San Giovanni Rotondo, Italy
San Giovanni Rotondo, Italy

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Lawitz E.,University of Texas Health Science Center at San Antonio | Mangia A.,Casa Sollievo Della Sofferenza Hospital | Wyles D.,University of California at San Diego | Rodriguez-Torres M.,Fundacion de Investigacion | And 19 more authors.
New England Journal of Medicine | Year: 2013

BACKGROUND: In phase 2 trials, the nucleotide polymerase inhibitor sofosbuvir was effective in previously untreated patients with chronic hepatitis C virus (HCV) genotype 1, 2, or 3 infection. METHODS: We conducted two phase 3 studies in previously untreated patients with HCV infection. In a single-group, open-label study, we administered a 12-week regimen of sofosbuvir plus peginterferon alfa-2a and ribavirin in 327 patients with HCV genotype 1, 4, 5, or 6 (of whom 98% had genotype 1 or 4). In a noninferiority trial, 499 patients with HCV genotype 2 or 3 infection were randomly assigned to receive sofosbuvir plus ribavirin for 12 weeks or peginterferon alfa-2a plus ribavirin for 24 weeks. In the two studies, the primary end point was a sustained virologic response at 12 weeks after the end of therapy. RESULTS: In the single-group study, a sustained virologic response was reported in 90% of patients (95% confidence interval, 87 to 93). In the noninferiority trial, a sustained response was reported in 67% of patients in both the sofosbuvir-ribavirin group and the peginterferon-ribavirin group. Response rates in the sofosbuvir-ribavirin group were lower among patients with genotype 3 infection than among those with genotype 2 infection (56% vs. 97%). Adverse events (including fatigue, headache, nausea, and neutropenia) were less common with sofosbuvir than with peginterferon. CONCLUSIONS: In a single-group study of sofosbuvir combined with peginterferon-ribavirin, patients with predominantly genotype 1 or 4 HCV infection had a rate of sustained virologic response of 90% at 12 weeks. In a noninferiority trial, patients with genotype 2 or 3 infection who received either sofosbuvir or peginterferon with ribavirin had nearly identical rates of response (67%). Adverse events were less frequent with sofosbuvir than with peginterferon. (Funded by Gilead Sciences; FISSION and NEUTRINO ClinicalTrials.gov numbers, NCT01497366 and NCT01641640, respectively.) Copyright © 2013 Massachusetts Medical Society.


Zeuzem S.,Goethe University Frankfurt | Dusheiko G.M.,University College London | Salupere R.,University of Tartu | Mangia A.,Casa Sollievo Della Sofferenza Hospital | And 12 more authors.
New England Journal of Medicine | Year: 2014

BACKGROUND: In clinical trials, treatment with a combination of the nucleotide polymerase inhibitor sofosbuvir and the antiviral drug ribavirin was associated with high response rates among patients with hepatitis C virus (HCV) genotype 2 infection, with lower response rates among patients with HCV genotype 3 infection. METHODS: We conducted a study involving patients with HCV genotype 2 or 3 infection, some of whom had undergone previous treatment with an interferon-based regimen. We randomly assigned 91 patients with HCV genotype 2 infection and 328 with HCV genotype 3 infection, in a 4:1 ratio, to receive sofosbuvir-ribavirin or placebo for 12 weeks. On the basis of emerging data from phase 3 trials indicating that patients with HCV genotype 3 infection had higher response rates when they were treated for 16 weeks, as compared with 12 weeks, the study was unblinded, treatment for all patients with genotype 3 infection was extended to 24 weeks, the placebo group was terminated, and the goals of the study were redefined to be descriptive and not include hypothesis testing. The primary end point was a sustained virologic response at 12 weeks after the end of therapy. RESULTS: Of the 419 patients who were enrolled and treated, 21% had cirrhosis and 58% had received previous interferon-based treatment. The criterion for a sustained virologic response was met in 68 of 73 patients (93%; 95% confidence interval [CI], 85 to 98) with HCV genotype 2 infection who were treated for 12 weeks and in 213 of 250 patients (85%; 95% CI, 80 to 89) with HCV genotype 3 infection who were treated for 24 weeks. Among patients with HCV genotype 3 infection, response rates were 91% and 68% among those without and those with cirrhosis, respectively. The most common adverse events were headache, fatigue, and pruritus. CONCLUSIONS: Therapy with sofosbuvir-ribavirin for 12 weeks in patients with HCV genotype 2 infection and for 24 weeks in patients with HCV genotype 3 infection resulted in high rates of sustained virologic response. Copyright © 2014 Massachusetts Medical Society.


