Search

Introduction In recent years, robot-assisted gait training (RAGT) has been proposed as therapy for balance and gait dysfunctions in people with multiple sclerosis (PwMS). Through this systematic review, we aimed to discuss the impact of RAGT on balance and gait outcomes. Furthermore, characteristics of the training in terms of robots used, participants characteristics, protocols and combined therapeutic approaches have been described. Evidence acquisition As part of the Italian Consensus on robotic rehabilitation "CICERONE" a systematic search was provided in PubMed, the Cochrane Library and PEDro to identify relevant studies published before December 2019. Only randomized control trials (RCT) involving RAGT for PwMS were included. PEDro scale was used to assess the risk of bias and the Oxford Center for Evidence-Based Medicine (OCEBM) was used to assess level of evidence of included studies. Evidence synthesis The search on databases resulted in 336 records and, finally, 12 studies were included. RAGT was provided with Exoskeleton in ten studies (6-40 session, 2-5 per week) and with end-effector in two studies (12 sessions, 2-3 per week) with large variability in terms of participants' disability. All the exoskeletons were combined with bodyweight support treadmill and movement assistance varied from 0% to 100% depending on participants' disability, two studies combined exoskeleton with virtual reality. The end-effector speed ranged between 1.3 and 1.8 km/h, with bodyweight support starting from 50% and progressively reduced. In seven out of twelve studies RAGT was provided in a multimodal rehabilitation program or in combination with standard physical therapy. There is level 2 evidence that RAGT has positive impact in PwMS, reaching the minimally clinically importance difference in Berg Balance Scale, six-minute walking test and gait speed. Conclusions In available RCT, RAGT is mostly provided with exoskeleton devices and improves balance and gait outcomes in a clinically meaningful way. Considering several advantages in terms of safety, motor assistance and intensity of training provided, RAGT should be promoted for PwMS with severe disability in a multimodal rehabilitation context as an opportunity to maximize recovery.

Background and purpose Rehabilitation plays a central role in stroke recovery. Besides conventional therapy, technological treatments have become available. The effectiveness and appropriateness of technological rehabilitation are not yet well defined; hence, research focused on different variables impacting recovery is needed. Results from the literature identified cognitive reserve (CR) as a variable impacting on the cognitive outcome. In this paper, the aim was to evaluate whether CR influences the motor outcome in patients after stroke treated with conventional or robotic therapy and whether it may influence one treatment rather than another. Methods Seventy-five stroke patients were enrolled in five Italian neurological rehabilitation centres. Patients were assigned either to a robotic group, rehabilitation by means of robotic devices, or to a conventional group, where a traditional approach was used. Patients were evaluated at baseline and after rehabilitation treatment of 6 weeks through the Action Research Arm Test (ARAT), the Motricity Index (MI) and the Barthel Index (BI). CR was assessed at baseline using the Cognitive Reserve Index (CRI) questionnaire. Results Considering all patients, a weak correlation was found between the CRI related to leisure time and MI evolution (r = 0.276; P = 0.02). Amongst the patients who performed a robotic rehabilitation, a moderate correlation emerged between the CRI related to working activities and MI evolution (r = 0.422; P = 0.02). Conclusions Our results suggest that CR may influence the motor outcome. For each patient, CR and its subcategories should be considered in the choice between conventional and robotic treatment.

Objective: The aims of the study were to compare mobility in multiple sclerosis, Parkinson disease, and stroke, and to quantify the relationship between mobility and participation restrictions. Design: This is a multicenter cross-sectional study. Included were compliant subjects with Parkinson disease, multiple sclerosis, and stroke seen for rehabilitation, with no comorbidities interfering with mobility. Functional scales were applied to each subject to investigate gait speed (10-meter walking test), balance while maintaining body position (Berg Balance Scale), dynamic balance and mobility (Timed Up and Go and Dynamic Gait Index), and participation (Community Integration Questionnaire). Results: Two hundred ninety-nine patients (111 multiple sclerosis, 94 Parkinson disease, and 94 stroke)were enrolled. Stroke had the slowest gait speed (mean gait speed = 0.9 m/sec) compared with Parkinson disease (1.1 m/sec), and multiple sclerosis (1.2 m/sec) (P < 0.001). Multiple sclerosis was more limited than Parkinson disease and stroke in dynamic balance both in the Timed Up and Go Test (multiple sclerosis = 16.7 secs, Parkinson disease = 11.4 secs, stroke = 14.0 secs; P < 0.001) and Dynamic Gait Index (multiple sclerosis = 11.6 points, Parkinson disease = 12.9 points, stroke = 13.6 points; P = 0.03); ability to maintain balance and body position (Berg Balance Scale) was more affected in stroke and Parkinson disease than multiple sclerosis (multiple sclerosis = 42.6 points, Parkinson disease = 39.4 points, stroke = 39.7 points; P = 0.03). Balance disorders were associated with participation restrictions but not gait speed. Conclusions: Neurological conditions have differing impacts on gait and balance, leading to different levels of participation restriction.

