Project SATURN- a real-world evidence data collaboration with existing European datasets in Osteogenesis Imperfecta to support future therapies.

Regulatory marketing authorisation is not enough to ensure patient access to new medicinal products. Health Technology Assessment bodies may require data on effectiveness, relative effectiveness, and cost-effectiveness. Healthcare systems may require data on clinical utility, savings, and budget impact. Furthermore, the exact requirements of these bodies vary country by country and sometimes even region to region, resulting in a patchwork of different data requirements to achieve effective, reimbursed patient access to new therapies. In addition, clinicians require data to make informed clinical management decisions. This requirement is of key importance in rare diseases where there is often limited data and clinical experience at the time of regulatory approval.This paper describes an innovative initiative that is called Project SATURN: Systematic Accumulation of Treatment practices and Utilization, Real world evidence, and Natural history data for the rare disease Osteogenesis Imperfecta. The objective of this project is to generate a common core dataset by utilising existing data sources to meet the needs of the various stakeholders and avoiding fragmentation through multiple approaches (e.g., a series of individual national requests/approaches, and unconnected with the regulators' potential requirements). It is expected that such an approach will reduce the time for patient access to life-changing medications. Whilst Project SATURN applies to Osteogenesis Imperfecta, it is anticipated that the principles could also be applied to other rare diseases and reduce the time for patient access to new medications.

Resistant hypertension and obstructive sleep apnea syndrome in therapy with continuous positive airway pressure: evaluation of blood pressure, cardiovascular risk markers and exercise tolerance.

OBJECTIVE: Resistant hypertension (RH) may be associated with Obstructive Sleep Apnea (OSA), determining a remarkable increase in cardiovascular risk. The aim of the study was to assess the effect of six months with continuous positive airway pressure (CPAP) treatment on blood pressure (BP) values, cardiovascular risk markers, and exercise tolerance in patients with RH and OSA. PATIENTS AND METHODS: Twenty-four patients with RH and OSA were recruited and 24-hour ambulatory BP, intima-media thickness (IMT), flow mediated dilation (FMD), renal resistive index (RRI), and endurance cardiopulmonary exercise testing (CPET) were obtained at enrollment and after 6-month treatment. RESULTS: Significant reduction in clinic systolic and diastolic BP, IMT, and RRI (p = 0.003, p = 0.009, p = 0.020, p = 0.04, respectively) and increase in the left ventricular ejection fraction (p = 0.035) were observed after a 6-month therapy with CPAP. Moreover, improvement in all polysomnographic parameters (number of apneas/hypopneas per hour (p < 0.001), number of episodes of night-time hemoglobin desaturation (ODI) (p = 0.010)), an improvement in Epworth Sleepiness Scale (p < 0.001), as well as in endurance time during constant workload CPET (p = 0.017) were observed too. CONCLUSIONS: CPAP treatment for six months reduces BP and improves cardiovascular risk and exercise tolerance in patients with RH and OSA. An extended cardiovascular assessment, including exercise testing, might be helpful in this population, given the possible reversibility of some endothelial dysfunction and atherosclerotic markers with CPAP treatment, as reported in our study.

Survival After Lung Transplant for Cystic Fibrosis in Italy: A Single Center Experience With 20 Years of Follow-up.

