THYROID DYSFUNCTION, RECOVERY, AND PROGNOSIS IN MELANOMA PATIENTS TREATED WITH IMMUNE CHECKPOINT INHIBITORS: A RETROSPECTIVE REVIEW

2020 ◽  
Vol 26 (1) ◽  
pp. 36-42 ◽  
Author(s):  
Mazen Al Mushref ◽  
Paul A. Guido ◽  
Frances A. Collichio ◽  
Dominic T. Moore ◽  
David R. Clemmons
Keyword(s):  
Thyroid Function ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Thyroid Dysfunction ◽  
Checkpoint Inhibitors ◽  
Thyroid Stimulating Hormone ◽  
Thyroid Function Tests ◽  
Melanoma Patients ◽  
Recovery Group ◽  
Stimulating Hormone

Objective: To describe thyroid dysfunction, factors associated with thyroid recovery, and survival in melanoma patients treated with immune checkpoint inhibitors that developed thyroid immune-related adverse events (irAEs). Methods: This was a retrospective study in a tertiary center from 2010–2017. We reviewed the charts of patients with melanoma that developed thyroid dysfunction after checkpoint inhibitor therapy. Cases with thyroid irAEs were grouped by recovery of thyroid function at 1 year. We collected a timeline of thyroid function tests, medication exposure, and survival and compared variables between the groups. We studied survival in comparison to a matched group without thyroid dysfunction. Results: A total of 186 melanoma patients received checkpoint inhibitors, and 17 (9%) had thyroid irAEs. Median time to abnormal thyroid-stimulating hormone was 38 days and followed a pattern of thyroiditis. Seven of 17 had thyroid recovery. In the no-recovery group, free thyroxine (T4) was often above 2 ng/dL (5/10 in no recovery, 0/7 in recovery; P = .04). In the recovery group, irAE grade was significantly lower, with 7/7 grade 1 ( P = .004). Exposure to glucocorticoids was associated with recovery (3/10 in no recovery, 6/7 in recovery; P = .049). There was no difference in overall survival between the thyroid dysfunction group and controls, or between those that received glucocorticoids or not. Conclusion: Certain aspects of thyroid irAEs may correlate with thyroid recovery, including grade 1 thyroid irAEs, exposure to glucocorticoids, and peak free T4 levels less than 2 ng/dL. Thyroid irAEs did not appear to be associated with change in survival nor did exposure to glucocorticoids. Abbreviations: ASCO = American Society of Clinical Oncology; CTLA-4 = cytotoxic T-lymphocyte–associated protein 4; irAE = immune-related adverse event; PD-1 = programmed cell death protein 1; T4 = thyroxine; TSH = thyroid-stimulating hormone

Biotin-induced thyroid stimulating hormone aberrations in the setting of immunotherapy

2021 ◽  
pp. 107815522110179
Author(s):  
Forrest N Ridgway ◽  
Kathryn A Gold ◽  
Linda C Barnachea
Keyword(s):  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Immune Checkpoint Blockade ◽  
Thyroid Stimulating Hormone ◽  
Thyroid Function Tests ◽  
Over The Counter ◽  
Routine Monitoring ◽  
Tsh Levels ◽  
Stimulating Hormone

Introduction Immune checkpoint inhibitors are associated with immune-mediated thyroid disease and other endocrinopathies. Biotin is an over-the-counter supplement known to interfere with lab assays, including thyroid function tests. Biotin-induced complications with lab monitoring during immunotherapy have not been previously reported. Case report We present a case of a 68-year old woman with hypothyroidism after initiating immune checkpoint blockade therapy and abnormal laboratory monitoring values while concurrently taking biotin supplements. Management & outcome: The patient was initiated on levothyroxine with subsequent dose increases over a period of weeks with resolution of symptoms and normalization of free thyroxine levels. Thyroid stimulating hormone (TSH) levels appeared to remain elevated until biotin supplements were held and levels normalized. Discussion The purpose of this report is to provide the first known incidence of biotin complicating the routine monitoring of immune checkpoint inhibitors with elevated TSH levels and to alert providers to elicit accurate medication histories regarding over-the-counter supplements.

scholarly journals SAT-463 Thyrotoxicosis from Nivolumab in a Patient with Preexisting Graves’ Disease

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Preethi Polavarapu ◽  
Padmaja Akkireddy
Keyword(s):  
Adverse Events ◽  
Thyroid Function ◽  
Autoimmune Thyroiditis ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Thyroid Dysfunction ◽  
Checkpoint Inhibitors ◽  
Graves Disease ◽  
Thyroid Function Tests ◽  
Free T4

