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The aim of the study was to investigate the 5-yr impact of surgery and somatostatin analogs (SSA) on glucose metabolism in acromegaly.We conducted an observational, prospective, comparative, nonrandomized study.The 100 patients (48 women, 52 men; median age, 49 yr) in the study were grouped as follows for treatment: SSA only (group A; n = 34); SSA followed by surgery (group B; n = 20); surgery only (group C; n = 30); and surgery followed by SSA (group D; n = 16).At diagnosis, 28% had impaired glucose tolerance, and 22% had diabetes mellitus; fasting glucose levels (4.13-10.60 mmol/liter) were best predicted by age (t = 2.88; P = 0.0049) and disease duration (t = 1.99; P = 0.049). After 60 months, fasting glucose levels reduced (-4.9 +/- 19.7%) in group A only, whereas they did not change in the other groups. In the 68 nondiabetic patients at baseline, fasting glucose levels increased by 0.7 +/- 11.2%, 7.5 +/- 10.3%, 4.3 +/- 10.4%, and 4.3 +/- 14.8% (P = 0.28), from groups A to D, respectively. Percentage change of fasting glucose in all patients receiving SSA was 1.9 +/- 12.3%, and in those not receiving SSA it was 6.4 +/- 10.8% (P = 0.13). Overall, prevalence of new onset of diabetes during SSA treatment was nine of 55 (16.4%) vs. three of 23 after surgery (13.0%, P = 0.98). Deterioration of glucose tolerance was correlated with increased body mass index (r = 0.49, P0.0001) and not with use of SSA or surgery (r = 0.06; P = 0.53), control or not of GH (r = -0.10, P = 0.31) and IGF-I (r = -0.12; P = 0.22).The results of this study demonstrate a similar deterioration of glucose tolerance after 60 months in patients receiving SSA or cured with surgery. Increase in body mass index was the major predictor of deterioration of glucose tolerance.

No head-to-head comparisons are available to analyze the efficacy of octreotide (LAR) and lanreotide (LAN) as first-line treatment of acromegaly.We compared the efficacy of these two drugs in 54 newly diagnosed patients (21 women, 33 men), 27 treated with LAR (10-30 mg every 28 days) and 27 with LAN (60-90 mg/28 days), for 12 months. Each LAR-treated patient was matched with one LAN-treated patient as for GH levels, sex, and age (+/-5 yr). Outcome measures were GH and IGF-I levels and tumor shrinkage and secondarily classical cardiovascular risk factors (total/HDL-cholesterol ratio, glucose tolerance), blood pressure and drug tolerability. In LAR- and in LAN-treated patients, respectively: GH and IGF-I were controlled in 21 (77.7%) and in 16 patients (59.3%; p=0.26); tumor shrinkage was absent (75%) in 4 and 4 patients (p=1). The total/HDL-cholesterol ratio and insulin levels significantly decreased while glucose levels significantly increased in both groups. None of the patients with normal glucose tolerance at diagnosis developed diabetes mellitus. Side effects were mostly at the gastrointestinal level and were similar with both drugs. In conclusion, newly diagnosed patients with acromegaly treated with LAR and LAN have no significantly different prevalence of disease control, tumor shrinkage, improvement of cardiovascular risk markers and side effects. Therefore, both drugs can be safely employed as first-line therapy of acromegaly.

OBJECTIVE: The objective of the study was to evaluate whether tumor shrinkage or GH and IGF-I levels achieved after 3 months predicted tumor shrinkage after 12 months of octreotide-long-acting release (LAR) treatment. PATIENTS: Patients included 67 patients with de novo acromegaly (33 women, 34 men; aged 20-82 yr) receiving LAR at a dose of 20 mg every 28 d for 3 months. Final LAR dose was 10 mg every 28 d in 4, 30 mg every 28 d in 39, 20 mg every 28 d in 24 patients. DESIGN: The design of the study was analytical, observational, open, and retrospective. OUTCOME MEASURES: Percent change in GH and IGF-I levels and tumor volume after 3 and 12 months of therapy was measured. Stepwise regression and receiving-operator characteristics analysis were used to calculate the optimal cutoff to predict 12 months tumor shrinkage at 12 months. RESULTS: The percent tumor shrinkage after 12 months was significantly correlated with GH, IGF-I, and tumor volume at 3 months and with the dose of LAR administered between 3 and 12 months. There was no correlation with gender, age, baseline GH levels and tumor volume. In a stepwise regression analysis, percent tumor shrinkage after 3 months was the best predictor of tumor shrinkage after 12 months (t = 5.92; P < 0.0001), followed by GH levels after 3 months (t = 2.86; P = 0.0056). To predict 50% or greater tumor shrinkage after 12 months, the best cutoff point of tumor shrinkage at 3 months was 22.1% [sensitivity (95% confidence interval) = 85.5% (71.2-95.4); specificity = 83.3% (65.3-94.3)], whereas that of GH levels after 3 months was 7.8 microg/liter [sensitivity = 70.3% (53.0-84.1); specificity = 93.3% (79.0-99.0)]. CONCLUSION: Tumor shrinkage achieved after 3 months of LAR treatment at 20 mg/28 d predicted tumor shrinkage at 12 months, provided that dosages were changed according to individual patients requirement.

The aim of this prospective study was to measure the thickness of the circumpapillary retinal nerve fibre layer (cpRNFL) and the ganglion cell complex (GCC) using spectral domain optical coherence tomography (SD-OCT) in a cohort of consecutive de novo patients with pituitary macroadenomas without chiasmal compression.Twenty-two consecutive patients with pituitary macroadenoma without chiasmal compression (16 men, 6 women, aged 45.2±14.6 years, 43 eyes) entered the study between September 2011 and June 2013. Among them, 31.8% harboured a growth hormone-secreting pituitary adenoma, 27.3% a prolactin-secreting pituitary adenoma, 27.3% a corticotrophin-secreting pituitary adenoma, and 13.6% a non-secreting pituitary tumour. Eighteen subjects (nine females, nine males, mean age 36.47±6.37 years; 33 eyes) without pituitary adenoma, with normal ophthalmic examination, served as controls. In both patients and controls, cpRNFL and GCC thicknesses were measured by SD-OCT.Patients were significantly older (P=0.02) than controls. Best corrected visual acuity, intraocular pressure, colour fundus photography, and automatic perimetry test were within the normal range in patients and controls. Conversely, cpRNFL (P=0.009) and GCC (P0.0001) were significantly thinner in patients than in controls. The average GCC (r=0.306, P=0.046) significantly correlated with the presence of arterial hypertension. OCT parameters did not differ significantly between patients with a tumour volume above the median and those with a tumour volume below the median.Pituitary macroadenomas, even in the absence of chiasmal compression, may induce GCC and retinal nerve fibre layer thinning. SD-OCT may have a role in the early diagnosis and management of patients with pituitary tumours.

