Clinical course of atypical parathyroid neoplasm with soft tissue extension.

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.

Combination Therapy of Physical Activity and Dexamethasone for Cancer-Related Fatigue: A Phase II Randomized Double-Blind Controlled Trial.

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.

Extraocular Muscle Enlargement and Thyroid Eye Disease-like Orbital Inflammation Associated with Immune Checkpoint Inhibitor Therapy in Cancer Patients.

PURPOSE: To describe thyroid eye disease (TED)-like orbital inflammatory syndrome in 3 cancer patients treated with immune checkpoint inhibitors. METHODS: All consecutive patients treated by the senior author who were receiving immune checkpoint inhibitors and developed TED-like orbital inflammation were included. RESULTS: Three cancer patients treated with immune checkpoint inhibitors developed orbital inflammation. The first patient was treated with a combination of a cytotoxic T-lymphocyte antigen-4 inhibitor and a programmed cell death protein 1 inhibitor and developed TED-like orbital inflammation with normal thyroid function and antibody levels. The second patient had a previous diagnosis of Graves disease without TED, and developed TED soon after initiating treatment with a programmed cell death protein 1 inhibitor. The third patient developed acute hyperthyroidism with symptomatic TED following treatment with an investigational cytotoxic T-lymphocyte antigen-4 inhibitor agent. All 3 patients were managed with either systemic steroids or observation, with resolution of their symptoms and without the need to halt immune checkpoint inhibitor treatment for their cancer. DISCUSSION AND CONCLUSIONS: TED-like orbital inflammation may occur as a side effect of immune checkpoint inhibitor therapy with anti-cytotoxic T-lymphocyte antigen-4 or anti-PD-1 inhibitors. To the best of their knowledge, this is the first reported case of TED as a result of programmed cell death protein 1 inhibitor monotherapy. All 3 patients were treated with systemic steroids and responded quickly while continuing treatment with immune checkpoint inhibitors for their cancer. With increasing use of this class of drugs, clinicians should be familiar with the clinical manifestations and treatments for this adverse reaction.

Extrathyroidal Extension: Does Strap Muscle Invasion Alone Influence Recurrence and Survival in Patients with Differentiated Thyroid Cancer?

BACKGROUND: According to the 8th edition American Joint Committee on Cancer staging system, extrathyroidal extension (ETE) and primary tumor size remain the principle determinants of T stage. However, impact of gross ETE into strap muscles on survival remains controversial. PATIENTS AND METHODS: A retrospective review of 2084 patients with ≤ 4 cm nonmetastatic differentiated thyroid cancer who underwent surgery between 2000 and 2015 was conducted. Patients were divided into three groups according to degree of ETE: no ETE (group 1), ETE into perithyroidal soft tissue (group 2), and gross ETE into strap muscle (group 3). Survivals were analyzed using Kaplan-Meier method and compared using log-rank test. Factors predictive of survival were analyzed using Cox proportional hazard model. RESULTS: Ten-year disease-free survival (DFS) of patients in groups 1-3 was 90, 82, and 83%, respectively (p = 0.003). On multivariate analysis, age ≥ 55 years, male sex, and pathologic N1b category predicted significantly worse DFS, while ETE into perithyroidal soft tissue or gross strap muscle invasion did not predict worse DFS. Overall survival (p = 0.957) and disease-specific survival (p =0.910) were not significantly different between the three groups. There was a statistically significant difference in locoregional recurrence-free survival between groups 1 and 2 [HR 2.02, 95% CI 1.06-3.94]. CONCLUSION: Gross strap muscle invasion may not be an important survival prognostic factor for staging purposes. Although both gross strap muscle invasion and perithyroidal soft tissue extension may be predictive for locoregional recurrence, the distinction between them may not be as important for postoperative risk stratification.

Recontacting Patients with Updated Genetic Testing Recommendations for Medullary Thyroid Carcinoma and Pheochromocytoma or Paraganglioma.

BACKGROUND: No guidelines exist regarding physicians' duty to inform former patients about novel genetic tests that may be medically beneficial. Research on the feasibility and efficacy of disseminating information and patient opinions on this topic is limited. METHODS: Adult patients treated at our institution from 1950 to 2010 for medullary thyroid cancer, pheochromocytoma, or paraganglioma were included if their history suggested being at-risk for a hereditary syndrome but genetic risk assessment would be incomplete by current standards. A questionnaire assessing behaviors and attitudes was mailed 6 weeks after an information letter describing new genetic tests, benefits, and risks was mailed. RESULTS: Ninety-seven of 312 (31.1%) eligible patients with an identified mailing address returned the questionnaire. After receiving the letter, 29.2% patients discussed genetic testing with their doctor, 39.3% considered pursuing genetic testing, and 8.5% underwent testing. Nearly all respondents (97%) indicated that physicians should inform patients about new developments that may improve their or their family's health, and 71% thought patients shared this responsibility. Most patients understood the letter (84%) and were pleased it was sent (84%), although 11% found it upsetting. CONCLUSIONS: Patients believe it is important for physicians to inform them of potentially beneficial developments in genetic testing. However, physician-initiated letters to introduce new information appear inadequate alone in motivating patients to seek additional genetic counseling and testing. Further research is needed regarding optimal methods to notify former patients about new genetic tests and corresponding clinical and ethical implications.

