Massimo Imbriaco

Effect of longacting somatostatin analogue on kidney and cyst growth in autosomal dominant polycystic kidney disease (ALADIN): a randomised, placebo-controlled, multicentre trial

BACKGROUND Autosomal dominant polycystic kidney disease slowly progresses to end-stage renal disease and has no effective therapy. A pilot study suggested that the somatostatin analogue octreotide longacting release (LAR) could be nephroprotective in this context. We aimed to assess the effect of 3 years of octreotide-LAR treatment on kidney and cyst growth and renal function decline in participants with this disorder. METHODS We did an academic, multicentre, randomised, single-blind, placebo-controlled, parallel-group trial in five hospitals in Italy. Adult (>18 years) patients with estimated glomerular filtration rate (GFR) of 40 mL/min per 1·73 m(2) or higher were randomly assigned (central allocation by phone with a computerised list, 1:1 ratio, stratified by centre, block size four and eight) to 3 year treatment with two 20 mg intramuscular injections of octreotide-LAR (n=40) or 0·9% sodium chloride solution (n=39) every 28 days. Study physicians and nurses were aware of the allocated group; participants and outcome assessors were masked to allocation. The primary endpoint was change in total kidney volume (TKV), measured by MRI, at 1 year and 3 year follow-up. Analyses were by modified intention to treat. This study is registered with ClinicalTrials.gov, NCT00309283. FINDINGS Recruitment was between April 27, 2006, and May 12, 2008. 38 patients in the octreotide-LAR group and 37 patients in the placebo group had evaluable MRI scans at 1 year follow-up, at this timepoint, mean TKV increased significantly less in the octreotide-LAR group (46·2 mL, SE 18·2) compared with the placebo group (143·7 mL, 26·0; p=0·032). 35 patients in each group had evaluable MRI scans at 3 year follow-up, at this timepoint, mean TKV increase in the octreotide-LAR group (220·1 mL, 49·1) was numerically smaller than in the placebo group (454·3 mL, 80·8), but the difference was not significant (p=0·25). 37 (92·5%) participants in the octreotide-LAR group and 32 (82·1%) in the placebo group had at least one adverse event (p=0·16). Participants with serious adverse events were similarly distributed in the two treatment groups. However, four cases of cholelithiasis or acute cholecystitis occurred in the octreotide-LAR group and were probably treatment-related. INTERPRETATION These findings provide the background for large randomised controlled trials to test the protective effect of somatostatin analogues against renal function loss and progression to end-stage kidney disease. FUNDING Polycystic Kidney Disease Foundation.

Circulating miR-29a, Among Other Up-Regulated MicroRNAs, Is the Only Biomarker for Both Hypertrophy and Fibrosis in Patients With Hypertrophic Cardiomyopathy

OBJECTIVES The purpose of this paper was to determine whether microRNAs (miRNAs) involved in myocardial remodeling were differentially expressed in the blood of hypertrophic cardiomyopathy (HCM) patients, and whether circulating miRNAs correlated with the degree of left ventricular hypertrophy and fibrosis. BACKGROUND miRNAs-small, noncoding ribonucleic acids (RNAs) that regulate gene expression by inhibiting RNA translation-modulate cellular function. Myocardial miRNAs modulate processes such as cardiomyocyte (CM) hypertrophy, excitation-contraction coupling, and apoptosis; non-CM-specific miRNAs regulate myocardial vascularization and fibrosis. Recently, the possibility that circulating miRNAs may be biomarkers of cardiovascular disease has been raised. METHODS Forty-one HCM patients were characterized with conventional transthoracic echocardiography and cardiac magnetic resonance. Peripheral plasma levels of 21 miRNAs were assessed by quantitative real-time polymerase chain reaction and were compared with levels in a control group of 41 age- and sex-matched blood donors. RESULTS Twelve miRNAs (miR-27a, -199a-5p, -26a, -145, -133a, -143, -199a-3p, -126-3p, -29a, -155, -30a, and -21) were significantly increased in HCM plasma. However, only 3 miRNAs (miR-199a-5p, -27a, and -29a) correlated with hypertrophy; more importantly, only miR-29a correlated also with fibrosis. CONCLUSIONS Our data suggest that cardiac remodeling associated with HCM determines a significant release of miRNAs into the bloodstream: the circulating levels of both cardiac- and non-cardiac-specific miRNAs are significantly increased in the plasma of HCM patients. However, correlation with left ventricular hypertrophy parameters holds true for only a few miRNAs (i.e., miR-199a-5p, -27a, and -29a), whereas only miR-29a is significantly associated with both hypertrophy and fibrosis, identifying it as a potential biomarker for myocardial remodeling assessment in HCM.

