An Overview of Cardiovascular Risk in Pituitary Disorders.

Cardiovascular comorbidities owing to hormonal excess or deficiency are the main cause of mortality in patients with pituitary disorders. In patients with Cushing's Disease, there is an increased prevalence of cardiovascular diseases and/or risk factors including visceral obesity, insulin resistance, atherosclerosis, arterial hypertension, dyslipidaemia, hypercoagulability as well as structural and functional changes in the heart, like cardiac hypertrophy and left ventricle (LV) dysfunction. Notably, these demonstrate limited reversibility even after remission. Furthermore, patients with acromegaly may manifest insulin resistance but also structural and functional heart changes, also known as "acromegalic cardiomyopathy". Patients with prolactinomas demonstrate an aggravation of metabolic parameters, obesity, dysregulation of glucose and lipid metabolism as well as endothelial dysfunction. Hypopituitarism and conventional hormonal replacement therapy may also contribute to an unhealthy metabolic status, which promotes atherosclerosis and may lead to premature mortality. This review discusses the literature on cardiovascular risk in patients with pituitary disorders to increase physician awareness regarding this aspect of management in patients with pituitary disorders.

Results of a prospective multicenter neuroendocrine tumor registry reporting on clinicopathologic characteristics of Greek patients.

BACKGROUND: The rare incidence of neuroendocrine neoplasms (NENs) has contributed to a paucity of large epidemiologic studies of patients with this condition. We investigated the occurrence and clinicopathologic features of NENs in Greece. METHODS: Between October 2010 and November 2012 we collected data on 246 newly diagnosed patients from a broad-based multi-institutional registry that comprises eight academic and hospital sites in Greece. The WHO 2010 pathologic classification and the 7th AJCC Staging system was applied in all cases. RESULTS: Of all patients 94 % had a sporadic and 6 % a multiple endocrine neoplasia tumor; 63.4 % were gastroenteropancreatic-(GEP)-NENs, 17.9 % Head & Neck NENs, 9.8 % NENs of Unknown Primary, 6.5 % Lung NENs and 2.4 % Pheochromocytomas. Gastric and pancreatic NENs were the most common primary sites. Poorly differentiated neuroendocrine carcinomas (NEC) were 9.3 %, all sporadic. Fifteen percent of patients were asymptomatic at presentation, 24 % had a first symptom of the disease related to endocrine syndrome and 61 % had symptoms related to locally advanced or metastatic disease. Metastatic disease was established in 25 % of tumors most frequently in the GEP NEN group. Findings are presented according to Ki-67 distribution. MRI had a higher diagnostic positive yield than Octreoscan. Somatostatin analogs, lanreotide and octreotide acetate, were prescribed at 38.5 & 61.5 % of NEN patients respectively and were found to be equally effective at providing symptomatic relief. CONCLUSIONS: This is to our knowledge the first study of a Greek tumor registry and one of the few European Registries providing information regarding clinicopathologic characteristics and therapies in patients with neuroendocrine tumors of various origin sites, beyond GEP NENs.

The Role of Somatostatin Analogues in the Control of Diarrhea and Flushing as Markers of Carcinoid Syndrome: A Systematic Review and Meta-Analysis.

BACKGROUND: Somatostatin analogues (SSAs) are the cornerstone of treatment for carcinoid syndrome (CS)-related symptoms. The aim of this systematic review and meta-analysis is to evaluate the percentage of patients achieving partial (PR) or complete response (CR) with the use of long-acting SSAs in patients with CS. METHODS: A systematic electronic literature search was conducted in PubMed, Cochrane, and Scopus to identify eligible studies. Any clinical trials reporting data on the efficacy of SSAs to alleviate symptoms in adult patients were considered as potentially eligible. RESULTS: A total of 17 studies reported extractable outcomes (PR/CR) for quantitative synthesis. The pooled percentage of patients with PR/CR for diarrhea was estimated to be 0.67 (95% confidence interval (CI): 0.52-0.79, I2 = 83%). Subgroup analyses of specific drugs provided no evidence of a differential response. With regards to flushing, the pooled percentage of patients with PR/CR was estimated to be 0.68 (95% CI: 0.52-0.81, I2 = 86%). Similarly, no evidence of a significant differential response in flushing control was documented. CONCLUSIONS: We estimate there is a 67-68% overall reduction in symptoms of CS associated with SSA treatment. However, significant heterogeneity was detected, possibly revealing differences in the disease course, in management and in outcome definition.