OBJECTIVES: Lung transplantation is currently the only treatment for end-stage respiratory failure in patients with cystic fibrosis (CF). In this study we retrospectively analyzed our experience since the start of the transplantation program in 1996 with focus on survival analysis. METHODS: All patients with CF who underwent lung transplant at our center were included (1996-2016). Survival analysis after lung transplant was performed using the Kaplan-Meier estimate, comparing by sex and by 4 eras (1996-2000, 2001-2005, 2006-2010, and 2011-2016). RESULTS: In a 20-year period, 243 patients with CF were listed for lung transplant; 123 patients (61 male, 62 female) underwent transplant, and 85 died while waiting for donor organs. The mean (SD) and median age at transplant was 27.7 (8.7) years and 26.9 years (range, 9.1 - 52.1 years), respectively. Mean (SD) forced expiratory volume in the first second was 27.6 (9.7)% predicted; 115 patients (92.0%) were pancreatic insufficient, and 43 patients (34.0%) had CF-related diabetes. Removing patients with CF who died within the first 3 postoperative months, the mean (SD) and median survival after transplant were 8.2 (5.7) years and 7.5 years (range, 3 months-20 years), respectively. Overall post-lung transplant 1-year survival was 93.6%, 5-year survival was 71.4%, 10-year survival was 53.6%, 15-year survival was 36.7%, and 20-year survival was 31.6%. We found no difference in survival between sex (P = .22) and among the 4 eras (P = .56). CONCLUSIONS: Survival after lung transplant in our single center is similar to international data.

Intrarenal hemodynamic and oxidative stress in patients with obstructive sleep apnea syndrome.

BACKGROUND: Oxygen desaturation and reoxygenation, related to intermittent hypoxia cycles due to upper airway obstruction, are major pathophysiologic features of obstructive sleep apnea syndrome (OSAS) and are thought to be responsible for an increased risk of cardiovascular diseases. Continuous positive airway pressure (CPAP) is therefore considered the gold standard in the management of OSAS. Further data demonstrated a high prevalence of OSAS in patients with altered renal function despite the underlying pathophysiological mechanisms that have not been clarified. This study aims to provide evidence on the reported high prevalence of endothelial dysfunction and alterations of the intrarenal hemodynamic in patients affected by OSAS. Furthermore, we evaluated the effect of a CPAP therapy on these endpoints. METHODS: Twenty patients were enrolled in a prospective study and underwent ultrasound examination to assess endothelial dysfunction, by collecting brachial flow-mediated dilation (FMD) and intrarenal artery stiffness, pre- and post a 30-day treatment with CPAP. RESULTS: Endothelial dysfunction and intrarenal artery stiffness significantly improved in all patients after a month of CPAP. In particular, we observed a significant reduction in the renal resistance index (RI) (p < 0.001) and systolic/diastolic ratio (S/D) ratio (p < 0.001) and a significant increase of FMD (p < 0.001). The apnea-hypopnea index (AHI) showed a negative correlation with Δ FMD (p < 0.05, r = -0.46). Conversely, a positive correlation exists between Δ RI and the oxygen desaturation index (ODI) (specificare la sigla) (p < 0.05, r = 0.46). CONCLUSIONS: Our study firstly showed a significant effect of CPAP on renal perfusion and endothelial function in OSAS patients without concomitant cardiovascular comorbidities.

Does caval reconstruction technique affect early graft function after liver transplantation? A preliminary analysis.

BACKGROUND: In the past decades, the inferior vena cava (IVC) reconstruction technique has undergone several evolutions, such as biopump, piggyback technique (PB), and laterolateral approach (LLPB). Several advantages are reported comparing the PB technique to biopump use. However, comparison between PB and LLPB has not been as well investigated. The aim of this study was to compare the results in terms of immediate graft function and intermediate graft survival among 3 subgroups characterized by distinct caval reconstruction techniques. METHODS: We retrospectively analyzed a cohort of 200 consecutive adult patients who underwent liver transplantation from January 2001 to December 2009. The patients were stratified according to 3 caval reconstructive techniques: biopump (n=135), PB (n=32) and LLPB (n=33). RESULTS: The LLPB group showed the shortest cold and warm ischemia times and the best immediate postoperative graft function. Survival analysis revealed LLPB patients to present the best 1-year graft survival rates: namely, 90.9% versus 75.0% and 74.1% among the PB and biopump groups, respectively (log-rank tests: LLPB vs biopump: P=.03; LLPB vs PB: P=.05). In our experience, LLPB showed the best graft survivals with an evident reduction in both cold and warm ischemia times. However, it is hard to obtain an irrefutable conclusion owing to the retrospective nature of this study, the small sample, and the different periods in which the groups were transplanted. CONCLUSIONS: LLPB technique was a safe procedure that minimized the sequelal of ischemia-reperfusion damage. This technique yielded results superior to venovenous bypass. No definitive conclusions can to be obtained in this study comparing classic PB or LLPB.

