Effect of sterilization irradiation on friction and wear of ultrahigh-molecular-weight polyethylene

The effect of sterilization gamma irradiation on the friction and wear properties of ultrahigh molecular weight polyethylene (UHMWPE) sliding against 316L stainless steel in dry air at 23 C was determined. A pin-on-disk apparatus was used. Experimental conditions included a 1-kilogram load, a 0.061- to 0.27-meter-per-second sliding velocity, and a 32000- to 578000-meter sliding distance. Although sterilization doses of 2.5 and 5.0 megarads greatly altered the average molecular weight and the molecular weight distribution, the friction and wear properties of the polymer were not significantly changed

IgD Multiple Myeloma Paraproteinemia as a Cause of Myositis

A 48-years old man was diagnosed an IgD-k multiple myeloma (MM) at age 38 years for which he successfully underwent chemotherapy and bone marrow transplant. He then developed a graft-versus-host disease (GVHD) whose manifestations included, three years later, a polymyositis, diagnosed at muscle biopsy and successfully treated with steroids. Few months after polymyositis remission, myeloma relapsed and the patient was treated with thalidomide for six years with good remission. Soon after thalidomide suspension, MM relapsed again and the patient came to our observation for a new onset of neuromuscular symptoms. He underwent both muscle and peripheral nerve biopsy to discriminate between myositis (paraproteinemia versus GVHD), amyloidosis, and thalidomide toxicity. The first muscle biopsy showed an inflammatory pattern with necrotic fibres, macrophagical invasion (CD68 positive), rare interstitial cellular infiltrates (CD8 positive and CD4 negative), widespread anti-HLA positivity and negative antiMAC. The second muscle biopsy showed the same inflammatory pattern plus an involvement of blood vessels. Direct immunofluorescence for IgD showed diffuse positivity along the sarcolemmal in both muscle biopsies. Sural nerve biopsy demonstrated both demyelinating and axonal aspects with no inflammatory infiltrates, but positivity for HLA and MAC. Congo Red was negative in both skeletal muscle and peripheral nerve

Iron overload alters the energy metabolism in patients with myelodysplastic syndromes: results from the multicenter FISM BIOFER study

Myelodysplastic syndromes (MDS) are hematological malignancies characterized by ineffective hematopoiesis and increased apoptosis in the bone marrow, which cause peripheral cytopenia. Mitochondria are key regulators of apoptosis and a site of iron accumulation that favors reactive oxygen species (ROS) production with detrimental effects on cell survival. Although the energy metabolism could represent an attractive therapeutic target, it was poorly investigated in MDS. The purpose of the study was to analyze how the presence of myelodysplastic hematopoiesis, iron overload and chelation impact on mitochondrial metabolism. We compared energy balance, OxPhos activity and efficiency, lactic dehydrogenase activity and lipid peroxidation in mononuclear cells (MNCs), isolated from 38 MDS patients and 79 healthy controls. Our data show that ATP/AMP ratio is reduced during aging and even more in MDS due to a decreased OxPhos activity associated with an increment of lipid peroxidation. Moreover, the lactate fermentation enhancement was observed in MDS and elderly subjects, probably as an attempt to restore the energy balance. The biochemical alterations of MNCs from MDS patients have been partially restored by the in vitro iron chelation, while only slight effects were observed in the age-matched control samples. By contrast, the addition of iron chelators on MNCs from young healthy subjects determined a decrement in the OxPhos efficiency and an increment of lactate fermentation and lipid peroxidation. In summary, MDS-MNCs display an altered energy metabolism associated with increased oxidative stress, due to iron accumulation. This condition could be partially restored by iron chelatio

Perspectives and Emotional Experiences of Patients With Chronic Myeloid Leukemia During ENESTPath Clinical Trial and Treatment-Free Remission: Rationale and Protocol of the Italian Substudy

