Genetic Basis of ACTH-Secreting Adenomas.

Cushing's disease represents 60-70% of all cases of Cushing's syndrome, presenting with a constellation of clinical features associated with sustained hypercortisolism. Molecular alterations in corticotrope cells lead to the formation of ACTH-secreting adenomas, with subsequent excessive production of endogenous glucocorticoids. In the last few years, many authors have contributed to analyzing the etiopathogenesis and pathophysiology of corticotrope adenomas, which still need to be fully clarified. New molecular modifications such as somatic mutations of USP8 and other genes have been identified, and several case series and case reports have been published, highlighting new molecular alterations that need to be explored. To investigate the current knowledge of the genetics of ACTH-secreting adenomas, we performed a bibliographic search of the recent scientific literature to identify all pertinent articles. This review presents the most recent updates on somatic and germline mutations underlying Cushing's disease. The prognostic implications of these mutations, in terms of clinical outcomes and therapeutic scenarios, are still debated. Further research is needed to define the clinical features associated with the different genotypes and potential pharmacological targets.

Cushing's Syndrome Effects on the Thyroid.

The most known effects of endogenous Cushing's syndrome are the phenotypic changes and metabolic consequences. However, hypercortisolism can exert important effects on other endocrine axes. The hypothalamus-pituitary-thyroid axis activity can be impaired by the inappropriate cortisol secretion, which determinates the clinical and biochemical features of the "central hypothyroidism". These findings have been confirmed by several clinical studies, which also showed that the cure of hypercortisolism can determine the recovery of normal hypothalamus-pituitary-thyroid axis activity. During active Cushing's syndrome, the "immunological tolerance" guaranteed by the hypercortisolism can mask, in predisposed patients, the development of autoimmune thyroid diseases, which increases in prevalence after the resolution of hypercortisolism. However, the immunological mechanism is not the only factor that contributes to this phenomenon, which probably includes also deiodinase-impaired activity. Cushing's syndrome can also have an indirect impact on thyroid function, considering that some drugs used for the medical control of hypercortisolism are associated with alterations in the thyroid function test. These considerations suggest the utility to check the thyroid function in Cushing's syndrome patients, both during the active disease and after its remission.

Somatostatin receptor ligands in acromegaly: clinical response and factors predicting resistance.

INTRODUCTION: Somatostatin (SST) receptor ligands (SRL), in particular those of first generation (Octreotide and Lanreotide), are widely used in medical treatment of acromegaly, but they assure biochemical control of disease (and the possibility of an improvement of clinical symptoms and tumor shrinkage), only in a subset of patients. DISCUSSION: The mechanisms underlying the so called "SRL resistance" are various and involve in particular SST receptor expression and molecular pathways of signal transduction. Different predictors of SRL response have been reported, including clinical and biochemical features (gender, age, growth hormone and insulin-like growth factor-I levels at diagnosis), and tumor characteristic (both at preoperative magnetic resonance imaging study and histopathology) as well as expression of SST receptors. In some cases, only a "partial resistance" to SST can be detected, probably due to the presence of other impaired molecular mechanisms involved in signal transduction, which compromise specific pathways and not others. This may explain some cases of dissociated response between biochemical control and tumor shrinkage.

Treatment with Synthetic Glucocorticoids and the Hypothalamus-Pituitary-Adrenal Axis.

Chronic glucocorticoid (GC) treatment represents a widely-prescribed therapy for several diseases in consideration of both anti-inflammatory and immunosuppressive activity but, if used at high doses for prolonged periods, it can determine the systemic effects characteristic of Cushing's syndrome. In addition to signs and symptoms of hypercortisolism, patients on chronic GC therapy are at risk to develop tertiary adrenal insufficiency after the reduction or the withdrawal of corticosteroids or during acute stress. This effect is mediated by the negative feedback loop on the hypothalamus-pituitary-adrenal (HPA) axis, which mainly involves corticotropin-release hormone (CRH), which represents the most important driver of adrenocorticotropic hormone (ACTH) release. In fact, after withdrawal of chronic GC treatment, reactivation of CRH secretion is a necessary prerequisite for the recovery of the HPA axis. In addition to the well-known factors which regulate the degree of inhibition of the HPA during synthetic GC therapy (type of compound, method of administration, cumulative dose, duration of the treatment, concomitant drugs which can increase the bioavailability of GCs), there is a considerable variation in individual physiology, probably related to different genetic profiles which regulate GC receptor activity. This may represent an interesting basis for possible future research fields.