Background and purpose Muscle-strengthening, stretching or proprioceptive treatments may slow symptom progression in Charcot-Marie-Tooth (CMT) neuropathy. The aim of the study was to evaluate safety and efficacy of treadmill training in CMT1A. Methods We planned a multicenter, prospective, randomized, single-blind, controlled study. We recruited 53 outpatients affected by CMT1A and randomized them into two treatment groups: one underwent stretching and proprioceptive exercise, whereas the other was additionally treated with treadmill training (TreSPE). Primary outcome measures (OMs) were the walking evaluations and secondary OM was the balance assessment. All participants were assessed at baseline and after 3 and 6 months of treatment. Results Most patients showed an improvement in at least one OM after 3 months [42/47 (89.4%)] and 6 months [38/40 (95%)] of treatment. No adverse events were reported in either group. Conclusions The most important finding was that both stretching and proprioceptive exercise and treadmill training had an objective benefit on patients affected by CMT disease, without causing overwork weakness. We had a low rate of drop out and did not find deterioration in motor performance. Our results also confirm that applying evidence-based medicine methods to rehabilitative research is the correct way to test the efficacy of a treatment.

Background The outcome measures (OMs) in clinical trials for Charcot-Marie-Tooth disease (CMT) still represent an issue. A recent study highlighted that three additional clinical OMs, the 10-Meter Walk Test (10MWT), the 9-Hole Peg Test, and foot dorsal flexion dynamometry, further improve discrimination between severely and mildly affected patients. Another study has recently assessed the validity and reliability of the 6-Minute Walk Test (6MWT). Aim The aim of this study was to identify the most useful scales in the clinical evaluation of CMT1A patients. Design Observational study of the baseline data collected in a multicenter, prospective, randomized, single blind, controlled study to evaluate the efficacy and safety of an innovative rehabilitation protocol based on treadmill training, stretching, respiratory, and proprioceptive exercises (TreSPE study) in CMT1A patients. Setting The outpatient service of the four Italian centers involved, which are specialized in hereditary neuropathies. Population Fifty-three subjects with a clinical and genetically confirmed diagnosis of CMT1A. Methods At baseline, in addition to the CMT Neuropathy Score, all subjects underwent walking evaluation (6MWT, 10MWT), balance assessment (Berg Balance Scale [BBS], Short Physical Performance Battery [SPPB]) and a subjective evaluation of quality of life (SF36) and walking ability (Walk12). Results Analyzing the baseline data, as expected, we found a strong correlation between walk and balance evaluation, proving the validity of these tests in investigating the functional impairment of CMT1A subjects. Particularly, we found that subjects with better balance control walk at higher speed and perceive less limitations in their physical activities or motor skills. This can be reconducted to the fact that ankle stability depends upon different factors such as anatomy integrity, muscle strength and proprioception. Conclusions We identify the 6MWT, 10MWT, and SPPB as the most useful scales, in addition to the CMTNS, to evaluate the functional impairment of CMT1A patients who retain their walking capability and we suggest the use of SPPB because of its rapidity to assess balance and gait disorders in clinical settings. Clinical rehabilitation impact In the clinical practice it is important to evaluate patients comprehensively but rapidly. These outcome measures can help us to correctly assess balance and walking ability in CMT1A patients.

Background Quality of bowel cleansing in hospitalized patients undergoing colonoscopy is often unsatisfactory. No study has investigated the inpatient or outpatient setting as cause of inadequate cleansing. Aims To assess degree of bowel cleansing in inpatients and outpatients and to identify possible predictors of poor bowel preparation in the two populations. Methods Prospective multicentre study on consecutive colonoscopies in 25 regional endoscopy units. Univariate and multivariate analysis with odds ratio estimation were performed. Results Data from 3276 colonoscopies were analyzed (2178 outpatients, 1098 inpatients). Incomplete colonoscopy due to inadequate cleansing was recorded in 369 patients (11.2%). There was no significant difference in bowel cleansing rates between in- and outpatients in both colonic segments. In the overall population, independent predictors of inadequate cleansing both at the level of right and left colon were: male gender (odds ratio, 1.20 [1.02–1.43] and 1.27 [1.05–1.53]), diabetes mellitus (odds ratio, 2.35 [1.68–3.29] and 2.12 [1.47–3.05]), chronic constipation (odds ratio, 1.60 [1.30–1.97] and 1.55 [1.23–1.94]), incomplete purge intake (odds ratio, 2.36 [1.90–2.94] and 2.11 [1.68–2.65]) and a runway time >12 h (odds ratio, 3.36 [2.40–4.72] and 2.53 [1.74–3.67]). Conclusions We found no difference in the rate of inadequate bowel preparation between hospitalized patients and outpatients.