Achievement of deep molecular response following treatment with a tyrosine kinase inhibitor (TKI) allows for treatment-free remission (TFR) in many patients with chronic myeloid leukemia (CML). Successful TFR is defined as the achievement of a sustained molecular response after cessation of ongoing TKI therapy. The phase 3 ENESTPath study was designed to determine the required optimal duration of consolidation treatment with the second-generation TKI, nilotinib 300 mg twice-daily, to remain in successful TFR without relapse after entering TFR for 12 months. The purpose of this Italian ‘patient’s voice CML’ substudy was to evaluate patients’ psycho-emotional characteristics and quality of life through their experiences of stopping treatment with nilotinib and entering TFR. The purpose of the present contribution is to early present the study protocol of an ongoing study to the scientific community, in order to describe the study rationale and to extensively present the study methodology. Patients aged ≥18 years with a confirmed diagnosis of Philadelphia chromosome positive BCR-ABL1+ CML in chronic phase and treated with front-line imatinib for a minimum of 24 months from the enrollment were eligible. Patients consenting to participate the substudy will have quality of life questionnaires and in-depth qualitative interviews conducted. The substudy will include both qualitative and quantitative design aspects to evaluate the psychological outcomes as assessed via patients’ emotional experience during and after stopping nilotinib therapy. Randomization is hypothesized to be a timepoint of higher psychological alert or distress when compared to consolidation and additionally any improvement in health-related quality of life (HRQoL) due to nilotinib treatment is expected across the timepoints (from consolidation, to randomization, and TFR). An association is also expected between dysfunctional coping strategies, such as detachments and certain personality traits, and psychological distress and HRQoL impairments. Better HRQoL outcomes are expected in TFR compared to the end of consolidation. This substudy is designed for in-depth assessment of all potential psycho-emotional variables and aims to determine the need for personalized patient care and counselling, and also guide clinicians to consider the psychological well-being of patients who are considering treatment termination. NCT number: NCT01743989, EudraCT number: 2012-005124-1

The Italian Multicentric Randomized OPTkIMA Trial on Fixed vs Progressive Intermittent TKI Therapy in CML Elderly Patients: 3-Years of Molecular Response and Quality of Life Monitoring After Completing the Treatment Plan

Background: Intermittent treatment with tyrosine kinase inhibitors (TKIs) is an option for elderly chronic myeloid leukemia (CML) patients who are often candidates for life-long treatment. Materials and Methods: The Italian phase III multicentric randomized Optimize TKIs Multiple Approaches (OPTkIMA) study aimed to evaluate if a progressive de-escalation of TKIs is able to maintain the molecular remission (MR)3.0 and to improve Health-Related Quality of Life (HRQoL) in CML elderly patients. Results: A total of 215 patients in stable MR3.0/MR4.0 were randomized to receive an intermittent TKI schedule 1 month ON-1 month OFF for 3 years (FIXED arm; n = 111) vs. a progressive de-escalation TKI dose up to one-third of the starting dose at the 3rd year (PROGRESSIVE arm; n = 104). Two hundred three patients completed the 3rd year of OPTkIMA study. At the last follow-up, MR3.0 loss was 27% vs. 46% (P =.005) in the FIXED vs PROGRESSIVE arm, respectively. None of these patients experienced disease progression. The 3-year probability of maintaining the MR3.0 was 59% vs. 53%, respectively (P =.13). HRQoL globally improved from the baseline to the 3rd year, without any significant difference between the 2 arms. After the 3rd year, the proportion of patients who was address to TKI discontinuation in the 2 arms was 36% (FIXED) vs. 58% (PROGRESSIVE) (P =.03). Conclusions: The intensification of intermittent TKI therapy is associated with a higher incidence of MR3.0 loss, but those patients who maintain the MR3.0 molecular response at the end of the study have been frequently considered eligible for TFR. The HRQoL generally improved during the de-escalation therapy in both randomization arms

Predictors of Response to Hydroxyurea and Switch to Ruxolitinib in HU-Resistant Polycythaemia VERA Patients: A Real-World PV-NET Study

