Abstract: Abstract non disponibile

Abstract: Oral iron is recommended as first line treatment of anemia in non-dialysis chronic kidney disease (ND-CKD) patients. Sucrosomial® iron, a new generation oral iron with high absorption and bioavailability and a low incidence of side effects, has shown to be not inferior to intravenous (IV) iron in the replacement of iron deficiency anemia in patients with ND-CKD. Besides the clinical benefit, it is also important to determine the comparative total costs of oral versus IV iron administrations. The aim of this study was to perform a cost-minimization analysis of oral Sucrosomial iron, compared with IV iron gluconate from an Italian societal perspective. Methods Cost analysis was performed on the 99 patients with ND-CKD and iron-deficiency anemia of the randomized trial by Pisani et al. Human and material resources utilization was recorded during each iron administration. According to study perspective, direct and indirect costs were considered. Costs for each resource unit were taken from official Italian sources. Probabilistic sensitivity analyses were carried out to test the robustness of the results. Results The base case analysis showed an average cost/cycle per patient of € 111 for oral iron and € 1302 for IV iron. Thus, the potential saving was equal to € 1191 per patient/cycle. The sensitivity analysis showed that the most sensitive driver is the time loss by patient and caregivers for the therapy and related-care, followed by the minutes of nursing care and the number of kilometres travelled to reach the referral centre. Discussion This study showed that oral Sucrosomial® iron could offer specific advantages in terms of potential savings, and allowed identifying some implications for future research. Such advantages still persist with the new single dose IV iron formulation available in the market, although to a lesser extent.

Abstract: Nilotinib is a selective BCR-ABL tyrosine kinase inhibitor (TKI) that has been shown to be more active than imatinib at inducing earlier and deeper molecular responses in the frontline treatment of chronic myeloid leukemia (CML; Larson, et al. Leukemia. 2012). ENEST1st (Evaluating Nilotinib Efficacy and Safety in clinical Trials as First-Line Treatment, NCT01061177) is the largest study ever in TKI-treated patients (pts) with CML. Its primary endpoint was the rate of MR4 (defined as BCR-ABL ≤ 0.01% on the International Scale [BCR-ABLIS] or undetectable BCR-ABL in cDNA with ≥ 10,000 ABL transcripts) at 18 mo. Molecular response (MR) was assessed by standardized quantitative polymerase chain reaction (RQ-PCR) in the 14-laboratory network of the European Treatment and Outcomes Study (EUTOS). Methods ENEST1st is a phase 3b, open-label study of nilotinib 300 mg twice daily (BID) in adults with newly diagnosed BCR-ABL-positive CML in chronic phase. MR was assessed every 3 mo by peripheral blood RQ-PCR at 1 of 14 EUTOS laboratories. Following completion of the 18-mo primary efficacy time point, all pts continued to receive treatment and were followed for an additional 6 mo. Results 1160 pts were screened, with 1086 eligible pts treated in 26 European countries. Overall, median age was 53 y (range, 18-91 y); 59.2% of pts were male, 96.9% had typical b2a2 and/or b3a2 BCR-ABL transcripts (intent-to-treat population for MR analyses), and 90.3% were Philadelphia chromosome–positive by bone marrow metaphase cytogenetics. Per protocol, efficacy and safety analyses were conducted in the initial 819 pts (75.4% of enrolled pts) who were on study for 24 mo or discontinued early. In this group, median age was 53 y (range, 18-91 y), and 58.5% were male; Sokal risk scores were low, intermediate, and high in 33.7%, 39.5%, and 18.7% of pts, respectively (8.1% missing). EUTOS scores were low in 83.8% and high in 9.2% of pts (7.0% missing). A total of 658 pts (80.3%) completed 24 mo of treatment; 161 pts (19.7%) discontinued early. The most common reasons for discontinuation included adverse events (AEs; 10.5%), withdrawal of consent (2.7%), and disease progression (as