| 1. |
- Crippa, Alessio, et al.
(author)
-
The ProBio trial : molecular biomarkers for advancing personalized treatment decision in patients with metastatic castration-resistant prostate cancer
- 2020
-
In: Trials. - : BioMed Central. - 1745-6215. ; 21:1
-
Journal article (peer-reviewed)abstract
- Background: Multiple therapies exist for patients with metastatic castration-resistant prostate cancer (mCRPC). However, their improvement on progression-free survival (PFS) remains modest, potentially explained by tumor molecular heterogeneity. Several prognostic molecular biomarkers have been identified for mCRPC that may have predictive potential to guide treatment selection and prolong PFS. We designed a platform trial to test this hypothesis.Methods: The Prostate-Biomarker (ProBio) study is a multi-center, outcome-adaptive, multi-arm, biomarker-driven platform trial for tailoring treatment decisions for men with mCRPC. Treatment decisions in the experimental arms are based on biomarker signatures defined as mutations in certain genes/pathways suggested in the scientific literature to be important for treatment response in mCRPC. The biomarker signatures are determined by targeted sequencing of circulating tumor and germline DNA using a panel specifically designed for mCRPC.Discussion: Patients are stratified based on the sequencing results and randomized to either current clinical practice (control), where the treating physician decides treatment, or to molecularly driven treatment selection based on the biomarker profile. Outcome-adaptive randomization is implemented to early identify promising treatments for a biomarker signature. Biomarker signature-treatment combinations graduate from the platform when they demonstrate 85% probability of improving PFS compared to the control arm. Graduated combinations are further evaluated in a seamless confirmatory trial with fixed randomization. The platform design allows for new drugs and biomarkers to be introduced in the study.Conclusions: The ProBio design allows promising treatment-biomarker combinations to quickly graduate from the platform and be confirmed for rapid implementation in clinical care.
|
|
| 2. |
- Grönberg, Annika, 1970-
(author)
-
Predictors of long-term glycemic control, pancreatic function and BMI trajectory in children with type 1 diabetes
- 2023
-
Doctoral thesis (other academic/artistic)abstract
- Background: The maintenance of normal metabolic control underpins all management of insulin dependent diabetes whether in terms of preserved beta-cell function, body composition, or family support. The hypothesis of this work was that preserved C-peptide predicts better glycemic control and lowers risk of severe hypoglycemia. It was additionally investigated whether Body Mass Index (BMI) and family structure contributes to the prediction of long-term glycemic control. Objectives: This thesis aimed to 1) identify the factors associated with residual C peptide production at least 10 years after diagnosis, 2) evaluate the association of BMI trajectory and long-term glycemic control, 3) identify early characteristics associated with rapid or slow decline of beta-cell function and how it affects the clinical course, and 4) investigate the relations of family structure at diagnosis and long-term glycemic control. Methods: Data from four cohorts were used: In the Uppsala cohort, measurement of long-term residual C-peptide was undertaken using ultrasensitive C-peptide ELISA in 73 children and adolescents <25 years, BMI trajectory prior diagnosis was evaluated in 295 children, while family structure at diagnosis was evaluated in 215 children in relation to glycemic control. In the Linköping cohort, stimulated C-peptide was assessed by mixed meal tolerance test in 50 children. Results: The cohort studies showed that better early glycemic control predicted long term residual C-peptide and that long term residual C-peptide, in turn, was protective against severe hypoglycemia. Additionally, BMI trajectory was predicted by BMI prior to the presentation of type 1 diabetes. There was no association with glycemic outcome. Children living in a whole family had a lower probability of long-term dysglycemia. Conclusions: Residual C-peptide is important for better glycemic control and to reduce complications in children with type 1 diabetes. Family structure, but not BMI trajectory, contributes to the prediction of long-term glycemic control. However, more research is needed to understand how to preserve the beta-cell function in children and to target and support families in those children with early deteriorating glycemic control to reduce future complications.
|
|
| 3. |
- Papantoniou, Dimitrios, et al.
(author)
-
Hypoalbuminemia, but not derived neutrophil to lymphocyte ratio (dNLR), predicts overall survival in neuroendocrine tumours undergoing peptide receptor radionuclide therapy : A retrospective, cohort study of 557 patients
- 2024
-
In: Journal of neuroendocrinology. - : John Wiley & Sons. - 0953-8194 .- 1365-2826.