: In polycythemia vera (PV), the prognostic relevance of an ELN-defined complete response (CR) to hydroxyurea (HU), the predictors of response, and patients' triggers for switching to ruxolitinib are uncertain. In a real-world analysis, we evaluated the predictors of response, their impact on the clinical outcomes of CR to HU, and the correlations between partial or no response (PR/NR) and a patient switching to ruxolitinib. Among 563 PV patients receiving HU for ≥12 months, 166 (29.5%) achieved CR, 264 achieved PR, and 133 achieved NR. In a multivariate analysis, the absence of splenomegaly (p = 0.03), pruritus (p = 0.002), and a median HU dose of ≥1 g/day (p < 0.001) remained associated with CR. Adverse events were more frequent with a median HU dose of ≥1 g/day. Overall, 283 PR/NR patients (71.3%) continued HU, and 114 switched to ruxolitinib. In the 449 patients receiving only HU, rates of thrombosis, hemorrhages, progression, and overall survival were comparable among the CR, PR, and NR groups. Many PV patients received underdosed HU, leading to lower CR and toxicity rates. In addition, many patients continued HU despite a PR/NR; however, splenomegaly and other symptoms were the main drivers of an early switch. Better HU management, standardization of the criteria for and timing of responses to HU, and adequate intervention in poor responders should be advised

Molecular response and quality of life in chronic myeloid leukemia patients treated with intermittent TKIs: First interim analysis of OPTkIMA study

31noBackground: Intermittent treatment with TKIs is an option for the great majority (70%–80%) of CML patients who do not achieve a stable deep molecular response and are not eligible for treatment discontinuation. For these patients, the only alternative is to assume TKI continuously, lifelong. Methods: The Italian phase III multicentric randomized OPTkIMA study started in 2015, with the aim to evaluate if a progressive de-escalation of TKIs (imatinib, nilotinib, and dasatinib) is able to maintain the molecular response (MR3.0) and to improve Health Related Quality of Life (HRQoL). Results: Up to December 2018, 166/185 (90%) elderly CML patients in stable MR3.0/MR4.0 completed the first year of any TKI intermittent schedule 1 month ON and 1 month OFF. The first year probability of maintaining the MR3.0 was 81% and 23.5% of the patients who lost the molecular response regained the MR3.0 after resuming TKI continuously. Patients’ HRQoL at baseline was better than that of matched peers from healthy population. Women was the only factor independently associated with worse baseline HRQoL (p > 0.0001). Overall, global HRQoL worsened at 6 (p < 0.001) but returned to the baseline value at 12 months and it was statistically significantly worse in women (p = 0.001). Conclusions: De-escalation of any TKI by 1 month ON/OFF schedule maintains the MR3.0/MR4.0 in 81% of the patients during the first 12–24 months. No patients progressed to accelerated/blastic phase, all the patients (23.5%) losing MR3.0 regained the MR3.0 and none suffered from TKI withdrawn syndrome. The study firstly report on HRQoL in elderly CML patients moving from a continuous daily therapy to a de-escalated intermittent treatment.openopenMalagola M.; Iurlo A.; Abruzzese E.; Bonifacio M.; Stagno F.; Binotto G.; D'Adda M.; Lunghi M.; Crugnola M.; Ferrari M.L.; Lunghi F.; Castagnetti F.; Rosti G.; Lemoli R.M.; Sancetta R.; Coppi M.R.; Corsetti M.T.; Rege Cambrin G.; Romano A.; Tiribelli M.; Russo Rossi A.; Russo S.; Aprile L.; Gandolfi L.; Farina M.; Bernardi S.; Polverelli N.; Roccaro A.M.; De Vivo A.; Baccarani M.; Russo D.Malagola, M.; Iurlo, A.; Abruzzese, E.; Bonifacio, M.; Stagno, F.; Binotto, G.; D'Adda, M.; Lunghi, M.; Crugnola, M.; Ferrari, M. L.; Lunghi, F.; Castagnetti, F.; Rosti, G.; Lemoli, R. M.; Sancetta, R.; Coppi, M. R.; Corsetti, M. T.; Rege Cambrin, G.; Romano, A.; Tiribelli, M.; Russo Rossi, A.; Russo, S.; Aprile, L.; Gandolfi, L.; Farina, M.; Bernardi, S.; Polverelli, N.; Roccaro, A. M.; De Vivo, A.; Baccarani, M.; Russo, D

