Adherence to and effectiveness of lenalidomide after 1 year of treatment in a real world setting

Background: In combination with dexamethasone, lenalidomide is prescribed in the oral treatment of Multiple Myeloma for patients who have received at least one previous therapy. Objective: The objective of this study is to evaluate medication adherence to lenalidomide of Multiple Myeloma patients, as well as Progression Free Survival and Overall Survival one year from the beginning of the treatment. Setting: The study was carried out in Pescara Hospital, in Italy. All Multiple Myeloma patients who began lenalidomide therapy between January 1, 2012 and June 30, 2016 were included in our study. Methods: Adherence to treatment was calculated by using the ratio between the Received Daily Dose and the Prescribed Daily Dose. Effectiveness in real world has been evaluated as Progression Free Survival and Overall Survival one year from the beginning of the treatment.Main outcomes measure: We assessed medication adherence and effectiveness of lenalidomide in the treatment of Multiple Myeloma. Results: Adherence to the overall mean treatment was 0.73 ± 0.15, relative to 81 patients evaluated in our study. 32% of patients achieved an adherence equal to or greater than 80%. Real-life effectiveness in terms of Progression Free Survival and Overall Survival showed values of ​​53.75% and 88%, respectively, one year from the beginning of treatment. Conclusion: The analysis of adherence in Multiple Myeloma patients treated with lenalidomide one year from the beginning of therapy reveal a concerning lack of adherence. Moreover, the lack of correlation of the levels of adherence with patient-related variables shows that, in the case of Multiple Myeloma, adherence is not related to personal, social and environmental characteristics that may determine each patient's correct treatment implementation, but is directly influenced by disease evolution

TET2 mutations in Ph-negative myeloproliferative neoplasms: identification of three novel mutations and relationship with clinical and laboratory findings

High-throughput DNA sequence analysis was used to screen for TET2 mutations in peripheral blood derived DNA from 97 patients with BCR-ABL-negative myeloproliferative neoplasms (MPNs). Overall six mutations in the coding region of the gene were identified in 7 patients with an overall mutational frequency of 7.2%. In polycythemia vera patients (n = 25) 2 mutations were identified (8%), and in those with essential thrombocythemia (n = 55) 2 mutations (3.6%); in those with unclassifiable MPN (n = 8) 3 mutations (37.5%). No primary myelofibrosis patients (n = 6) harboured TET2 mutations. Three unreported mutations were identified (p.P177fs, p.C1298del, and p.P411del), the first two in patients with unclassifiable MPN, the last in a patient with essential thrombocythemia. On multivariate analysis the diagnosis of an unclassifiable MPN was significantly related to the presence of TET2 mutations (P = 0.02; OR: 2.81; 95% CI 1.11-7.06). We conclude that TET2 mutations occur in both JAK2 V617F-positive and -negative MPNs and are more frequent in MPN-U patients. This could represent the biological link between the different classes of myeloid malignancies

Globigerinoides ruber, Globigerina bulloides and MAT derived paleotemperatures for the lasts 772 kyr from cores GL-852 and GL-854 (Santos Basin, Southwest Atlantic)

Expansions of coastal upwelling spots along the Brazilian coast were previously reported for Marine Isotope Stage (MIS) 5, but open questions remain regarding the climatic mechanisms and the periodicity of such changes. Based on two marine sediment cores, we provide evidence for multiple intensifications of the upwelling regime off the Southeast Brazilian margin (SBM) during several interglacials and highlight the major role of eccentricity as the responsible forcing. In addition, we show a two-step change in the upwelling regime across the Mid-Brunhes Event (MBE) and an increase in the amplitude of upwelling variability after this climatic transition. Our findings point to substantial modifications of the upwelling regions during several glacial-interglacial transitions that probably altered the regional marine productivity regime and the carbon budget

Bortezomib with thalidomide plus dexamethasone compared with thalidomide plus dexamethasone as induction therapy before, and consolidation therapy after, double autologous stem-cell transplantation in newly diagnosed multiple myeloma: A randomised phase 3 study

