Importance If not promptly recognized, endocrine dysfunction can be life threatening. The incidence and risk of developing such adverse events (AEs) following the use of immune checkpoint inhibitor (ICI) regimens are unknown. Objective To compare the incidence and risk of endocrine AEs following treatment with US Food and Drug Administration–approved ICI regimens. Data Sources A PubMed search through July 18, 2016, using the following keywords was performed: “ipilimumab,” “MDX-010,” “nivolumab,” “BMS-963558,” “pembrolizumab,” “MK-3475,” “atezolizumab,” “MPDL3280A,” and “phase.” Study Selection Thirty-eight randomized clinical trials evaluating the usage of these ICIs for treatment of advanced solid tumors were identified, resulting in a total of 7551 patients who were eligible for a meta-analysis. Regimens were categorized by class into monotherapy with a PD-1 (programmed cell death protein 1) inhibitor, a CTLA-4 (cytotoxic T-lymphocyte-associated protein-4) inhibitor, or a PD-L1 (programmed cell death 1 ligand 1) inhibitor, and combination therapy with PD-1 plus CTLA-4 inhibitors. Data Extraction and Synthesis The data were extracted by 1 primary reviewer (R.B.-S.) and then independently reviewed by 2 secondary reviewers (W.T.B. and A.C.G.-C.) following Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. Inferences on the incidence of AEs were made using log-odds random effects models. Main Outcomes and Measures Incidence of all-grade hypothyroidism, hyperthyroidism, hypophysitis, primary adrenal insufficiency, and insulin-deficient diabetes. Results Overall, 38 randomized clinical trials comprising 7551 patients were included in this systematic review and meta-analysis. The incidence of both hypothyroidism and hyperthyroidism was highest in patients receiving combination therapy. Patients on the combination regimen were significantly more likely to experience hypothyroidism (odds ratio [OR], 3.81; 95% CI, 2.10-6.91, P P  = .001) than patients on ipilimumab. Compared with patients on ipilimumab, those on PD-1 inhibitors had a higher risk of developing hypothyroidism (OR, 1.89; 95% CI, 1.17-3.05; P  = .03). The risk of hyperthyroidism, but not hypothyroidism, was significantly greater with PD-1 than with PD-L1 inhibitors (OR, 5.36; 95% CI, 2.04-14.08; P  = .002). While patients who received PD-1 inhibitors were significantly less likely to experience hypophysitis than those receiving ipilimumab (OR, 0.29; 95% CI, 0.18-0.49; P P  = .001). For primary adrenal insufficiency and insulin-deficient diabetes no statistical inferences were made due to the smaller number of events. Conclusions and Relevance Our study provides more precise data on the incidence of endocrine dysfunctions among patients receiving ICI regimens. Patients on combination therapy are at increased risk of thyroid dysfunction and hypophysitis.

https://jamanetwork.com/journals/jamaoncology/articlepdf/2655010/jamaoncology_BarrosoSousa_2017_oi_170065.pdf

Incidence of Endocrine Dysfunction Following the Use of Different Immune Checkpoint Inhibitor Regimens: A Systematic Review and Meta-analysis

Immune checkpoints are small molecules expressed by immune cells that play critical roles in maintaining immune homeostasis. Targeting the immune checkpoints cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed death 1 (PD-1) with inhibitory antibodies has demonstrated effective and durable antitumor activity in subgroups of patients with cancer. The US Food and Drug Administration has approved several immune checkpoint inhibitors (ICPis) for the treatment of a broad spectrum of malignancies. Endocrinopathies have emerged as one of the most common immune-related adverse events (irAEs) of ICPi therapy. Hypophysitis, thyroid dysfunction, insulin-deficient diabetes mellitus, and primary adrenal insufficiency have been reported as irAEs due to ICPi therapy. Hypophysitis is particularly associated with anti-CTLA-4 therapy, whereas thyroid dysfunction is particularly associated with anti-PD-1 therapy. Diabetes mellitus and primary adrenal insufficiency are rare endocrine toxicities associated with ICPi therapy but can be life-threatening if not promptly recognized and treated. Notably, combination anti-CTLA-4 and anti-PD-1 therapy is associated with the highest incidence of ICPi-related endocrinopathies. The precise mechanisms underlying these endocrine irAEs remain to be elucidated. Most ICPi-related endocrinopathies occur within 12 weeks after the initiation of ICPi therapy, but several have been reported to develop several months to years after ICPi initiation. Some ICPi-related endocrinopathies may resolve spontaneously, but others, such as central adrenal insufficiency and primary hypothyroidism, appear to be persistent in most cases. The mainstay of management of ICPi-related endocrinopathies is hormone replacement and symptom control. Further studies are needed to determine (i) whether high-dose corticosteroids in the treatment of ICPi-related endocrinopathies preserves endocrine function (especially in hypophysitis), and (ii) whether the development of ICPi-related endocrinopathies correlates with tumor response to ICPi therapy.