Abstract Introduction Thyroid dysfunction is one of the common immune-related adverse events associated with immune checkpoint inhibitors like Nivolumab. Thyroiditis or primary hypothyroidism is the most commonly reported presentation. Graves’ disease is less frequently reported. We report a case of preexisting Graves’ disease patient, on antithyroid meds who developed thyrotoxicosis followed by hypothyroidism after receiving Nivolumab therapy. Case 66 y/o female patient with newly diagnosed metastatic melanoma presented to us for evaluation of abnormal thyroid test after her second cycle of Nivolumab. She has a long-standing history of Graves’ disease and has been on methimazole since her diagnosis. Her baseline thyroid labs before the start of Nivolumab were within normal limits (on methimazole 2.5 mg daily). She presented with weight loss, palpitations, and tremors four weeks after the start of Nivolumab. On exam, she was tachycardic with tremors noted to outstretched hands and had diffusely enlarged thyroid. Repeat lab work done before her second cycle revealed suppressed TSH 0.02 (0.4-4.5 uIU/ml) with elevated free T4 and T3. Her TSI titers were elevated. Methimazole dose was increased to 10 mg daily, and follow up labs done in a month revealed TSH of 89 uIU/ml, Free T4 0.16 (0.76-1.8 ng/dl). Methimazole was completely stopped at this time. She continued to have elevated TSH despite being off of methimazole for more than a month, concerning for the development of hypothyroidism. She was started on levothyroxine, after which labs returned to normal. The patient continued on immunotherapy during this period. Discussion Immune checkpoint inhibitors have been increasingly used for cancer therapy. Endocrinopathies are the most common immune-related adverse events associated with the use of these agents, with thyroid dysfunction being more common. Our patient had well-controlled Graves’ disease and was on a stable dose of methimazole for years. She developed autoimmune thyroiditis four weeks after receiving immunotherapy and subsequently developed hypothyroidism. The literature search did not reveal cases of autoimmune thyroiditis in a patient with preexisting Graves’ disease. One study reported that the timeline for developing the thyrotoxic phase is five weeks, which is followed by the rapid development of either euthyroid or hypothyroid phase. Management during the thyrotoxic phase is usually beta-blockers. Current guidelines recommend checking thyroid function test before initiation of therapy and every two weeks after the diagnosis of thyrotoxicosis until they become euthyroid or hypothyroid. Our case illustrates that patients with preexisting Graves’ disease can develop thyroiditis after receiving immune checkpoint inhibitors, and hence, frequent monitoring with thyroid function tests is needed.

scholarly journals Management of thyroid disease in pregnancy – Room for improvement in the first trimester

2016 ◽  
Vol 9 (3) ◽  
pp. 126-129 ◽  
Author(s):  
Helen Robinson ◽  
Philip Robinson ◽  
Michael D’Emden ◽  
Kassam Mahomed
Keyword(s):  
General Practitioner ◽  
Thyroid Function ◽  
Thyroid Disease ◽  
Thyroid Dysfunction ◽  
First Trimester ◽  
Antenatal Clinic ◽  
Thyroid Stimulating Hormone ◽  
Thyroid Function Tests ◽  
In Pregnancy ◽  
Stimulating Hormone

Background First-trimester care of maternal thyroid dysfunction has previously been shown to be poor. This study evaluates early management of thyroid dysfunction in pregnancy in Australia. Methods Patients reviewed by the Obstetric Medicine team for thyroid dysfunction from 1 January 2012 to 30 June 2013 were included. Data were collected on gestation at referral from the patient’s general practitioner to the antenatal clinic, information provided in the referral letter, thyroid function tests and thyroid medications. Results Eighty-five women were included in the study. At the time of general practitioner referral to antenatal services, 19% of women with preexisting thyroid disease had no thyroid function tested. Forty-three percent had an abnormal thyroid-stimulating hormone defined as being outside the laboratory-specific pregnancy reference range if available, or outside the level of 0.1–2.5 mIu/L in the first trimester, 0.2–3.0 mIu/L in the second trimester and 0.3–3.0 mIu/L in the third trimester. Only 21% of women increased their thyroxine dose prior to their first antenatal clinic review. Conclusion This study highlights that a significant proportion of women with known thyroid disease either have untested thyroid function in the first trimester or a thyroid-stimulating hormone outside of levels recommended by guidelines.

