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1.
  • Grinberg, Marianna, et al. (författare)
  • Reaching the limits of prognostication in non-small cell lung cancer : an optimized biomarker panel fails to outperform clinical parameters.
  • 2017
  • Ingår i: Modern Pathology. - : Elsevier BV. - 0893-3952 .- 1530-0285. ; 30:7, s. 964-977
  • Tidskriftsartikel (refereegranskat)abstract
    • Numerous protein biomarkers have been analyzed to improve prognostication in non-small cell lung cancer, but have not yet demonstrated sufficient value to be introduced into clinical practice. Here, we aimed to develop and validate a prognostic model for surgically resected non-small cell lung cancer. A biomarker panel was selected based on (1) prognostic association in published literature, (2) prognostic association in gene expression data sets, (3) availability of reliable antibodies, and (4) representation of diverse biological processes. The five selected proteins (MKI67, EZH2, SLC2A1, CADM1, and NKX2-1 alias TTF1) were analyzed by immunohistochemistry on tissue microarrays including tissue from 326 non-small cell lung cancer patients. One score was obtained for each tumor and each protein. The scores were combined, with or without the inclusion of clinical parameters, and the best prognostic model was defined according to the corresponding concordance index (C-index). The best-performing model was subsequently validated in an independent cohort consisting of tissue from 345 non-small cell lung cancer patients. The model based only on protein expression did not perform better compared to clinicopathological parameters, whereas combining protein expression with clinicopathological data resulted in a slightly better prognostic performance (C-index: all non-small cell lung cancer 0.63 vs 0.64; adenocarcinoma: 0.66 vs 0.70, squamous cell carcinoma: 0.57 vs 0.56). However, this modest effect did not translate into a significantly improved accuracy of survival prediction. The combination of a prognostic biomarker panel with clinicopathological parameters did not improve survival prediction in non-small cell lung cancer, questioning the potential of immunohistochemistry-based assessment of protein biomarkers for prognostication in clinical practice.Modern Pathology advance online publication, 10 March 2017; doi:10.1038/modpathol.2017.14.
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2.
  • Mattsson, Sofia, et al. (författare)
  • Who enrols and graduates from web-based pharmacy education : experiences from Northern Sweden
  • 2018
  • Ingår i: Currents in pharmacy teaching and learning. - : Elsevier. - 1877-1297. ; 10:8, s. 1004-1012
  • Tidskriftsartikel (refereegranskat)abstract
    • Introduction: As a response to the shortage of prescriptionists in Northern Sweden, a web-based Bachelor of Science in Pharmacy program was introduced at Umea. University in 2003. This study explored who is likely to enrol and graduate from the web-based bachelor program and whether the program has addressed the shortage of prescriptionists in rural Northern Sweden.Methods: Data from three different sources were included in this study; the initial cohort including students admitted to the program in 2003 (survey), the entire cohort including all people admitted to the program between 2003 and 2014 (university's admissions data) and the alumni cohort including graduates who participated in an alumni survey in 2015.Results: A typical student of the web-based pharmacy program is female, over 30 years of age, married or in a de-facto relationship and has children. Furthermore, the students graduating before 2009 were more likely to live in Northern Sweden compared to those graduating later.Discussion and conclusion: The results indicate that the introduction of a web-based bachelor of pharmacy program at Umea. University was to some extent able to address the shortage of prescriptionists in Northern Sweden. Web-based education may potentially help address the maldistribution of health professionals by providing flexible education opportunities.
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3.
  • Andersen, Toril, et al. (författare)
  • Chitosan-Based Nanomedicine to Fight Genital Candida Infections : Chitosomes
  • 2017
  • Ingår i: Marine Drugs. - : MDPI. - 1660-3397. ; 15:3
  • Tidskriftsartikel (refereegranskat)abstract
    • Vaginal infections are associated with high recurrence, which is often due to a lack of efficient treatment of complex vaginal infections comprised of several types of pathogens, especially fungi and bacteria. Chitosan, a mucoadhesive polymer with known antifungal effect, could offer a great improvement in vaginal therapy; the chitosan-based nanosystem could both provide antifungal effects and simultaneously deliver antibacterial drugs. We prepared chitosan-containing liposomes, chitosomes, where chitosan is both embedded in liposomes and surface-available as a coating layer. For antimicrobial activity, we entrapped metronidazole as a model drug. To prove that mucoadhesivness alone is not sufficient for successful delivery, we used Carbopol-containing liposomes as a control. All vesicles were characterized for their size, zeta potential, entrapment efficiency, and in vitro drug release. Chitosan-containing liposomes were able to assure the prolonged release of metronidazole. Their antifungal activity was evaluated in a C. albicans model; chitosan-containing liposomes exhibited a potent ability to inhibit the growth of C. albicans. The presence of chitosan was crucial for the system's antifungal activity. The antifungal efficacy of chitosomes combined with antibacterial potential of the entrapped metronidazole could offer improved efficacy in the treatment of mixed/complex vaginal infections.
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4.
  • Andersen, Toril, et al. (författare)
  • Chitosan in Mucoadhesive Drug Delivery : Focus on Local Vaginal Therapy
  • 2015
  • Ingår i: Marine Drugs. - : MDPI. - 1660-3397. ; 13:1, s. 222-236
  • Tidskriftsartikel (refereegranskat)abstract
    • Mucoadhesive drug therapy destined for localized drug treatment is gaining increasing importance in today's drug development. Chitosan, due to its known biodegradability, bioadhesiveness and excellent safety profile offers means to improve mucosal drug therapy. We have used chitosan as mucoadhesive polymer to develop liposomes able to ensure prolonged residence time at vaginal site. Two types of mucoadhesive liposomes, namely the chitosan-coated liposomes and chitosan-containing liposomes, where chitosan is both embedded and surface-available, were made of soy phosphatidylcholine with entrapped fluorescence markers of two molecular weights, FITC-dextran 4000 and 20,000, respectively. Both liposomal types were characterized for their size distribution, zeta potential, entrapment efficiency and the in vitro release profile, and compared to plain liposomes. The proof of chitosan being both surface-available as well as embedded into the liposomes in the chitosan-containing liposomes was found. The capability of the surface-available chitosan to interact with the model porcine mucin was confirmed for both chitosan-containing and chitosan-coated liposomes implying potential mucoadhesive behavior. Chitosan-containing liposomes were shown to be superior in respect to the simplicity of preparation, FITC-dextran load, mucoadhesiveness and in vitro release and are expected to ensure prolonged residence time on the vaginal mucosa providing localized sustained release of entrapped model substances.
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5.
  • Andersen, Toril, et al. (författare)
  • Pectosomes and chitosomes as delivery systems for metronidazole : the one-pot preparation method
  • 2013
  • Ingår i: Pharmaceutics. - : M D P I AG. - 1999-4923. ; 5:3, s. 445-456
  • Tidskriftsartikel (refereegranskat)abstract
    • Mucoadhesive liposomes offer a potential for improved residence time of liposomal systems targeting contact with mucosal tissues, such as in buccal, oral, colon, and vaginal drug delivery. Most of the currently available methods rely on the coating of preformed liposomes by various mucoadhesive polymers. The aim of this study was to develop novel mucoadhesive system by the one-pot preparation method. The pectin- and chitosan-containing liposomes, namely pectosomes and chitosomes, were prepared by the modified solvent injection method. In order to optimize this novel delivery system, we used pectins and chitosans of both high and low degree of esterification/deacetylation (DE/DD), respectively. Sonication was applied to reduce the original vesicle size. All vesicles were characterized for their size, zeta potential, metronidazole entrapment, and stability. Both pectosomes and chitosomes were found to entrap more metronidazole than conventional plain liposomes. Preliminary data indicate that the polymer is present on the liposomal surface, embedded within inner liposomal bilayers, and entrapped inside the aqueous compartment. The next step in the evaluation of this system is the testing of its mucoadhesiveness.
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6.
  • Attebäck, Maria, et al. (författare)
  • Formulation Optimization of Extemporaneous Oral Liquids Containing Naloxone and Propranolol for Pediatric Use
  • 2022
  • Ingår i: Scientia pharmaceutica. - : MDPI. - 0036-8709 .- 2218-0532. ; 90:1
  • Tidskriftsartikel (refereegranskat)abstract
    • There is a need to develop dosage forms suitable for children to improve drug treatment. Extemporaneous compounding of drugs for children is one way to meet these needs. However, excipients generally considered as safe in adults may not be appropriate in dosage forms intended for children. The aim was to optimize the composition of two pediatric liquid preparations by substituting paraben as a microbiological preservative and ethanol as a solubilizer, with excipients more suitable for pediatric use. The oral liquids were Naloxone 1 mg/mL and Propranolol 10 mg/mL. Twelve different formulations were tested with propranolol and naloxone, respectively, during the screening process to select appropriate formulations. Sodium benzoate and glycerol were used as a preservative and solubilizer, respectively, and different pH of the formulations were evaluated. The formulations were characterized according to dispensed dose (dosing accuracy), viscosity and osmolality. The optimized formulations from the screening process were tested with two amounts of sodium benzoate and microbiological assays were performed. These formulations were shown to have satisfactory preservative properties and dosing accuracy. The results showed that the oral liquids could be prepared without the addition of solubilizer and with lower osmolality (naloxone), thus reducing the risk of gastrointestinal side effects.
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7.