Cabergoline (CAB) is widely used for the medical treatment of pituitary tumors, particularly those associated with hormone hypersecretion. Whether treatment with CAB is associated with an increased risk of clinically relevant cardiac valve disease in patients with pituitary tumors is still debated. In most studies, CAB has been found not associated with an increased risk of significant valvulopathy, and no correlation has been shown between valvular abnormalities and CAB duration or cumulative dose. This review provides an overview of the studies reporting on the outcome of CAB in terms of cardiac valve disease in patients with pituitary tumors.

In patients with acromegaly, somatostatin analogs (SSA) represent the first choice medical treatment. The long-acting SSA have been found to be effective in controlling growth hormone and IGF-I levels in a high percentage of patients, resulting in an improvement in the quality of life; moreover, these peptide analogs have a proven safety record and are generally well tolerated.The most commonly reported adverse events include injection-site discomfort and erythema, gastrointestinal (GI) disturbances such as diarrhea, abdominal pain, nausea and vomiting, biliary sludge or gallstones, and abnormal glucose metabolism. Most SSA-related adverse events are transient and of mild-to-moderate intensity, and the prevalence of such effects markedly and progressively decreases during treatment, so that treatment discontinuations due to adverse events are rare and commonly related to GI disturbances. Cholelithiasis represents the most serious complication of SSA, but is generally asymptomatic, and has been reported in 3 - 56% of patients. Whereas the effect of SSA on glucose metabolism is still controversial, several pieces of evidence have confirmed a modest and transient negative impact on glucose homeostasis. Also the novel SSA pasireotide has shown a safety profile as expected for a SSA, except for the degree of hyperglycemia.On the basis of these findings, a close and careful monitoring of gallbladder ultrasound and glucose levels is recommended in patients receiving SSA for medical treatment of acromegaly.

Il trattamento dei tumori ipofisari non GH-secernenti ha lo scopo di prevenire o limitare la compromissione della funzione ipofisaria, nonche le conseguenze dell’estensione a livello del chiasma ottico, dell’ipotalamo e dei seni cavernosi. La principale linea di trattamento di questi tumori dell’ipofisi e rappresentata dalla chirurgia, che e quasi sempre praticabile con approccio transfenoidale, con eccezione dei tumori molto voluminosi. Sebbene la resezione chirurgica determini una rapida decompressione del chiasma e dei nervi ottici e possa prevenire l’insorgenza o il peggioramento dell’ipopituitarismo, tuttavia, difficilmente permette una completa escissione del tumore, soprattutto in caso di estensione extrasellare. Residui tumorali si riscontrano nel 30–50% dei pazienti operati. La radioterapia viene considerata una terapia adiuvante nei pazienti con resezione chirurgica incompleta, allo scopo di prevenire la ricrescita del tumore e di ridurne i residui. Tale approccio terapeutico e, peraltro, gravato da alcuni aspetti negativi, come il lungo tempo richiesto per determinare un effetto completo, l’insorgenza di effetti collaterali acuti, come la neurite ottica e la necrosi cerebrale, e cronici, come l’induzione di ipopituitarismo. Inoltre, la ricrescita del tumore e la ricomparsa delle manifestazioni cliniche si verificano nel 20% dei casi trattati con radioterapia. Attualmente la terapia medica ha un suo razionale dopo l’intervento chirurgico e/o contemporaneamente alla radioterapia in attesa dei risultati di questa, nonche nei pazienti giovani al posto della radioterapia, allo scopo di preservare la fertilita, o negli anziani che non possono essere sottoposti ad intervento chirurgico. L’utilizzo degli analoghi della somatostatina nel trattamento di questi tumori e stato proposto sulla base dell’evidenza dell’espressione in vivo e in vitro dei recettori della somatostatina. Tuttavia, un’effettiva riduzione tumorale e stata dimostrata solo nel 13% di pazienti con adenomi clinicamente definiti non funzionanti (NFA) trattati con analoghi della somatostatina, indicando una scarsa correlazione tra espressione dei recettori per la somatostatina ed efficacia del trattamento con analoghi. Un discorso a parte merita il ruolo degli analoghi della somatostatina sulla cefalea e le alterazioni della funzione visiva. Un miglioramento di questi disturbi segue rapidamente l’inizio della terapia. Poiche non si assiste a nessuna contemporanea riduzione della massa tumorale, questo effetto sembra essere legato ad un’azione diretta degli analoghi sulla retina, sul nervo ottico e sulle strutture vascolari e cerebrali piuttosto che ad un’azione mediata dai recettori della somatostatina espressi dalle cellule tumorali. In conclusione, il trattamento con analoghi della somatostatina puo essere considerato come alternativa temporanea alla chirurgia o nell’intento di ottenere un miglioramento della cefalea e dei disturbi visivi. Recentemente e stato anche proposto il trattamento combinato con analoghi della somatostatina e dopamino-agonisti, sulla base di un possibile sinergismo di azione.

