Time to first remission and survival in patients with acromegaly: Evidence from the UK Acromegaly Register Study (UKAR).

OBJECTIVE: This study aimed to understand the effect of time to remission of acromegaly on survival in people living with acromegaly. DESIGN, PATIENTS AND MEASUREMENT: This cross-sectional study used data from the UK Acromegaly Register. We considered remission of acromegaly growth hormone controlled at ≤2 µg/L following the diagnosis of acromegaly. We used the accelerated failure time model to assess the effect of time to remission on survival in acromegaly. RESULTS: The study population comprises 3569 individuals with acromegaly, with a median age of diagnosis of 47.3 (36.5-57.8) years, 48% females and a majority white population (61%). The number of individuals with the first remission of acromegaly was 2472, and the median time to first remission was 1.92 (0.70-6.58) years. In this study, time to first remission in acromegaly was found to have a significant effect on survival (p < .001); for every 1-year increase in time to first remission, there was a median 1% reduction in survival in acromegaly. In an analysis adjusted for covariates, the survival rate was 52% higher (p < .001) in those who underwent surgery as compared to those who did not have surgery, 18% higher (p = .01) in those who received treatment with somatostatin analogues (SMA) as compared to those with dopamine agonists and 21% lower (p < .001) in those who received conventional radiotherapy as compared to those who did not receive radiotherapy. CONCLUSION: In conclusion, this population-based study conducted in patients with acromegaly revealed that faster remission time, surgical intervention and treatment with SMA are linked to improved survival outcomes.

Disease control of acromegaly does not prevent excess mortality in the long term: results of a nationwide survey in Italy.

OBJECTIVE: This study aimed to assess the long-term outcome of patients with acromegaly. DESIGN: This is a multicenter, retrospective, observational study which extends the mean observation period of a previously reported cohort of Italian patients with acromegaly to 15 years of follow-up. METHODS: Only patients from the centers that provided information on the life status of at least 95% of their original cohorts were included. Life status information was collected either from clinical records or from the municipal registry offices. Standardized mortality ratios (SMRs) were computed comparing data with those of the general Italian population. RESULTS: A total of 811 patients were included. There were 153 deaths, with 90 expected and an SMR of 1.7 (95% CI 1.4-2.0, p < 0.001). Death occurred after a median of 15 (women) or 16 (men) years from the diagnosis, without gender differences. Mortality remained elevated in the patients with control of disease (SMR 1.3, 95% CI 1.1-1.6). In the multivariable analysis, only older age and high IGF1 concentrations at last available follow-up visit were predictors of mortality. The oncological causes of death outweighed the cardiovascular ones, bordering on statistical significance with respect to the general population. CONCLUSIONS: Mortality remains significantly high in patients with acromegaly, irrespectively of disease status, as long as the follow-up is sufficiently long with a low rate of patients lost to follow-up. Therapy strategy including radiotherapy does not have an impact on mortality. Oncological causes of death currently outweigh the cardiovascular causes.

Descriptive Epidemiology and Survival Analysis of Acromegaly in Korea.

BACKGROUND: Acromegaly is a rare, slowly progressive disease. Its mechanism is not fully understood, and epidemiological research on Korean patients with acromegaly is scarce. The purpose of this study was to determine the incidence and prevalence of acromegaly and assess the comorbidities and survival benefits based on treatment options. METHODS: This nationwide population-based cohort study was conducted using data of the Korean Health Insurance Review and Assessment claims database to evaluate the incidence of newly diagnosed acromegaly cases during 2013-2017. RESULTS: During the 5-year period, 1,093 patients were newly diagnosed with acromegaly. The average annual incidence was 4.2 cases per million per year, and the prevalence was 32.1 cases per million during this period. The incidence of hypertension was low after medical treatment (hazard ratio, 0.257; 95% confidence interval, 0.082-0.808; P = 0.020), but the incidence of diabetes showed no significant difference across treatment modalities. Over a period of 6 years since diagnosis, we found that patients treated for acromegaly had a significantly higher survival rate than those untreated (P < 0.001). CONCLUSION: The annual incidence rate of Korean patients with acromegaly was similar to that reported in previous studies. Using nationwide population data, our study emphasized the importance of treatment in acromegaly patients.

Cardiovascular complications of acromegaly.