Farci P.,National Institute of Allergy and Infectious Diseases | Niro G.,Casa Sollievo della Sofferenza Hospital
Seminars in Liver Disease | Year: 2012

Hepatitis D is caused by infection with hepatitis D virus (HDV), a defective RNA virus that requires the obligatory helper function of hepatitis B virus (HBV) for its in vivo transmission. Thus, HDV is acquired only by coinfection with HBV or by superinfection of an HBV carrier. The clinical outcome of hepatitis D differs according to the modality of infection. Whereas coinfection evolves to chronicity in only 2% of the cases, superinfection results in chronic infection in over 90% of the cases. HDV is a highly pathogenic virus that causes acute, often fulminant hepatitis, as well as a rapidly progressive form of chronic viral hepatitis, leading to cirrhosis in 70 to 80% of the cases. The clinical picture of HDV disease is evolving as a consequence of a significant change in the epidemiology of HDV infection, which has led to a significant decline in incidence in Western countries, mainly as a result of universal HBV vaccination programs. However, in the face of a declining prevalence in areas of old endemicity like Europe, immigration poses a threat of HDV resurgence. The interaction of HDV with other hepatitis viruses or human immunodeficiency virus is complex and may lead to different patterns in terms of virologic expression and immunologic responses. Multiple viral infections are associated with rapid progression of liver fibrosis and eventually with the development of hepatocellular carcinoma. Hepatitis D is not a vanishing disease, and continuous efforts should be made to improve its prevention and treatment. Copyright © 2012 by Thieme Medical Publishers, Inc.


Brancati F.,Casa Sollievo della Sofferenza Hospital | Brancati F.,University of Chieti Pescara | Dallapiccola B.,Bambino Ges Children Hospital | Valente E.M.,Casa Sollievo della Sofferenza Hospital | Valente E.M.,Messina University
Orphanet Journal of Rare Diseases | Year: 2010

Joubert syndrome (JS) and related disorders (JSRD) are a group of developmental delay/multiple congenital anomalies syndromes in which the obligatory hallmark is the molar tooth sign (MTS), a complex midbrain-hindbrain malformation visible on brain imaging, first recognized in JS. Estimates of the incidence of JSRD range between 1/80,000 and 1/100,000 live births, although these figures may represent an underestimate. The neurological features of JSRD include hypotonia, ataxia, developmental delay, intellectual disability, abnormal eye movements, and neonatal breathing dysregulation. These may be associated with multiorgan involvement, mainly retinal dystrophy, nephronophthisis, hepatic fibrosis and polydactyly, with both inter- and intra-familial variability. JSRD are classified in six phenotypic subgroups: Pure JS; JS with ocular defect; JS with renal defect; JS with oculorenal defects; JS with hepatic defect; JS with orofaciodigital defects. With the exception of rare X-linked recessive cases, JSRD follow autosomal recessive inheritance and are genetically heterogeneous. Ten causative genes have been identified to date, all encoding for proteins of the primary cilium or the centrosome, making JSRD part of an expanding group of diseases called "ciliopathies". Mutational analysis of causative genes is available in few laboratories worldwide on a diagnostic or research basis. Differential diagnosis must consider in particular the other ciliopathies (such as nephronophthisis and Senior-Loken syndrome), distinct cerebellar and brainstem congenital defects and disorders with cerebro-oculo-renal manifestations. Recurrence risk is 25% in most families, although X-linked inheritance should also be considered. The identification of the molecular defect in couples at risk allows early prenatal genetic testing, whereas fetal brain neuroimaging may remain uninformative until the end of the second trimester of pregnancy. Detection of the MTS should be followed by a diagnostic protocol to assess multiorgan involvement. Optimal management requires a multidisciplinary approach, with particular attention to respiratory and feeding problems in neonates and infants. Cognitive and behavioral assessments are also recommended to provide young patients with adequate neuropsychological support and rehabilitation. After the first months of life, global prognosis varies considerably among JSRD subgroups, depending on the extent and severity of organ involvement. © 2010 Brancati et al; licensee BioMed Central Ltd.


