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Tyrosine kinase inhibitors (TKIs) have been recently introduced for treatment of different malignancies. Various cardiovascular toxicities have been reported with TKIs with hypertension being the most common adverse cardiovascular event. We report a case of a 60-year-old woman who developed left renal artery stenosis associated with renal atrophy in the context of metastatic papillary thyroid carcinoma treated with sorafenib. Renal atrophy was noticed during serial imaging studies to monitor cancer therapy. Clinically, she was asymptomatic without significant change in blood pressure. The glomerular filtration rate dropped from 88 ml/min/1.73 m[sup 2] at baseline to 56 ml/min/1.73 ml/min and partially recovered to 71 ml/min/1.73 m[sup 2] after renal artery stenting. To our knowledge, this will be the first known case of renal artery stenosis associated with TKI use. Physicians may need to investigate the possibility of developing renal artery stenosis in patients with unexplained worsening in kidney functions while on TKIs. [ABSTRACT FROM AUTHOR]

Background: The dabrafenib plus trametinib combination (DT) has revolutionized the treatment of BRAFV600E-mutated anaplastic thyroid carcinoma (BRAFm-ATC). However, patients eventually develop resistance and progress. Single-agent anti-PD-1 inhibitor spartalizumab has shown a median overall survival (mOS) of 5.9 months. Combination of immunotherapy with BRAF/MEK inhibitors (BRAF/MEKi) seems to improve outcomes compared with BRAF/MEKi alone, although no direct comparison is available. BRAF-targeted therapy before surgery (neoadjuvant approach) has also shown improvement in survival. We studied the efficacy and safety of DT plus pembrolizumab (DTP) compared with current standard-of-care DT alone as an initial treatment, as well as in the neoadjuvant setting. Methods: Retrospective single-center study of patients with BRAFm-ATC treated with first-line BRAF-directed therapy between January 2014 and March 2023. Three groups were evaluated: DT, DTP (pembrolizumab added upfront or at progression), and neoadjuvant (DT before surgery, and pembrolizumab added before or after surgery). The primary endpoint was mOS between DT and DTP. Secondary endpoints included median progression-free survival (mPFS) and response rate with DT versus DTP as initial treatments, and the exploratory endpoint was mOS in the neoadjuvant group. Results: Seventy-one patients were included in the primary analysis: n = 23 in DT and n = 48 in DTP. Baseline demographics were similar between groups, including the presence of metastatic disease at start of treatment (p = 0.427) and prior treatments with surgery (p = 0.864) and radiation (p = 0.678). mOS was significantly longer with DTP (17.0 months [confidence interval CI, 11.9–22.1]) compared with DT alone (9.0 months [CI, 4.5–13.5]), p = 0.037. mPFS was also significantly improved with DTP as the initial treatment (11.0 months [CI, 7.0–15.0]) compared with DT alone (4.0 months [CI, 0.7–7.3]), p = 0.049. Twenty-three patients were in the exploratory neoadjuvant group, where mOS was the longest (63.0 months [CI, 15.5–110.5]). No grade 5 adverse events (AEs) occurred in all three cohorts, and 32.4% had immune-related AEs, most frequently hepatitis and colitis. Conclusions: Our results show that in BRAFm-ATC, addition of pembrolizumab to dabrafenib/trametinib may significantly prolong survival. Surgical resection of the primary tumor after initial BRAF-targeted therapy in selected patients may provide further survival benefit. However, conclusions are limited by the retrospective nature of the study. Additional prospective data are needed to confirm this observation. [ABSTRACT FROM AUTHOR]

Purpose We aimed to investigate outcomes of locoregional radiation therapy (XRT) in parathyroid carcinoma (PC) patients at a single institution over 35 years. Methods and materials Retrospective review of PC patients who received postoperative locoregional XRT (1980-2015). Patients were grouped according to XRT after PC initial operation or after salvage surgery. All patients with a histopathological diagnosis of PC who had postoperative locoregional XRT at our institution were included. All patients with a histopathological diagnosis of uncertain malignancy, suggestive for malignancy, or atypical parathyroid tumors and those who had XRT outside our institution were excluded. Results Eight patients received XRT, 4 in each group, with a median follow-up of 12.5 years. The 4 patients who had XRT after initial surgery all had an oncologic operation, including ipsilateral thyroid lobectomy and central neck dissection, and all of these patients were disease-free at last follow-up. Of the 4 patients who received XRT after salvage surgery, only 1 remained disease free. There were no major complications/long-term side effects associated with XRT. Conclusions XRT is well tolerated as postoperative locoregional treatment of patients with PC. Whether it is needed, and the timing of administering XRT, remains to be established. [ABSTRACT FROM AUTHOR]

