| 1. |
- Arheden, A., et al.
(författare)
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Real-world data on PD-1 inhibitor therapy in metastatic melanoma
- 2019
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Ingår i: Acta Oncologica. - : Informa UK Limited. - 0284-186X .- 1651-226X. ; 58:7, s. 962-966
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Phase III studies of PD-1 inhibitors have demonstrated remarkable improvements in the survival of patients with metastatic melanoma (MM). If these results are generalizable to an unselected patient population treated in clinical routine is unknown. This study aimed to investigate and describe clinical efficacy and safety of PD-1 inhibitors in patients with MM treated in routine clinical practice. Material and methods: A retrospective descriptive study of patients with metastatic or inoperable cutaneous melanoma treated with PD-1 inhibitors at a single institution (Department of Oncology, Sahlgrenska University Hospital) from 1 September 2015 to 31 August 2017. Data were obtained from medical records. Results: A total of 116 patients were included in the analyses. The overall survival (OS) at 12-month follow-up was 70.2% and the median OS was 27.9 months. Patients with BRAF mutated tumors had increased OS, whereas ECOG PS >= 2, LDH > ULN and presence or history of brain metastases (stage M1d) were associated with impaired survival. Immune-related AEs of any grade occurred in 64 (55.2%) patients and 15 (12.9%) patients experienced immune-related AEs of grades 3 and 4. Notably, rheumatic adverse events occurred at a higher rate (15.5%) than previously reported. The occurrence of immune-related AEs was associated with a benefit in OS, while the severity of immune-related AEs did not affect survival, nor did the use of systemic corticosteroids. Conclusions: The efficacy and safety of PD1 inhibitors in routine clinical practice appear comparable to that described in clinical trials.
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| 2. |
- Bjursten, Henrik, et al.
(författare)
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Circulating particles during cardiac surgery.
- 2009
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Ingår i: Interactive Cardiovascular and Thoracic Surgery. - : Oxford University Press (OUP). - 1569-9285 .- 1569-9293.
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Tidskriftsartikel (refereegranskat)abstract
- Shed blood is known to be a source of lipid micro-emboli in cardiac surgery. The aim of this study was to characterize the occurrence of these particles at different stages of the operation, and to study their occurrence in the circulation at multiple time-points after the retransfusion of shed blood. 44 patients undergoing routine surgery with cardiopulmonary bypass were included. Blood was sampled from the surgical field at different sampling locations during the operation. Shed blood was collected in a transfusion bag and retransfused. After which, blood was sampled from the arterial line of the heart-lung machine. A Coulter counter was used for particle determinion. The mean volume of shed blood collected was 340+/-215 ml. Particles in the size range 10-60 microm were found at varying concentrations, with the highest concentrations being found in blood collected after cannulation and from the pleura. After retransfusion of this blood, a biphasic response was seen in the blood drawn from the efferent line of the heart-lung machine. Particles are found in shed blood at all times during cardiac surgery, and when this blood was retransfused an increase was seen in particle concentration in the heart-lung machine. Keywords: Particles; Lipid particles; Circulation; Shed mediastinal blood.
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| 3. |
- Bjursten, Sara
(författare)
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Checkpoint inhibitor-induced adverse events in the CNS - T-cell characteristics and biomarkers
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Immune checkpoint inhibitors (ICI) activate T cells to kill cancer cells by blocking inhibitory receptors PD-1 (nivolumab; nivo) or CTLA-4 (ipilimumab; ipi). Activated T cells can also attack any healthy organ, causing unpredictable immune related adverse events (irAE). The risk of irAE is highest when treating with ipi and nivo simultaneously. An adverse event of the central nervous system (CNS irAE) can cause paralysis and even death. CNS irAE is difficult to diagnose because of unspecific symptoms and no known blood tests that indicate CNS irAE. In addition, the immune mechanisms behind CNS irAE are unknown but T cells are likely to have a central role. The aim of this thesis is to identify blood tests (biomarkers) to facilitate early diagnosis of CNS irAE. The second aim is to identify which T cell subsets are associated with CNS irAE. We also wanted to establish the frequency of CNS irAE in a cohort of ipi+nivo treated patients. In paper I we describe how brain damage markers S100B and NfL in blood was high in a patient with severe CNS irAE. In paper II we investigated a cohort of 9 ipi+nivo treated patients with CNS irAE. In this cohort, S100B and NfL in blood increased significantly during CNS irAE and normalized during immunosuppression. CNS irAE was detected with a sensitivity of 100% (S100B) and 79% (NfL) and a specificity of 89% (S100B) and 74% (NfL). Interestingly, patients with CNS irAE had increased concentration of C-reactive protein (CRP) and liver enzymes (ALT/AST) in blood. In papers I and III , flow cytometry analysis demonstrated high proportion of T cells expressing costimulatory receptor ICOS in patients with CNS irAE. Finally, the frequency of CNS irAE in a cohort of 197 ipi+nivo treated patients was 4,6%, which is considerably higher than previously reported. In conclusion, our findings support that combined analysis of S100B and NfL in blood facilitates diagnosis and monitoring of CNS irAE. Increased CRP and liver enzymes in blood during CNS irAE may suggest shared immune mechanisms between CNS and hepatitis irAE. Also, our observations identify ICOS as a potential mediator of CNS irAE. Finally, CNS irAE may be more common than previously reported.