  • Backman, Max, et al. (författare)
  • Extending the immune phenotypes of lung cancer: Oasis in the desert
  • Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
    • Introduction: Tumor infiltrating immune cells are key elements of the tumor microenvironment and mediate the anti-tumor effects of immunotherapy. The aim of the study was to characterize patterns of immune cell infiltration in non-small cell lung cancer (NSCLC) in relation to tumor mutations and clinicopathological parameters. Methods: Lymphocytes (CD4+, CD8+, CD20+, FOXP3+, CD45RO+), macrophages (CD163+), plasma cells (CD138+), NK cells (NKp46+) and PD-L1+ were annotated on a tissue microarray including 357 operated NSCLC cases. Somatic mutations and tumor mutational burden were analyzed by targeted sequencing for 82 genes, and transcriptomic immune patterns were established in 197 patients based on RNAseq data. Results: We identified somatic mutations (TP53, NF1, KEAP1, CSMD3, LRP1B) that correlated with specific immune cell infiltrates. Hierarchical clustering revealed four immune classes: with (1) high immune cell infiltration (“inflamed”), (2) low immune cell infiltration (“desert”), (3) a mixed phenotype, and (4) a new phenotype with an overall muted inflammatory cell pattern but with an imprint of NK and plasma cells. This latter class exhibited low expression of immune response-related genes (e.g. CXCL9, GZMB, INFG, TGFB1), but was linked to better survival and therefore designated “oasis”. Otherwise, the four immune classes were not related to the presence of specific mutations (EGFR, KRAS, TP53) or histologic subtypes. Conclusion: We present a compartment-specific immune cell analysis in the context of the molecular and clinical background of NSCLC and identified the novel immune class “oasis”. The immune classification helps to better define the immunogenic potency of NSCLC in the era of immunotherapy. 
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8.
  • Backman, Max, et al. (författare)
  • Infiltration of NK and plasma cells is associated with a distinct immune subset in non‐small cell lung cancer
  • 2021
  • Ingår i: Journal of Pathology. - : John Wiley & Sons. - 0022-3417 .- 1096-9896. ; 255:3, s. 243-256
  • Tidskriftsartikel (refereegranskat)abstract
    • Immune cells of the tumor microenvironment are central but erratic targets for immunotherapy. The aim of this study was to characterize novel patterns of immune cell infiltration in non-small cell lung cancer (NSCLC) in relation to its molecular and clinicopathologic characteristics. Lymphocytes (CD3+, CD4+, CD8+, CD20+, FOXP3+, CD45RO+), macrophages (CD163+), plasma cells (CD138+), NK cells (NKp46+), PD1+, and PD-L1+ were annotated on a tissue microarray including 357 NSCLC cases. Somatic mutations were analyzed by targeted sequencing for 82 genes and a tumor mutational load score was estimated. Transcriptomic immune patterns were established in 197 patients based on RNA sequencing data. The immune cell infiltration was variable and showed only poor association with specific mutations. The previously defined immune phenotypic patterns, desert, inflamed, and immune excluded, comprised 30, 13, and 57% of cases, respectively. Notably, mRNA immune activation and high estimated tumor mutational load were unique only for the inflamed pattern. However, in the unsupervised cluster analysis, including all immune cell markers, these conceptual patterns were only weakly reproduced. Instead, four immune classes were identified: (1) high immune cell infiltration, (2) high immune cell infiltration with abundance of CD20+ B cells, (3) low immune cell infiltration, and (4) a phenotype with an imprint of plasma cells and NK cells. This latter class was linked to better survival despite exhibiting low expression of immune response-related genes (e.g. CXCL9, GZMB, INFG, CTLA4). This compartment-specific immune cell analysis in the context of the molecular and clinical background of NSCLC reveals two previously unrecognized immune classes. A refined immune classification, including traits of the humoral and innate immune response, is important to define the immunogenic potency of NSCLC in the era of immunotherapy. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.
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9.
  • Bemark, Mats, 1967, et al. (författare)
  • Limited clonal relatedness between gut IgA plasma cells and memory B cells after oral immunization
  • 2016
  • Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
  • Tidskriftsartikel (refereegranskat)abstract
    • Understanding how memory B cells are induced and relate to long-lived plasma cells is important for vaccine development. Immunity to oral vaccines has been considered short-lived because of a poor ability to develop IgA B-cell memory. Here we demonstrate that long-lived mucosal IgA memory is readily achieved by oral but not systemic immunization in mouse models with NP hapten conjugated with cholera toxin and transfer of B1-8high /GFP+ NP-specific B cells. Unexpectedly, memory B cells are poorly related to long-lived plasma cells and less affinity-matured. They are α4β7-integrin+ CD73+ PD-L2+ CD80+ and at systemic sites mostly IgM+, while 80% are IgA+ in Peyer's patches. On reactivation, most memory B cells in Peyer's patches are GL7+, but expand in germinal centres and acquire higher affinity and more mutations, demonstrating strong clonal selection. CCR9 expression is found only in Peyer's patches and appears critical for gut homing. Thus, gut mucosal memory possesses unique features not seen after systemic immunization. © 2016 The Author(s).
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10.
  • Berglund, Sofia, et al. (författare)
  • Granulocyte transfusions could benefit patients with severe oral mucositis after allogeneic hematopoietic stem cell transplantation
  • 2019
  • Ingår i: Vox Sanguinis. - : Wiley-Blackwell. - 0042-9007 .- 1423-0410. ; 114:7, s. 769-777
  • Tidskriftsartikel (refereegranskat)abstract
    • Background and objectives Mucositis is a common complication after allogeneic hematopoietic stem cell transplantation (HSCT), and is caused by a combination of conditioning-induced mucosal damage and severe neutropenia. The symptoms include oral and abdominal pain, inability to swallow food and fluids, and severe diarrhoea. Severe mucositis is associated with increased risk of Graft-versus-Host disease and infection. Granulocyte transfusions (GCX) could be a treatment option, and our objective was to study its feasibility and potential benefits. Material and methods This retrospective, single-centre study included 30 patients receiving GCX because of severe oral mucositis after HSCT during 2005-2017. Clinical outcome, response to GCX, change in opiate administration and adverse events were studied. Results Twenty-seven patients received GCX from donors pre-treated with steroids and G-CSF, and three from donors pre-treated with steroids only. Overall response was 83% (24/29 evaluable patients). Fifteen patients reached a complete response. In 14 of 24 responders, a reduction of the administration of opiate pain relief was seen. In eight patients this reduction was >= 50% of the dose. Adverse events (AEs) were reported in 14 cases, and were mild to moderate, and well manageable with symptomatic treatment. No life-threatening or fatal AEs were recorded. Conclusions These results indicate that GCX could be a safe and effective treatment for oral mucositis after HSCT with the potential to reduce the necessity of opiate analgesic treatment in this disorder. No severe AEs were seen in this study, but the risk for severe pulmonary AEs after GCX needs to be considered.
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11.
  • Bredenberg, Susanne, et al. (författare)
  • Evaluation of a sieve classification method for characterization of low-dose interactive mixtures
  • 2013
  • Ingår i: Pharmaceutical development and technology (Print). - : Informa Healthcare. - 1083-7450 .- 1097-9867. ; 18:6, s. 1366-1371
  • Tidskriftsartikel (refereegranskat)abstract
    • This study investigated a sieve classification method for evaluating carrier materials and particle size fractions, which could be a valuable tool in the early development of pharmaceutical dosage forms containing low-dose interactive mixtures. When developing new products based on interactive mixtures, it is essential to ensure that the drug particles are successfully deagglomerated and have adhered to the carrier particles. In this study, the effect on the demixing potential (DP) of low-dose interactive mixtures was assessed for various carrier particle sizes and surface textures. The model drug used was sodium salicylate and the tested carriers were lactose, mannitol, and isomalt. The results showed that the lowest DPs, i.e. the most mechanically stable mixtures, were obtained with lactose. Furthermore, for interactive mixtures, small carrier particles and/or a narrow carrier particle size range are essential for obtaining a low DP and high homogeneity. Calculation of the DP provided a reliable estimate of the quality of the low-dose interactive mixtures used in this study.
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12.
  • Cousins, Sara A. O., et al. (författare)
  • Land use history and site location are more important for grassland species richness than local soil properties
  • 2009
  • Ingår i: Nordic Journal of Botany. - : Wiley. - 0107-055X .- 1756-1051. ; 27, s. 483-489
  • Tidskriftsartikel (refereegranskat)abstract
    • Lately there has been a shift in Sweden from grazing species-rich semi-natural grasslands towards grazing ex-arable fields in the modern agricultural landscape. Grazing ex-arable fields contain a fraction of the plant species richness confined to semi-natural grasslands. Still, they have been suggested as potential target sites for re-creation of semi-natural grasslands. We asked to what extent does fine-scale variation in soil conditions, management history and site location effect local plant diversity in grazed ex-arable fields. We examined local soil conditions such as texture, pH, organic carbon, nitrogen (N) and extractable phosphate (P) and effects on plant richness in ten pairs of grazed ex-fields and neighbouring semi-natural grasslands in different rural landscapes. Each grassland pair where in the same paddock. A multivariate test showed that site location and land use history explained more of differences in species richness than local soil property variables. Plant species richness was positively associated to grazed ex-fields with low pH, low N and P levels. Sites with high plant richness in semi-natural grasslands also had more species in the adjacent grazed ex-fields, compared to sites neighbouring less species-rich semi-natural grasslands. Although both soil properties and species richness were different in grazed ex-fields compared to semi-natural grassland, the site location within a landscape, and vicinity to species-rich grasslands, can override effects of soil properties. In conclusion, if properly located, ex-arable fields may be an important habitat to maintain plant diversity at larger spatio-temporal scales and should considered as potential sites for grassland restoration.
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13.
