Stefan Jacobsson - Academia.edu (original) (raw)

Papers by Stefan Jacobsson

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The Journal of Urology, 2002

Journal of Pediatric Hematology/Oncology, 2009

Low levels of leukemia cells in the bone marrow, minimal residual disease (MRD), are considered t... more Low levels of leukemia cells in the bone marrow, minimal residual disease (MRD), are considered to be a powerful indicator of treatment response in acute lymphatic leukemia (ALL). A Nordic quality assurance program, aimed on standardization of the flow cytometry MRD analysis, has been established before implementation of MRD at cutoff level 10 as one of stratifying parameters in next Nordic Society of Pediatric Hematology and Oncology (NOPHO) treatment program for ALL. In 4 quality control (QC) rounds 15 laboratories determined the MRD levels in 48 follow-up samples from 12 ALL patients treated according to NOPHO 2000. Analysis procedures were standardized. For each QC round a compact disc containing data in list-mode files was sent out and results were submitted to a central laboratory. At cutoff level 10, which will be applied for clinical decisions, laboratories obtained a high concordance (91.6%). If cutoff level 10 was applied, the concordance would be lower (85.3%). The continuing standardization resulted in better concordance in QC3 and QC4 compared with QC1 and QC2. The concordance was higher in precursor B as compared with T-cell ALL. We conclude that after standardization, flow cytometry MRD detection can be reliably applied in international, multicenter treatment protocols.

European Journal of Haematology, 2010

Minimal residual disease (MRD) detection during the early treatment phase has become an important... more Minimal residual disease (MRD) detection during the early treatment phase has become an important stratification parameter in many childhood acute lymphoblastic leukaemia (ALL) treatment protocols. Here, we aimed to address the applicability of rearranged antigen-receptor genes as potential MRD markers using real-time quantitative polymerase chain reaction (RQ-PCR) in a Swedish population-based cohort. From 334 childhood ALL cases diagnosed during 2002-2006, we analysed 279 diagnostic samples (84%) by screening for rearranged immunoglobulin (IG) and T-cell receptor (TCR) genes. Allele-specific oligonucleotides were designed, and the sensitivity and quantitative level was determined for each target. Overall, clonal IG/TCR rearrangements were detected in 97% (236/244) of B-cell precursor ALL (BCP ALL) and 94% (33/35) of T-ALL. A sensitive RQ-PCR analysis (&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; or = 10(-4)) was obtained in 89% (216/244) of BCP ALL and in 74% (26/35) of T-ALL, whereas two sensitive targets were only available in 47% (115/244) of BCP ALL and 29% (10/35) of T-ALL cases. With the stratification threshold of &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt; or = 10(-3), which is applied in the current Nordic treatment protocol (NOPHO-ALL 2008) for the identification of high-risk patients, 93% of BCP ALL and 86% of T-ALL reached this quantitative range by at least one target gene. Taken together, this national retrospective study demonstrates that an IG/TCR target for MRD monitoring can be identified in the majority of childhood ALL cases, whereas identification of a second sensitive target gene needs to be improved.

$Research paper thumbnail of Low holotranscobalamin and cobalamins predict incident fractures in elderly men; the MrOS Sweden$

Bone, 2012

In a population-based study on cobalamin status and incident fractures in elderly men (n =790) wi... more In a population-based study on cobalamin status and incident fractures in elderly men (n =790) with an average follow-up of 5.9 years, we found that low levels of metabolically active and total cobalamins predict incident fractures, independently of body mass index (BMI), bone mineral density (BMD), plasma total homocysteine (tHcy), and cystatin C. Introduction Cobalamin deficiency in elderlies may affect bone metabolism. This study aims to determine whether serum cobalamins or holotranscobalamin (holoTC; the metabolic active cobalamin) predict incident fractures in old men. Methods Men participating in the Gothenburg part of the population-based Osteoporotic Fractures in Men (MrOS) Sweden cohort and without ongoing vitamin B medication were included in the present study (n =790; age range, 70-81 years). Results During an average follow-up of 5.9 years, 110 men sustained X-ray-verified fractures including 45 men with clinical vertebral fractures. The risk of fracture (adjusted for age, smoking, BMI, BMD, falls, prevalent fracture, tHcy, cystatin C, 25-OH-vitamin D, intake of calcium, and physical activity (fully adjusted)), increased per each standard deviation decrease in cobalamins (hazard ratio (HR), 1.38; 95 % confidence intervals (CI), 1.11-1.72) and holoTC (HR, 1.26; 95 % CI, 1.03-1.54), respectively. Men in the lowest quartile of cobalamins and holoTC (fully adjusted) had an increased risk of all fracture (cobalamins, HR=1.67 (95 % CI, 1.06-2.62);

