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Objective: To report the safety and efficacy results of patients enrolled in the Italian Nivolumab Renal Cell Cancer Expanded Access Programme. Patients and Methods: Patients with metastatic renal cell cancer (mRCC) previously treated with agents targeting the vascular endothelial growth factor pathway were eligible to receive nivolumab 3 mg/kg once every 2 weeks. Patients included in the analysis had received ≥1 dose of nivolumab and were monitored for adverse events (AEs) using Common Terminology Criteria for Adverse Events (CTCAE) v.4.0. Results: A total of 389 patients were enrolled between July 2015 and April 2016, of whom 18% were aged ≥75 years, 6.7% had non-clear cell RCC, 49.6% had bone and 8.2% brain metastases, and 79% had received ≥2 previous lines of therapy. The most common any-grade treatment-related AEs were fatigue (13%) and rash (9%). Twenty-two patients (5.7%) discontinued treatment because of AEs. There were no treatment-related deaths. The objective response rate was 23.1%. At a median follow-up of 12 months, the median progression-free survival was 4.5 months (95% confidence interval 3.7–6.2) and the 12-month overall survival rate was 63%. Similar survival rates were reported among patients with non-clear-cell histology, elderly patients, those with bone and/or brain metastases, and those who had received prior first-line sunitinib or pazopanib, or prior everolimus. Conclusion: The safety and efficacy observed were consistent with those reported in the pivotal Checkmate 025 trial. Results in patients with non-clear-cell mRCC who were elderly, pretreated with everolimus, and had bone and/or brain metastases encourage the use of nivolumab in these categories of patients. © 2018 The Authors BJU International

Infections are a major complication of solid organ transplants (SOTs). This study aimed to describe recipients’ characteristics, and the frequency and etiology of infections and transplant outcome in liver and lung SOTs, and to investigate exposures associated to infection and death in liver transplant recipients. The study population included recipients of SOTs performed in Italy during a 1-year period in ten Italian lung transplant units and eight liver transplant units. Data on comorbidities, infections, retransplantation, and death were prospectively collected using a web-based system, with a 6-month follow-up. The cumulative incidence of infection was 31.7% and 47.8% in liver and lung transplants, respectively, with most infections occurring within the first month after transplantation. Gram-negatives, which were primarily multidrug-resistant, were the most frequent cause of infection. Death rates were 0.42 per 1000 recipient-days in liver transplants and 1.41 per 1000 recipient-days in lung transplants. Infection after SOT in adult liver recipients is associated to an increased risk of death (OR = 13.25; p-value < 0.001). Given the frequency of infection caused by multidrug-resistant microorganisms in SOT recipients in Italy and the heavy impact of infections on the transplant outcome, the reinforcement of surveillance and control activities to prevent the transmission of multidrug-resistant microorganisms in SOT recipients represents a priority. The implementation of the study protocol in liver and lung transplant units and the sharing of results have increased the awareness about the threat due to antimicrobial resistance in the country.

Objective A multicentre observational study was aimed to assess the prevalence of late-onset Pompe disease (LOPD) in a large high-risk population, using the dried blood spot (DBS) as a main screening tool. Design/methods 17 Italian neuromuscular centres were involved in the late-onset Pompe early diagnosis (LOPED) study. Inclusion criteria were: (1) age ≥5 years, (2) persistent hyperCKaemia and (3) muscle weakness at upper and/or lower limbs (limb-girdle muscle weakness, LGMW). Acid α-glucosidase (GAA) activity was measured separately on DBS by fluorometric as well as tandem mass spectrometry methods. A DBS retest was performed in patients resulted positive at first assay. For the final diagnosis, GAA deficiency was confirmed by a biochemical assay in skeletal muscle, whereas genotype was assessed by GAA molecular analysis. Results In a 14-month period, we studied 1051 cases: 30 positive samples (2.9%) were detected by first DBS screening, whereas, after retesting, 21 samples were still positive. Biochemical and molecular genetic studies finally confirmed LOPD diagnosis in 17 cases (1.6%). The median time from the onset of symptoms/signs to diagnosis was 5 years. Among those patients, 35% showed presymptomatic hyperCKaemia and 59% showed hyperCKaemia+LGMW, whereas 6% manifested with LGMW. Conclusions LOPED study suggests that GAA activity should be accurately screened by DBS in all patients referring for isolated hyperCKaemia and/or LGMW. A timely diagnosis was performed in five patients with presymptomatic hyperCKaemia, but two had already manifested with relevant changes on muscle morphology and MRI. Consequently, enzyme replacement therapy was started in 14/17 patients, including the 2 patients still clinically presymptomatic but with a laboratory evidence of disease progression.

Background Albuminuria has been classically considered a marker of kidney damage progression in diabetic patients and it is routinely assessed to monitor kidney function. However, the role of a mild GFR reduction on the development of stage ≥3 CKD has been less explored in type 1 diabetes mellitus (T1DM) patients. Aim of the present study was to evaluate the prognostic role of kidney disease measures, namely albuminuria and reduced GFR, on the development of stage ≥3 CKD in a large cohort of patients affected by T1DM. Methods A total of 4284 patients affected by T1DM followed-up at 76 diabetes centers participating to the Italian Association of Clinical Diabetologists (Associazione Medici Diabetologi, AMD) initiative constitutes the study population. Urinary albumin excretion (ACR) and estimated GFR (eGFR) were retrieved and analyzed. The incidence of stage ≥3 CKD (eGFR 30% from baseline was evaluated. Results The mean estimated GFR was 98 ± 17 mL/min/1.73m2 and the proportion of patients with albuminuria was 15.3% (n = 654) at baseline. About 8% (n = 337) of patients developed one of the two renal endpoints during the 4-year follow-up period. Age, albuminuria (micro or macro) and baseline eGFR 90 ml/min/1.73m2 and normoalbuminuria, those with albuminuria at baseline had a 1.69 greater risk of reaching stage 3 CKD, while patients with mild eGFR reduction (i.e. eGFR between 90 and 60 mL/min/1.73 m2) show a 3.81 greater risk that rose to 8.24 for those patients with albuminuria and mild eGFR reduction at baseline. Conclusions Albuminuria and eGFR reduction represent independent risk factors for incident stage ≥3 CKD in T1DM patients. The simultaneous occurrence of reduced eGFR and albuminuria have a synergistic effect on renal function worsening. Electronic supplementary material The online version of this article (10.1186/s12882-018-1136-6) contains supplementary material, which is available to authorized users.

Propranolol is a vasoactive drug that shows antiangiogenic and antitumour activities in melanoma. However, it is unknown whether these activities are dose-dependent and whether there is a relationship between systemic vascular effects of propranolol and anti-melanoma activity.Effects of increasing doses of propranolol (10, 20, 30 and 40 mg·kgIn vitro analyses revealed that B16F10 cells expressed β-adrenoceptors, but neither isoprenaline, a β-adrenoceptor agonist, nor the β-blocker propranolol affected cancer cell proliferation. In vivo studies showed that the antitumour efficacy of propranolol follows a U-shaped biphasic dose-response curve. Low doses (10 and 20 mg·kgPropranolol inhibits melanoma growth in a U-shaped biphasic manner. A direct relationship exists between SVR and anti-melanoma activity.

Background Management of Anderson–Fabry disease (AFD) is contentious, particularly regarding enzyme replacement therapy (ERT). We report results of a Delphi consensus panel on AFD management. Methods A survey to gauge consensus among AFD experts was distributed online and responses were analysed. Statements on: 1) diagnosis; 2) when starting ERT; 3) management of ERT infusion and adverse reactions; and 4) follow-up/monitoring response to therapy and progression of disease were included. Responses without consensus were discussed with an enlarged panel and modified to reach consensus. Results 15 experts responded to the survey. After plenary discussion among the enlarged panel, consensus was reached on most statements. Key points were the use of a target organ biopsy to show Gb3 deposits in symptomatic women with negative molecular analysis, the need for ERT in symptomatic women and in all patients with persistent signs and symptoms ± organ damage. It was agreed to assess vital signs before ERT administration and use a 0.2 μL filter on infusion to reduce the risk of adverse reactions, that serum should be drawn prior to the first infusion for anti-agalsidase antibody analysis to have a baseline value if a subsequent adverse reaction appears, and that pre-medication is required in those with prior infusion reactions. Holter ECG monitoring, cardiac and brain MRI, renal parameters, and abdominal ultrasound were considered important for the assessment of disease progression and response at ERT. Conclusions This consensus supplies guidance to healthcare providers on best practice in the management of patients with AFD and indicates a need for more guidance.