Patterns of thyroid dysfunctions during treatment with immune checkpoint inhibitors (ICI) in 59 solid cancer patients.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e18567-e18567
Author(s):  
Yong Jiang ◽  
Li Yang ◽  
Yin Han ◽  
Yongshen Zhang ◽  
Feng-Ming Kong
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Thyroid Function ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Thyroid Dysfunction ◽  
Checkpoint Inhibitors ◽  
Small Cell ◽  
Small Cell Lung ◽  
Thyroid Dysfunctions

e18567 Background: Immune checkpoint inhibitors (ICI) have now become the mainstay treatment in patients with many kinds of cancers. Thyroid dysfunction as the most common endocrine toxicity is poorly understood. This study aimed to report hypothyroidism and exam its changing dynamtic in our first series of patients treated with ICI. Methods: This is a retrospective study. Patients received nivolumab or pembrolizumab between July 2018 and December 2019 were considered. Patient must have euthyroidism within the 3 months before immunotherapy and those had previous use of levothyroxine were excluded. They were monitored by thyroid function tests every cycle until stopping ICI. Patients must have received at least 3 cycles of antibody treatment. Results: Among 89 patients treated, 59 met the inclusion criteria. There were 33 males, 26 females, including 26 (44.1%) nivolumab, and 33 (55.9%) pembrolizumab. Median age was 62 years [range: 27-88]). Cancer diagnoses observed were non small cell lung cancer 17(28.8%), small cell lung cancer 4 (6.8%),liver cancer 9 (15.3%), head and neck cancer 5 (8.5%), esophageal cancer4 (6.8%) colon cancer 3 (5.1%), nasopharygeal carcinoma 3 (5.1%) melanoma 3 (5.1%) and other cancers 11(18.6%). There were 9 patients (15.3%) developed a thyroid dysfunction, including 5 females. Four patients had thyrotoxicosis (median onset: 8 weeks) followed by hypothyroidism. There were three types of thyroid dysfunctions: the first type patients 3 (33.3%) had a brief time period of TSH flair (peak 17.4-57.8) after the first cycle of ICI, followed by TSH dramatic drop companied with rising fT4, which usually returned to normal level during 3-4 cycles of . The other 4 patients (44.4%) with thyroid dysfunction presented with remarkably elevated TSH (15.43-125.2) after 3.5-10 months’ treatment, followed by hypothyroidism development with a need of levothyroxine. The remaining 1 patient had a third type of thyroid dysfunction with elevated TSH, elavated more while the treatment continue, the patient should be given levothyroxine as soon as possible. Additionally, 1 patient developed hypopituitarism presented with both low level of TSH and fT4 after 10 month treatment. There was no significant difference in patient characteristics between patients with hypothyroidism and those without. Conclusions: There are heterogeneity in thyroid function and hypothyroidism after ICI. Before more experience is gained, frequent monitoring of thyroid function during ICI is warranted for prompt management of the hypothyroidism.

scholarly journals History of Radiation to the Neck Increases the Risk of Denovo Thyroid Dysfunction after Receiving Immune Checkpoint Inhibitors

Endocrines ◽  
2020 ◽  
Vol 1 (2) ◽  
pp. 82-89
Author(s):  
Koosha Paydary ◽  
Muhammad Zain Farooq ◽  
Ankit Mangla
Keyword(s):  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Thyroid Dysfunction ◽  
Checkpoint Inhibitors ◽  
Univariate Analysis ◽  
Previous History ◽  
Thyroid Stimulating Hormone ◽  
Thyroid Disorder ◽  
Free T4 ◽  
History Of

Thyroid dysfunction is a common endocrine side effect of immune checkpoint inhibitors (ICI). We designed a retrospective study, including patients who received ICI for any cancer at our institution. Thyroid-stimulating hormone (TSH), free T4 levels, and time to development of thyroid dysfunction were measured, and medication used to treat thyroid dysfunction were identified. We reviewed the charts of 104 patients with complete records obtained from our tumor registry. A total of 91 patients were included in the analysis, after excluding 13 patients with a pre-existing thyroid disorder. Twenty-eight (30.77%) patients developed thyroid dysfunction after starting ICI. Race (p-0.048), age (p-0.014), history of radiation therapy (RT) to the neck (p-0.004), history of RT to the chest (p-0.012), and history of venous thrombosis (p-0.004) were significantly associated with thyroid dysfunction on univariate analysis. For multivariate analysis, the history of RT to the neck, adjusted for age, race, and sex, was significantly associated with thyroid dysfunction (adjusted OR-9.64, 95%CI: 1.88, 49.36, p-0.007). In patients receiving ICI for any type of cancer, the previous history of RT to the neck was significantly associated with the development of thyroid dysfunction after starting ICI.

scholarly journals Myxoedema coma caused by immunotherapy-related thyroiditis and enteritis

2021 ◽  
Vol 2021 ◽  
Author(s):  
Darran Mc Donald ◽  
Eirena Goulden ◽  
Garret Cullen ◽  
John Crown ◽  
Rachel K Crowley
Keyword(s):  
Malignant Melanoma ◽  
Thyroid Function ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Adverse Reactions ◽  
Checkpoint Inhibitors ◽  
Thyroid Function Tests ◽  
Absorption Test ◽  
Function Tests ◽  
Painless Thyroiditis

