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  • 1.
    Corvigno, Sara
    et al.
    Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden..
    Frodin, Magnus
    Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden..
    Wisman, G. Bea A.
    Univ Groningen, Univ Med Ctr Groningen, Dept Gynecol Oncol, Groningen, Netherlands..
    Nijman, Hans W.
    Univ Groningen, Univ Med Ctr Groningen, Dept Gynecol Oncol, Groningen, Netherlands..
    Van der Zee, Ate G. J.
    Univ Groningen, Univ Med Ctr Groningen, Dept Gynecol Oncol, Groningen, Netherlands..
    Jirstrom, Karin
    Lund Univ, Div Oncol & Pathol, Dept Clin Sci, Lund, Sweden..
    Nodin, Bjorn
    Lund Univ, Div Oncol & Pathol, Dept Clin Sci, Lund, Sweden..
    Hrynchyk, Ina
    City Clin Pathologoanat Bur, Minsk, Byelarus..
    Edler, David
    Karolinska Univ Hosp Solna, Dept Mol Med & Surg, Stockholm, Sweden..
    Ragnhammar, Peter
    Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden..
    Johansson, Martin
    Skanes Univ Sjukhus, Dept Lab Med, Malmo, Sweden..
    Dahlstrand, Hanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden..
    Mezheyeuski, Artur
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden..
    Ostman, Arne
    Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden..
    Multi-parametric profiling of renal cell, colorectal, and ovarian cancer identifies tumour-type-specific stroma phenotypes and a novel vascular biomarker2017In: The journal of pathology. Clinical research, ISSN 2056-4538, Vol. 3, no 3, p. 214-224Article in journal (Refereed)
    Abstract [en]

    A novel set of integrated procedures for quantification of fibroblast-rich stroma and vascular characteristics has recently been presented allowing discovery of novel perivascular and stromal biomarkers in colorectal, renal cell, and ovarian cancer. In the present study, data obtained through these procedures from clinically well-annotated collections of these three tumour types have been used to address two novel questions. First, data have been used to investigate if the three tumour types demonstrate significant differences regarding features such as vessel diameter, vessel density, and perivascular marker expression. Second, analyses of the cohorts have been used to explore the prognostic significance of a novel vascular metric, 'vessel distance inter-quartile range (IQR)' that describes intra-case heterogeneity regarding vessel distribution. The comparisons between the three tumour types demonstrated a set of significant differences. Vessel density of renal cell cancer was statistically significantly higher than in colorectal and ovarian cancer. Vessel diameter was statistically significantly higher in ovarian cancer. Concerning perivascular status, colorectal cancer displayed significantly higher levels of perivascular PDGFR-beta expression than the other two tumour types. Intra-case heterogeneity of perivascular PDGFR-beta expression was also higher in colorectal cancer. Notably, these fibroblast-dominated stroma phenotypes matched previously described experimental tumour stroma characteristics, which have been linked to differential sensitivity to anti-VEGF drugs. High 'vessel distance IQR' was significantly associated with poor survival in both renal cell cancer and colorectal cancer. In renal cell cancer, this characteristic also acted as an independent prognostic marker according to multivariate analyses including standard clinico-pathological characteristics. Explorative subset analyses indicated particularly strong prognostic significance of 'vessel distance IQR' in T stage 4 of this cancer type. Together, these analyses identified tumour-type-specific vascular-stroma phenotypes of possible functional significance, and suggest 'vessel distance IQR' as a novel prognostic biomarker.

  • 2.
    Gu, Xiaolian
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Boldrup, Linda
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Coates, Philip J.
    Fåhraeus, Robin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. Regional Centre for Applied Molecular Oncology (RECAMO), Masaryk Memorial Cancer Institute, Brno, Czech Republic; Institute of Molecular Genetics, University Paris 7, St. Louis Hospital, Paris, France .
    Wang, Lixiao
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Wilms, Torben
    Umeå University, Faculty of Medicine, Department of Clinical Sciences.
    Norberg-Spaak, Lena
    Umeå University, Faculty of Medicine, Department of Clinical Sciences.
    Sgaramella, Nicola
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Nylander, Karin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    High immune cytolytic activity in tumor-free tongue tissue confers better prognosis in patients with squamous cell carcinoma of the oral tongue2019In: The journal of pathology. Clinical research, ISSN 2056-4538, Vol. 5, no 4, p. 240-247Article in journal (Refereed)
    Abstract [en]

