Efficacy of pasireotide LAR for acromegaly: a prolonged real-world monocentric study.

Background: Acromegaly is caused by excessive growth hormone (GH) and insulin-like growth factor 1 (IGF1). Medical therapy plays a role as a treatment option for persistent disease after non-curative surgery or as a first-line therapy when surgery is not feasible. Pasireotide-LAR (Pas-LAR) is recommended for patients with acromegaly as second-line treatment. Aim: To evaluate the patients characteristics predictive of an adequate response to Pas-LAR and the long-term efficacy and safety of the Pas-LAR treatment. Methods: Data from 19 patients with active acromegaly, who were and resistant or intolerant to first-line medical therapy and were switched to pas-LAR have been retrospectively collected. We compared the baseline clinical and biochemical characteristics of patients who were found to respond to Pas-LAR therapy (responders, n=14) with those of patients who did not respond (non-responders, n=5). We then evaluated the Pas-LAR efficacy and safety during long-term follow-up in responders. Results: IGF1 normalization occurred in 71.4% of responders after one injection. IGF1 levels, [median(interquartile range) of the upper limit of the normal range (ULN) fold increase] were higher in non-responders compared to responders within the initial month of therapy [1.40(1.30-2.34) vs 0.70(0.55-1.25), respectively, p=0.009] and after three [1.77(1.74-2.29) vs 0.94(0.82-1.13), respectively, p=0.029] and six months [1.68(1.33-1.72) vs 1.00(0.65 -1.28), respectively, p=0.002]. Out of 6 patients with symptomatic headache (all in responder group), 5 and 1 reported the resolution and improvement of headache, respectively, already after the first injection. Median HbA1c levels tended to increase from baseline to 6 months both in responder (36 mMol/Mol to 42 mMol/Mol) and non-responder patients (45 mMol/Mol to 48 mMol/Mol). During long term follow up, in the responder group 2 new patients developed diabetes. Tumor shrinkage was observed in 6 out of 7 evaluated responders, with no cases of size increase during the long-term follow-up. Conclusion: Pas-LAR is effective and safe and the early identification of responders is possible just after the first administration.

Case Report: Opposite Tumoral and Hormonal Responses to Low-dose Pasireotide in Cushing's Disease.

BACKGROUND: Pasireotide is a multireceptor somatostatin analogue approved for the treatment of patients with Cushing's disease (CD) who are ineligible or poor candidates for pituitary surgery. Here we present a patient with severe recurrent CD who was treated with pasiretide and showed opposite results between hormonal levels and pituitary tumour size. CASE PRESENTATION: A 54-year-old woman was diagnosed with CD, a first surgical transsphenoidal procedure was performed at the time of diagnosis, and the disease recurred seven years later. She underwent a second transsphenoidal surgery, but despite apparent complete removal of the adenoma, the hypercortisolism worsened. Magnetic resonance imaging showed a tiny remnant of the adenoma adjacent to the cavernous sinus, and ketoconazole was started at a dose of 800 mg/day. Due to the persistence of pathological urinary free cortisol levels, 600 µg bid pasireotide was added. The combination therapy induced first normalisation of urinary free cortisol and later hypoadrenalism, so that ketoconazole was discontinued and pasireotide was maintained. A marked clinical improvement was achieved with pasireotide. Adrenal insufficiency persisted despite progressive tapering of the pasireotide dose to 150 mg once daily. Pituitary magnetic resonance imaging performed at 12 and 24 months during low-dose pasireotide treatment showed a few millimetres increase of the remnant. CONCLUSIONS: This report suggests that CD Pas induces an opposite effect between hormonal profile and increase of pituitary tumor size. This peculiar phenomenon may be a consequence of the unusually low doses of pasireotide needed to control hormonal hypersecretion.

ACTH Stimulation Test for the Diagnosis of Secondary Adrenal Insufficiency: Light and Shadow.

