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Enrico Torre,1 Sergio Di Matteo,2 Giacomo Matteo Bruno,3 Chiara Martinotti,2 Maria Chiara Valentino,2 Gianni Testino,4 Alberto Rebora,1 Luigi Carlo Bottaro,5 Giorgio Lorenzo Colombo3 1Diabetology and Metabolic Diseases Unit - ASL3, Genoa, Italy; 2S.A.V.E. Studi Analisi Valutazioni Economiche S.r.l., Health Economics & Outcomes Research, Milan, Italy; 3Department of Drug Sciences, University of Pavia, Pavia, Italy; 4Unit of Addiction and Hepatology - ASL3, Genoa, Italy; 5General Direction, ASL3, Genoa, ItalyCorrespondence: Giorgio Lorenzo Colombo, Department of Drug Sciences, School of Pharmacy, University of Pavia, Italy, Email giorgio.colombo@unipv.itBackground: Aim of our study is to evaluate the economic impact of NASH among diabetic population in Italy and potential benefits of treatments that can slow the disease progression.Methods: A Markov model was conducted from the Italian National Healthcare System perspective reporting results at 3, 5, 10 and 15 years. The model included NASH and T2DM patients with all stages of fibrosis (F0-F3), compensated cirrhosis (CC), decompensated cirrhosis (DCC), hepatocellular carcinoma (HCC), liver transplant (LT), post-LT and death. A 1-year model cycle length was considered, with each patient passing through the stages and exiting the model when reached one of mortality states. Transition probabilities and annual cost related to health states were derived from published literature. Moreover, the model made it possible to develop a scenario analysis to simulate the impact of treatments capable of slowing the disease progression in phases F0-F4 (CC).Results: The results highlighted an economic burden of NASH in T2DM patients of approximately € 1.4 billion, € 3.1 billion, and € 9.4 billion, respectively, after 3, 5 and 10 years, reaching about € 17.3 billion after 15 years. The slowing down of the progression in the early stages of the disease (fibrosis F0-CC) has led to significant savings corresponding to € 2.3 billion at 15 years. These savings were generated by the reduction of the patients in the advanced stages of the disease, which is linked to a reduction in deaths, equal to 92,208 deaths avoided over a 15-year time horizon.Conclusion: Patients with NASH and T2DM reported an important burden in Italy. It is important to investigate the potential clinical and economic benefits of antidiabetic drugs that have been shown to be effective in preventing the transition to advanced disease, simultaneously acting on the therapeutic goals of diabetic disease.Keywords: non-alcoholic steatohepatitis, type 2 diabetes mellitus, burden of illness, treatment perspectives