/pdf/endocrine-toxicity-of-cancer-immunotherapy-targeting-immune-c1wsl7w6u7.pdf

Endocrine Toxicity of Cancer Immunotherapy Targeting Immune Checkpoints.

Monoclonal antibodies targeting cytotoxic T-lymphocyte antigen-4 (CTLA-4), programed cell death 1 (PD-1), or its ligand (PD-L1) have become the mainstay for advanced malignancies. The incidence of endocrine adverse events provoked by these immune checkpoint inhibitors (ICI) is based on data from randomized controlled trials, which have their drawbacks. PubMed was searched through August 22nd, 2017, by 2 reviewers independently (J.d.F. and C.E.A.). Early phase I/II, phase III experimental trials, prospective and retrospective observational studies were included. The weighted incidence and risk ratio were estimated for hypophysitis, primary thyroid disease, primary adrenal insufficiency, and diabetes mellitus. Their management is discussed in a systematic review. A total of 101 studies involving 19 922 patients were included. Ipilimumab-treated patients experienced hypophysitis in 5.6% (95% CI, 3.9–8.1), which was higher than nivolumab (0.5%; 95% CI, 0.2–1.2) and pembrolizumab (1.1%; 95% CI, 0.5–2.6). PD-1/PD-L1 inhibitors had a higher incidence of thyroid dysfunction – particularly hypothyroidism (nivolumab, 8.0%; 95% CI, 6.4–9.8; pembrolizumab, 8.5%; 95% CI, 7.5–9.7; PD-L1, 5.5%; 95% CI, 4.4–6.8; ipilimumab, 3.8%; 95% CI, 2.6–5.5). Combination therapy was associated with a high incidence of hypothyroidism (10.2–16.4%), hyperthyroidism (9.4–10.4%), hypophysitis (8.8–10.5%), and primary adrenal insufficiency (5.2–7.6%). Diabetes mellitus and primary adrenal insufficiency were less frequent findings on monotherapy. Our meta-analysis shows a high incidence of endocrine adverse events provoked by single agent checkpoint blockade, further reinforced by combined treatment.

/pdf/a-systematic-review-and-meta-analysis-of-endocrine-related-1mtsj4dywt.pdf

A Systematic Review and Meta-Analysis of Endocrine-Related Adverse Events Associated with Immune Checkpoint Inhibitors.

Background: Although immune-related thyroiditis (irT) with immune checkpoint inhibitors (ICI) is a common consequence, its natural course and management recommendations are not well characterized i...

/pdf/immune-related-thyroiditis-with-immune-checkpoint-inhibitors-1hm5j24zsl.pdf

Immune-Related Thyroiditis with Immune Checkpoint Inhibitors.

Since 2011 six immune checkpoint inhibitors (ICI) have been approved to treat patients with many advanced solid tumor and hematological malignancies to improve their prognosis. Case reports of their endocrine immune-related adverse events [irAEs]) are increasingly published as more real-world patients with these malignancies are treated with these drugs. They alert physicians of a drug’s AEs (which may change during a drug’s life cycle) and contribute to post-marketing safety surveillance. Using a modified framework of Arksey and O’Malley, we conducted a scoping review of the spectrum and characteristics of ICI-induced endocrinopathies case reports before and after ICIs are marketed. In July 2017, we searched, without date and language restrictions, 4 citation databases for ICI-induced endocrinopathies. We also hand-searched articles’ references, contents of relevant journals, and ran supplemental searches to capture recent reports through January 2018. For this study, a case should have information on type of cancer, type of ICI, clinical presentation, biochemical tests, treatment plus temporal association of ICI initiation with endocrinopathies. Two endocrinologists independently extracted the data which were then summarized and categorized. One hundred seventy nine articles reported 451 cases of ICI-induced endocrinopathies - 222 hypopituitarism, 152 thyroid disorders, 66 diabetes mellitus, 6 primary adrenal insufficiencies, 1 ACTH-dependent Cushing’s syndrome, 1 hypoparathyroidism and 3 diabetes insipidus cases. Their clinical presentations reflect hormone excess or deficiency. Some were asymptomatic and others life-threatening. One or more endocrine glands could be affected. Polyglandular endocrinopathies could present simultaneously or in sequence. Many occur within 5 months of therapy initiation; a few occurred after ICI was stopped. Mostly irreversible, they required long-term hormone replacement. High dose steroids were used when non-endocrine AEs coexisted or as therapy in adrenal insufficiency. There was variability of information in the case reports but all met the study criteria to make a diagnosis. The spectrum of ICI-induced endocrinopathies is wide (5 glands affected) and their presentation varied (12 endocrinopathies). Clinical reasoning integrating clinical, biochemical and treatment information is needed to properly diagnose and manage them. Physicians should be vigilant for their occurrence and be able to diagnose, investigate and manage them appropriately at onset and follow-up.

