SummaryA phase II A study was conducted to evaluate the safety and efficacy of Givinostat, a novel Histone-Deacetylases inhibitor, in patients with Polycythaemia Vera (PV, n = 12), Essential Thrombocythaemia (ET, n = 1) and Myelofibrosis (n = 16), bearing the JAK2V617F mutation. The study was approved by the local ethics committees and all human participants gave written informed consent. Givinostat was given orally for 24 weeks at a starting dose of 50 mg twice daily. The median treatment duration was 20 weeks. Reasons for treatment discontinuation were disease progression (n = 6), grade 2 thrombocytopenia (n = 1), psychiatric symptoms (n = 1) and withdrawn consent (n = 2). A dose reduction was applied in 10 patients while a temporary interruption occurred in 15. Among 13 PV/ET patients, 1 complete, 6 partial and 4 no responses were documented at study end while 2 patients went off-study, prematurely. Three major responses were registered among 16 MF patients. Pruritus disappeared in most patients and reduction of splenomegaly was observed in 75% of PV/ET and 38% of MF patients. Reverse transcription polymerase chain reaction identified a trend to reduction of the JAK2V617F allele burden. Givinostat was well tolerated and could induce haematological response in most PV and some MF patients.

Objective. The current treatment options for systemic-onset juvenile idiopathic arthritis (JIA) are methotrexate, steroids, and biologic agents. This study was undertaken to evaluate the safety of the orally active histone deacetylase inhibitor givinostat (ITF2357) and its ability to affect the disease.Methods. Givinostat was administered orally, for up to 12 weeks at a dosage of 1.5 mg/kg/day, to 17 patients with systemic-onset JIA who had had active disease for >1 month. Disease activity was clinically assessed using the American College of Rheumatology Pediatric 30 (ACR Pedi 30), ACR Pedi 50, or ACR Pedi 70 criteria for improvement and a systemic feature score. The primary goal was safety and the primary efficacy end point was the number of patients completing 12 weeks of treatment who were responders.Results. Givinostat was safe and well tolerated, with adverse events (AEs) being mild or moderate, of short duration, and self-limited. The 17 patients from the intent-to-treat population reported a total of 44 AEs, and the 9 patients in the per-protocol population reported a total of 25. Six AEs in 3 patients (nausea, vomiting, and fatigue) were related to the study drug, but each resolved spontaneously and no patient was withdrawn from the study due to drug-related AEs. In the per-protocol population at week 4, the improvement as measured by the ACR Pedi 30, ACR Pedi 50, and ACR Pedi 70, respectively, was 77.8%, 55.6%, and 22.2%, and this increased further to 77.8%, 77.8%, and 66.7% at week 12. The most consistent finding was the reduction in the number of joints with active disease or with limited range of motion.Conclusion. After 12 weeks, givinostat exhibited significant therapeutic benefit in patients with systemiconset JIA, particularly with regard to the arthritic component of the disease, and showed an excellent safety profile.Histone deacetylases (HDAs) are intracellular enzymes that maintain nucleosome histones in a state of deacetylation so that DNA remains tightly bound and inaccessible to transcription factors. Inhibition of HDAs results in hyperacetylation of histones, which allows for the sufficient unraveling of DNA for binding transcription factors and the synthesis of messenger RNA (1,2). There is increasing evidence that HDA inhibitors may also exhibit antiinflammatory properties (3). ITF2357 (recently named givinostat) is a hydroxamic acid containing an HDA inhibitor, which reduces the production and release of several proinflammatory cytokines (tumor necrosis factor ␣, interleukin-1␤ [⌱L-1␤], interferon-␥, IL-6, and IL-12) from human blood monocytes (4) as well as in models of autoimmune diseases and inflammation, including models of arthritis and synovial cell functions (5,6).Systemic-onset juvenile idiopathic arthritis (JIA) is an example of combined autoinflammatory and autoimmune disease. Reduction of the painful and destructive arthritis component of the disease remains a goal that has still not been achieved even with anticytokine parenteral therapies (7,8). The primary objective of t...

Benign SCTs generally have favorable prognosis. Negative prognostic factors for SCT include solid tumors, those detected early in pregnancy, malignant histotypes, polyhydramnios, placentomegaly, and fetal hydrops.

Progress in perinatal and postoperative techniques has reduced the prognostic role of traditional risk factors in esophageal atresia (EA). This paper reports on 75 cases of esophageal anomalies observed between 1992 and 2002 and followed after surgery from a minimum of six months to a maximum of ten years (mean five years). The impact on survival of birth weight, week of delivery, associated anomalies and need of ventilatory support at birth are discussed. Twenty-four patients were born before 37 weeks of gestation, 18 weighed less than 2000 g.; major anomalies affected 11 neonates, 23 cases required mechanical ventilation at birth. Seventy-four patients were operated on with a 90.6% survival rate; no deaths were related to surgical treatment. Three cases required reoperation for postoperative complications. Birth weight and week of delivery did not seem to influence outcome; this is affected by severe associated cardiovascular anomalies and the need of ventilation at birth. Follow up at 24 months on 51 patients, revealed respiratory problems in 12 cases and severe gastro-esophageal reflux in 16. This affected quality of life of EA patients and required long term medical attention; improvement with growth was observed. No correlation between perinatal conditions and late sequelae could be demonstrated in our series.

SUMMARY. The authors report a case of recurrent anastomotic dehiscence following surgical repair of type C esophageal atresia according to the Gross classification. Surgical repair was followed by a recurrence, which was successfully managed with conservative treatment. Esophageal atresia with fistulization of the lower pouch in a male newborn with the VACTER association was repaired with a high-tension single-layer anastomosis. On the fifth postoperative day, major anastomotic dehiscence (> 4 mm) was diagnosed. The breach was re-sutured and the anastomosis reinforced with fibrin glue, but dehiscence recurred again 4 days later. Surgery was deferred and the infant was treated conservatively with continued chest-tube drainage and total parenteral nutrition. After 43 days, complete closure of the anastomosis was documented. Even major anastomotic dehiscence can be successfully managed with conservative treatment (chest-tube drainage, suspension of oral feedings, total parenteral nutrition). If the patient is otherwise stable, we feel that this approach should be attempted even when major leakage is present.