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Context The Afirma® GSC aids in risk stratifying indeterminate thyroid nodule cytology (ITN). The 2018 GSC validation study (VS) reported a sensitivity (SN) of 91%, specificity (SP) of 68%, positive predictive value (PPV) of 47%, and negative predictive value (NPV) of 96%. Since then, 13 independent real-world (RW) postvalidation studies have been published. Objective This study's objective is to compare the RW GSC performance to the VS metrics. Methods Rules and assumptions applying to this analysis include: (1) At least 1 patient with molecular benign results must have surgery for that study to be included in SN, SP, and NPV analyses. (2) Molecular benign results without surgical histology are considered true negatives (TN) (as are molecular benign results with benign surgical histology). (3) Unoperated patients with suspicious results are either excluded from analysis (observed PPV [oPPV] and observed SP [oSP]) or assumed histology negatives (false positives; conservative PPV [cPPV] and conservative SP [cSP]) 4. Noninvasive follicular thyroid neoplasm with papillary-like nuclear features is considered malignant. Results In RW studies, the GSC demonstrates a SN, oSP, oPPV, and NPV of 97%, 88%, 65%, 99% respectively, and conservative RW performance showed cSP of 80% and cPPV of 49%, all significantly higher than the VS except for SN and cPPV. There was also a higher benign call rate (BCR) of 67% in RW studies compared to 54% in the VS (P < 0.05). Conclusion RW data for the Afirma GSC demonstrates significantly better oSP and oPPV performance than the VS, indicating an increased yield of cancers for resected GSC suspicious nodules. The higher BCR likely increases the overall rate of clinical observation in lieu of surgery.

Background: Cytopathological evaluation of thyroid fine-needle aspiration biopsy (FNAB) specimens can fail to raise preoperative suspicion of medullary thyroid carcinoma (MTC). The Afirma RNA-sequencing MTC classifier identifies MTC among FNA samples that are cytologically indeterminate, suspicious, or malignant (Bethesda categories III-VI). In this study we report the development and clinical performance of this MTC classifier. Methods: Algorithm training was performed with a set of 483 FNAB specimens (21 MTC and 462 non-MTC). A support vector machine classifier was developed using 108 differentially expressed genes, which includes the 5 genes in the prior Afirma microarray-based MTC cassette. Results: The final MTC classifier was blindly tested on 211 preoperative FNAB specimens with subsequent surgical pathology, including 21 MTC and 190 non-MTC specimens from benign and malignant thyroid nodules independent from those used in training. The classifier had 100% sensitivity (21/21 MTC FNAB specimens correctly called positive; 95% confidence interval [CI] = 83.9-100%) and 100% specificity (190/190 non-MTC FNAs correctly called negative; CI = 98.1-100%). All positive samples had pathological confirmation of MTC, while all negative samples were negative for MTC on surgical pathology. Conclusions: The RNA-sequencing MTC classifier accurately identified MTC from preoperative thyroid nodule FNAB specimens in an independent validation cohort. This identification may facilitate an MTC-specific preoperative evaluation and resulting treatment.

Autoimmune toxicity occurs in up to 60% of patients treated with immune checkpoint inhibitor (ICI) therapy for cancer and represents an increasing clinical challenge for expanding the use of these treatments. To date, human immunopathogenic studies of immune-related adverse events (IRAEs) have relied on sampling of circulating peripheral blood cells rather than affected tissues. Here, we directly obtained thyroid specimens from individuals with ICI-thyroiditis, one of the most common IRAEs, and compared immune infiltrates with those from individuals with spontaneous autoimmune Hashimoto’s thyroiditis (HT) or no thyroid disease. Single-cell RNA sequencing revealed a dominant, clonally expanded population of thyroid-infiltrating cytotoxic CXCR6 + CD8 + T cells (effector CD8 + T cells) present in ICI-thyroiditis but not HT or healthy controls. Furthermore, we identified a crucial role for interleukin-21 (IL-21), a cytokine secreted by intrathyroidal T follicular (T FH ) and T peripheral helper (T PH ) cells, as a driver of these thyrotoxic effector CD8 + T cells. In the presence of IL-21, human CD8 + T cells acquired the activated effector phenotype with up-regulation of the cytotoxic molecules interferon-γ (IFN-γ) and granzyme B, increased expression of the chemokine receptor CXCR6, and thyrotoxic capacity. We validated these findings in vivo using a mouse model of IRAEs and further demonstrated that genetic deletion of IL-21 signaling protected ICI-treated mice from thyroid immune infiltration. Together, these studies reveal mechanisms and candidate therapeutic targets for individuals who develop IRAEs.