Enrico Torre,1 Giorgio Lorenzo Colombo,2 Sergio Di Matteo,3 Chiara Martinotti,3 Maria Chiara Valentino,3 Alberto Rebora,1 Francesca Cecoli,1 Eleonora Monti,1 Marco Galimberti,4 Paolo Di Bartolo,5 Germano Gaggioli,6 Giacomo Matteo Bruno2 1Endocrinology Diabetology and Metabolic Diseases Unit - ASL3, Genoa, Italy; 2Department of Drug Sciences, University of Pavia, Pavia, Italy; 3S.A.V.E. Studi Analisi Valutazioni Economiche S.r.l., Health Economics & Outcomes Research, Milan, Italy; 4DP Trade SA, Lugano, Switzerland; 5Diabetes Center of Ravenna, Romagna Diabetes Clinical Network, Romagna Local Health Authority, Ravenna, Italy; 6Cardiology Unit Villascassi Hospital - ASL3, Genoa, ItalyCorrespondence: Giorgio Lorenzo ColomboDepartment of Drug Sciences, School of Pharmacy, University of Pavia, Pavia, ItalyEmail giorgio.colombo@unipv.itBackground: In Italy, the adoption of a total lockdown has generated almost total suspension of outpatient visits except for emergencies. Even after lockdown, the pandemic fear created additional barriers to access the health services. The aim of our study is to evaluate the economic impact of the lockdown for COVID-19 on public health in Italy, focusing on its effects on diabetic population.Materials and Methods: We analyzed the impact of the lockdown on excess mortality and morbidity in the Italian diabetic population during 2020. The analysis was divided into several steps: a quantification of specialist visit reduction, the calculation of excess mortality in the diabetic population, the economic evaluation of the slowdown in the use of innovative diabetic therapies. Furthermore, the impact of the lockdown on the reduction of procedures and follow-up visits in diabetic population was evaluated. The overall impact of the pandemic and lockdown effects on costs and quality of life was then calculated.Results: During 2020, a drop of 28% in patient access has been observed. Diabetic patients recorded a twice higher mortality value compared to general population (20.4% vs 10.2%). The analysis of market data revealed a slowdown in consumption of new antidiabetic therapies (− 14%, 27% vs 41%). We estimated an expense of € 26.6 million for NHS and a loss of 257 utilities in diabetic population due to the missed benefits related to slowdown in innovative antidiabetic drugs use and non-optimal follow-up and control of diabetes complications. In simulation scenarios, we also estimated an overall expenditure ranging from € 38.7 to 94.0 million and a loss of 294– 836 utilities.Conclusion: Diabetic population paid a high tribute to pandemic and lockdown, both in terms of number of deaths and burden of diabetic complications, together with an overall deterioration of quality of life.Keywords: COVID-19, diabetes type II, diabetic complications, quality of life, economic impact

Context Colonic polyps occur in 30–40% of acromegalic patients, increasing the risk of colon carcinoma. Although debated, there is emerging evidence that metformin may play a protective role in diabetic and non-diabetic patients with colonic polyps and its use in chemoprevention is currently explored. Objective Evaluate the prevalence of colonic polyps in acromegalic patients treated or not with metformin and explore its possible protective role. Design Exploratory cross-sectional study in two tertiary Italian referral centres. Met hods: Out of 153 acromegalic patients, we selected 58 patients (36–82 years; f: 33) who had at least one colonoscopy performed within the first 2 years of diagnosis. Presence of colonic polyps/cancer and related risk factors, current metformin and acetylsalicylic acid intake, disease duration, therapies for acromegaly, hormonal and metabolic parameters were assessed. Results An overall prevalence of 36% polyps was found. Based on the presence of polyps, we identified two groups, comparable for age, BMI, disease duration, glucose, insulin, HOMA-IR, HbA1c, GH and IGF-I levels. Of the patients with polyps (including three adenocarcinomas) only 24% were treated with metformin vs 57% of patients without polyps. Multivariate analysis confirmed a significant negative association between colonic polyps and metformin intake (OR: 0.22, 95% CI: 0.06-0.77, P = 0.01), whereas no significant association was found between polyps and age (P = 0.10), overweight/obesity (P = 0.54), smoking (P = 0.15), acetylsalicylic acid intake (P = 0.99), disease duration (P = 0.96), somatostatin analogues treatment (P = 0.70). Conclusions These findings, though deriving from an exploratory study, could suggest a protective role of metformin on the development of colonic polyps in acromegaly, and need to be confirmed in an extended study population.