MANAGEMENT OF CATECHOLAMINE-SECRETING TUMORS IN PREGNANCY: A REVIEW.

OBJECTIVE: Catecholamine-secreting tumors (pheochromocytomas and paragangliomas) presenting during pregnancy are extremely rare, but they can be fatal to both mother and fetus. Recent discoveries in the genetic background of these tumors are expected to address an increasing number of at-risk women to prenatal diagnosis. METHODS: The literature was reviewed in order to provide clinicians with a practical and updated guide on how to manage this life-threatening condition. RESULTS: The clinical presentation of catecholamine-secreting tumors can be deceptive and mimic common disorders of pregnancy. Silent catecholamine-secreting tumors can become evident during pregnancy, and hypertension cannot be considered a hallmark for this condition: some women may be normotensive or develop orthostatic hypotension. Biochemical screening includes measurement of plasma free metanephrines or urinary fractioned metanephrines. Measurement of catecholamines, dopamine, and methoxytyramine can provide further information on tumor biology, location, and prognosis. Diagnostic imaging is limited, and medical treatment requires a cautious balance between hemodynamic control and effects on the fetoplacental unit. Several genes have been associated with syndromes including catecholamine-secreting tumors, and positive genetic testing can correlate with tumor behavior. Timing and modalities for tumor removal and delivery, including anesthetic management, depend on gestational age, maternal and fetal wellbeing, control of catecholamine excess, suspicion of multiple or malignant disease, and surgical accessibility to the tumor. CONCLUSION: A timely diagnosis and a multidisciplinary approach are the keys to improve pregnancy outcomes in patients with a catecholamine-secreting tumor; each case should be managed in a tertiary referral center.

Predicting Ovarian Activity in Women Affected by Early Breast Cancer: A Meta-Analysis-Based Nomogram.

BACKGROUND: The assessment of ovarian reserve in premenopausal women requiring anticancer gonadotoxic therapy can help clinicians address some challenging issues, including the probability of future pregnancies after the end of treatment. Anti-Müllerian hormone (AMH) and age can reliably estimate ovarian reserve. A limited number of studies have evaluated AMH and age as predictors of residual ovarian reserve following cytotoxic chemotherapy in breast cancer patients. MATERIALS AND METHODS: To conduct a meta-analysis of published data on this topic, we searched the medical literature using the key MeSH terms "amenorrhea/chemically induced," "ovarian reserve," "anti-Mullerian hormone/blood," and "breast neoplasms/drug therapy." Preferred Reporting Items for Systematic Reviews and Meta-Analyses statements guided the search strategy. U.K. National Health Service guidelines were used in abstracting data and assessing data quality and validity. Area under the receiver operating characteristic curve (ROC/AUC) analysis was used to evaluate the predictive utility of baseline AMH and age model. RESULTS: The meta-analysis of data pooled from the selected studies showed that both age and serum AMH are reliable predictors of post-treatment ovarian activity in breast cancer patients. Importantly, ROC/AUC analysis indicated AMH was a more reliable predictor of post-treatment ovarian activity in patients aged younger than 40 years (0.753; 95% confidence interval [CI]: 0.602-0.904) compared with those older than 40 years (0.678; 95% CI: 0.491-0.866). We generated a nomogram describing the correlations among age, pretreatment AMH serum levels, and ovarian activity at 1 year from the end of chemotherapy. CONCLUSION: After the ongoing validation process, the proposed nomogram may help clinicians discern premenopausal women requiring cytotoxic chemotherapy who should be considered high priority for fertility preservation counseling and procedures.