Enzyme replacement therapy in patients with Fabry disease: State of the art and review of the literature

Anderson-Fabry disease is an X-linked lysosomal storage disorder resulting from the deficiency of the hydrolytic enzyme alpha galactosidase A, with consequent accumulation of globotrioasoyl ceramide in cells and tissues of the body, resulting in a multi-system pathology including end organ failure. In the classical phenotype, cardiac failure, renal failure and stroke result in a reduced median life expectancy. The current causal treatment for Fabry disease is the enzyme replacement therapy (ERT): two different products, Replagal (agalsidase alfa) and Fabrazyme (agalsidase beta), have been commercially available in Europe for almost 10 years and they are both indicated for long-term treatment. In fact, clinical trials, observational studies and registry data have provided many evidences for safety and efficacy of ERT in improving symptoms of pain, gastrointestinal disturbances, hypohidrosis, left ventricular mass index, glomerular filtration rate and quality of life. Few data are available on comparison of the two treatments and on the clinical course of the disease. This article reviews the published evidence for clinical efficacy of the two available enzyme preparations.

Effects of enzyme replacement therapy in patients with Anderson-Fabry disease: a prospective long term cardiac magnetic resonance imaging study

Background: Anderson–Fabry disease is a multisystem X linked disorder of lipid metabolism frequently associated with cardiac symptoms, including left ventricular (LV) hypertrophy gradually impairing cardiac function. Evidence showing that enzyme-replacement therapy (ERT) can be effective in reducing LV hypertrophy and improving myocardial function in the long term is limited. Objective: This study aimed to assess the long-term effects of ERT with recombinant α-galactosidase A (agalsidase beta, Fabrazyme) on LV function and myocardial signal intensity in 11 patients with Anderson–Fabry disease. Patients: Eleven patients (eight males, three females) with varying stages of genetically confirmed Anderson–Fabry disease were examined by means of physical examination and magnetic resonance imaging before ERT with agalsidase beta at 1 mg/kg every other week (study 1) and after a mean treatment duration of 45 months (study 2). Results: At 45 months of treatment, LV mass and LV wall thickness had significantly reduced: 188 (SD 60) g versus 153 (47) g, and 16 (4) mm versus 14 (4) mm, respectively. Furthermore, a significant reduction in myocardial T2 relaxation times was noted in all myocardial regions, that is, interventricular septum 80 (5) ms versus 66 (8) ms, apex 79 (10) ms versus 64 (10) ms, and lateral wall 80 (8) ms versus 65 (16) ms. Changes in LV ejection fraction were not significant. Amelioration of clinical symptoms was observed in all patients. Conclusions: Long-term therapy with agalsidase beta at 1 mg/kg every 2 weeks was effective in significantly reducing LV hypertrophy, improving overall cardiac performance and ameliorating clinical symptoms in patients with Anderson–Fabry disease.