-
Journal article (peer-reviewed)abstract
- Several inflammation scores have shown association with survival outcomes for patients with neuroendocrine tumours (NET) treated with peptide receptor radionuclide therapy (PRRT). However, whether these scores add value to established prognostic factors remains unknown. In this retrospective, cohort study of 557 NET patients undergoing PRRT in a tertiary referral centre from 2005 to 2015, we examined inflammatory markers and scores previously associated with cancer outcomes, using Cox proportional hazard models and Akaike's information criterion. Lower albumin (hazard ratio [95% confidence interval], .91 [.87-.95] per unit), as well as higher C-reactive protein (CRP; 1.02 [1.01-1.02]), Glasgow Prognostic Score (GPS; 1 vs. 0: 1.67 [1.14-2.44], 2 vs. 0 3.60 [2.24-5.79]), CRP/albumin ratio (1.84 [1.43-2.37]) and platelet count (Plt) x CRP, but not white blood cell, neutrophil and thrombocyte counts or derived neutrophil to lymphocyte ratio (dNLR), were associated with shorter median overall survival (OS) in an adjusted analysis. The addition of parameters based on albumin and CRP, but not dNLR, to a base model including age, chromogranin A, the cell proliferation marker Ki-67, performance status, tumour site and previous treatments improved the predictive accuracy of the base model. In an exploratory analysis of patients with available erythrocyte sedimentation rate (ESR) and CRP, ESR emerged as the most powerful predictor. When added to a prognostic model for OS in NET patients treated with PRRT, most inflammation scores further improved the model. Albumin was the single marker adding most value to the set of established prognostic markers, whereas dNLR did not seem to improve the model's prognostic ability.
|
|
| 4. |
- Vilhjalmsson, Dadi, et al.
(author)
-
Transanal formation of anastomosis using C-REX device is feasible and effective in high anterior resection
- 2023
-
In: International Journal of Colorectal Disease. - 0179-1958. ; 38:1
-
Journal article (peer-reviewed)abstract
- Purpose: C-REX is a novel instrument for creating stapleless colorectal anastomosis by compression. The aim of this study was to evaluate the feasibility and effectiveness of C-REX in open and laparoscopic high anterior resections. Methods: A prospective clinical safety study on 21 patients reconstructed with C-REX colorectal anastomosis following high anterior resection of the sigmoid colon using two different devices for intraabdominal (n = 6) or transanal (n = 15) placement of the anastomotic rings. Any signs of complications were prospectively monitored by a predefined protocol. Anastomotic contact pressure (ACP) was measured via a catheter-based system, and time for evacuation of the anastomotic rings by the natural route was noted. Blood samples were collected daily, and flexible endoscopy was performed postoperatively to examine macroscopic appearance of the anastomoses. Results: One of six patients operated with the intraabdominal anastomosis technique with an ACP of 50 mBar had to be reoperated because of anastomotic leakage. None of the 15 patients operated with the transanal technique (5 open and 10 laparoscopic procedures) had anastomotic complications, and their ACP ranged between 145 and 300 mBar. C-REX rings were uneventfully expelled by the natural route in all patients after a median of 10 days. Flexible endoscopy showed well-healed anastomoses without stenosis in 17 patients and a moderate subclinical stricture in one patient. Conclusion: These results indicate that the novel transanal C-REX device is a feasible and effective method for colorectal anastomosis following high anterior resections, irrespective of open or laparoscopic approach. Moreover, C-REX allows measurement of intraoperative ACP and thereby a quantitative evaluation of the anastomotic integrity.
|
|
| 5. |
- Wiuf, Anders, et al.
(author)
-
The two-domain elevator-type mechanism of zinc-transporting ZIP proteins
- 2022
-
In: Science Advances. - : American Association for the Advancement of Science. - 2375-2548. ; 8:28
-
Journal article (peer-reviewed)abstract
- Zinc is essential for all organisms and yet detrimental at elevated levels. Hence, homeostasis of this metal is tightly regulated. The Zrt/Irt-like proteins (ZIPs) represent the only zinc importers in metazoans. Mutations in human ZIPs cause serious disorders, but the mechanism by which ZIPs transfer zinc remains elusive. Hitherto, structural information is only available for a model member, BbZIP, and as a single, ion-bound conformation, precluding mechanistic insights. Here, we elucidate an inward-open metal-free BbZIP structure, differing substantially in the relative positions of the two separate domains of ZIPs. With accompanying coevolutional analyses, mutagenesis, and uptake assays, the data point to an elevator-type transport mechanism, likely shared within the ZIP family, unifying earlier functional data. Moreover, the structure reveals a previously unknown ninth transmembrane segment that is important for activity in vivo. Our findings outline the mechanistic principles governing ZIP-protein transport and enhance the molecular understanding of ZIP-related disorders.
|
|
