Risk factors predicting the 'time to first fracture' and its association with imminent fractures: a substudy of the FRISBEE cohort.

Only previous glucocorticoid use and rheumatoid arthritis were predictors of an early fracture (< 2 years after inclusion). A shorter 'time to first fracture' was not an independent clinical risk factor for imminent fractures. PURPOSE: Risk factors for fragility fractures independent of BMD were assessed in several prediction models. However, predictors of a shorter 'time to first fracture' and its impact on imminent fractures are unknown. METHODS: We studied the concept of 'time to first fracture' in the FRISBEE ("Fracture RIsk Brussels Epidemiological Enquiry") cohort (3560 postmenopausal women). Validated fractures were divided into 3 groups: first fracture < 2 years, 2-5 years, and > 5 years after inclusion. Factors associated with first fracture risk were evaluated with uni- and multivariate analyses using Cox modeling. We examined 'time to first fracture' as a risk factor for imminent fractures in untreated subjects and in those receiving pharmacological treatment. RESULTS: Classical risk factors (age, prior fracture, fall history and low BMD) were associated with first fracture in all groups. Previous glucocorticoids and rheumatoid arthritis (RA) were predictors for fracture < 2 years. Imminent fractures were similar in subjects with or without osteoporosis treatment, despite a higher estimated 10-year risk of fragility fracture in those treated, suggesting that treatment is efficient. 'Time to first fracture' was not an independent risk factor for imminent fractures. CONCLUSION: Among the risk factors considered, previous glucocorticoid use and RA were predictors for early fracture, consistent with the concept of very high risk. The 'time to first validated fracture' was not an independent risk factor for imminent fractures. Patients with a first osteoporotic fracture should thus be considered at very high risk for re-fracture, independent of the 'time to first fracture'.

Durvalumab-induced thyroiditis in a patient with non-small cell lung carcinoma: a case report and review of pathogenic mechanisms.

BACKGROUND: Immune checkpoint inhibitors (ICI) targeting cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed cell death protein 1 and its ligand (PD-1/PD-L1) have become the current standard-of-care for advanced cancers. This novel therapeutic approach comes with its costs in the form of immune-related adverse events (irAE), including endocrinopathy. CASE PRESENTATION: A 63-year-old woman was diagnosed with a non-small cell lung carcinoma of the right superior lobe, cT3N2M0. She developed thyrotoxicosis followed by hypothyroidism induced by consolidation immunotherapy with durvalumab (anti-PD-L1). Analysis of the human leukocyte antigen (HLA) region showed HLA-DR4 (susceptible) and DR13 (protective). The possible mechanisms are subsequently discussed in detail. CONCLUSIONS: The case of a patient with thyroiditis associated with the PD-L1 inhibitor durvalumab is described, highlighting the need for proactive monitoring of thyroid hormone levels. Identifying biomarkers associated with an increased risk of ICI-induced side effects (such as HLA) is of interest for better patient selection, optimal management and improved understanding of the mechanisms involved.

Immune checkpoint inhibitor therapy for ACTH-secreting pituitary carcinoma: a new emerging treatment?

BACKGROUND: Pituitary carcinomas are rare but aggressive and require maximally coordinated multimodal therapies. For refractory tumors, unresponsive to temozolomide (TMZ), therapeutic options are limited. Immune checkpoint inhibitors (ICI) may be considered for treatment as illustrated in the present case report. CASE: We report a patient with ACTH-secreting pituitary carcinoma, progressive after multiple lines of therapy including chemotherapy with TMZ, who demonstrated disease stabilization by a combination of ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1) ICI therapy. DISCUSSION: Management of pituitary carcinoma beyond TMZ remains ill-defined and relies on case reports. TMZ creates, due to hypermutation, more immunogenic tumors and subsequently potential candidates for ICI therapy. This case report adds support to the possible role of ICI in the treatment of pituitary carcinoma. CONCLUSION: ICI therapy could be a promising treatment option for pituitary carcinoma, considering the mechanisms of TMZ-induced hypermutation with increased immunogenicity, pituitary expression of CTLA-4 and PD-L1, and the frequent occurrence of hypophysitis as a side effect of ICI therapy.

Acute Heart Failure as a First Presentation of Pheochromocytoma Complicated with "Inverted" Takotsubo Syndrome.

Takotsubo syndrome is a rare but emerging form of acute reversible myocardial injury characterized by transient systolic LV dysfunction, often related to emotional or physical stress. Pheochromocytoma is increasingly recognised as another possible trigger. Pheochromocytoma is a rare catecholamine-secreting tumour arising from chromaffin cells within the adrenal medulla or extra-adrenal paraganglia. The pathognomonic quartet of paroxysmal hypertension, palpitations, headache, and diaphoresis is rarely present, and diagnosis is often delayed. We describe a 43-year-old formerly healthy patient with an adrenal pheochromocytoma, presenting as an "inverted" takotsubo syndrome complicated with acute heart failure and pulmonary oedema.

Immune checkpoint inhibitors and type 1 diabetes mellitus: a case report and systematic review.