Treatment and surveillance of advanced, metastatic iodine-resistant differentiated thyroid cancer.

PURPOSE OF REVIEW: This review will focus on the management and treatment of metastatic thyroid cancer that is radioactive iodine refractory and review the new drugs and their mechanism of actions as well as their adverse events. RECENT FINDINGS: Until recently, there were no efficacious therapeutic modalities for these patients. With advancement in knowledge and research of the molecular aberrations and oncogenic mutations in thyroid cancer as well as further understanding the role of angiogenesis in tumor growth molecular pathogenesis, novel targeted therapies are available for these patients. Some of these drugs have successfully prolonged progression free survival and are now Food and Drug Administration approved. Additional agents are approved for the treatment of other types of cancers and are currently under investigation for differentiated thyroid cancer treatment. SUMMARY: Differentiated thyroid cancer (papillary and follicular) is the most common endocrine malignancy. It is generally known to have an excellent prognosis and patients are usually cured with the conventional primary treatments including surgery, radioactive iodine, and thyroid stimulating hormone suppression. A minor proportion of patients do not fully recover mainly because they develop radioactive iodine-resistant disease. These patients have few treatment options, which we aimed to describe here.

Comprehensive Genomic Profiling of Clinically Advanced Medullary Thyroid Carcinoma.

OBJECTIVE: The aim of this study was to determine the genomic alterations of cancer-related genes in advanced medullary thyroid carcinoma during the course of clinical care. METHODS: Hybrid-capture-based comprehensive genomic profiling was performed on 34 consecutive medullary thyroid carcinoma cases to identify all four classes of genomic alterations, and outcome for an index patient was collected. RESULTS: RET was mutated in 88% (30/34) of cases, with RET M918T being responsible for 70% (21/30) of the RET alterations. The other RET alterations were RET E632_L633del, C634R, C620R, C618G/R/S, V804M, and RET amplification. Two of the four RET wild-type patients harbored mutations in KRAS or HRAS (1/34 each). The next most frequent genomic alterations were amplifications of CCND1, FGF3, and FGF19 and alterations in CDKN2A (3/34 each). One case with a RET M918T mutation developed acquired resistance to progressively dose-escalated vandetanib. When the mTOR inhibitor everolimus was added to continued vandetanib treatment, the patient achieved a second 25% reduction of tumor volume (RECIST 1.1) for 8 months. CONCLUSIONS: Comprehensive genomic profiling identified the full breadth of RET alterations in metastatic medullary thyroid carcinoma and possible cooperating oncogenic driver alterations. This approach may refine the use of targeted therapy for these patients.

Oncologic progress for the treatment of parathyroid carcinoma is needed.

BACKGROUND AND OBJECTIVES: Parathyroid carcinoma (PC) is rare but potentially lethal. No standardized staging system or treatment guidelines have been established. We aimed to determine whether management of PC and patient outcomes have changed at our institution over the past 35 years. METHODS: Retrospective review of patients with PC at our institution between 1980 and 2015. Patients were grouped by date of initial surgery: group 1, 1980-2001; group 2, 2002-2015. RESULTS: About 57 patients (26 in group 1; 31 in group 2) were included. Group 2 had more female patients (61%) than group 1 (31%; P = 0.033). Patients in group 2 were older at the time of initial operation (mean age 48 years in group 1 (SD:14.3) and 56 years (SD:14.6) in group 2; P = 0.034). The 5-year OS rates were 82% (95%CI 59.6%, 93%) for group 1 and 72% (95%CI 45.0%, 87.7%) for group 2. The 5-year DFS rates were 62% (95%CI 36.4%, 79.9%) for group 1 and 66% (95%CI 40.6%, 82.2%) for group 2. CONCLUSION: Management of PC and patient outcomes (OS and DFS) have not significantly changed over the past 35 years at our institution. This rare malignancy needs oncologic improvement. J. Surg. Oncol. 2016;114:708-713. © 2016 Wiley Periodicals, Inc.