PURPOSE: Anaplastic thyroid carcinoma (ATC) uniformly present with aggressive disease, but the mutational landscape of tumors varies. We aimed to determine whether tumor mutations affect survival outcomes in ATC. MATERIALS AND METHODS: Patients who underwent mutation sequencing using targeted gene panels between 2005 and 2019 at a tertiary referral center were included. Associations between mutation status and survival outcomes were assessed using Cox proportional hazards models. RESULTS: A total of 202 patients were included, where 122 died of ATC (60%). The median follow-up was 31 months (interquartile range, 18-45 months). The most common mutations were in TP53 (59%), BRAF (41%), TERT promoter (37%), and the RAS gene family (22%). Clinicopathologic characteristics and overall survival (OS) significantly correlated with mutations in BRAF V600E and RAS , which were mutually exclusive. The BRAF V600E mutation was associated with the presence of a papillary thyroid carcinoma precursor and significantly better OS (median OS: 24 months). RAS -mutated patients more commonly presented without cervical lymph node involvement but had the worst OS (median OS: 6 months). Tumors that were wild-type for both BRAF and RAS were enriched for NF1 mutations and harbored intermediate prognosis (median OS: 15 months). In multivariate analyses, RAS mutations were associated with a more than 2.5-fold higher risk of death (adjusted hazard ratio, 2.64; 95% CI, 1.66 to 4.20) compared with BRAF V600E. In patients treated with BRAF-directed therapy (n = 60), disease progression occurred in 48% of patients (n = 29). The median progression-free survival was 14 months. The presence of a TP53 mutation was independently associated with reduced progression-free survival in BRAF V600E-mutated patients treated with BRAF-directed therapy (adjusted hazard ratio, 2.89; 95% CI, 1.35 to 6.21). CONCLUSION: Mutation analysis provides prognostic information in ATC and should be incorporated into routine clinical care. Largest study, to our knowledge, published to date to examine the impact of tumor mutations on survival outcomes in ATC, demonstrating that driver mutation status is a key determinant of survival outcomes. Data support routine assessment of tumor mutation profiles in ATC. [ABSTRACT FROM AUTHOR]

Background and Purpose: Neoadjuvant BRAF-directed therapy and immunotherapy followed by surgery improves survival in patients with BRAF V600E -mutant anaplastic thyroid carcinoma (ATC), more so in those who have complete ATC pathologic response. This study assesses the ability of FDG-PET to non-invasively detect residual high-risk pathologies including ATC and poorly differentiated thyroid carcinoma (PDTC) in the preoperative setting., Materials and Methods: This retrospective, single-center study included consecutive BRAF V600E -mutant ATC patients treated with at least 30 days of neoadjuvant BRAF-directed therapy and who underwent FDG-PET/CT within 30 days prior to surgery. The highest pathologic grade observed for every head and neck lesion resected was recorded. Each lesion on pre-operative PET/CT was retrospectively characterized. The primary endpoint was to contrast the standardized uptake normalized by lean body mass (SULmax) for lesions with residual high-risk (ATC, PDTC) versus low-risk pathologies (papillary thyroid carcinoma, negative). An optimal SULmax threshold was then identified using a ROC analysis, and the ability of this threshold to non-invasively and preoperatively risk-stratify patients by overall survival was then evaluated with a Kaplan-Meier plot., Results: 30 patients (mean age 66.5±9.0; 17 males) were included in this study, with 94 surgically sampled lesions. Of these lesions, 57 (60.6%) were low-risk (39 negative, 18 papillary thyroid carcinoma) and 37 (39.4%) were high-risk (29 ATC, 8 PDTC). FDG uptake was higher for high-risk compared to low-risk pathologies: median SULmax 5.01 [IQR 2.81 - 10.95] versus 1.29 [IQR 1.06 - 3.1] (P<.001, Mann-Whitney U test). The sensitivity, specificity, and accuracy for detecting high-risk pathologies at the optimal threshold of SULmax ≥ 2.75 were 0.784 [95% CI 0.628-0.886], 0.702 [95% CI 0.573-0.805], and 0.734 [95% CI 0.637-0.813], respectively. Patients with at least 1 high-risk lesion identified with the aforementioned cut-off had a worse prognosis compared to patients without high-risk lesions in the head and neck: median OS for the former group was 259 days and was not attained for the latter (P=.038, log-rank test)., Conclusions: Preoperative FDG-PET non-invasively identifies lesions with residual high-risk pathologies following neoadjuvant BRAF-directed targeted therapy and immunotherapy for BRAF-mutated ATC. FDG-PET avidity may serve as an early prognostic marker which correlates with residual high-risk pathology in BRAF-mutated ATC following neoadjuvant therapy., Abbreviations: ATC = anaplastic thyroid carcinoma; IQR = interquartile range; OS = overall survival; PDTC = poorly differentiated thyroid carcinoma; PTC = papillary thyroid carcinoma; ROC = receiver operating characteristic; SUL= standardized uptake value normalized by lean body mass., Competing Interests: The authors declare no conflicts of interest related to the content of this article., (© 2024 by American Journal of Neuroradiology.)

Importance: Anaplastic thyroid carcinoma (ATC) is a rare and lethal cancer. Although progress has been made in recent years in patients with mutated BRAF tumors, those who respond initially eventually die of their disease; furthermore, there are no approved therapies for non-BRAF mutated tumors., Objective: To determine whether treatment with matched-targeted therapy plus immune checkpoint inhibitors were associated with improved overall survival (OS)., Design, Setting, and Participants: A phase 2 trial at a single center, tertiary institution with parallel cohorts, assigning treatment with targeted therapy according to the tumor mutation status. Patients with mutated BRAF V600E tumors received vemurafenib/cobimetinib plus atezolizumab (cohort 1); those with mutated RAS (NRAS, KRAS, or HRAS) or NF1/2 tumors received cobimetinib plus atezolizumab (cohort 2). Patients without any of these variants were assigned to receive bevacizumab plus atezolizumab (cohort 3). Patients were enrolled from August 3, 2017, to July 7, 2021. All consecutive, systemic therapy-naive patients with ATC with active disease and who met eligibility criteria were considered for participation. The analysis was conducted in September 2023., Interventions: Patients were assigned to targeted therapy based on the driver mutation as follow: BRAF V600E (cohort 1, vemurafenib plus cobimetinib), RAS/NF (cohort 2, cobimetinib), or non-BRAF/RAS/NF (cohort 3, bevacizumab). All received atezolizumab., Main Outcomes and Measures: The primary outcome of the study was median OS of the entire targeted therapy cohort, compared with historical median OS of 5 months., Results: Forty-three patients with ATC were enrolled in the targeted therapy cohorts, of which 42 were included in the primary analysis. The median OS in patients across these 3 cohorts was 19 months (95% CI, 7.79-43.24). Median OS and progression-free survival per cohort were as follows: cohort 1: 43 months (95% CI, 16-not estimable [NE]), 13.9 months (6.6-64.1); cohort 2: 8.7 months (95% CI, 5.1-37.0) and 4.8 months (1.8-14.7); cohort 3 (vascular endothelial growth factor inhibitor group): 6.21 months (4.1-NE) and 1.3 months (1.3-NE), respectively., Conclusions and Relevance: In this nonrandomized clinical trial, atezolizumab combined with targeted therapy resulted in a longer median OS than historical landmark, achieving the study's primary end point, with cohort 1 achieving the longest OS., Trial Registration: ClinicalTrials.gov Identifier: NCT03181100.