Supplementary data, tables and figures

Thyroid disorders have emerged as one of the most common immune-related adverse events (irAE), yet optimum management and biomarkers to predict vulnerable individuals remain to be explored. High-dose glucocorticoid (HDG) therapy is routinely recommended for irAEs. However, systematic analysis of the impact of glucocorticoid therapy on the outcome of immune-checkpoint inhibitor (ICI)–induced thyroid disorders is lacking. We analyzed 151 patients with or without ICI-related thyroid disorders. We divided the patients with ICI-related thyroid disorders into two subgroups: those with and without HDG treatment. Our results showed no significant differences between HDG and no HDG groups in terms of the median duration of thyrotoxicosis: 28 (range, 7–85) and 42 (range, 14–273) days, the median time to conversion from thyrotoxicosis to hypothyroidism: 39 days (range, 14–169) and 42 days (range, 14–315) days, the median time to onset of hypothyroidism: 63 (range, 21–190) and 63 (range, 14–489) days, and the median maintenance dose of levothyroxine: 1.5 (range, 0.4–2.3) μg/kg/day, and 1.3 (range, 0.3–2.5) μg/kg/day. The median pretreatment TSH was 2.3 (range, 0.3–5.2) mIU/L and 1.7 (range, 0.5–4.5) mIU/L in patients with and without ICI-related thyroid disorders, respectively. Baseline TSH was significantly higher in patients who developed ICI-related thyroid disorders (P = 0.05). Subgroup analysis revealed significantly higher baseline TSH in male but not in female patients with ICI-induced thyroid dysfunction. Our results show that HDG treatment did not improve the outcome of ICI-related thyroid disorders.

Supplemental Figure 4. Effect of Selumetinib treatment on expression of antigen processing machinery (APM), cytokines, signal transducer of activation and transcription (STAT), and MHC class I molecule genes in thyroid cancer cell lines. Mean fold change in gene expression in papillary thyroid cancer cell lines (A) BCPAP, (B) K-1, or (C) TPC-1 following selumetinib (10μM) treatment relative to vehicle control is shown (statistical significant difference from 1 is indicated by an asterix, pTAP1, STAT1, STAT6, and LMP2 with selumetinib, though these differences did not meet statistical significance. Notably, increases in expression of APM genes were greatest in K-1, the cell line showing greatest phenotypic response to selumetinib treatment. In addition, the expression of IFNγ, IFNα1A, and IFNα2A was down-regulated in BCPAP and TPC-1 and of IFNα2A in K-1, supporting the additive effect of interferon and selumetinib therapy seen in these cell lines. Mean fold change increases in the gene expression of HLA-A, B, C and beta-2 microglobulin (β2m) for each cell line are shown for illustration purposes and paralleled phenotypic changes observed by flow cytometry for these cell lines.

Supplemental Table 2. Clinical and pathologic data for 33 subjects with papillary thyroid cancer.

Purpose: To evaluate MHC class I expression on papillary thyroid cancer (PTC) and analyze changes in MHC expression and associated immune activation with current and experimental treatments for thyroid cancer using in vitro PTC cell lines.Experimental Design: MHC class I expression and assessment of tumor-infiltrating leukocyte populations were evaluated by immunohistochemistry. PTC cell lines were analyzed for HLA-ABC expression by flow cytometry following tyrosine kinase inhibitor, IFNα or IFNγ, or radiation treatment. Functional changes in antigenicity were assessed by coculture of allogeneic donor peripheral blood leukocytes (PBL) with pretreated or untreated PTC cell lines and measurement of T-cell activation and cytokine production.Results: Both MHC class I and β2-microglobulin expression was reduced or absent in 76% of PTC specimens and was associated with reduced tumor-infiltrating immune cells, including effector (CD3+, CD8+, CD16+) and suppressor (FoxP3+) populations. Treatment of PTC cell lines with the MEK1/2 inhibitor selumetinib or IFN increased HLA-ABC expression. This phenotypic change was associated with increased T-cell activation (�25+ of CD3+) and IL2 production by PBL cocultured with treated PTC cell lines. Additive effects were seen with combination selumetinib and IFN treatment.Conclusions: MHC class I expression loss is frequent in human PTC specimens and represents a significant mechanism of immune escape. Increased antigenicity following selumetinib and IFN treatment warrants further study for immunotherapy of progressive PTC. Clin Cancer Res; 20(23); 6034–44. ©2014 AACR.