Life after ruxolitinib: Reasons for discontinuation, impact of disease phase, and outcomes in 218 patients with myelofibrosis

Background: After discontinuing ruxolitinib, the outcome of patients with myelofibrosis reportedly has been poor. The authors investigated whether disease characteristics before the receipt of ruxolitinib may predict drug discontinuation in patients with myelofibrosis and whether reasons for drug discontinuation, disease phase at discontinuation, and salvage therapies may influence the outcome. Methods: A centralized electronic clinical database was created in 20 European hematology centers, including clinical and laboratory data for 524 patients who received ruxolitinib for myelofibrosis. Results: At 3\ua0years, 40.8% of patients had stopped ruxolitinib. Baseline predictors of drug discontinuation were: intermediate-2\u2013risk/high-risk category (Dynamic International Prognostic Score System), a platelet count <100 7109 per liter, transfusion dependency, and unfavorable karyotype. At last contact, 268 patients (51.1%) had discontinued therapy, and the median drug exposure was 17.5\ua0months. Fifty patients (18.7%) died while taking ruxolitinib. The reasons for discontinuation in the remaining 218 patients were the lack (22.9%) or loss (11.9%) of a spleen response, ruxolitinib-related adverse events (27.5%), progression to blast phase (23.4%), ruxolitinib-unrelated adverse events (9.2%), and allogeneic transplantation during response (5.1%). The median survival after ruxolitinib was 13.2\ua0months and was significantly better in the 167 patients who discontinued ruxolitinib in chronic phase (27.5 vs 3.9\ua0months for those who discontinued in blast phase; P\ua0<.001). No survival differences were observed among patients who discontinued ruxolitinib in chronic phase because of lack of response, loss of response, or ruxolitinib-related adverse events. The use of investigational agents and/or ruxolitinib rechallenge were associated with improved outcome. Conclusions: The survival of patients with myelofibrosis after discontinuation of ruxolitinib is poor, particularly for those who discontinue in blast phase. Salvage therapies can improve outcome, emphasizing the need for novel therapies

Ruxolitinib discontinuation syndrome: incidence, risk factors, and management in 251 patients with myelofibrosis

none36Ruxolitinib discontinuation syndrome: incidence, risk factors, and management in 251 patients with myelofibrosisopenPalandri F.; Palumbo G.A.; Elli E.M.; Polverelli N.; Benevolo G.; Martino B.; Abruzzese E.; Tiribelli M.; Tieghi A.; Latagliata R.; Cavazzini F.; Bergamaschi M.; Binotto G.; Crugnola M.; Isidori A.; Caocci G.; Heidel F.; Pugliese N.; Bosi C.; Bartoletti D.; Auteri G.; Cattaneo D.; Scaffidi L.; Trawinska M.M.; Stella R.; Ciantia F.; Pane F.; Cuneo A.; Krampera M.; Semenzato G.; Lemoli R.M.; Iurlo A.; Vianelli N.; Cavo M.; Breccia M.; Bonifacio M.Palandri, F.; Palumbo, G. A.; Elli, E. M.; Polverelli, N.; Benevolo, G.; Martino, B.; Abruzzese, E.; Tiribelli, M.; Tieghi, A.; Latagliata, R.; Cavazzini, F.; Bergamaschi, M.; Binotto, G.; Crugnola, M.; Isidori, A.; Caocci, G.; Heidel, F.; Pugliese, N.; Bosi, C.; Bartoletti, D.; Auteri, G.; Cattaneo, D.; Scaffidi, L.; Trawinska, M. M.; Stella, R.; Ciantia, F.; Pane, F.; Cuneo, A.; Krampera, M.; Semenzato, G.; Lemoli, R. M.; Iurlo, A.; Vianelli, N.; Cavo, M.; Breccia, M.; Bonifacio, M