Acromegaly is a chronic disease due to growth hormone (GH) and insulin-like growth factor 1 (IGF-1) excess. It is associated with various systemic complications including cardiovascular disease. Arterial hypertension occurs in about 20% to 30% of patients. Its pathogenesis is mainly related to the increase in plasma volume secondary to a sodium retaining actions of GH and IGF-1 in the kidney, but abnormalities in vessel architecture and reactivity participate. Left ventricular hypertrophy and diastolic dysfunctions were frequently reported in echo-based studies and are mostly mild and without clinical consequences. Recent cardiac MRI studies described a much lower frequency of myocardial hypertrophy than echo-based assessments. Progression to systolic dysfunction with congestive heart failure is nowadays very rare. Risk of coronary heart disease and of clinically significant arrythmias does not seem to be increased. Acromegaly-related cardiac valve abnormalities may be related to fibrotic changes and seem to persist after effective treatment of acromegaly. Advances in acromegaly treatment over the last decades significantly diminished the cardiovascular burden of the disease, with the cardiovascular disease anymore being the leading cause of death.

Prolonged diagnostic delay in acromegaly is associated with increased morbidity and mortality.

CONTEXT: Clinical features of acromegaly develop insidiously. Its diagnosis may therefore be delayed. OBJECTIVE: Our aim was to study diagnostic delay and its impact on morbidity and mortality in a nationwide cohort of patients with acromegaly. DESIGN: Adult patients diagnosed with acromegaly between 2001 and 2013 were identified in the Swedish National Patient Registry. Diagnostic codes for predefined comorbidities associated with acromegaly were recorded between 1987 and 2013. Diagnostic delay was calculated as the time between the first registered comorbidity and the diagnosis of acromegaly. RESULTS: A total of 603 patients (280 men, 323 women) with acromegaly were included. Mean (s.d.) diagnostic delay was 5.5 (6.2) years (median (minimum, maximum) 3.3 (0.0-25.9)) Diagnostic delay was 1-<5 years in 23% patients; 5-<10 years in 17%; and ≥10 years in 24%. No delay was recorded in 36% of patients. Overall, mean (s.d.) number of comorbidities was 4.1 (2.5) and was higher in patients with longer diagnostic delay (P < 0.0001). Overall, observed number of deaths was 61 (expected 42.2), resulting in a standardized mortality ratio (SMR) of 1.45 (95% CI: 1.11-1.86). Increased mortality was only found in patients with the longest diagnostic delay (1.76, 95% CI: 1.12-2.65). In the other groups, no statistically significant increase in mortality was recorded, with the numerically lowest SMR observed in patients without diagnostic delay (1.18; 95% CI: 0.68-1.92). CONCLUSIONS: The diagnosis of acromegaly is delayed in most patients. Prolonged diagnostic delay is associated with increased morbidity and mortality.

Determinants of morbidities and mortality in acromegaly

ABSTRACT Acromegaly is a systemic disease associated with increased morbidity, presenting cardiovascular, metabolic, respiratory, neoplastic, endocrine, articular and bone complications. Most of these comorbidities can be prevented or delayed with adequate disease treatment and, more recent studies with the use of modern treatments of acromegaly, have shown a change in the severity and prevalence of these complications. In addition, acromegaly is associated with increased mortality, but recent studies (especially those published in the last decade) have shown a different scenario than older studies, with mortality no longer being increased in adequately controlled patients and a change in the main cause of death from cardiovascular disease to malignancy. In this review, we discuss this changing face of acromegaly summarizing current knowledge and evidence on morbimortality of the disease. Arch Endocrinol Metab. 2019;63(6):630-7

Sleep apnea and cardiovascular complications of the acromegaly. Response to the medical treatment.