We aimed to analyze bone mineralization and the effect of different risk factors for osteoporosis in postmenopausal women. We studied 2,756 postmenopausal subjects out of ≥10,000 records from the ROIS registry in the frame of the PROF Project, a population study carried out in Salento (Taranto, Brindisi, Lecce) from 2009 to 2012. All subjects were assessed by phalangeal Quantitative Ultrasound (QUS) to evaluate their bone mineralization (assessed by Amplitude Dependent Speed of Sound, AD-SoS) and the association between demineralization and the presence of other conditions or risk factors. Mean age was 64±9.5 years and mean BMI was 28.7±3.5 Kg/m2. Pearson correlation analyses revealed a negative association between bone mineralization (AD-SoS) and BMI (P

Introduction: Hyperprolactinemia and hypogonadism are reportedly associated with an impaired metabolic profile. The current study aimed at investigating the effects of testosterone replacement and cabergoline (CAB) treatment on the metabolic profile in male hyperprolactinemic patients. Patients and Methods: Thirty-two men with prolactinomas, including 22 with total testosterone (TT) 8 nmol/l (non-HG, 31%), were entered in the study. In all patients, metabolic parameters were assessed at diagnosis and after 12- and 24-month treatment. Results: Compared to non-HG patients, at baseline the HG patients had higher waist circumference (WC). TT significantly correlated with body mass index (BMI). Twelve-month CAB induced PRL normalization in 84%. HG prevalence significantly decreased (28%) and non-HG prevalence significantly increased (72%). Anthropometric and lipid parameters, fasting insulin (FI), insulin sensitivity index (ISI₀), homeostatic model assessment of insulin secretion (HOMA-β) and homeostatic model assessment of insulin resistance (HOMA-IR) significantly improved compared to baseline. TT was the best predictor for FI. Percent change (Δ) of TT significantly correlated with ΔCholesterol, ΔWeight and ΔBMI. Compared to non-HG patients, the HG patients had a higher weight, BMI, WC and HOMA-β. In HG, testosterone replacement was started. After 24 months, PRL normalized in 97%. HG prevalence significantly decreased (6%) and non-HG prevalence significantly increased (94%). Anthropometric and lipid parameters, FI, ISI₀, HOMA-β and HOMA-IR significantly improved compared to baseline, with FI, ISI₀, HOMA-β and HOMA-IR further ameliorating compared to the 12-month evaluation. Compared to non-HG patients, the HG patients still had a higher weight, BMI and WC. Conclusions: In hyperprolactinemic hypogonal men, proper testosterone replacement induces a significant improvement in the metabolic profile, even though the amelioration in the lipid profile might reflect the direct action of CAB.

BackgroundMortality in acromegaly strictly depends on optimal control of GH and IGF1 levels. Modern medical therapy with somatostatin analogs (SSAs) and GH receptor antagonists (GHRAs) is not available in many countries due to funding restrictions. This retrospective, comparative, cohort study investigated the impact of different treatment modalities on disease control (GH and IGF1) and mortality in acromegaly patients.MethodsTwo cohorts of patients with acromegaly from Bulgaria (n=407) and Campania, Italy (n=220), were compared, and mortality rates were evaluated during a 10-year period (1999–2008).ResultsThe major difference in treatment approach between cohorts was the higher utilization of SSAs and GHRAs in Italy, leading to a decreased requirement for radiotherapy. Significantly more Italian than Bulgarian patients had achieved disease control (50.1 vs 39.1%, P=0.005) at the last follow-up. Compared with the general population, the Bulgarian cohort had a decreased life expectancy with a standardized mortality ratio (SMR) of 2.0 (95% CI 1.54–2.47) that was restored to normal in patients with disease control – SMR 1.25 (95% CI 0.68–1.81). Irradiated patients had a higher cerebrovascular mortality – SMR 7.15 (95% CI 2.92–11.37). Internal analysis revealed an independent role of age at diagnosis and last GH value on all-cause mortality and radiotherapy on cerebrovascular mortality. Normal survival rates were observed in the Italian cohort: SMR 0.66 (95% CI 0.27–1.36).ConclusionsSuboptimal biochemical control was associated with a higher mortality in the Bulgarian cohort. Modern treatment options that induce a strict biochemical control and reduce the necessity of radiotherapy might influence the life expectancy. Other factors, possibly management of comorbidities, could contribute to survival rates.

Il saggio parte dalla reinterpretazione dell'art. 97 Cost. per cogliere le linee evolutive della trasfigurazione della funzione amministrativa come amministrazione "di servizio", in connessione con la nuova conformazione dell'elemento psicologico della responsabilità amministrativa. Partendo da tale premessa si giunge alla conclusione che la più qualificata definizione legislativa dell'elemento psicologico della colpa produce un progressivo restringimento dell'area di applicabilità della responsabilità amministrativa, finendo per incidere sulla sfera stessa di cognizione della Corte dei conti e sull'ambito concreto della sua giurisdizione. Inoltre, sulla base della giurisprudenza della stessa Corte dei conti, si cerca di dimostrare che l'elemento psicologico della colpa grave si connota di una propria "tipicità" nell'illecito contabile, ancorché per il suo accertamento possa farsi riferimento alla tradizionale concezione "normativa" della colpa. Il lavoro si conclude col tentativo di enucleazione di figure sintomatiche tipiche ai fini della configurazione dell'eccesso di "potere finanziario".

Introduction: Hyperprolactinemia has been implicated in the pathogenesis of obesity and glucose intolerance and is reportedly associated with an impaired metabolic profile. The current study aimed at investigating the effects of 12- and 60-month treatment with cabergoline (CAB) on metabolic syndrome (MetS) in patients with prolactinomas. Patients and Methods: 61 patients with prolactinomas (13 men, 48 women, 41 with microadenoma, 20 with macroadenoma), aged 34.4 ± 10.3 years, entered the study. In all patients, prolactin (PRL) and metabolic parameters were assessed at diagnosis and after 12 and 60 months of continuous CAB treatment. MetS was diagnosed according to NCEP-ATP III criteria. Results: Compared to baseline, CAB induced a significant decrease in PRL with complete normalization in 93% of patients after the 60-month treatment. At baseline, MetS prevalence was significantly higher in patients with PRL above (34.5%) than in those with PRL lower (12.5%) than the median (129 μg/l, p = 0.03). MetS prevalence significantly decreased after 12 (11.5%, p = 0.039) and 60 (5.0%, p = 0.001) months compared to baseline (28.0%). At both evaluations the lipid profile significantly improved compared to baseline. Fasting insulin and homeostatic model assessment of insulin resistance significantly decreased after 1 year of CAB (p = 0.012 and p = 0.002, respectively) and further improved after 60 months (p = 0.000). The visceral adiposity index significantly decreased after the 60-month treatment (p = 0.000) compared to baseline. At the 5-year evaluation CAB dose was the best predictor of percent decrease in fasting insulin (t = 2.35, p = 0.022). Conclusions: CAB significantly reduces MetS prevalence and improves the adipose tissue dysfunction index. The improvement in PRL, insulin sensitivity and other metabolic parameters might reflect the direct effect of CAB.