Model for end-stage liver disease score versus simplified acute physiology score criteria in acute renal failure after liver transplantation.

Hepatic function and renal failure are closely related among patients with end-stage liver disease (ESLD) due to splanchnic hemodynamic mechanisms that characterize advanced decompensated cirrhosis. Acute renal failure (ARF) is a frequent complication that occurs immediately post-orthotopic liver transplantation (OLT). The Model for End-stage Liver Disease (MELD) score describes the survival of patients with ESLD awaiting OLT related to the severity of liver disease. The Simplified Acute Physiology Score (SAPS II) is a mortality prediction model that scores the severity of illness among intensive care unit patients. In a previous study we observed an association between ARF post-OLT and a higher MELD score, but it was not clear whether this association depends on the grade of ESLD or on the critical condition of liver transplant patients. The aim of this study was to evaluate the association of ARF with MELD score and/or SAPS II criteria among liver transplant patients. We analyzed 46 patients with ESLD who underwent deceased donor OLT. All patients were evaluated at baseline and in the first 7 days post-OLT. According to the RIFLE classification, the incidence of the worst grade of ARF post-OLT was 19.2%. These patients showed significantly higher MELD scores, while there was no association with systemic parameters related to the critical patient's condition or with the mortality score as evaluated by SAPS II criteria. We confirmed the association between renal failure and hepatic function among liver transplant patients. A more severe degree of hepatic dysfunction before OLT was associated with a greater incidence of ARF that can adversely affect patient survival.

Polyomavirus BK replication in liver transplant candidates with normal renal function.

Polyomavirus-associated nephropathy (PVAN) has a predilection for kidney rather than for other solid organ transplants such as the liver. Immunosuppression is widely recognized to be a major risk factor for PVAN development. Since end-stage liver disease (ESLD) patients are immunocompromised and immunosuppression is a major cause of BK virus reactivation, we sought to evaluate BK virus replication in patients listed for liver transplantation. From April to October 2010, we enrolled 20 patients listed for liver transplantation. BK virus load was measured by quantitative real-time polymerase chain reaction on plasma and urine samples. Viremia occurred in only 1 among 20 patients. We hypothesized that in ESLD patients, the low prevalence of BK virus infection may be related to the prevalent impairment of antibacterial immunity rather than to the viral-specific one. In BK virus reactivation, not only the immunodepressive state itself, but also the specific immunologic mechanisms involved may have a role.

Chronic kidney disease-epidemiology formula and model for end-stage liver disease score in the assessment of renal function in candidates for liver transplantation.

Assessment of renal function in patients with end-stage liver disease (ESLD) awaiting liver transplantation (OLT) is critical. Various conditions may cause renal damage in ESLD. Renal and liver functions are intertwined due to splanchnic hemodynamic relationships; renal failure rarely occurs in patients without advanced decompensated cirrhosis. The recent literature suggests that evaluation of renal function should include an assessment of liver function. The aim of this study was to evaluate different methods to estimate glomerular filtration rate (GFR) in patient among ESLD candidates for OLT over 1 year. We also correlated renal and hepatic functions. Fifty-two cirrhotic patients Model for End-Stage Liver Disease [MELD] > 10) were enrolled in the study. All patients were evaluated at baseline and every 4 months (T1-T4) thereafter for 1 year. The GFR was calculated by creatinine clearance, and estimated by Cockroft and Gault, Modified Diet Renal Disease (MDRD) 4 and 6 variable and Chronic Kidney Disease-Epidemiology (CKD-EPI) formulae. Hepatic functions were evaluated by MELD score, albumin, bilirubin, and International Normalized Ratio (INR). We observed not statistically significant increase mean value of MELD score, bilirubin, serum creatinine, and blood urea nitrogen and a reduced serum sodium. There were no significant differences among various methods to evaluate GFR at each time over 1 year. We did not observe any association between renal and hepatic function, except at T4 for MELD and GFR estimated with MDRD 4 (P = .009) and 6 (P = .008) parameters or CKD-EPI (P = .036), and MELD and sodium (P = .001). Our results showed that evaluation of renal function in cirrhosis should include an evaluation of hepatic function. In our case, MDRD and CKD-EPI seemed to be the more accurate formulae to evaluate renal function in relation to hepatic function.