  • Dillner, Joakim, et al. (författare)
  • Antibodies to SARS-CoV-2 and risk of past or future sick leave
  • 2021
  • Ingår i: Scientific Reports. - : Springer Nature. - 2045-2322. ; 11:1
  • Tidskriftsartikel (refereegranskat)abstract
    • The extent that antibodies to SARS-CoV-2 may protect against future virus-associated disease is unknown. We invited all employees (n=15,300) at work at the Karolinska University Hospital, Stockholm, Sweden to participate in a study examining SARS-Cov-2 antibodies in relation to registered sick leave. For consenting 12,928 healthy hospital employees antibodies to SARS-CoV-2 could be determined and compared to participant sick leave records. Subjects with viral serum antibodies were not at excess risk for future sick leave (adjusted odds ratio (OR) controlling for age and sex: 0.85 [95% confidence interval (CI) (0.85 (0.43-1.68)]. By contrast, subjects with antibodies had an excess risk for sick leave in the weeks prior to testing [adjusted OR in multivariate analysis: 3.34 (2.98-3.74)]. Thus, presence of viral antibodies marks past disease and protection against excess risk of future disease. Knowledge of whether exposed subjects have had disease in the past or are at risk for future disease is essential for planning of control measures.Trial registration: First registered on 02/06/20, ClinicalTrials.gov NCT04411576.
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14.
  • Djureinovic, Dijana, et al. (författare)
  • Detection of autoantibodies against cancer-testis antigens in non-small cell lung cancer
  • 2018
  • Ingår i: Lung Cancer. - : Elsevier BV. - 0169-5002 .- 1872-8332. ; 125, s. 157-163
  • Tidskriftsartikel (refereegranskat)abstract
    • Cancer testis antigens (CTAs) are defined as proteins that are specifically expressed in testis or placenta and their expression is frequently activated in cancer. Due to their ability to induce an immune response, CTAs may serve as suitable targets for immunotherapy. The aim of this study was to evaluate if there is reactivity against CTAs in the plasma of non-small cell lung cancer (NSCLC) patients through the detection of circulating antibodies. To comprehensively analyse auto-antibodies against CTAs the multiplexing capacities of suspension bead array technology was used. Bead arrays were created with 120 protein fragments, representing 112 CTAs. Reactivity profiles were measured in plasma samples from 133 NSCLC patients and 57 cases with benign lung diseases. Altogether reactivity against 69 antigens, representing 81 CTAs, was demonstrated in at least one of the analysed samples. Twenty-nine of the antigens (45 CTAs) demonstrated exclusive reactivity in NSCLC samples. Reactivity against CT47A genes, PAGE3, VCX, MAGEB1, LIN28B and C12orf54 were only found in NSCLC patients at a frequency of 1%-4%. The presence of autoantibodies towards these six antigens was confirmed in an independent group of 34 NSCLC patients.In conclusion, we identified autoantibodies against CTAs in the plasma of lung cancer patients. The reactivity pattern of autoantibodies was higher in cancer patients compared to the benign group, stable over time, but low in frequency of occurrence. The findings suggest that some CTAs are immunogenic and that these properties can be utilized as immune targets.
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15.
  • Djureinovic, Dijana, et al. (författare)
  • Profiling cancer testis antigens in non-small-cell lung cancer
  • 2016
  • Ingår i: JCI INSIGHT. - : American Society for Clinical Investigation. - 2379-3708. ; 1:10
  • Tidskriftsartikel (refereegranskat)abstract
    • Cancer testis antigens (CTAs) are of clinical interest as biomarkers and present valuable targets for immunotherapy. To comprehensively characterize the CTA landscape of non-small-cell lung cancer (NSCLC), we compared RNAseq data from 199 NSCLC tissues to the normal transcriptome of 142 samples from 32 different normal organs. Of 232 CTAs currently annotated in the Caner Testis Database (CTdatabase), 96 were confirmed in NSCLC. To obtain an unbiased CTA profile of NSCLC, we applied stringent criteria on our RNAseq data set and defined 90 genes as CTAs, of which 55 genes were not annotated in the CTdatabase, thus representing potential new CTAs. Cluster analysis revealed that CTA expression is histology dependent and concurrent expression is common. IHC confirmed tissue-specific protein expression of selected new CTAs (TKTL1, TGIF2LX, VCX, and CXORF67). Furthermore, methylation was identified as a regulatory mechanism of CTA expression based on independent data from The Cancer Genome Atlas. The proposed prognostic impact of CTAs in lung cancer was not confirmed, neither in our RNAseq cohort nor in an independent meta-analysis of 1,117 NSCLC cases. In summary, we defined a set of 90 reliable CTAs, including information on protein expression, methylation, and survival association. The detailed RNAseq catalog can guide biomarker studies and efforts to identify targets for immunotherapeutic strategies.
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19.
  • Edlund, Karolina, et al. (författare)
  • Prognostic Impact of Tumor Cell Programmed Death Ligand 1 Expression and Immune Cell Infiltration in NSCLC
  • 2019
  • Ingår i: Journal of Thoracic Oncology. - : Elsevier BV. - 1556-0864 .- 1556-1380. ; 14:4, s. 628-640
  • Tidskriftsartikel (refereegranskat)abstract
    • Introduction: Infiltration of T and B/plasma cells has been linked to NSCLC prognosis, but this has not been thoroughly investigated in relation to the expression of programmed death ligand 1 (PD-L1). Here, we determine the association of lymphocytes and PD-L1 with overall survival (OS) in two retrospective cohorts of operated NSCLC patients who were not treated with checkpoint inhibitors targeting the programmed death 1/PD-L1 axis. Moreover, we evaluate how PD-L1 positivity and clinicopathologic factors affect the prognostic association of lymphocytes.Methods: Cluster of differentiation (CD) 3 (CD3)-, CD8-, CD4-, forkhead box P3 (FOXP3)-, CD20-, CD79A-, and immunoglobulin kappa constant (IGKC)-positive immune cells, and tumor PD-L1 positivity, were determined by immunohistochemistry on tissue microarrays (n = 705). Affymetrix data was analyzed for a patient subset, and supplemented with publicly available transcriptomics data (N = 1724). Associations with OS were assessed by Kaplan-Meier plots and uni- and multivariate Cox regression.Results: Higher levels of T and B plasma cells were associated with longer OS (p = 0.004 and p < 0.001, for CD8 and IGKC, respectively). Highly proliferative tumors with few lymphocytes had the worst outcome. No association of PD-L1 positivity with OS was observed in a nonstratified patient population; however, a significant association with shorter OS was observed in never-smokers (p = 0.009 and p = 0.002, 5% and 50% cutoff). Lymphocyte infiltration was not associated with OS in PD-L1–positive tumors (50% cutoff). The prognostic association of lymphocyte infiltration also depended on the patients’ smoking history and histologic subtype.Conclusions: Proliferation, PD-L1 status, smoking history, and histology should be considered if lymphocyte infiltration is to be used as a prognostic biomarker.
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20.
  • Elfving, Hedvig, et al. (författare)
  • Programmed Cell Death Ligand 1 Immunohistochemistry : A Concordance Study Between Surgical Specimen, Biopsy, and Tissue Microarray
  • 2019
  • Ingår i: Clinical Lung Cancer. - : Elsevier BV. - 1525-7304 .- 1938-0690. ; 20:4, s. 258-262.e1
  • Tidskriftsartikel (refereegranskat)abstract
    • Programmed cell death ligand 1 (PD-L1) expression within the same lung cancer tissue is variable. In this study we evaluated if the PD-L1 expression on small biopsy specimens represent the PD-L1 status of the corresponding resection specimen. Our results indicate a relative good agreement between biopsy and surgical specimens, with a discordance in approximately 10% of the cases. Background: The immunohistochemical analysis of programmed cell death ligand 1 (PD-L1) expression in tumor tissue of non-small-cell lung cancer patients has now been integrated in the diagnostic workup. Analysis is commonly done on small tissue biopsy samples representing a minimal fraction of the whole tumor. The aim of the study was to evaluate the correlation of PD-L1 expression on biopsy specimens with corresponding resection specimens. Materials and Methods: In total, 58 consecutive cases with preoperative biopsy and resected tumor specimens were selected. From each resection specimen 2 tumor cores were compiled into a tissue microarray (TMA). Immunohistochemical staining with the antibody SP263 was performed on biopsy specimens, resection specimens (whole sections), as well as on the TMA. Results: The proportion of PD-L1-positive stainings were comparable between the resection specimens (48% and 19%), the biopsies (43% and 17%), and the TMAs (47% and 14%), using cutoffs of 1% and 50%, respectively (P > .39 all comparisons). When the resection specimens were considered as reference, PD-L1 status differed in 16%/5% for biopsies and in 9%/9% for TMAs (1%/50% cutoff). The sensitivity of the biopsy analysis was 79%/82% and the specificity was 90%/98% at the 1%/50% cutoff. The Cohens kappa value for the agreement between biopsy and tumor. was 0.70 at the 1% cutoff and 0.83 at the 50% cutoff. Conclusion: The results indicate a moderate concordance between the analysis of biopsy and whole tumor tissue, resulting in misclassification of samples in particular when the lower 1% cutoff was used. Clinicians should be aware of this uncertainty when interpreting PD-L1 reports for treatment decisions.
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21.
