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| 2. |
- Berglund, Åke, et al.
(författare)
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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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Ingår i: Investigational new drugs. - : Springer Science and Business Media LLC. - 0167-6997 .- 1573-0646. ; 33:6, s. 1232-1241
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Tidskriftsartikel (refereegranskat)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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| 3. |
- Carlier, Charlotte, et al.
(författare)
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Preclinical activity of melflufen (J1) in ovarian cancer
- 2016
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Ingår i: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 7:37, s. 59322-59335
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Tidskriftsartikel (refereegranskat)abstract
- Ovarian cancer carries a significant mortality. Since symptoms tend to be minimal, the disease is often diagnosed when peritoneal metastases are already present. The standard of care in advanced ovarian cancer consists of platinum-based chemotherapy combined with cytoreductive surgery. Unfortunately, even after optimal cytoreduction and adjuvant chemotherapy, most patients with stage III disease will develop a recurrence. Intraperitoneal administration of chemotherapy is an alternative treatment for patients with localized disease. The pharmacological and physiochemical properties of melflufen, a peptidase potentiated alkylator, raised the hypothesis that this drug could be useful in ovarian cancer and particularily against peritoneal carcinomatosis. In this study the preclinical effects of melflufen were investigated in different ovarian cancer models. Melflufen was active against ovarian cancer cell lines, primary cultures of patient-derived ovarian cancer cells, and inhibited the growth of subcutaneous A2780 ovarian cancer xenografts alone and when combined with gemcitabine or liposomal doxorubicin when administered intravenously. In addition, an intra-and subperitoneal xenograft model showed activity of intraperitoneal administered melflufen for peritoneal carcinomatosis, with minimal side effects and modest systemic exposure. In conclusion, results from this study support further investigations of melflufen for the treatment of peritoneal carcinomatosis from ovarian cancer, both for intravenous and intraperitoneal administration.
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- Edelstam, Greta, et al.
(författare)
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Optimised gynaecological examination with a new pelvic examination chair
- 2019
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Ingår i: Sexual & Reproductive HealthCare. - : Elsevier BV. - 1877-5756 .- 1877-5764. ; 19, s. 84-87
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Tidskriftsartikel (refereegranskat)abstract
- Objective: The present aim was to contribute to improving the traditional pelvic examination chair with vertical leg support and to evaluate patients' and examiners' experience of a new gyneacological and urological examination chair with heated upholstery.Study design: A new gynaecological and urological examination chair was constructed with laterally adjustable leg support, a foot-plate and the perineum exposed only during the examination procedure. Patients (n = 131) with or without endometriosis were invited to participate in an anonymous questionnaire survey concerning how they experienced a gynaecological examination.Main outcome measures: The patients and the gynaecologists who performed the examinations answered questionnaires evaluating the examination procedure in the traditional and in the new gynaecological and urological examination chair, respectively. The questionnaires asked about comfort, heating, integrity and the experience of pelvic examination with vertical or lateral leg support. The examination times were measured with a stopwatch.Results: The majority of the answers (n = 131) were significantly (p < 0.05-0.001) in favour of the new concept with lateral leg support and with increased comfort and integrity. The average examination time was significantly shortened and the patients more relaxed in the new gynaecological and urological examination chair.Conclusion: The traditional gynaecological chair with vertical leg support has remained basically unchanged for many years. The present study showed that the pelvic examination procedure can be significantly optimized with easy patient-friendly adaptations.
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| 5. |
- Edelstam, Greta, et al.
(författare)
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Pertubation with lidocaine - a non-hormonal, long-term treatment of dysmenorrhea due to endometriosis
- 2012
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Ingår i: Sexual & Reproductive HealthCare. - : Elsevier. - 1877-5756 .- 1877-5764. ; 3:2, s. 93-94
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Tidskriftsartikel (refereegranskat)abstract
- The major symptoms of endometriosis are dysmenorrhea and infertility. Pertubations with lidocaine have been shown to reduce dysmenorrhea and have an enhancing effect on fertility. Different concentrations of lidocaine were evaluated in a randomized, double-blind study of pre-ovulatory pertubations with lidocaine solutions in women with dysmenorrhea. The patients had laparoscopically diagnosed endometriosis and normal fallopian tubes. Ninety pertubations were carried out without complications on 26 patients during up to six cycles. The effect was evaluated by means of questionnaires where a clinically significant reduction of dysmenorrhea was reported. Pertubation with lidocaine can be a non-hormonal treatment option for dysmenorrhea. (C) 2012 Elsevier B.V. All rights reserved.
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| 6. |
- Johansson, Dongni, 1988, et al.