Phosphate may promote the onset and progression of chronic nephropathies. Here we evaluated the relationships between baseline serum phosphate levels, disease progression, and response to ACE inhibition in 331 patients with proteinuric nephropathies in the prospective Ramipril Efficacy In Nephropathy (REIN) trial. Independent of treatment, patients with phosphate levels in the highest two quartiles progressed significantly faster either to ESRD or to a composite endpoint of doubling of serum creatinine or ESRD compared with patients with phosphate levels below the median (P < 0.001). Results were similar when we analyzed phosphate as a continuous variable (P ≤ 0.004). The renoprotective effect of ramipril decreased as serum phosphate increased (P ≤ 0.008 for interaction); this modification of the treatment effect by phosphate persisted despite adjusting for potential confounders such as GFR and urinary protein. In summary, these data suggest that phosphate is an independent risk factor for progression of renal disease among patients with proteinuric CKD, and high levels of phosphate may even attenuate the renoprotective effect of ACE inhibitors. Future trials should test whether reducing serum phosphate improves renal outcomes and optimizes the renoprotective effect of ACE inhibition.

Severe intraoperative bleeding is one of the main problems during liver transplantation. Acquired hemostatic defects, namely primary or secondary hyperfibrinolysis, are considered significant pathogenetic events. Antithrombin III (ATIII), the main physiological serine protease inhibitor, has a critical role in the regulation of hemostasis. 29 patients with post necrotic cirrhosis undergoing liver transplantation were randomized to receive or not ATIII replacement therapy before the induction of anaesthesia and thereafter throughout surgery. Activation of both coagulation and fibrinolysis (increase of thrombin-antithrombin complexes, fibrin and fibrinogen degradation products) were demonstrated in both groups. Blood loss and transfusion requirements were not affected by ATIII administration.

Ibuprofen, a chiral non-steroidal anti-inflammatory drug chemically related to fenoprofen and naproxen, has moderate but definite anti-inflammatory, analgesic and antipyretic properties, with considerably less gastrointestinal adverse effect than other drugs in the same family. Currently available in the market are preparations in which bioavailability of ibuprofen is increased by salification with various salts. We have investigated the pharmacological properties of one such salt, ibuprofen-arginine, of biological interest because l-arginine acts as substrate of the nitric oxide (NO) synthesising enzymes. Using epithelial HeLa cells expressing the endothelial NO synthase we show that ibuprofen-arginine releases NO and that this NO protects against the cytotoxic apoptogenic effects of staurosporine. We also found that ibuprofen-arginine is endowed with enhanced anti-inflammatory effects with respect to ibuprofen, as shown by reduced hind paw oedema, neutrophil infiltration and chondrocyte apoptosis in collagen-induced mouse arthritis, a model of chronic inflammation. NO has pleiotropic beneficial effects that may contribute to limit inflammation and anti-inflammatory compounds able to release NO display higher efficacy than the parent drugs in defined clinical settings. Our results open the possibility that NO generation contributes to the enhanced anti-inflammatory effects of ibuprofen-arginine vs. ibuprofen, suggesting co-administration of anti-inflammatory drugs and arginine as an additional way to exploit the beneficial effects of NO.

Previous studies have shown similar effects of rabeprazole and omeprazole, when used at the same dose in the treatment of reflux oesophagitis. However, such studies have been conducted as superiority studies but interpreted as equivalence ones.To properly assess the comparative efficacy of rabeprazole and omeprazole in inducing complete endoscopic healing and symptom relief in patients with reflux oesophagitis.Patients (n=560) with Savary-Miller grade I-III reflux oesophagitis were randomised in a double-blind, double-dummy fashion to rabeprazole or omeprazole 20 mg once daily for 4-8 weeks. Then, patients endoscopically healed and symptomatically relieved were openly maintained with rabeprazole 10 mg or 2x10 mg once daily (in the event of clinical and/or endoscopic relapse) for a maximum of 48 weeks.After 4-8 weeks of treatment, healing (primary end-point) was observed in 228/233 (97.9%) patients in the rabeprazole group and in 231/237 (97.5%) in the omeprazole one (equivalence effect demonstrated by p0.0001 at Blackwelder test and an upper confidence limit at 97.5% of 0.023). However, rabeprazole was faster in inducing heartburn relief than omeprazole (2.8+/-0.2 versus 4.7+/-0.5 days of therapy to reach the first day with satisfactory heartburn relief, p=0.0045 at log-rank test). In the maintenance phase, 15.2% of patients had an endoscopic and/or clinical relapse.Rabeprazole is equivalent to omeprazole in healing reflux oesophagitis, but shows a faster activity on reflux symptoms in the early treatment phase.