Growth Hormone Deficiency in Patients with Chronic Heart Failure and Beneficial Effects of Its Correction

CONTEXT A reduced activity of the GH/IGF-I axis in chronic heart failure (CHF) has been described by several independent groups and is associated with poor clinical status and outcome. OBJECTIVE The aim of the current study was to investigate the prevalence of GH deficiency in a patient population with CHF and evaluate the cardiovascular effects of GH replacement therapy. DESIGN AND SETTING The randomized, single-blind, controlled trial was conducted at the Federico II University. PARTICIPANTS One hundred fifty-eight patients with CHF, New York Heart Association class II-IV, underwent a GH stimulation test. Sixty-three patients satisfied the criteria for GH deficiency, and 56 of them were enrolled in the trial. INTERVENTION The treated group (n = 28) received GH at a replacement dose of 0.012 mg/kg every second day (approximately 2.5 IU). MAIN OUTCOMES MEASURES Changes in physical performance and various cardiovascular indexes were measured. RESULTS GH replacement therapy improved quality of life score (from 46 +/- 5 to 38 +/- 4; P < 0.01), increased peak oxygen uptake and exercise duration (from 12.9 +/- .9 to 14.5 +/- 1 ml/kg x min and from 520 +/- 36 to 586 +/- 43 sec, respectively; P < 0.01), and flow-mediated vasodilation (from 8.8 +/- 1.3 to 12.7 +/- 1.2%; P < 0.01). GH increased left ventricular ejection fraction (from 34 +/- 2 to 36 +/- 2%; P < 0.01) and reduced circulating N-terminal pro-brain natriuretic peptide levels (from 3201 +/- 900 to 2177 +/- 720 pg/ml; P = 0.006). No significant changes from baseline were observed in controls. CONCLUSIONS As many as 40% of patients with CHF are GH deficient. GH replacement therapy in these patients improves exercise capacity, vascular reactivity, left ventricular function, and indices of quality of life.

Noninvasive diagnosis of small bowel Crohn's disease: Combined use of bowel sonography and Tc-99m-hmpao leukocyte scintigraphy

Background: Crohns disease (CD) is frequently localized in the small bowel, with the diagnosis of disease and the assessment of its extension made by ileo‐colonoscopy (IC) and small bowel enteroclysis (SBE). Transabdominal bowel sonography (BS) and Tc‐99m‐HMPAO leukocyte scintigraphy (LS) are increasingly used for the diagnosis of CD because of their minimal invasiveness, reproducibility, and acceptable costs. Methods: From March 2000 to July 2003, we performed IC, SBE, BS, and LS in 84 patients with either suspected or known small bowel CD. Results: Small bowel CD was present in 50 patients, whereas the other 34 patients received a different diagnosis. Sensitivity, specificity, positive and negative predictive values, and diagnostic accuracy were, respectively, 98%, 97%, 98%, 97%, and 0.97 for SBE; 92%, 97%, 98%, 88%, and 0.94 for BS; and 90%, 93%, 96%, 85%, and 0.92 for LS. In addition, the combined use of BS and LS led to overall sensitivity, specificity, positive and negative predictive values, and diagnostic accuracy of 100%, 93%, 96%, 100%, and 0.97, respectively. BS showed a fair concordance with SBE in terms of location (k = 0.71) and a correlation with the extension of the disease (r = 0.67, P < 0.001). LS showed a concordance with SBE with regard to location in about one‐half the population (k = 0.54), whereas it was less effective than SBE in defining disease extension. Conclusions: BS and LS are 2 accurate techniques for the diagnosis of small bowel CD, and their combined use can be recommended as an early diagnostic approach to patients in which the disease is suspected. SBE remains the best procedure for the definition of the location and extension of the disease.