indicated by the investigator; 1.7%). MR4 rate at 18 mo was 43.0% (95% CI, 39.3-46.8). Rates of major MR (MMR, BCR-ABLIS ≤ 0.1%), MR4, and MR4.5 (BCR-ABLIS ≤ 0.0032% or undetectable cDNA with ≥ 32,000 ABL transcripts) at 18 and 24 mo are shown in the Table. Cumulative incidence of MR4 by 18 mo was 50.1%. All pts were followed up for progression or death for 24 months after start of treatment: 7 pts (0.85%) experienced progression to accelerated phase/blast crisis (AP/BC) while on core treatment or after discontinuation. Overall, 12 pts (1.5%) died; 2 of them died following progression to AP/BC. The safety profile of nilotinib was similar to that observed in other frontline studies. The most common AEs of any relationship were rash (21.4%), pruritus (16.8%), and headache (15.0%); most AEs were grade 1-2. Rates of grade 3-4 hematological AEs were low, with thrombocytopenia and neutropenia reported in 8.2% and 2.9% of pts, respectively. Peripheral arterial occlusive disease (PAOD) occurred in 13 pts (1.6%), ischemic heart disease in 31 (3.8%), and ischemic cerebrovascular conditions in 4 (0.5%). Three cases of pain in extremities are under investigation for potential relationship to PAOD. Conclusions ENEST1st confirms that frontline nilotinib results in high rates of deeper and earlier MR and very low rates of progression to AP/BC. By 18 mo, half of pts achieved a response of MR4. This MR4 rate supports the use of frontline nilotinib as a treatment of choice on which to develop treatment-free remission studies. Finally, the molecular response rates measured in a standardized and validated network of 14 EUTOS laboratories in ENEST1st provide prospective confirmation of the centrally reviewed molecular response rates reported in the ENESTnd trial. Disclosures: Giles: Novartis: Consultancy, Research Funding. Baccarani:Novartis: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Ariad: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Pfizer: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau. Brümmendorf:Novartis: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Patents & Royalties, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Ariad: Consultancy. Mahon:Novartis: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Brisol Myers Squibb: Consultancy, Honoraria; Ariad: Honoraria; Pfizer: Honoraria. Rosti:Novartis: Consultancy, Speakers Bureau; Bristol Myers Squibb: Consultancy, Speakers Bureau; Ariad: Consultancy, Speakers Bureau; Roche: Speakers Bureau; Pfizer: Speakers Bureau. Saglio:Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; Ariad: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Steegmann:Novartis: Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol Myers Squibb: Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau. Ossenkoppele:Novartis: Consultancy, Research Funding, Speakers Bureau; Bristol Myers Squibb: Consultancy, Speakers Bureau. Echeveste:Celgene: Consultancy; Novartis: Consultancy. Gattermann:Novartis: Honoraria, Research Funding, Speakers Bureau. Griskevicius:Novartis: Consultancy, Research Funding. le Coutre:Novartis: Honoraria, Research Funding, Speakers Bureau; Bristol Myers Squibb: Honoraria; Pfizer: Honoraria. Masszi:Novartis: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Rea:Novartis: Honoraria; Bristol Myers Squibb: Honoraria; Pfizer: Honoraria; Ariad: Honoraria. Richter:Novartis: Consultancy, Research Funding, Speakers Bureau; Bristol Myers Squibb: Consultancy, Speakers Bureau. Stentoft:Novartis: Consultancy, Financial support for relevant congress participation Other, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Danish Regions: Membership on an entity’s Board of Directors or advisory committees. Tulliez:Novartis: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Schuld:Novartis: Employment, Equity Ownership. Pellegrino:Novartis: Employment. Walasek:Novartis: Employment. Cross:Novartis: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria. Hochhaus:Novartis: Research Funding; Bristol Myers Squibb: Research Funding; Ariad: Research Funding; Pfizer: Research Funding.