Importance: BRAF/MEK inhibitors revolutionized the treatment of BRAF V600E-variant anaplastic thyroid carcinoma (BRAFv-ATC), offering improved outcomes for patients with this previously incurable disease., Observations: Anaplastic thyroid carcinoma (ATC) accounts for approximately half of thyroid cancer-related deaths. It presents as a rapidly growing tumor that often invades locoregional structures and spreads to distant sites early; therefore, prompt diagnosis, staging, and treatment initiation are of the essence in the treatment of ATC. Although most oncologists will encounter a patient with ATC in their practice, the rarity of this disease makes treatment challenging, particularly because those with BRAFv-ATC no longer have a dismal prognosis. BRAF/MEK kinase inhibitors have transformed the outlook and treatment of BRAFv-ATC. Therefore, molecular profiling to identify these patients is critical. More recently, the addition of immunotherapy to BRAF/MEK inhibitors as well as the use of the neoadjuvant approach were shown to further improve survival outcomes in BRAFv-ATC. Many of these recent advances have not yet been incorporated in the currently available guidelines, allowing for disparities in the treatment of patients with BRAFv-ATC across the US. With the increasing complexity in the management of BRAFv-ATC, this Consensus Statement aims to formulate guiding recommendations from a group of experts to facilitate therapeutic decision-making., Conclusions and Relevance: This Consensus Statement from the FAST (Facilitating Anaplastic Thyroid Cancer Specialized Treatment) group at MD Anderson Cancer Center emphasizes that rapid identification of a BRAF V600E pathogenic variant and timely initiation of sequential therapy are critical to avoid excess morbidity and mortality in patients with BRAFv-ATC. In the past decade, remarkable progress has been made in the treatment of patients with BRAFv-ATC, justifying these new evidence-based recommendations reached through a consensus of experts from a high-volume center.

Background and Objectives: The American Joint Committee on Cancer (AJCC) TNM staging system defines atypical parathyroid neoplasia (APN) as tumor in situ (Tis) and reserves the definition of parathyroid carcinoma (PC) to parathyroid tumor with invasion into surrounding structures. Because the parathyroid gland has no true capsule, "extension" with APN versus microscopic "invasion" of surrounding soft tissue can be difficult and confusing for clinicians. We aimed to determine the clinical course of atypical parathyroid neoplasm with and without soft tissue extension and parathyroid carcinoma with only soft tissue invasion (pT1) and to report the outcomes., Methods: Following an IRB-approved protocol, we identified all patients treated for parathyroid neoplasm or cancer at our single tertiary care cancer center from 1990 to 2021. We excluded all patients with evidence of clinical or pathologic gross invasion into surrounding structures (pT2 or higher), lymph node involvement, or metastatic disease. By definition, this excluded all cases where the distinction was clinically evident to the surgeon at the time of the operation based on finding a hard, firm, sticky, or discolored parathyroid gland. Only patients with pathologic T1 (pT1) parathyroid carcinoma or APN were included. All pathologic examinations were independently re-reviewed by a single designated expert senior endocrine pathologist. The definition of APN strictly followed the WHO definition of a clinically worrisome lesion having features including fibrous bands or increased mitotic rate, necrosis, or trabecular growth that did not meet robust criteria for frank invasion. Pathologic T1 disease was defined as invasion limited to soft tissue. Analyses were performed using R version 4.0.2 and Jamovi., Results: Of all PC patients at our institution, only 71 met the strict inclusion criteria of APN or pT1. Forty-four patients had pT1 disease and 27 had APN: 12 of the APN had soft tissue extension, and 15 had no soft tissue extension. The groups were similar with regard to age at diagnosis (p = 0.328). The average follow-up duration was 84 months from initial surgical intervention. Of the 12 with APN, one patient (1/12; 8%) with soft tissue extension recurred, developed distant metastases, and subsequently died during follow up. Of the 44 patients with pT1 PC, six developed distant metastases and 13 (13/44; 30%) died during the follow-up period. One patient with APN and soft tissue extension recurred and died and no patient with APN and no soft tissue extension died., Conclusions: Patients with APN and extension into soft tissue have a clinical course similar to that of APN without soft tissue extension. APN with soft tissue extension is a different disease from pT1 disease with invasion of soft tissue. The pTis classification appears justified for APN with and without soft tissue extension., (© 2024 Wiley Periodicals LLC.)

