| 1. |
- Berglund, Åke, et al.
(author)
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First-in-human, phase I/IIa clinical study of the peptidase potentiated alkylator melflufen administered every three weeks to patients with advanced solid tumor malignancies
- 2015
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In: Investigational new drugs. - : Springer Science and Business Media LLC. - 0167-6997 .- 1573-0646. ; 33:6, s. 1232-1241
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Journal article (peer-reviewed)abstract
- Purpose Melflufen (melphalan flufenamide, previously designated J1) is an optimized and targeted derivative of melphalan, hydrolyzed by aminopeptidases overexpressed in tumor cells resulting in selective release and trapping of melphalan, and enhanced activity in preclinical models. Methods This was a prospective, single-armed, open-label, first-in-human, dose-finding phase I/IIa study in 45 adult patients with advanced and progressive solid tumors without standard treatment options. Most common tumor types were ovarian carcinoma (n = 20) and non-small-cell lung cancer (NSCLC, n = 11). Results In the dose-escalating phase I part of the study, seven patients were treated with increasing fixed doses of melflufen (25-130 mg) Q3W. In the subsequent phase IIa part, 38 patients received in total 115 cycles of therapy at doses of 30-75 mg. No dose-limiting toxicities (DLTs) were observed at 25 and 50 mg; at higher doses DLTs were reversible neutropenias and thrombocytopenias, particularly evident in heavily pretreated patients, and the recommended phase II dose (RPTD) was set to 50 mg. Response Evaluation Criteria In Solid Tumors (RECIST) evaluation after 3 cycles of therapy (27 patients) showed partial response in one (ovarian cancer), and stable disease in 18 patients. One NSCLC patient received nine cycles of melflufen and progressed after 7 months of therapy. Conclusions In conclusion, melflufen can safely be given to cancer patients, and the toxicity profile was as expected for alkylating agents; RPTD is 50 mg Q3W. Reversible and manageable bone marrow suppression was identified as a DLT. Clinical activity is suggested in ovarian cancer, but modest activity in treatment of refractory NSCLC.
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| 2. |
- Ekmark-Lewén, Sara, et al.
(author)
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Early fine motor impairment and behavioral dysfunction in (Thy-1)-h[A30P] alpha-synuclein mice
- 2018
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In: Brain and Behavior. - : WILEY. - 2162-3279 .- 2162-3279. ; 8:3
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Journal article (peer-reviewed)abstract
- Introduction: Intraneuronal inclusions of alpha-synuclein are commonly found in the brain of patients with Parkinson's disease and other a-synucleinopathies. The correlation between alpha-synuclein pathology and symptoms has been studied in various animal models. In (Thy-1)-h[A30P] alpha-synuclein transgenic mice, behavioral and motor abnormalities were reported from 12 and 15 months, respectively. The aim of this study was to investigate whether these mice also display symptoms at earlier time points.Methods: We analyzed gait deficits, locomotion, and behavioral profiles in (Thy-1)-h[A30P] alpha-synuclein and control mice at 2, 8, and 11 months of age. In addition, inflammatory markers, levels of alpha-synuclein oligomers, and tyrosine hydroxylase reactivity were studied.Results: Already at 2 months of age, transgenic mice displayed fine motor impairments in the challenging beam test that progressively increased up to 11 months of age. At 8 months, transgenic mice showed a decreased general activity with increased risk-taking behavior in the multivariate concentric square field test. Neuropathological analyses of 8- and 11-month-old mice revealed accumulation of oligomeric alpha-synuclein in neuronal cell bodies. In addition, a decreased presence of tyrosine hydroxylase suggests a dysregulation of the dopaminergic system in the transgenic mice, which in turn may explain some of the motor impairments observed in this mouse model.Conclusions: Taken together, our results show that the (Thy-1)-h[A30P] alpha-synuclein transgenic mouse model displays early Parkinson's disease-related symptoms with a concomitant downregulation of the dopaminergic system. Thus, this should be an -appropriate model to study early phenotypes of alpha-synucleinopathies.
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| 3. |
- Geisler, Christian H., et al.