Leiomyosarcoma of the inferior vena cava (IVC) is a rare tumor that frequently produces non-specific symptoms. Surgical treatment is complex. In this review of our experience, we highlight replacement modalities of the vena cava or other vessels after complete tumor resection.During the last 20 years, we treated 12 patients (6 women and 6 men; age range, 38-72 years) with IVC leiomyosarcoma, all apparently free of distant metastases. Tumor location, graft patency, long-term survival and tumor recurrence were recorded. The tumor arose from the IVC in 8 patients; in 2 cases the intracaval mass reached the right atrium; in 4 patients the tumor arose from the femoroiliac axis. Surgical approach was by sternolaparotomy in 5 cases and by median xyphopubic access in 7. Extracorporeal circulation (ECC) was needed in 2 cases. All tumors were removed by en bloc resection. The IVC was directly sutured in 2 patients and patched in 4; no reconstruction was necessary in 2 patients; the IVC was replaced in the remaining cases. Four patients had an additional arteriovenous fistula. One patient underwent bifurcated Dacron graft replacement of the aortic carrefour involved by tumor.Two patients died postoperatively. One patient developed late stenosis of the polytetrafluoroethylene (PTFE) graft, which was treated by stenting. The mean follow-up period was 35 months. The 4-year survival rate was 51% and survival free of recurrence was 63%.Leiomyosarcoma of the IVC is an uncommon tumor that produces non-specific symptoms. In the absence of distant malignancy, an aggressive approach can obtain late survival free of recurrence.

The aim of the study was to evaluate the possibility of reducing the blood loss during elective surgery for abdominal aortic aneurysms using particular intraoperative surgical expedients. From 1993 to 1999, 200 patients were recruited into the study. We performed 90 aorto-aortic, 84 aorto-bisiliac, 4 aorto-iliac-femoral, 12 aorto-bisiliac-hypogastric, and 10 aorto-bifemoral reconstructions. Several surgical techniques were used and are described in detail. The mortality rate was 3.5%. Haemoglobinaemia 24 hours after the operation had decreased by 2.5 +/- 0.9 g/dl. In 67% of cases the estimated blood loss was lower than 300 ml. There were no transfusions in 44% of cases, and autologous transfusions in 17%. The average estimated blood loss was 350 ml, with mean reinfusion of 0.98 blood units. Our study suggests the possibility (44%) of avoiding the use of blood transfusions thanks to intraoperative blood saving by means of particular surgical techniques.

Primary aortoenteric fistula is a very rare consequence of the evolution of an abdominal aortic aneurysm (AAA). The 3rd and 4th portion of the duodenum are involved in up to 80% of all cases. Frequently, gastrointestinal bleeding represents the first symptom, and diagnosis is difficult because of the aspecific clinical presentation and course, characterized by alternating remission and relapse; this is the reason why surgical treatment is usually delayed and therefore such events are managed as emergencies with a preoperative and intraoperative high death rate. We report the case of a 76-year-old man with a primary aortoduodenal fistula, who was submitted to gastric resection according to Billroth II 20 years before. This case could be interesting for its anatomical peculiarities favourable to the formation of the fistula.

To estimate from 2D and 3D-CT the anatomical defects that are most likely to be responsible for posttraumatic enophthalmos.The morphology and dimensions of the orbit and of fat content were investigated in 25 patients 6-12 months after treatment for complex orbital fractures by image analysis and volumetric estimation from 2D and 3D-CT.The shape of orbit was very often changed from conical to more rounded due to enlargement of the posterior segment. The retrobulbar fat appeared fragmented and dislocated posteriorly. No changes were observed in the structural appearance or radiodensity of either the orbital fat or muscles. There was reduced sagittal eye projection, increased width of the orbital rim, downward dislocation of the posteromedial orbital floor, and increased volume in the posttraumatic orbits which was significantly different (P0.05). Enophthalmos was correlated with orbital volume and height of the retrobulbar portion of the orbit. The volume of fat did not correlate with enophthalmos.Posttraumatic enophthalmos appears to be more commonly related to failure in correcting the orbital volume and in reducing the outward dislocation of the posterior orbital floor and not to changes in the fat content.

Type 2 diabetes mellitus (T2DM) is associated with an increased risk of colorectal cancer (CRC). The aim of the study is to evaluate the prevalence of CRC in a cohort of Caucasian patients with T2DM and the association with other variables previously known to be related with increased risk of CRC. We retrospectively evaluated the data of 741 consecutive Caucasian patients with T2DM who underwent colonoscopic screening in our tertiary referral center. A control cohort of 333 patients with thyroid disease was selected to evaluate the difference in the incidence of CRC. At a median follow-up of 132.5 months (range 33.3-175.7), 67 cases of cancer (prevalence 9%) occurred; among these, 14 cases of CRC were reported (prevalence 1.88%) among the diabetic patients, while only two case (one of these was a CRC) (overall prevalence 0.006%, prevalence of CRC 0.003%) occurred in the control group; the difference between the prevalence of CRC was statistically significant (chi-square 4.21, p=0.04). The median duration of T2DM to CRC diagnosis was 168 months (range 12-768). At the univariate analysis, older age (p=0.001, r 0.138) and diabetes duration (p=0.001, r 0.138) were related to higher risk of cancer, while metformin seems to be protective towards cancer (p=0.07, r -0.098). In the subset of patients with CRC, the age (RR = 2.25; 95% CI: 0.30 - 17.31; p less than 0.001), the diabetes duration (RR = 1.93; 95% CI: 0.25 – 14.77; p = 0.001) and the sulphonylureas treatment (RR = 2.33; 95% CI: 0.78 – 7.38; p = 0.007) were independently correlated with CRC. In our study, the prevalence of CRC in the cohort of patients with T2DM was higher compared to that from the National Tumor Register in 2010 (0.5%). Furthermore, we could speculate that sulphonylureas may play a role in CRC carcinogenesis impairing the physiological insulin secretion.

The aim of this study was to retrospectively compare early and one-year results of open surgery (OS) for critical limb ischemia (CLI) in patients who underwent primary surgery and in patients operated after a previous failure of endovascular treatment (EV).Between January 2004 and December 2007, 460 patients (304 males, 156 females) aged between 46 and 95 (average age 72) underwent OS or EV for CLI. We performed 273 EV (47%) and 307 OS (53%) procedures. In 98 patients (21.3%) the procedures were bilateral. EV procedures were intraluminal, subintimal or both, with selective stenting. OS procedures were distal bypass grafts. OS involved 34 dialysed patients, 159 patients with CLI non-dialysed and not previously submitted to EV treatment (group 1, control group) and 114 patients with failure of previous EV treatment (group 2), frequently performed in different and non surgical centers, 8% of EV failure in our series in this time. We retrospectively compared the early and one-year results in the last two groups of patients in terms of level of revascularization, primary patency, amputation and mortality.By-pass grafts were autologous vein in 94% and PTFE in 6%. Revascularizations have been directed to the tibial or to the plantar arteries at the ankle or foot. Those directed to the plantars were respectively 54% (52% dorsalis pedis, 36% retromalleolar posterior tibial, 12% medial plantar artery) in the control group and 76% (66% dorsalis pedis, 18% retromalleolar posterior tibial, 16% medial plantar artery) in patients with previous failed PTA (P0.001). Early primary patency, mortality and amputation free survival were respectively in the control group and in patients with previous failure of PTA: 93.7% vs. 76.3% (P0.001), 2.5% vs. 3.5% (P0.5), 95% vs. 93% (P0.5). One-year primary patency, mortality and amputation free survival were respectively in the control group and patients with previous failure of PTA: 86.03% vs. 70.87% (P0.25), 14.93% vs. 17.56% (P0.5), 78.1% vs. 68.5% (P0.1).After failure of EV therapy, the subsequent open surgery was more distal and technically demanding. Its results were significantly worse when compared with standard CLI patients, with an increase rate of redo. Our data suggest that EV should not be attempted as the first choice in every patient affected by CLI, and we believe that OS still is the primary treatment for the most advanced clinical situations.