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., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: The dabrafenib plus trametinib combination (DT) has revolutionized the treatment of BRAF V600E -mutated anaplastic thyroid carcinoma (BRAFm-ATC). However, patients eventually develop resistance and progress. Single-agent anti-PD-1 inhibitor spartalizumab has shown a median overall survival (mOS) of 5.9 months. Combination of immunotherapy with BRAF/MEK inhibitors (BRAF/MEKi) seems to improve outcomes compared with BRAF/MEKi alone, although no direct comparison is available. BRAF-targeted therapy before surgery (neoadjuvant approach) has also shown improvement in survival. We studied the efficacy and safety of DT plus pembrolizumab (DTP) compared with current standard-of-care DT alone as an initial treatment, as well as in the neoadjuvant setting. Methods: Retrospective single-center study of patients with BRAFm-ATC treated with first-line BRAF-directed therapy between January 2014 and March 2023. Three groups were evaluated: DT, DTP (pembrolizumab added upfront or at progression), and neoadjuvant (DT before surgery, and pembrolizumab added before or after surgery). The primary endpoint was mOS between DT and DTP. Secondary endpoints included median progression-free survival (mPFS) and response rate with DT versus DTP as initial treatments, and the exploratory endpoint was mOS in the neoadjuvant group. Results: Seventy-one patients were included in the primary analysis: n  = 23 in DT and n  = 48 in DTP. Baseline demographics were similar between groups, including the presence of metastatic disease at start of treatment ( p  = 0.427) and prior treatments with surgery ( p  = 0.864) and radiation ( p  = 0.678). mOS was significantly longer with DTP (17.0 months [confidence interval CI, 11.9-22.1]) compared with DT alone (9.0 months [CI, 4.5-13.5]), p  = 0.037. mPFS was also significantly improved with DTP as the initial treatment (11.0 months [CI, 7.0-15.0]) compared with DT alone (4.0 months [CI, 0.7-7.3]), p  = 0.049. Twenty-three patients were in the exploratory neoadjuvant group, where mOS was the longest (63.0 months [CI, 15.5-110.5]). No grade 5 adverse events (AEs) occurred in all three cohorts, and 32.4% had immune-related AEs, most frequently hepatitis and colitis. Conclusions: Our results show that in BRAFm-ATC, addition of pembrolizumab to dabrafenib/trametinib may significantly prolong survival. Surgical resection of the primary tumor after initial BRAF-targeted therapy in selected patients may provide further survival benefit. However, conclusions are limited by the retrospective nature of the study. Additional prospective data are needed to confirm this observation.

The treatment of advanced, radioiodine refractory, differentiated thyroid cancers (RR-DTCs) has undergone major advancements in the last decade, causing a paradigm shift in the management and prognosis of these patients. Better understanding of the molecular drivers of tumorigenesis and access to next generation sequencing of tumors have led to the development and Food and Drug Administration (FDA)-approval of numerous targeted therapies for RR-DTCs, including antiangiogenic multikinase inhibitors, and more recently, fusion-specific kinase inhibitors such as RET inhibitors and NTRK inhibitors. BRAF + MEK inhibitors have also been approved for BRAF -mutated solid tumors and are routinely used in RR-DTCs in many centers. However, none of the currently available treatments are curative, and most patients will ultimately show progression. Current research efforts are therefore focused on identifying resistance mechanisms to tyrosine kinase inhibitors and ways to overcome them. Various novel treatment strategies are under investigation, including immunotherapy, redifferentiation therapy, and second-generation kinase inhibitors. In this review, we will discuss currently available drugs for advanced RR-DTCs, potential mechanisms of drug resistance and future therapeutic avenues., Competing Interests: RD has received grant funding from Eisai, Exelixis, AstraZeneca, and Merck and has participated in advisory boards for Exelixis and Bayer. MC has received grant funding from Genentech and Merck and has received consulting fees from Exelixis and Bayer. MH has received grant funding from Eli Lilly & Co. and has participated in a steering committee for Eli Lilly & Co. NB has received grant funding from GSK, has received consulting fees from Eisai and Loxo and has participated in advisory board for Exelixis. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Hamidi, Hofmann, Iyer, Cabanillas, Hu, Busaidy and Dadu.)

Background: Despite the high frequency of cancer-related fatigue (CRF) and its debilitating effects on the quality of life of patients with advanced cancer, there are limited treatment options available. Treatments including physical activity (PA) or dexamethasone (Dex) improve CRF; however, they have lower adherence rates (PA) or long-term adverse effects (Dex). The aim of this study was to determine the feasibility of and preliminary results for the combination of PA and Dex in improving CRF., Methods: In this phase II randomized controlled trial, patients with advanced cancer and CRF scores of ≥4/10 on the Edmonton Symptom Assessment Scale were eligible. Patients were randomized to standardized PA for 4 weeks with either 4 mg of Dex (LoDex arm) or 8 mg of Dex (HiDex arm) twice a day for 7 days. Feasibility and change in the Functional Assessment of Cancer Illness Therapy-Fatigue subscale (FACIT-F) from baseline to day 8 and day 29 (primary outcome) were assessed. Secondary outcomes included changes in fatigue dimensions (FACIT-General, Patient-Reported Outcomes Measurement Information System [PROMIS]-Fatigue)., Results: A total of 60 of 67 (90%) patients were evaluable. All patients were adherent to study medication. We found that 84% and 65% of patients in the LoDex arm and 96% and 68% of patients in the HiDex arm were adherent to aerobic and resistance exercise, respectively. The FACIT-F effect size in the LoDex arm was 0.90 (P<.001) and 0.92 (P<.001) and the effect size in the HiDex arm was 0.86 and 1.03 (P<.001 for both) at days 8 and 29, respectively. We found significant improvements in the Functional Assessment of Cancer Therapy-Physical (P≤.013) and the PROMIS-Fatigue (P≤.003) at days 8 and 29 in both arms. Mixed-model analysis showed a significant improvement in the FACIT-F scores at day 8 (P<.001), day 15 (P<.001), and day 29 (P=.002). Changes in the FACIT-F scores were not significantly different between patients in the 2 arms (P=.86)., Conclusions: Our study found that the combination therapy of PA with Dex was feasible and resulted in the improvement of CRF. The improvement was seen for up to 3 weeks after the discontinuation of Dex. Further larger studies are justified., Clinicaltrials: gov identifier: NCT02491632.