A rare case of juvenile hypertension: coexistence of type 2 multiple endocrine neoplasia -related bilateral pheochromocytoma and reninoma in a young patient with ACE gene polymorphism.

BACKGROUND: Pheochromocytoma and reninoma represent two rare diseases causing hypertension. We here reported a rare case of association between type 2 multiple endocrine neoplasia related bilateral pheochromocytoma and reninoma. Moreover, polymorphism of ACE gene, which is known to be related to an increase of cardiovascular risk, has been found in the same patient. CASE PRESENTATION: A 24 year old Caucasian man came to our attention for severe hypertension, resistant to anti-hypertensive polytherapy. At the age of twenty he had undergone total thyroidectomy with lymphadenectomy for medullary carcinoma. Genetic testing showed a RET mutation of codon 918 (exon 16) not documented in other family members. During the follow-up, a progressive increase of urinary metanephrines and catecholamines was recorded. Our evaluation confirmed the presence of severe hypertension (220/140 mmHg) and a severe increase of urinary catecholamines and metanephrines. Due to the presence of hypokalemia, other causes of hypertension were researched leading to the discovery of hyperreninemia (236 µUI/ml) with mild hyperaldosteronism, and a mild increase of the renal artery resistance at ultrasound. An abdominal MRI showed multiple adrenal masses and a right kidney nodular lesion of about 2 cm. The patient underwent bilateral adrenalectomy and right nephrectomy, and histology confirmed the presence of bilateral pheochromocytoma and right reninoma. The post-surgery laboratory evaluation showed a rapid reduction of the urinary metanephrines while plasma renin level remained low in spite of the bilateral adrenalectomy without any mineralocorticoid supplementation. To further investigate these unusual feature, we performed genetic testing for the ACE gene, which revealed the presence of ACE I/D polymorphism. CONCLUSION: This unique report describes the association between two rare causes of hypertension in the same patient. Furthermore, the absence of requirement of mineralocorticoid supplementation in spite of bilateral adrenalectomy, represent an uncommon and interest finding.

Testicular and inguinal lymph node metastases of medullary thyroid cancer: a case report and review of the literature.

BACKGROUND: The involvement of the testis by metastatic medullary thyroid carcinoma has never been described before. We describe the first case of metastatic medullary thyroid carcinoma affecting testis and inguinal lymph nodes. CASE PRESENTATION: A 73-year-old Caucasian man was referred to undergo urologic surgery due to a painless nodule in the right testis and an homolateral inguinal lymphoadenomegaly. The patient had a history of medullary thyroid carcinoma with relapsing disease to the spine and lung nodules. Serum calcitonin and CEA levels were 175 pg/ml and 22 ng/ml, respectively. With suspected testicular cancer, the patient underwent radical right orchiectomy with the excision biopsy of the right inguinal lymph node. Histopathology and immunohistochemistry revealed that both the lesions were due to metastases from medullary thyroid carcinoma. CONCLUSION: Metastases to the testis and inguinal lymph nodes may be due to various solid and hematological tumors. This case, despite its rarity, suggests that testis and inguinal lymph nodes should be considered as potential secondary sites of medullary thyroid carcinoma as well.

Treating Hypopituitarism in the Over 65s: Review of Clinical Studies.

The current increase of life expectancy is associated with the presence of endocrine diseases in the elderly. The management of hypopituitarism in this group of patients is a challenging task. A correct diagnosis, which represents an essential requisite for an appropriate medical treatment, can be difficult because of the physiological changes occurring in pituitary function with aging, which may lead to challenges in the interpretation of laboratory results. Furthermore, the treatment requires several careful considerations: the need to restore the hormonal physiology with replacement therapies must be balanced with the need to avoid the risks of the over-replacement, especially in the presence of concomitant cardiovascular and metabolic disease. Interactions with other drugs able to modify the absorption and/or the metabolism of hormonal replacement therapies should be considered, in particular for the treatment of hypoadrenalism and hypothyroidism. The most important challenges stem from the lack of specific studies focused on the management of hypopituitarism in older people.