The traumatic rupture of thoracic aorta is a surgical emergency with high risk of morbidity and mortality.We describe the case of an atypical rupture of retro-cardiac thoracic aorta with dissection of brachiocephalic trunk and spleen trauma occurred after a road accident. TC scan and perioperative angiography showed an atypical rupture of thoracic aorta.A combined treatment, endovascular for retro-cardiac thoracic aorta and surgical for brachiocephalic artery, has been useful to diminish the hemodynamic and organ ischemic problems associated with open surgery.

Concomitant abdominal aortic and common iliac artery aneurysms occur in 40% of cases. However, giant common iliac artery aneurysms were rarely described in the current literature. The aim of the present study is to describe the successful treatment of a giant right common iliac artery aneurysm associated with infrarenal abdominal aortic aneurysm.We present a case of aorto-iliac aneurysm, with giant right common iliac artery aneurysm, responsible of bladder and right psoas muscle compression. Through a midline laparotomy, an aortobisiliac prosthetic repair was performed, associated with prosthetic revascularization of the right internal iliac artery and inferior mesenteric artery.Postoperative recovery was uncomplicated and the patient was discharged on postoperative day 7 in good health and has remained so up to the most recent 12-month follow-up.Giant common IA aneurysms represent a very rare pathology, more often associated with infrarenal abdominal aortic aneurysm. After clinical examination, ultrasonography represents the first imaging modality to make diagnosis but CT scan is the gold standard for definitive conclusions, offering accurate anatomical details that are essential to choose the better strategy of treatment. Open surgery represents the gold standard, while endovascular repair has emerged more recently. However results about interventional treatment are not yet described in literature.La presenza contemporanea di un aneurisma dell’aorta addominale sottorenale e delle arterie iliache comuni ricorre nel 40% dei casi. Gli aneurismi giganti delle arterie iliache rappresentano una patologia rara. Lo scopo del presente studio è quello di descrivere un caso di aneurisma gigante dell’arteria iliaca comune di destra associato ad un aneurisma dell’aorta addominale sottorenale, trattato chirurgicamente con successo.Nel presente studio descriviamo un caso di aneurisma aorto-iliaco, con un aneurisma gigante dell’arteria iliaca comune di destra, responsabile di compressione della vescica e del muscolo psoas, che rappresenta il più grande aneurisma iliaco descritto fino ad ora in letteratura. Attraverso una laparotomia mediana, è stato eseguito un bypass protesico aorto-bisiliaco, associato alla rivascolarizzazione protesica dell’arteria iliaca interna destra e dell’arteria mesenterica inferiore. Non ci sono state complicanze nel periodo postoperatorio.Non ci sono state complicanze postoperatorie ed il paziente è stato dimesso in settima giornata in buone condizioni cliniche. A 1 anno dall’intervento il paziente ha eseguito Angio-TC di controllo che dimostra regolare pervietà del bypass, in assenza di complicanze.Gli aneurismi iliaci giganti rappresentano una patologia molto rara. Dopo l’esame clinico, l’ecocolor- doppler rappresenta la prima tecnica diagnostica ma solamente l’Angio-TC può dare tutti i dettagli anatomici necessari per scegliere il trattamento più adeguato. La chirurgia open rappresenta il gold standard per il trattamento, tuttavia recentemente è stato descritto un caso di trattamento endovascolare, ma non sono ancora noti i risultati a lungo termine di quest’ultimo tipo di trattamento.

Objectives A prospective cohort study was conducted in Italy in order to describe the microbiologic aspects of colonization/infection by carbapenemase-producing Enterobacteriaceae (CPE) in donors and recipients of lung and liver transplants and the possible CPE transmission from donors to recipients. Methods Between 15 January 2014 and 14 January 2015, all recipients of solid organ transplants (SOT) at ten lung and eight liver transplantation centres and the corresponding donors were enrolled. Screening cultures to detect CPE were performed in donors, and screening and clinical cultures in recipients with a 28-day microbiologic follow-up after receipt of SOT. Detection of carbapenemase genes by PCR, genotyping by multilocus sequence typing, and pulsed-field gel electrophoresis and whole-genome sequencing were performed. Results Of 588 screened donors, 3.4% were colonized with CPE. Of the liver first transplant recipients (n = 521), 2.5% were colonized before receipt of SOT and 5% acquired CPE during follow-up. CPE colonization was higher in lung first transplant recipients (n = 111, 2.7% before SOT and 14.4% after SOT). CPE infections occurred in 1.9% and 5.3% of liver or lung recipients, respectively. CPE isolates were mostly Klebsiella pneumoniae carbapenemase (KPC)-producing K. pneumoniae belonging to CG258. Three events of donor–recipient CPE transmission, confirmed by whole-genome sequencing and/or pulsed-field gel electrophoresis, occurred in lung recipients: two involving K. pneumoniae sequence type 512 and one Verona integron-encoded metallo-β-lactamase (VIM)-producing Enterobacter aerogenes. Conclusions This study showed a low risk of donor–recipient CPE transmission, indicating that donor CPE colonization does not necessarily represent a contraindication for donation unless colonization regards the organ to be transplanted. Donor and recipient screening remains essential to prevent CPE transmission and cross-infection in transplantation centres.

To implement split liver transplantation (SLT) a mandatory-split policy has been adopted in Italy since August 2015: donors aged 18-50years at standard risk are offered for SLT, resulting in a left-lateral segment (LLS) graft for children and an extended-right graft (ERG) for adults. We aim to analyze the impact of the new mandatory-split policy on liver transplantation (LT)-waiting list and SLT outcomes, compared to old allocation policy. Between August 2015 and December 2016 out of 413 potentially “splittable” donors, 252 (61%) were proposed for SLT, of whom 53 (21%) donors were accepted for SLT whereas 101 (40.1%) were excluded because of donor characteristics and 98 (38.9%) for absence of suitable pediatric recipients. The SLT rate augmented from 6% to 8.4%. Children undergoing SLT increased from 49.3% to 65.8% (P=.009) and the pediatric LT-waiting list time dropped (229 [10-2121] vs 80 [12-2503] days [P=.045]). The pediatric (4.5% vs 2.5% [P=.398]) and adult (9.7% to 5.2% [P20kg (HR=5.113, P=.048) in LLS, and ischemic time >8hours (HR=2.475, P=.048) in ERG were identified as predictors of graft failure. A national mandatory-split policy maximizes the SLT donor resources, whose selection criteria can be safely expanded, providing favorable impact on the pediatric LT-waiting list and priority for adult sick LT candidates.

Anderson-Fabry disease (FD) is a rare, progressive, multisystem storage disorder caused by the partial or total deficit of the lysosomal enzyme &alpha, galactosidase A (&alpha, Gal A). It is an X-linked, lysosomal enzymopathy due to mutations in the galactosidase alpha gene (GLA), encoding the &alpha, Gal A. To date, more than 900 mutations in this gene have been described. In our laboratories, the study of genetic and enzymatic alterations related to FD was performed in about 17,000 subjects with a symptomatology referable to this disorder. The accumulation of globotriaosylsphingosine (LysoGb3) was determined in blood of positives. Exonic mutations in the GLA gene were detected in 471 patients (207 Probands and 264 relatives): 71.6% of mutations were associated with the classic phenotype, 19.8% were associated with the late-onset phenotype, and 8.6% of genetic variants were of unknown significance (GVUS). The accumulation of LysoGb3 was found in all male patients with a mutation responsible for classic or late-onset FD. LysoGb3 levels were consistent with the type of mutations and the symptomatology of patients. &alpha, Gal A activity in these patients is absent or dramatically reduced. In recent years, confusion about the pathogenicity of some mutations led to an association between non-causative mutations and FD. Our study shows that the identification of FD patients is possible by associating clinical history, GLA gene analysis, &alpha, Gal A assay, and blood accumulation of LysoGB3. In our experience, LysoGB3 can be considered a reliable marker, which is very useful to confirm the diagnosis of Fabry disease.