Secondary Adrenal Insufficiency (SAI) is a condition characterized by inappropriately low ACTH secretion due to a disease or injury to the hypothalamus or the pituitary. The evaluation when suspected is often challenging for the non-specific symptoms, the rarity of the disease, and the pitfalls associated with laboratory tests. A prompt and correct diagnosis of SAI is essential because although an adequate hormonal replacement therapy could be lifesaving, inappropriate life-long therapy with steroids can be harmful. The gold standard test for assessing the hypothalamus-pituitary-adrenal axis (HPA) is the insulin tolerance test (ITT), but due to safety issues is not widely used. Conversely, the ACTH stimulation test is a safer and well-tolerated tool for SAI diagnosis. However, data about its diagnostic accuracy show great variability due to both technical and interpretative aspects, such as dose, route of administration, the timing of the test, and assay used for cortisol measurements. Consequently, the clinical background of the patient and the pretest probability of HPA axis impairment become of paramount importance. We aimed to summarize the recent literature evidence in the conduction and interpretation of the ACTH stimulation test for the diagnosis of SAI to provide updated insights on its correct use in clinical practice.

Osilodrostat in Cushing's disease: the management of its efficacy and the pitfalls of post-surgical results.

Summary: Osilodrostat is a novel, orally administered cortisol synthesis inhibitor, approved in 2020 by the European Medicines Agency (EMA) for the treatment of Cushing's syndrome in adults. A significant amount of the studies currently available in the literature focus on treatment in patients with Cushing's disease. However, data collected from patients treated with osilodrostat in real-life settings still represents a small entity. For this reason, in this article, we will discuss two real-life cases of patients with Cushing's disease treated with this drug. The first report is about a 35-year-old woman with an adrenocorticotrophic hormone (ACTH)-secreting adenoma. After non-curative trans-nasal-sphenoidal (TNS) surgery, due to a small remnant of the adenoma, medical therapy with osilodrostat achieved fast and effective biochemical and clinical response. During treatment, progressive increase of ACTH levels and an enlargement of the pituitary remnant were documented, with planned radiosurgical treatment. The second case reports a 32-year-old man diagnosed with Cushing's disease in 2020, who, after surgery refusal, started osilodrostat at progressively up-titrated doses, according to 24 h urinary free cortisol levels, up to 5 mg twice a day. With osilodrostat, the patient reached biochemical and clinical control of disease until TNS surgery in October 2021, with complete remission. The first post-surgical biochemical assessment was equivocal in spite of a transient clinical hypoadrenalism, reverted after 2 months with the restoration of physiological hypothalamic-pituitary-adrenal axis (HPA) function. Learning points: Osilodrostat is a potent oral drug viable for Cushing's disease as medical therapy when surgery is not feasible or remission cannot be reached. Osilodrostat proves to be a safe drug and its main adverse effect is hypoadrenalism, due to the adrenolytic action of the compound. Osilodrostat needs a very tailored approach in its clinical use because there is no correlation between the level of hypercortisolism pre-treatment and the dose required to reach disease control.

Clinical Management of Acromegaly: Therapeutic Frontiers and New Perspectives for Somatostatin Receptor Ligands (SRLs).

Somatostatin receptor ligands (SRLs) represent a true milestone in the medical therapy for acromegaly. The first-generation SRLs (FG-SRLs), octreotide and lanreotide, have demonstrated good efficacy in disease control and tumor shrinkage, and are still considered first-line medical therapies. The development of long-acting release (LAR) formulations has certainly improved the therapeutic tolerability of these drugs, although many patients still experience therapy-related burden. As such, new formulations have recently been developed to improve adherence and therapeutic efficacy and more solutions are on the way. In the case of FG-SRL-resistant disease, pasireotide, the only second generation SRL currently available, demonstrated superiority in disease control and tumor shrinkage compared to FG-SRLs. However, its use in clinical practice is still limited due to concern for impairment in glucose homeostasis. In this review, we discuss the news about the present and future role of SRLs in acromegaly, exploring the therapeutical frontiers of this drug class. Moreover, we provide practical guidance on the use of pasireotide, based on the data in the literature and our clinical experience.

A Tale of Two Hypersecreting Adrenal Neoplasms in the Heartland of COVID-19 Pandemic, Lombardy, Italy.

In this study, we report the management, in Lombardy, Italy, of one patient with Cushing's syndrome due to adrenal adenoma and another one with pheochromocytoma, whose surgeries were deferred owing to the COVID-19 pandemic.

Autoimmune Polyendocrine Syndrome Complicated by Pulmonary Hypertension.

