.3362DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7411939PMC
September 2020

HEREDITARY ENDOCRINE TUMOURS: CURRENT STATE-OF-THE-ART AND RESEARCH OPPORTUNITIES: The state of science in medullary thyroid carcinoma: current challenges and unmet needs.

Endocr Relat Cancer 2020 08;27(8):T27-T39

Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer, Houston, TX, USA.

The 16th International Multiple Endocrine Neoplasia Workshop (MEN2019) held in Houston, TX, USA, focused on emerging topics in the pathogenesis and therapy of malignant endocrine tumors associated with MEN syndromes. With MEN-2 syndromes, the most common malignancy is medullary thyroid carcinoma (MTC). In the spirit of the original MEN meeting workshop model, the conference included didactic lectures and interactive working groups of clinicians and researchers focused on the state of science in MTC and ongoing challenges or unmet needs in the understanding of MTC and to develop strategies to address these issues.
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http://dx.doi.org/10.1530/ERC-20-0110DOI Listing
August 2020

Papillary Thyroid Cancer-Aggressive Variants and Impact on Management: A Narrative Review.

Adv Ther 2020 07 1;37(7):3112-3128. Epub 2020 Jun 1.

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

Introduction: Aggressive variants of papillary thyroid cancer (PTC) have been described with increasing frequency. These variants include diffuse sclerosing variant, tall cell variant, columnar cell variant, solid variant, and hobnail variant.

Methods: We have performed a review of the more aggressive variants of PTC with respect to main characteristics, histological and molecular features, and the consequences that the knowledge of these variants should have in the treatment of the patients.

Results: At the present time, we do not know the prognostic value of these aggressive PTC variants. The extent of the surgical treatment and adjuvant therapy necessary should be decided on the basis of the extent of the tumor at presentation and the opinion of experienced clinicians.

Conclusion: These aggressive variants should be known by clinicians, to avoid underdiagnosis, and treated according to the latest recommendations in the literature.
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http://dx.doi.org/10.1007/s12325-020-01391-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7467416PMC
July 2020

Endocrine surgery in the Coronavirus disease 2019 pandemic: Surgical Triage Guidelines.

Head Neck 2020 06 30;42(6):1325-1328. Epub 2020 Apr 30.

Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

Background: In the face of the COVID-19 pandemic, cancer care has had to adapt rapidly given the Centers for Disease Control and Prevention and the American College of Surgeons (ACS) issuing recommendations to postpone nonurgent surgeries.

Methods: An institutional multidisciplinary group of Head and Neck Surgical Oncology, Surgical Endocrinology, and Medical Endocrinology devised Surgical Triaging Guidelines for Endocrine Surgery during COVID-19, aligned with phases of care published by the ACS.

Results: Phases of care with examples of corresponding endocrine cases are outlined. Most cases can be safely postponed with active surveillance, including most differentiated and medullary thyroid cancers. During the most acute phase, all endocrine surgeries are deferred, except thyroid tumors requiring acute airway management.

Conclusions: These guidelines provide context for endocrine surgery within the spectrum of surgical oncology, with the goal of optimal individualized multidisciplinary patient care and the expectation of significant resource diversion to care for patients with COVID-19.
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http://dx.doi.org/10.1002/hed.26169DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7262055PMC
June 2020

Head and neck surgical oncology in the time of a pandemic: Subsite-specific triage guidelines during the COVID-19 pandemic.

Head Neck 2020 06;42(6):1194-1201

Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

Background: COVID-19 pandemic has strained human and material resources around the world. Practices in surgical oncology had to change in response to these resource limitations, triaging based on acuity, expected oncologic outcomes, availability of supportive resources, and safety of health care personnel.

Methods: The MD Anderson Head and Neck Surgery Treatment Guidelines Consortium devised the following to provide guidance on triaging head and neck cancer (HNC) surgeries based on multidisciplinary consensus. HNC subsites considered included aerodigestive tract mucosa, sinonasal, salivary, endocrine, cutaneous, and ocular.

Recommendations: Each subsite is presented separately with disease-specific recommendations. Options for alternative treatment modalities are provided if surgical treatment needs to be deferred.

