The Pathophysiology and Treatment of Hypertension in Patients With Cushing's Syndrome

When hypertension, a pathology that is frequently found in the general population, presents in a young patient, secondary causes such as Cushing's syndrome (CS), a rare disease characterized by long-term elevated cortisol levels, should be considered. Present in ~80% of CS patients independently of their age and sex, hypertension is one of the pathology's most prevalent, alarming features. Its severity is principally associated with the duration and intensity of elevated cortisol levels. Prompt diagnosis and rapid initiation of treatment are important for reducing/delaying the consequences of hypercortisolism. Glucocorticoid excess leads to hypertension via a variety of mechanisms including mineralocorticoid mimetic activity, alterations in peripheral and renovascular resistance, and vascular remodeling. As hypertension in CS patients is caused by cortisol excess, treating the underlying pathology generally contributes to reducing blood pressure (BP) levels, although hypertension tends to persist in approximately 30% of cured patients. Surgical removal of the pituitary tumor remains the first-line treatment for both adrenocorticotropin hormone (ACTH) dependent and independent forms of the syndrome. In light of the fact that surgery is not always successful in curing the underlying disease, it is essential that other treatments be considered and prescribed as needed. This article discusses the mechanisms involved in the pathogenesis of CS and the pros and the cons of the various antihypertensive agents that are presently available to treat these patients

Dynamic testing for differential diagnosis of ACTH-dependent Cushing Syndrome: a systematic review and meta-analysis

Objective Diagnostic accuracy of testing currently used for differential diagnosis of Cushing’s disease (CD) vs ectopic adrenocorticotropic hormone (ACTH) secretion (EAS) is difficult to interpret. The present study aimed to identify and evaluate diagnostic accuracy of corticotropin-releasing hormone (CRH) test, desmopressin test, and high-dose dexamethasone suppression test (HDDST) when used to establish a CD or EAS diagnosis. Design This study is a systematic review of the literature and meta-analysis. Methods MEDLINE, OVID, and Web of Science databases were searched for articles published between the years 1990-2021. Articles included described at least one test(s) (CRH, desmopressin, or HDDST) and diagnostic reference standard(s) (histopathology, petrosal sinus sampling, surgical remission, imaging, and long-term follow-up) to establish a CD or EAS diagnosis. Results Sixty-two studies were included: 43 reported use of HDDST, 32 CRH test, and 21 desmopressin test. After analysis a CRH test was found to have the highest sensitivity in detecting CD (ACTH 86.9%, 95% confidence interval [CI] 82.1-90.6, cortisol 86.2%, 95%CI 78.3-91.5) and the highest specificity in detecting EAS (ACTH 93.9%, 95%CI 87-98.3, cortisol 89.4%, 95%CI 82.8-93.7). This resulted in a high diagnostic odds ratio (58, 95%CI 43.25-77.47), large area under the curve, and a receiver-operating characteristic (ROC) of 0.934. The diagnostic accuracy of HDDST and desmopressin test(s) was lower than that of the CRH test. Conclusion The meta-analysis indicates that a patient with a positive ACTH response after a CRH test is highly likely to have CD. Further studies analysing role of dynamic testing in addition to imaging are needed

Diabetes mellitus secondary to Cushing's disease

Associated with important comorbidities that significantly reduce patients’ overall wellbeing and life expectancy, Cushing’s disease (CD) is the most common cause of endogenous hypercortisolism. Glucocorticoid excess can lead to diabetes, and although its prevalence is probably underestimated, up to 50% of patients with CD have varying degrees of altered glucose metabolism. Fasting glycemia may nevertheless be normal in some patients in whom glucocorticoid excess leads primarily to higher postprandial glucose levels. An oral glucose tolerance test should thus be performed in all CD patients to identify glucose metabolism abnormalities. Since diabetes mellitus (DM) is a consequence of cortisol excess, treating CD also serves to alleviate impaired glucose metabolism. Although transsphenoidal pituitary surgery remains the first-line treatment for CD, it is not always effective and other treatment strategies may be necessary. This work examines the main features of DM secondary to CD and focuses on antidiabetic drugs and how cortisol-lowering medication affects glucose metabolism

Second line tests in the differential diagnosis of neoplastic and non-neoplastic hypercortisolism: a systematic review and meta-analysis