  • Elfving, Hedvig, et al. (författare)
  • Tumor Heterogeneity Confounds Lymphocyte Metrics in Diagnostic Lung Cancer Biopsies
  • 2024
  • Ingår i: Archives of Pathology & Laboratory Medicine. - : Archives of Pathology and Laboratory Medicine. - 0003-9985 .- 1543-2165. ; 148:1, s. e18-e24
  • Tidskriftsartikel (refereegranskat)abstract
    • Context.—The immune microenvironment is involved in fundamental aspects of tumorigenesis, and immune scores are now being developed for clinical diagnostics. Objective.—To evaluate how well small diagnostic biopsies and tissue microarrays (TMAs) reflect immune cell infiltration compared to the whole tumor slide, in tissue from patients with non–small cell lung cancer. Design.—A TMA was constructed comprising tissue from surgical resection specimens of 58 patients with non–small cell lung cancer, with available preoperative biopsy material. Whole sections, biopsies, and TMA were stained for the pan-T lymphocyte marker CD3 to determine densities of tumor-infiltrating lymphocytes. Immune cell infiltration was assessed semiquantitatively as well as objectively with a microscopic grid count. For 19 of the cases, RNA sequencing data were available. Results.—The semiquantitative comparison of immune cell infiltration between the whole section and the biopsy displayed fair agreement (intraclass correlation coefficient [ICC], 0.29; P ¼ .01; CI, 0.03–0.51). In contrast, the TMA showed substantial agreement compared with the whole slide (ICC, 0.64; P , .001; CI, 0.39–0.79). The grid-based method did not enhance the agreement between the different tissue materials. The comparison of CD3 RNA sequencing data with CD3 cell annotations confirmed the poor representativity of biopsies as well as the stronger correlation for the TMA cores. Conclusions.—Although overall lymphocyte infiltration is relatively well represented on TMAs, the representativity in diagnostic lung cancer biopsies is poor. This finding challenges the concept of using biopsies to establish immune scores as prognostic or predictive biomarkers for diagnostic applications.
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22.
  • Eltahir, Mohamed, et al. (författare)
  • Plasma Proteomic Analysis in Non-Small Cell Lung Cancer Patients Treated with PD-1/PD-L1 Blockade
  • 2021
  • Ingår i: Cancers. - : MDPI. - 2072-6694. ; 13:13
  • Tidskriftsartikel (refereegranskat)abstract
    • Simple Summary Immunotherapy leads to highly variable responses in lung cancer patients. We assessed the value of a blood-based test to predict which patients would benefit from this new treatment modality. We determined that some patients have higher and lower levels of immune markers in their blood samples, and that this is related to better survival without tumor growth. The blood test has the potential to help select the optimal therapy for lung cancer patients. Checkpoint inhibitors have been approved for the treatment of non-small cell lung cancer (NSCLC). However, only a minority of patients demonstrate a durable clinical response. PD-L1 scoring is currently the only biomarker measure routinely used to select patients for immunotherapy, but its predictive accuracy is modest. The aim of our study was to evaluate a proteomic assay for the analysis of patient plasma in the context of immunotherapy. Pretreatment plasma samples from 43 NSCLC patients who received anti-PD-(L)1 therapy were analyzed using a proximity extension assay (PEA) to quantify 92 different immune oncology-related proteins. The plasma protein levels were associated with clinical and histopathological parameters, as well as therapy response and survival. Unsupervised hierarchical cluster analysis revealed two patient groups with distinct protein profiles associated with high and low immune protein levels, designated as "hot" and "cold". Further supervised cluster analysis based on T-cell activation markers showed that higher levels of T-cell activation markers were associated with longer progression-free survival (PFS) (p < 0.01). The analysis of single proteins revealed that high plasma levels of CXCL9 and CXCL10 and low ADA levels were associated with better response and prolonged PFS (p < 0.05). Moreover, in an explorative response prediction model, the combination of protein markers (CXCL9, CXCL10, IL-15, CASP8, and ADA) resulted in higher accuracy in predicting response than tumor PD-L1 expression or each protein assayed individually. Our findings demonstrate a proof of concept for the use of multiplex plasma protein levels as a tool for anti-PD-(L)1 response prediction in NSCLC. Additionally, we identified protein signatures that could predict the response to anti-PD-(L)1 therapy.
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23.
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24.
  • Enell, Sofia, et al. (författare)
  • Rättigheter som ”token”, egenansvar och egenvärde – : Barn och ungas förståelse av rättigheter i låst institutionsvård
  • 2023
  • Ingår i: Nordisk socialrättslig tidskrift. - : Stockholms universitet. - 2000-6500. ; :2023 35-36, s. 7-38
  • Tidskriftsartikel (refereegranskat)abstract
    • In Sweden, the recent debate on youth crime has focused on strengthening repressive measures. At the same time, government work is underway to strengthen children’s rights. Young people who are placed for the purpose of care in secure youth care (locked institutions) are placed at the intersection of these two trends. Starting from a critical children’s rights perspective, we explore how young people understand rights in a secure care environment and discuss how these understandings relates to central principals, laws and conventions. We start from the concrete situations and contexts in which rights are to be realized in order to contribute to a better understanding of the importance of rights in a secure care environment. The empirical data consists of 15 youth interviews, at four institutions. Three understandings of rights are identified; rights as tokens where rights are seen as something symbolic and without meaning, rights as self-responsibility where rights are seen as conditional on the young people’s actions and, rights as fundamental value where rights are understood as respect for one’s own and others’ human dignity, regardless of their actions. The three understandings of rights can be linked to different care contexts and to the relationship between staff and young people. Taken together, the young people’s understandings highlight the importance of basic principles of dignity and respect on equal terms, as well as the right of children deprived of their liberty to be helped to reintegrate into society. Implications for the operation of secure youth care are highlighted.
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25.
  • Gabrielsson, Linda, et al. (författare)
  • Palmitoylethanolamide for the treatment of pain : pharmacokinetics, safety and efficacy
  • 2016
  • Ingår i: British Journal of Clinical Pharmacology. - : Wiley. - 0306-5251 .- 1365-2125. ; 82:4, s. 932-942
  • Forskningsöversikt (refereegranskat)abstract
    • Palmitoylethanolamide (PEA) has been suggested to have useful analgesic properties and to be devoid of unwanted effects. Here, we have examined critically this contention, and discussed available data concerning the pharmacokinetics of PEA and its formulation. Sixteen clinical trials, six case reports/pilot studies and a meta-analysis of PEA as an analgesic have been published in the literature. For treatment times up to 49days, the current clinical data argue against serious adverse drug reactions (ADRs) at an incidence of 1/200 or greater. For treatment lasting more than 60days, the number of patients is insufficient to rule out a frequency of ADRs of less than 1/100. The six published randomized clinical trials are of variable quality. Presentation of data without information on data spread and nonreporting of data at times other than the final measurement were among issues that were identified. Further, there are no head-to-head clinical comparisons of unmicronized vs. micronized formulations of PEA, and so evidence for superiority of one formulation over the other is currently lacking. Nevertheless, the available clinical data support the contention that PEA has analgesic actions and motivate further study of this compound, particularly with respect to head-to-head comparisons of unmicronized vs. micronized formulations of PEA and comparisons with currently recommended treatments.
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26.
  • Goldmann, Torsten, et al. (författare)
  • PD-L1 amplification is associated with an immune cell rich phenotype in squamous cell cancer of the lung
  • 2021
  • Ingår i: Cancer Immunology and Immunotherapy. - : Springer Nature. - 0340-7004 .- 1432-0851. ; 70:9, s. 2577-2587
  • Tidskriftsartikel (refereegranskat)abstract
    • Gene amplification is considered to be one responsible cause for upregulation of Programmed Death Ligand-1 (PD-L1) in non-small cell lung cancer (NSCLC) and to represent a specific molecular subgroup possibly associated with immunotherapy response. Our aim was to analyze the frequency of PD-L1 amplification, its relation to PD-L1 mRNA and protein expression, and to characterize the immune microenvironment of amplified cases. The study was based on two independent NSCLC cohorts, including 354 and 349 cases, respectively. Tissue microarrays were used to evaluate PD-L1 amplification by FISH and PD-L1 protein by immunohistochemistry. Immune infiltrates were characterized immunohistochemically by a panel of immune markers (CD3, CD4, CD8, PD-1, Foxp3, CD20, CD138, CD168, CD45RO, NKp46). Mutational status was determined by targeted sequencing. RNAseq data was available for 197 patients. PD-L1 amplification was detected in 4.5% of all evaluable cases. PD-L1 amplification correlated only weakly with mRNA and protein expression. About 37% of amplified cases were negative for PD-L1 protein. PD-L1 amplification did not show any association with the mutational status. In squamous cell cancer, PD-L1 amplified cases were enriched among patients with high tumoral immune cell infiltration and showed gene expression profiles related to immune exhaustion. In conclusion, PD-L1 amplification correlates with PD-L1 expression in squamous cell cancer and was associated with an immune cell rich tumor phenotype. The correlative findings help to understand the role of PD-L1 amplification as an important immune escape mechanism in NSCLC and suggest the need to further evaluate PD-L1 amplification as predictive biomarker for checkpoint inhibitor therapy.
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27.
  • Grindegård, Linnéa, et al. (författare)
  • Association Between EEG Patterns and Serum Neurofilament Light After Cardiac Arrest: A Post Hoc Analysis of the TTM Trial.
