Clonally expanded, thyrotoxic effector CD8+ T cells driven by IL-21 contribute to checkpoint inhibitor thyroiditis.

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 (TFH) and T peripheral helper (TPH) 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.

Bethesda III and IV Thyroid Nodules Managed Nonoperatively After Molecular Testing With Afirma GSC or Thyroseq v3.

CONTEXT: Molecular testing has improved risk stratification and increased nonoperative management for patients with indeterminate thyroid nodules, but data on the long-term outcomes of current molecular tests Afirma Gene Sequencing Classifier (GSC) and Thyroseq v3 are limited. OBJECTIVE: To determine the rate of delayed operation and the false negative rate of the Afirma GSC and Thyroseq v3 in Bethesda III and IV thyroid nodules. METHODS: Prospective follow-up of a single center, randomized, clinical trial comparing the performance of Afirma GSC and Thyroseq v3 in the diagnosis of indeterminate thyroid nodules at the University of California, Los Angeles (UCLA). Consecutive participants who underwent thyroid biopsy in the UCLA health system with Bethesda III and IV cytology from August 2017 to November 2019. The main outcome measure was false negative rate of molecular testing. RESULTS: Of 176 indeterminate nodules with negative or benign molecular test results, 14 (8%) nodules underwent immediate resection, with no malignancies found on surgical pathology. Nonoperative management with active surveillance was pursued for 162 (92%) nodules with benign or negative test results. The median surveillance was 34 months (range 12-60 months), and 44 patients were lost to follow-up. Of 15 nodules resected during surveillance, 1 malignancy was found (overall false negative rate of 0.6%). This was a 2.7 cm minimally invasive Hurthle cell carcinoma that initially tested negative with Thyroseq v3 and underwent delayed resection due to sonographic growth during surveillance. CONCLUSIONS: The majority of Bethesda III/IV thyroid nodules with negative or benign molecular test results are stable over 3 years of follow-up. These findings support the high sensitivity of current molecular tests and their role in ruling out malignancy in indeterminate thyroid nodules.

Spontaneous retroclival hematoma in pituitary apoplexy: case series.

OBJECT: Pituitary apoplexy is a rare and potentially life-threatening disorder that is most commonly characterized by a combination of sudden headache, visual disturbance, and hypothalamic/hormonal dysfunction. In many cases, there is hemorrhagic infarction of an underlying pituitary adenoma. The resulting clinical symptoms are due to compression of the remaining pituitary, cavernous sinuses, or cranial nerves. However, there are only 2 case reports in the literature describing spontaneous retroclival expansion of hemorrhage secondary to pituitary apoplexy. Ten cases of this entity with a review of the literature are presented here. METHODS: This is a single-institution retrospective review of 2598 patients with sellar and parasellar masses during the 10-year period between 1999 and 2009. The pituitary and brain MRI and MRI studies were reviewed by 2 neuroradiologists for evidence of apoplexy, with particular attention given to retroclival extension. RESULTS: Eighteen patients (13 men and 5 women; mean age 54 years) were identified with presenting symptoms of sudden onset of headache and ophthalmoplegia, and laboratory findings consistent with pituitary apoplexy. Ten of these patients (8 men and 2 women; mean age 55 years) had imaging findings consistent with retroclival hematoma. CONCLUSIONS: Retroclival hemorrhage was seen in the majority of cases of pituitary apoplexy (56%), suggesting that it is more common than previously thought.

Pituitary magnetic resonance imaging for sellar and parasellar masses: ten-year experience in 2598 patients.

CONTEXT: Sellar and parasellar masses present with overlapping clinical and radiological features ranging from asymptomatic incidental presentations and hormonal effects to compressive local mass effects. Pituitary masses are diagnosed with increased frequency with magnetic resonance imaging (MRI) advancements and availability, but indications and diagnostic outcomes of MRI screening for sellar lesions are not defined. Although pituitary adenomas are the most frequently encountered sellar mass lesions, other etiologies should be considered in the differential diagnosis of a sellar mass. SETTING: The study was conducted at a tertiary pituitary center. PATIENTS: This study was a retrospective review of 2598 subjects undergoing at least one pituitary MRI scan from 1999 to 2009. MAIN OUTCOME MEASURE: Prevalence and diagnosis of specific sellar and parasellar masses as screened by pituitary MRI. RESULTS: The most common indications for pituitary imaging, excluding known mass follow-up, were for evaluation of hyperprolactinemia or hypogonadism. A normal pituitary gland was reported in 47% of subjects undergoing pituitary MRI. The most common pituitary adenomas initially identified by MRI included prolactinoma (40%), nonfunctioning adenoma (37%), and GH adenoma (13%). Nonadenomatous sellar masses accounted for 18% of visible lesions, of which the most common were Rathke's cleft cyst (19%), craniopharyngioma (15%), and meningioma (15%). Metastases accounted for 5% of nonpituitary lesions and breast cancer was the most common primary source. CONCLUSIONS: Half of all pituitary MRI scans performed in a large patient population yielded no visible lesion. Nonadenomatous pituitary lesions should be considered in the diagnosis of sellar masses observed on MRI, and a high clinical suspicion is required to exclude the presence of a nonfunctioning pituitary adenoma.