Afdhal N.,Beth Israel Deaconess Medical Center | Zeuzem S.,Goethe University Frankfurt | Kwo P.,Indiana University | Chojkier M.,University of California at San Diego | And 20 more authors.
New England Journal of Medicine | Year: 2014

BACKGROUND: In phase 2 studies, treatment with the all-oral combination of the nucleotide polymerase inhibitor sofosbuvir and the NS5A inhibitor ledipasvir resulted in high rates of sustained virologic response among previously untreated patients with hepatitis C virus (HCV) genotype 1 infection. METHODS: We conducted a phase 3, open-label study involving previously untreated patients with chronic HCV genotype 1 infection. Patients were randomly assigned in a 1:1:1:1 ratio to receive ledipasvir and sofosbuvir in a fixed-dose combination tablet once daily for 12 weeks, ledipasvir-sofosbuvir plus ribavirin for 12 weeks, ledipasvir-sofosbuvir for 24 weeks, or ledipasvir-sofosbuvir plus ribavirin for 24 weeks. The primary end point was a sustained virologic response at 12 weeks after the end of therapy. RESULTS: Of the 865 patients who underwent randomization and were treated, 16% had cirrhosis, 12% were black, and 67% had HCV genotype 1a infection. The rates of sustained virologic response were 99% (95% confidence interval [CI], 96 to 100) in the group that received 12 weeks of ledipasvir-sofosbuvir; 97% (95% CI, 94 to 99) in the group that received 12 weeks of ledipasvir-sofosbuvir plus ribavirin; 98% (95% CI, 95 to 99) in the group that received 24 weeks of ledipasvir-sofosbuvir; and 99% (95% CI, 97 to 100) in the group that received 24 weeks of ledipasvir-sofosbuvir plus ribavirin. No patient in either 12-week group discontinued ledipasvir- sofosbuvir owing to an adverse event. The most common adverse events were fatigue, headache, insomnia, and nausea. CONCLUSIONS: Once-daily ledipasvir-sofosbuvir with or without ribavirin for 12 or 24 weeks was highly effective in previously untreated patients with HCV genotype 1 infection. (Funded by Gilead Sciences; ION-1 ClinicalTrials.gov number NCT01701401.) Copyright © 2014 Massachusetts Medical Society.


Niro G.A.,Casa Sollievo della Sofferenza Hospital | Smedile A.,University of Turin
Current Infectious Disease Reports | Year: 2012

Hepatitis delta virus (HDV) is a unique human virus, showing similarities with plant viroids. Although impressive knowledge on virus structure and replication has been achieved, several questions like HBV/HDV interaction and post translational modifications of HD antigens remain to be answered. Potential targets for therapeutic strategies are now emerging. To date, eight major genotypes of the HDV have been identified. The HDV-1 is the prevailing genotype in Europe, but migration phenomena may change this profile. Immune response is likely to play an important role in the pathogenesis of HDV-induced liver disease; few data are available on T cells response either during infection and therapy. HDV usually suppresses HBV replication; recent studies show as viral dominances may change over time. Delta infection leads to severe liver disease, with different patterns of progression to liver fibrosis and decompensation. Beside the association between HDV/HBV and HCC is demonstrated a risk specifically related to HDV remains controversial. © 2011 Springer Science+Business Media, LLC.


Buzzonetti L.,Bambino Gesu Childrens Hospital | Laborante A.,Casa Sollievo della Sofferenza Hospital | Petrocelli G.,Bambino Gesu Childrens Hospital
Journal of Cataract and Refractive Surgery | Year: 2010

We describe a variant of the big-bubble technique in deep anterior lamellar keratoplasty (DALK) assisted by the IntraLase femtosecond laser, which we call IntraBubble. The use of the 60 kHz IntraLase femtosecond laser allows dissection of the pre-Descemet-plane lamella to a predefined corneal depth and creation of a channel in the posterior stroma 50 μm above the endothelium into which a smooth cannula for air injection can be introduced. We lengthened the channel created by the laser using a pointed dissector. Eleven consecutive patients with keratoconus were treated, and all procedures were completed as DALK. The big bubble was achieved in 8 eyes (73%). In 3 cases (27%), intraoperative microperforations occurred and the procedures were completed with hand dissection without complications. This new application of femtosecond laser technology could lead to standardization of the big-bubble technique in DALK. © 2010 ASCRS and ESCRS.