Bone Metabolism Effects of Medical Therapy in Advanced Renal Cell Carcinoma.

The medical therapy of advanced renal cell carcinoma (RCC) is based on the use of targeted therapies, such as tyrosine kinase inhibitors (TKI) and immune-checkpoint inhibitors (ICI). These therapies are characterized by multiple endocrine adverse events, but the effect on the bone is still less known. Relatively few case reports or small case series have been specifically focused on TKI and ICI effects on bone metabolism. However, the importance to consider these possible side effects is easily intuitable because the bone is one of the most frequent metastatic sites of RCC. Among TKI used in RCC, sunitinib and sorafenib can cause hypophosphatemia with increased PTH levels and low-normal serum calcium levels. Considering ICI, nivolumab and ipilimumab, which can be used in association in a combination strategy, are associated with an increased risk of hypocalcemia, mediated by an autoimmune mechanism targeted on the calcium-sensing receptor. A fearsome complication, reported for TKI and rarely for ICI, is osteonecrosis of the jaw. Awareness of these possible side effects makes a clinical evaluation of RCC patients on anticancer therapy mandatory, especially if associated with antiresorptive therapy such as bisphosphonates and denosumab, which can further increase the risk of these complications.

Discovery, preclinical development, and clinical application of pralsetinib in the treatment of thyroid cancer.

INTRODUCTION: The use of targeted drug therapies has substantially increased in the treatment of RET-mutated thyroid and other solid cancers over the last decade. Multi-Kinase Inhibitors (MKI) have been approved by FDA, but limited efficacies and side effects make them uneasy to tolerate. Pralsetinib is an oral highly selective RET inhibitor drug that has been generated and clinically validated to have higher potency and less toxicity. AREAS COVERED: The present paper offers a brief summary of RET-related thyroid cancer genetics, an overview of the preclinical development of pralsetinib and reviews its clinical validation in the treatment of thyroid cancer. EXPERT OPINION: Pralsetinib is a new generation oral treatment that has been approved by the FDA for patients with RET-mutated thyroid cancer. Pralsetinib showed a safer toxicity profile compared to previously approved MKI, probably due to lower inhibition of other tyrosine kinases, especially VEGFR. The approval study ARROW trial showed that patients with RET-mutant medullary thyroid cancer had a better overall response rate to pralsetinib compared to standard-of-care treatments. Additional clinical trials or data enrichment of existing databases are desirable in order to verify and further describe the clinical benefit of pralsetinib in such patients to fully understand its pharmacological profile.

Immune Checkpoint Inhibitors as a Threat to the Hypothalamus-Pituitary Axis: A Completed Puzzle.

Immune checkpoint inhibitors (ICI) prolong the survival in an increasing number of patients affected by several malignancies, but at the cost of new toxicities related to their mechanisms of action, autoimmunity. Endocrine toxicity frequently occurs in patients on ICI, but endocrine dysfunctions differ based on the ICI-subclass, as follows: agents targeting the CTLA4-receptor often induce hypophysitis and rarely thyroid dysfunction, which is the opposite for agents targeting the PD-1/PD-L1 axis. Recently, few cases of central diabetes insipidus have been reported as an adverse event induced by both ICI-subclasses, either in the context of anterior hypophysitis or as selective damage to the posterior pituitary or in the context of hypothalamitis. These new occurrences demonstrate, for the first time, that ICI-induced autoimmunity may involve any tract of the hypothalamic-pituitary axis. However, the related pathogenic mechanisms remain to be fully elucidated. Similarly, the data explaining the endocrine system susceptibility to primary and ICI-induced autoimmunity are still scarce. Since ICI clinical indications are expected to expand in the near future, ICI-induced autoimmunity to the hypothalamic-pituitary axis presents as a unique in vivo model that could help to clarify the pathogenic mechanisms underlying both the dysfunction induced by ICI to the hypothalamus-pituitary axis and primary autoimmune diseases affecting the same axis.

Grading Central Diabetes Insipidus Induced by Immune Checkpoint Inhibitors: A Challenging Task.

