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2.
  • Backman, Max, et al. (författare)
  • Characterization of Patterns of Immune Cell Infiltration in NSCLC
  • ????
  • Ingår i: Journal of Thoracic Oncology. - Elsevier. - 1556-0864.
  • Tidskriftsartikel (refereegranskat)abstract
    • Introduction: Tumor infiltrating immune cells are key elements of the tumor microenvironment and mediate the antitumor effects of immunotherapy. The aim of the study was to characterize the patterns of immune cell infiltration in NSCLC in relation to tumor mutations and clinicopathologic parameters. Methods: Lymphocytes (CD3+, CD4+, CD8+, CD20+, FOXP3+, CD45RO+), macrophages (CD163+), plasma cells (CD138+), natural killer (NK) cells (NKp46+), and programmed death-ligand 1 (PD-L1+) were annotated on a tissue microarray including 357 patients who had undergone operations for NSCLC. Somatic mutations and tumor mutational burden were analyzed by targeted sequencing for 82 genes, and transcriptomic immune patterns were established in 197 patients on the basis of 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. Importantly, the identified immune classes on the basis of tissue staining could not be translated into RNA expression signatures extracted from crude NSCLC tissue. Conclusions: We presented 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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3.
  • Backman, Max, et al. (författare)
  • Extending the immune phenotypes of lung cancer: Oasis in the desert
  • ????
  • Annan publikation (övrigt vetenskapligt)abstract
    • <p>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. </p><p>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. </p><p>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. </p><p>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. </p>
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4.
  • Biswas, Dhruva, et al. (författare)
  • A clonal expression biomarker associates with lung cancer mortality
  • 2019
  • Ingår i: Nature Medicine. - Nature Publishing Group. - 1078-8956. ; 25:10, s. 1540-1548
  • Tidskriftsartikel (refereegranskat)abstract
    • An aim of molecular biomarkers is to stratify patients with cancer into disease subtypes predictive of outcome, improving diagnostic precision beyond clinical descriptors such as tumor stage1. Transcriptomic intratumor heterogeneity (RNA-ITH) has been shown to confound existing expression-based biomarkers across multiple cancer types2–6. Here, we analyze multi-region whole-exome and RNA sequencing data for 156 tumor regions from 48 patients enrolled in the TRACERx study to explore and control for RNA-ITH in non-small cell lung cancer. We find that chromosomal instability is a major driver of RNA-ITH, and existing prognostic gene expression signatures are vulnerable to tumor sampling bias. To address this, we identify genes expressed homogeneously within individual tumors that encode expression modules of cancer cell proliferation and are often driven by DNA copy-number gains selected early in tumor evolution. Clonal transcriptomic biomarkers overcome tumor sampling bias, associate with survival independent of clinicopathological risk factors, and may provide a general strategy to refine biomarker design across cancer types.
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5.
  • Breimer, Lars H., et al. (författare)
  • Immune checkpoint inhibitors of the PD-1/PD-L1-axis in non-small cell lung cancer : promise, controversies and ambiguities in the novel treatment paradigm
  • 2020
  • Ingår i: Scandinavian Journal of Clinical and Laboratory Investigation. - Taylor & Francis. - 0036-5513 .- 1502-7686. ; s. 1-10
  • Forskningsöversikt (refereegranskat)abstract
    • <p>Immune checkpoint inhibitors (ICIs) have received much attention not least for melanoma since the award of the Nobel prize in 2018. Here, we review the current state of knowledge about the use of these monoclonal antibodies (mAbs) in non-small cell lung cancer (NSCLC). These drugs have generally been conditionally approved on limited early data and there are few long-term follow-up data from randomized clinical trials. The effect observed for NSCLC thus far is, on average, moderately better than that obtained with chemotherapy. Severe side-effects are more common than might have been expected. The drugs themselves are expensive and are associated with time-consuming histopathologic testing even though the predictive value of these tests can be discussed. In addition, monitoring for side-effects involves increased workload and budgetary expense for clinical chemistry laboratories. Here, we review and summarize the current knowledge, controversies and ambiguities of ICIs for the treatment of NSCLC.</p>
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6.
  • Breimer, Lars H., et al. (författare)
  • Immune checkpoint inhibitors of the PD-1/PD-L1-axis in non-small cell lung cancer : promise, controversies and ambiguities in the novel treatment paradigm
  • ????
  • Ingår i: Scandinavian Journal of Clinical and Laboratory Investigation. - Informa Healthcare. - 0036-5513.
  • Forskningsöversikt (refereegranskat)abstract
    • Immune checkpoint inhibitors (ICIs) have received much attention not least for melanoma since the award of the Nobel prize in 2018. Here, we review the current state of knowledge about the use of these monoclonal antibodies (mAbs) in non-small cell lung cancer (NSCLC). These drugs have generally been conditionally approved on limited early data and there are few long-term follow-up data from randomized clinical trials. The effect observed for NSCLC thus far is, on average, moderately better than that obtained with chemotherapy. Severe side-effects are more common than might have been expected. The drugs themselves are expensive and are associated with time-consuming histopathologic testing even though the predictive value of these tests can be discussed. In addition, monitoring for side-effects involves increased workload and budgetary expense for clinical chemistry laboratories. Here, we review and summarize the current knowledge, controversies and ambiguities of ICIs for the treatment of NSCLC.
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7.
