Pituitary aggressive tumors and carcinomas: epidemiological, molecular, clinical, radiological, pathological and therapeutic characterization

Knowledge about epidemiological, clinical, molecular and pathological characteristics of pituitary aggressive tumors and carcinomas is still scant, and strong evidence about the best therapeutic approach is yet to be achieved. The current study has confirmed pituitary carcinomas to be exceptionally rare, but highlighted that atypical tumors might be more common than previously thought. Apart from the clear-cut definition of atypical and malignant pituitary tumors, based on WHO criteria and on the presence of distant metastases, respectively, nowadays tumors size, recurrence, laterosellar extension and responsiveness to conventional medical treatments appear to be the best clinical and radiological criteria to discriminate pituitary tumors with a true aggressive behavior. Conversely, tumor invasiveness is not a good predictor of tumor aggressiveness and cannot discriminate pituitary atypical and malignant tumors from typical and benign adenomas. Radiotherapy and medical treatments remain the most commonly used therapeutic approaches for pituitary aggressive tumors, but fail to induce the achievement of disease control in most patients. Experience with new target therapies, such as pasireotide and everolimus, is still scant, however in vitro data support the use of combined treatment with pasireotide and everolimus as potential valid alternative treatment in patients with aggressive pituitary tumors poorly responsive to conventional medical treatments. Drug responsiveness can be, however, influenced by specific tumor receptor eterogeneity, tachyphylaxis or other factors influencing drug effectiveness, such as somatostatin receptors and mTOR components expression profile, and in turn early identification of molecular markers able to predict responsiveness to treatment might drive endocrinologists through the choice of the best individualized adjuvant therapy in patients with pituitary aggressive tumors and carcinomas

Growth hormone nadir during oral glucose load depends on waist circumference, gender and age: normative data in 231 healthy subjects.

Objective  (i) To analyse the predictors of GH suppression after standard glucose load (oGTT) in the healthy population and (ii) to establish the 97th percentile of GH nadir post-oGTT according to these variables. Design  Analytical, retrospective. Measurements  GH nadir after oGTT. Subjects  Two hundred and thirty-one healthy subjects (113 women, 118 men 15-80 years) were studied. Results  The GH nadir after glucose load ranged from 0·01 (<assay detection limit) to 0·65 μg/l was higher in women and was inversely correlated with age, BMI, waist circumference, waist/hip, total cholesterol, triglycerides, basal and maximal glucose and basal insulin levels and directly correlated with basal GH levels, IGF-I SDS and HDL-cholesterol (P values ranging 0·004-<0·0001). On multistep regression analysis, the best predictors of nadir GH levels were waist circumference (t = -9·64, P < 0·0001), gender (t = -3·86, P = 0·0001) and age (t = -3·63, P = 0·0003). The results of comparative analysis among subjects grouped according to these variable showed different results in GH nadir in premenopausal women with waist circumference ≤88 cm (97th percentile 0·65 μg/l), in premenopausal women with waist circumference ≤88 cm and in men of any age with waist circumference ≤102 cm (97th percentile 0·33 μg/l) and in subjects of either gender and any age with waist circumference >88 cm in women and 102 cm in men (97th percentile 0·16 μg/l). Conclusions  The results of this study show that GH nadir after oGTT should be analysed according to gender, menopausal status and waist circumference. The GH cut-off should be limited to the assay used

Glucose Abnormalities Associated to Prolactin Secreting Pituitary Adenomas

The pathogenesis of obesity and alterations in glucose profile have been linked to PRL excess, as it is reportedly associated with metabolic syndrome in thereabout one third of patients. In vitro exposure of pancreatic islet to PRL is known to stimulate insulin secretion and β-cell proliferation, and in turn overexpression of PRL in β-cells increases insulin release and β-cell replication. PRL excess has been found to worsen glucose profile because it reduces glucose tolerance and induces insulin resistance either in obese and non-obese patients. To note, pancreatic β-cells and adipocytes widely express dopamine receptors type 2, and dopamine has been hypothesized to play a key role as modulator of insulin and adipose functions. The dopamine agonists bromocriptine and cabergoline significantly improve abnormalities in glucose profile and reduce the prevalence of metabolic syndrome in a remarkable proportion of patients, regardless of whether body weight and PRL status may change. However, in men with hyperprolactinemia complicated by hypogonadism, testosterone replacement can ameliorate insulin resistance and abnormalities in glucose metabolism. Therefore, in patients with PRL-secreting pituitary adenomas control of PRL excess by dopamine agonists is mandatory to improve glucose and insulin abnormalities

Sex disparities in COVID-19 severity and outcome : are men weaker or women stronger?