During the past few years, the short-term graft survival after kidney transplantation has improved dramatically, a phenomenon not paralleled by an increase in the long-term graft survival. This is due to the progressive renal injury and dysfunction known as chronic transplant nephropathy or 'chronic rejection', a process that involves both immune and non-immune factors. Immunological factors include T- and B-cell recognition of alloantigens, cytomegalovirus infection, and endothelial cell activation followed by vascular smooth cells proliferation. Among nonimmune mechanisms, proteinuria and hypertension play a relevant role. Moreover, the reduced number of functioning nephrons may trigger an inflammatory process that, eventually, contributes to the loss of the graft. Several studies have documented the efficacy of blocking the renin-angiotensin system (RAS) in reducing proteinuria and preventing renal function deterioration in experimental models of chronic rejection. Early results are promising. However, available clinical trials are rather limited in terms of number of patients enrolled, consequently they cannot be considered definitive. Since several pathogenetic factors are involved in the progression of chronic transplant nephropathy, a multidrug approach with specific immunosuppressants and RAS-blocking drugs has been proposed to control/prevent chronic injury and progressive renal deterioration. Preliminary results in experimental models are promising. Data from prospective clinical trials are, however, mandatory to confirm the efficacy of a polypharmacological strategy in preventing chronic rejection.

We investigated in ninety Caucasian pediatric patients the impact of the main polymorphisms occurring in CYP3A, CYP2D6, ABCB1 and ABCG2 genes on second-generation antipsychotics plasma concentrations, and their association with the occurrence of adverse drug reactions. Patients with the CA/AA ABCG2 genotype had a statistically significant lower risperidone plasma concentration/dose ratio (Ct/ds) (P-value: 0.007) and an higher estimated marginal probability of developing metabolism and nutrition disorders as compared to the ABCG2 c.421 non-CA/AA genotypes (P-value: 0.008). Multivariate analysis revealed that the ABCG2 c.421 CA/AA genotype was found associated to a higher hazard (P-value: 0.004) of developing adverse drug reactions classified as metabolism and nutrition disorders. The ABCB1 2677TT/3435TT genotype had a statistically significant lower aripiprazole Ct/ds if compared with patients with others ABCB1 genotypes (P-value: 0.026). Information obtained on ABCB1 and ABCG2 gene variants may result useful to tailor treatments with these drugs in Caucasian pediatric patients.The Pharmacogenomics Journal advance online publication, 18 July 2017; doi:10.1038/tpj.2017.38.

Purpose: Direct oral anticoagulants (DOACs) are recommended in preference to vitamin K antagonists (VKAs) for stroke prevention in patients with atrial fibrillation (AF) eligible for oral anticoagulation therapy; however, data and clinical experiences supporting the use of DOACs in patients with a body mass index ≥40 kg/m2 or weight >120 kg remain limited. The aim of this study was to evaluate the pharmacokinetic properties of DOACs in patients with AF and extreme obesity. Methods: We enrolled all consecutive patients with AF and extreme obesity undergoing treatment with DOACs followed up at Monaldi Hospital, Naples, Italy. To determine peak plasma and trough levels of DOACs, plasma samples were collected at 2nd, 4th, 6th, and 12th hours from the last dose intake in patients receiving apixaban and dabigatran and at the 2nd, 4th, 6th, and 24th hours in those receiving edoxaban and rivaroxaban. The DOACs’ peak and trough plasma levels obtained from our study population were compared with those sourced from pharmacokinetic studies among patients without obesity, defined as a normal reference range in the literature. If at least 1 peak or trough plasma level was found ​​below or above the normal reference ranges, the patients were classified as having out-of-range DOAC plasma levels. Study population was then divided into in-range and out-of-range groups. Baseline characteristics, including DOAC treatment, were compared between the 2 groups. Univariate and multivariate logistic regression analysis were performed to identify baseline variables associated with DOACs’ plasma concentration out of the expected range. Findings: A total of 58 patients (mean [SD] age, 70.93 [8.73] years; 40% female) with extreme obesity (mean [SD] body mass index. 44.43 [3.54] kg/m2) and AF while undergoing DOAC treatment were included in the present study. In 9 patients (15.5 %), the DOAC plasma concentrations were out of the expected ranges (out-of-range group);, indicating a greater likelihood of edoxaban 30 mg treatment (33% vs 2%; P < 0.01) and inappropriate DOAC underdosing (56% vs 4%; P < 0.005) compared with the in-range group. According to the multivariate logistic analysis (P = 0.0011), the inappropriate DOAC underdosing (hazard ratio = 29.37; P = 0.0002) was an independent predictor of DOAC plasma levels out of the expected ranges. Implications: Patients with extreme obesity and AF who were receiving DOAC therapy had DOAC plasma concentrations in the expected range. The inappropriate DOAC underdosing seems to be the only independent clinical factor associated with a plasma concentration of the drug out of the expected range.