(författare)
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Individualization of levodopa treatment using a microtablet dispenser and ambulatory accelerometry
- 2018
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Ingår i: CNS Neuroscience & Therapeutics. - : Wiley. - 1755-5930 .- 1755-5949. ; 24:5, s. 439-447
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Tidskriftsartikel (refereegranskat)abstract
- Aim: This 4-week open-label observational study describes the effect of introducing a microtablet dose dispenser and adjusting doses based on objective free-living motor symptom monitoring in individuals with Parkinson's disease (PD). Methods: Twenty-eight outpatients with PD on stable levodopa treatment with dose intervals of ≤4 hour had their daytime doses of levodopa replaced with levodopa/carbidopa microtablets, 5/1.25 mg (LC-5) delivered from a dose dispenser device with programmable reminders. After 2 weeks, doses were adjusted based on ambulatory accelerometry and clinical monitoring. Results: Twenty-four participants completed the study per protocol. The daily levodopa dose was increased by 15% (112 mg, P < 0.001) from period 1 to 2, and the dose interval was reduced by 12% (22 minutes, P = 0.003). The treatment adherence to LC-5 was high in both periods. The MDS-UPDRS parts II and III, disease-specific quality of life (PDQ-8), wearing-off symptoms (WOQ-19), and nonmotor symptoms (NMS Quest) improved after dose titration, but the generic quality-of-life measure EQ-5D-5L did not. Blinded expert evaluation of accelerometry results demonstrated improvement in 60% of subjects and worsening in 25%. Conclusions: The introduction of a levodopa microtablet dispenser and accelerometry aided dose adjustments improve PD symptoms and quality of life in the short term.
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| 7. |
- Lu, Yingchang, et al.
(författare)
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New loci for body fat percentage reveal link between adiposity and cardiometabolic disease risk
- 2016
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- To increase our understanding of the genetic basis of adiposity and its links to cardiometabolic disease risk, we conducted a genome-wide association meta-analysis of body fat percentage (BF%) in up to 100,716 individuals. Twelve loci reached genome-wide significance (P<5 × 10(-8)), of which eight were previously associated with increased overall adiposity (BMI, BF%) and four (in or near COBLL1/GRB14, IGF2BP1, PLA2G6, CRTC1) were novel associations with BF%. Seven loci showed a larger effect on BF% than on BMI, suggestive of a primary association with adiposity, while five loci showed larger effects on BMI than on BF%, suggesting association with both fat and lean mass. In particular, the loci more strongly associated with BF% showed distinct cross-phenotype association signatures with a range of cardiometabolic traits revealing new insights in the link between adiposity and disease risk.
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| 10. |
- Memedi, Mevludin, 1983-, et al.
(författare)
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Construction of levodopa-response index from wearable sensors for quantifying Parkinson's disease motor functions
- 2016
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- The goal of this study was to investigate the feasibility of wrist worn motion sensors to objectively measure motor functions in Parkinson’s disease (PD). More specifically, the aim was to construct a sensor-based levodopa-response index (SBLRI) and evaluate its clinimetric properties (convergent validity and internal consistency). Nineteen advanced PD patients and 22 healthy controls were recruited in a single center, open label, single dose clinical trial in Sweden. The subjects performed standardized motor tasks while wearing one sensor on each wrist and one on each ankle. Each sensor unit consisted of three-dimensional accelerometer and gyroscope. The patients were video recorded and the videos were blindly rated by three independent movement disorder specialists. The clinical scores were given using the Treatment Response Scale (TRS) on a scale from -3 = ‘Very Off’ to 0 = ‘On’ to +3 = ‘Very dyskinetic’. The clinical assessments were based on the overall motor function of the patients. A mean TRS was defined as the mean of the three specialists’ assessments per time point. The measurements were repeated over several time points following a single levodopa/carbidopa morning dose (50% over normal to induce dyskinesias). Sensor measurements during rapid alternating movements of hands were processed with time series analysis methods to calculate spatiotemporal parameters designed to measure bradykinesia and dyskinesia. For each hand, 96 spatiotemporal parameters were calculated and their average scores were then used in a principal component analysis to reduce the dimensionality by retaining 6 principal components. These components were then used as predictors to support vector machines and to be mapped to the mean TRS ratings of the three specialists and to calculate the SBLRI. For this analysis, a 10-fold stratified cross-validation was performed. The SBLRI was strongly correlated to mean TRS with a Pearson correlation coefficient of 0.79 (CI: 0.74-0.83, p<0.001). The 95% confidence interval for the mean squared error of SBLRI on patients data was ± 1.62 with a mean value of 0.57 whereas on healthy controls data was ± 1 with a mean value of 0.27. The sensor-based spatiotemporal parameters had good internal consistency with a Cronbach’s Alpha coefficient of 0.87 and significantly differed between patients and healthy controls. The results demonstrated that the SBLRI had good clinimetric properties for measuring motor functions (Off and dyskinesia) in PD patients. The method could also distinguish hand rotation movements exhibited by patients from those exhibited by healthy controls. The SBLRI provides effect-time profiles, which could be useful during therapy individualization of advanced PD patients.
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