Acromegaly is a rare disease characterized by high levels of growth hormone (GH) and insulin-like growth factor 1 (IGF-1). The excess of GH leads to the development of different manifestations in different organs, from subtle signs in the bones and soft tissues to the development of respiratory and cardiac insufficiency. In the cardiovascular system, the GH/IGF-1 axis exerts its influence on three major aspects: myocyte growth and structure, cardiac contractility and vascular function. In this article, we review the different cardiovascular and respiratory complications as well as the effects of the different treatments on these complications. Cardiovascular complications that occur in acromegaly are known as "acromegalic cardiomyopathy," and include ventricular hypertrophy, impaired diastolic and systolic function, valve diseases, coronary artery disease, and arrhythmias. Acromegaly is also associated with relevant complications of the respiratory system, mainly sleep apnea and respiratory insufficiency. Regarding treatment, there are different therapeutic strategies. Surgery is the first-choice treatment, but in general, half of patients will require adjuvant treatments, such as medical treatment (somatostatin analogues, dopamine agonists and GH receptor antagonists) or radiotherapy. The treatment can improve some complications of acromegaly, such as left ventricular hypertrophy, hypertension, or obstructive sleep apnea. On the other hand, when strict control of the disease is achieved, a reduction in mortality and cardiovascular morbidity is assured, reaching rates similar to those of the general population.

Systemic Complications of Acromegaly and the Impact of the Current Treatment Landscape: An Update.

Acromegaly is a chronic systemic disease with many complications and is associated with increased mortality when not adequately treated. Substantial advances in acromegaly treatment, as well as in the treatment of many of its complications, mainly diabetes mellitus, heart failure, and arterial hypertension, were achieved in the last decades. These developments allowed change in both prevalence and severity of some acromegaly complications and furthermore resulted in a reduction of mortality. Currently, mortality seems to be similar to the general population in adequately treated patients with acromegaly. In this review, we update the knowledge in complications of acromegaly and detail the effects of different acromegaly treatment options on these complications. Incidence of mortality, its correlation with GH (cumulative exposure vs last value), and IGF-I levels and the shift in the main cause of mortality in patients with acromegaly are also addressed.

Postoperative use of somatostatin analogs and mortality in patients with acromegaly.

Objective To assess the effect of somatostatin analogs (SSAs) on mortality in relation to disease control of acromegaly after pituitary surgery. Design A retrospective study in two large tertiary referral centers in The Netherlands. Methods Overall, 319 patients with acromegaly in whom pituitary surgery was performed as primary therapy between January 1980 and July 2017 were included. Postoperative treatment with SSA was prescribed to 174 (55%) patients because of persistent or recurrent disease. Disease control at last visit was assessed by IGF1 standard deviation score (SDS). Adequate disease control was defined as IGF1 SDS ≤2. Univariate determinants of mortality and standardized mortality ratios (SMRs) were calculated for groups with and without SSA at any moment postoperatively and at last visit. Results In total, 27 deaths were observed. In univariate analysis, determinants of mortality were inadequate disease control (relative risk (RR): 3.41, P = 0.005), surgery by craniotomy (RR: 3.53, P = 0.013) and glucocorticoid substitution (RR: 2.11, P = 0.047). There was a strong trend toward increased mortality for patients who used SSA (RR: 2.01, P = 0.067) and/or dopamine agonists (RR: 2.54, P = 0.052) at last visit. The SMR of patients with adequate disease control who used SSA at any moment postoperatively (1.07, P = 0.785) and at last visit (1.19; P = 0.600) was not increased. Insufficiently controlled patients had a significantly raised SMR (3.92, P = 0.006). Conclusions Postoperative use of SSA is not associated with increased mortality in patients with acromegaly who attain adequate disease control. In contrast, inadequate disease control, primary surgery by craniotomy and glucocorticoid substitution are associated with increased mortality.

Determinants of morbidities and mortality in acromegaly.

Acromegaly is a systemic disease associated with increased morbidity, presenting cardiovascular, metabolic, respiratory, neoplastic, endocrine, articular and bone complications. Most of these comorbidities can be prevented or delayed with adequate disease treatment and, more recent studies with the use of modern treatments of acromegaly, have shown a change in the severity and prevalence of these complications. In addition, acromegaly is associated with increased mortality, but recent studies (especially those published in the last decade) have shown a different scenario than older studies, with mortality no longer being increased in adequately controlled patients and a change in the main cause of death from cardiovascular disease to malignancy. In this review, we discuss this changing face of acromegaly summarizing current knowledge and evidence on morbimortality of the disease. Arch Endocrinol Metab. 2019;63(6):630-7.

Mortality in acromegaly decreased in the last decade: a systematic review and meta-analysis.