Abstract: Background Tyrosine kinase inhibitors (TKIs) are the standard of care for pts with CP-CML. Current recommendation is to continue TKI therapy indefinitely but previous studies indicate that pts with deep and sustained molecular responses (MRs) on imatinib (IM) may achieve long-lasting TFR. Nilotinib (NIL) at 300mg BID induces higher rates of deep MRs compared to IM and high dose NIL (400mg BID) enables a substantial proportion of pts who do not obtain MR4 (BCR-ABL1IS £ 0.01%) or MR4.5 (BCR-ABL1IS £ 0.0032%) with IM to reach such deep MRs levels, potentially compatible with TFR. However, optimal duration of treatment with NIL to ensure the highest rate of TFR after treatment discontinuation is unknown. Objective ENESTPath was designed to assess the optimal duration of NIL therapy that is necessary to achieve and maintain TFR upon treatment discontinuation in pts pretreated with IM. Methods ENESTPath is a randomized, phase III study enrolling CP-CML pts who after at least 2 years (yrs) of IM therapy achieved a complete cytogenetic response (CCyR), but not yet a MR4. After enrollment, pts were assigned to receive NIL at 300 mg BID for 2 yrs or 3 yrs (Arm 1 and Arm 2, respectively). Patients who will obtain a stable MR4 or better for at least 12 months (mo) will enter the TFR phase. Primary endpoint is to evaluate the proportion of pts in both arms who will remain in TFR for ≥1 yr after NIL discontinuation. Results 620 pts were enrolled in the study between May-2013 & Apr-2015. In this interim analysis, the first 300 pts (mean age 50.8 yrs; 63.7% male) enrolled and treated with NIL for ≥1 yr have been included. Baseline characteristics are detailed in the Table. By 12 mo of NIL treatment, cumulative incidences of newly acquired MR4 and MR4.5 were 57.4% and 30.5%, respectively. Further analysis of MR4 achievement showed that pts with a major molecular response (MMR: BCR-ABL1IS 〉 0.01% - ≤0.1%) at baseline had a higher probability to achieve a MR4 than those lacking MMR at baseline, with a cumulative incidence of MR4 by 12 months of 64.8% and 30.8%, respectively (Figure). Adverse events (AEs) were mostly of grade 1-2, manageable with supportive care or NIL dose interruption/reduction and included pruritus (19%), headache (9%), skin rash (9%), upper abdominal pain (8%) and constipation (7%). Grade 3-4 hematologic AEs were uncommon. The incidence of grade 3-4 laboratory abnormalities was low: lipase increase, hyperglycemia, ALT and AST increase, hyperbilirubinemia and hypercholesterolemia reported in 3.7%, 1.3%, 1%, 0.7%, 0.3%, 0.3% pts, respectively. Grade 3-4 ischemic cardiovascular events were experienced by 5% of pts including peripheral artery occlusive disease (1.7%) and coronary artery disease (3.7%) (1 pt experienced both AEs). Sub-analyses aiming to evaluate the impact of baseline SCOREa CV risk factor on the onset of arterial ischemic events are currently ongoing. Results on 168 pts showed grade 3-4 ischemic CV events in 19% of pts who were at very high or high risk (n = 47) compared to 1.7% of in pts with moderate or low risk (n = 121). During the first 12 mo, 48 (16%) pts discontinued NIL therapy: 32 discontinued due to AEs/laboratory abnormalities, 12 withdrew consent, 4 due to other reasons (protocol deviation, pregnancy and non-compliance). No patients left the study due to progression to AP/BP. Till date there were no on-treatment deaths. Conclusions This interim analysis shows that a switch to NIL at lower doses than in prior studies (300mg BID instead of 400mg BID) induces high rates of MR4 and MR4.5 in pts without such MR levels on IM. The safety profile of NIL at 300mg BID is consistent with that described in other prospective studies.Thus a switch to NIL for pts not achieving a deep MR during IM therapy is predicted to substantially increase the probability of achieving TFR requirements. A longer follow-up is necessary to assess what may be the best duration of NIL prior to treatment discontinuation. aRisk factors evaluated by applying the SCORE chart proposed by the European Society of Cardiology Table 1. Table 1. Figure 1. Figure 1. Disclosures Rea: Novartis: Honoraria; BMS: Honoraria; Ariad: Honoraria; Pfizer: Honoraria. Rosti:Bristol Myers