Summary Thyroid dysfunction is among the most common immune-related adverse reactions associated with immune checkpoint inhibitors. It most commonly manifests as painless thyroiditis followed by permanent hypothyroidism. This usually causes mild toxicity that does not interfere with oncological treatment. In rare instances, however, a life-threatening form of decompensated hypothyroidism called myxoedema coma may develop. We present a case of myxoedema coma in a woman in her sixties who was treated with a combination of CTLA-4 and PD-1 immune checkpoint inhibitors; for stage four malignant melanoma. She became hypothyroid and required thyroxine replacement after an episode of painless thyroiditis. Six months after the initial diagnosis of malignant melanoma, she presented to the emergency department with abdominal pain, profuse diarrhoea, lethargy and confusion. She was drowsy, hypotensive with a BP of 60/40 mmHg, hyponatraemic and hypoglycaemic. Thyroid function tests (TFTs) indicated profound hypothyroidism with a TSH of 19 mIU/L, and undetectable fT3 and fT4, despite the patient being compliant with thyroxine. She was diagnosed with a myxoedema coma caused by immune-related enteritis and subsequent thyroxine malabsorption. The patient was treated with i.v. triiodothyronine (T3) and methylprednisolone in the ICU. While her clinical status improved with T3 replacement, her enteritis was refractory to steroid therapy. A thyroxine absorption test confirmed persistent malabsorption. Attempts to revert to oral thyroxine were unsuccessful. Unfortunately, the patient’s malignant melanoma progressed significantly and she passed away four months later. This is the first reported case of myxoedema coma that resulted from two distinct immune-related adverse reactions, namely painless thyroiditis and enterocolitis. Learning points Myxoedema coma, a severe form of decompensated hypothyroidism is a rare immunotherapy-related endocrinopathy. Myxedema coma should be treated with either i.v. triiodothyronine (T3) or i.v. thyroxine (T4). Intravenous glucocorticoids should be co-administered with thyroid hormone replacement to avoid precipitating an adrenal crisis. Thyroid function tests (TFTs) should be monitored closely in individuals with hypothyroidism and diarrhoea due to the risk of thyroxine malabsorption. A thyroxine absorption test can be used to confirm thyroxine malabsorption in individuals with persistent hypothyroidism.

scholarly journals Evaluation of the modified immune prognostic index to prognosticate outcomes in metastatic uveal melanoma patients treated with immune checkpoint inhibitors

2021 ◽  
Vol 10 (8) ◽  
pp. 2618-2626
Author(s):  
Michael S. Sander ◽  
Igor Stukalin ◽  
Isabelle A. Vallerand ◽  
Siddhartha Goutam ◽  
Benjamin W. Ewanchuk ◽  
...  
Keyword(s):  
Uveal Melanoma ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Prognostic Index ◽  
Melanoma Patients

scholarly journals The Efficacy of Anti-PD-L1 Treatment in Melanoma Is Associated with the Expression of the ECM Molecule EMILIN2

2021 ◽  
Vol 22 (14) ◽  
pp. 7511
Author(s):  
Albina Fejza ◽  
Maurizio Polano ◽  
Lucrezia Camicia ◽  
Evelina Poletto ◽  
Greta Carobolante ◽  
...  
Keyword(s):  
Gene Expression ◽  
Effective Treatment ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Tumor Hypoxia ◽  
Melanoma Cells ◽  
Vessel Normalization ◽  
Melanoma Patients

The use of immune checkpoint inhibitors has revolutionized the treatment of melanoma patients, leading to remarkable improvements in the cure. However, to ensure a safe and effective treatment, there is the need to develop markers to identify the patients that would most likely respond to the therapies. The microenvironment is gaining attention in this context, since it can regulate both the immunotherapy efficacyand angiogenesis, which is known to be affected by treatment. Here, we investigated the putative role of the ECM molecule EMILIN-2, a tumor suppressive and pro-angiogenic molecule. We verified that the EMILIN2 expression is variable among melanoma patients and is associated with the response to PD-L1 inhibitors. Consistently, in preclinical settings,the absence of EMILIN-2 is associated with higher PD-L1 expression and increased immunotherapy efficacy. We verified that EMILIN-2 modulates PD-L1 expression in melanoma cells through indirect immune-dependent mechanisms. Notably, upon PD-L1 blockage, Emilin2−/− mice displayed improved intra-tumoral vessel normalization and decreased tumor hypoxia. Finally, we provide evidence indicating that the inclusion of EMILIN2 in a number of gene expression signatures improves their predictive potential, a further indication that the analysis of this molecule may be key for the development of new markers to predict immunotherapy efficacy.

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