OBJECTIVE: To compare the acromegaly mortality rates with those expected for the general population from studies published before and after 2008. METHODS: We performed a systematic review and included observational studies in which the number of deaths observed in acromegaly was compared with the expected mortality for the general population mortality observed/expected (O/E). The following electronic databases were used as our data sources: EMBASE, MEDLINE and LILACS. From the observed and expected deaths, we recalculated all standardized mortality ratios (SMR) and their respective confidence intervals (95% CI), which were plotted in a meta-analysis using the software RevMan 5.3. RESULTS: We identified 2303 references, and 26 studies fulfilled our eligibility criteria. From the 17 studies published before 2008, the mortality in acromegaly was increased, while from the nine studies published after 2008, the mortality was not different from the general population (SMR: 1.35, CI: 0.99-1.85). In six studies where somatostatin analogs (SAs) were used as adjuvant treatment, acromegaly mortality was not increased (SMR: 0.98, CI: 0.83-1.15), whereas in series including only patients treated with surgery and/or radiotherapy, mortality was significantly higher (SMR: 2.11; CI: 1.54-2.91). In studies published before and after 2008, the mortality was not increased in patients who achieved biochemical control, while it was higher in those with active disease. Cancer has become a leader cause of deaths in acromegaly patients in the last decade, period in which life expectancy improved. CONCLUSION: Mortality in acromegaly is normalized with biochemical control and decreased in the last decade with the more frequent use of SAs as adjuvant therapy. Increased life expectancy has been associated with more deaths due to cancer.

Cancer Incidence in Patients With Acromegaly: A Cohort Study and Meta-Analysis of the Literature.

Context: Acromegaly has been associated with increased risk of cancer morbidity and mortality, but research findings remain conflicting and population-based data are scarce. We therefore examined whether patients with acromegaly are at higher risk of cancer. Design: A nationwide cohort study (1978 to 2010) including 529 acromegaly cases was performed. Incident cancer diagnoses and mortality were compared with national rates estimating standardized incidence ratios (SIRs). A meta-analysis of cancer SIRs from 23 studies (including the present one) was performed. Results: The cohort study identified 81 cases of cancer after exclusion of cases diagnosed within the first year [SIR 1.1; 95% confidence interval (CI), 0.9 to 1.4]. SIRs were 1.4 (95% CI, 0.7 to 2.6) for colorectal cancer, 1.1 (95% CI, 0.5 to 2.1) for breast cancer, and 1.4 (95% CI, 0.6 to 2.6) for prostate cancer. Whereas overall mortality was elevated in acromegaly (SIR 1.3; 95% CI, 1.1 to 1.6), cancer-specific mortality was not. The meta-analysis yielded an SIR of overall cancer of 1.5 (95% CI, 1.2 to 1.8). SIRs were elevated for colorectal cancer, 2.6 (95% CI, 1.7 to 4.0); thyroid cancer, 9.2 (95% CI, 4.2 to 19.9); breast cancer, 1.6 (1.1 to 2.3); gastric cancer, 2.0 (95% CI, 1.4 to 2.9); and urinary tract cancer, 1.5 (95% CI, 1.0 to 2.3). In general, cancer SIR was higher in single-center studies and in studies with <10 cancer cases. Conclusions: Cancer incidence rates were slightly elevated in patients with acromegaly in our study, and this finding was supported by the meta-analysis of 23 studies, although it also suggested the presence of selection bias in some earlier studies.

Decreasing mortality and changes in treatment patterns in patients with acromegaly from a nationwide study.

CONTEXT: New therapeutic strategies have developed for the management of acromegaly over recent decades. Whether this has improved mortality has not been fully elucidated. OBJECTIVE: The primary aim was to investigate mortality in a nationwide unselected cohort of patients with acromegaly. Secondary analyses included time trends in mortality and treatment patterns. DESIGN: A total of 1089 patients with acromegaly were identified in Swedish National Health Registries between 1987 and 2013. To analyse time trends, the cohort was divided into three periods (1987-1995, 1996-2004 and 2005-2013) based on the year of diagnosis. MAIN OUTCOME MEASURES: Using the Swedish population as reference, standardized mortality ratios (SMRs) were calculated with 95% confidence intervals (CIs). RESULTS: Overall SMR was 2.79 (95% CI: 2.43-3.15) with 232 observed and 83 expected deaths. Mortality was mainly related to circulatory diseases (SMR: 2.95, 95% CI: 2.35-3.55), including ischemic heart disease (2.00, 1.35-2.66) and cerebrovascular disease (3.99, 2.42-5.55) and malignancy (1.76, 1.27-2.26). Mortality decreased over time, with an SMR of 3.45 (2.87-4.02) and 1.86 (1.04-2.67) during the first and last time period, respectively (P = .015). During the same time periods, the frequency of pituitary surgery increased from 58% to 72% (P < 0.001) and the prevalence of hypopituitarism decreased from 41% to 23% (P < 0.001). CONCLUSIONS: Excess mortality was found in this nationwide cohort of patients with acromegaly, mainly related to circulatory and malignant diseases. Although still high, mortality significantly declined over time. This could be explained by the more frequent use of pituitary surgery, decreased prevalence of hypopituitarism and the availability of new medical treatment options.