/pdf/spectrum-of-immune-checkpoint-inhibitors-induced-17k689aecx.pdf

Spectrum of immune checkpoint inhibitors-induced endocrinopathies in cancer patients: a scoping review of case reports

Objective. Thyroid disease has been reported among the endocrinopathies that can occur after treatment with ipilimumab. Graves' disease, however, has been rarely reported with this medication. Here we report a case of Graves' disease diagnosed after initiation of ipilimumab in a patient with melanoma. Methods. We present the clinical presentation and management course of this patient followed by a related literature review. Results. A 67-year-old male with metastatic melanoma was started on ipilimumab. He developed hyperthyroidism after two doses of ipilimumab. The cause of hyperthyroidism was determined to be Graves' disease. Ipilimumab was held and the patient was started on methimazole with return to euthyroid status. Ipilimumab was resumed and the patient continued methimazole during the course of ipilimumab therapy, with controlled hyperthyroidism. Restaging studies following four cycles of ipilimumab showed complete response in the lungs, with residual melanoma in the neck. The patient then underwent total thyroidectomy and left neck dissection as a definitive treatment for both hyperthyroidism and residual melanoma. Conclusion. Graves' disease can develop after starting ipilimumab and methimazole can be an effective treatment. For patients whose hyperthyroidism is well-controlled on methimazole, ipilimumab may be resumed with close monitoring.

/pdf/treatment-of-ipilimumab-induced-graves-disease-in-a-patient-26kds949r0.pdf

Treatment of Ipilimumab Induced Graves' Disease in a Patient with Metastatic Melanoma.

Background: Thyroglobulin (Tg) measurement in patients with positive antithyroglobulin antibodies (anti-TgAbs) is not reliable. Tg measurement using liquid chromatography–tandem mass spectrometry (LC/MS) may be useful in this setting. Methods: This is a retrospective study with the objective of determining the accuracy of Tg-LC/MS in patients with thyroid cancer with anti-TgAbs. All patients with follicular cell-derived thyroid cancer (TC) who had thyroglobulin measured using LC/MS assay from November 1, 2013, to November 7, 2014, were evaluated. The frequency of detectable Tg-LC/MS was evaluated, with a functional sensitivity (FS) of 0.5 ng/mL in patients with structural disease. Then performance of Tg-LC/MS versus Tg immunometric assay (IMA) was compared using either Immulite assay (Tg-1) with a FS of 0.9 ng/mL or Beckman assay (Tg-B) with a FS of 0.1 ng/mL in detecting structural disease in patients with positive anti-TgAbs. Results: A total of 154 consecutive patients were included in this evaluation....

Thyroglobulin Liquid Chromatography-Tandem Mass Spectrometry Has a Low Sensitivity for Detecting Structural Disease in Patients with Antithyroglobulin Antibodies.

The South Asian population is rapidly ageing and sarcopenia is likely to become a huge burden in this region if proper action is not taken in time. Several sarcopenia guidelines are available, from the western world and from East Asia. However, these guidelines are not fully relevant for the South Asian healthcare ecosystem. South Asia is ethnically, culturally, and phenotypically unique. Additionally, the region is seeing an increase in non-communicable lifestyle disease and obesity. Both these conditions can lead to sarcopenia. However, secondary sarcopenia and sarcopenic obesity are either not dealt with in detail or are missing in other guidelines. Hence, we present a consensus on the screening, diagnosis and management of sarcopenia, which addresses the gaps in the current guidelines. This South Asian consensus gives equal importance to muscle function, muscle strength, and muscle mass; provides cost-effective clinical and easy to implement solutions; highlights secondary sarcopenia and sarcopenic obesity; lists commonly used biomarkers; reminds us that osteo-arthro-muscular triad should be seen as a single entity to address sarcopenia; stresses on prevention over treatment; and prioritizes non-pharmacological over pharmacological management. As literature is scarce from this region, the authors call for more South Asian research guided interventions. 