Purpose: The receptor tyrosine kinase rearranged during transfection (RET) can be oncogenically activated by gene fusions or point mutations. Multikinase inhibitors such as cabozantinib, lenvatinib and vandetanib have demonstrated activity in RET-dependent malignancies, and selective RET inhibitors (Selpercatinib and Pralsetinib) are in clinical trials. However, the responsiveness of RET-dependent malignancies to immune checkpoint inhibitors (ICIs) is unknown. We compared the time to treatment discontinuation (TTD) for ICI versus non-ICI therapy in patients with malignancies harbouring activating RET mutations or fusions (RET+)., Methods: A retrospective review of all RET+ patients who were referred to the phase I clinical trials programme at the University of Texas MD Anderson Cancer Center was conducted. TTD was estimated using Kaplan-Meier analysis. Multivariate analysis using the Cox proportional hazard model was performed to identify independent risk factors of treatment discontinuation., Results: Of 70 patients who received systemic therapy for RET+ malignancies, 20 (28.6%) received ICI and 50 (71.4%) received non-ICI therapy. Non-ICI therapy was associated with decreased risk for treatment discontinuation compared with ICI in the overall population (HR=0.31; 95% CI 0.16-0.62; p=0.000834) and in patients with RET point mutations (HR=0.13; 95% CI 0.04-0.45; p=0.00134). In patients with RET fusions, non-ICI therapy was associated with a non-statistically significant decreased risk of treatment discontinuation (HR=0.59; 95% CI 0.25-1.4; p=0.24). ICI therapy and a diagnosis other than medullary thyroid cancer (MTC) were independent risk factors for treatment discontinuation., Conclusion: Our study supports the prioritisation of non-ICI over ICI therapy in patients with RET+ tumours., Competing Interests: Competing interests: VS reports grants and other from Loxo Oncology/ Eli Lilly, grants from Roche/ Genentech, grants and other from Novartis, grants from Bayer, grants from GlaxoSmithKline, grants from Nanocarrier, grants from Vegenics, grants from Celgene, grants from Northwest Biotherapeutics, grants from Berghealth, grants from Incyte, grants from Fujifilm, grants and other from Pharmamar, grants from D3, grants from Pfizer, grants from Multivir, grants from Amgen, grants from Abbvie, grants from Alfa-sigma, grants from Agensys, grants from Boston Biomedical, grants from Idera Pharma, grants from Inhibrx, grants from Exelixis, grants from Blueprint medicines, grants and other from Medimmune, grants from Altum, grants from Dragonfly therapeutics, grants from Takeda, grants from National Comprehensive Cancer Network, grants from NCI-CTEP and UT MD Anderson Cancer Center, grants from Turning point therapeutics, grants from Boston Pharmaceuticals, other from Helsinn, from R-Pharma US, other from INCYTE, other from QED pharma, other from ASCO, other from ESMO, other from Medscape, during the conduct of the study. FM-B reports other from Arduro BioTech, other from DebioPharm, grants and other from eFFECTOR Therapeutics, other from F. Hoffman-La Roche Ltd, grants and other from Genentech, other from IBM Watson, other from Jackson Laboratory, other from Kolon Life Science, other from OrigiMed, other from PACT Pharma, other from Parexel International, other from Pfizer, other from Samsung Bioepis, other from Seattle Genetics, other from Tyra Biosciences, other from Xencor, other from Zymeworks, other from Alkermes, other from Immunomedics, other from Inflection Biosciences, other from Mersana Therapeutics, grants and other from Puma Biotechnology, other from Silverback Therapeutics, other from Spectrum Pharmaceuticals, grants from Aileron Therapeutics, grants from AstraZeneca, grants from Bayer Healthcare Pharmaceutical, grants from Calithera Biosciences, grants from Curis, grants from CytomX Therapeutics, grants from Daiichi Sankyo Co Ltd, grants from Debiopharm International, grants from Novartis, grants from Taiho Pharmaceutical Co, other from Chugai Biopharmaceuticals, other from Mayo Clinic, other from Rutgers Cancer Institute of New Jersey, other from Beth Israel Deaconess Medical Center, outside the submitted work. MIH reports other from Blueprint Medicines, other from Loxo Oncology, other from Eli Lilly and Co, outside the submitted work. JL reports personal fees from Foundation Medicine, during the conduct of the study; personal fees from Foundation Medicine, other from Roche, outside the submitted work., (© Author (s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. Published by BMJ on behalf of the European Society for Medical Oncology.)

Background: The BRAF V600E 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 V600E -mutated ATC, a BRAF inhibitor (dabrafenib) in combination with an MEK inhibitor (trametinib) is FDA approved. BRAF inhibitors have also shown efficacy in BRAF V600E -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. Patients: Herein, we describe four patients with thyroid cancer treated with selective BRAF inhibitors, who developed a RAS mutation in addition to the BRAF V600E mutation at progression. Results: Patients 1 and 3 acquired a KRAS G12V mutation in the progressive tumor, patient 2 acquired a NRAS Q61K mutation in a progressive lymph node, and patient 4 acquired NRAS G13D mutation on liquid biopsy performed at the time of radiographic disease progression. Conclusion: Similar to the melanoma experience, the emergence of RAS mutations appears to act as a mechanism of resistance to BRAF inhibitors in thyroid cancers.