BACKGROUND: Enzyme replacement therapy (ERT) has deeply modified the clinical history of Infantile Onset Pompe Disease (IOPD). However, its long-term effectiveness is still not completely defined. Available data shows a close relationship between clinical outcome and patients' cross-reactive immunological status (CRIM), being CRIM-negative status a negative prognostic factor. At the same time limited data are available on the long-term treatment in CRIM-positive infants. METHODS: A retrospective multicentre observational study was designed to analyse the long-term effectiveness of ERT in IOPD. Thirteen Italian centres spread throughout the country were involved and a cohort of 28 patients (15 females, 13 males, born in the period: February 2002-January 2013) was enrolled. IOPD diagnosis was based on clinical symptoms, enzymatic and molecular analysis. All patients received ERT within the first year of life. Clinical, laboratory, and functional data (motor, cardiac and respiratory) were collected and followed for a median period of 71 months (5 years 11 months). RESULTS: Median age at onset, diagnosis and start of ERT were 2, 3 and 4 months, respectively. CRIM status was available for 24/28 patients: 17/24 (71%) were CRIM-positive. Nineteen patients (67%) survived > 2 years: 4 were CRIM-negative, 14 CRIM-positive and one unknown. Six patients (5 CRIM-positive and one unknown) never needed ventilation support (21,4%) and seven (6 CRIM-positive and one unknown: 25%) developed independent ambulation although one subsequently lost this function. Brain imaging study was performed in 6 patients and showed peri-ventricular white matter abnormalities in all of them. Clinical follow-up confirmed the better prognosis for CRIM-positive patients, though a slow, progressive worsening of motor and/or respiratory functions was detected in 8 patients. CONCLUSIONS: These data are the result of the longest independent retrospective study on ERT in IOPD reported so far outside clinical trials. The data obtained confirmed the better outcome of the CRIM-positive patients but at the same time, showed the inability of the current therapeutic approach to reverse or stabilize the disease progression. The results also evidenced the involvement of central nervous system in Pompe disease. To better understand the disease clinical history and to improve treatment efficacy larger multicentre studies are needed as well as the development of new therapeutic approaches.

Split-liver transplantation has been proposed as an alternative to whole liver (WL) transplantation to expand the donor pool, but studies comparing adult longterm outcomes between the 2 methods are conflicting and limited. This is the first Italian multicenter study that retrospectively analyzed 119 matched-pair recipients of whole and extended right grafts (ERGs) for longterm survival outcomes. In the overall population, WL recipients showed higher patient survival at 1 (93% versus 73%), 5 (87% versus 65%), and 10 years (83% versus 60%) after transplantation compared with split-liver recipients (P < 0.001); graft survivals of WL recipients were also superior at 1 (90% versus 76%), 5 (84% versus 57%), and 10 years (81% versus 52%) posttransplant (P < 0.001). However, among the 81 matched pairs that survived the first posttransplant year, 5- and 10-year patient survivals were 90% and 81% for split recipients and 99% and 96% for whole recipients, respectively (P = 0.34). The 5- and 10-year graft survivals were also comparable: 87% and 77% for split recipients, and 86% and 82% for whole recipients (P = 0.86). Cox regression analysis identified donor age >50, donor-to-recipient weight ratio < 1, retransplantation status, and United Network for Organ Sharing I-IIA status as risk factors for partial graft use. There were no significant differences in 5-year outcomes based on center volume. In conclusion, we demonstrate that adult liver transplantation with ERGs can achieve longterm success comparable with that of whole grafts in appropriate patients but should be selectively used in patients with risk factors. Liver Transplantation 23 1384–1395 2017 AASLD.

Despite the worldwide acceptance of split liver transplantation (SLT) as a strategy to expand a limited donor pool, problems still exist in its widespread application.1 The technique of “conventional” SLT divides the liver of a heart-beating donor into an extended right graft (ERG) and a left lateral segment graft (LLS), including Couinaud segments I, IV–VIII, and segments II–III, respectively.2,3 Recent single-center series of either in situ or ex situ SLT reported results comparable to whole liver transplantation (WLT).3–16 The ideal split liver donor should be between 14 and 50 years of age, with good liver function, serum sodium level

BACKGROUND: Outcomes of split-liver transplantation (SLT) with pediatric donors have never been specifically reported. METHODS: A prospective multicenter study on SLT using donors younger than 15 years was conducted. Thirty-nine split-liver procedures generating a left lateral segment (LLS) and an extended right graft (ERG) were performed. In three cases, no recipient was found for ERG. In all but one case, the celiac trunk was maintained with LLS. Data were available for 67 grafts (90% of the total): 38 LLSs and 9 ERGs transplanted into 46 children and 20 ERGs transplanted into 20 adults. Sixty-two (93%) grafts were used for primary transplants and five (7%) for retransplantation. SLT were performed with 15 donors 10 years of age and less and with 24 between 11 and 15 years. RESULTS: Median follow-up was 24 months. Two-year patient and graft survival were 87% and 82%. Patient and graft survivals were not significantly different between pediatric and adult recipients, between recipients from donors 10 years of age and less and those between 11 and 15 years, and between recipients of LLS and ERG. Arterial complications occurred in 6% of cases (8% in the < or = 10 year donors group, 5% in the 11-15 year donors group). The incidence of other complications was similar between groups. CONCLUSIONS: SLT with pediatric donors, even younger than 10 years, provided results comparable with those achievable using adult donors. The similar incidence of arterial complications among patients receiving LLS or ERG suggests that maintenance of the celiac trunk with LLS is not detrimental for right-sided grafts

INTRODUCTION: We report our experience of in situ split-liver transplantation (SLT) for adult patients and compare the results with those achieved with whole-liver transplantation (WLT). METHOD: From November 1997 to December 2003, 109 liver transplantation were performed in 104 adult patients including 90 WLT (83%) and 19 SLT (17%) grafts. Fifteen extended right grafts (ERG, segments I + IV to VIII) were obtained with in situ split-liver procedures, generating also left lateral segment grafts, which were transplanted at our institution or elsewhere. Four left lobe (LL, segments I to IV) and right lobe (segments V to VIII) grafts were obtained by a modified in situ procedure for adult recipients. UNOS status, percentage of primary or secondary transplantation, and underlying liver disease were similar among patients receiving whole versus split grafts. Donors were older in whole than ERG cohorts (53 vs 26 years, P < .001). Procurement parameters and intraoperative profiles of transplant procedure were comparable among the groups. RESULTS: Median follow-up was 18 months (range: 1 to 73). Four patients with whole (4%) and no patient with ERG underwent retransplantation (P = NS). One- and 3-year patient survivals were 86% and 79% with WLT versus 93% and 93% with ERG (P = NS). One- and 3-year graft survivals were 84% and 75% with WLT versus 93%, and 93% with ERG (P = NS). Incidence of vascular complications was 8% with WLT, 13% with ERG (P = NS). The incidence of biliary complications was 13% in WLT, 27% in ERG (P = NS). CONCLUSIONS: The use of ERG from in situ split livers for adult transplantation allowed us to obtain results comparable or even better than those obtained with WLT. Split-liver transplantation is an effective, safe mechanism to expand the cadaveric donor pool.