Grazie ai progressi dell’industria, i farmaci oggi a disposizione per la terapia medica dell’acromegalia sono diversificati e hanno permesso, rispetto al passato, e in associazione alla chirurgia, di aumentare la percentuale di pazienti che raggiunge l’obiettivo terapeutico. Tuttavia, nonostante la disponibilita di diverse strategie terapeutiche, ancora una significativa quota di pazienti non raggiunge il controllo di malattia ed e considerata resistente alla monoterapia. Per questo motivo la ricerca sta sviluppando nuove molecole e formulazioni per la cura dell’acromegalia, ma soprattutto si stanno avvicendando in questi ultimi anni anche nuove strategie e schemi innovativi, come le terapia combinate, mirate a migliorare l’outcome della terapia medica stessa. Oltre alla chirurgia, quindi, oggi nella pratica clinica gli analoghi della somatostatina (SSA) rappresentano il farmaco di prima scelta e sono infatti ampiamente utilizzati in prima linea, o come pre-trattamento all’intervento, oltre che nel classico schema adiuvante. I dopamino-agonisti (DA), di largo impiego soprattutto in passato, sono oggi utilizzati in casi selezionati con minima attivita di malattia, o in associazione agli SSA. Il pegvisomant, l’unico antagonista del recettore del GH oggi disponibile, indicato in pazienti gia sottoposti a intervento chirurgico e che risultino resistenti o intolleranti alla terapia con SSA, permette di normalizzare i livelli di IGF-I in un’alta percentuale di pazienti non controllati, anche questo farmaco, non agendo sul tumore ipofisario, viene frequentemente impiegato in associazione agli SSA. Per pazienti resistenti anche a queste strategie, sono in sviluppo nuovi farmaci (panligandi e molecole chimeriche somatostatina/dopamina) i cui risultati preliminari sembrano essere molto promettenti.

Introduction and Aim: Acromegalic patients have an increased risk for the development of colorectal cancer. For this reason, since 1996, screening colonoscopy has been recommended in all patients with acromegaly. The aim of our study was to assess the feasibility and to evaluate the results of computed tomography (CT)-colonography in acromegaly. Patients and Methods: We examined 23 acromegalic patients with no history of colorectal cancer (11 females and 12 males; age range 18–79 yr; disease duration range 1–15 yr) with CT-colonography. Twenty of them underwent traditional colonoscopy after the CT-colonography. Results: CT-colonography examination results were adequate in 17 of 23 cases (73%). CT-colonography found 12 polyps in eight patients, 95% confirmed by traditional colonoscopy. One polyp was a sigmoid cancer, and the diagnosis was confirmed at surgery. There were no polyps found by traditional colonoscopy that CT-colonography was not able to identify. The lesions were located in right colon (two), transversum (three), left colon (five), and sigmoid colon (two). Patient acceptance of the technique was good in 65%, medium in 20%, and poor in 15%. Conclusion: For the first time we have demonstrated that CT-colonography has the potential ability to replace traditional colonoscopy in acromegalic patients. CT-colonography could be used as a screening modality for colon cancer in acromegaly.

Context: Gastrointestinal abnormalities in acromegaly include dolichomegacolon, slow colonic transit, and increased prevalence of colonic polyps. Conversely, no data are available on the small intestine. Objective: The aim of the study was to investigate the orocecal transit time (OCTT) and the presence of small intestinal bacterial overgrowth (SIBO). Patients: A total of 41 acromegalic patients and 30 sex- and age-matched control subjects entered the study. Acromegalic patients were classified according to the medical treatment with somatostatin analogs as “treated” (n = 22) and “untreated” (n = 19), whereas according to the disease control, as “controlled” (n = 17), “uncontrolled” (n = 10), and “partially controlled” (n = 14). Patients and controls completed a questionnaire and underwent a standardized 10-g lactulose hydrogen breath test to determine the OCTT and presence of SIBO. SIBO-positive patients underwent eradication with rifaximine. Results: An increased prevalence of SIBO (18 of 41 vs. 1 of 30; P < 0.0001) and a significantly delayed OCTT (169.53 ± 8.15 vs. 107.25 ± 6.56 min; P < 0.0001) were evidenced in patients compared with controls. No significant statistical differences were found between “treated” or “untreated” patients positive for SIBO or between “controlled,” “partially controlled,” and “uncontrolled” patients. OCTT was significantly delayed in “treated” vs. “untreated” patients (183.21 ± 9.01 and 158.89 ± 6.38, respectively; P = 0.02) and in patients compared with controls (105.75 ± 6.34; P < 0.0001). Rifaximine eradicated SIBO in more than 50% of patients who underwent treatment. Conclusions: These data demonstrate for the first time that SIBO occurs more frequently in acromegalic patients, however, it can be successfully treated by a specific antibiotic. Medical therapy with somatostatin analogs does not affect SIBO prevalence. OCTT resulted significantly prolonged in both “treated” and “untreated” patients, suggesting that acromegaly determines per se an impairment of the intestinal motility. Indeed, disease control seems irrelevant on the delayed OCTT, suggesting that this alteration might be an irreversible complication of acromegaly, probably related to an autonomic intestinal disorder, as we have previously demonstrated at the cardiac level.