Comparison between multislice CT and MR imaging in the diagnostic evaluation of patients with pancreatic masses

PurposeThis study compared the results of multislice computed tomography (MSCT) and high-field magnetic resonance imaging (MRI) in the diagnostic evaluation of pancreatic masses.Materials and methodsForty patients with clinical and ultrasonographic evidence of pancreatic masses underwent MSCT and MRI. The majority of patients (31/40, 78%) had proven malignant pancreatic tumours (24 ductal adenocarcinoma, six mucinous cystadenocarcinoma, one intraductal papillary mucinous carcinoma), whereas the remaining patients (9/40, 22%) were found to have benign lesions (eight chronic pancreatitis, one serous cystadenoma). Results of the imaging studies were compared with biopsy (n=33) and/or histology (n=7) findings to calculate sensitivity, specificity, accuracy and positive (PPV) and negative (NPV) predictive value for correct identification of tumours and evaluation of resectability of malignancies.ResultsBoth for tumour identification and resectability, MSCT and MRI had comparable diagnostic accuracy, with no statistically significant differences between them. Tumour identification CT/MRI: accuracy 98/98%, sensitivity 100/100%, specificity 88/88%, PPV 97/97%, NPV 100/100%; tumour resectability CT/MRI: accuracy 94/90%, sensitivity 92/88%, specificity 100/100%, PPV 100/100%, NPV 78/70%.ConclusionsMRI represents a valid diagnostic alternative to CT in the evaluation of patients with pancreatic masses, both for correct identification and characterisation of primary lesions and to establish resectability in the case of malignancies. New high-field MRI equipment allows optimal imaging quality with good contrast resolution in evaluating the upper abdomen.RiassuntoObiettivoScopo del nostro studio è stato effettuare un confronto dei risultati della tomografia computerizzata (TC) multistrato e della risonanza magnetica (RM) ad alto campo nella valutazione diagnostica di pazienti con masse pancreatiche.Materiali e metodiSono stati studiati 40 pazienti con evidenza clinico-ecografica di masse pancreatiche, di cui la maggioranza (78%; n=31) con tumori pancreatici maligni di diverso tipo istologico (adenocarcinoma duttale=24, cistoadenocarcinoma mucinoso=6, carcinoma mucinoso papillifero intraduttale=1); nei restanti 9 pazienti (22%) sono state dimostrate lesioni espansive di tipo benigno da pancreatite cronica (n=8) o da cistoadenoma sieroso (n=1); tutti i pazienti sono stati sottoposti a TC ed RM; i risultati degli esami di imaging sono stati confrontati con i dati bioptici (n=33) e/o istologici (n=7) ai fini del calcolo dei valori diagnostici di sensibilità, specificità, accuratezza, valori predittivi positivo (VPP) e negativo (VPN) per la corretta identificazione dei tumori maligni e la valutazione dell’eventuale resecabilità chirurgica delle lesioni.RisultatiSia per l’identificazione delle lesioni neoplastiche che per la valutazione della resecabilità chirurgica, la TC e la RM hanno mostrato valori di accuratezza diagnostica comparabili senza differenze statisticamente significative; identificazione del tumore TC/RM: accuratezza=98%/98%, sensibilità=100%/100%, specificità=88%/88%, VPP=97%/97%, VPN=100%/100%; resecabilità del tumore TC/RM: accuratezza=94%/90%, sensibilità=92%/88%, specificità=100%/100%, VPP=100%/100%, VPN=78%/70%.ConclusioniLa RM rappresenta una valida alternativa diagnostica all’esame TC nei pazienti con lesioni espansive del pancreas; in particolare, la RM consente sia la corretta identificazione e caratterizzazione delle masse pancreatiche che la valutazione dell’eventuale resecabilità chirurgica in caso di malignità; l’alto campo magnetico delle nuove apparecchiature permette di ottenere un’ottima qualità delle immagini RM che mostrano un’elevata risoluzione di contrasto nello studio dell’addome superiore.

Dual-time-point 18F-FDG PET/CT versus dynamic breast MRI of suspicious breast lesions.