  • 2022
  • Ingår i: Neurology. - 1526-632X .- 0028-3878. ; 98:24
  • Tidskriftsartikel (refereegranskat)abstract
    • Electroencephalography (EEG) is widely used for prediction of neurological outcome after cardiac arrest. To better understand the relationship between EEG and neuronal injury, we explore the association between EEG and neurofilament light (NFL) as a marker of neuroaxonal injury. We evaluate whether highly malignant EEG patterns are reflected by high NFL levels. Additionally, we explore the association of EEG backgrounds and EEG discharges with NFL.Post-hoc analysis of the Target Temperature Management after out-of-hospital cardiac arrest (TTM)-trial. Routine EEGs were prospectively performed after the temperature intervention ≥36 hours post-arrest. Patients who awoke or died prior to 36 hours post-arrest were excluded. EEG-experts blinded to clinical information classified EEG background, amount of discharges and highly malignant EEG patterns according to the standardized American Clinical Neurophysiology Society terminology. Prospectively collected serum samples were analyzed for NFL after trial completion. The highest available concentration at 48 or 72-hours post-arrest was used.262/939 patients with EEG and NFL data were included. Patients with highly malignant EEG patterns had 2.9 times higher NFL levels than patients with malignant patterns and NFL levels were 13 times higher in patients with malignant patterns than those with benign patterns (95% CI: 1.4-6.1 and 6.5-26.2 respectively, effect size 0.47, p<0.001). Both background and the amount of discharges were independently strongly associated with NFL levels (p<0.001). The EEG background had a stronger association with NFL levels than EEG discharges (R2=0.30 and R2=0.10, respectively). NFL levels in patients with a continuous background were lower than for any other background (95% CI for discontinuous, burst-suppression and suppression, respectively: 2.26-18.06, 3.91-41.71 and 5.74-41.74, effect size 0.30 and p<0.001 for all). NFL levels did not differ between suppression and burst-suppression. Superimposed discharges were only associated with higher NFL levels if the EEG background was continuous.Benign, malignant, and highly malignant EEG patterns reflect the extent of brain injury as measured by NFL in serum. The extent of brain injury is more strongly related to the EEG background than superimposed discharges. Combining EEG and NFL may be useful to better identify patients misclassified by single methods.clinicaltrials.gov, NCT01020916.
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28.
  • Gulyas, Miklos, et al. (författare)
  • COX-2 expression and effects of celecoxib in addition to standard chemotherapy in advanced non-small cell lung cancer.
  • Tidskriftsartikel (refereegranskat)abstract
    • Inhibition of cyclooxygenase-2 (COX-2) is proposed as a treatment option in several cancer types. However, in non-small cell lung cancer (NSCLC), phase III trials have failed to demonstrate a benefit of adding COX-2 inhibitors to standard chemotherapy. The aim of this study was to analyse COX-2 expression in tumor and stromal cells as predictive biomarker for COX-2 inhibition.Methods: In the multicenter phase III trial, 316 patients with advanced NSCLC were randomized to receive celecoxib (400 mg b.i.d.) or placebo up to one year in addition to a two-drug platinum-based chemotherapy combination. In a subset of 122 patients, archived tumor tissue was available for immunohistochemical analysis of COX-2 expression in tumor and stromal cells.Results: An updated analysis of all 316 patients included in the original trial, and of the 122 patients with available tumor tissue, showed no survival differences between the celecoxib and placebo arms (HR 1.01; 95%CI 0.81-1.27 and HR 1.12; 95%CI 0.78-1.61, respectively). Similarly, in patients with high COX-2 expression in tumor cells (n=71) or stromal cells (n=55), survival did not differ significantly between patients who received celecoxib or placebo (HR 1.07; 95%CI 0.74-1.54 and HR 0.80; 95%CI 0.56-1.15). No significant interaction effect between COX-2 score in tumor or stromal cells and celecoxib effect on survival was detected (p=0.48 and 0.25, respectively).Conclusion: In this subgroup analysis of patients with advanced NSCLC, we could not detect any significant interaction between COX-2 expression in tumor or stromal cells and outcome of celecoxib treatment in addition to standard chemotherapy.
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29.
  • Gulyas, Miklos, et al. (författare)
  • COX-2 expression and effects of celecoxib in addition to standard chemotherapy in advanced non-small cell lung cancer.
  • 2018
  • Ingår i: Acta Oncologica. - : Taylor & Francis. - 0284-186X .- 1651-226X. ; 57:2, s. 244-250
  • Tidskriftsartikel (refereegranskat)abstract
    • Aim: Inhibition of cyclooxygenase-2 (COX-2) is proposed as a treatment option in several cancer types. However, in non-small cell lung cancer (NSCLC), phase III trials have failed to demonstrate a benefit of adding COX-2 inhibitors to standard chemotherapy. The aim of this study was to analyze COX-2 expression in tumor and stromal cells as predictive biomarker for COX-2 inhibition.Methods: In a multicenter phase III trial, 316 patients with advanced NSCLC were randomized to receive celecoxib (400 mg b.i.d.) or placebo up to one year in addition to a two-drug platinum-based chemotherapy combination. In a subset of 122 patients, archived tumor tissue was available for immunohistochemical analysis of COX-2 expression in tumor and stromal cells. For each compartment, COX-2 expression was graded as high or low, based on a product score of extension and intensity of positively stained cells.Results: An updated analysis of all 316 patients included in the original trial, and of the 122 patients with available tumor tissue, showed no survival differences between the celecoxib and placebo arms (HR 1.01; 95% CI 0.81–1.27 and HR 1.12; 95% CI 0.78–1.61, respectively). High COX-2 scores in tumor (n = 71) or stromal cells (n = 55) was not associated with a superior survival outcome with celecoxib vs. placebo (HR =0.96, 95% CI 0.60–1.54; and HR =1.51; 95% CI 0.86–2.66), and no significant interaction effect between COX-2 score in tumor or stromal cells and celecoxib effect on survival was detected (p = .48 and .25, respectively).Conclusions: In this subgroup analysis of patients with advanced NSCLC treated within the context of a randomized trial, we could not detect any interaction effect of COX-2 expression in tumor or stromal cells and the outcome of celecoxib treatment in addition to standard chemotherapy.
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30.
  • Gustafsson, Maria, et al. (författare)
  • Education Satisfaction among Pharmacy Graduates in Sweden
  • 2021
  • Ingår i: Pharmacy. - : MDPI. - 2226-4787. ; 9:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Education satisfaction is considered important for development of a professional identity and to increase learning. The aim was to investigate and compare education satisfaction over time among pharmacists who have graduated from the pharmacy programs at Umea University, Sweden. Data concerning education satisfaction were collected using an alumni survey of pharmacists who graduated between 2015 and 2018. This was compared with pharmacists graduating between 2006 and 2014. The majority of the pharmacy graduates were very satisfied with their education (96%) and thought that the programs gave them a clear professional identity (92%). No differences in education satisfaction between graduation years 2015 and 2018 and 2006 and 2014 were found. A majority of the graduates considered that the knowledge and skills acquired during their education were useful in their present job (83%). Of the graduates who thought that the studies gave them a clear professional identity, a higher proportion were satisfied with their job (p < 0.001) and thought that their work duties reflected their studies (p = 0.005). Exploring education satisfaction may help educators to further develop the education and to better prepare the students for their professional working life.
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31.
  • Gustafsson, Maria, et al. (författare)
  • Pharmacists' satisfaction with their work : Analysis of an alumni survey
  • 2018
  • Ingår i: Research in Social and Administrative Pharmacy. - : Elsevier. - 1551-7411 .- 1934-8150. ; 14:7, s. 700-704
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: The level of job satisfaction among practicing pharmacists is important because it has been found to affect job performance and employee turnover. The Swedish pharmacy market has undergone major changes in recent years, and little is known about pharmacists' job satisfaction.Objectives: The objective of this study was to investigate the level of job satisfaction and associated factors among graduates from the web-based pharmacy programs at Umea University.Methods: Job satisfaction of pharmacists was measured as part of an alumni survey conducted with those who graduated from the pharmacy programmes between 2006 and 2014. Data analysis included descriptive statistics, and logistic regression was used to explore factors affecting job satisfaction.Results: The total number of graduates who completed the survey was 222 (response rate 43%.) The majority of respondents were female (95%), and most were employed at a community pharmacy (85%). The mean age was 39.7 years. The majority of graduates (91%) were satisfied with their job "most of the time" or "all of the time", and 87% of the respondents would "definitely" or "maybe" choose the same career again. The multivariate analysis showed that increasing years in the current position (OR: 0.672 (0.519-0.871)) was associated with lower job satisfaction. Older age (OR: 1.123 (1.022-1.234)), the perception that the knowledge and skills acquired during university education is useful in the current job (OR: 4.643 (1.255-17.182)) and access to continuing professional development (OR: 9.472 (1.965 -45.662)) were associated with higher job satisfaction.Conclusion: Most graduates from the web-based pharmacy programmes were satisfied with their current job. Access to continuing professional development seems to be important for the level of job satisfaction among pharmacists.
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32.
  • Gustafsson, Maria, et al. (författare)
  • Students' satisfaction with a web-based pharmacy program in a re-regulated pharmacy market
  • 2017
  • Ingår i: Pharmacy. - : MDPI AG. - 2226-4787. ; 5:3
  • Tidskriftsartikel (refereegranskat)abstract
    • In response to the shortage of pharmacists in Northern Sweden, a web-based Bachelor of Science in Pharmacy program was established at Umeå University in 2003. In 2009, the Swedish pharmacy market was re-regulated from a state monopoly to an open market, but it is unknown what impact this has had on education satisfaction. The objectives of this study were to examine the level of satisfaction among graduates from a web-based pharmacy program and to describe what subjects and skills students would have liked more or less of in their education. A secondary objective was to compare the level of satisfaction before and after the Swedish pharmacy market was re-regulated. A cross-sectional survey was conducted in 2015 with all alumni who had graduated from the pharmacy program between 2006 and 2014 (n = 511), and responses to questions about graduates' satisfaction with the program were analyzed (n = 200). Most graduates (88%) agreed or strongly agreed that the knowledge and skills acquired during their education were useful in their current job. The graduates stated that they would have wanted more applied pharmacy practice and self-care counselling, and fewer social pharmacy and histology courses. Further, 82% stated that they would start the same degree program if they were to choose again today, and 92% agreed or strongly agreed that they would recommend the program to a prospective student. Graduates were more likely to recommend the program after the re-regulation (p = 0.007). In conclusion, pharmacy graduates were very satisfied with their education, and no negative effects of the re-regulation could be observed on program satisfaction.