PDF file, 5811K, Supplemental Table 1. Antibody clones used for flow cytometry, immunocytochemistry, and western blotting studies. Supplemental Table 2. Phenotype analysis of TLBR cell lines by flow cytometry. Supplemental Figure 1. Cytogenetic analyses of TLBR cell lines. Supplemental Figure 2. Immunocytochemistry of TLBR cell lines. Supplemental Figure 3. Sensitivity of TLBR cell lines to 5-aza-2'-deoxycytidine (AZA). Supplemental Figure 4. Notch signaling in TLBR cell lines.

Supplemental Figure 3. Effect of specific BRAFV600E or radiation on PTC cell line MHC class I expression. (A) The effect of in vitro treatment of PTC cell lines with BRAFV600E-specific tyrosine kinase inhibitors vemurafenib or PLX 4720 on HLA-ABC expression as measured by flow cytometry. (B) The effect of 30 or 60Gy radiation treatment on HLA-ABC expression by PTC cell lines as measured by flow cytometry with data shown as mean +SEM. Representative flow cytometry histograms for HLA-ABC expression are shown to the right. (C) T cell activation measured as the CD25+ fraction of CD3+ T cells or (D) IL-2 production in PBL-PTC cell line co-cultures after PTC tumor cells were pre-treated with radiation. For C and D, data shown are mean (n=4) +SEM, with statistically significant difference from vehicle-treated PTC indicated by *** p

Supplemental Table 1. Primer sequences for qRT-PCR. Forward and reverse primer sequences are shown for each gene examined, in 5' to 3' direction.

Purpose: Anaplastic lymphoma kinase (ALK)–negative, T-cell, anaplastic, non–Hodgkin lymphoma (T-ALCL) in patients with textured saline and silicone breast implants is a recently recognized clinical entity for which the etiology and optimal treatment remain unknown.Experimental Design: Using three newly established model cell lines from patient biopsy specimens, designated T-cell breast lymphoma (TLBR)-1 to -3, we characterized the phenotype and function of these tumors to identify mechanisms of cell survival and potential therapeutic targets.Results: Cytogenetics revealed chromosomal atypia with partial or complete trisomy and absence of the NPM-ALK (2;5) translocation. Phenotypic characterization showed strong positivity for CD30, CD71, T-cell CD2/5/7, and antigen presentation (HLA-DR, CD80, CD86) markers, and interleukin (IL)-2 (CD25, CD122) and IL-6 receptors. Studies of these model cell lines showed strong activation of STAT3 signaling, likely related to autocrine production of IL-6 and decreased SHP-1. STAT3 inhibition, directly or by recovery of SHP-1, and cyclophosphamide–Adriamycin–vincristine–prednisone (CHOP) chemotherapy reagents, effectively kill cells of all three TLBR models in vitro and may be pursued as therapies for patients with breast implant–associated T-ALCLs.Conclusions: The TLBR cell lines closely resemble the primary breast implant–associated lymphomas from which they were derived and as such provide valuable preclinical models to study their unique biology. Clin Cancer Res; 18(17); 4549–59. ©2012 AACR.

Supplemental Figure 2. Peripheral blood leukocyte controls for tumor cell line co-cultures showing baseline and increased IL-2 production and T cell activation after CD3/CD28 stimulation. Healthy donor peripheral blood leukocytes (PBL) were cultured alone in the presence or absence of anti-CD3/CD28 stimulation beads, as experimental controls for tumor cell line-PBL co-cultures. Mean (n=4) IL-2 production and T cell activation (percent CD25+ of CD3+ T-cells) is shown.

Supplemental Figure 1. Immunohistochemical staining for tumor-infiltrating leukocyte populations in papillary thyroid cancer specimens and control tissues. Examples of positive and negative staining are shown (original magnification 400x), with black arrows demonstrating instances of positively stained target cells for each stain.