Association of Pathology Markers with Somatostatin Analogue Responsiveness in Acromegaly.

Background: Somatotroph adenomas (SAs) exhibit a variable responsiveness to somatostatin analogue (SS-a) treatment, a process that is not well understood. We investigated established and novel histological markers as predictors of SS-a responsiveness. Methods: We retrospectively investigated pathology samples from 36 acromegalic patients that underwent transsphenoidal surgery. Clinical, hormonal, and imaging data were available in 24/36 patients, before and after SS-a treatment. Specimens were semiquantitatively analyzed with immunocytochemistry for Ki-67, KER, SSTR-2, SSTR-5, ZAC-1, E-cadherin, and AIP. Results: Collectively, 18 (50%) adenomas were each classified as densely/sparsely granulated somatotroph adenomas (DGSAs/SGSAs), respectively. Patients that received preoperative SS-a had lower expression of SSTR-2 compared to those that did not (2.0 (1.0, 3.0) vs. 3.0 (3.0, 3.0), p = 0.042). Compared with DGSAs, SGSAs had higher Ki-67 labeling index (LI) (1.0 (0.5, 1.0) vs. 2.0 (1.0, 3.5), p = 0.013), and a higher proportion of high MR T2 signal (1 (6%) vs. 6 (33%), p = 0.035), and tended to express less ZAC-1 (p = 0.061) and E-cadherin (p = 0.067). In linear regression corrected for baseline growth hormone (GH), ZAC-1 immunostaining was significantly associated with a decrease in GH levels after SS-a treatment (beta (95% confidence interval): -1.53 (-2.80, -0.26), p = 0.021). No markers were associated with changes in circulating insulin-like growth factor-I (IGF-I) after treatment with SS-a. Conclusion: The novel marker ZAC-1 was associated with GH response to medical treatment with SS-a. The SGSA cases were characterized by higher Ki-67 values and MR T2 signals indicative of an inferior response to SS-a. These findings improve our understanding of the mechanisms underlying SA response to medical treatment.

Androgen deprivation monotherapy usage in non-metastatic prostate cancer: results from eight European countries.

INTRODUCTION: The aim of this study was to investigate the attitudes towards use of androgen deprivation therapy (ADT) as monotherapy for localized or locally advanced prostate cancer (PC). MATERIAL AND METHODS: A survey using a 28-item, structured, quantitative questionnaire about the management of patients with PC was conducted in eight European countries between February and May 2018. Survey recipients were selected from a private database of healthcare providers. RESULTS: Overall, 375 physicians completed the survey (response rate, 58%). Participants were urologists (71.2%) or medical oncologists (28.8%), with a mean practice duration of 19.9 years and with university hospital or cancer center (41.6%), non-teaching hospital (38.4%) or private-sector clinic (20.0%) affiliations. Median proportions of physicians considering ADT as monotherapy to treat patients with PC in different risk groups varied between countries, but overall were: high/very high-risk, 60%; intermediate-risk, 30%; low-risk, 7.5%. The use of ADT monotherapy in the different risk groups also varied by medical specialty and type of affiliation. Proportions of participants applying different target thresholds for testosterone (T) levels also varied by country, but overall were: <50 ng/dL, 29.9%; <32 ng/dL, 4.8%; <20 ng/dL, 54.3%; castration but no specific target, 11%. More than half of participants (58.7%) determined target T levels only when prostate-specific antigen level was increased. CONCLUSIONS: Our multinational survey provides evidence that PC management varies across European countries and with clinical context, and frequently diverges from European Association of Urology (EAU) - European Society for Radiotherapy and Oncology (ESTRO) - European Society of Urogenital Radiology (ESUR) - International Society of Geriatric Oncology (SIOG) guidelines. Strategies for effective implementation of evidence-based recommendations in clinical practice may be needed to optimize patient outcomes.