Contains fulltext : 220431.pdf (Publisher’s version ) (Closed access) BACKGROUND: Disordered thyroid hormone transport, due to mutations in the SLC16A2 gene encoding monocarboxylate transporter 8 (MCT8), is characterised by intellectual and motor disability resulting from cerebral hypothyroidism and chronic peripheral thyrotoxicosis. We sought to systematically assess the phenotypic characteristics and natural history of patients with MCT8 deficiency. METHODS: We did an international, multicentre, cohort study, analysing retrospective data from Jan 1, 2003, to Dec 31, 2019, from patients with MCT8 deficiency followed up in 47 hospitals in 22 countries globally. The key inclusion criterion was genetically confirmed MCT8 deficiency. There were no exclusion criteria. Our primary objective was to analyse the overall survival of patients with MCT8 deficiency and document causes of death. We also compared survival between patients who did or did not attain full head control by age 1.5 years and between patients who were or were not underweight by age 1-3 years (defined as a bodyweight-for-age Z score

Objective: The aim of this study was (1) to investigate the application of texture analysis of choline PET/CT images in prostate cancer (PCa) patients and (2) to propose a machine-learning radiomics model able to select PET features predictive of disease progression in PCa patients with a same high-risk class at restaging. Material and methods: Ninety-four high-risk PCa patients who underwent restaging Cho-PET/CT were analyzed. Follow-up data were recorded for a minimum of 13 months after the PET/CT scan. PET images were imported in LIFEx toolbox to extract 51 features from each lesion. A statistical system based on correlation matrix and point-biserial-correlation coefficient has been implemented for features reduction and selection, while Discriminant analysis (DA) was used as a method for features classification in a whole sample and sub-groups for primary tumor or local relapse (T), nodal disease (N), and metastatic disease (M). Results: In the whole group, 2 feature (HISTO_Entropy_log10; HISTO_Energy_Uniformity) results were able to discriminate the occurrence of disease progression at follow-up, obtaining the best performance in DA classification (sensitivity 47.1%, specificity 76.5%, positive predictive value (PPV) 46.7%, and accuracy 67.6%). In the sub-group analysis, the best performance in DA classification for T was obtained by selecting 3 features (SUVmin; SHAPE_Sphericity; GLCM_Correlation) with a sensitivity of 91.6%, specificity 84.1%, PPV 79.1%, and accuracy 87%; for N by selecting 2 features (HISTO = _Energy Uniformity; GLZLM_SZLGE) with a sensitivity of 68.1%, specificity 91.4%, PPV 83%, and accuracy 82.6%; and for M by selecting 2 features (HISTO_Entropy_log10 - HISTO_Entropy_log2) with a sensitivity 64.4%, specificity 74.6%, PPV 40.6%, and accuracy 72.5%. Conclusion: This machine learning model demonstrated to be feasible and useful to select Cho-PET features for T, N, and M with valuable association with high-risk PCa patients’ outcomes. Key Points: • Artificial intelligence applications are feasible and useful to select Cho-PET features. • Our model demonstrated the presence of specific features for T, N, and M with valuable association with high-risk PCa patients’ outcomes. • Further prospective studies are necessary to confirm our results and to develop the application of artificial intelligence in PET imaging of PCa.

Background: Radium 223 (RA223) is currently administered as part of a therapeutic sequence with the other life-prolonging agents (LPAs) for metastatic castration-resistant prostate cancer (mCRPC). Patients & methods: We retrospectively reviewed the clinical records of patients who had received at least three LPAs including RA223. Results: Median overall survival (OS) from the start of first-line treatment was 39.8 months, with the patients who completed all six planned courses of RA223 having a longer OS than those who did not (53.2 vs 29.5 months; p

Aims Fabry cardiomyopathy is characterized by glycosphingolipid storage and increased myocardial trabeculation has also been demonstrated. This study aimed to explore by cardiac magnetic resonance whether myocardial trabecular complexity, quantified by endocardial border fractal analysis, tracks phenotype evolution in Fabry cardiomyopathy. Methods and results Study population included 20 healthy controls (12 males, age 32±9) and 45 Fabry patients divided into three groups: 15 left ventricular hypertrophy (LVH)-negative patients with normal T1 (5 males, age 28±13; Group 1); 15 LVH-negative patients with low T1 (9 males, age 33±9.6; Group 2); 15 LVH-positive patients (11 males, age 53.5±9.6; Group 3). Trabecular fractal dimensions (Dfs) (total, basal, mid-ventricular, and apical) were evaluated on cine images. Total Df was higher in all Fabry groups compared to controls, gradually increasing from controls to Group 3 (1.27±0.02 controls vs. 1.29±0.02 Group 1 vs. 1.30±0.02 Group 2 vs. 1.34±0.02 Group 3; P Conclusion Fabry cardiomyopathy is characterized by a progressive increase in Df of endocardial trabeculae together with shortening of T1 values. Myocardial trabeculation is increased before the presence of detectable sphingolipid storage, thus representing an early sign of cardiac involvement.

BackgroundThe coronavirus disease 2019 (COVID-19) pandemic has overwhelmed the health systems worldwide. Data regarding the impact of COVID-19 on cancer patients (CPs) undergoing or candidate for immune checkpoint inhibitors (ICIs) are lacking. We depicted the practice and adaptations in the management of patients with solid tumors eligible or receiving ICIs during the COVID-19 pandemic, with a special focus on Campania region.MethodsThis survey (25 questions), promoted by the young section of SCITO (Società Campana di ImmunoTerapia Oncologica) Group, was circulated among Italian young oncologists practicing in regions variously affected by the pandemic: high (group 1), medium (group 2) and low (group 3) prevalence of SARS-CoV-2–positive patients. For Campania region, the physician responders were split into those working in cancer centers (CC), university hospitals (UH) and general hospitals (GH). Percentages of agreement, among High (H) versus Medium (M) and versus Low (L) group for Italy and among CC, UH and GH for Campania region, were compared by using Fisher’s exact tests for dichotomous answers and χ2 test for trends relative to the questions with 3 or more options.ResultsThis is the first Italian study to investigate the COVID-19 impact on cancer immunotherapy, unique in its type and very clear in the results. The COVID-19 pandemic seemed not to affect the standard practice in the prescription and delivery of ICIs in Italy. Telemedicine was widely used. There was high consensus to interrupt immunotherapy in SARS-CoV-2–positive patients and to adopt ICIs with longer schedule interval. The majority of the responders tended not to delay the start of ICIs; there were no changes in supportive treatments, but some of the physicians opted for delaying surgeries (if part of patients’ planned treatment approach). The results from responders in Campania did not differ significantly from the national ones.ConclusionOur study highlights the efforts of Italian oncologists to maintain high standards of care for CPs treated with ICIs, regardless the regional prevalence of COVID-19, suggesting the adoption of similar solutions. Research on patients treated with ICIs and experiencing COVID-19 will clarify the safety profile to continue the treatments, thus informing on the most appropriate clinical conducts.

Purpose: To evaluate the fracture risk and survival outcomes in patients with metastatic castration-resistant prostate cancer (mCRPC) who received sequentially abiraterone acetate (AA) and radium 223 [223Ra]RaCl2 in the daily clinical practice. Materials: We retrospectively reviewed the records of mCRPC patients who received [223Ra]RaCl2 immediately after progressing during an AA treatment line in everyday clinical practice. Results: We reviewed data of a consecutive series of 94 mCRPC patients. Most of the patients (85.1%) received [223Ra]RaCl2 as second- or third-line treatment. [223Ra]RaCl2 treatment was well-tolerated; there were only four cases of grade 3 anaemia, two cases of grade 3 leukopenia and one case of grade 3 neutropenia. The overall fracture rate is 2.1%; one fracture was recorded during the course of [223Ra]RaCl2 treatment, and one was recorded 1 month after its end. The fractures both occurred at metastatic sites. Median OS from [223Ra]RaCl2 start was more than 14 months regardless of the treatment line when [223Ra]RaCl2 was administered. Conclusion: The findings of this study show that the treatment with [223Ra]RaCl2 immediately after AA was active and safe with a very low risk of a fracture. Thus, the present observational report makes a valuable contribution to the current debate concerning the risks and benefits of including [223Ra]RaCl2 in the therapeutic algorithm.