Annals of Hematology, 2006

Immune surveillance of tumours is mediated by cytotoxic T cells (CTL) that recognise tumour antig... more Immune surveillance of tumours is mediated by cytotoxic T cells (CTL) that recognise tumour antigen. Reduced reactivity of CTL towards tumour cells could thus lead to disease progression and loss of tumour control. In B-cell chronic lymphocytic leukaemia (B-CLL), the function of tumour-reactive CTL seems to correlate inversely to disease stage. Inhibitory NK cell receptors are known to suppress the CTL response upon interaction with major histocompatibility complex (MHC) class I and increased expression of such receptors on CTL may inhibit the antitumour response. So, the aim of this study was to investigate the expression of NK cell inhibitory receptors on CTL in B-CLL patients and if such expression correlated to disease stage. CD8+ T cells from B-CLL patients in Binet stage A (n=26) and stage C (n=14) and healthy controls (n=14) were analysed for the expression of killer immunoglobulin-like receptors (KIR) CD158a (KIR2DL1), CD158b (KIR2DL2), CD158e (KIR3DL1) and the C-type lectin receptor CD94, by flow cytometry analysis. Patients with advanced disease (Binet stage C) had a significantly greater percentage of CTL expressing CD158b, CD158e and CD94 than patients with nonprogressive disease (Binet stage A) and healthy controls. Stage C patients also had a significantly higher percentage of CTL expressing CD158a than stage A patients. No statistically significant differences were found between Binet A patients and healthy controls. Our results suggest that increased expression of KIR and CD94 on CTL in advanced stage B-CLL may potentially contribute to the impaired anti-tumour immune response in these patients.

