Journal Staff

This thesis describes the development and rationalization of processes involved in a new methodology developed in our group, minor enantiomer recycling. The first part of the thesis addresses mechanistic studies of one of the reactions involved in minor enantiomer recycling, dual Lewis acid-Lewis base catalyzed acetylcyanation of aldehydes. The methodology uses a combination of a chiral titanium-salen  complex with a tertiary amine as a catalytic  system  in  the enantioselective  synthesis  of  O-acylated  cyanohydrins from aldehydes and ketonitriles. Mechanistic investigations revealed that the rate-determining step in the reaction changes, depending on the nature of the aldehyde that was used. It was also concluded that cyanohydrin is coordinated to the Lewis acid in the acylation step. The second part of the thesis deals with minor enantiomer recycling, a highly selective one-pot recycling system. In a first step the product is formed as a minor and a major enantiomer by asymmetric catalysis. Recycling of the minor enantiomer, by selective kinetic resolution, regenerates the starting material. Continuous addition of a second reagent, also involved in a coupled exergonic process, leads to an increase of both yield and enantiomeric excess. Recycling procedures for the synthesis of O-acylated and O-formylated cyanohydrins have been developed with high yield and high enantiomeric excess of the products. The study includes development of the systems, comparison to other methodologies in asymmetric catalysis, and attempts to understand the processes involved.  QC 20141202</p

Прилад для вимірювання розмірів деталей із низькомодульних матеріалів

Background: Enhanced secondary preventive follow-up after stroke or transient ischemic attack (TIA) is necessary for improved adherence to recommendations regarding blood pressure (BP) and low-density lipoprotein cholesterol (LDL-C) levels. We investigated whether nurse-led, telephone-based follow-up was more efficient than usual care at improving BP and LDL-C levels at 12 months after hospital discharge. Methods: We randomized 537 patients to either nurse-led, telephone-based follow-up (intervention) or usual care (control). BP and LDL-C measurements were performed at 1 month (baseline) and 12 months post-discharge. Intervention group patients who did not meet target values at baseline received additional follow-up, including titration of medication and lifestyle counselling, to reach treatment goals (BP &lt; 140/90 mmHg, LDL-C &lt; 2.5 mmol/L). Results: At 12 months, mean systolic BP, diastolic BP and LDL-C was 3.3 (95% CI 0.3 to 6.3) mmHg, 2.3 mmHg (95% CI 0.5 to 4.2) and 0.3 mmol/L (95% CI 0.1 to 0.4) lower in the intervention group compared to controls. Among participants with values above the treatment goal at baseline, the difference in systolic BP and LDL-C was more pronounced (8.0 mmHg, 95% CI 4.0 to 12.1, and 0.6 mmol/L, 95% CI 0.4 to 0.9). A larger proportion of the intervention group reached the treatment goal for systolic BP (68.5 vs. 56.8%, p = 0.008) and LDL-C (69.7% vs. 50.4%, p &lt; 0.001). Conclusions: Nurse-led, telephone-based secondary preventive follow-up, including medication adjustment, was significantly more efficient than usual care at improving BP and LDL-C levels by 12 months post-discharge

Pre-treatment health-related quality of life parameters have prognostic impact in patients >65 years with newly diagnosed mantle cell lymphoma : The Nordic Lymphoma Group MCL4 (LENA-BERIT) experience

Mantle cell lymphoma (MCL) is a rare, often aggressive type of B-cell lymphoma with poor survival and no cure. Cancer and cancer treatment has a negative impact on health-related quality of life (HRQOL) both during active disease and in the long term, and improvement of HRQOL is a crucial objective of cancer therapy in older patients and no curative intent. Baseline HRQOL has in other lymphoma populations been shown to be predictive of outcome. Here, we explored HRQOL, and its association with survival, by the EORTC QLQ-C30 questionnaire, before, during and after chemotherapy in a patient cohort with MCL, treated within the NLG-MCL4 trial, designed to evaluate the addition of lenalidomide (LEN) to rituximab-bendamustine (R-B) as first-line treatment. Fifty-one patients were enrolled, median age was 71 years (range 62-84), 37 were men (73%). Pre-treatment HRQOL was similar to scores from the reference population with healthy individuals. During treatment, HRQOL deteriorated, but reverted to the same level as the reference population after treatment. There was a correlation between physical function (p = 0.001) and role function (p = 0.006) at baseline and WHO performance status, but not with other clinical or genetic prognostic factors. None of the baseline factors were predictive for treatment related to HRQOL in this cohort. Pre-treatment physical (p = 0.011) and role function (p = 0.032) were independent factors associated with overall survival, and physical function (p = 0.002) was also associated with progression free survival. These findings may possibly be used to design support during treatment and improve rehabilitation. Further investigations are needed for assessment of long-term HRQOL.Peer reviewe

Futures of Fixing : Exploring the life of product users in circular economy repair society scenarios

A Circular Economy (CE) constitutes one pathway towards realising sustainable productionand consumption. Here, the repair of broken products (compared to replacement) consti-tutes an important strategy to keep products in the economy for longer, thereby reducingwaste, as well as the need to extract resources and emit pollution in the manufacture of areplacement product. In today’s world, repair does not necessarily constitute the naturalresponse to product breakage. However, increasing legislative efforts and grassroots move-ments are attempting to change that and make repair accessible, affordable and culturallyacceptable. The question is what such a society – where repair is normalised – would be like