Currently Predictive Maintenance (PM) represents one of the most interesting topics in automation industry. The research of advanced predictive techniques is strictly connected with the availability of data provided by field devices inside a plant. The framework Field Data Catcher (FieldDC) presented in this paper proposes a solution to the problem of transporting information from field devices to a central database, where advanced diagnostic algorithms can be performed. A key feature of the framework is its possibility of operating regardless the type of field devices and communication protocols. To achieve this goal, the framework uses the functionality provided by FDT/DTM (Field Device Tool/Device Type Manager), an open technology that standardizes the communication and configuration interface between all field devices and host systems.

The objective of this study is to assess the secretory pattern of GH after Oral Glucose Tolerance Test (OGTT) or day-curve (DC), in relation with IGF-I and to evaluate the influence of therapy on OGTT. A retrospective analysis in 279 OGTTs performed in 93 acromegalic patients in our unit from January 1988 to December 2005, in 77 patients also DC data were retrived. GH concentration was evaluated by 3 different systems (RIA, IRMA and chemiluminescence assays), and IGF-I by two RIAs. About 12% of OGTT samples were discordant with the baseline, while discordance between nadir and 120th minute was much lower (5%), with all discordant values, except one, near the cut-off lines. Correlation between DC and OGTT data was around 0.99 among all values, discordance rate between nadir and minimum DC was much lower than that with mean DC. In almost 80% of cases there was a complete concordance between OGTT and DC results, and in about 30% IGF-I was discordant with GH. Correlation analysis between IGF-I and GH was highest with DC data and lowest with OGTT baseline (T0). Considering different treatments discrepancy rates between GH and IGF-I were comparable. The best GH parameter is the minimum GH DC, although in the clinical practice the evaluation of OGTT GH in association with IGF-I is the most practical approach. In this case, the basal and T120 GH values can replace multiple sampling. Different treatment modalities do not influence the discordance rate between GH and IGF-I.

ContextMammographic density is a strong independent risk factor for breast cancer, whose prevalence in acromegaly is still controversial.ObjectiveTo compare breast density in premenopausal acromegalic patients and controls and to determine whether density correlated with disease duration, GH, and IGF1 levels.Design, setting and participantsA prospective study involving 30 patients and 60 controls matched for age and body mass index.InterventionsA quantitative computer-aided mammographic density estimation (MDEST) and a qualitative blind evaluation by two experienced radiologists using the breast imaging reporting and data system (BI-RADS) was performed. Totally, 60 (acromegaly) and 120 (controls) craniocaudal and mediolateral oblique mammograms were evaluated in both patients and controls.Main outcome measuresBreast density.ResultsPatients showed a significantly (Pk=0.63 and k=0.85). In patients grouped according to disease activity (17 controlled and 13 uncontrolled) and medical therapy (15 treated and 15 untreated), no differences were found. All these groups had significantly increased mammographic breast density compared with controls (PA positive correlation was found between mammographic breast density, IGF1 values and disease duration (r=0.29 and r=0.39), whereas it was not found with GH (r=−0.02).ConclusionsMammographic breast density in premenopausal acromegalic patients is significantly higher than controls and positively correlated with IGF1 and disease duration.