European Journal of Heart Failure, 2010

Chronic heart failure (HF) is often accompanied by high co-morbidity and mortality and remains on... more Chronic heart failure (HF) is often accompanied by high co-morbidity and mortality and remains one of the leading causes of death in the western world. The syndrome differs greatly between younger and elderly individuals in many respects, such as prevalence, aetiology, symptomatology, pathophysiology, and comorbidity. Owing to this heterogeneity, there is a need for multiple objective parameters to facilitate diagnosis, prognosis, and therapy. Over the last decade, the inclusion of the natriuretic peptides, brain natriuretic peptide (BNP) and N-terminal pro-brain natriuretic peptide (NT-proBNP), as biomarkers in the management of HF has greatly improved our ability to diagnose and make prognostic prediction in HF patients. However, their added benefits in guiding therapy remain controversial, especially among the elderly. In addition, elevation of these peptides occurs in many clinical conditions. Therefore, natriuretic peptides are not always sufficient, in particular when they are increased to only a moderate level. Other biomarkers have been identified, such as inflammatory cytokines, high-sensitivity C-reactive protein, natriuretic peptides, neurohormones as well as markers of remodelling and oxidative stress, which could be beneficial for diagnosis and prognosis. Recently, elevated red cell distribution width (RDW) has been identified and proposed to be of importance. Red cell distribution width is a measure of the variability in size of circulating erythrocytes and is expressed as the coefficient of variation of the erythrocyte volume. As several routine haematology instruments can analyse erythrocyte volume, RDW is available in most clinical settings. It has been known for some time that elevated RDW predicts poor outcome in both diseased and normal populations. It is therefore not surprising that RDW can also predict mortality in patients with HF. Three studies published recently in this Journal have shown that elevated RDW predicts mortality in HF independently of BNP or NT-proBNP, thus adding RDW to our repertoire of prognostic markers in patients with HF. However, this remains to be confirmed in a larger population study. Moreover, to serve as a prognostic marker is one aspect and to function as a biomarker for improved therapy is another. In combination with other outcome predictors, the clinical use of RDW will be greatly enhanced if it can be used to guide effective therapy. In addition, there is a low relationship between high RDW and mortality, limiting its predictive value for the individual patient. Finally, the value of RDW is instrument-dependent, forcing each laboratory to establish its own reference values. It is therefore important to identify the underlying mechanism that links high RDW to poor prognosis in HF and to examine whether the connection is upstream or downstream of the failing heart. A common underlying cause of high RDW is iron or B12/folate deficiency, where normal erythrocytes are mixed with smaller or larger ones produced during the deficiency. A similar increase in RDW occurs during iron and B12/folate replacement therapy when the reticulocyte count increases. Red cell distribution width is also increased following blood transfusions, as well as in haemolytic anaemia and thrombotic conditions where erythrocytes are fragmented in the circulation. Elevated RDW is also associated with liver disease, alcohol abuse, inflammatory conditions, and renal disease, but here the mechanism behind the variation in erythrocyte size is more complex. In the February 2010 issue of the European Journal of Heart Failure, Januzzi and co-workers presented findings of RDW in acute HF. They concluded that RDW seems to carry added prognostic information above NT-proBNP. Together with two studies published in the December issue, these studies in acute HF and RDW clearly demonstrate that RDW is independent of anaemia. The study from Januzzi and co-workers indicates, perhaps unexpectedly, that RDW is not linked to inflammation, iron, or B12/ folate deficiency or to blood transfusion, although the number of patients actually analysed for these parameters was low. In contrast, another recently published study indicates that markers of iron deficiency, inflammation, and renal impairment all correlated well with high RDW in a population with HF, indicating that RDW could in fact be a non-specific marker of many different conditions, all of which can result in a worsening of the HF prognosis. The CHARM study revealed a strong correlation between elevated bilirubin and poor outcome in HF, suggesting that haemolytic processes could be one link between elevated RDW and poor

EJIFCC, 2001

The dominating mechanism for iron delivery to tissues is the internalisation of the transferrin r... more The dominating mechanism for iron delivery to tissues is the internalisation of the transferrin receptor-diferric transferrin complex. Other ways for iron to enter cells exist but do not contribute significantly to the cellular iron homeostasis in humans. Once the complex has been endocytosed, iron is released to the cytosol for further transport inside the cell, for example to the mitochondria. The receptor-apotransferrin complex recycles to the cell surface for a renewed round of iron uptake. A fraction of the transferrin receptors are cleaved inside the endocytotic vesicle and finally shed into the blood as truncated transferrin receptor monomers complexed with apotransferrin. The serum concentrations of these so called serum transferrin receptors (sTfR) correlate with erythropoietic activity and tissue iron demands. This review will focus on the clinical value of sTfR measurements.

Toxicology letters, 2010

One of the most common dose limiting adverse effects in cancer treatment is myelotoxicity. The ai... more One of the most common dose limiting adverse effects in cancer treatment is myelotoxicity. The aim of this study was to develop an in vitro method for measuring potential myelotoxic properties of a drug candidate in a high throughput setting. Human CD34(+) progenitor cells from umbilical cord blood were plated in 384-well microplates with drugs in liquid culture, supplemented with specific cytokines for the granulocytopoietic-macrophage lineage. After 7 or 14 days of proliferation and differentiation the cells were analyzed using the automated non-clonogenic fluorometric microculture cytotoxicity assay (FMCA). Two types of assays setups were evaluated, the FMCA-GM7 where cells were exposed to drugs directly after thawing and cytotoxicity measured on day 7 in contrast to the FMCA-GM14 where the cells were cultured 7 days prior to plating and drug exposure, with viability analysis on day 14 of differentiation. Drug sensitivity was similar in both assays and method validation was performed using 24 drugs with known myelotoxic profile (acyclovir, bortezomib, busulfan, carboplatin, chloramphenicol, chlorpromazine, cisplatin, cytarabine, clozapine, doxorubicin, erlotinib, etoposide, 5-fluorouracil, fludarabine, gefitinib, gemcitabine, hydroxyurea, imatinib, lomustine, melphalan, sorafenib, sunitinib, taxol and 6-thioguanine). The 50% inhibitory concentrations (IC(50)) from the FMCA-GM7 and the FMCA-GM14 correlated highly (r = 0.83) and (r = 0.82), respectively, with IC(50) from the established clonogenic assay (CFU-GM), obtained from the literature. The current data suggests that the FMCA-GM could offer a simple and robust alternative to the CFU-GM assay in preclinical hematotoxicity studies.