Background: In prehypertrophic Fabry disease, low myocardial T1 values, reflecting sphingolipid storage, are associated with early structural and ECG changes. The correlations between T1 values and functional parameters have not been explored. Furthermore, the potential prognostic role of T1 in predicting disease worsening is still unknown. Methods: ECG, 2D echocardiography, cardiopulmonary test, and cardiac magnetic resonance were performed in 44 Fabry patients without left ventricular hypertrophy (35.7±14.5 years, 68.2% females). After a 12-month follow-up, clinical stability was evaluated using Fabry Stabilization Index. Results: At baseline, T1 values showed a negative correlation with left ventricular mass ( r =−0.79; P r =−0.79; P r =−0.54; P r =−0.49; P r =−0.61; P 20%) at follow-up. Higher left ventricular wall thickness (odds ratio, 2.61; CI, 1.04–6.57; P =0.04), left atrial volume (odds ratio, 1.24; CI, 1.02–1.51; P =0.03), and lower T1 values (odds ratio, 0.98; CI, 0.96–0.99; P =0.03) at baseline were independently associated with clinical worsening at follow-up. Conclusions: In prehypertrophic Fabry disease, low T1 values correlate with early electrocardiographic, morphological cardiac changes, and worsening of global disease severity but are not associated with functional abnormalities. The presence of low T1 values is a risk factor for disease worsening, thus representing a potential new tool in prognostic stratification and therapeutic approach.

BACKGROUND: Ramucirumab-alone or combined with paclitaxel-represents one of the main options for patients failing first-line treatment for advanced gastric cancer. OBJECTIVE: The RAMoss study aimed to evaluate the safety and efficacy profile of ramucirumab in the "real-life setting". PATIENTS AND METHODS: Patients from 25 Italian hospitals started therapy consisting of ramucirumab 8 mg/kg i.v. d1,15q28 with or without paclitaxel 80 mg/m2 i.v. d1,8,15q28. The primary endpoint was safety, and secondary endpoints were overall response rate (ORR), progression-free survival (PFS), and overall survival (OS). RESULTS: One hundred sixty-seven patients with disease progression on first-line therapy received ramucirumab as monotherapy (10%) or combined with paclitaxel (90%). Median treatment duration was 4 months (1-17 months). Global incidence of grade (G) 3-4 toxicity was 9.6%, and for neutropenia 5.4%; treatment was discontinued due to toxicity in 3% of patients. The most frequent adverse events (AE) were G1-2 fatigue (27.5%), G1-2 neuropathy (26.3%), and G1-2 neutropenia (14.9%). ORR was 20.2%. Stable disease was observed in 39.2% of patients, with a disease control rate of 59.4%. With a median follow-up of 11 months, median PFS was 4.3 months (95% confidence interval [CI] 4.1-4.7), whereas median OS was 8.0 months (95% CI: 7.09-8.9). In a multivariate analysis, ECOG performance status

Split-liver transplantation has been perceived as an important strategy to increase the supply of liver grafts by creating 2 transplants from 1 allograft. The Eurotransplant Liver Allocation System (ELAS) envisages that the extended right lobes (ERLs) after splitting (usually in the pediatric center) are almost exclusively shipped to a second center. Whether the ELAS policy impacts the graft and patient survival of extended right lobe transplantation (ERLT) in comparison to whole liver transplantation (WLT) recipients remains unclear. Data on all liver transplantations performed between 2007 and 2013 were retrieved from the Eurotransplant Liver Follow-up Registry (n = 5351). Of these, 5013 (269 ERL, 4744 whole liver) could be included. The impact of the transplant type on patient and graft survival was evaluated using univariate and multivariate proportional hazard models adjusting for demographics of donors and recipients. Cold ischemia times were significantly prolonged for ERLTs (P0.001). Patient survival was not different between ERLT and WLT. In the univariate analysis, ERLT had a significantly higher risk for retransplantation (P = 0.02). For WLT, the risk for death gradually and significantly increased with laboratory Model for End-Stage Liver Disease (MELD) scores of20. For ERLT, this effect was seen already with laboratory MELD scores of14. These results mandate a discussion on how to refine the splitting policy to avoid excess retransplant rates in ERL recipients and to further improve transplant outcomes of these otherwise optimal donor organs. Liver Transplantation 24 26-34 2018 AASLD.

Background Autosomal recessive hypercholesterolemia (ARH) is a rare inherited lipid disorder. In Sardinia, differently from other world regions, the mutated allele frequency is high. It is caused by mutations in the low-density lipoprotein receptor adaptor protein 1 gene. Fourteen different mutations have been reported so far; in Sardinia, 2 alleles (ARH1 and ARH2) explain most of the cases. Four ARH patients, all carriers of the ARH1 mutation, have been identified in mainland Italy and 2 in Sicily. Objective The objectives of the study were to improve the molecular diagnosis of familial hypercholesterolemia (FH) and to estimate the frequency of the ARH1 allele in 2 free-living Sicilian populations. Methods We sequenced by targeted next-generation sequencing 20 genes related to low-density lipoprotein metabolism in 50 hypercholesterolemic subjects. Subjects from 2 free-living populations from Northern (Ventimiglia Heart Study, 848 individuals) and Southern Sicily (Zabut Zabut Aging Project, 1717 individuals) were genotyped for ARH1 allele. Results We identified 1 homozygous carrier of the ARH1 mutation among the 50 hypercholesterolemic outpatients. Population-based genotyping of ARH1 in 2565 subjects allowed the identification of 1 heterozygous carrier. The overall estimated allele frequency of ARH1 in Sicily was 0.0002 (0.02%). Conclusions The identification of a new case of ARH in Sicily among 50 clinically diagnosed FH highlights the importance of next-generation sequencing analysis as tool to improve the FH diagnosis. Our results also indicate that ARH1 carrier status is present in ∼1:2500 of Sicilian inhabitants, confirming that ARH is extremely rare outside Sardinia.

Background Selection of the right or left living donor kidney for transplantation is influenced by many variables. In the present multi centric study including 21 Italian transplant centres, we evaluated whether centre volume or surgical technique may influence the selection process. Methods Intra- and perioperative donor data, donor kidney function, and recipient and graft survival were collected among 693 mini-invasive living donor nephrectomies performed from 2002 to 2014. Centre volume (LOW, 1-50 cases; HIGH, >50 cases) and surgical technique (FULL-LAP, full laparoscopic and robotic; HA-LAP, hand-assisted laparoscopy; MINI-OPEN, mini-lumbotomy) were correlated with selection of right or left donor kidney and with donor and recipient outcome. Results HIGH-volume centres retrieved a higher rate of donor right kidneys (29.3% versus 17.6%, P

Major concerns about donor morbidity and mortality still limit the use of living donor liver transplantation (LDLT) to overcome the organ shortage. The present study assessed donor safety in LDLT in Italy reporting donor postoperative outcomes in 246 living donation procedures performed by 7 transplant centers. Outcomes were evaluated over 2 time periods using the validated Clavien 5-tier grading system, and several clinical variables were analyzed to determine the risk factors for donor morbidity. Different grafts were obtained from the 246 donor procedures (220 right lobe, 10 left lobe, and 16 left lateral segments). The median follow-up after donation was 112 months. There was no donor mortality. One or more complications occurred in 82 (33.3%) donors, and 3 of them had intraoperative complications (1.2%). Regardless of graft type, the rate of major complications (grade ≥ 3) was 12.6% (31/246). The overall donor morbidity and the rate of major complications did not differ significantly over time: 26 (10.6%) donors required hospital readmission throughout the follow-up period, whereas 5 (2.0%) donors required reoperation. Prolonged operative time (>400 minutes), intraoperative hypotension (systolic < 100 mm Hg), vascular abnormalities, and intraoperative blood loss (>300 mL) were multivariate risk factors for postoperative donor complications. In conclusion, from the standpoint of living donor surgery, a meticulous and well-standardized technique that reduces operative time and prevents blood loss and intraoperative hypotension may reduce the incidence of donor complications. Transparency in reporting results after LDLT is mandatory, and we should continue to strive for zero donor mortality. Liver Transplantation 23 184–193 2017 AASLD.