The recent depiction of dopamine receptors (DRs) in tumors that cause Cushing’s syndrome (CS) has renewed the debate about the dopamine control on pituitary-adrenal axis, and opened interesting new perspectives for medical treatment of CS. The new insights arise from the recent accurate characterization of DR subtypes expression within tumors causing CS, the discovery of new mechanisms, such as the dimerization between DRs and other G-protein coupled receptors (CPCRs), including somatostatin receptors (SSTRs), and the recent availability of new agents targeting these receptor subtypes. Corticotropic adenomas express DR subtype 2 (D2R), together with different SSTR subtypes (ssts), in particular sst5. In vitro, activation of D2R inhibits ACTH release in the majority of cultures of corticotropic cells, whereas, in vivo, dopaminergic agents display an inhibitory effect on cortisol levels in a subset of patients with CS. In animal models the receptor profile can be deeply modulated in specific environmental conditions, that may resemble the different clinical phases of CS. The new insights about DRs and receptor-targeting drugs may offer different approaches for medical treatment of CS: combination therapies with different types of compounds, treatment with novel molecules (hybrid compounds) with a wider spectrum of activity, or even pretreatment manipulation of receptor profile. Finally, recent studies showed that D2R is also significantly expressed in ectopic ACTH-secreting tumors and in both normal and tumoral adrenal tissues. Dopamine-agonists may decrease cortisol levels in a number of these patients, strengthening the current (re)emerging interest in DRs as possible targets for medical treatment of CS.

To evaluate GH and IGF-I control and tumour shrinkage in newly diagnosed patients with acromegaly treated first-line with lanreotide-Autogel (ATG) 120 mg. Design Open, prospective.Twenty-six patients (17 women, aged 31-70 years): eight enclosed and 12 extrasellar (eight invasive) macroadenomas and six microadenomas (one invasive). ATG 120 mg initially given every 4 weeks for 12 weeks; then intervals between injections increased to every 6 or 8 weeks if GH levels wereor= 2.5 or1 microg/l (equal to 6.5 and 2.6 mU/l), respectively.Final dosage was ATG 120 mg every 4 weeks in nine patients (34.6%), every 6 weeks in eight patients (30.8%) and every 8 weeks in the remaining nine patients (34.6%). After 12 months, both GH and IGF-I were controlled in 14 patients (53.8%). The mean tumour volume decreased from 1405 +/- 1827 mm(3) at study entry to 960 +/- 1381 mm(3) after 6 months, and 799 +/- 1161 mm(3) after 12 months (P0.0001). Overall tumour shrinkage was 35.8 +/- 28.1% after 6 months and 48.4 +/- 27.6% after 12 months. After 12 months, 20 patients (76.9%) achieved25% tumour shrinkage: 12 of 14 with controlled disease (85.7%) and 8 of 12 with noncontrolled disease (66.7%; P = 0.49). Hyperhydrosis, paresthesiae and arthralgias significantly reduced after treatment. No patient withdrew from the study because of adverse events.ATG 120 mg in newly diagnosed patients with acromegaly controls GH and IGF-I secretion in 53.8% and inducesor= 25% tumour shrinkage in 76.9% during a 12-month period. The treatment was associated with improvement of clinical symptoms and with a good safety profile.

Gender differences in leptin, ghrelin, and adiponectinlevels have been described in a normal population. This is importantfor understanding differences between males and females in theregulation of food intake, weight gain, body fat distribution, andcardiovascular risk. It is unclear how endogenous and exogenoussex hormones may regulate circulating levels of these factors.Transsexuals during hormonal treatment may represent an idealmodel to ascertain the role of exogenous sex hormones on theseparameters. In this study, our objective was to evaluate adiponectin,ghrelin, and leptin levels in transsexual subjects during hormonetherapy and to compare the results of males and females. Subjectswere 26 nondiabetic transsexuals, which included 15 male-to-female(M-to-F, group 3) and 11 female-to-male (F-to-M, group 4)individuals, and 29 age- and BMI-matched controls, which included15 males (group 1) and 14 females (group 2). Results showed thatleptin levels were significantly lower in group 1 compared with group2(P 5 .04) and group 3 (P 5 .01); no differences were recordedbetween the other groups. Adiponectin levels were significantlyhigher in group 3 compared with group 4 (P 5 .03). No differenceswere found between the 4 groups for ghrelin levels. In conclusion,our data confirm the sexual dimorphism in serum leptin levels innormal subjects and demonstrate an increase in M-to-F transsexu-als. While ghrelin does not show any sexual differences and seemsnot to be influenced by exogenous sex hormone administration, thelower adiponectin levels in F-to-M transsexuals during treatmentconfirm that androgens may decrease plasma adiponectin levels.This latter observation suggests that F-to-M transsexual patientscould have a higher cardiovascular risk.Key words: Cardiovascular risk, sexual hormones, metabolicparameters.J Androl 2008;29:580–585