Background Little is known about the impact of over-the-counter ketone supplementation, used by patients to promote weight loss, on ketosis and serum ketone values. Recent literature suggests that acute ingestion of exogenous ketones leads to increased blood beta-hydroxybutyrate and decreased blood glucose1. Clinical Case A 61-year-old man with a history of type 2 diabetes mellitus, atrial fibrillation, hypertension, and hyperlipidemia presented as a transfer to the neurocritical care ICU from an outside hospital for subarachnoid hemorrhage secondary to intracranial saccular aneurysm. His admission hemoglobin A1c was 9.9% (ref 4.4-5.6), blood glucose was 205 mg/dL (ref 70-99), beta-hydroxybutyrate was markedly elevated at 26.2 mg/dL (ref 0-3), and urinalysis showed 80mg/dL ketones (ref 0). Serum toxicology screen was notable for detectable acetone 8mg/dL (ref: none detected). His lactate was 2 mmol/L (ref 0.5-1.9), Cr 0.99mg/dL (0.67-1.17), and HCO3 22 mmol/L (ref 22-27). Arterial blood gas showed pH of 7.37 (ref 7.38-7.47), and an anion gap metabolic acidosis (AGMA) of 15 mmol/L (ref Conclusion This is one of the first cases to report profound ketosis in a hospitalized patient likely secondary to exogenous ketone supplementation. Ketosis secondary to nutritional supplementation should be considered once more common etiologies are ruled out. Additional research is needed to determine the role of exogenous ketone use on metabolism and glycemic control. References: Falkenhain, Kaja et al. "Effects of Exogenous Ketone Supplementation on Blood Glucose: A Systematic Review and Meta-Analysis." Advances in nutrition (Bethesda, Md.), nmac036. 5 Apr. 2022 Presentation: No date and time listed

The Afirma GSC aids in the clinical decision making for patients with indeterminate thyroid nodule cytology (ITN). The 2018 GSC validation study was a prospective, multi-center study, conducted on a patient cohort with ITN. All patients underwent surgery without known genomic information and were assigned a histopathology diagnosis by an expert panel blinded to all genomic information. The results showed a sensitivity (SN) of 91%, specificity (SP) of 68%, positive predictive value (PPV) of 47%, and negative predictive value (NPV) of 96% at a cancer prevalence of 24%. Since then, 13 independent GSC post-validation studies have been published. This study's objective is to compare the real world (RW) GSC performance to the validation study metrics. Rules and assumptions applying to this analysis include: 1. At least one patient with molecular benign results must have surgery for that study to be included in SN, SP and NPV analysis and in these studies, molecular benign results without surgical histology are considered true negatives (TN) (as are the molecular benign results with benign surgical histology) 2. Patients with suspicious results that do not have surgery are either excluded from the analysis (generating an observed PPV (oPPV) and observed SP (oSP)) or assumed as histology negatives (false positives - generating a conservative PPV (cPPV) and conservative SP (cSP)) 3. NIFTP is considered malignant. Rule #1 excluded two studies from SN, SP and NPV analysis. Data from all studies were pooled using a random-effects model. All analyses were done using R package meta (version 4.18-2). In the RW, the GSC demonstrates a SN, oSP, oPPV and NPV of 97%, 88%, 65%, 99% respectively, and conservative RW performance of cSP at 80% and cPPV at 49%. A statistically significant improvement is observed for oSP, cSP, oPPV, and NPV (p Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

BackgroundThe SARS-CoV-2 virus has infected and killed millions of people worldwide. Breast cancer is the most prevalent cancer in women and few studies have investigated the outcomes of patients with a history of breast cancer and COVID-19. We report the clinical outcomes of patients with invasive breast cancer who tested positive for SARS-CoV-2, including hospitalization and death, and evaluate demographic and cancer-related factors associated with these outcomes.PatientsPatients with a history of invasive breast cancer and positive SARS-CoV-2 test from January 1 to December 31, 2020 at two large, academic Los Angeles health systems were included.MethodsRetrospective chart review of the electronic medical record was performed. Data for demographic and cancer-related factors were manually abstracted. Relationships between outcomes and clinical variables were evaluated using Fisher's exact test and linear regression analysis.ResultsAmong a total of 132 patients, 40 (30.3%) were hospitalized, while 11 (8.3%) required intensive care support, and 8 patients (6.1%) died. Older age and presence of one or more additional comorbidities were associated with hospitalization and death (P=.010, P=.003, P=.034, P < .001). Hispanic/Latinx ethnicity was associated with hospitalization (P=.047). Cancer treatment was not associated with hospitalization or death.ConclusionIn our diverse, multi-center, breast cancer cohort, Hispanic/Latinx ethnicity, older age and presence of other comorbidities were associated with worse outcomes from COVID-19. Breast cancer treatment, including surgery, radiation, systemic therapy, and endocrine therapy, was not associated with hospitalization in our cohort. Further studies are needed to explore the relationship between breast cancer and COVID-19 outcomes.

