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Nature Reviews. Endocrinology Jul 2021Immune checkpoint inhibitors (ICIs) are monoclonal antibodies that target two key signalling pathways related to T cell activation and exhaustion, by binding to and... (Review)
Review
Immune checkpoint inhibitors (ICIs) are monoclonal antibodies that target two key signalling pathways related to T cell activation and exhaustion, by binding to and inhibiting cytotoxic T lymphocyte antigen 4 (CTLA4) or PD1 and its ligand PDL1. ICIs, such as nivolumab, pembrolizumab and ipilimumab, are approved for the treatment of numerous and diverse cancer types, in various combination regimens, and are now an established cornerstone of cancer therapeutics. Toxicities induced by ICIs are autoimmune in nature and are referred to as immune-related adverse events (irAEs); these events can affect any organ system in an unpredictable fashion. Importantly, irAEs can manifest as endocrinopathies involving the thyroid (hypothyroidism or thyrotoxicosis), pituitary (hypophysitis), adrenal glands (adrenal insufficiency) and pancreas (diabetes mellitus). These events are a frequent source of acute and persistent morbidity in patients treated with ICIs and can even be fatal. Over the past few years, there has been a growing understanding of the underlying pathogenesis of irAEs that has led to the development of more effective management strategies. Herein, we review the current understanding of the pathobiology, clinical manifestations and treatment approaches to endocrine toxicities arising from ICIs.
Topics: Antineoplastic Agents, Immunological; Drug-Related Side Effects and Adverse Reactions; Endocrine System Diseases; Humans; Immune Checkpoint Inhibitors; Immune System; Immunotherapy; Neoplasms
PubMed: 33875857
DOI: 10.1038/s41574-021-00484-3 -
The Journal of Clinical Endocrinology... Jan 2022Hypophysitis is defined as inflammation of the pituitary gland that is primary or secondary to a local or systemic process. Differential diagnosis is broad (including... (Review)
Review
Hypophysitis is defined as inflammation of the pituitary gland that is primary or secondary to a local or systemic process. Differential diagnosis is broad (including primary tumors, metastases, and lympho-proliferative diseases) and multifaceted. Patients with hypophysitis typically present with headaches, some degree of anterior and/or posterior pituitary dysfunction, and enlargement of pituitary gland and/or stalk, as determined by imaging. Most hypophysitis causes are autoimmune, but other etiologies include inflammation secondary to sellar tumors or cysts, systemic diseases, and infection or drug-induced causes. Novel pathologies such as immunoglobulin G4-related hypophysitis, immunotherapy-induced hypophysitis, and paraneoplastic pituitary-directed autoimmunity are also included in a growing spectrum of this rare pituitary disease. Typical magnetic resonance imaging reveals stalk thickening and homogenous enlargement of the pituitary gland; however, imaging is not always specific. Diagnosis can be challenging, and ultimately, only a pituitary biopsy can confirm hypophysitis type and rule out other etiologies. A presumptive diagnosis can be made often without biopsy. Detailed history and clinical examination are essential, notably for signs of underlying etiology with systemic manifestations. Hormone replacement and, in selected cases, careful observation is advised with imaging follow-up. High-dose glucocorticoids are initiated mainly to help reduce mass effect. A response may be observed in all auto-immune etiologies, as well as in lymphoproliferative diseases, and, as such, should not be used for differential diagnosis. Surgery may be necessary in some cases to relieve mass effect and allow a definite diagnosis. Immunosuppressive therapy and radiation are sometimes also necessary in resistant cases.
Topics: Adult; Aged; Autoimmunity; Diagnosis, Differential; Female; Humans; Hypophysitis; Magnetic Resonance Imaging; Male; Pituitary Gland; Rare Diseases
PubMed: 34528683
DOI: 10.1210/clinem/dgab672 -
European Journal of Endocrinology Dec 2022Immune checkpoint inhibitors (ICI) have revolutionized cancer treatment but are associated with significant autoimmune endocrinopathies that pose both diagnostic and...
Immune checkpoint inhibitors (ICI) have revolutionized cancer treatment but are associated with significant autoimmune endocrinopathies that pose both diagnostic and treatment challenges. The aim of this guideline is to provide clinicians with the best possible evidence-based recommendations for treatment and follow-up of patients with ICI-induced endocrine side-effects based on the Grading of Recommendations Assessment, Development, and Evaluation system. As these drugs have been used for a relatively short time, large systematic investigations are scarce. A systematic approach to diagnosis, treatment, and follow-up is needed, including baseline tests of endocrine function before each treatment cycle. We conclude that there is no clear evidence for the benefit of high-dose glucocorticoids to treat endocrine toxicities with the possible exceptions of severe thyroid eye disease and hypophysitis affecting the visual apparatus. With the exception of thyroiditis, most endocrine dysfunctions appear to be permanent regardless of ICI discontinuation. Thus, the development of endocrinopathies does not dictate a need to stop ICI treatment.