Carnevale V.,Casa Sollievo della Sofferenza Hospital | Romagnoli E.,University of Rome La Sapienza | D'Erasmo L.,University of Rome La Sapienza | D'Erasmo E.,University of Rome La Sapienza
Nutrition, Metabolism and Cardiovascular Diseases | Year: 2014

This review focuses on the mechanisms determining bone fragility in patients with type 2 diabetes mellitus (T2DM). Despite bone mineral density (BMD) is usually normal or more often increased in these patients, fracture incidence is high, probably because of altered bone "quality". The latter seems to depend on several, only partly elucidated, mechanisms, such as the increased skeletal content of advanced glycation end-products causing collagen deterioration, the altered differentiation of bone osteogenic cells, the altered bone turnover and micro-architecture. Disease duration, its severity and metabolic control, the type of therapy, the presence or absence of complications, as like as the other known predictors for falls, are all relevant contributing factors affecting fracture risk in T2DM. In these patients the estimate of fracture risk in the everyday clinical practice may be challenging, due to the lower predictive capacity of both BMD and risk factors-based algorithms (e.g. FRAX). © 2014 Elsevier B.V.


Buzzonetti L.,Bambino Gesu Childrens Hospital | Laborante A.,Casa Sollievo Della Sofferenza Hospital | Petrocelli G.,Casa Sollievo Della Sofferenza Hospital
Journal of Refractive Surgery | Year: 2011

PURPOSE: To report 1-year follow-up in 11 of 13 eyes with keratoconus treated by deep anterior lamellar keratoplasty with a combined femtosecond laser lamellar resection followed by a big-bubble dissection. METHODS: Thirteen eyes with keratoconus were treated. Recipient and donor were prepared with the 60-kHz IntraLase femtosecond laser (Abbott Medical Optics). In the recipient, the femtosecond laser, after performing a lamellar cut 100 μm above the thinnest corneal point (measured by Pentacam [Oculus Optikgeräte GmbH]), was used to make a mushroom-shaped resection (anterior diameter, 9 mm; posterior diameter, 8 mm) from the same depth. In the donor, the mushroom lamellar thickness was calculated according to an original model based on the recipient preoperative corneal thickness. Upon removal of the recipient lamella, air was injected into the residual stroma to achieve a big bubble. The keratectomy was continued up to Descemet membrane. The donor was fit into place and sutured using interrupted sutures, which were removed by 8 months postoperative. Corrected distance visual acuity (CDVA) and refractive astigmatism were calculated by manifest refraction, whereas topographic astigmatism and corneal thickness were measured by Pentacam. RESULTS: A big bubble was successfully achieved in 11 eyes. Twelve months after surgery, mean CDVA was 0.52±1.2 (decimal), and refractive sphere and cylinder were -1.50±1.70 diopters (D) and 2.00±2.60 D, respectively. Three (27%) of 11 eyes at 1 year had a manifest refraction spherical equivalent within 1.00 D of emmetropia. Topographic astigmatism was 2.90±1.60 D. The thinnest corneal point was 519±27 μm. CONCLUSIONS: This combination of a femtosecond laser lamellar dissection with a big-bubble technique can improve the standardization of deep anterior lamellar keratoplasty for keratoconus. Copyright © SLACK Incorporated.


Cascavilla N.,Casa Sollievo della Sofferenza Hospital | Bisceglia M.,Casa Sollievo Della Sofferenza Hospital | D'Arena G.,Casa Sollievo della Sofferenza Hospital
International Journal of Immunopathology and Pharmacology | Year: 2010

We report a 50-year-old man who presented with a 5-year history of an intermittent widespread pruritic urticarioid rash and fever, fatigue, arthralgia and a monoclonal immunoglobulin-M paraprotein. The patient was initially treated with antihistamines and corticosteroids without the disappearance of symptoms. A skin biopsy from the urticarial rash on the thorax was performed, revealing dermal mononuclear and polymorphonuclear cell infiltrate and normal epidermis. A diagnosis of Schnitzler's syndrome (SS), a rare disorder in which the simultaneous occurrence of monoclonal gammopathy and chronic urticaria is usually observed, was made. After an unsuccessful trial with rituximab at a dosage of 375 mg/sqm weekly for 4 consecutive weeks, the patient was treated with anakinra, an inhibitor of interleukin-1α that is thought to be involved in the pathogenesis of the disease, at a dose of 100 mg daily given subcutaneously. He showed a prompt response to the drug and he is still well and symptom-free after 12 months of follow-up. On the basis of both this experience and the review of the literature we conclude that anakinra may be a promising option for the treatment of SS. However, these results need to be confirmed on a larger number of patients. Copyright © by BIOLIFE, s.a.s.

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