Central diabetes insipidus (CDI) is a rare endocrine disease deriving from an insufficient production or secretion of anti-diuretic hormone. Recently, CDI has been reported as a rare side effect triggered by immune checkpoint inhibitors (ICI) in cancer patients. Despite its current rarity, CDI triggered by ICI is expected to affect an increasing number of patients because of the expanding use of these effective drugs in a growing number of solid and hematologic malignancies. An appropriate assessment of the severity of adverse events induced by anticancer agents is crucial in their management, including dosing adjustment and temporary withdrawal or discontinuation treatment. However, assessment of the severity of CDI induced by ICI may be challenging, as its main signs and symptoms (polyuria, dehydration, weight loss, and hypernatremia) can be incompletely graded. Indeed, the current grading system of toxicity induced by anticancer treatments does not include polyuria. Additionally, dehydration in patients affected by diabetes insipidus, including ICI-induced CDI, is different in certain aspects from that due to other conditions seen in cancer patients, such as vomiting and diarrhea. This prompted us to reflect on the need to grade polyuria, and how to grade it, and to consider a specific grading system for dehydration associated with CDI induced by ICI. Here we propose a new grading system for polyuria and dehydration, as critical symptoms of the CDI syndrome occurring in patients on ICI treatment, to obtain better management of both the adverse event and the triggering drugs.

Immune Checkpoint Inhibitor-Induced Central Diabetes Insipidus: Looking for the Needle in the Haystack or a Very Rare Side-Effect to Promptly Diagnose?

Immune checkpoint inhibitors have improved the survival in patients affected by an increasing number of malignancies, but they may also trigger various autoimmune side-effects, including endocrinopathies. Very rarely, immune checkpoint inhibitors have been reported to cause central diabetes insipidus. However, with their expanding use, the likelihood that oncologists will face this endocrine adverse event is expected to increase. By reviewing the limited literature on central diabetes insipidus induced by immune checkpoint inhibitors, some inconsistencies emerge in the diagnosis and the management of patients presenting with this toxicity, together with difficulties related to classifying its severity. Until now, specific guidelines on the management of central diabetes insipidus induced by immune checkpoint inhibitors are lacking. In clinical practice, endocrinological consultation may relieve medical oncologists from difficulties in treating this side-effect; oncologists, however, remain responsible for its early diagnose and the management of the causative drugs. To this aim, some practical suggestions are advised for the multidisciplinary management of cancer patients presenting with central diabetes insipidus induced by immune checkpoint inhibitors.

Medullary Thyroid Cancer with Ectopic Cushing's Syndrome: A Case Report and Systematic Review of Detailed Cases from the Literature.

Background: Medullary thyroid cancer (MTC) is a neuroendocrine tumor arising from parafollicular C-cells of the thyroid gland that, in rare cases, can cause a paraneoplastic ectopic Cushing's syndrome (ECS). The development of Cushing's syndrome (CS) in MTC patients is generally associated with advanced disease and poor prognosis. Summary: We described a case of severe CS due to MTC in a young male. We performed a systematic review to identify cases of ECS due to MTC. We searched PubMed, Scopus, and Web of Science for publications between database inception and February 2022 and we collected the patient characteristics, disease presentation, employed treatment strategies, and disease outcomes. In addition to our patient, we identified 96 cases of ECS due to MTC reported in literature. Mean age at diagnosis was 44.4 years (range 10-84), and there was a male predominance (male:female [M:F] = 1.8:1). Most patients (51%) presented with metastatic disease at diagnosis and showed severe hypercortisolism. Seventeen patients developed distant metastasis and hypercortisolism during follow-up. Interestingly, in 48% of patients, the diagnosis of CS followed the diagnosis of MTC with a median time of 48 months but, among patients in whom the diagnosis was concomitant (38%), symptoms due to hypercortisolism were frequently the reason for seeking medical advice. Pathology results showed evidence of adrenocorticotropic hormone (ACTH) or corticotropin releasing hormone (CRH) positive cells in 76% of patients in whom they were tested. The management of hypercortisolism was challenging in most patients with 48% requiring, eventually, definitive treatment with bilateral adrenalectomy (BLA). Recently, some limited evidence has emerged regarding tyrosine kinase inhibitors (TKIs) treatment for hypercortisolism in patients with ECS due to MTC. Despite limited information on survival, prognosis was generally poor and the main causes of death were either complications of CS or disease progression. Conclusions: Despite its rarity, MTC should be considered in the differential diagnosis of ECS. Management of hypercortisolism is a key factor to improve the patient's symptoms but it is often challenging and BLA is frequently required. Further studies are needed for investigating the role of TKIs in patients with MTC with ECS.

