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CONTEXT: Next-generation sequencing (NGS) analysis of sporadic medullary thyroid carcinoma (sMTC) has led to increased detection of somatic mutations, including RET M918T, which has been considered a negative prognostic indicator. OBJECTIVE: This study aimed to determine the association between clinicopathologic behavior and somatic mutation identified on clinically motivated NGS. METHODS: In this retrospective cohort study, patients with sMTC who underwent NGS to identify somatic mutations for treatment planning were identified. Clinicopathologic factors, time to distant metastatic disease (DMD), disease-specific survival (DSS), and overall survival (OS) were compared between somatic mutations. RESULTS: Somatic mutations were identified in 191 sMTC tumors, including RET M918T (53.4%), other RET codons (10.5%), RAS (18.3%), somatic RET indels (8.9%), and RET/RAS wild-type (WT) status (8.9%). The median age at diagnosis was 50 years (range, 11-83); 46.1% were female. When comparing patients with RET M918T, RET-Other, and RET WT (which included RAS and RET/RAS WT), there were no differences in sex, TNM category, systemic therapy use, time to DMD, DSS, or OS. On multivariate analysis, older age at diagnosis (HR 1.05, P < .001; HR 1.06, P< .001) and M1 stage at diagnosis (HR 3.17, P = .001; HR 2.98, P = .001) were associated with decreased DSS and OS, respectively, but mutation cohort was not. When comparing RET M918T to RET indels there was no significant difference in time to DMD, DSS, or OS between the groups. CONCLUSION: Somatic RET mutations do not portend compromised DSS or OS in a cohort of sMTC patients who underwent clinically motivated NGS.

BackgroundIn 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.ObjectiveFollowing 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.MethodsThis 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.ResultsThe 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.ConclusionsPatients, 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.

BackgroundCOVID-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.MethodsThe 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.RecommendationsEach subsite is presented separately with disease-specific recommendations. Options for alternative treatment modalities are provided if surgical treatment needs to be deferred.ConclusionThese 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.

BackgroundCOVID-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.MethodsThe 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.RecommendationsEach subsite is presented separately with disease-specific recommendations. Options for alternative treatment modalities are provided if surgical treatment needs to be deferred.ConclusionThese 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.

A 65-year-old patient presented with recurrent, locally advanced poorly differentiated thyroid cancer despite 2 neck surgeries, and with newly diagnosed brain and skull base metastases. He was treated with palliative stereotactic radiosurgery to the brain and skull base lesions. Thereafter, as no targetable genetic alteration was identified and antiangiogenic multikinase inhibitors were deemed at high risk of hemorrhagic complications, off-label systemic therapies were considered. The mechanistic target of rapamycin (mTOR) inhibitor everolimus could not be obtained due to lack of insurance coverage, so the patient was treated with single-agent pembrolizumab. He showed an initial remarkable response, but unfortunately had disease progression in the neck and upper mediastinum after 1 year of therapy. At that time, he was treated with external beam radiotherapy, with concomitant pembrolizumab. He was then found to have an CTSB::ALK fusion, which has previously been described in 2 cases of thyroid cancer. However, as he showed a positive response to radiation with pembrolizumab, he continued single-agent immune checkpoint inhibition and had a persistent marked response almost a year after completing radiation. The patient was then followed at an outside institution and was transitioned to hospice at time of progression per his preference. He died 4 years after his initial diagnosis. [ABSTRACT FROM AUTHOR]