Squibb: Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau. Cross:Qiagen: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Ariad: Consultancy, Honoraria, Research Funding. Hellman:Novartis: Research Funding; BMS: Research Funding. Niederwieser:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Almeida:Shire: Speakers Bureau; Bristol Meyer Squibb: Speakers Bureau; Novartis: Consultancy; Celgene: Consultancy. Dezzani:Novartis: Employment. Pellegrino:Novartis: Employment. Costantini:Novartis: Employment. Walasek:Novartis: Employment. Saglio:Bristol-Myers Squibb: Consultancy, Honoraria; Novartis Pharmaceutical Corporation: Consultancy, Honoraria; ARIAD: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. Steegmann:Pfizer: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Ariad: Honoraria, Research Funding. Baccarani:NOVARTIS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; PFIZER: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ARIAD Pharmaceuticals, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Abstract: Emphysematous pyelitis is a rare urinary infection with gas formation in the excretory system. Diabetes mellitus and urinary tract obstruction are the main risk factors. Most patients are women over 60 years old. The pathogenesis is unknown. Diabetes mellitus and the elevated glucose levels may create a favorable microenvironment for gas-forming microbes, but it does not exhaustively explain clinical and pathological symptoms. Escherichia Coli and Klebsiella Pneumoniae are the most involved bacteria. Clinical features are the same as other forms of pyelonephritis e.g. fever, chills, flank abdominal pain, nausea and vomiting. Ultrasonography, and especially computed tomography (CT) are important diagnostic tools for demonstration of gas within pelvicalyceal system, urethers or even in bladder. Use of parenteral antibiotic, relief of urinary tract obstruction if present, percutaneous catheter drainage of gas and purulent material and nephrectomy are the mainstays of therapy. This report introduces a case of bilateral emphysematous pyelitis with emphasis on its ultrasound presentation. This is one of the few cases of bilateral emphysematous pyelitis reported in literature. Method A 49-year-old female presented to the emergency with asthenia, epistaxis, orthostatic hypotension and nocturnal cramps. Two months before she was referred to Department of Nephrology for proteinuria. In that occasion, renal ultrasound showed normal kidneys and renal biopsy was performed. She started oral therapy with corticosteroid for ANCA-negative vasculitis and iatrogenic diabetes mellitus occurred. She was admitted again to our Department of Nephrology, blood test was performed and revealed: white cell count 20.500/ml; glucose 243 mg/dl; serum creatinine 2.3 mg/dl; C-reactive protein, 0.65 mg/dl ( & lt; 0.5), procalcitonin 2.05 µg/l (nv & lt; 0.5). Urine culture was positive for E. Coli. Results Renal ultrasound revealed the presence, in both kidney pelvises, of multiple and diffuse hyperechogenic images associated with some reverberation artefacts. The ultrasound findings were unusual and of doubtful interpretation: staghorn calculi, encrusted pyelitis, gas? (Fig. 1, 2). Reverberation artifacts give rise the suspicion of gas presence in kidney pelvises, usually absent in case of staghorn calculi and encrusted pyelitis. CT confirmed the diagnosis of bilateral emphysematous pyelitis due to the diffuse presence of gas within the renal calyces, also extending to the ureters and bladder lumen (Fig. 3). We promptly started parental antimicrobial therapy with cefalosporine. After one week we observed a clinical and laboratory improvement, and the renal ultrasound revealed the resolution of bilateral pelvises alteration (Fig. 4). Conclusion In emphysematous pyelitis, renal ultrasound is characteristic due to the presence of diffuse hyperechogenic images located in the renal pelvis associated with some reverberation artifacts, usually absent in case of renal stones. Therefore, the renal ultrasound in association with clinical and laboratory findings, especially in patient with positive urine culture, should arouse the suspicion of emphysematous pyelitis to start promptly antimicrobial therapy, even when CT examination is not immediately available.