OBJECTIVE The purpose of our study was to compare dual-time-point (18)F-FDG PET/CT, performed with the patient in the prone position, and contrast-enhanced MRI in patients with suspected breast malignancy. SUBJECTS AND METHODS Forty-four patients with 55 breast lesions underwent two PET/CT scans (dual-time-point imaging) in the prone position and breast MRI. Sensitivity, specificity, and overall accuracy were calculated. In addition, the average percentage of change in standard uptake values (Delta%SUV(max)) between time point 1 and time point 2 was calculated for PET/CT. A final histopathologic diagnosis was available for all patients. RESULTS MRI showed an overall accuracy of 95%, with sensitivity and specificity of 98% and 80%. Conversely, dual-time-point PET/CT showed an accuracy of 84% for lesions with an SUV(max) > or = 2.5 or with a positive Delta%SUV(max), with sensitivity and specificity of 80% and 100% versus 69% accuracy, 62% sensitivity (both, p < 0.001), and 100% specificity (p not significant) for single-time-point PET/CT. On PET/CT, malignant lesions showed an increase in FDG between time points 1 and 2, with a Delta%SUV(max) of 11 +/- 24. Benign lesions showed either no change or a decrease in SUV(max) between time points 1 and 2, with a Delta%SUV(max) of -21 +/- 7. CONCLUSION A dual time point improves PET/CT accuracy in patients with a suspected breast malignancy over single-time-point PET/CT. On PET/CT, FDG is increasingly taken up over time in breast tumors; conversely, benign lesions show a decrease in FDG uptake over time. These changes in SUV might represent a reliable parameter that can be used to differentiate benign from malignant lesions of the breast on PET/CT examination.

MRI Characterization of Myocardial Tissue in Patients with Fabry's Disease

OBJECTIVE Fabrys disease is a multisystem X-linked disorder of lysosomal metabolism frequently associated with left ventricular (LV) hypertrophy. In this study, we aimed to assess whether myocardial T2 relaxation time determined by a black blood multiecho multishot MRI sequence could be used to evaluate cardiac involvement in patients with Fabrys disease. CONCLUSION Myocardial T2 relaxation time is prolonged in patients with Fabrys disease compared with that of hypertrophic patients and healthy control subjects. MRI may be useful for the characterization of myocardial tissue in patients with Fabrys disease.

Whole-Body FDG-PET in Patients with Recurrent Colorectal Carcinoma: A Comparative Study with CT

Purpose: To assess the clinical accuracy of whole-body 2-[F-18]-fluoro-2-deoxy-D-glucose-positron emission tomography (FDG-PET) in the diagnosis of recurrent colorectal carcinoma in comparison to conventional computed tomography (CT).Materials and methods: Forty patients with suspected recurrent colorectal carcinoma based on either progressive serial carcinoemrbyonic antigen (CEA) serum elevation or positive/equivocal CT findings underwent whole-body FDG-PET. PET results were compared with those of CT and correlated to the final histopathological and clinical findings.Results: A final diagnosis was obtained at 93 sites in 35 patients by histology and in 5 patients by clinical follow up of at least 6 months. Of the 93 sites, 53 were determined to be malignant and 40 benign. FDG-PET evaluated on a 5-point scale (0-4) showed a positive and negative predictive value in the range of 96-98% and 83-93% respectively as the threshold for positivity was moved from 0 through 3. By comparison, CT, also evaluated on a 5-point scale showed a positive and negative predictive value in the range of 75-88% and 67-71% respectively. The area under the fitted receiver operating characteristic curve for PET: A(PET) = 0.96 +/- 0.02 was significantly greater (P < 0.001) than that observed for CT: A(CT) = 0.77 +/- 0.06. The distribution of maximum standardized uptake value (SUVmax) showed that all negative lesions have SUVmax below 5.0 whereas 75% of positive lesions were above 5.0 pointing to the fact that disease positivity is more likely in lesions with high SUV values.Conclusion: The results of this study confirm that whole-body FDG-PET is more accurate than conventional CT in the staging of patients with suspected recurrent colorectal carcinoma.