Background: Immune checkpoint inhibitors (ICI) have revolutionized the treatment of many advanced cancers but are recognized to cause treatment-limiting immune-related adverse events (IrAE). ICI-associated thyroiditis is the most common endocrine IrAE and usually resolves to permanent hypothyroidism. Optimal thyroid hormone replacement in these patients remains unclear. We report the levothyroxine (LT4) dose needed to achieve stable euthyroid state in patients with hypothyroidism from ICI-associated thyroiditis, with comparison to patients with Hashimoto's thyroiditis (HT) and athyreotic state. Methods: We conducted a retrospective study of adults with ICI-associated hypothyroidism treated with LT4 at an academic medical center. Patient data were collected from the electronic medical record. Cases had ICI exposure followed first by hyperthyroidism and then subsequent hypothyroidism. Controls were HT (positive thyroid autoantibodies, requiring LT4) and athyreotic (total thyroidectomy or radioiodine ablation, requiring LT4) patients. Patients with central hypothyroidism, thyroid cancer, pregnancy, gastrointestinal stromal tumors, and use of L-triiodothyronine were excluded. Our primary outcome compared LT4 dose needed to achieve euthyroid state (thyrotropin 0.3-4.7 mIU/L over >6 consecutive weeks) for ICI-associated hypothyroidism, HT, and athyreotic patients, considering the impact of age and possible interfering medications by linear regression modeling. Secondary analysis considered the impact of endocrine specialty care on the time to euthyroid state. Results: One hundred three patients with ICI-associated thyroiditis were identified. Sixty-six of the 103 patients achieved euthyroid state; 2 with intrinsic thyroid gland function recovery and 64 on LT4. The mean LT4 dose achieving stable euthyroid state was 1.45 ± standard deviation (SD) 0.47 mcg/[kg·day] in ICI-associated hypothyroidism, 1.25 ± SD 0.49 mcg/[kg·day] in HT, and 1.54 ± SD 0.38 mcg/[kg·day] in athyreotic patients, using actual body weight. The difference in dose between ICI-associated hypothyroidism and HT was statistically significant (p = 0.0093). Dosing differences were not explained by age or use of interfering medications. Conclusions: ICI-associated thyroiditis represents an increasingly recognized cause of hypothyroidism. Our study demonstrates that patients with ICI-associated hypothyroidism have different thyroid hormone dosing requirements than patients with HT. Based on our findings and prior reports, we recommend that in patients with ICI-associated thyroiditis LT4 therapy be started at an initial weight-based dose of 1.45 mcg/[kg·day] once serum free thyroxine levels fall below the reference range.

The 2015 American Thyroid Association (ATA) guidelines recommended that low-risk, differentiated thyroid cancers (DTC) between 1 and 4 cm may be treated with thyroid lobectomy alone. We sought to determine the effect of these guideline changes on the rate of completion thyroidectomy (CT) for low-risk DTC and factors influencing surgical decision-making. All patients from 2014 to 2018 who received an initial thyroid lobectomy at our institution with final pathology demonstrating DTC were included. Patients were divided into “pre” and “post” guideline cohorts (2014–2015 and 2016–2018, respectively). The rate of CT was compared between the two cohorts. Patient demographics and tumor characteristics were examined for association with CT. A total of 163 patients met study criteria: 63 patients in the 2014–2015 (“pre”) and 100 in the 2016–2018 (“post”) group. In the “pre” period, 41 (65.1%) patients received CT compared with 43 (43.0%) in the “post” period (p