Context Thyroid differentiation score (TDS), calculated based on mRNA expression levels of 16 genes controlling thyroid metabolism and function, has been proposed as a measure to quantify differentiation in papillary thyroid carcinoma (PTC). Objective The objective of this study is to determine whether TDS is associated with survival outcomes across patient cohorts. Methods Two independent cohorts of patients with PTC were used: (1) The Cancer Genome Atlas (TCGA) thyroid cancer study (N = 372), (2) MD Anderson Cancer Center (MDACC) cohort (N = 111). The primary survival outcome of interest was progression-free interval (PFI). Association with overall survival (OS) was also explored. The Kaplan–Meier method and Cox proportional hazards models were used for survival analyses. Results In both cohorts, TDS was associated with tumor and nodal stage at diagnosis as well as tumor driver mutation status. High TDS was associated with longer PFI on univariable analyses across cohorts. After adjusting for overall stage, TDS remained significantly associated with PFI in the MDACC cohort only (adjusted hazard ratio [aHR] 0.67, 95% CI 0.52-0.85). In subgroup analyses stratified by tumor driver mutation status, higher TDS was most consistently associated with longer PFI in BRAFV600E -mutated tumors in the MDACC cohort after adjusting for overall stage (TCGA: aHR 0.60, 95% CI 0.33-1.07; MDACC: aHR 0.59, 95% CI 0.42-0.82). For OS, increasing TDS was associated with longer OS in the overall MDACC cohort (aHR = 0.78, 95% CI 0.63-0.96), where the median duration of follow-up was 12.9 years. Conclusion TDS quantifies the spectrum of differentiation status in PTC and may serve as a potential prognostic biomarker in PTC, mostly promisingly in BRAFV600E -mutated tumors. [ABSTRACT FROM AUTHOR]

Context Pediatric papillary thyroid carcinoma (PTC) is usually treated with total thyroidectomy followed by radioactive iodine (RAI). Recently, RAI has been used more selectively based on surgical pathology and postoperative dynamic risk stratification (DRS). Objective To describe patients with pediatric PTC not initially treated with RAI and their disease outcomes. Methods This was an ambispective study at a tertiary cancer center of patients < 19 years diagnosed from January 1, 1990, to December 31, 2021, with stage 1 PTC who intentionally were not treated with RAI within a year of diagnosis. We assessed clinical characteristics, management, and disease outcomes using DRS. Results Of 490 PTC patients, we identified 93 eligible patients (median age at diagnosis 16 years; 87% female), including 46 (49%) with cervical lymph node metastases. Initial management included total thyroidectomy ± neck dissection (n = 69, 75%), lobectomy ± neck dissection (n = 20, 21%), or a Sistrunk procedure for ectopic PTC (n = 4, 4%). After a median follow-up of 5.5 years (range 1-26), most patients (85/93; 91%) remained disease-free with no further therapy. Persistent (n = 5) or recurrent (n = 3) disease was found in 9% of the entire cohort. Four patients ultimately received RAI, of which only 1 clearly benefitted, and additional surgery was performed or planned in 4 patients, 2 of whom had an excellent response at last follow-up. Conclusion Selected pediatric PTC patients, even those with lymph node metastases, may not require therapeutic 131I and can avoid the unnecessary risks of RAI while still benefitting from the excellent long-term outcomes that are well described for this disease. [ABSTRACT FROM AUTHOR]

Background: Two selective RET inhibitors (RETis) are effective in treating REarranged during Transfection (RET)-altered medullary thyroid carcinoma (MTC), but clinical trials did not distinguish responses between hereditary MTC (hMTC) and sporadic MTC (sMTC) cases. We reviewed our single-center experience using a RETi to treat advanced hMTC. Methods: We conducted a retrospective cohort study of patients with hMTC treated with a selective RETi at a tertiary cancer center. The primary outcome was overall response rate using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Secondary end points included overall survival (OS), progression-free survival (PFS), biochemical response rate, and safety. Results: We identified 23 evaluable patients as follows: 15 (65%) multiple endocrine neoplasia (MEN)2A and 8 (35%) MEN2B. Median age at start of RETi was 51 years (range, 15–79). All patients had distant metastases, and 52% (12/23) had received prior systemic therapy (median = 1, range, 0–3). Patients were treated with selpercatinib (n = 13) or pralsetinib (n = 10), 57% (13/23) within a clinical trial. Median duration of RETi was 25 months (range, 3–72) with 11/23 (48%) patients remaining on drug at data cutoff due to an ongoing response. Median duration of follow-up was 49 months (range, 9–72). Best radiographical response was partial response in 18 (78%) and stable disease in 5 (22%) patients. Median OS was 51 months (confidence interval, 40.5–61.3); median PFS was not reached. Most common adverse events (AEs) were increased alanine aminotransferase (ALT) (48%) and aspartate aminotransferase (26%), dry mouth (39%), QT interval prolongation (39%), fatigue (35%), and hypertension (26%). AEs led to dose reductions in eight (35%) patients. No grade 5 treatment-related AEs occurred. While the germline nature of the RET pathogenic variant in hMTC could hypothetically result in increased drug-related toxicity, the incidence of most AEs, other than grade 1–2 ALT elevation and QT interval prolongation, was comparable to published clinical trials. Conclusions: In patients with advanced hMTC, selective RETis appear safe and effective with outcomes similar to clinical trial cohorts, which mostly comprised patients with sMTC. Duration of response and AE profile was similar to sMTC, although longer follow-up and larger patient numbers are needed to confirm this. [ABSTRACT FROM AUTHOR]