Myocardial inflammation in Duchenne Muscular Dystrophy as a precipitating factor for heart failure: a prospective study.

BACKGROUND: In patients with Duchenne Muscular Dystrophy (DMD), the absent or diminished dystrophin leads to progressive skeletal muscle and heart failure. We evaluated the role of myocardial inflammation as a precipitating factor in the development of heart failure in DMD. METHODS: 20 DMD patients (aged 15-18 yrs) and 20 age-matched healthy volunteers were studied and followed-up for 2 years. Evaluation of myocarditis with cardiovascular magnetic resonance imaging (CMR) was performed using STIR T2-weighted (T2W), T1-weighted (T1W) before and after contrast media and late enhanced images (LGE). Left ventricular volumes and ejection fraction were also calculated. Myocardial biopsy was performed in patients with positive CMR and immunohistologic and polymerase chain reaction (PCR) analysis was employed. RESULTS: In DMD patients, left ventricular end-diastolic volume (LVEDV) was not different compared to controls. Left ventricular end-systolic volume (LVESV) was higher (45.1 +/- 6.6 vs. 37.3 +/- 3.8 ml, p < 0.001) and left ventricular ejection fraction (LVEF) was lower (53.9 +/- 2.1 vs. 63 +/- 2.4%, p < 0.001). T2 heart/skeletal muscle ratio and early T1 ratio values in DMD patients presented no difference compared to controls. LGE areas were identified in six DMD patients. In four of them with CMR evidence of myocarditis, myocardial biopsy was performed. Active myocarditis was identified in one and healing myocarditis in three using immunohistology. All six patients with CMR evidence of myocarditis had a rapid deterioration of left ventricular function during the next year. CONCLUSIONS: DMD patients with myocardial inflammation documented by CMR had a rigorous progression to heart failure.

Myocarditis as a precipitating factor for heart failure: evaluation and 1-year follow-up using cardiovascular magnetic resonance and endomyocardial biopsy.

AIMS: The aim of this study was to evaluate myocarditis as a precipitating factor for heart failure using cardiovascular magnetic resonance (CMR) and endomyocardial biopsy. METHODS AND RESULTS: Eighty-five patients with suspected myocarditis and 20 controls were evaluated. Seventy-one patients with positive CMR were referred for endomyocardial biopsy and re-evaluation after 1 year. Cardiovascular magnetic resonance was performed using STIR T2-weighted (T2W), early T1-weighted (EGE), and late gadolinium-enhanced (LGE) images. Immunohistological and polymerase chain reaction (PCR) analysis of myocardial specimens was employed. In patients with myocarditis, T2 and EGE were increased compared with controls (2.6 ± 0.9 vs. 1.57 ± 0.13, P < 0.001 and 7.9 ± 5.5 vs. 3.59 ± 0.08, P < 0.001, respectively). Late gadolinium enhancement was found in all myocarditis patients. Endomyocardial biopsy performed in 50 of 71 patients with positive CMR showed positive immunohistology in 48% and presence of infectious genomes in 80% (mainly Chlamydia, Herpes, and Parvovirus B19). Left ventricular ejection fraction (LVEF) was significantly decreased compared with controls (47.7 ± 19.2 vs. 64 ± 0.2, P < 0.001). After 1 year, CMR showed normalization of T2 and EGE, and decreased LGE. Left ventricular ejection fraction increased in 36.5% of patients, remained stable in 56.5% and decreased in 7% of patients, in whom biopsy showed persistence of the initial infective agents. A negative correlation was identified between EGE, LGE, and LVEF. Patients with positive biopsies had lower LVEFs. CONCLUSION: In a Greek population with myocarditis, Chlamydia with viruses was a common finding. Cardiovascular magnetic resonance and PCR proved useful for the detection of myocarditis; EGE and LGE had the best correlation for the development of heart failure. Persistence of the initially detected infective agents was identified in patients who deteriorated further.

Myocardial inflammation in autoimmune diseases: investigation by cardiovascular magnetic resonance and endomyocardial biopsy.