Factors affecting early versus late remission in acromegaly following stereotactic radiosurgery.

Stereotactic radiosurgery (SRS) is a well-established treatment modality for patients with acromegaly. Our previously published study demonstrated a median time to remission of 29 months. This study aims to identify factors affecting the timing of remission and also to quantify the rate of late remission. This is a retrospective analysis of acromegaly patients who underwent SRS between 1988 and 2016. Early and late remissions were defined based on our prior median remission time of 29 months. The median imaging and endocrine follow-ups are 66 and 104.8 months, respectively. Multivariate analysis was conducted to analyze factors leading to late remission. A total number of 157 patients, of those 102 (64.9%) patients achieved remission. of those 102 patients, 62 patients (60.7%) had remission in less than 29 months (early remission) whereas 40 patients (39.3%) achieved remission later than (late remission) 29 months. The two groups differed significantly in the time interval between the last resection and the first SRS (p = 0.040) whole sella radiosurgery (p = 0.025) or radiosurgery to the cavernous sinus (p = 0.041). Competing risk analysis showed the interval between resection and SRS was significantly longer in the late remission group (HR 1.013, 95% CI 1.004-1.02; p = 0.007). Fifty-one of 157 patients (32.5%) developed a new endocrine deficiency following SRS. Those with shorter time between resection and SRS were more likely to achieve early remission. While most patients achieve remission in less than 4 years, the latency of effect with SRS yields a small percentage of patients achieving remission beyond that time point.

Complications of acromegaly: cardiovascular, respiratory and metabolic comorbidities.

Acromegaly is associated with an enhanced mortality, with cardiovascular and respiratory complications representing not only the most frequent comorbidities but also two of the main causes of deaths, whereas a minor role is played by metabolic complications, and particularly diabetes mellitus. The most prevalent cardiovascular complications of acromegaly include a cardiomyopathy, characterized by cardiac hypertrophy and diastolic and systolic dysfunction together with arterial hypertension, cardiac rhythm disorders and valve diseases, as well as vascular endothelial dysfunction. Biochemical control of acromegaly significantly improves cardiovascular disease, albeit completely recovering to normal mainly in young patients with short disease duration. Respiratory complications, represented mainly by sleep-breathing disorders, particularly sleep apnea, and respiratory insufficiency, frequently occur at the early stage of the disease and, although their severity decreases with disease control, this improvement does not often change the indication for a specific therapy directed to improve respiratory function. Metabolic complications, including glucose and lipid disorders, are variably reported in acromegaly. Treatments of acromegaly may influence glucose metabolism, and the presence of diabetes mellitus in acromegaly may affect the choice of treatments, so that glucose homeostasis is worth being monitored during the entire course of the disease. Early diagnosis and prompt treatment of acromegaly, aimed at obtaining a strict control of hormone excess, are the best strategy to limit the development or reverse the complications and prevent the premature mortality.

Mortality in acromegaly: a 20-year follow-up study.