Clinical journal of sport medicine : official journal of the Canadian Academy of Sport Medicine, Jan 27, 2017

To determine the serum hepcidin concentration and standard hematological parameters in a group of... more To determine the serum hepcidin concentration and standard hematological parameters in a group of female adolescent athletes, compared with a group of nonathlete females. A case-control study. A senior high school for athletes in Gothenburg, Sweden. All female athletes (70), at the school were offered to take part. Fifty-six athletes accepted. From a random sample of age-matched nonathletes, 71 students were recruited to the control group. Iron deficiency (ID) was determined by levels of serum iron, total iron-binding capacity, transferrin saturation (TS), and ferritin. Serum hepcidin was determined by a mass spectrometry method. All samples were taken at least 12 hours after training. The main result was the finding of a significantly elevated serum hepcidin level in the athlete group, 4.7 nmol/L compared with 3.3 nmol/L (P < 0.001) in the nonathlete group. In the athlete group, the serum iron concentration was significantly lower, 14.0 μmol/L compared with 17.6 μmol/L (P = 0.00...

Journal of Neuroimmunology, 2016

Contemporary evidence supports that MS immunopathology starts in the peripheral lymphatic system.... more Contemporary evidence supports that MS immunopathology starts in the peripheral lymphatic system. However, the site and character of crucial initiating events are unknown. We examined subsets of the first stages of blood cells in the bone marrow of 9 MS patients and 11 neurologically healthy controls using FACS analysis. The proportion of natural killer T cells was lower (P=0.045) in the bone marrow of MS patients, but proportions of hematogenous stem cells, myeloblasts, and B cell precursor subsets in the bone marrow did not differ between MS patients and controls. In this pilot study with a limited number of samples we found no deviation of the early B cell lineage in bone marrow from MS patients.

Minimal residual disease (MRD) assessment is a powerful prognostic factor for determining the ris... more Minimal residual disease (MRD) assessment is a powerful prognostic factor for determining the risk of relapse in childhood acute lymphoblastic leukaemia (ALL). In this Swedish multi-centre study of childhood ALL diagnosed between 2002 and 2006, the MRD levels were analysed in 726 follow-up samples in 228 children using real-time quantitative polymerase chain reaction (RQ-PCR) of rearranged immunoglobulin/T-cell receptor genes and multicolour flow cytometry (FCM). Using an MRD threshold of 0·1%, which was the sensitivity level reached in all analyses, the concordance between RQ-PCR and FCM MRD values at day 29 was 84%. In B-cell precursor ALL, an MRD level of ≥0·1% at day 29 predicted a higher risk of bone marrow relapse (BMR) with both methods, although FCM was a better discriminator. However, considering the higher median MRD values achieved with RQ-PCR, a higher MRD cut-off (≥0·2%) improved the predictive capacity of RQ-PCR. In T-ALL, RQ-PCR was notably superior to FCM in predicting risk of BMR. That notwithstanding, MRD levels of ≥0·1%, detected by either method at day 29, could not predict isolated extramedullary relapse. In conclusion, the concordance between RQ-PCR and FCM was high and hence both methods are valuable clinical tools for identifying childhood ALL cases with increased risk of BMR.

The Electronic Journal of the International Federation of Clinical Chemistry, 2001