Topics: Humans; Immune Checkpoint Inhibitors; Neoplasms; Endocrine System Diseases; Hypophysitis; Drug-Related Side Effects and Adverse Reactions
PubMed: 36149449
DOI: 10.1530/EJE-22-0689 -
The Lancet. Oncology Dec 2021Combination nivolumab plus ipilimumab was efficacious in patients with asymptomatic melanoma brain metastases (MBM) in CheckMate 204, but showed low efficacy in patients...
Long-term outcomes of patients with active melanoma brain metastases treated with combination nivolumab plus ipilimumab (CheckMate 204): final results of an open-label, multicentre, phase 2 study.
BACKGROUND
Combination nivolumab plus ipilimumab was efficacious in patients with asymptomatic melanoma brain metastases (MBM) in CheckMate 204, but showed low efficacy in patients with symptomatic MBM. Here, we provide final 3-year follow-up data from the trial.
METHODS
This open-label, multicentre, phase 2 study (CheckMate 204) included adults (aged ≥18 years) with measurable MBM (0·5-3·0 cm in diameter). Asymptomatic patients (cohort A) had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 and no neurological symptoms or baseline corticosteroid use; symptomatic patients (cohort B) had an ECOG performance status of 0-2 with stable neurological symptoms and could be receiving low-dose dexamethasone. Nivolumab 1 mg/kg plus ipilimumab 3 mg/kg was given intravenously every 3 weeks for four doses, followed by nivolumab 3 mg/kg every 2 weeks for up to 2 years, until disease progression or unacceptable toxicity. The primary endpoint was intracranial clinical benefit rate (complete responses, partial responses, or stable disease lasting ≥6 months) assessed in all treated patients. Intracranial progression-free survival and overall survival were key secondary endpoints. This study is registered with ClinicalTrials.gov, NCT02320058.
FINDINGS
Between Feb 19, 2015, and Nov 1, 2017, 119 (72%) of 165 screened patients were enrolled and treated: 101 patients were asymptomatic (cohort A; median follow-up 34·3 months [IQR 14·7-36·4]) and 18 were symptomatic (cohort B; median follow-up 7·5 months [1·2-35·2]). Investigator-assessed intracranial clinical benefit was observed in 58 (57·4% [95% CI 47·2-67·2]) of 101 patients in cohort A and three (16·7% [3·6-41·4]) of 18 patients in cohort B; investigator-assessed objective response was observed in 54 (53·5% [43·3-63·5]) patients in cohort A and three (16·7% [3·6-41·4]) patients in cohort B. 33 (33%) patients in cohort A and three (17%) patients in cohort B had an investigator-assessed intracranial complete response. For patients in cohort A, 36-month intracranial progression-free survival was 54·1% (95% CI 42·7-64·1) and overall survival was 71·9% (61·8-79·8). For patients in cohort B, 36-month intracranial progression-free survival was 18·9% (95% CI 4·6-40·5) and overall survival was 36·6% (14·0-59·8). The most common grade 3-4 treatment-related adverse events (TRAEs) were increased alanine aminotransferase and aspartate aminotransferase (15 [15%] of 101 patients each) in cohort A; no grade 3 TRAEs occurred in more than one patient each in cohort B, and no grade 4 events occurred. The most common serious TRAEs were colitis, diarrhoea, hypophysitis, and increased alanine aminotransferase (five [5%] of each among the 101 patients in cohort A); no serious TRAE occurred in more than one patient each in cohort B. There was one treatment-related death (myocarditis in cohort A).
INTERPRETATION
The durable 3-year response, overall survival, and progression-free survival rates for asymptomatic patients support first-line use of nivolumab plus ipilimumab. Symptomatic disease in patients with MBM remains difficult to treat, but some patients achieve a long-term response with the combination.
FUNDING
Bristol Myers Squibb.
Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Female; Follow-Up Studies; Humans; Ipilimumab; Male; Melanoma; Middle Aged; Nivolumab; Prognosis; Survival Rate
PubMed: 34774225
DOI: 10.1016/S1470-2045(21)00545-3 -
ENeurologicalSci Sep 2021•A patient exhibited IgG4-related hypothalamo-hypophysitis.•Prominent high-signal areas of swelling were observed in the hypothalamus, tuber cinereum, infundibulum,...
•A patient exhibited IgG4-related hypothalamo-hypophysitis.•Prominent high-signal areas of swelling were observed in the hypothalamus, tuber cinereum, infundibulum, and bilateral optic nerve systems.•MRI T1WI with contrast media demonstrated enhanced neurohypophysis and cystic swelling, and compressed anterior pituitary.•MRI findings improved rapidly after 4 days of steroid therapy.
PubMed: 34466672
DOI: 10.1016/j.ensci.2021.100362