| 1. |
- Borch, Troels Holz, et al.
(författare)
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Clinical efficacy of T-cell therapy after short-term BRAF-inhibitor priming in patients with checkpoint inhibitor-resistant metastatic melanoma
- 2021
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Ingår i: Journal for ImmunoTherapy of Cancer. - : BMJ. - 2051-1426. ; 9:7
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: Despite impressive response rates following adoptive transfer of autologous tumor-infiltrating lymphocytes (TILs) in patients with metastatic melanoma, improvement is needed to increase the efficacy and broaden the applicability of this treatment. We evaluated the use of vemurafenib, a small-molecule BRAF inhibitor with immunomodulatory properties, as priming before TIL harvest and adoptive T cell therapy in a phase I/II clinical trial. METHODS: 12 patients were treated with vemurafenib for 7 days before tumor excision and during the following weeks until TIL infusion. TILs were grown from tumor fragments, expanded in vitro and reinfused to the patient preceded by a lymphodepleting chemotherapy regimen and followed by interleukin-2 infusion. Extensive immune monitoring, tumor profiling and T cell receptor sequencing were performed. RESULTS: No unexpected toxicity was observed, and treatment was well tolerated. Of 12 patients, 1 achieved a complete response, 8 achieved partial response and 3 achieved stable disease. A PR and the CR are ongoing for 23 and 43 months, respectively. In vitro anti-tumor reactivity was found in TILs from 10 patients, including all patients achieving objective response. Serum and tumor biomarker analyses indicate that baseline cytokine levels and the number of T cell clones may predict response to TIL therapy. Further, TCR sequencing suggested skewing of TCR repertoire during in vitro expansion, promoting certain low frequency clonotypes. CONCLUSIONS: Priming with vemurafenib before infusion of TILs was safe and feasible, and induced objective clinical responses in this cohort of patients with checkpoint inhibitor-resistant metastatic melanoma. In this trial, vemurafenib treatment seemed to decrease attrition and could be considered to bridge the waiting time while TILs are prepared.
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| 2. |
- Kjaer, Per, et al.
(författare)
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GLA:D-(R) Back group-based patient education integrated with exercises to support self-management of back pain- development, theories and scientific evidence-
- 2018
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Ingår i: BMC Musculoskeletal Disorders. - : BMC. - 1471-2474. ; 19
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundClinical guidelines recommend that people with back pain be given information and education about their back pain, advice to remain active and at work, and exercises to improve mobility and physical activity. Guidelines, however, rarely describe how this is best delivered. The aim of this paper is to present the development, theories, and underlying evidence for GLA:D Back - a group education and exercise program that translates guideline recommendations into a clinician-delivered program for the promotion of self-management in people with persistent/recurrent back pain.MethodsGLA:D Back, which included a rationale and objectives for the program, theory and evidence for the interventions, and program materials, was developed using an iterative process. The content of patient education and exercise programs tested in randomised trials was extracted and a multidisciplinary team of expert researchers and clinicians prioritised common elements hypothesised to improve back pain beliefs and management skills. The program was tested on eight people with persistent back pain in a university clinic and 152 patients from nine primary care physiotherapy and chiropractic clinics. Following feedback from the clinicians and patients involved, the working version of the program was created.ResultsEducational components included pain mechanisms, pain modulation, active coping strategies, imaging, physical activity, and exercise that emphasised a balance between the sum of demands and the individuals capacity. These were operationalised in PowerPoint presentations with supporting text to aid clinicians in delivering two one-hour patient education lectures.The exercise program included 16 supervised one-hour sessions over 8weeks, each comprising a warm-up section and eight types of exercises for general flexibility and strengthening of six different muscle groups at four levels of difficulty. The aims of the exercises were to improve overall back fitness and, at the same time, encourage patients to explore variations in movement by incorporating education content into the exercise sessions.ConclusionFrom current best evidence about prognostic factors in back pain and effective treatments for back pain, research and clinical experts developed a ready-to-use structured program - GLA:D (R) Back - to support self-management for people with persistent/recurrent back pain.
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| 3. |
- Ris, Inge, et al.
(författare)
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Adapting the determinants of implementation behavior questionnaire to evaluate implementation of a structured low back pain programme using mixed-methods
- 2021
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Ingår i: Health Science Reports. - : John Wiley & Sons. - 2398-8835. ; 4:2
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Tidskriftsartikel (refereegranskat)abstract
- Background and Aims: Best-practice low back pain (LBP) primary care programmes have been developed based on evidence-based clinical guidelines and implemented in Sweden and Denmark. The theoretical domains framework (TDF) was utilized in the design of the implementation strategy. Based on the TDF domains, the Determinants of Implementation Behavior Questionnaire (DIBQ) has been developed to evaluate implementation determinants, but its feasibility and validity need to be tested and adapted to study specific contexts. This study aimed to tailor the DIBQ for evaluation of implementation for LBP primary care programmes. The objectives were to (a) translate the DIBQ into Swedish and Danish, (b) adapt the DIBQ into DIBQ-tailored (DIBQ-t) to study content validity, (c) test the DIBQ-t for feasibility, and (d) perform validity testing of DIBQ-t.Methods: We used a mixed-methods design. First, forward translation of the DIBQ, then adaptation into DIBQ-t using qualitative face validity and quantitative content validity was done. Finally, to determine feasibility and construct validity using confirmatory factor analyses, we used data from DIBQ-t collected after the programmes' 2-day course.Results: The final DIBQ-t included 28 items describing 10 of the original 18 DIBQ domains and was considered feasible. A total of 598 clinicians out of 609 responded to the DIBQ-t, with only 2‰ of the items missing. The confirmatory factor analyses showed a good fit after removing two items with the lowest domain loading. The DIBQ-t maintained linkage to all domains within the Behavioral Change Wheel. The clinicians' expectations, according to the DIBQ-t, indicate facilitating determinants outweighing barriers at the initiation of implementation processes.Conclusions: The study resulted in a feasible and valid version of a questionnaire for evaluating clinicians' expectations regarding implementation determinants of best-practice LBP primary care programmes.
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| 4. |
- Rydberg, Patrik, et al.
(författare)
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Transition-State Docking of Flunitrazepam and Progesterone in Cytochrome P450
- 2008
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Ingår i: J.Chem.Theory Comput.. - : American Chemical Society (ACS). ; 4, s. 673-681
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Tidskriftsartikel (refereegranskat)abstract
- We have developed a method to dock a transition-state structure into the active site of an enzyme. Such an approach is more discriminative than standard docking when looking for substrates of an enzyme, because a transition state has more sterical restrictions than a nonreactive state. We use an accurate and tailored force field for the transition-state for the hydroxylation reaction in cytochrome P450, obtained with the Q2MM method. We apply this method to the docking of two drugs, progesterone and flunitrazepam, to the active sites of two human cytochromes P450, 2C9 and 3A4. We obtain a qualitative agreement compared to experiments, both for hydrogen atoms bound to the same carbon atom (for which the force-field energies are directly comparable) and for general sites on the drug molecules, if the method is combined with an estimate of the intrinsic reactivity of the various sites. However, the method does not rank all the sites correctly. It is not significantly improved if the proteins are allowed to relax locally or if it is combined with the MM/PBSA approach, which fully accounts for the protein flexibility and explicitly treats solvation and entropy effects. On the other hand our method performs better than standard docking with the GOLD software or predictions of metabolic sites with the MetaSite software.
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