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| 4. |
- Bjursten, Sara, et al.
(författare)
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Concentrations of S100B and neurofilament light chain in blood as biomarkers for checkpoint inhibitor-induced CNS inflammation
- 2024
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Ingår i: EBioMedicine. - 2352-3964. ; 100
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Tidskriftsartikel (refereegranskat)abstract
- Background Cancer treatment with immune checkpoint inhibition (ICI) can cause immune -related adverse events in the central nervous system (CNS irAE). There are no blood biomarkers to detect CNS irAE. We investigated if concentrations of S100 -calcium -binding protein B (S100B) and neurofilament light chain (NfL) in blood can be used as biomarkers for CNS irAE and assessed the incidence of CNS irAE in a cohort of ICI -treated patients. Methods In this single -centre, retrospective cohort study, we examined medical records and laboratory data of 197 consecutive patients treated with combined CTLA-4 and PD -1 inhibition (ipilimumab; ipi + nivolumab; nivo) for metastatic melanoma or renal cell carcinoma. CNS irAE was diagnosed using established criteria. Concentrations of S100B and NfL in blood were measured in patients with CNS irAE and in 84 patients without CNS irAE. Findings Nine of 197 patients (4.6%) fulfilled criteria for CNS irAE. S100B and NfL in blood increased during CNS inflammation and normalized during immunosuppression. CNS irAE was detected with a sensitivity of 100% (S100B) and 79% (NfL) and a specificity of 89% (S100B) and 74% (NfL). Patients with CNS irAE had simultaneous increased concentration of C -reactive protein (CRP) (9/9) and alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) in blood (8/9). Interpretation Analysis of S100B, NfL and CRP in blood facilitates the diagnosis of CNS irAE. CNS irAE may be more common than previously reported. There may be shared immune mechanisms between CNS and hepatitis irAE.
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| 5. |
- Bjursten, Sara, et al.
(författare)
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Early rise in brain damage markers and high ICOS expression in CD4+and CD8+T cells during checkpoint inhibitor-induced encephalomyelitis
- 2021
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Ingår i: Journal for Immunotherapy of Cancer. - : BMJ. - 2051-1426. ; 9:7
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Tidskriftsartikel (refereegranskat)abstract
- We report a case of rapid eradication of melanoma brain metastases and simultaneous near-fatal encephalomyelitis following double immune checkpoint blockade. Brain damage marker S-100B and C reactive protein increased before symptoms or signs of encephalomyelitis and peaked when the patient fell into a coma. At that point, additional brain damage markers and peripheral T cell phenotype was analyzed. The analyses were repeated four times during the patient's recovery. Axonal damage marker neurofilament light polypeptide (NFL) and astrocytic damage marker glial fibrillar acidic protein (GFAP) were very high in blood and cerebrospinal fluid and gradually normalized after immunosuppression and intensive care. The costimulatory receptor inducible T cell costimulatory receptor (ICOS) was expressed on a high proportion of CD4+ and CD8+T cells as encephalomyelitis symptoms peaked and then gradually decreased in parallel with clinical improvement. Both single and double immune checkpoint inhibitor-treated melanoma patients with other serious immune-related adverse events (irAE) (n=9) also expressed ICOS on a significantly higher proportion of CD4+ and CD8+T cells compared with controls without irAE (n=12). In conclusion, our results suggest a potential role for ICOS on CD4+ and CD8+T cells in mediating encephalomyelitis and other serious irAE. In addition, brain damage markers in blood could facilitate early diagnosis of encephalitis.
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| 6. |
- Bjursten, Sara, et al.
(författare)
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Response to BRAF/MEK Inhibition in A598_T599insV BRAF Mutated Melanoma
- 2019
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Ingår i: Case Reports in Oncology. - : S. Karger AG. - 1662-6575. ; 12:3, s. 872-879
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Tidskriftsartikel (refereegranskat)abstract
- Approximately 50% of patients with metastatic melanoma harbor an activating BRAF mutation. Tumors with activating mutation BRAF gene proliferate excessively and can be treated with targeted BRAF-inhibitors in combination with MEK inhibitors. The most common BRAF mutation occurs at amino acid position 600. Other BRAF mutations are rare and their predictive value for treatment response to BRAF/MEK inhibition is low. Here, we report on a patient with a BRAF A598_T599insV mutated melanoma, a mutation that has only been described in one previous melanoma patient in which the treatment response to BRAF/MEK inhibition was transient. Our patient had a large ulcerated metastasis that showed a durable complete response implying that BRAF/MEK inhibition should be considered a treatment option for this mutation. We analyzed circulating cell-free tumor DNA (ctDNA) carrying the BRAF A598_T599insV mutation throughout treatment. The allele frequency of BRAF A598_T599insV decreased during regression of the tumors, indicating that this method has potential to monitor treatment response. Our case demonstrates durable response to BRAF/MEK inhibition in a melanoma patient carrying a BRAF A598_T599insV mutation. In addition, we show that allele frequency analysis of A598_T599insV mutation in blood using ultrasensitive sequencing can be used to monitor treatment response.