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33.
  • Gustafsson, Maria, et al. (författare)
  • Swedish Pharmacy Students' Expectations and Perceptions of Their Education and Future Pharmacy Profession
  • 2019
  • Ingår i: Pharmacy. - : MDPI. - 2226-4787. ; 7:4
  • Tidskriftsartikel (refereegranskat)abstract
    • Distance education is becoming more and more common, and today distance education is well established within academic settings. The aim was to investigate first-year pharmacy students' expectations and perceptions of web-based pharmacy programs and of their future profession. Furthermore, student characteristics were compared over time. A questionnaire was distributed to all first-year students admitted to the pharmacy programs at Umea University in 2017. The students were asked questions about their background, motives for choosing pharmacy education, and their expectations and perceptions of their education and profession. Factors of most importance when choosing the education were: the education is interesting, leads to an interesting job, and is web-based. The students' expectations of the education were high, and they want to learn as much as possible and be well prepared for their future profession. Regarding the students' perception of their future profession, three themes were identified: to help other people, professional development, and employment related issues. Student characteristics have changed over the years, suggesting that the web-based pharmacy education and the flexibility it entails attracts other groups of students today compared with when the programs started.
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34.
  • Hagen, Eirik, et al. (författare)
  • Use of interactive mixtures to obtain mini-tablets with high dose homogeneity for paediatric drug delivery
  • 2016
  • Ingår i: Journal of Drug Delivery Science and Technology. - : Elsevier BV. - 1773-2247. ; 34, s. 51-59
  • Tidskriftsartikel (refereegranskat)abstract
    • Mini-tablets are suitable for children since they are easy to swallow and offer dose flexibility by adjustment of the number of units. The main objective was to investigate the use of interactive mixtures as a means to obtain high dose homogeneity in mini-tablets. The effect of carrier particle properties, mixing time, mixing equipment and sample size on homogeneity was evaluated. Micronized sodium salicylate (1% w/w) was mixed with different size fractions of spray-dried and granulated mannitol. The degree of homogeneity was expressed as the relative standard deviation (RSD). Mini-tablets were prepared from the interactive mixtures and characterized with respect to uniformity of mass and content, dose homogeneity, tablet strength, wetting time and disintegration time. Generally, RSD decreased with increasing mixing times, and levelled out around 3-4%. The lowest RSD was achieved with carrier particles of intermediate sizes; 125-180 mu m, 180-250 mu m and 250-355 mu m. The tumbling mixer was considered to be more suitable than the planetary mixer and longer mixing times were required to reach high degree of homogeneity in the smaller sample size. Mini-tablets showed high dose homogeneity as well as appropriate tensile strength and disintegration time to be suitable as orally disintegrating mini-tablets for children.
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35.
  • Hansson, Anna, 1984-, et al. (författare)
  • Biogas production in the industrial symbiosis context – facilitating collaboration through digitalization
  • 2024
  • Ingår i: 5THCESUST2024: 5TH SYMPOSIUM ON CIRCULAR ECONOMY AND SUSTAINABILITY.
  • Konferensbidrag (refereegranskat)abstract
    • Improving sustainability performance and adapting to circular economy principles in operational business strategies are becoming increasingly prioritized. In this pursuit, the concept of industrial symbiosis (IS) has become increasingly relevant. IS represents a collaborative approach where the interplay of material, residual waste, energy, and infrastructure exchanges aims to yield not only economic and environmental advantages for the participating companies but also substantial societal benefits by using resources more efficiently. Biogas production is such an example, it can reduce greenhouse gas emissions since it can produce heat and electricity, replace renewable fuel for vehicles, or be used as input material for industrial use. The digestate from biogas production can also be used as an effective agricultural fertilizer to replace chemical fertilizers which are produced using fossil energy.Digital tools and platforms in IS can be used to different extent depending on businesses levels of digital maturity (the extent to which businesses adapt to ongoing digital change and integrate digitalization). Digital tools and platforms hold a central role for developing various advantages in biogas-based IS, but since the digital maturity for IS focusing on biogas production is uncertain, the current efficiency obtained by tools and platforms is unknown. Therefore, through semi-structured interviews and study visits, this study assesses stakeholder collaboration and use of digital tools at five IS sites with biogas production in Sweden. It explores (i) current digital maturity and collaboration characteristics amongst established biogas-based IS, and (ii) needs amongst stakeholders for development of digital tools and platforms to promote digital maturity, monitoring, collaboration, and knowledge exchange in current and future IS structures.Preliminary results of the on-going study show that the use of digital tools varies depending on the character and size of resource flows that are included in the collaboration, and due to the internal digital maturity of the involved companies. In general, the use of digital tools for stakeholder interaction is on low or medium level, in which manual handling is required and little is automated. This complies with the sites being relatively small, and the number of stakeholders involved are relatively few. Moreover, the preliminary results show that the interest of future development of digital tools is found to be related to business development and expanded market opportunities through diversified raw material use, increased production, and new distribution channels. In addition, a demand of digital platforms for exchange of experience and competence supply has been identified.
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36.
  • Hellberg, Emma, et al. (författare)
  • Evaluation of dissolution techniques for orally disintegrating mini-tablets
  • 2021
  • Ingår i: Journal of Drug Delivery Science and Technology. - : Elsevier. - 1773-2247. ; 61
  • Tidskriftsartikel (refereegranskat)abstract
    • Mini-tablets are suitable for paediatric as well as geriatric use since they may provide flexible and accurate dosing and administration. Due to the minute tablet size, there is a need for new standardized quality evaluation procedures and conventional techniques may have to be adopted. The main objective of the study was to evaluate different dissolution techniques for orally disintegrating mini-tablets. Dissolution tests using mini-paddle apparatus were compared with standard size paddle apparatus, and the effect of paddle rotation speed was evaluated. Also, the filter choice, and its impact on dissolution, was considered. Sodium salicylate was used as a model drug substance and was mixed with different size fractions of mannitol. The powder mixtures were compacted into 2 mm flat faced tablets. The mini-tablets were characterized regarding weight and content uniformity, tensile strength, friability, disintegration and dissolution. Similar dissolution profiles were obtained with both mini and standard equipment. The paddle rotation speed affected the dissolution profiles; a low paddle speed resulted in a slower dissolution. Furthermore, choosing a chemically inert filter will increase the likelihood of obtaining reliable and accurate results. An appropriately designed dissolution test using mini-paddle apparatus is required prior to further implementation in quality control procedures.
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37.
  • Hikmet Noraddin, Feria, et al. (författare)
  • Expression of cancer-testis antigens in the immune microenvironment of non-small cell lung cancer
  • 2023
  • Ingår i: Molecular Oncology. - : John Wiley & Sons. - 1574-7891 .- 1878-0261. ; 17:12, s. 2603-2617
  • Tidskriftsartikel (refereegranskat)abstract
    • The antigenic repertoire of tumors is critical for successful anti-cancer immune response and the efficacy of immunotherapy. Cancer-testis antigens (CTAs) are targets of humoral and cellular immune reactions. We aimed to characterize CTA expression in non-small cell lung cancer (NSCLC) in the context of the immune microenvironment. Of 90 CTAs validated by RNA sequencing, eight CTAs (DPEP3, EZHIP, MAGEA4, MAGEB2, MAGEC2, PAGE1, PRAME, and TKTL1) were selected for immunohistochemical profiling in cancer tissues from 328 NSCLC patients. CTA expression was compared with immune cell densities in the tumor environment and with genomic, transcriptomic, and clinical data. Most NSCLC cases (79%) expressed at least one of the analyzed CTAs, and CTA protein expression correlated generally with RNA expression. CTA profiles were associated with immune profiles: high MAGEA4 expression was related to M2 macrophages (CD163) and regulatory T cells (FOXP3), low MAGEA4 was associated with T cells (CD3), and high EZHIP was associated with plasma cell infiltration (adj. P-value < 0.05). None of the CTAs correlated with clinical outcomes. The current study provides a comprehensive evaluation of CTAs and suggests that their association with immune cells may indicate in situ immunogenic effects. The findings support the rationale to harness CTAs as targets for immunotherapy.
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38.
  • Hikmet Noraddin, Feria, et al. (författare)
  • Expression of cancer-testis antigens in the immune microenvironment of non-small cell lung cancer.
  • 2023
  • Ingår i: Molecular oncology. - : John Wiley & Sons. - 1878-0261 .- 1574-7891. ; 17:12, s. 2603-2617
  • Tidskriftsartikel (refereegranskat)abstract
    • The antigenic repertoire of tumors is critical for successful anti-cancer immune response and the efficacy of immunotherapy. Cancer-testis antigens (CTAs) are targets of humoral and cellular immune reactions. We aimed to characterize CTA expression in non-small cell lung cancer (NSCLC) in the context of the immune microenvironment. Of 90 CTAs validated by RNA sequencing, eight CTAs (DPEP3, EZHIP, MAGEA4, MAGEB2, MAGEC2, PAGE1, PRAME, and TKTL1) were selected for immunohistochemical profiling in cancer tissues from 328 NSCLC patients. CTA expression was compared with immune cell densities in the tumor environment and with genomic, transcriptomic, and clinical data. Most NSCLC cases (79%) expressed at least one of the analyzed CTAs, and CTA protein expression correlated generally with RNA expression. CTA profiles were associated with immune profiles: high MAGEA4 expression was related to M2 macrophages (CD163) and regulatory T cells (FOXP3), low MAGEA4 was associated with T cells (CD3), and high EZHIP was associated with plasma cell infiltration (adj. P-value <0.05). None of the CTAs correlated with clinical outcomes. The current study provides a comprehensive evaluation of CTAs and suggests that their association with immune cells may indicate insitu immunogenic effects. The findings support the rationale to harness CTAs as targets for immunotherapy.