https://doi.org/10.1016/j.afos.2022.04.001

South Asian Working Action Group on SARCOpenia (SWAG-SARCO) – A consensus document

Aim Prolactinoma, a prolactin (PRL) secreting functioning pituitary tumor, is the most common of all pituitary adenomas (PA) accounting for 40-60% and dopamine agonists (DA) are the cornerstone of treatment. The aim of this study was to review the clinical presentation, treatment modalities and therapeutic outcomes of patients with prolactinomas in the South Asia region. Methods This retrospective study was conducted in the Endocrinology Department of Shaukat Khanum Memorial Cancer Hospital and Research Centre from December 2011 till December 2019. Medical records were used to retrieve for patient’s demographics, clinical features at diagnosis, PRL levels and size of prolactinoma on MRI at diagnosis and after start of dopamine agonists and outcome of medical management. Results A total of 107 patients were included in this study. Mean age at diagnosis was 35 (22-54) years for men and 32 (18-50) years for women and 66.4% (71) of the patients were females. Our study included 38 (35.5%) microadenoma, 50 (46.7%) macroadenoma and 19 (17.8%) giant adenomas. At presentation, the most common symptom among females was menstrual irregularity/amenorrhea seen in 73.2% of females and among males was visual disturbance (80.6%). A significant reduction in PRL levels was seen within six to 12 months of treatment. Mean PRL levels decreased from 3162.8 ng/ml to 1.52 ng/ml. A notable decrease in tumor size was seen with medical management, mean adenoma size decreased from 2.18 cm to 1.04 cm. With cabergoline (CAB) 83.3% biochemical cure was seen compared to bromocriptine (BRC) which has 60.4%. The radiological response rate in CAB and BRC groups was 65.45% and 60%, respectively. Complete resolution of adenoma was seen in 13 patients (nine were microadenoma, two macro and two giant adenomas). The prolactin level at diagnosis was positively correlated with maximum tumor diameter (r = 0.469, P = 0.001). Two patients developed cerebrospinal fluid (CSF) rhinorrhea and the defect was repaired in both patients. Median follow-up duration was 40 (12-288) months. Conclusion Clinical presentation and demographics of prolactinoma are the same in our region when compared to the rest of the world. Cabergoline is superior to bromocriptine in prolactin normalization and tumor shrinkage but still bromocriptine is being used in a significant number of patients in low-income countries as first-line due to its low cost.

/pdf/prolactinoma-clinical-characteristics-management-and-outcome-1scxikjy.pdf

Prolactinoma: Clinical Characteristics, Management and Outcome

L ingual thyroid and thyroid hemiagenesis are rare thyroid developmental abnormalities. These conditions can be present with other thyroid diseases, whether functional ones involving abnormal thyroid hormone levels, or structural ones such as presence of thyroid nodules, however the association with thyroid cancer and lingual thyroid or thyroid hemiagenesis is rare. In addition to that, when thyroid hemiagenesis is present, it is usually in the left lobe. We describe here a pregnant patient who presented with metastatic cervical nodes from thyroid cancer who was found on imaging to have right thyroid hemiagenesis. After she underwent an initial surgery for thyroid cancer and metastatic nodal disease, she was then later discovered to have a lingual thyroid. In this case we report this extremely rare combination and also discuss the potential implications of this association on the diagnosis and management of these patients particularly initial surgery and imaging studies needed for the thyroid cancer.

Umal Azmat

Papers

Treatment of Ipilimumab Induced Graves' Disease in a Patient with Metastatic Melanoma.

Thyroglobulin Liquid Chromatography-Tandem Mass Spectrometry Has a Low Sensitivity for Detecting Structural Disease in Patients with Antithyroglobulin Antibodies.

South Asian Working Action Group on SARCOpenia (SWAG-SARCO) – A consensus document

Prolactinoma: Clinical Characteristics, Management and Outcome

A Case of a Rare Association Between Right Thyroid Hemiagenesis, Lingual Thyroid, and Papillary Thyroid Cancer