Massive ovarian edema in a prepubertal girl without signs of virilization or early puberty.

Massive ovarian edema is a rare cause of ovarian enlargement in young women. This article describes the case in a nine-year-old girl without signs of virilization or early puberty. The patient underwent laparotomy and a right oophorectomy was performed. The final pathology was massive ovarian edema. Awareness of this rare and benign lesion in young women and pediatric patients may allow a conservative management avoiding oophorectomy in some cases.

Ileocaecal valve atresia: our surgical approach.

BACKGROUND: Atresia of ileocaecal valve is the rarest type of intestinal atresia; there are very few reports on it in the literature and all cases described to date were treated with ileocolic resection. METHODS: We present a rare case of ileocaecal valve atresia, the third in the literature, in which a "different" technical approach was employed as an alternative to the usual surgical technique (ileocolic resection). The described case came to our attention in a patient presenting with complicated intestinal perforation in whom we performed an ileal stoma after an unsuccessful conservative approach. Approximately four months later we operated her to close the stoma: during this procedure we discovered the colic valve atresia and treated it by creating a "new ileocaecal valve" and carrying out an appendectomy. After a 7-year follow-up no complications have occurred and the girl enjoys very good health. CONCLUSIONS: We conclude that performing a plasty of Bauhin's valve is a valid alternative to intestinal resection in such cases of atresia even if, according to some authors, the resection of the ileocaecal valve was not associated with increased morbidity and mortality (3).

High-frequency oscillatory ventilation versus conventional mechanical ventilation in congenital diaphragmatic hernia.

AIMS: Newborns affected by congenital diaphragmatic hernia (CDH) are high-risk patients: today the mortality is still elevated and is essentially due to severe pulmonary hypoplasia, pulmonary hypertension and the absence of surfactant. High-Frequency Oscillatory Ventilation (HFOV) seems to be a good pre- and postoperative technique in cases of CDH. PATIENTS AND METHODS: We report our experience in the treatment of CDH; since 1987 we have followed 44 patients. We divided them into two different groups in accordance with the ventilation technique used: Group I (1987-1994): 25 patients treated with conventional mechanical ventilation (CMV); Group II (1994-1997): 19 patients treated with HFOV used since the first day of life until clinical stabilisation and also prolonged during surgery and in the postoperative period. RESULTS: 37 patients (84%) underwent surgery with closure of the diaphragmatic defect. We had a very good improvement in survival, rising from 67% (CMV) to 94% (HFOV) of the patients operated on, reaching an overall survival of 56% vs 79%. CONCLUSIONS: The use of HFOV for the treatment of CDH has proved to be a valuable technique for pre-operative stabilisation and for intra- and postoperative respiratory treatment, above all for newborns with CDH.

Rhabdomyoma of a rare type in a child: case report and literature review.

We describe a 9-year-old boy who presented with dyspnea and with a neck mass which was initially described as a thyroid nodule. At the end of the diagnostic-therapeutic research this mass was finally diagnosed as an adult rhabdomyoma originating from the mediastinum. This is an extremely rare tumor which is usually found in the adult population.

Presence of telomerase activity in different musculoskeletal tumor histotypes and correlation with aggressiveness.