A 24-years old female was admitted for acute renal failure, melanoderma, hyponatremia, and hyperkalemia. The clinical suspicion of Addison's disease was confirmed by laboratory test and the appropriate replacement therapy with corticosteroids and fludrocortisone was started. In the meantime primary hypothyroidism and diabetes mellitus type 1 were disclosed and treated, thus fulfilling a diagnosis of autoimmune polyendocrine syndrome type 2. Eighteen months later she was admitted for right-sided heart failure. The work-up allowed to diagnose pulmonary arterial hypertension. Here, we report the clinical course and discuss the putative link between these two rare diseases.

False Positive of 68Ga-DOTATATE PET-CT in a Paraganglioma.

BACKGROUND: Functional imaging with 68Ga-DOTATATE PET-CT is widely employed to detect both primary and metastatic pheochromocytomas and paragangliomas (PGL), but its results may be occasionally misleading as in the case here reported. CASE PRESENTATION: We report here a 75-year-old woman with an interaortocaval PGL that was diagnosed after a hypertensive crisis occurring during the resection of a kidney tumor. 68Ga-DOTATATE PET-CT disclosed pathologic uptake in the abdomen and at the iliac crest. After the resection of the abdominal tumor, with the histological confirmation of PGL, arterial blood pressure and metanephrine levels were normalized. Genetic testing was negative. Thereafter, the bone lesion increased in size and became painful, requiring multiple medications. A selective biopsy disclosed a metastatic lesion arising from the renal tumor. CONCLUSION: The false-positive result of 68Ga-DOTATATE PET-CT is discussed.

Hyponatremia after anticoagulant treatment: a rare cause of adrenal failure

A 69-year-old male was admitted for severe hyponatremia disclosed after an accidental fall. He was anticoagulated from 2 months after the implantation of a biologic aortic valve prosthesis. The work-up disclosed adrenal failure and MRI showed bilateral adrenal hemorrhage. Clinical picture and lab parameters normalized quickly after the appropriate replacement treatment. Anticoagulation excess should be added to the list of drugs potentially causing hyponatremia. Learning points: •• Hyponatremia requires a complete and timely workup in order to start an appropriate treatment for the improvement of clinical conditions. •• History is crucial: a detailed list of drugs potentially causing hyponatremia should be collected. Anticoagulants should be added to the list, mostly in the event of excessive anticoagulation. •• Intra-adrenal hemorrhage is a rare cause of hyponatremia and adrenal failure. •• The ACTH test is still the gold standard for the diagnosis of hypoadrenalism.

Effective long-term temozolomide rechallenge in a macroprolactinoma

We describe the 20-year course of a 63-year-old male with a macroprolactinoma that acquired resistance to treatment and aggressive behavior after a 4-year successful treatment with cabergoline. He was submitted to multiple surgical resections by a skilled surgeon, fractionated radiotherapy and was eventually treated with temozolomide. After a first 6-month standard cycle, a relapse occurred and he was treated again successfully. Learning points: •• Prolactinomas are the most frequent type of pituitary adenoma. •• They usually have a benign course. •• In most cases dopamine-agonist drugs, mainly cabergoline, are first-line (and usually only) treatment. •• Occasionally prolactinomas can have or acquire resistance to treatment and/or aggressive behavior. •• Temozolomide (TMZ), an oral alkylating drug, can be effective in such aggressive tumors. •• Multimodal treatment (surgery, radiation, cabergoline and TMZ) is warranted in aggressive pituitary tumors. •• We describe here successful rechallenge with TMZ after relapse occurring 18 months after a first TMZ cycle.

Six controversial issues on subclinical Cushing's syndrome.

Subclinical Cushing's syndrome is a condition of hypercortisolism in the absence of signs specific of overt cortisol excess, and it is associated with an increased risk of diabetes, hypertension, fragility fractures, cardiovascular events and mortality. The subclinical Cushing's syndrome is not rare, being estimated to be between 0.2-2 % in the adult population. Despite the huge number of studies that have been published in the recent years, several issues remain controversial for the subclinical Cushing's syndrome screening, diagnosis and treatment. The Altogether to Beat Cushing's syndrome Group was founded in 2012 for bringing together the leading Italian experts in the hypercortisolism-related diseases. This document represents the Altogether to Beat Cushing's syndrome viewpoint regarding the following controversial issues on Subclinical Cushing's syndrome (SCS): (1) Who has to be screened for subclinical Cushing's syndrome? (2) How to screen the populations at risk? (3) How to diagnose subclinical Cushing's syndrome in patients with an adrenal incidentaloma? (4) Which consequence of subclinical Cushing's syndrome has to be searched for? (5) How to address the therapy of choice in AI patients with subclinical Cushing's syndrome? (6) How to follow-up adrenal incidentaloma patients with subclinical Cushing's syndrome surgically or conservatively treated? Notwithstanding the fact that most studies that faced these points may have several biases (e.g., retrospective design, small sample size, different criteria for the subclinical Cushing's syndrome diagnosis), we believe that the literature evidence is sufficient to affirm that the subclinical Cushing's syndrome condition is not harmless and that the currently available diagnostic tools are reliable for identifying the majority of individuals with subclinical Cushing's syndrome.