Introduction: The clinical and hormonal overlap between neoplastic (CS) and non-neoplastic (NNH/pCS) hypercortisolism is a well-known challenge. The gold standard for the diagnosis of NNH/pCS is the resolution/lack of progression of the hypercortisolism over an adequate follow-up period. Various dynamic tests have been proposed to allow an early discrimination between these conditions, but to date there is no agreement on which of them should be used. Aim: To provide an overview of the available tests and to obtain a quantitative synthesis of their diagnostic performance in discriminating NNH/pCS from CS. Methods: An extensive search in Ovid (including Cochrane, Medline and Embase databases) was performed for articles published between 1990 and 2022. The included articles applied one or more second-line tests to differentiate NNH/pCS from CS patients. For the NNH/pCS group, we admitted the inclusion of patients presenting clinical features and/or biochemical findings suggestive of hypercortisolism despite apparent lack of a pCS-related condition. Results: The electronic search identified 339 articles. After references analysis and study selection, we identified 9 studies on combined dexamethasone-corticotropin releasing hormone (Dex-CRH) test, 4 on Desmopressin test and 3 on CRH test; no study on Dex-Desmopressin met the inclusion criteria. Dex-CRH test provided the highest sensitivity (97%, 95CI% [88%; 99%]). CRH tests showed excellent specificity (99%, 95%CI [0%; 100%]), but its sensitivity was lacking. Although metaregression analysis based on diagnostic odds ratio failed to provide a gold standard, CRH test (64.77, 95%CI [0.15; 27174.73]) seemed to lack in performance compared to the others (Dex-CRH 138.83, 95%CI [49.38; 390.32] and Desmopressin 110.44, 95%CI [32.13; 379.63]). Discussion: Both Dex-CRH and Desmopressin tests are valid tools in discriminating NNH/pCS from CS patients, with the first probably achieving slightly better performance and the latter being more suitable for clinical practice. We do not recommend CRH test alone in this setting, although its combination with other tests could be further researched. Further studies are needed on this topic, possibly focusing on mild Cushing’s Disease and clinically well-characterized NNH/pCS patients

CT Texture Analysis of Adrenal Pheochromocytomas: a Pilot Study

Abstract: Since radiomics is a promising field of research, we tried to study the application of CT texture analysis in pheochromocytomas (PCCs) and the correlation between the features extracted and the secretory and histopathological data. 17 patients affected by surgically removed PCCs were retrospectively enrolled. Before surgery, all patients underwent contrast-enhanced CT. Patients had catecholamine secretion data available and Adrenal gland Scaled Score (PASS) of the histopathological examination. After a resampling of all CT images, the PCCs were delineated using the LifeX software in all three phases (unenhanced, arterial, and venous) and 58 texture parameters were extracted for each volume of interest. Through the Mann-Whitney test, the correlation between the hormonal hypersecretion, the malignancy score of the lesion (PASS>4), and texture parameters were studied. In the comparison between secreting and non-secreting catecholamine tumors the parameters DISCRETIZED_HUpeak e GLZLM_GLNU in the unenhanced phase and GLZLM_SZE, CONVENTIONAL_HUmean, CONVENTIONAL_HUQ3, DISCRETIZED_HUmean, DISCRETIZED_AUC_CSH, GLRLM_HGRE and GLZLM_SZHGE in the venous phase showed a statistically significant difference (p<0.01) while in the comparison between tumours with low and high PASS the parameters GLZLM_GLNU in unenhanced phase and GLRLM_GLNU e GLRLM_RLNU in the venous phase showed a statistically significant difference. CT texture analysis of pheochromocytomas can be a useful tool for the identification of malignant lesions and lesions that present hormonal hypersecretion