Telomerase is a ribonucleoprotein enzyme that maintains the protective structures at the ends of eukaryotic chromosomes, called telomeres. Telomerase activity was observed and correlated with aggressiveness in different neoplasms such as breast, prostate, blood and brain cancers, among others. To investigate whether telomerase activity is an index of aggressiveness in bone and soft tissue lesions of the extremities, 66 biopsy samples from our tissue bank were studied. These samples included 43 high-grade sarcomas, 9 aggressive benign tumors and 14 totally benign lesions. The samples were collected from patients homogeneously treated at the Rizzoli Orthopaedic Institute with a follow-up ranging from 4 to 11 years (median, 7 years). A non-radioactive polymerase chain reaction-based enzyme-linked immunosorbent assay was used for the study. All tumors investigated were positive for telomerase activity. Among benign lesions, only 2 aneurysmal bone cysts showed higher telomerase activity than the cut-off point, whereas all the other benign lesions had lower activity. Our results indicate that high levels of telomerase activity in bone and soft tissue lesions correlate with more aggressive clinical behavior in patients treated with surgery alone. An interesting inverse correlation between telomerase activity and occurrence of pulmonary metastasis was detected in osteosarcoma patients treated with chemotherapy. A parallel increase of telomerase activity and malignancy was observed in the adipose and cartilagineous tissue lesions. Our data suggest that telomerase activity could be considered a marker of tumor aggressiveness for bone and soft tissue lesions. The results obtained in osteosarcoma samples suggest that low levels of telomerase activity may be predictive of the prognosis and should influence the therapeutic protocol.

Prenatal diagnosis of bladder exstrophy: what counseling?

PURPOSE: Bladder exstrophy has recently become one of the several congenital malformations detectable prenatally by fetal ultrasonography, which implies the necessity of a correct prognostic evaluation of quality of life on which therapeutic termination of pregnancy may depend within the temporal limits stated by the law. While maintaining a preeminently informative role, prenatal counseling has gained increasing relevance for the quality of life long-term prognosis in adults affected by bladder exstrophy, particularly in regard to urinary continence, and sexual and reproductive problems in male and female individuals. We report a case of bladder exstrophy diagnosed at 22 week of gestation, and comprehensively review the literature on prenatal diagnostic tools and procedures as well as long-term followup in such cases. MATERIALS AND METHODS: At week 22 of gestation a woman underwent prognostic counseling due to the diagnosis of fetal bladder exstrophy made by prenatal ultrasound. After counseling the parents elected pregnancy termination. In addition, literature data were analyzed in regard to quality of life and bladder exstrophy. RESULTS: We believe that the rarity of the prenatal diagnosis of this abnormality has resulted in the lack of a comprehensive review of necessary counseling criteria. CONCLUSIONS: We suggest what we consider to be a valid counseling approach for parents after a prenatal diagnosis of bladder exstrophy.

A series of 17 cases of congenital cystic adenomatoid malformation of the lung: management and outcome.

During a 5-year-period, 17 cases of congenital adenomatoid malformation of the lung were observed in the Department of Pediatric Surgery of Bologna University-S. Orsola-Malpighi Hospital; 16 cases were diagnosed in utero by ultra-sound. 13 patients had prenatal diagnosis between 21 and 23 weeks of gestation; 2 cases were diagnosed at 25 weeks and another one at 26 weeks. The other case came from another hospital, and the diagnosis was accidentally detected postnatally. In 3 cases the parents decided to terminate the pregnancy 3 cases had spontaneous improvement during the last weeks of gestation, and were perfectly normal at birth. One case was lost to follow-up; all remaining patients underwent resection. Among these patients only one was a nonsurvivor, while 9 have completely recovered. However, one patient developed persistent pulmonary hypertension, which could successfully be treated with drugs, another underwent laser treatment for laryngeal stenosis due to intubation. A special epidemiological information: 13 out 17 cases (76.5%) were female.