International audience; The aim of this study was to collect data from patients who underwent liver transplantation (LT) for adenomatosis; to analyze the symptoms, the characteristics of the disease, and the recipient outcomes; and to better define the role of LT in this rare indication. This retrospective multicenter study, based on data from the European Liver Transplant Registry, encompassed patients who underwent LT for adenomatosis between January 1, 1986, and July 15, 2013, in Europe. Patients with glycogen storage disease (GSD) type IA were not excluded. This study included 49 patients. Sixteen patients had GSD, and 7 had liver vascular abnormalities. The main indications for transplantation were either a suspicion of hepatocellular carcinoma (HCC; 15 patients) or a histologically proven HCC (16 patients), but only 17 had actual malignant transformation (MT) of adenomas. GSD status was similar for the 2 groups, except for age and the presence of HCC on explants (P = 0.030). Three patients with HCC on explant developed recurrence after transplantation. We obtained and studied the pathomolecular characteristics for 23 patients. In conclusion, LT should remain an extremely rare treatment for adenomatosis. Indications for transplantation primarily concern the MT of adenomas. The decision should rely on morphological data and histological evidence of MT. Additional indications should be discussed on a case-by-case basis. In this report, we propose a simplified approach to this decision-making process.

BACKGROUND: In liver transplantation (LT), modern immunosuppressive protocol is focused on early corticosteroid (CS) weaning. The aim of the study was to investigate all early transplant-related complications using Clavien grading system, in order to identify a significant relation in two homogenous groups of consecutive liver transplanted patients, only different for steroid avoidance in immunosuppressive regimen. MATERIALS AND METHODS: One group was treated with a tacrolimus-based CS-free immunosuppressive protocol, the other one underwent tacrolimus plus low dose CS therapy. The preoperative continuous variables analyzed were age, gender, model for end-stage liver disease (MELD) score, and the pre-allocation score for predicting survival following liver transplantation (P-SOFT). RESULTS: There were 39 patients in Group A (CS free) (37.9%), and 64 patients in Group B (CS on board) (62.1%). No statistically significant differences between the two groups were detected regarding the incidence and Clavien grade of complications (P = 0.116). No significant relation was revealed between Clavien rate of complications and tacrolimus-based CS-free immunosuppressive protocol, comparing the two subgroup of patient with P-SOFT score < 6 and ≥ 6 (P = 0.193). This association was noted comparing the two subgroups on tacrolimus plus low dose CS regimen (P = 0.013). CONCLUSION: In this series, the use of CS in sick patient is associated with higher morbidity identified by the Clavien classification.

Research has indicated that beliefs about inflated responsibility, beliefs about perceived control over anxiety-related events and reactions (anxiety control) and metacognitive beliefs about the need to control thoughts are associated with obsessive compulsive symptoms. In the current study we tested a mediation model of the interactions between these variables in predicting obsessive compulsive symptoms. Thirty-seven individuals with obsessive compulsive disorder and 31 controls completed the following self-report instruments: the Responsibility Attitude Scale, the Anxiety Control Scale, the Beliefs about Need to Control Thoughts sub-scale of the Metacognitions Questionnaire 30, and the Padua Inventory. Mann-Whitney U tests revealed that participants in the clinical group scored significantly higher than those in the non-clinical group on all variables. In the mediation model we found that the relationship between beliefs about inflated responsibility and obsessive compulsive symptoms was fully mediated by anxiety control and beliefs about the need to control thoughts. These findings provide support for the significant role played by beliefs about control in predicting the severity of obsessive compulsive symptoms.

The aim of this study was to determine the impact of two reperfusion techniques on the peri-operative hemodynamic changes and early post-operative graft function of adult patients undergoing orthotopic liver transplantation. Material and methods: From June 2003 to May 2004, 50 consecutive liver transplants were performed and divided into two groups: group A, 25 patients, portal vein flush with 500 cm3 of Ringer's lactate without vena caval venting. Group B, 25 patients, vena caval venting with no portal vein flush. Donor and recipient characteristics were similar in both groups. Sixty-four different parameters were analyzed, and Pearson's χ2 test and t-test were used for statistical analysis, p0.05. Results: One patient (4%) in group B experienced a post-reperfusion syndrome (PRS). Pearson's χ2 test found a significant relationship between the analyzed parameters and the two different reperfusion techniques for 10 parameters (t-test analysis showed a significant difference between the two groups in favor of group A). Conclusions: In our transplant center, portal vein flush without vena caval venting provided a lower incidence of hemodynamic changes in the peri-operative period after liver transplantation and earlier recovery of the graft function.

Right-brain-damaged patients with unilateral spatial neglect are usually unaware (anosognosic) about their spatial deficits. However, in the scientific literature there is a lack of systematic and quantitative evaluation of this kind of unawareness, despite the negative impact of anosognosia on rehabilitation programs. This study investigated anosognosia for neglect-related impairments at different clinical tasks, by means of a quantitative assessment. Patients were tested in two different conditions (before and after execution of each task), in order to evaluate changes in the level of awareness of neglect-related behaviours triggered by task execution. Twenty-nine right-brain-damaged patients (17 with left spatial neglect) and 27 neurologically unimpaired controls entered the study. Anosognosia for spatial deficits is not pervasive, with different tasks evoking different degrees of awareness about neglect symptoms. Indeed, patients showed a largely preserved awareness about their performance in complex visuo-motor spatial and reading tasks; conversely, they were impaired in evaluating their spatial difficulties in line bisection and drawing from memory, showing over-estimation of their performance. The selectivity of the patients' unawareness of specific manifestations of spatial neglect is further supported by their preserved awareness of performance at a linguistic task, and by the absence of anosognosia for hemiplegia. This evidence indicates that discrete processes are involved in the aware monitoring of cognitive and motor performance, which can be selectively compromised by brain damage. Awareness of spatial difficulties is supported by a number of distinct components, and influenced by the specific skills required to perform a given task. (C) 2014 Elsevier Ltd. All rights reserved.

Objective: Right-brain-damaged patients with left spatial neglect make perseveration errors in target cancellation tasks. A recent study (Ronchi, Posteraro, Fortis, Bricolo, & Vallar, 2009) showed that perseveration occurred more frequently in star than in letter cancellation, possibly due to different stimulus disposition. In this study we investigated the role of the spatial organization of targets (scattered vs. arranged) of the star and letter cancellation tasks in eliciting omission and perseveration errors; the role of impairments of divided attentional resources; and the lesion correlates of perseveration. Method: Thirty-three right-brain-damaged patients (27 with neglect, and six without neglect; 17 showing perseveration, 16 of them with spatial neglect) were given two versions of the star and letter cancellation tasks (with stimuli scattered or in rows), and a dual task. Results: A scattered target disposition increased omission and perseveration errors. Target type modulated differently omission and perseveration, with the former being more elicited by verbal targets, and the latter occurring more frequently in the star cancellation task, with scattered stimuli. Perseveration behavior was unrelated to deficits of divided attention, as assessed by the dual task. Lesion analysis indicated damage to the right insula as a neural correlate of perseveration. Conclusions: A display including nonverbal (star) and scattered targets brings about more perseveration errors. Target type and organization modulate in a different fashion omission and perseveration, suggesting the involvement of independent pathological mechanisms, which, however, do not implicate deficits of divided attention. The role of insular damage in motor perseveration in spatial neglect is discussed.