Background: The cyclin-dependent-kinase inhibitor/retinoblastoma pathway has been implicated in sporadic medullary thyroid carcinoma tumorigenesis. Somatic CDKN2C loss has been associated with decreased overall survival in medullary thyroid carcinoma patients. We evaluated CDKN2C loss in a prospective clinical environment using a novel Clinical Laboratory Improvement Amendments-certified assay to confirm its association with aggressive disease and to interrogate response to targeted therapy., Methods: Patients with advanced sporadic medullary thyroid carcinoma underwent tumor genotyping for the purpose of management of targeted therapy and prognostication., Results: Of patients with informative CDKN2C assay results, 30 (51.8%) were haploinsufficient/1N and 28 (48.3%) were 2N. Forty patients (69.0%) had a somatic RET mutation, and 36.9% had alterations of both genes. Thirty patients (51.7%) were treated with systemic therapy. Presence of genetic alterations in CDKN2C or RET did not predict treatment response. Patients with 1N CDKN2C loss had significantly shorter time-to-distant-metastasis than patients with normal copy number (P = .03)., Conclusion: This is the first evaluation in the clinical setting of CDKN2C haploinsufficiency in sporadic medullary thyroid carcinoma. Although a larger cohort and longer follow-up will be required, loss seems to be associated with more aggressive disease and may indicate patients that might receive benefit from treatment with a CDK inhibitor., (Copyright © 2019 Elsevier Inc. All rights reserved.)

We sought to develop an immunohistochemical (IHC) tool to support the diagnosis of parathyroid carcinoma (PC) and help differentiate it from atypical parathyroid neoplasms (atypical) and benign adenomas. Distinguishing PC from benign parathyroid neoplasms can be challenging. Many cases of PC are histopathologically borderline for definitive malignancy. Recently, individual IHC biomarkers have been evaluated to aid in discrimination between parathyroid neoplasms. PC, atypical parathyroid neoplasms, and parathyroid adenomas treated at our institution from 1997 to 2014 were studied retrospectively. IHC analysis was performed to evaluate parafibromin, retinoblastoma (RB), protein gene product 9.5 (PGP9.5), Ki67, galectin-3, and E-cadherin expression. Receiver operating characteristic (ROC) analysis and multivariable logistic regression model for combinations of biomarkers were evaluated to classify patients as PC or atypical/adenoma. A diagnostic nomogram using 5 biomarkers was created for PC. Sixty-three patients were evaluated. The percent staining of parafibromin (p < 0.0001), RB (p = 0.04), Ki67 (p = 0.02), PGP9.5 (p = 0.04), and Galectin-3 (p = 0.01) differed significantly in the three diagnostic groups. ROC analysis demonstrated that parafibromin had the best performance in discriminating PC from atypical/adenoma; area under the curve (AUC) was 81% (cutoff, 92.5%; sensitivity rate, 64%; specificity rate, 87%). We created a diagnostic nomogram using a combination of biomarkers; AUC was 84.9% (95% confidence interval, 73.4-96.4%). The optimism-adjusted AUC for this model was 80.5% (mean absolute error, 0.043). A diagnostic nomogram utilizing an immunoexpression, a combination of immunohistochemical biomarkers, can be used to help differentiate PC from other parathyroid neoplasms, thus potentially improving diagnostic classification.

Introduction: Subclassification of atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS) is encouraged in the Bethesda System. In our practice, we subclassified AUS/FLUS into 3 subcategories: atypical follicular cells of undetermined significance (ACUS) for cases with cytologic atypia; follicular lesion (FL) for cellular cases with follicular cells with-minimal or no atypia, arranged in a macro- and micro-follicular pattern with scant colloid; and indeterminate follicular lesion, favor benign (IFL-FB) for cases with few clusters of follicular cells without atypia associated with minimal or no colloid. The objective of our study was to evaluate the prevalence, clinical management, and risk of malignancy for each subcategory., Materials and Methods: We retrospectively identified ultrasound-guided fine-needle aspiration (US-FNA) of thyroid cases that were subcategorized as ACUS, IFL-FB, and FL at our-institution during 2014-2016. The results of US-FNA were correlated with clinical outcome in the subsequent 2 years including repeat US-FNA, thyroid surgery, and clinical/imaging follow-up., Results: Of 3207 thyroid US-FNA cases, 718 (22.4%) cases were included in the study. Of these 718 cases, 104 (14.5%) were subcategorized as ACUS, 166 (23.1%) as FL, and 448 (62.4%) as IFL-FB. The surgery rate was 39.4% (41 of 104) for ACUS, 13.6% (61 of 448) for IFL-FB, and 27.1% (45 of 166) for FL. The risk of malignancy (ROM) was 25% (26 of 104) for ACUS, and 2.9% (13 of 448) for IFL-FB, 6.0% (10 of 166) for FL. The surgery rate and ROM was significantly higher for ACUS in comparison to IFL-FB (P < 0.05) and FL (P < 0.05)., Conclusions: Subclassification of AUS/FLUS into 3 groups based on cytopathologic findings alone not only improved the triage of patients for subsequent clinical management but also effectively stratified the risk of malignancy., (Copyright © 2019 American Society of Cytopathology. Published by Elsevier Inc. All rights reserved.)