BACKGROUND: After ruxolitinib discontinuation, the outcome of patients with myelofibrosis (MF) is poor with scarce therapeutic possibilities. METHODS: The authors performed a subanalysis of an observational, retrospective study (RUX-MF) that included 703 MF patients treated with ruxolitinib to investigate 1) the frequency and reasons for ruxolitinib rechallenge, 2) its therapeutic effects, and 3) its impact on overall survival. RESULTS: A total of 219 patients (31.2%) discontinued ruxolitinib for ≥14 days and survived for ≥30 days. In 60 patients (27.4%), ruxolitinib was rechallenged for ≥14 days (RUX-again patients), whereas 159 patients (72.6%) discontinued it permanently (RUX-stop patients). The baseline characteristics of the 2 cohorts were comparable, but discontinuation due to a lack/loss of spleen response was lower in RUX-again patients (P =.004). In comparison with the disease status at the first ruxolitinib stop, at its restart, there was a significant increase in patients with large splenomegaly (P 10 mg twice daily predicted better spleen (P =.05) and symptom improvements (P =.02), the reasons for/duration of ruxolitinib discontinuation and the use of other therapies before rechallenge were not associated with rechallenge efficacy. At 1 and 2 years, 33.3% and 48.3% of RUX-again patients, respectively, had permanently discontinued ruxolitinib. The median overall survival was 27.9 months, and it was significantly longer for RUX-again patients (P =.004). CONCLUSIONS: Ruxolitinib rechallenge was mainly used in intolerant patients; there were clinical improvements and a possible survival advantage in many cases, but there was a substantial rate of permanent discontinuation. Ruxolitinib rechallenge should be balanced against newer therapeutic possibilities.

Recommendations for dyslipidemia management aimed at reducing arterial occlusive events (AOEs) have been recently published. So far, no data have been reported on the management of dyslipidemia in chronic myeloid leukemia (CML) patients treated with nilotinib. We investigated 369 CML adult patients, stratified according to the new Systematic Coronary Risk Evaluation (SCORE) scoring system. Plasma levels of cholesterol, HDL, LDL, and triglycerides were measured prior to the start of nilotinib and after 3, 6, and 12months. The 5-year cumulative incidence of AOEs was 15.9%. Patients with cholesterol levels > 200mg/dL and LDL > 70mg/dL 3months after treatment showed a significantly higher incidence of AOEs (21.9 ± 4.6% vs 6.2 ± 2.5, P= 0.003). Patients belonging to the high and very high SCORE risk group showed a significant increase of AOEs (34.4 ± 6% vs 10 ± 2.1%, P< 0.001). In multivariate analysis, both high cholesterol and LDL levels and a high and very high SCORE risk remained significantly associated with the risk of AOEs (P= 0.008; HR = 3.5; 95% CI = 1.4–8.7 and P < 0.001; HR = 4.4; 95% CI = 2–9.8, respectively). Overall, 78 patients (21.1%) presented dyslipidemia at the time of CML diagnosis and 88 (23.3%) after starting nilotinib, but only 26 of them (29.5%) were treated with statins. Low LDL and cholesterol plasma levels are associated with a significant lower risk of AOEs in CML patients treated with nilotinib in the real life.

No abstract available

Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) is the standard treatment of diffuse large B-cell lymphoma (DLBCL). Primary DLBCL of the central nervous system (CNS) (primary central nervous system lymphoma [PCNSL]) is an exception because of the low CNS bioavailability of related drugs. NGR–human tumor necrosis factor (NGR-hTNF) targets CD13+ vessels, enhances vascular permeability and CNS access of anticancer drugs, and provides the rationale for the treatment of PCNSL with R-CHOP. Herein, we report activity and safety of R-CHOP preceded by NGR-hTNF in patients with PCNSL relapsed/refractory to high-dose methotrexate-based chemotherapy enrolled in a phase 2 trial. Overall response rate (ORR) was the primary endpoint. A sample size of 28 patients was considered necessary to demonstrate improvement from 30% to 50% ORR. NGR-hTNF/R-CHOP would be declared active if ≥12 responses were recorded. Treatment was well tolerated; there were no cases of unexpected toxicities, dose reductions or interruptions. NGR-hTNF/R-CHOP was active, with confirmed tumor response in 21 patients (75%; 95% confidence interval, 59%-91%), which was complete in 11. Seventeen of the 21 patients with response to treatment received consolidation (ASCT, WBRT, and/or lenalidomide maintenance). At a median follow-up of 21 (range, 14-31) months, 5 patients remained relapse-free and 6 were alive. The activity of NGR-hTNF/R-CHOP is in line with the expression of CD13 in both pericytes and endothelial cells of tumor vessels. High plasma levels of chromogranin A, an NGR-hTNF inhibitor, were associated with proton pump inhibitor use and a lower remission rate, suggesting that these drugs should be avoided during TNF-based therapy. Further research on this innovative approach to CNS lymphomas is warranted. The trial was registered as EudraCT: 2014-001532-11.