OBJECTIVE: To better define the rare adverse event (AE) of diabetes mellitus associated with immune checkpoint inhibitors (ICIs). DESIGN AND METHODS: We report the case of a lung cancer patient with diabetic ketoacidosis (DKA) and autoimmune thyroiditis during pembrolizumab treatment. We provide a systematic review of all published cases (PubMed/Web of Science/Cochrane, through November 2018) of autoimmune diabetes mellitus related to blockade of the cytotoxic T-lymphocyte antigen 4 (CTLA-4)-, programmed cell death 1 (PD-1) receptor or its ligand (PD-L1) or combination (ICI) therapy. RESULTS: Our literature search identified 90 patient cases (our case excluded). Most patients were treated with anti-PD-1 or anti-PD-L1 as monotherapy (79%) or in combination with CTLA-4 blockade (15%). On average, diabetes mellitus was diagnosed after 4.5 cycles; earlier for combination ICI at 2.7 cycles. Early-onset diabetes mellitus (after one or two cycles) was observed during all treatment regimens. Diabetic ketoacidosis was present in 71%, while elevated lipase levels were detected in 52% (13/25). Islet autoantibodies were positive in 53% of patients with a predominance of glutamic acid decarboxylase antibodies. Susceptible HLA genotypes were present in 65% (mostly DR4). Thyroid dysfunction was the most frequent other endocrine AE at 24% incidence in this patient population. CONCLUSION: ICI-related diabetes mellitus is a rare but often life-threatening metabolic urgency of which health-care professionals and patients should be aware. Close monitoring of blood glucose and prompt endocrine investigation in case of hyperglycemia is advisable. Predisposing factors such as HLA genotype might explain why some individuals are at risk.

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

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.

Successful Pretreatment Using Plasma Exchange before Thyroidectomy in a Patient with Amiodarone-Induced Thyrotoxicosis.

INTRODUCTION: Amiodarone, used for the management of tachyarrhythmias, is associated with both hypothyroidism and thyrotoxicosis. Total thyroidectomy is an effective procedure for promptly reducing circulating thyroid hormone levels. It has been proposed in patients who have severe amiodarone-induced thyrotoxicosis (AIT) or are refractory to medical therapy, or when such therapy is contraindicated. Therapeutic plasma exchange (TPE) may be considered as a pretreatment for restoring a euthyroid state preoperatively, thereby reducing a patient's symptoms and the potential perioperative risk associated with thyrotoxicosis. CASE REPORT: We describe the case of a 62-year-old man with type 2 AIT who presented with severe unremitting thyrotoxicosis after 8 weeks of medical therapy with glucocorticosteroids, thiamazole, and potassium perchlorate. Given the severity of his presentation, a total thyroidectomy was indicated. TPE was performed preoperatively and was successful in rapidly restoring euthyroidism. This dramatically improved the patient's symptoms which had been suggestive of ischemic heart disease. Subsequently, the patient underwent total thyroidectomy under general anesthesia without any major complications. CONCLUSION: TPE is successful in rapidly restoring a clinical and biochemical euthyroid state, and may be used to decrease the perioperative risks associated with thyroidectomy in patients with life-threatening thyrotoxicosis or in cases refractory to medical treatment.

Incidence of Thyroid-Related Adverse Events in Melanoma Patients Treated With Pembrolizumab.

CONTEXT: Immune checkpoint blockade is associated with endocrine-related adverse events. Thyroid dysfunction during pembrolizumab therapy, an anti-programmed cell death 1 (PD-1) receptor monoclonal antibody, remains to be fully characterized. OBJECTIVE: To assess the incidence and characteristics of pembrolizumab-associated thyroid dysfunction. DESIGN AND SETTING: Thyroid function was monitored prospectively in melanoma patients who initiated pembrolizumab within an expanded access program at a referral oncology center. 18Fluorodeoxyglucose uptake on positron emission tomography/computed tomography (18FDG-PET/CT) was reviewed in cases compatible with inflammatory thyroiditis. PATIENTS: Ninety-nine patients with advanced melanoma (age, 26.3-93.6 years; 63.6% females) who received at least one administration of pembrolizumab. MAIN OUTCOME MEASURES: Patient characteristics, thyroid function (TSH, free T4), thyroid autoantibodies, and 18FDG-PET/CT. RESULTS: Eighteen adverse events of thyroid dysfunction were observed in 17 patients. Thyrotoxicosis occurred in 12 patients, of which nine evolved to hypothyroidism. Isolated hypothyroidism was present in six patients. Levothyroxine therapy was required in 10 of 15 hypothyroid patients. Thyroid autoantibodies were elevated during thyroid dysfunction in four of 10 cases. Diffuse increased 18FDG uptake by the thyroid gland was observed in all seven thyrotoxic patients who progressed to hypothyroidism. CONCLUSIONS: Thyroid dysfunction is common in melanoma patients treated with pembrolizumab. Hypothyroidism and thyrotoxicosis related to inflammatory thyroiditis are the most frequent presentations. Serial measurements of thyroid function tests are indicated during anti-PD-1 monoclonal antibody therapy. Thyrotoxicosis compatible with inflammatory thyroiditis was associated with diffuse increased 18FDG uptake by the thyroid gland. The prospective role of thyroid autoantibodies should be further investigated, together with the histopathological correlates.

Polyneuropathy in a young Belgian patient: A novel heterozygous mutation in the WNK1/HSN2 gene.

Hereditary sensory autonomic neuropathy (HSAN) is a rare condition, predominantly affecting the peripheral sensory nervous system, although variable motor and dysautonomic symptoms can be present. At least 7 clinical types of HSAN have been described, and different genetic mutations have been identified for each of these. HSAN IIA (OMIM #201300) is characterized by loss of pain and loss of temperature and touch sensation, with onset usually before the first decade. The mode of inheritance is autosomal recessive.(1) The causative gene, WNK1/HSN2, is located on locus 12p13.33 and is an isoform of the WNK1 (lysine deficient protein kinase 1) gene, which contains the HSN2 exon.(2,3) We describe 2 new heterozygous mutations in the WNK1/HSN2 gene in a Belgian patient with early-onset sensory polyneuropathy.