OBJECTIVE: It is unclear whether mortality still is increased in acromegaly and whether there are gender-related differences. We dynamically assessed outcome during long-term follow-up in our nationwide cohort. PATIENTS AND METHODS: We studied standardized mortality ratios (SMRs) relative to the general population and causes of death in acromegaly (n=333) compared with age- and gender-matched controls (n=4995). RESULTS: During 20 (0-33) years follow-up, 113 (34%) patients (n=333, 52% women) and 1334 (27%) controls (n=4995) died (P=0.004). SMR (1.9, 95% CI: 1.53-2.34, P<0.001) and all-cause mortality (OR 1.6, 95% CI: 1.2-2.2, P<0.001) were increased in acromegaly. Overall distribution of causes of death (P<0.001) differed between patients and controls but not cardiovascular (34% vs 33%) or cancer deaths (27% vs 27%). In acromegaly, but not in controls, causes of deaths shifted from 44% cardiovascular and 28% cancer deaths during the first decade, to 23% cardiovascular and 35% cancer deaths during the next two decades. In acromegaly, cancer deaths were mostly attributed to pancreatic adenocarcinoma (n=5), breast (n=4), lung (n=3) and colon (n=3) carcinoma. In acromegaly, men were younger than women at diagnosis (median 44.5 vs 50 years, P<0.001) and death (67 vs 76 years, P=0.0015). Compared with controls, women (36% vs 25%, P<0.01), but not men (31% vs 28%, P=0.44), had increased mortality. CONCLUSIONS: In acromegaly, men are younger at diagnosis and death than women. Compared with controls, mortality is increased during 20 years of follow-up, especially in women. Causes of deaths shift from predominantly cardiovascular to cancer deaths.

MANAGEMENT OF ENDOCRINE DISEASE: Acromegaly and cancer: an old debate revisited.

Based on experimental and animal models, epidemiological data from non-acromegaly populations, and longitudinal and cross-sectional cohorts of patients with acromegaly, a potential association between acromegaly and cancer has long been hypothesized, in particular colorectal cancer, and, to a lesser extent, breast, thyroid and prostate cancers. The exact mechanisms underlying this potential association have not been fully elucidated. Results from studies examining cancer incidence and mortality in acromegaly have been inconsistent, with some demonstrating increased risk, whereas others show no increase. This article reviews the existing data relating to cancer risk and mortality in acromegaly, exploring the limitations of study designs and the impact of changes in disease control and patient outcomes over time.

The impact of diabetes mellitus on the survival of patients with acromegaly.

INTRODUCTION: An increased risk of mortality in patients with uncontrolled acromegaly has been reported in several studies. We aimed to assess the impact of co-morbidities on the survival of patients with acromegaly after long-term treatment and follow-up. MATERIAL AND METHODS: A retrospective analysis was performed for 285 patients with active acromegaly, who were admitted to the Chang Gung Memorial Hospital, Taiwan between 1978 and 2012. Of these patients, 106 (37.2%) were diagnosed with diabetes mellitus (DM). During the follow-up period, 21 cases of histological proved malignant in acromegalic patients, and DM with acromegaly had a higher incidence of malignancy (13.2% vs. 3.8%; p < 0.01). The 5-, 10-, and 20-year survival rates were 93.1%, 86.9%, and 84.7% for the DM group, respectively, and 96.5%, 96.5%, and 96.5% for the non-DM group, respectively. After a mean follow-up of 15.1 ± 0.6 years, age, DM, coronary heart disease, and malignancy were found to be significant factors of mortality. Control of growth hormone and IGF-1 levels also conferred a marginal survival benefit. CONCLUSIONS: DM and malignancy significantly influence the survival of patients with acromegaly; thus, these patients need close follow-up and appropriate therapy. (Endokrynol Pol 2016; 67 (5): 501-506).

Current therapies and mortality in acromegaly.

UNLABELLED: Acromegaly is a rare disease most frequently due to a GH secreting pituitary adenoma. Without an appropriate therapy, life of patients with acromegaly can be shortened with ten years. Pituitary surgery is usually the first line therapy for GH secreting pituitary adenomas. A meta-analysis proved that mortality is much lower in operated patients, even uncured, than the entire group of patients and is similar with the general population in patients with GH<1 µg/ L. For the patients with hypersecreting postoperative remnant tumor, those with low chance of surgical cure or with life-threatening comorbidities, medical therapies are available: somatostatin receptor analogues (SRA), dopamine agonists (DA) and GH receptor antagonists. Studies with >30% utilization of SRAs reported a lower mortality ratio than studies with lower percentages of SRA administration. Although therapy with DA has long been used in patients with acromegaly, there are no studies reporting its effect on mortality, but its efficacy is limited by the low remission rate obtained. The use of conventional external radiotherapy, although with good remission rate in time, was linked with increased mortality, mostly due to cerebrovascular diseases. CONCLUSION: Mortality in acromegaly can be reduced to expected levels from general population by using modern therapies either in monotherapy or by using multimodal approaches in experienced centers.