Cushing's syndrome, induced by an endogenous or exogenous cortisol excess, and acromegaly, the clinical syndrome caused by growth hormone (GH) excess in adulthood, as well as the disease induced by GH deficiency (GHD), represent perfect models for the evaluation of the effects induced by chronic exposure in vivo, respectively, to cortisol and GH/IGF-1 excess or deficiency on the complex structure of the tendons as well as on the related post-traumatic repair mechanism. Although the literature is still scant, here in main scientific evidence on this topic is summarized in order to provide suggestions about the management of the above mentioned illnesses, to translate such information in the field of sports medicine and/or traumatology, and to increase and to disseminate knowledge on this misunderstood theme.

CONTEXT: Impaired glucose tolerance and diabetes mellitus are frequently present in acromegalic patients in whom the degree of impaired glucose metabolism seems directly correlated with GH levels. Microalbuminuria is reported to be directly correlated with insulin resistance, and both conditions predict cardiovascular disease mortality. OBJECTIVE: Our objective was to investigate the microalbuminuria levels as a marker of endothelial dysfunction in acromegalic patients. DESIGN: We conducted an observational, multicenter, open prospective study. SUBJECTS: Subjects included 74 patients with active acromegaly (52 with normal glucose tolerance, 16 with impaired glucose tolerance, and six with diabetes), and 50 healthy subjects matched for age, gender, and body mass index were studied as controls. RESULTS: In the whole group, mean GH and IGF-I levels were 24.2+/-3.9 ng/ml and 700.1+/-23.0 microg/liter, respectively. The insulin sensitivity index (ISI) in the patients was lower than in the controls (P

Objectif Etudier la prevalence de mutations ponctuelles et de grands rearrangements du gene AIP dans une population de patients atteints d’adenome hypophysaire (a prolactine, GH, mixte, non secretant, ACTH ou TSH). Materiel et methodes Un sequencage complet du gene AIP a ete realise sur 1411 patients entre 2006 et 2014 (les cas familiaux ont ete exclus de l’etude). En cas de forte suspicion clinique, un multiplex ligation-dependent probe amplification (MLPA) a ete realise afin de visualiser les deletions ou duplications de grande taille. Resultats Sur 1179 probands, 71 cas (5,9 %) presentaient une mutation deletere ( n = 44, 3,7 %) ou un variant de signification inconnue ( n = 27, 2,2 %). La majorite des mutations se presentait sous forme de mutations faux-sens (36 %), non-sens (33 %), petites deletions (16 %), grandes deletions (5 %), synonymes (5 %), et de perte du codon d’initiation (5 %). Quarante-huit pour cent des mutations etaient situees dans l’exon 6, les autres etaient reparties sur les 5 exons restants. Les mutations R304X, R304Q et R271W semblent constituer un hotspot dans l’exon 6 (29 % des mutations observees). Discussion Malgre une situation preferentielle des mutations dans l’exon 6, le sequencage de l’integralite du gene AIP reste necessaire. Les grandes deletions sont rares, les grandes duplications absentes de notre etude, et posent la question de la restriction de l’analyse MLPA a des populations de patients ciblees (FIPA, gigantisme, adenomes pediatriques…).

Somatostatin is a hypothalamic inhibitor of pituitary growth hormone secretion and cell proliferation, binding to five distinct receptor subtypes (sstr1–5). Since native somatostatin has a short half-life, somatostatin analogues with a longer half-life have been developed for therapeutic purposes. Octreotide and lanreotide are currently available for treatment of acromegaly, binding with high-affinity sstr2 and sstr5. Octreotide, the first somatostatin analogue used in the medical therapy of acromegaly, was initially given subcutaneously at doses of 100–500 μg three times daily. The introduction of new depot formulations, such as octreotide long-acting release, slow-release lanreotide and lanreotide-autogel, improved patients compliance of long-term therapy, overcoming the inconvenience of multiple daily administration. The treatment with somatostatin analogues induces biochemical control and tumour shrinkage in about 50–70% and 30–60% of patients with acromegaly, respectively. However, the efficacy of this therapy lies on an adequate expression of sstr2 and sstr5 on tumor cells. In the past, somatostatin receptor expression was tested in vivo by 111 In -diethylenetriaminepentaacetate- d -Phe-octreotide scintigraphy: this method has been abandoned since normal pituitary tissue can be visualised by 111 In -diethylenetriaminepentaacetate- d -Phe-octreotide scintigraphy. Currently, the somatostatin receptorial profile can be characterised by autoradiography, molecular biology techniques and immunohistochemistry on surgically removed tumor tissue. These methods may offer an individualised approach sparing patients from unnecessary treatment.

Acromegaly is a chronic debilitating disorder resulting from excessive secretion of growth hormone (GH) and consequent increase in insulin-like growth factor I (IGF-I), usually caused by a pituitary somatotroph adenoma. Effective treatment aims to ameliorate symptoms and signs of the disease and to lower mortality rate. In particular, high morbidity and mortality are partly related to the presence of insulin resistance due to the action of GH on liver, muscle and adipose tissue. Insulin resistance and/or reduced insulin sensitivity physiologically result in hypersecretion of insulin from the pancreas. This compensatory state of hyperinsulinemia is felt to be a first and more important marker for this condition. Adequate control of GH excess by surgery or pharmacotherapy is associated with decreased insulin resistance, resulting in reduced plasma insulin and glucose levels or improved glucose tolerance. Despite divergent effects of both somatostatin and somatostatin analogs on GH, insulin and glucagon secretion, and glucose absorption, treatment with the somatostatin analogs octreotide and lanreotide has only limited effects on glucose metabolism. However, glucose sensitivity has been formally examined using a hyperinsulinemic euglycemic clamp only in a minority of studies. Treatment with the GH-receptor antagonist pegvisomant improves insulin sensitivity, thus decreasing circulating fasting insulin and glucose levels. Assessment of insulin secretion and glucose levels in acromegalic patients during administration of the above compounds is thus mandatory.