Early liver regeneration was studied in a series of 70 patients who underwent right hepatectomy for living donation between November 2004 and January 2010. Liver regeneration was evaluated with multidetector computed tomography (MDCT) at a mean of 61.07 days after surgery. Presurgical variables [eg, age, weight, height, body mass index (BMI), liver function tests, creatinine levels, platelet counts, international normalized ratio, and glucose levels] and variables detected with preoperative MDCT imaging [eg, main portal vein diameter, steatosis, original liver volume, and spleen volume (SV)] were investigated as potential predictors of liver regeneration. The future remnant liver volume (FRLV) was preoperatively calculated with a virtual surgical cut. Liver function tests and creatinine levels were recorded on the 30th postoperative day. In addition, the onset of postoperative complications occurring within 90 days of surgery was analyzed, and the complications were codified according to the 5 tiers of the Clavien-Dindo classification. In 26 of the 70 patients (37.14%), 100% or greater hepatic regeneration had occurred at 2 months. There was no association between the clinical outcome and the liver regeneration rate. A stepwise multiple regression analysis showed that a higher BMI (coefficient = 0.035, P < 0.0001) and preoperative parameters such as a smaller FRLV (coefficient = -0.002, P < 0.0001) and a greater SV/FRLV ratio (coefficient = 1.196, P < 0.0001) were predictors of greater liver regeneration. Liver Transpl, 2012. © 2012 AASLD.

We describe the clinical features, muscle pathology features, and molecular studies of seven patients with Chanarin-Dorfman syndrome (CDS) or neutral lipid storage disease and ichthyosis (NLSDI), a multisystem triglyceride storage disease with massive accumulation of lipid droplets in muscle fibers. All patients presented with congenital ichthyosiform erythroderma, cytoplasmic lipid droplets in blood cells, mild to severe hepatomegaly, and increased serum CK levels and liver enzymes. Three patients showed muscle symptoms and three had steathorrea. Molecular analysis identified five mutations, three of which are novel. These findings expand the clinical and mutational spectrum and underline the genetic heterogeneity of this disease.

Alagille syndrome (AS) is a dominantly inherited, multisystem disorder involving the liver, heart, eyes, face, and skeleton. From October 1997 through July 2004, 260 pediatric orthotopic liver transplantations (OLTx) were performed in 231 patients. This report describes 21 patients of median age 1.95 years (range, 0.7-16.7) who had alagille syndrome. We present the technical features of the OLTx, incidence and type of complications, medical conditions related to the syndrome, need for retransplantation, as well as patient and graft survival rates. A split liver technique was used in 16 patients (76%) who received a left lateral segment (LLS) graft whereas 7 patients (33%) received a whole liver. Only cadaveric donors were used. The major surgical complications requiring reintervention in 11 patients (52%) included biliary problems (19%) and vascular complications (17%). One case of hepatic artery thrombosis required retransplantation. Three recipients (14%) died. All other patients are alive with an actuarial survival rate of 90% at 1 year and 80% at 5 years. The actuarial graft survival rate is 85% at 1 year and 75% at 5 years. Patients with AS, despite the associated cardiovascular anomalies, can be treated successfully by a combined approach between cardiologist, radiologist, cardiothoracic, and liver transplant surgeons. With careful planning and operative management, the results are comparable with those obtained with other more common cholestatic diseases.

In this study we analyzed the features of 12 patients who underwent liver transplantation for progressive familial intrahepatic cholestasis (Byler's disease [BD]) in view of the technical features of the OLTx, incidence and type of complications, need for retransplantation, as well as patient and graft survivals. BD was the indication in 12 patients of median age 1.32 years and median weight 10 kg. Median follow-up was 670 days. Major surgical complications requiring reintervention occurred in three patients. No thrombosis of the hepatic artery was observed. Infections with positive blood cultures were diagnosed in four patients. One patient had a biliary anastomotic stenosis successfully treated by percutaneous techniques. Four patients had episodes of acute rejection treated with steroids. Two patients were retransplanted, both of whom died in the early postoperative period due to hepatic vein thrombosis and venoenteric fistula. The actuarial patient and graft survival was 83% at 1 year and 83% at 5 years. Split-liver grafts represent an excellent organ supply for these patients, achieving good results with no mortality on the waiting list.

Early portal vein thrombosis (PVT) represents a serious complication after liver transplantation (OLTx). From October 1997 through July 2004, 260 OLTx were performed in 231 children, including 189 of left lateral segments (LLS). We retrospectively analyzed the incidence and the outcome of early PVT in this group. A daily doppler US scan was performed during the first week after transplantation. Early PVT occurred in 14 patients (8%), 10 males and four females of median age 0.77 years. The main indication for primary transplantation was biliary atresia (10), followed by Byler's disease (2), acute liver failure on cryptogenetic cirrhosis (1), and Alagille syndrome (1). Four children underwent retransplantation; three cases of thrombectomy and revision of the anastomosis, two children were treated with beta blockers, one of whom had a later failed attempt at percutaneous revascularization and eventually a meso-caval shunt. Five patients were followed with observation and no treatment. Among the four patients who died, three were in the retransplantation group and one in the thrombectomy and revision of the anastomosis group; the overall mortality was 28%. With a median follow up of 399 days, 10 patients are alive with an actuarial survival at 1 and 5 years of 72%, and graft survival rates at 1 and 5 years of 64%. PVT represents a serious complication after pediatric OLTx with LLS grafts. Prompt detection and aggressive surgical treatment in selected cases are required to reduce the mortality and graft loss.

Background. End-stage cholestatic liver disease (ESCLD) is the main indication for liver replacement in children. Pediatric cadaver-organ-donor shortage has prompted the most important evolutions in the technique of liver transplantation, in particular living-donor liver transplantation (LDLT) and split-liver transplantation (SLT). Methods. Between November 1997 and June 2001, 127 children with ESCLD were evaluated for liver transplantation, and 124 underwent 138 liver transplantations after a median time of 40 days. Causes of liver disease were congenital biliary atresia (n=96), Alagille's syndrome (n=12), Byler's disease (n=8), and other cholestatic diseases (n=8). Results. Ninety (73%) patients received a split-liver graft, 28 (23%) a whole liver, and 6 (4%) a reduced-size liver. Overall 2- and 4-year patient survival rates were 93% and 91%, respectively; the 2- and 4-year graft-survival rates were 84% and 80%, respectively. In split-liver recipients, 4-year patient and graft-survival rates were 91% and 83%, respectively; these were 93% and 78%, respectively, in whole-liver recipients and 67% and 63%, respectively, in reduced-size liver recipients. Retransplantation rate was 11%, whereas mortality rate was 8%. Overall incidence of vascular and biliary complication were 16% and 27%, respectively. Conclusions. SLT can provide liver grafts for children with ESCLD with an outcome similar to the one reported following LDLT, eliminating mortality while they are on a transplantation wait list. The need for pediatric LDLT should be reevaluated and programs of SLT strongly encouraged and supported at a national and international level.

Ornithine transcarbamylase deficiency (OTCD) is an X-linked urea cycle disorder due to a defect of the mithocondrial enzyme ornithine transcarbamylase (OTC). Genetic analysis in nine unrelated Italian patients affected by OTCD (one male patient and eight female manifesting carriers) led to the detection of three novel mutations and six previously reported mutations in the OTC gene. The analysis was performed by direct sequencing of OTC cDNA, OTC exons, and intron-exon boundaries and enzymatic restriction analysis on the patients' genomic DNA and total RNA isolated from peripheral blood lymphocytes. In the male patient the new mutation S132P due to the nucleotide change c.394T>C was identified. In a manifesting carrier the nucleotide change c.292G>A that leads to the novel amino acid substitution E98K was identified; this mutation is close to the OTC protein's carbamyl phospate binding site. In another manifesting carrier the OTC cDNA analysis revealed the normally spliced transcript and an aberrant transcript with an insertion of two nucleotides (c.77-78insAG). In the patient's genomic DNA we identified a new transvertion IVS1-3C>G at the heterozygous state; this nucleotide change generates a new splice acceptor site in intron 1 that induces an RNA splicing defect. This insertion causes a frame shift in OTC cDNA ORF and leads to a premature stop codon. The previously described mutations N161S, R141Q, T178M, R92X, A208T, M268T were identified in the other six manifesting carriers.