The coronavirus disease 2019 (COVID-19) outbreak, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a global public health issue which has profound effects on most aspects of societal well-being, including physical and mental health. A plethora of studies globally have suggested the existence of a sex disparity in the severity and outcome of COVID-19 patients, mainly due to mechanisms of virus infection, immune response to the virus, development of systemic inflammation, and consequent systemic complications, particularly thromboembolism. Epidemiological data report a sex difference in the severity of COVID-19, with a more favorable course of the disease in women compared to men regardless of age, although the rate of SARS-CoV-2 infection seems to be similar in both sexes. Sex hormones, including androgens and estrogens, may not only impact virus entry and load, but also shape the clinical manifestations, complications, and ultimately the outcome of the disease. The current review comprehensively summarizes the current literature on sex disparities in susceptibility and outcome of COVID-19 as well as the literature underpinning the pathophysiological and molecular mechanisms, which may provide a rationale to a sex disparity. These mechanisms include sex hormone influence on factors that facilitate virus entry and priming, immune and inflammatory response, as well as coagulation and thrombosis diathesis. Based on present evidence, women appear to be relatively protected from COVID-19 because of a more effective immune response and a less pronounced systemic inflammation, with consequent moderate clinical manifestations of the disease, together with a lesser predisposition to thromboembolism. Conversely, men appear to be particularly susceptible to COVID-19 because of a less effective immune response with consequent severe clinical manifestations of the disease, together with a greater predisposition to thromboembolism. In the elderly, generally characterized by the phenomenon of inflammaging, sex disparities in overall mortality following SARS-CoV-2 infection are even more palpable as elderly men appear to be more prone to severe COVID-19 because of a greater predisposition to infections, a weaker immune defense, and an enhanced thrombotic state compared to women. The information revealed from the review highlights potential novel therapeutic approaches employing the administration of hormonal or antihormonal therapy in combination with antiviral drugs in COVID-19 patients.https://www.karger.com/Journal/Home/223855hj2022Immunolog

Comparison of the effects of primary somatostatin analogue therapy and pituitary adenomectomy on survival in patients with acromegaly: a retrospective cohort study

Objective: Acromegalic patients have an increased risk of mortality. The objective of this study was to compare the effect of different therapies for acromegaly on mortality. Design and methods: The mortality rate of 438 consecutive acromegalic patients was compared with that of the general population using the standardized mortality ratio (SMR); the effect of different therapies on survival was evaluated using Cox regression analysis. Results: Twenty patients (4.5%) died between 1999 and 2009. Age- and sex-adjusted SMR was 0.70 (95% CI 0.43–1.08). The Cox regression analysis revealed that, in the whole population, both general risk factors (age and physical status) and specific factors for acromegaly (macroadenoma, hypopituitarism and uncontrolled disease) were associated with death. The most compromised patients at diagnosis had a higher mortality rate (PZ0.001), which also occurred in patients with controlled acromegaly. Death occurred in 2.4% (adenomectomy), 2.6% (adenomectomy followed by somatostatin analogue (SSA) therapy) and 11.4% (SSA therapy as the primary therapy) of the patients. The risk of death was higher in patients receiving SSA therapy as the primary therapy (hazard ratio (HR) 5.52, 95% CI 1.06–28.77, PZ0.043) than in all patients submitted to adenomectomy; however, a higher risk of death occurred only in diabetic patients treated with SSAs alone (HR 21.94, 95% CI 1.56–309.04, PZ0.022). Radiotherapy was associated with an increased risk of mortality, which occurred in patients with the more locally advanced disease. Conclusions: Therapies for acromegaly and comorbidities have lowered the risk of mortality to the level of the general population; the effect of SSA therapy alone or that following pituitary adenomectomy was comparable to that of curative neurosurgery on survival in non-diabetic patients; on the contrary, SSA therapy as the primary therapy may be less effective than adenomectomy in reducing mortality rate in diabetic patients

The dual targeting of insulin and insulin-like growth factor 1 receptor enhances the mTOR inhibitor-mediated antitumor efficacy in hepatocellular carcinoma