Background Thalidomide plus dexamethasone (TD) is a standard induction therapy for myeloma. We aimed to assess the efficacy and safety of addition of bortezomib to TD (VTD) versus TD alone as induction therapy before, and consolidation therapy after, double autologous stem-cell transplantation in newly diagnosed multiple myeloma. Methods Patients (aged 18-65 years) with previously untreated symptomatic myeloma were enrolled from 73 sites in Italy between May, 2006, and April, 2008, and data collection continued until June 30, 2010. Patients were randomly allocated (1:1 ratio) by a web-based system to receive three 21-day cycles of thalidomide (100 mg daily for the first 14 days and 200 mg daily thereafter) plus dexamethasone (40 mg daily on 8 of the first 12 days, but not consecutively; total of 320 mg per cycle), either alone or with bortezomib (1•3 mg/m2 on days 1, 4, 8, and 11). The randomisation sequence was computer generated by the study coordinating team and was stratified by disease stage. After double autologous stem-cell transplantation, patients received two 35-day cycles of their assigned drug regimen, VTD or TD, as consolidation therapy. The primary endpoint was the rate of complete or near complete response to induction therapy. Analysis was by intention to treat. Patients and treating physicians were not masked to treatment allocation. This study is still underway but is not recruiting participants, and is registered with ClinicalTrials.gov, number NCT01134484, and with EudraCT, number 2005-003723-39. Findings 480 patients were enrolled and randomly assigned to receive VTD (n=241 patients) or TD (n=239). Six patients withdrew consent before start of treatment, and 236 on VTD and 238 on TD were included in the intentionto- treat analysis. After induction therapy, complete or near complete response was achieved in 73 patients (31%, 95% CI 25•0-36•8) receiving VTD, and 27 (11%, 7•3-15•4) on TD (p<0•0001). Grade 3 or 4 adverse events were recorded in a significantly higher number of patients on VTD (n=132, 56%) than in those on TD (n=79, 33%; p<0•0001), with a higher occurrence of peripheral neuropathy in patients on VTD (n=23, 10%) than in those on TD (n=5, 2%; p=0•0004). Resolution or improvement of severe peripheral neuropathy was recorded in 18 of 23 patients on VTD, and in three of five patients on TD. Interpretation VTD induction therapy before double autologous stem-cell transplantation significantly improves rate of complete or near complete response, and represents a new standard of care for patients with multiple myeloma who are eligible for transplant. Funding Seràgnoli Institute of Haematology at the University of Bologna, Bologna, Italy. © 2010 Elsevier Ltd

A high-temporal multiproxy study of sediment core GL1090

Paleoceanographic reconstructions from the Brazil Current are scarce and lack the required temporal resolution to appropriately represent its variability during key periods of the last glacial-interglacial cycles. Here, we present the first high-temporal resolution multiproxy reconstruction of the Brazil Current at 24 °S covering the last 185 ka. During the last and penultimate glacial periods, our Mg/Ca-derived sea surface temperature (SST) record shows a strong cooling at ca. 47 and ca. 156 ka, respectively, that is followed by a warming trend from late-Marine Isotope Stage (MIS) 3 to MIS 1 and from late-MIS 6 to MIS5e, respectively. Importantly, the Brazil Current warmed uninterruptedly towards Termination I (II) after the low SST at ca. 47 and ca. 156 ka, with no SST minima during the Last Glacial Maximum or penultimate glacial maximum. The reason for the strong cooling and the warming trend during late-MIS 3 and late-MIS 6 could reside in the favorable obliquity configuration. However, this mechanism is not sufficient to sustain the warming observed for the rest of the last and penultimate glacial periods. We propose that the change in the Atlantic meridional overturning circulation (AMOC), as described in the literature, from a 'warm' to a 'cold mode' for MIS 2 and MIS 6 is responsible for the accumulation of warm waters in the subtropical western South Atlantic, preventing SST minima during the last and penultimate glacial maxima in the region. Change in benthic d13C corroborates that a fundamental modification in the AMOC mode might have triggered the heat accumulation. Our data also show a sudden increase in SST and surface salinity during the last glacial descent (MIS 4), indicating that the western portion of the subtropical gyres may have acted as a heat and salt reservoir, while higher latitude climates transited to a glacial background. Our findings imply that the AMOC 'cold mode' induces heat storage in the subtropical western South Atlantic and, because of that, the last two regional SST minima occurred out-of-phase with the glacial maxima of higher latitudes