The Prevalence and Impact of Hyperglycemia and Hyperlipidemia in Patients With Advanced Cancer Receiving Combination Treatment With the Mammalian Target of Rapamycin Inhibitor Temsirolimus and Insulin Growth Factor-Receptor Antibody Cixutumumab.

BACKGROUND: Cixutumumab (a humanized monoclonal antibody against insulin-like growth factor-1 receptor [IGF-1R]) and the mammalian target of rapamycin (mTOR) inhibitor temsirolimus were combined in a phase I study of patients with advanced cancer. We investigated the prevalence of metabolic toxicities, their management, and impact on outcome. METHODS: The temsirolimus dose was 25 mg or 37.5 mg i.v. weekly with escalating doses of cixutumumab (3, 5, or 6 mg/kg i.v. weekly). No patients with diabetes or hyperlipidemia at baseline were eligible until the expansion cohort. We assessed metabolic derangements in our patient cohort, their management, and their association with tumor shrinkage, time to progression (TTP) and overall survival (OS). RESULTS: Of the 57 patients analyzed, hyperglycemia was seen in 36 (63%) (grade 1-2: 33 [58%]; grade 3-4: 3 [5%]). The median blood sugar level (fasting and nonfasting) across cohorts was 149 mg/dL (upper limit of normal: 110 mg/dL). No patient developed diabetic ketoacidosis or nonketotic hyperosmolar coma or pancreatitis during treatment. Median maximum triglyceride, cholesterol, and low-density lipoprotein levels achieved were 247 mg/dL (range: 65-702 mg/dL), 243 mg/dL (range: 103-424 mg/dL), and 153 mg/dL (range 50-375 mg/dL), respectively. Higher glucose levels were associated with more RECIST tumor shrinkage (r = -.30 [95% confidence interval: -.52, -.03; p = .03]). There was no association between metabolic toxicities of the mTOR and IGF-1R combination and TTP or OS. CONCLUSION: The combination of temsirolimus and cixutumumab was safe and resulted in manageable metabolic toxicities. More tumor shrinkage was seen in patients who developed these adverse events. Although perhaps limited by the small number of patients, no significant association was discerned between hyperglycemia, hypertriglyceridemia, or hypercholesterolemia and TTP or OS. IMPLICATIONS FOR PRACTICE: Results of this study show that the combination of temsirolimus and cixutumumab is safe. The most common side effects, hyperglycemia and hyperlipidemia, are tolerable and manageable. This combination of therapies should not be withheld from diabetic patients and patients with high cholesterol levels. Collaboration between oncologist and endocrinologist allows for individualized treatment and better control of these adverse events, with few dose interruptions and reductions. Supportive care and close monitoring is needed. Those patients who develop hyperglycemia or hypercholesterolemia may benefit more from the drug.

Efficacy and tolerability of different starting doses of sorafenib in patients with differentiated thyroid cancer.

Sorafenib has proven efficacy in advanced differentiated thyroid cancer (DTC), but many patients must reduce the dose or discontinue treatment because of toxicity. The tolerability and efficacy of lower starting doses of sorafenib for DTC remain largely unstudied. Methods. We retrospectively examined overall survival, time to treatment failure, time to progression, discontinuation rates, and dose-reduction and interruption rates in patients with metastatic DTC treated with first-line sorafenib outside of a clinical trial. Two patient groups were compared; group 1 received the standard starting dose of 800 mg/day, and group 2 received any dose lower than 800 mg/day. Results. We included 75 adult patients, with 51 in group 1 and 24 in group 2. Mean age at diagnosis was 54 years, and 56% were male. The most common histologies included 43% papillary thyroid cancer of the conventional type, 15% papillary thyroid cancer of the follicular variant, and 15% Hürthle cell carcinoma. Time to treatment failure was 10 months (95% confidence interval [CI]: 5.6-14.3) in group 1 and 8 months (95% CI: 3.4-12.5) in group 2 (p = .56). Median overall survival was 56 months (95% CI: 30.6-81.3) in group 1 and 30 months (95% CI: 16.1-43.8) in group 2 (p = .08). Rates of discontinuation due to disease progression were 79% in group 1 and 91% in group 2, and 21% in group 1 and 9% in group 2 (p = .304) stopped treatment because of toxicity. Dose-reduction rates were 59% and 43% (p = .29), and interruption rates were 65% and 67% (p = .908) in group 1 and group 2, respectively. Conclusion. Efficacy and tolerability of sorafenib in treatment-naïve DTC patients does not appear to be negatively influenced by lower starting daily doses.

Adrenal ganglioneuroma: features and outcomes of 27 cases at a referral cancer centre.