Bilateral inferior petrosal sinus sampling.

Simultaneous bilateral inferior petrosal sinus sampling (BIPSS) plays a crucial role in the diagnostic work-up of Cushing's syndrome. It is the most accurate procedure in the differential diagnosis of hypercortisolism of pituitary or ectopic origin, as compared with clinical, biochemical and imaging analyses, with a sensitivity and specificity of 88-100% and 67-100%, respectively. In the setting of hypercortisolemia, ACTH levels obtained from venous drainage of the pituitary are expected to be higher than the levels of peripheral blood, thus suggesting pituitary ACTH excess as the cause of hypercortisolism. Direct stimulation of the pituitary corticotroph with corticotrophin-releasing hormone enhances the sensitivity of the procedure. The procedure must be undertaken in the presence of hypercortisolemia, which suppresses both the basal and stimulated secretory activity of normal corticotrophic cells: ACTH measured in the sinus is, therefore, the result of the secretory activity of the tumor tissue. The poor accuracy in lateralization of BIPSS (positive predictive value of 50-70%) makes interpetrosal ACTH gradient alone not sufficient for the localization of the tumor. An accurate exploration of the gland is recommended if a tumor is not found in the predicted area. Despite the fact that BIPSS is an invasive procedure, the occurrence of adverse events is extremely rare, particularly if it is performed by experienced operators in referral centres.

Effectiveness of low-dose pasireotide in a patient with Cushing's disease: antiproliferative effect and predictivity of a short pasireotide suppression test.

This case shows efficacy of low-dose pasireotide in biochemical and clinical control of severe hypercortisolism and in tumor volume reduction in a patient with an ACTH-secreting macroadenoma. The drug may be an option for long-term treatment in some patients where control of tumor mass is an important clinical endpoint.

Pitfalls in genetic analysis of pheochromocytomas/paragangliomas-case report.

CONTEXT: About 35% of patients with pheochromocytoma/paraganglioma carry a germline mutation in one of the 10 main susceptibility genes. The recent introduction of next-generation sequencing will allow the analysis of all these genes in one run. When positive, the analysis is generally unequivocal due to the association between a germline mutation and a concordant clinical presentation or positive family history. When genetic analysis reveals a novel mutation with no clinical correlates, particularly in the presence of a missense variant, the question arises whether the mutation is pathogenic or a rare polymorphism. OBJECTIVE: We report the case of a 35-year-old patient operated for a pheochromocytoma who turned out to be a carrier of a novel SDHD (succinate dehydrogenase subunit D) missense mutation. With no positive family history or clinical correlates, we decided to perform additional analyses to test the clinical significance of the mutation. METHODS: We performed in silico analysis, tissue loss of heterozygosity analysis, immunohistochemistry, Western blot analysis, SDH enzymatic assay, and measurement of the succinate/fumarate concentration ratio in the tumor tissue by tandem mass spectrometry. RESULTS: Although the in silico analysis gave contradictory results according to the different methods, all the other tests demonstrated that the SDH complex was conserved and normally active. We therefore came to the conclusion that the variant was a nonpathogenic polymorphism. CONCLUSIONS: Advancements in technology facilitate genetic analysis of patients with pheochromocytoma but also offer new challenges to the clinician who, in some cases, needs clinical correlates and/or functional tests to give significance to the results of the genetic assay.

Succinate dehydrogenase subunit B mutations modify human neuroblastoma cell metabolism and proliferation.