Hypertension is a commonly reported comorbidity in patients diagnosed with chronic myeloid leukemia (CML), and its management represents a challenge in patients treated with 2nd- or 3rd-generation tyrosine kinase inhibitors (TKIs), considering their additional cardiovascular (CV) toxicity. The renin angiotensin system (RAS) contributes to hypertension genesis and plays an important role in atherosclerosis development, proliferation, and differentiation of myeloid hematopoietic cells. We analyzed a cohort of 192 patients with hypertension at CML diagnosis, who were treated with 2nd- or 3rd-generation TKIs, and evaluated the efficacy of RAS inhibitors (angiotensin-converting enzyme inhibitors (ACEi) and angiotensin-II receptor blockers (ARBs)) in the prevention of arterial occlusive events (AOEs), as compared with other drug classes. The 5-year cumulative incidence of AOEs was 32.7 ± 4.2%. Patients with SCORE ≥ 5% (high-very-high) showed a significantly higher incidence of AOEs (33.7 ± 7.6% vs 13.6 ± 4.8%, p = 0.006). The AOE incidence was significantly lower in patients treated with RAS inhibitors (14.8 ± 4.2% vs 44 ± 1%, p < 0.001, HR = 0.283). The difference in the low and intermediate Sokal risk group was confirmed but not in the high-risk group, where a lower RAS expression has been reported. Our data suggest that RAS inhibitors may represent an optimal treatment in patients with hypertension and CML, treated with 2nd or 3rdG TKIs.

The impact of ruxolitinib therapy on evolution to blast phase (BP) in patients with myelofibrosis (MF) is still uncertain. In 589 MF patients treated with ruxolitinib, we investigated incidence and risk factors for BP and we described outcome according to disease characteristics and treatment strategy. After a median follow-up from ruxolitinib start of 3 years (range 0.1-7.6), 65 (11%) patients transformed to BP during (93.8%) or after treatment. BP incidence rate was 3.7 per 100 patient-years, comparably in primary and secondary MF (PMF/SMF) but significantly lower in intermediate-1 risk patients (2.3 vs 5.6 per 100 patient-years in intermediate-2/high-risk patients, P

No abstract available.

Not available.

Ruxolitinib (RUX), the first JAK1/JAK2 inhibitor approved for myelofibrosis (MF) therapy, has recently been associated with the occurrence of second primary malignancies (SPMs), mainly lymphomas and non-melanoma skin cancers (NMSCs). We analyzed the incidence, risk factors and outcome of SPMs in 700 MF patients treated with RUX in a real-world context. Median follow-up from starting RUX was 2·9years. Overall, 80 (11·4%) patients developed 87 SPMs after RUX start. NMSCs were the most common SPMs (50·6% of the cases). Multivariate analysis demonstrated that male sex [hazard ratio (HR): 2·37, 95% confidence interval (95%CI): 1·22–4·60, P=0·01] and thrombocytosis>400×109/l at RUX start (HR:1·98, 95%CI: 1·10–4·60, P=0·02) were associated with increased risk for SPMs. Risk factors for NMSC alone were male sex (HR: 3·14, 95%CI: 1·24–7·92, P=0·02) and duration of hydroxycarbamide and RUX therapy>5years (HR: 3·20, 95%CI: 1·17–8·75, P=0·02 and HR: 2·93, 95%CI: 1·39–6·17, P=0·005 respectively). In SPMs excluding NMSCs, male sex (HR: 2·41, 95%CI: 1·11–5·25, P=0·03), platelet>400×109/l (HR: 3·30, 95%CI: 1·67–6·50, P=0·001) and previous arterial thromboses (HR: 3·47, 95%CI: 1·48–8·14, P=0·004) were shown to be associated with higher risk of SPMs. While it is reassuring that no aggressive lymphoma was documented, active skin surveillance is recommended in all patients and particularly after prolonged hydroxycaramide therapy; oncological screening should be triggered by thrombocytosis and arterial thrombosis, particularly in males.

Background Limited information is available regarding the rate of long-term cardiovascular (CV) mortality in chronic myeloid leukaemia (CML) patients treated with second- and third-generation tyrosine kinase inhibitors (2ndG/3rdG TKIs) in the real-life practice. Methods We identified 656 consecutive CML patients treated with nilotinib, dasatinib, bosutinib and ponatinib. Results The 15-year CV-mortality free survival was 93 ± 2.8%. Age ≥65 years (p = 0.005) and a positive history of CV disease (p = 0.04) were significantly associated with a lower CV-mortality free survival. CV disease accounted for 16.5% and 5% of potential years of life lost (PYLL) in male and female patients, respectively. The standard mortality ratio (SMR) following ischemic heart disease (IHD) was 3.9 in males and 3.8 in female patients, meaning an excess of IHD deaths observed, in comparison with the population of control. Conclusion. Prevention strategies based on CV risk factors, in particular in those patients with a previous history of CV disease, should be considered.