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39.
  • Horie, Masafumi, et al. (författare)
  • An integrative transcriptome analysis reveals a functional role for thyroid transcription factor-1 in small cell lung cancer
  • 2018
  • Ingår i: Journal of Pathology. - : Wiley. - 0022-3417 .- 1096-9896. ; 246:2, s. 154-165
  • Tidskriftsartikel (refereegranskat)abstract
    • Small cell lung cancer (SCLC) is a neuroendocrine tumour that exhibits rapid growth and metastatic spread. Although SCLC represents a prototypically undifferentiated cancer type, thyroid transcription factor-1 (TTF-1, gene symbol NKX2-1), a master regulator for pulmonary epithelial cell differentiation and lung morphogenesis, is strongly upregulated in this aggressive cancer type. The aim of this study was to evaluate a functional role for TTF-1 in SCLC. We demonstrated that achaete-scute complex homolog 1 (ASCL1), an essential transcription factor for neuroendocrine differentiation, positively regulated TTF-1 in SCLC cell lines. Subsequently, we described genes and microRNAs (miRNAs) that were possibly controlled by TTF-1 and identified nuclear factor IB (NFIB), a recently characterised driver of SCLC progression, as a transcriptional target of TTF-1. Our findings shine light on a regulatory axis in SCLC consisting of ASCL1/TTF-1/NFIB that potentially contributes to the tumourigenesis of SCLC.
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40.
  • Isaksson, Johan, et al. (författare)
  • Highly elevated systemic inflammation is a strong independent predictor of early mortality in advanced non-small cell lung cancer
  • 2022
  • Ingår i: Cancer Treatment and Research Communications. - : Elsevier. - 2468-2942. ; 31
  • Tidskriftsartikel (refereegranskat)abstract
    • BackgroundAmple evidence support inflammation as a marker of outcome in non-small cell lung cancer (NSCLC). Here we explore the outcome for a subgroup of patients with advanced disease and substantially elevated systemic inflammatory activity.MethodsThe source cohort included consecutive patients diagnosed with NSCLC between January 2016 – May 2017 (n = 155). Patients with active infection were excluded. Blood parameters were examined individually, and cut-offs (ESR > 60 mm, CRP > 20 mg/L, WBC > 10 × 109, PLT > 400 × 109) were set to define the group of hyperinflamed patients. A score was developed by assigning one point for each parameter above cut-off (0–4 points).ResultsHigh systemic inflammation was associated with advanced stage and was seldom present in limited NSCLC. However, the one year survival of patients in stage IIIB-IV (n = 93) with an inflammation score of ≥2 was 0% compared to 33% and 50% among patients with a score of 1 and 0 respectively. The effect of a high inflammation score on overall survival remained significant in multi-variate analysis adjusted for confounding factors. The independent hazard ratio of an inflammation score ≥ 2 in multi-variate analysis (HR 3.43, CI 1.76–6.71) was comparable to a change in ECOG PS from 0 to 2 (HR 2.42, CI 1.13–5.18).ConclusionOur results show that high level systemic inflammation is a strong independent predictor of poor survival in advanced stage NSCLC. This observation may indicate a need to use hyperinflammation as an additional clinical parameter for stratification of patients in clinical studies and warrants further research on underlying mechanisms linked to tumor progression.
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41.
  • Karlsson, Anna, et al. (författare)
  • Gene Expression Profiling of Large Cell Lung Cancer Links Transcriptional Phenotypes to the New Histological WHO 2015 Classification
  • 2017
  • Ingår i: Journal of Thoracic Oncology. - : ELSEVIER SCIENCE INC. - 1556-0864 .- 1556-1380. ; 12:8, s. 1257-1267
  • Tidskriftsartikel (refereegranskat)abstract
    • Introduction: Large cell lung cancer (LCLC) and large cell neuroendocrine carcinoma (LCNEC) constitute a small proportion of NSCLC. The WHO 2015 classification guidelines changed the definition of the debated histological subtype LCLC to be based on immunomarkers for adenocarcinoma and squamous cancer. We sought to determine whether these new guidelines also translate into the transcriptional landscape of lung cancer, and LCLC specifically.Methods: Gene expression profiling was performed by using Illumina V4 HT12 microarrays (Illumina, San Diego, CA) on samples from 159 cases (comprising all histological subtypes, including 10 classified as LCLC WHO 2015 and 14 classified as LCNEC according to the WHO 2015 guidelines), with complimentary mutational and immunohistochemical data. Derived transcriptional phenotypes were validated in 199 independent tumors, including six WHO 2015 LCLCs and five LCNECs.Results: Unsupervised analysis of gene expression data identified a phenotype comprising 90% of WHO 2015 LCLC tumors, with characteristics of poorly differentiated proliferatiVe cancer, a 90% tumor protein p53 gene (TP53) mutation rate, and lack of well-known NSCLC oncogene driver alterations. Validation in independent data confirmed aggregation of WHO 2015 LCLCs in the specific phenotype. For LCNEC tumors, the unsupervised gene expression analysis suggested two different transcriptional patterns corresponding to a proposed genetic division of LCNEC tumors into SCLC-like and NSCLC-like cancer on the basis of TP53 and retinoblastoma 1 gene (RB1) alteration patterns.Conclusions: Refined classification of LCLC has implications for diagnosis, prognostics, and therapy decisions. Our molecular analyses support the WHO 2015 classification of LCLC and LCNEC tumors, which herein follow different tumorigenic paths and can accordingly be stratified into different transcriptional subgroups, thus linking diagnostic immunohistochemical staining driven classification with the transcriptional landscape of lung cancer.
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42.
  • Khan, Omar M., 1980, et al. (författare)
  • Geranylgeranyltransferase type I (GGTase-I) deficiency hyperactivates macrophages and induces erosive arthritis in mice.
  • 2011
  • Ingår i: The Journal of clinical investigation. - 1558-8238. ; 121:2, s. 628-39
  • Tidskriftsartikel (refereegranskat)abstract
    • RHO family proteins are important for the function of inflammatory cells. They are modified with a 20-carbon geranylgeranyl lipid in a process catalyzed by protein geranylgeranyltransferase type I (GGTase-I). Geranylgeranylation is viewed as essential for the membrane targeting and activity of RHO proteins. Consequently, inhibiting GGTase-I to interfere with RHO protein activity has been proposed as a strategy to treat inflammatory disorders. However, here we show that mice lacking GGTase-I in macrophages develop severe joint inflammation resembling erosive rheumatoid arthritis. The disease was initiated by the GGTase-I-deficient macrophages and was transplantable and reversible in bone marrow transplantation experiments. The cells accumulated high levels of active GTP-bound RAC1, CDC42, and RHOA, and RAC1 remained associated with the plasma membrane. Moreover, GGTase-I deficiency activated p38 and NF-κB and increased the production of proinflammatory cytokines. The results challenge the view that geranylgeranylation is essential for the activity and localization of RHO family proteins and suggest that reduced geranylgeranylation in macrophages can initiate erosive arthritis.
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43.
  • La Fleur, Linnea, et al. (författare)
  • Expression of scavenger receptor MARCO defines a targetable tumor-associated macrophage subset in non-small cell lung cancer
  • 2018
  • Ingår i: International Journal of Cancer. - : WILEY. - 0020-7136 .- 1097-0215. ; 143:7, s. 1741-1752
  • Tidskriftsartikel (refereegranskat)abstract
    • Tumor-associated macrophages (TAMs) are attractive targets for immunotherapy. Recently, studies in animal models showed that treatment with an anti-TAM antibody directed against the scavenger receptor MARCO resulted in suppression of tumor growth and metastatic dissemination. Here we investigated the expression of MARCO in relation to other macrophage markers and immune pathways in a non-small cell lung cancer (NSCLC) cohort (n=352). MARCO, CD68, CD163, MSR1 and programmed death ligand-1 (PD-L1) were analyzed by immunohistochemistry and immunofluorescence, and associations to other immune cells and regulatory pathways were studied in a subset of cases (n=199) with available RNA-seq data. We observed a large variation in macrophage density between cases and a strong correlation between CD68 and CD163, suggesting that the majority of TAMs present in NSCLC exhibit a protumor phenotype. Correlation to clinical data only showed a weak trend toward worse survival for patients with high macrophage infiltration. Interestingly, MARCO was expressed on a distinct subpopulation of TAMs, which tended to aggregate in close proximity to tumor cell nests. On the transcriptomic level, we found a positive association between MARCO gene expression and general immune response pathways including strong links to immunosuppressive TAMs, T-cell infiltration and immune checkpoint molecules. Indeed, a higher macrophage infiltration was seen in tumors expressing PD-L1, and macrophages residing within tumor cell nests co-expressed MARCO and PD-L1. Thus, MARCO is a potential new immune target for anti-TAM treatment in a subset of NSCLC patients, possibly in combination with available immune checkpoint inhibitors.
  •  
44.