Conclusion: These guidelines are intended to help clinicians caring for patients with HNC appropriately allocate resources during a health care crisis, such as the COVID-19 pandemic. We continue to advocate for individual consideration of cases in a multidisciplinary fashion based on individual patient circumstances and resource availability.
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http://dx.doi.org/10.1002/hed.26206DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7267348PMC
June 2020

Facial nerve electrodiagnostics for patients with facial palsy: a clinical practice guideline.

Eur Arch Otorhinolaryngol 2020 Jul 8;277(7):1855-1874. Epub 2020 Apr 8.

International Head and Neck Scientific Group, Padua, Italy.

Purpose: Facial nerve electrodiagnostics is a well-established and important tool for decision making in patients with facial nerve diseases. Nevertheless, many otorhinolaryngologist-head and neck surgeons do not routinely use facial nerve electrodiagnostics. This may be due to a current lack of agreement on methodology, interpretation, validity, and clinical application. Electrophysiological analyses of the facial nerve and the mimic muscles can assist in diagnosis, assess the lesion severity, and aid in decision making. With acute facial palsy, it is a valuable tool for predicting recovery.

Methods: This paper presents a guideline prepared by members of the International Head and Neck Scientific Group and of the Multidisciplinary Salivary Gland Society for use in cases of peripheral facial nerve disorders based on a systematic literature search.

Results: Required equipment, practical implementation, and interpretation of the results of facial nerve electrodiagnostics are presented.

Conclusion: The aim of this guideline is to inform all involved parties (i.e. otorhinolaryngologist-head and neck surgeons and other medical specialists, therapeutic professionals and the affected persons) and to provide practical recommendations for the diagnostic use of facial nerve electrodiagnostics.
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http://dx.doi.org/10.1007/s00405-020-05949-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7286870PMC
July 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

Acquired Secondary RAS Mutation in BRAF-Mutated Thyroid Cancer Patients Treated with BRAF Inhibitors.

Thyroid 2020 09 7;30(9):1288-1296. Epub 2020 May 7.

Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

The BRAF mutation is the most common driver mutation in papillary thyroid cancer (PTC) and anaplastic thyroid cancer (ATC). This mutation is considered actionable and, for BRAF-mutated ATC, a BRAF inhibitor (dabrafenib) in combination with an MEK inhibitor (trametinib) is FDA approved. BRAF inhibitors have also shown efficacy in BRAF-mutated PTC. However, as with all targeted therapies, resistance to these drugs eventually develops. It is essential that we understand the mechanisms of resistance to the BRAF inhibitors in thyroid cancer to develop future strategies to effectively treat these patients and improve survival. Herein, we describe four patients with thyroid cancer treated with selective BRAF inhibitors, who developed a RAS mutation in addition to the BRAF mutation at progression. Patients 1 and 3 acquired a KRAS mutation in the progressive tumor, patient 2 acquired a NRAS mutation in a progressive lymph node, and patient 4 acquired NRAS mutation on liquid biopsy performed at the time of radiographic disease progression. Similar to the melanoma experience, the emergence of RAS mutations appears to act as a mechanism of resistance to BRAF inhibitors in thyroid cancers.
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http://dx.doi.org/10.1089/thy.2019.0514DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7869871PMC
September 2020

African Head and Neck Society Clinical Practice guidelines for thyroid nodules and cancer in developing countries and limited resource settings.

Head Neck 2020 08 7;42(8):1746-1756. Epub 2020 Mar 7.

Department of Otohinolaryngology, University of Cape Town, Cape Town, South Africa.

Background: International thyroid nodule and cancer management guidelines generally fail to take into account potential limitations in diagnostic and treatment resources.

Methods: Thyroid cancer specialists from the African Head and Neck Society and American Head & Neck Society Endocrine Section developed guidelines for diagnosis and management of thyroid nodules and cancer in low resource settings. Recommendations were based on literature review and expert opinion, with level of evidence defined.

Results: Using the ADAPTE process, diagnostic and treatment algorithms were adapted from the National Comprehensive Cancer Network (NCCN). Low resource settings were simulated by systematically removing elements such as availability of laboratory testing, hormone replacement, imaging, and cytopathology from NCCN guidelines.

Conclusions: Successful management of thyroid nodules and cancer in low resource settings requires adaptation of treatment methodologies. These guidelines define specific scenarios where either more or less aggressive intervention for thyroid pathology may be advisable based on limited available resources.
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http://dx.doi.org/10.1002/hed.26094DOI Listing
August 2020
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