Ibrutinib, lenalidomide, and rituximab in relapsed or refractory mantle cell lymphoma (PHILEMON) : a multicentre, open-label, single-arm, phase 2 trial

Background Regimens based on ibrutinib alone and lenalidomide and rituximab in combination show high activity in patients with relapsed or refractory mantle cell lymphoma. We hypothesised that the combination of all three drugs would improve efficacy compared with previously published data on either regimen alone. Methods In this multicentre, open-label, single-arm, phase 2 trial, we enrolled patients aged 18 years or older with relapsed or refractory mantle cell lymphoma who had previously been treated with at least one rituximab-containing regimen, an Eastern Cooperative Oncology Group performance status score of 0-3, and at least one site of measurable disease, and who met criteria for several laboratory-assessed parameters. Treatment was divided into an induction phase of 12 cycles of 28 days with all three drugs and a maintenance phase with ibrutinib and rituximab only (cycle duration 56 days), given until disease progression or unacceptable toxicity. In the induction phase, patients received intravenous (375 mg/m(2)) or subcutaneous (1400 mg) rituximab once a week during cycle 1 and then once every 8 weeks. Oral ibrutinib (560 mg once a day) was given to patients every day in the cycle, whereas oral lenalidomide (15 mg once a day) was given on days 1-21. The primary endpoint was overall response assessed in the intention-totreat population according to Lugano criteria. Safety analysis included all patients who received the treatment, irrespective of eligibility or duration of treatment. The trial is ongoing, but is no longer accruing patients, and is registered with ClinicalTrials. gov, number NCT02460276. Findings Between April 30, 2015, and June 1, 2016, we enrolled 50 patients with relapsed or refractory mantle cell lymphoma at ten centres in Sweden, Finland, Norway, and Denmark. At a median follow-up of 17.8 months (IQR 14.7-20.9), 38 (76%, 95% CI 63-86) patients had an overall response, including 28 (56%, 42-69) patients who had a complete response and ten (20%, 11-33) who had a partial response. The most common grade 3-4 adverse events were neutropenia (in 19 [38%] of 50 patients), infections (in 11 [22%] patients), and cutaneous toxicity (in seven [14%] patients). There were three treatment-related deaths during the study, two due to sepsis and one due to embolic stroke. Interpretation Our results provide preliminary evidence that the triplet combination of ibrutinib, lenalidomide, and rituximab is an active regimen in patients with relapsed or refractory mantle cell lymphoma, and should be evaluated in a prospective randomised controlled trial.Peer reviewe

Molecular Monitoring after Autologous Stem Cell Transplantation and Preemptive Rituximab Treatment of Molecular Relapse; Results from the Nordic Mantle Cell Lymphoma Studies (MCL2 and MCL3) with Median Follow-Up of 8.5 Years

The main objectives of the present study were to monitor minimal residual disease (MRD) in the bone marrow of patients with mantle cell lymphoma (MCL) to predict clinical relapse and guide preemptive treatment with rituximab. Among the patients enrolled in 2 prospective trials by the Nordic Lymphoma Group, 183 who had completed autologous stem cell transplantation (ASCT) and in whom an MRD marker had been obtained were included in our analysis. Fresh samples of bone marrow were analyzed for MRD by a combined standard nested and quantitative real-time PCR assay for Bcl-1/immunoglobulin heavy chain gene (IgH) and clonal IgH rear-rangements. Significantly shorter progression-free survival (PFS) and overall survival (OS) was demonstrated for patients who were MRD positive pre-ASCT (54 patients) or in the first analysis post-ASCT (23 patients). The median PFS was only 20 months in those who were MRD-positive in the first sample post-ASCT, compared with 142 months in the MRD-negative group (PPeer reviewe

miR-18b overexpression identifies mantle cell lymphoma patients with poor outcome and improves the MIPI-B prognosticator

Recent studies show that mantle cell lymphoma (MCL) express aberrant miRNA profiles, however, the clinical effect of miRNA expression has not previously been examined and validated in prospective, large, homogenously treated cohorts. We analyzed diagnostic MCL samples from the Nordic MCL2 and MCL3 clinical trials, in which all patients had received Rituximab-high-dose cytarabin alternating with Rituximab-maxiCHOP, followed by BEAM and autologous stem cell support. We performed genome-wide miRNA microarray profiling of 74 diagnostic MCL samples from the MCL2 trial (screening cohort). Differentially expressed miRNAs were re-analyzed by qRT-PCR. Prognostic miRNAs were validated by qRT-PCR in diagnostic MCL samples from 94 patients of the independent MCL3 trial (validation cohort). Three miRNAs (miR-18b, miR-92a, miR-378d) were significantly differentially expressed in patients who died from MCL in both the screening- and the validation cohort. MiR-18b was superior to miR-92a and miR-378d in predicting high risk. Thus, we generated a new MIPI-B-miR prognosticator, combining expression-levels of miR-18b with MIPI-B data. This prognosticator improved identification of high risk patients compared to MIPI-B with regard to cause-specific survival (P=0.015), overall survival (P=0.006) and progression-free survival (P<0.001). Transfection of two MCL cell lines with miR-18b decreased their proliferation rate without inducing apoptosis, suggesting miR-18b may render MCL cells resistant to chemotherapy by decelerating cell proliferation. Thus, we conclude that overexpression of miR-18b identifies patients with poor prognosis in two large prospective MCL cohorts and adds prognostic information to MIPI-B. MiR-18b may reduce the proliferation rate of MCL cells as a mechanism of chemoresistance