The ancient Greek poet Sappho and the first case report of the fight-or-flight response.

Sappho has always been regarded as one of the greatest lyric poets of ancient Greece. Her famous poem Fragment 31 V., also known as the "Ode to Jealousy", accurately describes the profound emotional reaction triggered by the sight of her beloved. The poet's precise description of each sign and symptom triggered by this arousal makes Sappho 31 V., to the best of our knowledge, the first analytical description of the acute stress response, the so-called "fight-or-flight" response, in human history. Here, Fragment 31 V. is re-read from a medical point of view, correlating the ancient Greek lyric text, the corresponding medical terms, and the underlying catecholamine mechanism of action.

Cortisol circadian rhythm and jet-lag syndrome: evaluation of salivary cortisol rhythm in a group of eastward travelers.

PURPOSE: The activity of the hypothalamus-pituitary-adrenal axis plays a crucial role as an endogenous stress-reactive system. Lifestyle and work often interfere with the endogenous circadian rhythms and can modify the physiological patterns of stress-hormones secretion, including cortisol. We evaluated the cortisol circadian rhythm in the "jet-lag syndrome" that is the most known condition associated with the desynchronization of the circadian rhythm. METHODS: To assess the modifications of cortisol secretion after a long-haul flight, we compared baseline and post-travel salivary cortisol rhythm in a group of 28 healthy eastward travelers (from the U.S.A. or Canada to Italy). The salivary samples were collected about 1 week before the departure at 11 p.m. on day 0 and at 8 a.m., 12 a.m. (midday) and 11 p.m. on day 1 (R0). The same samples were obtained after the landing, the day they flew back home (R1). RESULTS: Statistical analysis showed a significant difference between R0 and R1 for each sample considered (p < 0.005). In particular, the post-travel salivary cortisol levels detected at 11 p.m. both on day 0 and on day 1, were significantly higher than at baseline. Post-travel morning salivary cortisol levels were lower compared with basal rhythm and increased during the morning, reaching the acrophase at 12 a.m. CONCLUSIONS: In eastward travelers, crossing more than five time zones, the cortisol circadian rhythm after the return to the East "remained behind," being synchronized with the West time. This impaired cortisol secretion can contribute to the pathogenesis of the jet-lag syndrome.

Medical Approaches in Adrenocortical Carcinoma.

Adrenocortical carcinoma (ACC) represents one of the most aggressive endocrine tumors. In spite of a correct therapeutic strategy based on a multidisciplinary approach between endocrinologist, surgeon and oncologist, the prognosis is often poor. Surgery is the mainstay treatment in ACC. Mitotane, a dichloro-diphenyl-trichloro-ethane derivate, represents the main medical treatment of ACC in consideration of its adrenocytolitic activity and it is mainly employed as adjuvant treatment after complete surgical resection and for the treatment of advanced ACC. However, the use of mitotane as adjuvant therapy is still controversial, also in consideration of the retrospective nature of several studies. The recurrence of disease is frequent, especially in advanced disease at the diagnosis. Therefore, in these contexts, conventional chemotherapy must be considered in association with mitotane, being the combination etoposide, doxorubicin and cisplatin (EDP) the standard of care in this setting. A more modern therapeutic approach, based on the need of a salvage therapy for advanced ACC that progresses through first-line EDP, is focused on molecular-targeted therapies. However, robust clinical trials are necessary to assess the real efficacy of these treatments.