BACKGROUND: Adrenal ganglioneuroma (AGN) is a rare neurogenic tumour that can mimic other adrenal neoplasms. Limited information, mostly derived from small cases series, is available for AGN. METHODS: A retrospective review for AGNs seen at a tertiary referral centre describing important features to distinguish AGN from other adrenal neoplasms. RESULTS: Of 53 ganglioneuromas, 27 were AGNs. Median age was 31 years (range, 1·7-64 years) and median tumour size was 8 cm (range, 1·5-20 cm). Seventeen AGNs (63%) were detected incidentally and nine patients (33%) presented with abdominal/back discomfort. Catecholamine levels, available for 21 patients, were normal. On computed tomography (CT), most AGNs were homogenous and well circumscribed with a median density of 32·5 Hounsfield units (HU) on unenhanced CT; 40 HU on postcontrast venous phase; and 66·5 HU on delayed postcontrast phase. On magnetic resonance imaging (MRI), AGNs had hypo-intense signal on T1-weighted images with heterogeneous hyperintense signal on T2-weighted images. In four patients, there was no tumour growth during median follow-up of 48 months (range, 21-60 months). One patient had malignant peripheral nerve sheath tumour arising from AGN. Thirteen patients with resected AGN had no recurrence during a median follow-up of 50 months (range, 2-135 months). CONCLUSIONS: We herein describe the largest AGN series reported to date. Isolated AGNs do not produce catecholamines and have CT imaging characteristics that can help in distinguishing them from other adrenal and para-adrenal neoplasms. The natural history of AGNs is usually benign, although local extra-adrenal extension or malignant transformation can rarely occur.

Checkpoint Inhibition in Addition to Dabrafenib/Trametinib for BRAFV600E-Mutated Anaplastic Thyroid Carcinoma.

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.

Pediatric Medullary Thyroid Carcinoma: Clinical Presentations and Long-Term Outcomes in 144 Patients Over 6 Decades.

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.

Anti-Programmed Death Ligand 1 Plus Targeted Therapy in Anaplastic Thyroid Carcinoma: A Nonrandomized Clinical Trial.

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.

Decreasing utilization for postoperative radiation therapy in locoregionally advanced medullary thyroid cancer.

BACKGROUND: Use of postoperative radiation therapy (PORT) in locoregionally advanced medullary thyroid cancer (MTC) remains controversial. The objective was to evaluate the effect of PORT on locoregional control (LRC) and overall survival (OS). METHODS: Retrospective cohort study of 346 MTC patients separated into PORT and no-PORT cohorts. Relative indications for PORT, as well as changes in patterns of treatment, were recorded. RESULTS: 49/346 (14%) received PORT. PORT was associated with worse OS; adjusted HR = 2.0 (95%CI 1.3-3.3). PORT was not associated with improved LRC, even when adjusting for advanced stage (Stage III p = 0.892; Stage IV p = 0.101). PORT and targeted therapy were not associated with improved OS compared to targeted therapy alone; adjusted HR = 1.2 (95%CI 0.3-4.1). CONCLUSIONS: Use of PORT in MTC has decreased and its indications have become more selective, coinciding with the advent of effective targeted therapies. Overall, PORT was not associated with improved LRC or OS.

Initial Management of BRAF V600E-Variant Anaplastic Thyroid Cancer: The FAST Multidisciplinary Group Consensus Statement.

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.

Current update on medullary thyroid carcinoma.

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.

Review article: new treatments for advanced differentiated thyroid cancers and potential mechanisms of drug resistance.

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.

Redifferentiation Therapy-Returning to Our Roots in a Post-Kinase Inhibitor World.

Radioactive iodine (RAI) treatment is an effective treatment for differentiated thyroid cancer (DTC); however, many patients are refractory. Using targeted drugs to reinduce RAI sensitivity ("redifferentiation therapy") has long been sought after as the holy grail in endocrine oncology. See related article by Weber et al., p. 4194.

Molecular mechanisms of resistance to kinase inhibitors and redifferentiation in thyroid cancers.

Protein kinases play critical roles in cell survival, proliferation, and motility. Their dysregulation is therefore a common feature in the pathogenesis of a number of solid tumors, including thyroid cancers. Inhibiting activated protein kinases has revolutionized thyroid cancer therapy, offering a promising strategy in treating tumors refractory to radioactive iodine treatment or cytotoxic chemotherapies. However, despite satisfactory early responses, these drugs are not curative and most patients inevitably progress due to drug resistance. This review summarizes up-to-date knowledge on various mechanisms that thyroid cancer cells develop to bypass protein kinase inhibition and outlines strategies that are being explored to overcome drug resistance. Understanding how cancer cells respond to drugs and identifying novel molecular targets for therapy still represents a major challenge for the treatment of these patients.