Background Risk of death is particularly high in patients with a previous history of arterial occlusive events (AOEs) and the probability for a recurrent event is around 20%. Little is known about recurrent AOE and the role of secondary prevention in patients with Chronic Myeloid Leukemia (CML) with previous AOE, treated with second- and third-generation tyrosine kinase inhibitors (2ndG/3rdG TKIs), nilotinib, dasatinib, bosutinib and ponatinib. Methods We identified a real-life cohort of 57 consecutive adult CML patients treated with 2ndG/3rdG TKI. All patients had a previous history of AOE. Ongoing use of secondary prevention of AOE (including antiplatelet agents, anticoagulant therapy, and statins) before starting a 2ndG/3rdG TKI was recorded, as well as CV risk factors. Results The 60-month cumulative incidence rate of recurrent AOEs was 47.8 ± 10.9%. Despite a history of AOE, 10 patients (16%) were not receiving secondary preventative measures. Patients treated with nilotinib and ponatinib showed a higher incidence of recurrent AOEs (76.7 ± 14.3% and 64 ± 20.1%, respectively) than those treated with dasatinib and bosutinib (44 ± 24.2% and 30.5 ± 15.5%, respectively) (p = 0.01). Only treatment with a 2ndG/3rdG TKI given as second or subsequent line therapy showed a significant association with an increased incidence of recurrent AOE (p = 0.039). Overall, 17 recurrent AOEs were observed; 3 CV-related deaths were reported. Conclusion CML patients with a previous history of AOE treated with 2ndG/3rdG TKI represent a particular patient population with a higher probability of experiencing a recurrent AOE; individualized treatment is needed to optimize secondary prevention.

Arterial occlusive events (AOEs) represent emerging complications in chronic myeloid leukemia (CML) patients treated with ponatinib. We identified 85 consecutive CML adult patients who were treated with ponatinib in 17 Italian centers. Patients were stratified according to the Systematic Coronary Risk Evaluation (SCORE) assessment, based on sex, age, smoking habits, systolic blood pressure, and total cholesterol levels. The 60-month cumulative incidence rate of AOEs excluding hypertension was 25.7%. Hypertension was reported in 14.1% of patients. The median time of exposure to ponatinib was 28months (range, 3-69months). Patients with a high to very high SCORE risk showed a significantly higher incidence rate of AOEs (74.3% vs 15.2%, P&nbsp

Recently, the myelofibrosis secondary to PV and ET prognostic model (MYSEC-PM) was introduced to assess prognosis in myelofibrosis (MF) secondary to polycythemia vera and essential thrombocythemia (post-PV and post-ET MF), replacing the International Prognostic Scoring System (IPSS) and/or Dynamic IPSS (DIPSS) that was applied for primary MF (PMF). In a cohort of 421 ruxolitinib (RUX)-treated patients (post-PV and post-ET MF: 44.2%), we evaluated the following: (1) disease phenotype, responses, and toxicity to RUX; and (2) performance of the MYSEC-PM in post-PV or post-ET ME. While the IPSS failed to correctly stratify post-PV or post-ET MF patients at diagnosis, the MYSEC-PM identified 4 risk categories projected at significantly different survival probability (P < .001). Additionally, the MYSEC-PM maintained a prognostic value in post-PV and post-ET MF also when used over time, at RUX start. Notably, the MYSEC-PM reclassified 41.8% and 13.6% of patients into a lower and higher risk category, respectively. Finally, patients at intermediate-1 risk had significantly higher spleen responses and lower hematological toxicities compared to higher risk patients. Compared to PMF, post-PV and post-ET MF presented a more hyperproliferative disease, with higher leukocyte and/or platelet count and hemoglobin levels both at diagnosis and at RUX start. Despite comparable response rates, post-PV and post-ET MF had lower rate of RUX-induced anemia and thrombocytopenia at 3 and 6 months. The study validates MYSEC-PM in post-PV and post-ET MF prognostication. Post-PV or post-ET MF represents a separate entity compared to PMF in terms of clinical manifestations and toxicity to RUX. (C) 2018 Elsevier Inc. All rights reserved.