Paragangliomas (PGLs) are rare neuroendocrine tumours. About 30-40 % of these tumours are mutated in one of the different susceptibility genes, including those encoding the different subunits of the succinate dehydrogenase, a complex involved both in the tricarboxylic acid cycle and in the oxygen transport chain. The aim of this work was to investigate whether SDHB mutations may account for alterations in cell metabolism and functions. Since human PGL cell lines are not available, we used the neuroblastoma cell line (SK-N-AS) stably transfected with the wild-type human SDHB or different SDHB-mutated constructs carrying some significant mutations found in our patients affected by PGLs. Similarly to succinate dehydrogenase (SDH)-mutated tumour cells, mutated SK-N-AS clones showed reduced SDH enzyme activity. All clones showed normal citrate synthase activity, reduced oxygen consumption and reduced carbonic anhydride production, thus demonstrating a decreased in mitochondrial metabolism. In two of the three mutated SK-N-AS, we also found an increase in HIF1α expression. Surprisingly and unexpectedly, in all the SDHB-mutated clones, we found a significant decrease in glucose uptake and in lactate culture medium concentration, suggesting also a decrease of cytosolic metabolism. Finally, we found that these energetic changes were associated to an increase in cell proliferation and migration. Overall, these data demonstrate that although SDHB mutations significantly downregulate both mitochondrial and cytoplasmic cellular metabolism, these mutations are associated to an upregulation of some cellular functions, such as growth rate and invasiveness.

Updated and new perspectives on diagnosis, prognosis, and therapy of malignant pheochromocytoma/paraganglioma.

Malignant pheochromocytomas/paragangliomas are rare tumors with a poor prognosis. Malignancy is diagnosed by the development of metastases as evidenced by recurrences in sites normally devoid of chromaffin tissue. Histopathological, biochemical, molecular and genetic markers offer only information on potential risk of metastatic spread. Large size, extraadrenal location, dopamine secretion, SDHB mutations, a PASS score higher than 6, a high Ki-67 index are indexes for potential malignancy. Metastases can be present at first diagnosis or occur years after primary surgery. Measurement of plasma and/or urinary metanephrine, normetanephrine and metoxytyramine are recommended for biochemical diagnosis. Anatomical and functional imaging using different radionuclides are necessary for localization of tumor and metastases. Metastatic pheochromocytomas/paragangliomas is incurable. When possible, surgical debulking of primary tumor is recommended as well as surgical or radiosurgical removal of metastases. I-131-MIBG radiotherapy is the treatment of choice although results are limited. Chemotherapy is reserved to more advanced disease stages. Recent genetic studies have highlighted the main pathways involved in pheochromocytomas/paragangliomas pathogenesis thus suggesting the use of targeted therapy which, nevertheless, has still to be validated. Large cooperative studies on tissue specimens and clinical trials in large cohorts of patients are necessary to achieve better therapeutic tools and improve patient prognosis.

Head and neck paragangliomas: genetic spectrum and clinical variability in 79 consecutive patients.

Head and neck paragangliomas (HNPGLs) are neural crest-derived tumors. In comparison with paragangliomas located in the abdomen and the chest, which are generally catecholamine secreting (sPGLs) and sympathetic in origin, HNPGLs are, in fact, parasympathetic in origin and are generally nonsecreting. Overall, 79 consecutive patients with HNPGL were examined for mutations in SDHA, SDHB, SDHC, SDHD, SDHAF2, VHL, MAX, and TMEM127 genes by PCR/sequencing. According to a detailed family history (FH) and clinical, laboratory (including metanephrines), and instrumental examinations, patients were divided into three groups: a) patients with a positive FH for HNPGL (index cases only), b) patients with a negative FH and multiple HNPGLs (synchronous or metachronous) or HNPGL associated with an sPGL, and c) patients with negative FH and single HNPGL. The ten patients in group a) proved to be SDHD mutation carriers. The 16 patients in group b) proved to be SDHD mutation carriers. Among the 53 patients in group c), ten presented with germ-line mutations (three SDHB, three SDHD, two VHL, and two SDHAF2). An sPGL was found at diagnosis or followed up in five patients (6.3%), all were SDHD mutation carriers. No SDHC, SDHA, MAX, and TMEM127 mutations were found. In SDHD mutation carriers, none of the patients affected by HNPGL associated with sPGL presented missense mutations. In conclusion, a positive FH or the presence of multiple HNPGLs is a strong predictor for germ-line mutations, which are also present in 18.8% of patients carefully classified as sporadic. The most frequently mutated gene so far is SDHD but others, including SDHB, SDHAF2, and VHL, may also be affected.