Context: Autonomic nervous system imbalance is related to cardiovascular risk. Heart rate variability (HRV) indexes are associated with age, race, and sex, but the role of sex hormones is still unknown. Objective: To evaluate sympathovagal balance (SB) in transsexuals. Patients: Eighteen transsexual subjects, 12 male-to-female (group 1) and 6 female-to-male (group 2), compared with 34 age-matched controls: 17 males (group 3) and 17 females (group 4). Autonomic testing of SB was performed by Power Spectral Analysis (PSA) of HRV in clinostatism (c) and orthostatism (o). PSA identifies power peaks: high frequency (HF) expresses vagal activity, while low frequency (LF) expresses sympathetic activity. Results: Group 1 showed lower LFc than groups 2, 3, and 4 (p

Pituitary tumors can cause symptoms of mass effect and hormonal hypersecretion that can be reversed with surgical resection or debulking of the adenoma, radiotherapy, or medical treatment. Medical treatment is the primary choice for prolactinomas because dopamine agonists are very effective in the treatment of these tumors, with rates of control (tumor size reduction and hormone suppression) as high as 80–90% for microprolactinomas and 60–75% for macroprolactinomas. The function of dopamine receptors in other histotypes of pituitary adenoma is still debated. However, new insights into receptor physiology and the introduction of new clinically available, as well as experimental, compounds have reopened a potential role of dopaminergic drugs in the medical treatment of pituitary tumors. The differences between the effectiveness and the resistance to different dopaminergic agents, the new challenging results from clinical and experimental studies, as well as the future of dopamine agonists in the therapy of pituitary tumors are discussed.

Criteria to define the response to somatostatin (SS) analogs (SSA) in acromegaly are based on biochemical control of the disease. However, the mechanisms of action of SSAs in inhibiting tumor growth and hormonal secretion are only partially understood, and the two effects may occur independently.The objective of the study was to investigate the dissociation between antiproliferative and antisecretive effects of SSA in an octreotide-resistant patient displaying dramatic tumor shrinkage during primary therapy with octreotide LAR.We characterized somatostatin and dopamine D(2) receptor expression by immunohistochemistry and real-time RT-PCR. The effects of different receptor-selective, bispecific analogs, and chimeric somatostatin/dopamine compounds on GH secretion and cell proliferation in primary cell cultures of the tumor were assessed.The expression of SS receptor subtypes (sst)(5) and D(2) receptor was higher, compared with the other receptor subtypes. GH inhibition by SS-14 and the two chimeric somatostatin/dopamine compounds was scant but greater than subtype-selective and sst(2)/sst(5) bispecific agonists. Conversely, cell growth was potently inhibited by all test substances. However, SS-14, sst(2)/sst(5) bispecific agonist, and chimeric molecules were more potent than the other compounds.The significant antiproliferative effect of octreotide seems to be related to the higher expression of sst(5) and the negligible antihormonal effect to the lower expression of sst(2). However, activation of multiple receptors by new analogs may produce better control of tumor cell activities. The dissociation between antisecretive and antiproliferative effects observed in vivo and in vitro confirms that SSAs may induce tumor shrinkage despite the lack of effect on GH secretion.