Purpose: Available guidelines on therapeutic drug monitoring of second-generation antipsychotics were designed for adults; therefore, they cannot be transferred as such in pediatric patients, who may have different drug absorption, distribution, metabolism, and elimination. Moreover, available tools that guide dosing in neuropsychiatric pediatric patients are scant, leading to the possibility of reduced efficacy and/or increased risks of toxicity. Here we describe the results of observational therapeutic drug monitoring conducted in three pediatric neuropsychiatry units across Italy in 2012-2014, with the following aims: (1) to describe the distribution of plasma concentrations of second-generation antipsychotics in our pediatric patients and (2) to identify clinical covariates associated with plasma drug levels. Methods: Five hundred fifty-six plasma trough concentrations of the second-generation antipsychotics risperidone (plus 9-hydroxy-risperidone), aripiprazole, olanzapine, and quetiapine were measured from 172 pediatric outpatients overall. The distribution of drug concentrations was described and correlated with drug doses and clinical variables. Results: Risperidone plasma levels were lower than in adults (median 13.6 ng/ml), with a high inter-patient (78.9 %) but lower intra-patient (34.2 %) variability. In multiple regression analyses, risperidone plasma levels depended only on drug dose (p < 0.001). Aripiprazole plasma levels were similar to those described in adults (median 165.8 ng/ml) and were widely distributed, with an inter-patient variability of 81.1 %, while the intra-patient variability was much lower (29.3 %). Multiple regression analyses indicated that aripiprazole plasma levels were influenced by the daily doses (p < 0.001) and by the number of concomitant drugs (p < 0.01). Conclusion: Our study described the distribution of plasma levels of SGAs in a real-life setting involving pediatric patients, significantly increasing the amount of available data for this fragile population. If confirmed in larger dataset, these data may contribute to the definition of optimal therapeutic window for risperidone and aripiprazole plasma levels in pediatric patients.

Target organs express antigens directly recognized by antigen-specific T cells, thereby precipitating rejection. When early T-cell activation is inhibited, there is a low risk of rejection. We sought to determine the predictive values of serial posttransplant blood cyclosporine trough (C(0)) concentrations to minimize the risk for a first rejection episode compared with 2-hour postdose (C(2)) drug concentrations. The final aim of the study was to identify a concentration range for the best predictive pharmacokinetic parameter that should be targeted to reduce the risk of rejection. This possibility was explored in 334 de novo kidney transplant recipients who participated in the prospective, multicenter Mycophenolate Steroid-Sparing Trial. Among measurements performed during the first 6 months postsurgery, cyclosporine C(0) levels measured early after transplantation were the strongest predictor of acute graft rejection. Levels within 300 to 440 ng/mL were associated with the lowest risk of rejection, while patients with levels lower than 300 ng/mL showed a more than double risk. Cyclosporine trough values predicted allograft rejection with an accuracy of 74%, while C(2) levels had no predictive value. These findings underline the need to target cyclosporine therapy early posttransplant to modulate T-cell activation.

The purpose of this study was to investigate retrospectively the mRNA expression of genes involved in different DNA repair pathways implicated in processing platinum-induced damage in 171 chemotherapy-naïve ovarian tumours and correlate the expression of the different genes with clinical parameters. The expression of genes involved in DNA repair pathways (PARP1, ERCC1, XPA, XPF, XPG, BRCA1, FANCA, FANCC, FANCD2, FANCF and PolEta), and in DNA damage transduction (Chk1 and Claspin) was measured by RT-PCR in 13 stage I borderline and 77 stage I and 88 III ovarian carcinomas. ERCC1, XPA, XPF and XPG genes were significantly less expressed in stage III than in stage I carcinoma; BRCA1, FANCA, FANCC, FANCD2 gene expressions were low in borderline tumours, higher in stage I carcinomas and lower in stage III samples. High levels of ERCC1, XPA, FANCC, XPG and PolEta correlated with an increase in Overall Survival (OS) and Progression Free Survival (PFS), whilst high BRCA1 levels were associated with PFS on univariate analysis. With multivariate analyses no genes retained an association when adjusted by stage, grade and residual tumour. A tendency towards a better PFS was observed in patients with the highest level of ERCC1 and BRCA1 after platinum-based therapy than those given both platinum and taxol. The expression of DNA repair genes differed in borderline stage I, stage I and stage III ovarian carcinomas. The role of DNA repair genes in predicting the response in ovarian cancer patients seems far from being established.

Background P63 belongs to the 'p53 family' whose role in cancer progression has been recently revisited in light of the plethora of splicing variants that are generated. We analyzed the expression of the full-length TAp63 gene and its dominant-negative form deltaNp63 in ovarian cancer biopsies to correlate their expression with clinical outcome. Materials and methods Real-time RT-PCR analysis was used to determine the levels of TAp63 and deltaNp63 in 83 stage I and in 86 stage III ovarian cancer biopsies and in seven human ovarian cancer cell. Results TAp63 levels were comparable in stage I and stage III, but deltaNp63 levels increased 77-fold in stage III, independently of the p53 status. Patients with high deltaNp63 expression had the worst overall survival (OS); patients with a deltaNp63/TAp63 ratio >2 had a poor OS. Patients with a high deltaNp63/TAp63 ratio were those with a poor response to platinum-based therapy. Conclusions Data indicate a role for deltaNp63 as a potential biomarker to predict patient's outcome and tumor progression in ovarian cancer. This would have particularly clinical relevance in ovarian cancer where the high rate of mortality reflects our lack of knowledge of molecular mechanisms underlying cell progression toward malignancy.