Checkpoint inhibitor (ICI) immunotherapy leverages the body’s own immune system to attack cancer cells but leads to unwanted autoimmune side effects in up to 60% of patients. Such immune related adverse events (IrAE) may lead to treatment interruption, permanent organ dysfunction, hospitalization and premature death. Thyroiditis is one of the most common IrAE, but the cause of thyroid IrAE remains unknown. Here we present a novel mouse model in which checkpoint inhibitor therapy leads to multi-organ autoimmune infiltrates and show that activation and infiltration of Type 3 immune cells including IL17A+RORγt+CD4+(T helper 17 or Th17) and gamma delta 17 (γδT17) T cells promote thyroid IrAE development. IL-17A+T cells were similarly found in thyroid specimens from cancer patients treated with ICI who developed thyroid IrAE. Furthermore, antibody-based inhibition of IL-17A, a clinically available therapy, significantly reduced thyroid IrAE development in ICI-treated mice. Finally, combination of IL-17A neutralization with ICI treatment in multiple tumor models did not reduce ICI anti-tumor efficacy. These studies suggest that targeting Th17 and γδ17 function may reduce IrAE without impairing ICI anti-tumor efficacy and may be a generalizable strategy to address IL17-mediated IrAE.

Differentiated thyroid cancer (DTC) is the most common thyroid cancer and is frequently encountered in clinical practice. The incidence of DTC has increased significantly over the past three decades. Surgical resection, radioactive iodine (RAI), and levothyroxine suppression therapy remain the primary modalities for DTC treatment. Active surveillance for low-risk thyroid cancer may be an alternative to immediate surgery for appropriately selected patients. Patient characteristics influence treatment selection and intensity. In the subset of patients with progressive distant metastatic disease, not amenable to treatment with surgery or RAI, novel agents, including targeted therapies and immunotherapy, should be considered.

Background: Gene panels are routinely used to assess predisposition to hereditary cancers by simultaneously testing multiple susceptibility genes and/or variants. More recently, genetic panels have been implemented as part of solid tumor malignancy testing assessing somatic alterations. One example is targeted variant panels for thyroid nodules that are not conclusively malignant or benign upon fine-needle aspiration (FNA). We systematically reviewed published studies from 2009 to 2018 that contained genetic data from preoperative FNA specimens on cytologically indeterminate thyroid nodules (ITNs) that subsequently underwent surgical resection. Pooled prevalence estimates per gene and variant, along with their respective positive predictive values (PPVs) for malignancy, were calculated. Summary: Our systematic search identified 540 studies that were supplemented by 18 studies from bibliographies or personal files. Sixty-one studies met all inclusion criteria and included >4600 ITNs. Overall, 26% of nodules contained at least 1 variant or fusion. However, half of them did not include details on the specific gene, variant, and/or complete fusion pair reported for inclusion toward PPV calculations. The PPVs of genomic alterations reported at least 10 times were limited to BRAFV600E (98%, 95% confidence interval [CI 96–99%]), PAX8/PPARG (55% [CI 34–78%]), HRASQ61R (45% [CI 22–72%]), BRAFK601E (42% [CI 19–68%]), and NRASQ61R (38% [CI 23–55%]). Excluding BRAFV600E, the pooled PPV for all other specified variants and fusions was 47%. Multiple variants within the same nodule were identified in ∼1% of ITN and carried a cumulative PPV of 77%. Conclusions: The chance that a genomic alteration predicts malignancy depends on the individual variant or fusion detected. Only five alterations were reported at least 10 times; BRAFV600E had a PPV of 98%, while the remaining four had individual PPVs ranging from 38% to 55%. The small sample size of most variants and fusion pairs found among ITNs, however, limits confidence in their individual PPV point estimates. Better specific reporting of genomic alterations with cytological category, histological subtype, and cancer staging would facilitate better understanding of cancer prediction, and the independent contribution of the genomic profile to prognosis.

Graves' disease (GD) is caused by the stimulation of thyrotropin receptors by autoantibodies. We compared the diagnostic accuracy of the thyroid-stimulating immunoglobulin (TSI) bioassay and thyrotropin-binding inhibitory immunoglobulin (TBII) assay in differentiating GD from other causes of thyrotoxicosis.We retrospectively evaluated 493 patients with thyrotoxicosis who were tested with the third-generation TSI and TBII assays simultaneously. Patients were classified according to the clinical, histopathologic, and imaging criteria into the following groups: positive reference group (PRG) (patients with GD), negative reference group (NRG) (patients without GD), and inconclusive group (patients without a definitive diagnosis).TSI and TBII assays were concordant in 88% of the cases and showed a strong positive correlation (rTSI and TBII assays showed similar performance in differentiating GD from other causes of thyrotoxicosis in a real-world sample of patients with active thyrotoxicosis. In combination, both tests showed little benefit compared with the TBII assay alone. Thyrotropin receptor antibody assay results should be carefully interpreted in patients with mild GD or longstanding disease.