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| 7. |
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| 8. |
- Eyjolfsson, Atli, et al.
(författare)
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Characterization of lipid particles in shed mediastinal blood.
- 2008
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Ingår i: Annals of Thoracic Surgery. - : Elsevier BV. - 1552-6259 .- 0003-4975. ; 85:3, s. 978-981
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Shed mediastinal blood is known to be a source of microemboli in cardiac surgery. The aim of this study was to characterize in detail the lipid particles found in this blood. METHODS: Blood samples were collected from 24 patients undergoing routine cardiac surgery with cardiopulmonary bypass. Arterial and shed blood was analyzed using the Coulter counter technique to establish the number and size of particles. The composition of these lipid particles was compared with that of adipose tissue from the mediastinum using gas chromatography. Scanning electron microscopy was used to visualize the lipid particles in samples of shed blood. RESULTS: Lipid particles in the size range of 10 to 60 microm were characterized in shed mediastinal blood, and more than 300,000 particles per milliliter of blood were found. Triglyceride profiles in these lipid particles and in adipose tissue were similar, suggesting that their origin is the mediastinum. Scanning electron microscopy showed spherical formations corresponding in size to the particles counted using the Coulter counter. CONCLUSIONS: During the past decade attention has focused on microembolism in cardiac surgery, and this study has helped define the problem. Different strategies, such as eliminating the use of shed mediastinal blood or purifying the blood by different techniques, may improve the results of cardiac surgery in the future.
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| 9. |
- Eyjolfsson, Atli, et al.
(författare)
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Comparison between transcranial Doppler and coulter counter for detection of lipid micro embolization from mediastinal shed blood reinfusion during cardiac surgery.
- 2011
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Ingår i: Perfusion. - : SAGE Publications. - 1477-111X .- 0267-6591. ; 26:5, s. 519-523
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: Lipid micro embolization (LME) from re-transfused shed blood has been postulated to be a potential reason for short- and long-term cognitive dysfunction after cardiac surgery. The purpose of this investigation was to evaluate if transcranial Doppler (TCD) has the capacity to detect LME. METHODS: Thirteen patients undergoing cardiopulmonary bypass surgery were investigated. Each patient's cerebral circulation was monitored with transcranial Doppler during the first two minutes after re-transfusion of shed blood and blood was simultaneously sampled and characterised by a Coulter counter. RESULTS: Strong correlation was found between embolic loads, as measured by transcranial Doppler and Coulter counter (r=0.79, P<0.005). CONCLUSIONS: This pilot study shows that non-invasive monitoring by transcranial Doppler could be a potential tool to monitor LME during cardiopulmonary bypass surgery.
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| 10. |
- Eyjolfsson, Atli, et al.
(författare)
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Lipid emboli distribution in cardiac surgery is dependent on the state of emulsification
- 2012
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Ingår i: Scandinavian Cardiovascular Journal. - : Informa UK Limited. - 1651-2006 .- 1401-7431. ; 46:1, s. 51-56
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Tidskriftsartikel (refereegranskat)abstract
- Objective. Lipid embolizations from retransfused shed blood during cardiac surgery have been shown to enter the circulation and end up in different organs. The purpose of this investigation was to evaluate differences in the kinetics and deposition between emulsified and non-emulsified lipid emboli in a porcine model. Design. Twelve animals were anesthetized and put on cardiopulmonary bypass. A shed-blood phantom (6 animals given emulsified and 6 given non-emulsified lipids) was produced from arterial blood, saline, and tritium-labeled triolein. The phantom was infused into the cardiopulmonary bypass circuit. Arterial and venous blood samples were taken at short intervals. Tissue samples were taken post-mortem from examined organs and prepared for scintillation counting. Levels of radioactivity were used to measure lipid emboli content in blood and tissue. Results. Emulsified lipid emboli generated a 5-fold higher embolic load in the arterial and a 12-fold higher in the venous circulation, compared with non-emulsified lipid emboli. Emulsified lipid micro emboli resulted in a 2-15-fold higher tissue deposition in investigated organs compared with non-emulsified lipid micro emboli. Conclusions. This study shows that the state of emulsion significantly alter the kinetics and tissue deposition of lipid emboli. Emulsified lipid emboli give higher embolic load in the arterial and venous circulation, and higher tissue deposition versus non-emulsified lipid emboli. In both groups, the embolic load was higher in the arterial circulation than on the venous side.
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