Background: When achieved, complete surgical resection improves outcomes in anaplastic thyroid carcinoma (ATC). However, most ATC patients present with advanced inoperable disease, often with impending airway obstruction, increased hemorrhage risk, and significant dysphagia. Novel treatment strategies are critically needed to improve disease control and decrease locoregional morbidity. The objective of this study was to determine the feasibility and effectiveness of a neoadjuvant regimen by using dabrafenib with trametinib followed by surgical resection in patients with initially unresectable BRAF V600E -mutated ATC. Methods: Case series of six consecutive patients with BRAF V600E -mutated ATC diagnosed between January 2017 and February 2018. Pathologic confirmation of ATC was obtained before treatment. BRAF V600E status was ascertained via immunohistochemistry or sequencing of circulating tumor DNA. All patients received dabrafenib and trametinib (DT) followed by surgical resection and adjuvant chemoradiation. Three patients also received pembrolizumab. Results: Complete surgical resection was achieved in all patients. Histopathologic analyses of resected specimens showed high pathologic response rates with significantly decreased ATC viability and residual papillary thyroid carcinoma components. Overall survival at six months and one year was 100% and 83%, respectively. Locoregional control rate was 100%. Two patients died of distant metastases without evidence of locoregional disease at 8 and 14 months from diagnosis. The remaining four patients had no evidence of disease at the last follow-up. Conclusions: We report the first series in the literature of BRAF V600E -mutated ATC patients with locoregionally advanced disease treated with DT followed by surgical resection. We demonstrated feasibility of complete resection, decreased need for tracheostomy, high pathologic response rates, and durable locoregional control with symptom amelioration.

Background: Four distinct tumor microenvironments have been proposed based on the expression of programmed death-ligand 1 and the presence of tumor-infiltrating lymphocytes: immunotype I (adaptive resistance, tumor-infiltrating lymphocytes+ and programmed death-ligand 1+); immunotype II (immunologic ignorance, tumor-infiltrating lymphocytes- and programmed death-ligand 1-); immunotype III (intrinsic induction; tumor-infiltrating lymphocytes- and programmed death-ligand 1+); and immunotype IV (tolerance, tumor-infiltrating lymphocytes+ and programmed death-ligand 1-). These subtypes may predict tumor response to immunotherapy. We hypothesized that parathyroid neoplasms may have tumor immunogenic expression that can later be used to guide treatment., Methods: We assessed retrospectively the immunohistochemical expression of programmed death-ligand 1 and the presence of tumor-infiltrating lymphocytes (CD3+ and CD8+) and macrophages (CD68+) in parathyroid carcinomas and in atypical parathyroid neoplasms treated at the M. D. Anderson Cancer Center from 1996 to 2016. Using intratumoral digital image analysis, the programmed death-ligand 1 H score was calculated with a standardized formula for predominant staining. The tumor-infiltrating lymphocytes per square millimeter of intratumoral areas were quantified., Results: Within 30 specimens (17 parathyroid carcinomas and 13 atypical parathyroid neoplasms), there was no difference in the median programmed death-ligand 1 H score between the two groups (P = .57). Four parathyroid carcinoma cases had programmed death-ligand 1 H scores ≥1 associated with CD3+ and CD8+ tumor cell density; 2 of them had distant metastases. Parathyroid carcinomas had a lesser median CD3+ density (P = .04) and a lesser median CD8+ density (P =.07) than did atypical parathyroid neoplasms. Median CD68+ density did not differ between groups (P = .22)., Conclusion: Parathyroid carcinomas tended to have immune-ignorant and immune-tolerant microenvironments within the neoplasm (immunotypes II and IV). Of the parathyroid carcinoma microenvironments, 17 had patterns of programmed death-ligand 1 and tumor-infiltrating lymphocytes expression (immunotype I), suggesting possible benefit from immunotherapy. In addition, both parathyroid carcinomas and parathyroid neoplasms expressed CD68+. Further exploration of these potential biomarkers as a target in cancer therapies is needed., (Published by Elsevier Inc.)

Importance: Lymph node metastases are common in papillary thyroid cancer (PTC), yet the impact of nodal metastases on survival remains unclear. Lymph node density (LND) is the ratio between the number of positive lymph nodes excised and the total number of excised lymph nodes. Lymph node density has been suggested as a prognostic factor in many types of cancer., Objective: To evaluate the prognostic role of LND in PTC., Design, Setting, and Participants: This cohort study reviewed medical records of patients with PTC who were treated at the University of Texas MD Anderson Cancer Center between January 1, 2000, and December 31, 2015. Survival and recurrence outcomes were calculated by using the Kaplan-Meier method. Significant variables on univariate analysis were subjected to a Cox proportional hazards regression multivariate model., Main Outcomes and Measures: Primary study outcome was disease-specific survival (DSS); other measurements included overall survival (OS)., Results: The study cohort included data for 2542 patients (1801 [71%] male; median age, 48 years [range, 18-97 years]) with a median follow-up of 55 months (range, 4-192 months). The 10-year disease-specific survival rate was 98% for patients with LND of 0.19 or less, compared with 90% for those with LND greater than 0.19 (effect size, 8%; 95% CI, 4%-15%). The 10-year overall survival was 87% for patients with LND of 0.19 or less, compared with 79% for patients with LND greater than 0.19 (effect size, 8%; 95% CI, 3%-15%). Multivariable analysis revealed that LND greater than 0.19 was independently associated with an adverse DSS (hazard ratio [HR], 4.11; 95% CI, 2.11-8.97) and OS (HR, 1.96; 95% CI, 1.24-4.11). Subgroup analysis of patients with 18 or more lymph nodes analyzed revealed that LND greater than 0.19 remained a significant marker for DSS (HR, 2.94; 95% CI, 1.36-9.81) and OS (HR, 2.26; 95% CI, 1.12-5.34). Incorporating LND into the current American Joint Committee on Cancer staging system successfully stratified risk groups compared with the traditional TNM staging system., Conclusions and Relevance: This single-institute study demonstrates the reproducibility of LND as a predictor of outcomes in PTC. Lymph node density can potentially assist in identifying patients with poorer survival who may benefit from more aggressive adjuvant therapy.