Personalized medical treatment for pituitary adenoma

Introduction and Aim: Pituitary adenomas are common neoplasms, with a reported prevalence of about one case in 1000 subjects. Patients with pituitary adenomas show significant morbidity due to pituitary hormone hypersecretion or deficiencies, mass effects and infiltration of the surrounding tissues. Although trans-sphenoidal surgery and radiotherapy are largely used to treat patients with pituitary adenomas, the overall long-term remission rate is not complete, beside side effects of surgery or brain irradiation. Therefore, medical treatments with pituitary-directed drugs are increasingly used in patients with secreting pituitary adenomas, especially when surgery fails or is not indicated, or awaiting for effects of radiotherapy. Somatostatin analogues (SSA) have been the mainstay of the medical treatment of GH-secreting adenomas, and nowadays are also used to treat ACTH-secreting pituitary adenomas, since these tumours express several types of somatostatin receptors (SSTR), with the prevalence of SSTR type 2 in the GH-secreting PA and of SSTR type 5 in the ACTH-secreting. Regrettably, 50% of patients with GH- secreting and 60% with ACTH- secreting pituitary adenomas do not respond to medical treatment with pituitary-directed drugs, or present only a partial hormonal reduction. Receptor desensitization, internalization and intra-cellular trafficking of SSTR could explain at least partially the lack of response, hence more data and knowledge about these cellular processes are urgently needed. Moreover, pituitary adenomas are not always benignant: some aggressive cases (up to 15-20% in all series) are characterized by rapid regrowth after first surgery, invasion of the surrounding structure, resistance to medical therapy, therefore the term Pituitary Neuroendocrine Tumor (PitNET) should be actually used. The aims of this PhD project are to describe the role of medical treatment in patients with PitNET, in order to study the efficacy of available compounds; applicate the combination of medical treatment in clinical practice; analyse the differential effects (if existing) of medical treatment compared to surgery (considered the best curative treatment). Materials and methods: Among our cohort of patients (120 with GH-, 134 with ACTH-, 171 with PRL-, 6 with TSH- secreting PitNET, 150 with non-secreting PitNET), we retrospectively and prospectively analysed clinical, radiological and pathological features of patient. Considering the treatment of aggressive PitNET or patients with Cushing’s Syndrome, we focused our attention to everolimus, temozolomide (TMZ) and metyrapone (MET) treatment. In some case, primary cell culture were used to study the effect of medical treatment. Results: Regarding medical treatment, we considered the use of everolimus, TMZ, cabergoline and MET. 1. In a patient with tuberous sclerosis complex (TSC) and silent gonadotroph PitNET we tested the efficacy of everolimus, observing a reduction of cell viability after an in vitro treatment of PitNET’s derived primary cells. TSC analysis retrieved no disease-associated variants with the exception of the heterozygous intronic variant c.4006-71C>T found in TSC2: the computational tools predicted a gain of a new splice site with consequent intron retention, not confirmed by an in-vitro analysis of patient’s lymphocyte derived RNA. 2. Regarding TMZ in aggressive PitNET, we conducted an Italian survey on 31 patients: 11 patients (35.5%) had reduction of the tumor during TMZ treatment, while 6 patients (19.4%) had progression of disease. Median follow-up after start of TMZ was 18 months. Seven patients presented disease progression. The 2-yr recurrence-free survival was 62% (95% C.I., 34 -99%). Seven patients died of progressive disease. The 2-yr and 4-yr survival rates were 90% (95% C.I., 77-100%) and 56% (95% C.I., 26-85%). Moreover, we treated a patient with a combined cabergoline+TMZ treatment, achieving excellent results. 3. Considering MET in patients with Cushing’s Syndrome, patients were treated with a median dose of 1000 mg for 9 months. UFC and LNSC decreased quickly after the first month of treatment (-67% and -57% from baseline), with sustained UFC normalization up to 12 and 24 months (in 13 and 6 patients, respectively). UFC and LNSC normalized later (after 3-6 months) in patients with severe hypercortisolism (>5-fold baseline UFC). Regarding last visit, 70% and 37% of patients normalized UFC and LNSC, respectively. Body weight reduction (-4kg) was observed after UFC normalization. Severe side-effects were not reported, half female patients complained hirsutism, and blood pressure was not increased. 4. In patients with acromegaly, a significant proportion of patients developed Central Adrenal Insufficiency (CA) over time: while primary or secondary medical treatment did not contribute to the risk of CAI, repeated surgery or radiotherapy affected pituitary-adrenal axis. CAI was diagnosed in 18% of patients (10/57) after surgery, and in 53% (9/17) after radiotherapy (p=0.01). Considering those aspects related to predict the effects of medical treatment with SSA in acromegaly, we studied the role of AIP-AHR and GIPR pathway. Considering AIP-AHR axis, involved in the detoxification of endocrine disruptors and chemical pollutants, we observed that acromegaly is more biochemically severe and resistant to SSA treatment in patients living in highly polluted areas, especially if they also carry specific AHR and/or AIP gene variants. Moreover, we found a stimulatory effect of IGF-1 on GIP promoter support in GIPR-expressing somatotropinomas, suggesting a novel molecular pathway able to induce GH-secreting PitNET. Conclusions: In this complex scenario, understanding the physio-pathology of PitNET is the beginning of personalized treatment. In clinical practice, a multidisciplinary team for the management of patients is fundamental, to suggest the correct treatment plan, tailored to the patient