The current survey study investigated the recurrence rate of hyperprolactinemia after cabergoline (CAB)-induced pregnancy and after lactation as well as safety of CAB exposure during early gestation. PATIENTS AND METHODS: From 1997-2008, 143 pregnancies were recorded in 91 patients with hyperprolactinemia (age 30.4 ± 4.7 yr, 76 microadenomas, 10 macroadenomas, and five nontumoral hyperprolactinemia). CAB therapy was discontinued within wk 6 of gestation in all. Pregnancies were monitored until delivery or termination, during and after lactation, twice yearly up to 60 months. The incidence of abortions, premature delivery, and fetal malformations was also analyzed. RESULTS: Pregnancies resulted in 13 (9.1%) spontaneous abortions and 126 (88.1%) live births. No neonatal malformations and/or abnormalities were recorded. In 29 of 91 patients (three with macroadenomas), treatment with CAB had to be restarted within 6 months after lactation because of hyperprolactinemia recurrence, whereas in 68% of cases, no additional therapy was required up to 60 months. No tumor mass enlargement was observed. All patients but three were breastfeeding, 35 (38.5%) for less than 2 months and 56 (61.5%) for 2-6 months. Three months after cessation of lactation and 60 months after pregnancy, no difference in prolactin levels was found between patients nursing for less than 2 months and 2-6 months. CONCLUSIONS: Fetal exposure to CAB at conception does not induce any increased risk of miscarriage or malformations. Pregnancy is associated with normalization of prolactin levels in 68% of patients. Breastfeeding does not increase the recurrence rate of hyperprolactinemia.

Pregnancy is becoming a relatively common event in patients with pituitary tumors (PT), due to the increasing availability of medical treatments, which control pituitary diseases associated with the development of PT. However, the presence of PT and its treatment may be a disturbing factor for pregnancy, and pregnancy significantly influences the course and the management of PT. This review summarizes the knowledge about the management of PT during pregnancy and the occurrence of pregnancy in patients with pre-existent PT, focusing on secreting PT characterized by hormonal excess and on clinically non-functioning PT often associated to hormone deficiency, which configure the hypopituitaric syndrome.

ObjectiveTo evaluate the effects of short- and long-term treatment with pegvisomant (PEG) on arrhythmias in acromegalic patients resistant to long-term, high-dose therapy with somatostatin analogs (SA).Materials and methodsThirteen patients entered the study. All patients started PEG at initial dose of 10 mg daily and then titrated to 5 mg every 6 weeks on the basis of IGF1. A standard 24-h electrocardiography registration was performed in all patients at baseline and after 6 and 18 months of PEG to evaluate: mean (HR), maximum (MHR), and minimum (mHR) heart rate; pauses number (P) and duration (PD); supraventricular episodes (SEs) number and duration (SED); and ventricular ectopic beats (EB) number and duration (EBD). Left ventricular mass (LVM) was also evaluated by standard echocardiography.ResultsA slight but not significant decrease in HR, MHR, and mHR was observed after 6-month PEG, whereas a significant decrease in HR (P=0.03), MHR (P=0.05), and mHR (P=0.05) was found after 18-month PEG compared with baseline. LVM significantly (P=0.05) correlated with MRH (r=−0.50) after short-term treatment, and with HR (r=−0.54) and mHR (r=−0.55) after long-term treatment. Long-term PEG induced the complete recovery of arrhythmias recorded at baseline in one patient and the improvement of rhythm disorders developed after 6-month therapy in another patient. The prevalence of conduction disturbances passed from 15 to 7.7% after long-term PEG.ConclusionsLong-term treatment with PEG reduces HR, MHR, and mHR and improves rhythm abnormalities in acromegaly.

To evaluate the metabolic effects of first-line somatostatin analogues or surgery in acromegaly. Retrospective, comparative, 12-month follow-up. Two hundred and thirty one patients (123 men, age 47.32 ± 14.63 years) with active acromegaly, first line treatments were somatostatin analogues in 151 (65.4%) and surgery in 80 (34.6%). Metabolic syndrome (MS) parameters, glucose, insulin and GH during oral glucose tolerance test, stimulated insulin sensitivity by insulin sensitivity index (ISI Matsuda), early and total insulin-secretion rate by insulinogenic index and AUC(INS), visceral adiposity function, expressed by visceral adipose index (VAI). Somatostatin analogues treatment improved all MS parameters and significantly reduced fasting glucose (P < 0.001), HbA1c (P = 0.014) and the prevalence of DM (P = 0.003) when disease control was achieved. Both somatostatin analogues and surgery improved ISI Matsuda (P < 0.001) and reduced AUC(INS) (P < 0.001) and VAI (P < 0.001 and P = 0.003, respectively). Only in controlled somatostatin analogues-treated patients a significant reduction in insulinogenic index (P = 0.010) was observed. ISI Matsuda showed a significant independent correlation with IGF-1 levels (β = -0.258; P = 0.001) and VAI score (β = -0.430; P < 0.001). VAI was independently correlated with IGF-1 (β = 0.183; P = 0.004). Both somatostatin analogues and surgery can safely be used as first-line therapy in acromegaly, without any untoward effects on glucose tolerance. The control of acromegaly is the main determinant of beneficial effects on general features of insulin sensitivity. VAI could represent an additional link between disease control and insulin sensitivity.