Introduction Anaplastic thyroid cancer (ATC), characterized by an undifferentiated morphology, is arguably one of the most lethal malignancies. According to Surveillance, Epidemiology and End Results (SEER) data (released April 2021) [...], The deadliest anaplastic thyroid cancer (ATC) often transforms from indolent differentiated thyroid cancer (DTC); however, the complex intratumor transformation process is poorly understood. We investigated an anaplastic transformation model by dissecting both cell lineage and cell fate transitions using single-cell transcriptomic and genetic alteration data from patients with different subtypes of thyroid cancer. The resulting spectrum of ATC transformation included stress-responsive DTC cells, inflammatory ATC cells (iATCs), and mitotic-defective ATC cells and extended all the way to mesenchymal ATC cells (mATCs). Furthermore, our analysis identified 2 important milestones: (a) a diploid stage, in which iATC cells were diploids with inflammatory phenotypes and (b) an aneuploid stage, in which mATCs gained aneuploid genomes and mesenchymal phenotypes, producing excessive amounts of collagen and collagen-interacting receptors. In parallel, cancer- associated fibroblasts showed strong interactions among mesenchymal cell types, macrophages shifted from M1 to M2 states, and T cells reprogrammed from cytotoxic to exhausted states, highlighting new therapeutic opportunities for the treatment of ATC.

Context Sporadic medullary thyroid carcinoma (sMTC) rarely occurs in childhood and no studies have specifically focused on this entity. Objective To describe the clinical presentations and long-term outcomes of a large cohort of children and young adults with sMTC compared with hereditary MTC (hMTC). Methods Retrospective study of 144 patients diagnosed with MTC between 1961 and 2019 at an age ≤ 21 years and evaluated at a tertiary referral center. Results In contrast to hMTC (n = 124/144, 86%), patients with sMTC (n = 20/144, 14%) are older (P <.0001), have larger tumors (P <.0001), a higher initial stage grouping (P =.001) and have more structural disease (P =.0045) and distant metastases (DM) (P =.00084) at last follow-up, but are not more likely to die from MTC (P =.42). Among 77 patients diagnosed clinically, not by family history (20/20 sMTC and 57/124 hMTC), there was no difference in the initial stage (P =.27), presence of DM at diagnosis (P = 1.0), disease status at last follow-up (P =.13), overall survival (P =.57), or disease-specific survival (P =.87). Of the 12 sMTC tumors that underwent somatic testing, 11 (91%) had an identifiable alteration: 10 RET gene alterations and 1 ALK fusion. Conclusion sMTC is primarily a RET-driven disease that represents 14% of childhood-onset MTC in this cohort. Pediatric sMTC patients are older, present with clinical disease at a more advanced TNM classification, and have more persistent disease at last follow-up compared with hMTC, but these differences disappear when comparing those presenting clinically. Somatic molecular testing should be considered in sMTC patients who would benefit from systemic therapy. [ABSTRACT FROM AUTHOR]