Mineralocorticoid treatment in adrenal insufficiency

Context: Fludrocortisone (FC) is the mineralocorticoid (MC) replacement treatment for patients with primary adrenal insufficiency (PAI). Objective: To explore the dose of FC treatment and its relationship with glucocorticoid therapy, sodium, potassium and renin levels. Design: longitudinal study. Setting: monocentric cohort. Patients: Data of 193 patients with PAI (130 autoimmune) were collected during baseline (T0), intermediate (T1) and last follow-up visit (T2, respectively after 38 and 35 months). Main Outcome Measure: Utility of endocrine and clinical parameters to titrate FC dose. Results: FC dose (50-75 μg/daily) was stable in the follow-up in half patients. The MC activity of FC was dose-dependent: we observed a positive linear correlation between FC dose and sodium (r= 0.132) and negative linear correlation between FC and potassium (r= -0.162) or renin (r= -0.131, all p 60 months, p <0.05). Higher doses of FC were observed in patients with low-normal renin, especially in autoimmune PAI (86 vs 65 μg/daily, p <0.05). On the contrary, reduced sodium and increased potassium levels were observed in patients with high renin at T2. The number of cardiovascular events (15 in the whole cohort) was similar in patients sorted by renin levels or FC dose. Conclusions: low-doses of FC are sufficient in most patients with PAI and can be further reduced in long-term follow-up. Renin and electrolytes are marker of MC activity: they should be routinely evaluated and used to titrate FC treatment

EtherSolve: Computing an Accurate Control-Flow Graph from Ethereum Bytecode

Motivated by the immutable nature of Ethereum smart contracts and of their transactions, quite many approaches have been proposed to detect defects and security problems before smart contracts become persistent in the blockchain and they are granted control on substantial financial value. Because smart contracts source code might not be available, static analysis approaches mostly face the challenge of analysing compiled Ethereum bytecode, that is available directly from the official blockchain. However, due to the intrinsic complexity of Ethereum bytecode (especially in jump resolution), static analysis encounters significant obstacles that reduce the accuracy of exiting automated tools. This paper presents a novel static analysis algorithm based on the symbolic execution of the Ethereum operand stack that allows us to resolve jumps in Ethereum bytecode and to construct an accurate control-flow graph (CFG) of the compiled smart contracts. EtherSolve is a prototype implementation of our approach. Experimental results on a significant set of real world Ethereum smart contracts show that EtherSolve improves the accuracy of the execrated CFGs with respect to the state of the art available approaches. Many static analysis techniques are based on the CFG representation of the code and would therefore benefit from the accurate extraction of the CFG. For example, we implemented a simple extension of EtherSolve that allows to detect instances of the re-entrancy vulnerability

Le mutazioni somatiche nelle surrenali di pazienti con ipoaldosteronismo primitivo non guarito dalla surrenectomia suggeriscono un meccanismo condiviso fra la malattia unilaterale e bilaterale

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Case report: The lesson from opioid withdrawal symptoms mimicking paraganglioma recurrence during opioid deprescribing in cancer pain

Pain is one of the predominant and troublesome symptoms that burden cancer patients during their whole disease trajectory: adequate pain management is a fundamental component of cancer care. Opioid are the cornerstone of cancer pain relief therapy and their skillful management must be owned by physicians approaching cancer pain patients. In light of the increased survival of cancer patients due to advances in therapy, deprescription should be considered as a part of the opioid prescribing regime, from therapy initiation, dose titration, and changing or adding drugs, to switching or ceasing. In clinical practice, opioid tapering after pain remission could be challenging due to withdrawal symptoms’ onset. Animal models and observations in patients with opioid addiction suggested that somatic and motivational symptoms accompanying opioid withdrawal are secondary to the activation of stress-related process (mainly cortisol and catecholamines mediated). In this narrative review, we highlight how the lack of validated guidelines and tools for cancer patients can lead to a lower diagnostic awareness of opioid-related disorders, increasing the risk of developing withdrawal symptoms. We also described an experience-based approach to opioid withdrawal, starting from a case-report of a symptomatic patient with a history of metastatic pheochromocytoma-paraganglioma