Deregulation of mTOR and IGF pathways is frequent in hepatocellular carcinoma (HCC), thus mTOR and IGF1R represent suitable therapeutic targets in HCC. The aim of this study was to evaluate the effects of mTOR inhibitors (mTORi) and OSI-906, blocker of IGF1R/IR, on HCC cell proliferation, viability, migration and invasion, and alpha-fetoprotein (α-FP) secretion. In HepG2 and HuH-7 we evaluated, the expression of mTOR and IGF pathway components; the effects of Sirolimus, Everolimus, Temsirolimus and OSI-906 on cell proliferation; the effects of Sirolimus, OSI-906, and their combination, on cell secretion, proliferation, viability, cell cycle, apoptosis, invasion and migration. Moreover, intracellular mechanisms underlying these cell functions were evaluated in both cell lines. Our results show that HepG2 and HuH-7 present with the same mRNA expression profile with high levels of IGF2. OSI-906 inhibited cell proliferation at high concentration, while mTORi suppressed cell proliferation in a dose-time dependent manner in both cell lines. The co-treatment showed an additive inhibitory effect on cell proliferation and viability. This effect was not related to induction of apoptosis, but to G0/G1 phase block. Moreover, the co-treatment prevented the Sirolimus-induced AKT activation as escape mechanism. Both agents demonstrated to be differently effective in inhibiting α-FP secretion. Sirolimus, OSI-906, and their combination, blocked cell migration and invasion in HuH-7. These findings indicate that, co-targeting of IGF1R/IR and mTOR pathways could be a novel therapeutic approach in the management of HCC, in order to maximize antitumoral effect and to prevent the early development of resistance mechanisms

Erratum to: Prospective, long-term study of the effect of cabergoline on valvular status in patients with prolactinoma and idiopathic hyperprolactinemia.

Peer reviewe

A pharmacoeconomic analysis from Italian guidelines for the management of prolactinomas

Background: Prolactinoma, the most common pituitary adenoma, is usually treated with dopamine agonist (DA) therapy like cabergoline. Surgery is second-line therapy, and radiotherapy is used if surgical treatment fails or in relapsing macroprolactinoma. Objective: This study aimed to provide economic evidence for the management of prolactinoma in Italy, using a cost-of-illness and cost-utility analysis that considered various treatment options, including cabergoline, bromocriptine, temozolomide, radiation therapy, and surgical strategies. Methods: The researchers conducted a systematic literature review for each research question on scientific data- bases and surveyed a panel of experts for each therapeutic procedure's specific drivers that contributed to its total cost. Results: The average cost of the first year of treatment was euro2,558.91 and euro3,287.40 for subjects with micro- prolactinoma and macroprolactinoma, respectively. Follow-up costs from the second to the fifth year after ini- tial treatment were euro798.13 and euro1,084.59 per year in both groups. Cabergoline had an adequate cost-utility profile, with an incremental cost-effectiveness ratio (ICER) of euro3,201.15 compared to bromocriptine, based on a willingness-to-pay of euro40,000 per quality-adjusted life year (QALY) in the reference economy. Endoscopic sur- gery was more cost-effective than cabergoline, with an ICER of euro44,846.64. Considering a willingness-to-pay of euro40,000/QALY, the baseline findings show cabergoline to have high cost utility and endoscopic surgery just a tad above that. Conclusions: Due to the favorable cost-utility profile and safety of surgical treatment, pituitary surgery should be considered more frequently as the initial therapeutic approach. This management choice could lead to better outcomes and an appropriate allocation of healthcare resources

Acromegaly at diagnosis in 3173 patients from the Liège Acromegaly Survey (LAS) Database

Acromegaly is a rare disorder caused by chronic growth hormone (GH) hypersecretion. While diagnostic and therapeutic methods have advanced, little information exists on trends in acromegaly characteristics over time. The Liège Acromegaly Survey (LAS) Database, a relational database, is designed to assess the profile of acromegaly patients at diagnosis and during long-term follow-up at multiple treatment centers. The following results were obtained at diagnosis. The study population consisted of 3173 acromegaly patients from ten countries; 54.5% were female. Males were significantly younger at diagnosis than females (43.5 vs 46.4 years; P 3100 patients is the largest international acromegaly database and shows clinically relevant trends in the characteristics of acromegaly at diagnosis