IMPORTANCE Despite performing total thyroidectomy (TT), postoperative radioactive iodine (RAI) imaging often demonstrates the presence of residual thyroid tissue within the operative bed. OBJECTIVE To measure the extent of TT using postoperative RAI imaging and assessing serum thyroglobulin (Tg) level for patients with differentiated thyroid carcinoma (DTC). DESIGN, SETTING, AND PARTICIPANTS We evaluated 245 patients undergoing TT for clinically staged cT1-3N0M0 DTC, who underwent diagnostic postoperative RAI imaging. INTERVENTIONS Total thyroidectomy. MAIN OUTCOMES AND MEASURES On the basis of quantitative measurements, RAI uptake (RAIU) in the thyroid bed of 0.2% of administered activity was selected as the cutpoint to determine the presence or absence of thyroid remnant. RESULTS By postoperative RAI imaging, TT in 106 patients (43%) resulted in RAIU of less than 0.2%. In the remaining 139 patients (57%), there was measurable iodine-avid thyroid tissue and/or tumor in the thyroid bed (n = 117 [84%]), the neck (n = 4 [3%]), or both (n = 18 [13%]). For the entire study population, mean 24-hour RAIU was 0.62%. Stimulated serum Tg levels were obtained in 232 of 245 patients (95%). Measurable stimulated Tg level (≥1 ng/mL) (to convert to micrograms per liter, multiply by 1) was found in 26 of 102 patients (25%) without thyroid remnant and in 87of 133 patients (65%) with thyroid remnant (P &lt; .001). CONCLUSIONS AND RELEVANCE A goal of postthyroidectomy RAIU of less than 0.2% helps maximize the likelihood of an unmeasurable postoperative Tg level, potentially simplifying follow-up evaluation and reducing the use of postoperative RAI in order to facilitate surveillance.

Sorafenib is U.S. Food and Drug Adminstration-approved for the treatment of renal cell carcinoma and hepatocellular carcinoma and has been combined with numerous other targeted therapies and chemotherapies in the treatment of many cancers. Unfortunately, as with other RAF inhibitors, patients treated with sorafenib have a 5% to 10% rate of developing cutaneous squamous cell carcinoma (cSCC)/keratoacanthomas. Paradoxical activation of extracellular signal-regulated kinase (ERK) in BRAF wild-type cells has been implicated in RAF inhibitor-induced cSCC. Here, we report that sorafenib suppresses UV-induced apoptosis specifically by inhibiting c-jun-NH(2)-kinase (JNK) activation through the off-target inhibition of leucine zipper and sterile alpha motif-containing kinase (ZAK). Our results implicate suppression of JNK signaling, independent of the ERK pathway, as an additional mechanism of adverse effects of sorafenib. This has broad implications for combination therapies using sorafenib with other modalities that induce apoptosis.

Objective: This article will review the multimodality imaging spectrum of medullary thyroid carcinoma (MTC) with an emphasis on anatomic and functional imaging. Recent advances in the molecular cytogenetics of this tumor and the impact on diagnosis, prognosis, and development of novel targeted therapy will be discussed., Conclusion: MTC is a neuroendocrine tumor with unique clinicopathologic and radiologic features compared with other thyroid malignancies. Imaging plays an important role in the optimal management of this malignancy.

Purpose: Ras/Raf/MAPK kinase/ERK and rearranged in transformation (RET) kinase pathways are important in thyroid cancer. We tested sorafenib, a B-Raf, RET, and vascular endothelial growth factor receptor kinase inhibitor, combined with tipifarnib, a farnesyltransferase inhibitor that inactivates Ras and other farnesylated proteins., Patients and Methods: We treated 35 patients with differentiated thyroid cancer (DTC) and medullary thyroid cancer (MTC) in a phase I trial. Sorafenib and tipifarnib were given for 21 d with 7 d rest in each 28-d cycle., Results: We enrolled 22 patients with metastatic DTC (16 papillary, five follicular, and one poorly differentiated) and 13 patients with MTC, of whom 15 with DTC and 10 with MTC reached first restaging. When tissue was available, eight of 15 DTC patients (53%) had B-Raf mutations; eight of 13 MTC (61.5%) patients had RET mutations. MTC partial response rate was 38% (five of 13) (duration = 9+, 12, 13, 16+, and 34+ months), stable disease of at least 6 months was 31% (four of 13). The DTC partial response rate was 4.5% (one of 22), and stable disease of at least 6 months was 36% (eight of 22). Median progression-free survival for all 35 patients was 18 months (95% confidence interval, 14.6 to not reached months). Median overall survival has not been reached, with a median follow-up of 24 months with 80% overall survival. Grade 1-2 toxicities were mainly rash, fatigue, and diarrhea. The most common grade 3-4 toxicities were rash, rise in amylase/lipase, and fatigue., Conclusions: Inhibiting the Ras/Raf/MAPK kinase/ERK and RET kinase pathways with sorafenib and tipifarnib is well tolerated and active against thyroid cancer.