  • La Fleur, Linnea, et al. (författare)
  • Mutation patterns in a population-based non-small cell lung cancer cohort and prognostic impact of concomitant mutations in KRAS and TP53 or STK11
  • 2019
  • Ingår i: Lung Cancer. - : Elsevier BV. - 0169-5002 .- 1872-8332. ; 130, s. 50-58
  • Tidskriftsartikel (refereegranskat)abstract
    • OBJECTIVES: Non-small cell lung cancer (NSCLC) is a heterogeneous disease with unique combinations of somatic molecular alterations in individual patients, as well as significant differences in populations across the world with regard to mutation spectra and mutation frequencies. Here we aim to describe mutational patterns and linked clinical parameters in a population-based NSCLC cohort.MATERIALS AND METHODS: Using targeted resequencing the mutational status of 82 genes was evaluated in a consecutive Swedish surgical NSCLC cohort, consisting of 352 patient samples from either fresh frozen or formalin fixed paraffin embedded (FFPE) tissues. The panel covers all exons of the 82 genes and utilizes reduced target fragment length and two-strand capture making it compatible with degraded FFPE samples.RESULTS: We obtained a uniform sequencing coverage and mutation load across the fresh frozen and FFPE samples by adaption of sequencing depth and bioinformatic pipeline, thereby avoiding a technical bias between these two sample types. At large, the mutation frequencies resembled the frequencies seen in other western populations, except for a high frequency of KRAS hotspot mutations (43%) in adenocarcinoma patients. Worse overall survival was observed for adenocarcinoma patients with a mutation in either TP53, STK11 or SMARCA4. In the adenocarcinoma KRAS-mutated group poor survival appeared to be linked to concomitant TP53 or STK11 mutations, and not to KRAS mutation as a single aberration. Similar results were seen in the analysis of publicly available data from the cBioPortal. In squamous cell carcinoma a worse prognosis could be observed for patients with MLL2 mutations, while CSMD3 mutations were linked to a better prognosis.CONCLUSION: Here we have evaluated the mutational status of a NSCLC cohort. We could not confirm any survival impact of isolated driver mutations. Instead, concurrent mutations in TP53 and STK11 were shown to confer poor survival in the KRAS-positive adenocarcinoma subgroup.
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45.
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46.
  • Lindskog, Cecilia, et al. (författare)
  • Immunohistochemistry-based prognostic biomarkers in NSCLC : novel findings on the road to clinical use?
  • 2015
  • Ingår i: Expert Review of Molecular Diagnostics. - : Informa UK Limited. - 1473-7159 .- 1744-8352. ; 15:4, s. 471-490
  • Forskningsöversikt (refereegranskat)abstract
    • Prognostication of non-small cell lung cancer is principally based on stage, age and performance status. This review provides an overview of 342 potential prognostic biomarkers in non-small cell lung cancer described between January 2008 and June 2013, evaluating the association between immunohistochemical protein expression and survival endpoint. Numerous studies proposed prognostic biomarkers, but many were only evaluated in a single patient cohort, and a large number of biomarkers revealed inconclusive findings when analyzed in more than one study. Only 26 proteins first described after 2008 (ALDH1A1, ANXA1, BCAR1, CLDN1, EIF4E, EZH2, FOLR1, FOXM1, IL7R, IL12RB2, KIAA1524, CRMP1, LOX, MCM7, MTA1, MTDH, NCOA3, NDRG2, NEDD9, NES, PBK, PPM1D, SIRT1, SLC7A5, SQSTM1 and WNT1) demonstrated a consistent prognostic association in two or more independent patient cohorts, thus qualifying as promising candidates for diagnostic use. Raised quality standards for study design and antibody validation, and integration of preclinical findings with clinical needs are clearly warranted.
  •  
47.
  • Magalhaes, Isabelle, et al. (författare)
  • Facing the future : challenges and opportunities in adoptive T cell therapy in cancer
  • 2019
  • Ingår i: Expert Opinion on Biological Therapy. - : Taylor & Francis Group. - 1471-2598 .- 1744-7682. ; 19:8, s. 811-827
  • Tidskriftsartikel (refereegranskat)abstract
    • INTRODUCTION: In recent years, immunotherapy for the treatment of solid cancer has emerged as a promising therapeutic alternative. Adoptive cell therapy (ACT), especially T cell-based, has been found to cause tumor regression and even cure in a percentage of treated patients. Checkpoint inhibitors further underscore the potential of the T cell compartment in the treatment of cancer. Not all patients respond to these treatments; however, many challenges remain.AREAS COVERED: This review covers the challenges and progress in tumor antigen target identification and selection, and cell product manufacturing for T cell ACT. Tumor immune escape mechanisms and strategies to overcome those in the context of T cell ACT are also discussed.EXPERT OPINION: The immunotherapy toolbox is rapidly expanding and improving, and the future promises further breakthroughs in the T cell ACT field. The heterogeneity of the tumor microenvironment and the multiplicity of tumor immune escape mechanisms pose formidable challenges to successful T cell immunotherapy in solid tumors, however. Individualized approaches and strategies combining treatments targeting different immunotherapeutic aspects will be needed in order to expand the applicability and improve the response rates in future.
  •  
48.
  • Mattsson, Anna, et al. (författare)
  • Developmental exposure to a mixture of perfluoroalkyl acids (PFAAs) affects the thyroid hormone system and the bursa of Fabricius in the chicken
  • 2019
  • Ingår i: Scientific Reports. - : Nature Publishing Group. - 2045-2322. ; 9:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Perfluoroalkyl acids (PFAAs) are ubiquitous environmental contaminants and eggs and nestlings of raptors and fish-eating birds often contain high levels of PFAAs. We studied developmental effects of a mixture of ten PFAAs by exposing chicken embryos to 0.5 or 3 μg/g egg of each compound in the mixture. Histological changes of the thyroid gland were noted at both doses and increased expression of mRNA coding for type III deiodinase was found at 0.5 μg/g egg. Serum concentrations of the free fraction of thyroid hormones (T3 and T4) were reduced by the PFAA mixture at 3 µg/g egg, which is in line with a decreased synthesis and increased turnover of thyroid hormones as indicated by our histological findings and the decreased mRNA expression of type III deiodinase. The relative weight of the bursa of Fabricius increased at a dose of 3 μg/g egg in females. The bursa is the site of B-cell development in birds and is crucial for the avian adaptive immune system. Analysis of plasma and liver concentrations of the mixture components showed differences depending on chain length and functional group. Our results highlight the vulnerability of the thyroid hormone and immune systems to PFAAs.
  •  
49.
  • Mattsson, Johanna Sofia Margareta, et al. (författare)
  • Consistent mutation status within histologically heterogeneous lung cancer lesions
  • 2012
  • Ingår i: Histopathology. - : Wiley. - 0309-0167 .- 1365-2559. ; 61:4, s. 744-748
  • Tidskriftsartikel (refereegranskat)abstract
    • Aims: Activating epidermal growth factor receptor (EGFR) and KRAS mutations characterize molecular subgroups of non-small-cell lung cancer (NSCLC) with a strong predictive value for response to EGFR inhibitor therapy. However, the temporal occurrence and clonal stability of these mutations during the course of cancer progression are debated. The aim of this study was to characterize the presence of EGFR and KRAS mutations in histologically different areas of primary NSCLC lesions. Methods and results: Formalin-fixed paraffin-embedded cancer specimens from six cases with EGFR mutations and five cases with KRAS mutations were selected from a pool of primary resected NSCLC patients. From each tumour, three morphologically distinct areas were manually microdissected and analysed for the presence of mutations. The results demonstrated consistent EGFR and KRAS mutation status in the different histological areas of all primary tumours. Conclusions: The results support the concept that activating EGFR and KRAS mutations are oncogenic events that are consistently present throughout the primary tumour independently of histological heterogeneity. Thus, for molecular diagnostics, any part of the tumour is likely to be representative for EGFR and KRAS mutation testing.
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50.
  • Mattsson, Johanna Sofia Margareta, 1985-, et al. (författare)
  • Inconsistent results in the analysis of ALK rearrangements in non-small cell lung cancer
  • 2016
  • Ingår i: BMC Cancer. - London, United Kingdom : Springer Science and Business Media LLC. - 1471-2407. ; 16
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Identification of targetable EML4-ALK fusion proteins has revolutionized the treatment of a minor subgroup of non-small cell lung cancer (NSCLC) patients. Although fluorescence in situ hybridization (FISH) is regarded as the gold standard for detection of ALK rearrangements, ALK immunohistochemistry (IHC) is often used as screening tool in clinical practice. In order to unbiasedly analyze the diagnostic impact of such a screening strategy, we compared ALK IHC with ALK FISH in three large representative Swedish NSCLC cohorts incorporating clinical parameters and gene expression data.Methods: ALK rearrangements were detected using FISH on tissue microarrays (TMAs), including tissue from 851 NSCLC patients. In parallel, ALK protein expression was detected using IHC, applying the antibody clone D5F3 with two different protocols (the FDA approved Ventana CDx assay and our in house Dako IHC protocol). Gene expression microarray data (Affymetrix) was available for 194 patients.Results: ALK rearrangements were detected in 1.7% in the complete cohort and 2.0% in the non-squamous cell carcinoma subgroup. ALK protein expression was observed in 1.9% and 1.5% when applying the Ventana assay or the in house Dako protocol, respectively. The specificity and accuracy of IHC was high (>99%), while the sensitivity was between 69% (Ventana) and 62% (in house Dako protocol). Furthermore, only 67% of the ALK IHC positive cases were positive in both IHC assays. Gene expression analysis revealed that 6/194 (3%) tumors showed high ALK gene expression (≥6AU) and of them only three were positive by either FISH or IHC.Conclusion: The overall frequency of ALK rearrangements based on FISH was lower than previously reported. The sensitivity of both IHC assays was low, and the concordance between the FISH and the IHC assays poor, questioning current strategies to screen with IHC prior to FISH or completely replace FISH by IHC.
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