(author)
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Nordic MCL2 trial update : six-year follow-up after intensive immunochemotherapy for untreated mantle cell lymphoma followed by BEAM or BEAC plus autologous stem-cell support: still very long survival but late relapses do occur
- 2012
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In: British Journal of Haematology. - : Wiley. - 0007-1048 .- 1365-2141. ; 158:3, s. 355-362
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Journal article (peer-reviewed)abstract
- Mantle cell lymphoma (MCL) is a heterogenic non-Hodgkin lymphoma entity, with a median survival of about 5 years. In 2008 we reported the early based on the median observation time of 4 years results of the Nordic Lymphoma Group MCL2 study of frontline intensive induction immunochemotherapy and autologous stem cell transplantation (ASCT), with more than 60% event-free survival at 5 years, and no subsequent relapses reported. Here we present an update after a median observation time of 6.5 years. The overall results are still excellent, with median overall survival and response duration longer than 10 years, and a median event-free survival of 7.4 years. However, six patients have now progressed later than 5 years after end of treatment. The international MCL Prognostic Index (MIPI) and Ki-67-expression were the only independent prognostic factors. Subdivided by the MIPI-Biological Index (MIPI + Ki-67, MIPI-B), more than 70% of patients with low-intermediate MIPI-B were alive at 10 years, but only 23% of the patients with high MIPI-B. These results, although highly encouraging regarding the majority of the patients, underline the need of a risk-adapted treatment strategy for MCL.
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| 4. |
- Hetland, M. L., et al.
(author)
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Active conventional treatment and three different biological treatments in early rheumatoid arthritis: phase IV investigator initiated, randomised, observer blinded clinical trial
- 2020
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In: Bmj-British Medical Journal. - : BMJ. - 1756-1833. ; 371
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Journal article (peer-reviewed)abstract
- OBJECTIVE To evaluate and compare benefits and harms of three biological treatments with different modes of action versus active conventional treatment in patients with early rheumatoid arthritis. DESIGN Investigator initiated, randomised, open label, blinded assessor, multiarm, phase IV study. SETTING Twenty nine rheumatology departments in Sweden, Denmark, Norway, Finland, the Netherlands, and Iceland between 2012 and 2018. PARTICIPANTS Patients aged 18 years and older with treatment naive rheumatoid arthritis, symptom duration less than 24 months, moderate to severe disease activity, and rheumatoid factor or anti-citrullinated protein antibody positivity, or increased C reactive protein. INTERVENTIONS Randomised 1:1:1:1, stratified by country, sex, and anti-citrullinated protein antibody status. All participants started methotrexate combined with (a) active conventional treatment (either prednisolone tapered to 5 mg/day, or sulfasalazine combined with hydroxychloroquine and intraarticular corticosteroids), (b) certolizumab pegol, (c) abatacept, or (d) tocilizumab. MAIN OUTCOME MEASURES The primary outcome was adjusted clinical disease activity index remission (CDAI <= 2.8) at 24 weeks with active conventional treatment as the reference. Key secondary outcomes and analyses included CDAI remission at 12 weeks and over time, other remission criteria, a non-inferiority analysis, and harms. RESULTS 812 patients underwent randomisation. The mean age was 54.3 years (standard deviation 14.7) and 68.8% were women. Baseline disease activity score of 28 joints was 5.0 (standard deviation 1.1). Adjusted 24 week CDAI remission rates were 42.7% (95% confidence interval 36.1% to 49.3%) for active conventional treatment, 46.5% (39.9% to 53.1%) for certolizumab pegol, 52.0% (45.5% to 58.6%) for abatacept, and 42.1% (35.3% to 48.8%) for tocilizumab. Corresponding absolute differences were 3.9% (95% confidence interval -5.5% to 13.2%) for certolizumab pegol, 9.4% (0.1% to 18.7%) for abatacept, and -0.6% (-10.1% to 8.9%) for tocilizumab. Key secondary outcomes showed no major differences among the four treatments. Differences in CDAI remission rates for active conventional treatment versus certolizumab pegol and tocilizumab, but not abatacept, remained within the prespecified non-inferiority margin of 15% (per protocol population). The total number of serious adverse events was 13 (percentage of patients who experienced at least one event 5.6%) for active conventional treatment, 20 (8.4%) for certolizumab pegol, 10 (4.9%) for abatacept, and 10 (4.9%) for tocilizumab. Eleven patients treated with abatacept stopped treatment early compared with 20-23 patients in the other arms. CONCLUSIONS All four treatments achieved high remission rates. Higher CDAI remission rate was observed for abatacept versus active conventional treatment, but not for certolizumab pegol or tocilizumab versus active conventional treatment. Other remission rates were similar across treatments. Non-inferiority analysis indicated that active conventional treatment was non-inferior to certolizumab pegol and tocilizumab, but not to abatacept. The results highlight the efficacy and safety of active conventional treatment based on methotrexate combined with corticosteroids, with nominally better results for abatacept, in treatment naive early rheumatoid arthritis.
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| 5. |
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| 6. |
- Lindström, Veronica, et al.