Checkpoint inhibitor (ICI) immunotherapy leverages the body’s own immune system to attack cancer cells but leads to unwanted autoimmune side effects in up to 60% of patients. Such immune related adverse events (IrAE) lead to treatment interruption, permanent organ dysfunction, hospitalization and premature death. Thyroiditis is one of the most common IrAE, but the cause of thyroid IrAE remains unknown. Here we present a novel mouse model in which checkpoint inhibitor therapy leads to multi-organ autoimmune infiltrates and show that activation and infiltration of Type 3 immune cells including IL17A+ RORγt+ CD4+ (T helper 17 or Th17) and gamma delta 17 (γδT17) T cells promote thyroid IrAE development. In parallel, Th17 and γδT17 cells were similarly expanded in cancer patients treated with ICI. Furthermore, antibody-based inhibition of IL-17A, a clinically available therapy, significantly reduced thyroid IrAE development in ICI-treated mice. Finally, combination of IL-17A neutralization with ICI treatment in a mouse tumor model did not reduce ICI anti-tumor efficacy and indeed showed a trend toward enhancement. These studies suggest that targeting Th17 and γδ17 function may reduce IrAE without impairing ICI anti-tumor efficacy and may be a generalizable strategy to address IL17-mediated IrAE.

Thyroid nodules and thyroid cancer are common conditions and may be identified during pregnancy. The comprehensive evaluation of thyroid nodules during pregnancy includes a medical history, physical examination, ultrasound assessment, and (when indicated) an ultrasound-guided fine-needle aspiration biopsy. Most thyroid cancers detected during pregnancy will not grow nor pose significant risk during gestation, and thyroid surgery in pregnant women poses higher risks than in nonpregnant women. Through a balanced and informed approach to the clinical care of this unique population, outcomes can be optimized for both the mother and the fetus.

Background: The Bethesda System for Reporting Thyroid Cytopathology (BSRTC) is used to interpret fine-needle aspiration (FNA) cytology of thyroid nodules in children and adults. Nodule management is guided by the implied malignancy risk of each cytological category, which has been derived from adult populations. Whether these implied risks are applicable to pediatric thyroid nodules remains uncertain. We compared malignancy rates between pediatric and adult thyroid nodules within each cytological category. Methods: We evaluated consecutive thyroid nodules ≥1 cm that underwent FNA at the Boston Children's Hospital and Brigham and Women's Hospital from 1998 to 2016. All cytology was interpreted by a single cytopathology group according to the BSRTC. Malignancy rates were compared between pediatric (

Context The impact of Hashimoto thyroiditis (HT) on the risk of thyroid cancer and its accurate detection remains unclear. The presence of a chronic lymphocytic infiltration imparts a logical mechanism potentially altering neoplastic transformation, while also influencing the accuracy of diagnostic evaluation. Methods We performed a prospective, cohort analysis of 9851 consecutive patients with 21,397 nodules ≥1 cm who underwent nodule evaluation between 1995 and 2017. The definition of HT included (i) elevated thyroid peroxidase antibody (TPOAb) level and/or (ii) findings of diffuse heterogeneity on ultrasound, and/or (iii) the finding of diffuse lymphocytic thyroiditis on histopathology. The impact of HT on the distribution of cytology and, ultimately, on malignancy risk was determined. Results A total of 2651 patients (27%) were diagnosed with HT, and 3895 HT nodules and 10,168 non-HT nodules were biopsied. The prevalence of indeterminate and malignant cytology was higher in the HT vs non-HT group (indeterminate: 26.3% vs 21.8%, respectively, P < 0.001; malignant: 10.0% vs 6.4%, respectively, P < 0.001). Ultimately, the risk of any nodule proving malignant was significantly elevated in the setting of HT (relative risk, 1.6; 95% CI, 1.44 to 1.79; P < 0.001), and was maintained when patients with solitary or multiple nodules were analyzed separately (HT vs non-HT: 24.5% vs 16.3% solitary; 22.1% vs 15.4% multinodular; P < 0.01). Conclusion HT increases the risk of thyroid malignancy in any patient presenting for nodule evaluation. Diffuse sonographic heterogeneity and/or TPOAb positivity should be used for risk assessment at time of evaluation.