Acromegaly is a slow progressive disease characterized by exaggerated somatic growth and distorted proportion arising from hypersecretion of growth hormone (GH) and insulin-like growth factor 1 IGF-1. The estimated prevalence of the disease is 40 cases per million population with three to four new cases per million population per year. Diagnosis is made biochemically by the findings of increased serum GH concentrations, not suppressed following a 75 g oral glucose load (OGTT), and an increase in IGF-I levels, the main GH-dependent growth factor. A random GH level lower than 0.4 μg/L and GH nadir below 1.0 μg/L after OGTT with an IGF-I value in the age- and sex-matched normal range exclude the diagnosis of acromegaly. In 95% of cases acromegaly is induced by a pituitary adenoma, demonstrated by MRI. Acromegaly is associated with increased morbidity and mortality for cardiovascular and respiratory complications, whereas neoplasms seem to be a minor cause of increased risk of death. Other associated diseases are osteoarthritis, carpal tunnel syndrome, fatigue, visual abnormalities, and reproductive disorders. Acromegaly results in premature death because of prolonged elevation of GH and IGF-I levels, and a strong biochemical control improves well-being and restores life expectancy to normal. The main goals of medical treatment of acromegaly include normalization of biochemical markers of disease activity, improvement in signs and symptoms of the disease, removal or reduction of tumor mass, and preservation of pituitary function. This chapter discusses the effects of biochemical control of acromegaly on cardiovascular diseases, metabolic complications, respiratory abnormalities, malignancies, and bone alterations.

ObjectiveGenetic disorders of calcium metabolism arise in a familial or sporadic setting. The calcium-sensing receptor (CASR) plays a key role in maintaining calcium homeostasis and study of theCASRgene can be clinically useful in determining etiology and appropriate therapeutic approaches. We report two cases of novelCASRgene mutations that illustrate the varying clinical presentations and discuss these in terms of the current understanding of CASR function.Patients and methodsA 16-year-old patient had mild hypercalcemia associated with low-normal urinary calcium excretion and normal-to-high parathyroid hormone (PTH) levels. Because of negative family history, familial hypocalciuric hypercalcemia was originally excluded. The second patient was a 54-year-old man with symptomatic hypocalcemia, hyperphosphatemia, low PTH, and mild hypercalciuria. Familial investigation revealed the same phenotype in the patient's sister. The coding region of theCASRgene was sequenced in both probands and their available first-degree relatives.ResultsThe first patient had a novel heterozygous inactivatingCASRmutation in exon 4, which predicted a p.A423K change; genetic analysis was negative in the parents. The second patient had a novel heterozygous activatingCASRmutation in exon 6, which predicted a p.E556K change; the affected sister of the proband was also positive.ConclusionsWe reported two novel heterozygous mutations of theCASRgene, an inactivating mutation in exon 4 and the first activating mutation reported to date in exon 6. These cases illustrate the importance of genetic testing ofCASRgene to aid correct diagnosis and to assist in clinical management.

ContextThe most frequent cause of death in acromegaly is cardiomyopathy.ObjectiveTo evaluate determinants of acromegalic cardiomyopathy.DesignObservational, open, controlled, retrospective study.SubjectsTwo hundred and five patients with newly diagnosed active acromegaly (108 women and 97 men; median age 44 years) and 410 non-acromegalic subjects sex- and age-matched with the patients.Main outcome measuresLeft ventricular (LV) mass index (LVMi), transmitral inflow early-to-atrial (E/A) peak velocity ratio, and LV ejection fraction (LVEF) were measured by Doppler echocardiography to determine the prevalence of LV hypertrophy (LVH), diastolic and systolic dysfunction. The role of age, estimated disease duration, body mass index, GH and IGF1 levels, systolic and diastolic blood pressure, lipid profile and glucose tolerance in determining different features of the acromegalic cardiomyopathy was investigated.ResultsCompared with controls, the patients had lower E/A, LVEF, high-density lipoprotein (HDL)-cholesterol levels and higher LVMi, total- and low-density lipoprotein (LDL)-cholesterol, triglycerides, glucose and insulin levels, homeostatic model assessment of insulin resistance (HOMA-R) and HOMA-β. The relative risk to develop mild (odds ratio (OR)=1.67 (1.05–2.66); P=0.027) or severe hypertension (OR=1.58 (1.04–2.32); P=0.027), arrhythmias (OR=4.93 (1.74–15.9); P=0.001), impaired fasting glucose/impaired glucose tolerance (OR=2.65 (1.70–4.13); PP=0.0009), LVH (OR=11.9 (7.4–19.5); PPPt=2.4, P=0.02) and systolic dysfunction (t=−2.77, P=0.006) was disease duration and that of diastolic dysfunction was patient's age (t=−3.3, P=0.001). Patients with an estimated disease duration of >10 years had a relative risk to present cardiac complications three times higher than patients with estimated disease duration ≤5 years.ConclusionsThe prevalence of different features of cardiomyopathy is 3.3–14.2 times higher in the acromegalic than in the non-acromegalic population. The major determinant of cardiomyopathy is disease duration.

Somatostatin analogs (SA) are widely used in acromegaly, either as first-line or adjuvant treatment after surgery. First-line treatment with these drugs is generally used in the patients with macroadenomas or in those with clinical conditions so severe as to prevent unsafe reactions during anesthesia. Generally, the response to SA takes into account both control of GH and IGF-I excess, with consequent improvement of clinical symptoms directly related to GH and IGF-I excess, and tumor shrinkage. This latter effect is more prominent in the patients treated first-line and bearing large macroadenomas, but it is also observed in patients with microadenomas, even with little clinical implication. Predictors of response are patients' gender, age, initial GH and IGF-I levels, and tumor mass, as well as adequate expression of somatostatin receptor types 2 and 5, those with the highest affinity for octreotide and lanreotide. Only sporadic cases of somatostatin receptor gene mutation or impaired signaling pathways have been described in GH-secreting tumors so far. The response to SA also depends on treatment duration and dosage of the drug used, so that a definition of resistance based on short-term treatments using low doses of long-acting SA is limited. Current data suggest that response to these drugs is better analyzed taking together biochemical and tumoral effects because only the absence of both responses might be considered as a poor response or resistance. This latter evidence seems to occur in 25% of treated patients after 12 months of currently available long-acting SA.

BackgroundThe GH/insulin-like growth factor 1 axis is physiologically involved in the regulation of electrolytes and water homeostasis by kidneys, and influences glomerular filtration and tubular re-absorption processes. The aim of the study was to investigate renal structure and function in acromegalic patients during active disease and disease remission.PatientsThirty acromegalic patients (15 males and 15 females), aged 32–70 years, were enrolled for the study. Tende novopatients had active disease, whereas 20 patients showed disease remission 1 year after medical treatment with somatostatin analogs (SA) (ten patients) or surgery (ten patients). Thirty healthy subjects matched for age, gender, and body surface area were enrolled as controls.ResultsIn both active (A) and controlled (C) patients, creatinine clearance (PPPPPPPPPPPPr=0.871,Pr=0.639,PConclusionsThe results of the current study demonstrated that acromegaly affects both renal structure and function. The observed changes are not completely reversible after disease remission.