(author)
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Immunotherapy targeting alpha-synuclein, with relevance for future treatment of Parkinson's disease and other Lewy body disorders
- 2014
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In: Immunotherapy. - 1750-743X .- 1750-7448. ; 6:2, s. 141-153
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Research review (peer-reviewed)abstract
- Immunotherapy targeting a-synuclein has evolved as a potential therapeutic strategy for neurodegenerative diseases, such as Parkinson's disease, and initial studies on cellular and animal models have shown promising results. alpha-synuclein vaccination of transgenic mice reduced the number of brain inclusions, whereas passive immunization studies demonstrated that antibodies against the C-terminus of alpha-synuclein can pass the blood-brain barrier and affect the pathology. In addition, preliminary evidence suggests that transgenic mice treated with an antibody directed against alpha-synuclein oligomers/protofibrils resulted in reduced levels of such species in the CNS. The underlying mechanisms of immunotherapy are not yet fully understood, but may include antibody-mediated clearance of pre-existing aggregates, prevention of protein propagation between cells and microglia-dependent protein clearance. Thus, immunotherapy targeting alpha-synuclein holds promise, but needs to be further developed as a future disease-modifying treatment in Parkinson's disease and other alpha-synucleinopathies.
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| 7. |
- Molarius, Anu, et al.
(author)
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Mental health symptoms in relation to socio-economic conditions and lifestyle factors : a population-based study in Sweden
- 2009
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In: BMC Public Health. - : Springer Science and Business Media LLC. - 1471-2458. ; 9, s. 302-
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Journal article (peer-reviewed)abstract
- Background: Poor mental health has large social and economic consequences both for the individual and society. In Sweden, the prevalence of mental health symptoms has increased since the beginning of the 1990s. There is a need for a better understanding of the area for planning preventive activities and health care. Methods: The study is based on a postal survey questionnaire sent to a random sample of men and women aged 18-84 years in 2004. The overall response rate was 64%. The area investigated covers 55 municipalities with about one million inhabitants in central part of Sweden. The study population includes 42,448 respondents. Mental health was measured with self-reported symptoms of anxiety/depression (EQ-5D, 5th question). The association between socio-economic conditions, lifestyle factors and mental health symptoms was investigated using multivariate multinomial logistic regression models. Results: About 40% of women and 30% of men reported that they were moderately or extremely anxious or depressed. Younger subjects reported poorer mental health than older subjects, the best mental health was found at ages 65-74 years. Factors that were strongly and independently related to mental health symptoms were poor social support, experiences of being belittled, employment status (receiving a disability pension and unemployment), economic hardship, critical life events, and functional disability. A strong association was also found between how burdensome domestic work was experienced and anxiety/depression. This was true for both men and women. Educational level was not associated with mental health symptoms. Of lifestyle factors, physical inactivity, underweight and risk consumption of alcohol were independently associated with mental health symptoms. Conclusion: Our results support the notion that a ground for good mental health includes balance in social relations, in domestic work and in employment as well as in personal economy both among men and women. In addition, physical inactivity, underweight and risk consumption of alcohol are associated with mental health symptoms independent of socio-economic factors.
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| 8. |
- Molarius, Anu, et al.
(author)
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Socioeconomic conditions, lifestyle factors, and self-rated health among men and women in Sweden
- 2007
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In: European Journal of Public Health. - : Oxford University Press (OUP). - 1101-1262 .- 1464-360X. ; 17:2, s. 125-133
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Journal article (peer-reviewed)abstract
- Background: Socioeconomic conditions and lifestyle factors have been found to be related to self-rated health, which is an established predictor of morbidity and mortality. Few studies, however, have investigated the independent effect of material and psychosocial conditions as well as lifestyle factors on self-rated health. Methods: The association between socioeconomic conditions, lifestyle factors, and self-rated health was investigated using a postal survey questionnaire sent to a random population sample of men and women aged 18-79 years during March-May 2000. The overall response rate was 65%. The area investigated covers 58 municipalities in the central part of Sweden. Multivariate odds ratios for poor self-rated health were calculated for a range of variables. A total of 36 048 subjects with full data were included in the analysis. Similar analyses of the influence of working conditions were conducted among those employed aged 18-64 years (17 820 subjects). Results: The overall prevalence of poor self-rated health was 7% among men and 9% among women. Poor self-rated health was most common among persons who had been belittled, who had experienced economic hardship, who lacked social support, or who had retired early. A low educational level was independently associated with poor self-rated health among men, but not among women. Physically inactive as well as underweight and obese subjects were more likely to have poor self-rated health than other subjects. Working conditions associated with poor self-rated health were dissatisfaction with work, low job control and worry about losing one's job. Conclusion: While a cross-sectional study does not allow definite conclusions as to which factors are determinants and which are consequences of poor self-rated, the present findings support the notion that both psychosocial and material conditions as well as lifestyle factors are independently related with poor self-rated health.
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