Switching From Immediate-Release to Fractionated Dual-Release Hydrocortisone May Improve Metabolic Control and QoL in Selected Primary Adrenal Insufficiency Patients.

Objective: The use of once-daily dual-release HC (DR-HC) in primary adrenal insufficiency (PAI) is often associated with benefits in metabolic parameters when compared to immediate-release HC (IR-HC). In this study, we evaluated the effects on clinical, biochemical and metabolic parameters of switching from IR-HC to lower-dose DR-HC given both in once and fractionated daily doses. Methods: Twenty autoimmune-PAI subjects were included. Patients on 30 mg/day divided in three doses IR-HC regimen (group A) were switched to DR-HC 25 mg/day given in two daily doses (20 mg in the morning and 5 mg at 2.00 p.m.); patients on 25 mg/day divided in two doses IR-HC regimen (group B) were switched to DR-HC 20 mg once daily. Biochemical and metabolic parameters, BMI and quality of life (QoL) were evaluated at the baseline and six months after the switch. Results: Our small non-randomized study with short follow up showed significant benefits in both group A and group B without any apparent side-effects. After the switch to DR-HC, a significant decrease in adrenocorticotropic hormone (ACTH), HbA1c, total cholesterol, triglycerides, LDL, cholesterol, BMI as well as a significant improvement in QoL, were observed in both groups. At 6 months, ACTH levels were lower in group A while HbA1C and total cholesterol were lower in group B. Conclusion: The DR-HC is a valid and effective therapeutic strategy to improve the metabolic control and the QoL in PAI. The reduction of ACTH levels with DR-HC regimens reflects a better biochemical control of PAI, obtained by using a lower dose and more physiological HC formulation. Both once-daily and fractionated daily doses of DR-HC showed advantages compared with IR-HC formulation.

Immunoassay Interference on Thyroid Function Tests During Treatment with Nivolumab.

Background: Immune checkpoint inhibitors (ICIs) are associated with several endocrine side effects. In particular, the use of programmed cell death protein-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) inhibitors is related to a higher incidence of thyroid dysfunction. Patient Findings: An 85 years-old patient, diagnosed with a metastatic melanoma treated with nivolumab, presented to our hospital with severe ICI-related thyrotoxicosis. Diagnosis was complicated by a biochemical interference on thyroid hormones assay, probably induced by nivolumab. Summary: Baseline laboratory examination conducted before onset of anticancer therapy showed normal thyroid function test (TFTs). A few days after receiving the second nivolumab administration, the patient developed a severe thyrotoxicosis. According to destructive thyroiditis, in a short period thyrotropin (TSH) levels normalized and rapidly increased, but free thyroxine (fT4) levels were inappropriately elevated and did not decrease as expected. The sample was processed by using a Siemens Centaur® immunoassay. We reanalyzed the same sample at another laboratory and with a different immunoassay method (Roche Elecsys®). The results obtained from this assay confirmed severe hypothyroidism with appropriately low fT4 levels. We suspected a possible nivolumab-associated interference on the fT4 assay. Therefore, we subjected the same sample to a polyethylene glycol (PEG) 6000 precipitation, a simple method for the removal of macromolecules, before assaying for fT4 levels. Evaluation of the post-PEG-precipitation sample (Siemens Centaur immunoassay) revealed appropriately low fT4 levels. The patient was started on levothyroxine (LT4) therapy, with monthly TFT monitoring using the Roche immunoassay. Approximately 9 months after starting nivolumab therapy, the patient was advised treatment cessation. A month later, the TFTs were retested on a Siemens Centaur immunoassay, and appropriate fT4 levels were observed in accordance with normal TSH levels on adequate LT4 replacement therapy. Conclusions: We report a possible novel nivolumab-induced biochemical interference on assays of fT4 levels. The hypothesis of a biochemical drug-induced interference is further supported by the disappearance of the interference after the withdrawal of nivolumab. Further studies are needed to prove the biochemical mechanisms of this interference.