Cushing’s syndrome (CS) causes metabolic abnormalities that determine an increased cardiovascular risk not only during the active phase of the disease but also for a long time after cure. Cardiovascular complications, such as premature atherosclerosis, coronary artery disease, heart failure, and stroke, in patients with CS cause a mortality rate higher than that observed in a normal population. The increased cardiovascular risk is mainly due to metabolic complications, such as metabolic syndrome, but also to vascular and cardiac alterations such as atherosclerosis and cardiac structural and functional changes. In the clinical management of patients with CS the focus should be on identifying the global cardiovascular risk and the aim should be to control not only hypertension but also other correlated risk factors, such as obesity, glucose intolerance, insulin resistance, dyslipidemia, endothelial dysfunction and the prothrombotic state. Considering that remission from hypercortisolism is often difficult to achieve and that the cardiovascular risk can persist even during disease remission, care and control of all cardiovascular risk factors should be one of the primary goals during the follow-up of these patients.

The objective of the study was to evaluate the efficacy of 5 yr of depot somatostatin analogs (SSAs) as first-line therapy in acromegaly.Primary measures were fasting GH 2.5 microg/liter or less and IGF-I normalized for age and tumor shrinkage. Secondary measures were control of hypertension, arrhythmias, left ventricular hypertrophy, diastolic and systolic dysfunction, and change in lipid and glucose profile.Patients included 45 de novo patients (18 women and 27 men, aged 20-82 yr); 28 were treated with octreotide-long-acting release and 17 with lanreotide.GH was controlled in 100% and IGF-I levels in 97.8%, tumor shrinkage was 74.9 +/- 22.1 and 78.2+/-14.5%, in the octreotide-long-acting release and lanreotide groups, respectively. There was a significant improvement in the prevalence of hypertension (from 46.7 to 22.2%, P = 0.027), arrhythmias (from 17.8% to zero, P = 0.01), left ventricular hypertrophy (from 82.2 to 42.2%, P0.0001), diastolic dysfunction (from 60.0 to 15.6%, P0.0001), systolic dysfunction (from 40.0 to 4.4%, P0.0001), and hypertriglyceridemia (from 40.0 to 4.4%, P0.0001). The prevalence of impaired glucose tolerance (IGT; from 28.9 to 20.0%. P = 0.46) and diabetes mellitus (from 22.4 to 31.1%, P = 0.64) did not change.In patients with severe comorbidities and those who refuse surgery, 5 yr of exclusive SSA therapy induce successful control of GH and IGF-I; tumor shrinkage (by median 80%), and improvement of hypertension, cardiac performance; and dyslipidemia. No patient was withdrawn from treatment because of side effects, and glucose tolerance was stable. We suggest that first-line SSA treatment may be safely continued in patients with acromegaly, according to an individual patient's indications and preferences.

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.

OBJECTIVE: The objective of the study was to investigate whether first-line surgery or somatostatin analogs (SSA) have a different outcome on cardiomyopathy after 12 months. DESIGN: This was a retrospective, comparative, nonrandomized study. PATIENTS: Fifty-six patients treated with SSA and 33 operated on by transsphenoidal approach participated in the study. For the purposes of this study, only controlled patients were included. MEASUREMENTS: Primary outcome measures were changes in left ventricular mass index, diastolic (early to atrial mitral flow velocity), and systolic performance (left ventricular ejection fraction). Secondary outcome measures were reduction of total to high-density lipoprotein-cholesterol ratio as a cardiovascular risk parameter, and improvement of glucose profile and pituitary function as indirect causes of cardiovascular improvement. RESULTS: SSA and surgery groups were similar for gender, age, estimated disease duration, GH and IGF-I levels, and severity of cardiomyopathy lipid and glucose profile. Twelve months after treatment in both groups, left ventricular mass index, early to atrial mitral flow velocity, diastolic blood pressure, and heart rate decreased significantly, whereas only in SSA-treated patients, left ventricular ejection fraction increased significantly. The total to high-density lipoprotein-cholesterol ratio significantly reduced only in SSA-treated patients, whereas fasting glucose levels significantly decreased only in surgery-treated patients. A normal pituitary function was found in 46.4% of SSA- and 36.4% of surgery-treated patients, with results unchanged in the former and slightly reduced in the latter. CONCLUSIONS: Twelve months after first-line treatment with SSA or surgery, we found a similar improvement in left ventricular hypertrophy and diastolic filling. In contrast, systolic function improved more evidently in SSA-treated patients. Both a direct effect of SSA and a more preserved pituitary function might explain these results.

This chapter discusses the effects of biochemical control of acromegaly on cardiovascular diseases, metabolic complications, respiratory abnormalities, malignancies and bone alterations. Acromegaly is associated with increased morbidity and mortality for cardiovascular and respiratory complications, whereas neoplasms seem to be a minor cause of increased risk of death. Other associated diseases are osteoarthritis, carpal tunnel syndrome, fatigue, visual abnormalities and reproductive disorders. Acromegaly results in premature death because of prolonged elevation of GH an IGF-I levels, and a strong biochemical control improves well-being and restores life expectancy to normal. The main goals of medical treatment of acromegaly include normalization of biochemical markers of disease activity, improvement in signs and symptoms of the disease, removal or reduction of tumor mass and preservation of pituitary function.