INTRODUCTION: Myocardial inflammation often coexists with different types of autoimmune diseases. Our aim was to investigate the presence of myocarditis in these patients by Cardiovascular Magnetic Resonance (CMR) and endomyocardial biopsy. PATIENTS-METHODS: Twenty patients, aged 20-55 yrs with autoimmune diseases and cardiac symptoms (3 with Takayasu's arteritis, 3 with systemic lupus erythematosus, 5 with rheumatoid arthritis, 7 with autoimmune thyroid disease and 2 with systemic sclerosis) and 20 patients with the same autoimmune diseases but without cardiac symptoms (controls) were studied. The presence of myocarditis and LV function were evaluated by CMR. Myocarditis was documented using T2-weighted (T2-W), T1-weighted (T1-W) before and after contrast media injection and late enhanced images. In 10 patients (positive for myocarditis by CMR with either low LVEF or recent increase in troponin), endomyocardial biopsy was also performed. Myocardial specimens were evaluated by histology and polymerase chain reaction techniques (PCR). RESULTS: Myocarditis was identified in 18/20 patients by CMR. In the T2-W images the signal ratio of myocardium to skeletal muscle was 1.89+/-0.25 (control values 1.57+/-0.13, p<0.05). From the T1-W images the relative myocardial enhancement was 11.31+/-11.18 (control values 3.09+/-0.05, p<0.05). Epicardial late gadolinium enhanced areas were identified in 18/20. In myocardial specimens, histology revealed inflammation in 5/10 (50%) and PCR documented viral or microbial genomes in 8/10 (80%). Positive histology and PCR were in agreement with 50% and 80% of positive CMR examinations, respectively. Herpes virus was identified in 3/10, Adeno in 1/10, Coxsackie B6 in 1/10, echo in 1/10, Parvo-B19 in 3/10, CMV in 1/10 and Chlamydia trachomatis in 8/10. CONCLUSIONS: Myocardial inflammation is a common finding in patients with autoimmune diseases and cardiac symptoms. The diagnosis can be confirmed by CMR, which is a noninvasive and reliable tool for the investigation of these patients.

A comparison of magnetic resonance imaging and cardiac biopsy in the evaluation of heart iron overload in patients with beta-thalassemia major.

OBJECTIVES: To apply magnetic resonance imaging (MRI) for the assessment of myocardial iron deposition in patients with beta-thalassemia and compare the results with cardiac biopsy data. BACKGROUND: Myocardial iron accumulation is the main cause for cardiac complications in beta-thalassemia. METHODS: Twenty-five consecutive thalassemic patients were studied using a 0.5-T (Tesla) system, ECG-gated, with echo time (TE) = 17-68 ms. T2 relaxation time of the interventricular septum was calculated assuming simple monoexponential decay. A heart T2 relaxation time value of 32 ms was used for the discrimination between high and low iron deposition. Heart biopsy was performed within a week after the MRI study. Patients with stainable iron in more than 50% of the myofibrils were graded as having severe iron deposition. A serum ferritin level below 2000 ng/mL was considered as an indication of successful chelation. RESULTS: Seven of the 25 patients had heart biopsy indicative of low iron deposition (Group L) and the remaining 18 patients had heart biopsy indicative of high iron deposition (Group H). T2 relaxation time of the heart (T2H) was lower in Group H compared to Group L (31.5 +/- 3.9 (range: 28-40) ms vs. 35.7 +/- 3.7 (range: 29-40) ms, P = 0.026). The T2H was in agreement with heart biopsy in 86% of the patients in Group L and in 78% of the patients in Group H (overall agreement 80%). Similarly, serum ferritin levels were in agreement with heart biopsy in 28% and 88%, respectively (overall agreement 72%). In Group L, MRI was in better agreement with biopsy compared to serum ferritin (86% vs. 28%, P < 0.05). A receiver operating characteristic curve (ROC) analysis confirmed that a T2 relaxation time of 32 ms had the highest discriminating ability for the corresponding biopsy outcome. CONCLUSIONS: Heart T2 relaxation time appears in agreement with cardiac biopsy, both in high and low iron deposition, and may become a useful non-invasive index in beta-thalassemia.