  • Brunnström, Hans, et al. (författare)
  • A 76-year-old man with cognitive and neurological symptoms
  • 2009
  • Ingår i: Brain Pathology. - Wiley-Blackwell. - 1750-3639. ; 19:4, s. 4-731
  • Tidskriftsartikel (övrigt vetenskapligt)abstract
    • A 76-year-old man presented with cognitive symptoms, followed by headache and weakness of the lower limbs and left arm. The clinical course was progressive but fluctuating. On magnetic resonance imaging (MRI), a contrast-enhancing lesion 1 cm in diameter was seen in the left temporal lobe. This lesion became attenuated and a new contrast-enhancing lesion 1 x 2 cm was seen in the left frontal lobe on a subsequent MRI. Following additional tests, treatment with corticosteroids for presumptive neurosarcoidosis was started, however, he soon expired. At autopsy, there was a tumor-like mass in the left frontal lobe. Pathologic evaluation revealed a primary T-cell lymphoma of the central nervous system (CNS). CNS T-cell lymphomas may be difficult to diagnose, even histologically, due to their frequent small cell morphology and lack of significant atypia.
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8.
  • Brunnström, Hans, et al. (författare)
  • Cause of death in patients with dementia disorders.
  • 2009
  • Ingår i: European Journal of Neurology. - Wiley-Blackwell. - 1351-5101. ; 16, s. 488-492
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Investigations on cause of death may provide valuable information about life expectancy and on conditions of terminal dementia care, which perhaps can be ameliorated. Methods: The autopsy reports were studied on all patients (n = 524; 55.3% females; median age 80 years) with a clinically and neuropathologically diagnosed dementia disorder who underwent a complete autopsy at the University Hospital in Lund, Sweden, during 1974-2004. Results: The two most common causes of death were bronchopneumonia (38.4%) and ischaemic heart disease (23.1%), whilst neoplastic diseases were uncommon (3.8%). In a general population of elderly studied for comparison, bronchopneumonia accounted for 2.8%, ischaemic heart disease for 22.0%, and neoplasm for 21.3% of the deaths. Amongst the demented patients, circulatory and respiratory system diseases were the causes of death in 23.2% and 55.5% of the Alzheimer patients, respectively, whilst the corresponding figures were 54.8% and 33.1% for the patients with vascular dementia. Conclusions: In patients with dementia, pneumonia as the immediate cause of death may reflect a terminal stage in which patient care and feeding is difficult to manage well. Knowledge about what actually causes death is of value in the terminal care of patients with dementia disorders.
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9.
  • Brunnström, Hans, et al. (författare)
  • Cerebrospinal fluid biomarker results in relation to neuropathological dementia diagnoses.
  • 2010
  • Ingår i: Alzheimer's & Dementia. - Wiley. - 1552-5279. ; 6:2, s. 104-109
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: Clinical dementia diagnoses are not always consistent with neuropathological findings. As correct diagnosis is important for treatment and care, new diagnostic possibilities for dementia are in demand. Cerebrospinal fluid biomarkers should ideally be able to identify ongoing processes in the brain, but need to be further compared with neuropathological findings for evaluation of their diagnostic validity. METHODS: This study included 43 patients with a clinical dementia disorder. All patients were neuropathologically examined at the University Hospital in Lund, Sweden, during the years 2001-2008, and all had a lumbar puncture carried out as part of the clinical investigation during the time of cognitive impairment. RESULTS: Of eight patients, five with Alzheimer's disease had elevated total tau protein (T-tau) and decreased amyloid beta 1-42 protein (Abeta42), while both values for the other three patients were normal. Slightly elevated T-tau and/or decreased Abeta42 were also seen in several patients with other dementia diagnoses such as Lewy body disease, frontotemporal lobar degeneration and vascular dementia. Furthermore, T-tau levels did not differ markedly between patients with morphologically tau-positive and tau-negative frontotemporal lobar degeneration. Also, seven of nine patients with Creutzfeldt-Jacob disease exhibited pronounced elevation in T-tau concentration. CONCLUSION: From this rather limited study, being the first of its kind in Sweden, we may conclude that there is no perfect concordance between cerebrospinal fluid biomarker levels and pathological findings, which should be taken into account in the clinical diagnostic setting.
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10.
  • Brunnström, Hans, et al. (författare)
  • Clinicopathological concordance in dementia diagnostics.
  • 2009
  • Ingår i: The American Journal of Geriatric Psychiatry. - Elsevier. - 1545-7214. ; 17:8, s. 664-670
  • Tidskriftsartikel (refereegranskat)abstract
    • OBJECTIVE: Accurate distinction between dementia subtypes is important for patient care and pharmacological treatment. Continuing systematic comparisons of clinical and neuropathological dementia diagnoses may provide a basis for further improvement of the diagnostic procedure. The purpose of this study was to investigate concordance between clinical dementia diagnosis and neuropathological findings in the specialized dementia care. METHODS: Inclusion required 1) a clinical dementia disorder diagnosed at a hospital-based memory clinic and 2) a neuropathological examination within the Department of Pathology at the University Hospital in Lund, Sweden, during the years 1996-2006. A total of 176 consecutive patients fulfilled the criteria and were thus included. Clinical dementia diagnoses were obtained from the medical records and compared with the neuropathological findings. RESULTS: The clinical and pathological dementia diagnoses were in full accordance in 86 (49%) of the patients (kappa 0.37). In an additional 24 (14%) cases, the clinical diagnosis corresponded with some but not all pathological components judged to contribute to the dementia disorder. Of the patients with clinical Alzheimer disease, 84% (46/55) had a significant Alzheimer component with or without other significant pathology at neuropathological examination. The corresponding figure for vascular dementia (VaD) was 59% (24/41), for frontotemporal dementia 74% (20/27), for combined Alzheimer and VaD 25% (4/16), and for dementia with Lewy bodies 67% (6/9). CONCLUSIONS: This study shows that clinical dementia diagnoses do not always correspond with neuropathological changes. It stresses the importance of neuropathological examination in research and in daily clinical practice.
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