This analytical, observational, retrospective, case-control study was designed to describe clinical presentation, biochemical disease severity, presence, and severity of metabolic and cardiovascular complications in patients diagnosed as having acromegaly at 60 yr or older (no.=57) as compared to sex- and age-matched healthy controls. Patients and controls underwent a complete endocrine, metabolic, and cardiovascular check-up. The age at diagnosis was equally distributed between 60 to 75 yr while only a minority of the patients (5.3%) was diagnosed after 75 yr. Median GH and IGF-I levels were 15 microg/l and 557 microg/l. The prevalence of microadenomas, enclosed macroadenomas, and extrasellar/invasive macroadenomas was 30%, 49%, and 21%, respectively. All patients had joint complaints and goiter (euthyroid in 65% and pre-toxic/toxic in 35%), 82% had hypertension, 58% diabetes and 54% had both. As compared to controls, a higher number of patients were receiving treatment with anti-arrhythmiacs (p=0.033), anti-aggregants (p=0.013), levothyroxine (p=0.015), and metformin (p=0.022). Nevertheless, the patients had higher systolic and diastolic blood pressure, heart rate, left ventricular mass index, lipids, glucose and insulin levels as well as percent function of beta cells than controls. In conclusion, the high prevalence of systemic complications makes elderly acromegalics more susceptible than controls to cardiovascular events. We suggest that an accurate clinical check-up and, possibly, a more aggressive treatment of hypertension and diabetes are required in elderly acromegalics.

CONTEXT: Hyperinsulinemia is associated with colon carcinoma in the general population. Patients with acromegaly are considered to be at risk for developing colonic lesions and typically have hyperinsulinemia. OBJECTIVE: Our objective was to evaluate the role of fasting insulin levels on the prevalence of colonic adenomatous polyps or adenocarcinoma in acromegaly. DESIGN: This is an analytical, observational, prospective study. Patients: A total of 210 patients (111 women, 99 men, age 20-82 yr) undergoing complete colonoscopy at diagnosis of acromegaly were included in this study. RESULTS: Colonic lesions were found in 81 patients (38.6%), and consisted of hyperplastic polyps in 33 (15.7%), adenomatous polyps in 42 (20.0%), and adenocarcinoma in six patients (2.8%). Polyps were single in 22 cases (27.1%). Fasting insulin levels were significantly lower in patients without lesions (16.0 +/- 7.5 mU/liter) than in patients with hyperplastic polyps (22.4 +/- 8.8 mU/liter; P < 0.01), adenomatous polyps (38.0 +/- 15.9 mU/liter; P < 0.0001), and adenocarcinoma (59.0 +/- 30.6 mU/liter; P < 0.0001). Fasting insulin levels were also lower in patients with hyperplastic polyps than in those with adenomatous polyps (P < 0.01). The odds ratio for harboring colonic adenomas was 14.8 (95% confidence interval 4.4-51.2; P < 0.0001) and 8.6 times higher (95% confidence interval 2.8-29.0; P < 0.0001) in patients with fasting insulin levels in the upper tertile [>/=27.1 mIU/liter (n = 28)] compared with the lower [12.1 to

AIM: The aim of the current study was to evaluate the effect of short-term (6 months) and long-term (18 months) treatment with pegvisomant on cardiac structure and performance in patients with acromegaly. PATIENTS: Seventeen patients (nine women, eight men, 27-61 yr) with active acromegaly entered and 12 completed the long-term study. After a baseline evaluation, including measurement of hemodynamic, biochemical, and hormonal parameters, and a standard Doppler echocardiography, treatment with pegvisomant was started at the initial dose of 10 mg/d, increasing by 5 mg/d every 6 wk on the basis of IGF-I levels until normalization or the achievement of a maximal dose of 40 mg/d. RESULTS: After short-term treatment, IGF-I levels were normalized in 10 of the 17 (59%) patients. Left ventricular mass index (LVMi) was significantly decreased without changes in diastolic and systolic performance. After long-term treatment, IGF-I levels were normalized in 10 of the 12 (83%) patients. Blood glucose and serum insulin levels were decreased compared with baseline. LVMi was further decreased compared with short-term treatment, so that the prevalence of left ventricle hypertrophy decreased from 50% at baseline to 17% after 18 months of treatment. Moreover, ejection fraction as well as early to late (atrial) peak velocity ratio (E/A) were significantly increased, whereas isovolumic relaxation time was significantly decreased compared with baseline, demonstrating an improvement of both diastolic and systolic function. A significant correlation was found between the change in IGF-I levels and that of left ventricular ejection fraction. In general, the prevalence of cardiac insufficiency was present in 13 of the 17 (76%) patients at baseline and in one (8%) patient after 18 months of treatment. CONCLUSIONS: Long-term treatment with the GH receptor antagonist improves acromegalic cardiomyopathy by decreasing cardiac hypertrophy and enhancing diastolic and systolic function, and consequently partially or completely reverting the cardiac insufficiency.

BACKGROUND: This analytical, retrospective study was designed to select cut-off thresholds of mean GH levels during a diurnal profile and nadir GH levels after oral glucose tolerance test (OGTT) according to age to diagnose surgical remission of acromegaly. METHODS: One hundred forty-one patients (76 women, aged 44 +/- 15 years and 65 men, aged 43 +/- 13 years) were included in this study. For the purpose of this study, remission was based on insulin-like growth factor-I (IGF-I) levels in the normal range for age. Diagnostic accuracy was analysed by receiving-operator characteristics (ROC) curves in the entire series, and in young (20-40 years), middle-aged (41-60 years) and older patients (> 60 years), separately. RESULTS: Sixty patients (42.6%) had normal IGF-I levels after surgery. In the entire series, in young and in middle-aged patients, the ROC analysis showed that optimum cut-off for mean GH levels was 2.3 microg/l (diagnostic accuracy range, 94-97%) whereas that for nadir GH after OGTT were, respectively, 0.85, 0.9 and 0.8 microg/l (diagnostic accuracy range, 90-95%). In the older patients, the optimum cut-off selected for mean GH levels was 1.4 microg/l and that for nadir GH after OGTT was 0.5 microg/l (diagnostic accuracy, 100% for both). The comparative analysis of the ROC curves did not show any significant difference between mean GH and nadir GH after OGTT (P = 0.21). CONCLUSIONS: The criteria currently accepted for diagnosing post-surgical remission of acromegaly have high diagnostic accuracy only in the patients aged below 60 years. In older patients, lower cut-offs (i.e. = 1.4 microg/l for fasting GH and = 0.5 microg/l for nadir GH after OGTT) predict normal IGF-I levels. Mean GH levels during a diurnal profile have similar diagnostic accuracy of nadir GH levels after OGTT. This suggests that OGTT is not necessary to establish surgical cure.