    Immune cells and cytolytic activity within the tumor microenvironment are being intensively studied. Through transcriptome profiling, immune cell enumeration using the xCell tool and cytolytic activity quantification according to granzyme A (GZMA) and perforin (PRF1) mRNA levels, we investigated immunoreactivity in tumor and/or tumor‐free tongue tissue samples from 31 patients with squamous cell carcinoma of the oral tongue and 14 healthy individuals (control tongue tissues). We found significantly altered immune cell compositions (p < 0.001) and elevated cytolytic activity (p < 0.001) in tumor compared to tumor‐free samples, and altered infiltration of a subset of immune cells (e.g. CD8+ T cells, p < 0.01) as well as increased cytolytic activity (p < 0.001) in tumor‐free compared to control samples. Controlling for patient age at diagnosis and tumor stage, Cox regression analysis showed that high cytolytic activity in tumor‐free samples associated with improved disease‐free survival (hazard ratio= 4.20, 95% CI = 1.09–16.20, p = 0.037). However, the degree of cytolytic activity in tumor samples did not provide prognostic information. Taken together, our results show the presence of cancer‐related immune responses in clinically tumor‐free tongue in patients with squamous cell carcinoma of the oral tongue. Measuring cytolytic activity in tumor‐free tongue samples contralateral to tumor might thus be an effective approach to predict clinical outcome.

  • 3.
    Paulsson, Janna
    et al.
    Department of Oncology-Pathology Cancer Center Karolinska, Karolinska Institutet Stockholm, Sweden.
    Rydén, Lisa
    Division of Surgery, Department of Clinical Sciences Lund UniversityLundSweden; Department of Surgery Skåne University Hospital Lund, Sweden.
    Strell, Carina
    Department of Oncology-Pathology Cancer Center Karolinska, Karolinska Institutet Stockholm, Sweden.
    Frings, Oliver
    Department of Oncology-Pathology Cancer Center Karolinska, Karolinska Institutet Stockholm, Sweden.
    Tobin, Nicholas P
    Department of Oncology-Pathology Cancer Center Karolinska, Karolinska Institutet Stockholm, Sweden.
    Fornander, Tommy
    Department of Oncology-Pathology Cancer Center Karolinska, Karolinska Institutet Stockholm, Sweden.
    Bergh, Jonas
    Department of Oncology-PathologyCancer Center Karolinska, Karolinska InstitutetStockholmSweden; Radiumhemmet, Karolinska University Hospital Stockholm, Sweden.
    Landberg, Göran
    Department of Pathology Sahlgrenska Cancer Centre, University of Gothenburg Gothenburg, Sweden.
    Stål, Olle
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Östman, Arne
    Department of Oncology-Pathology Cancer Center Karolinska, Karolinska Institutet Stockholm, Sweden.
    High expression of stromal PDGFRß is associated with reduced benefit of tamoxifen in breast cancer2017In: The journal of pathology. Clinical research, ISSN 2056-4538, Vol. 3, no 1, p. 38-43Article in journal (Refereed)
    Abstract [en]

    Cancer-associated fibroblasts (CAFs) regulate tumour growth, metastasis and response to treatment. Recent studies indicate the existence of functionally distinct CAF subsets. Suggested mechanisms whereby CAFs can impact on treatment response include paracrine signalling affecting cancer cell drug sensitivity and effects on tumour drug uptake. PDGFRß is an important regulator of fibroblasts. Experimental studies have linked PDGFRß-positive fibroblasts to metastasis and also to reduced tumour drug uptake. This study has investigated the potential role of PDGFRß-positive fibroblasts in response to adjuvant tamoxifen treatment of breast cancer. Analyses of two breast cancer collections from randomised studies analysing adjuvant tamoxifen treatment in early breast cancer demonstrated significant benefit of tamoxifen in the group with low stromal PDGFRß, which was not observed in the group with high stromal PDGFRß. In general terms these findings provide novel evidence, derived from analyses of randomised clinical studies, of response-predictive capacity of a marker-defined subset of CAFs and, more specifically, identify stromal PDGFRß as a marker related to tamoxifen benefit in early breast cancer.

  • 4.
    Seiron, Peter
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Wiberg, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Kuric, Enida
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Krogvold, Lars
    Oslo Univ Hosp, Div Paediat & Adolescent Med, Oslo, Norway.
    Jahnsen, Frode L.
    Oslo Univ Hosp, Dept Pathol, Oslo, Norway.
    Dahl-Jorgensen, Knut
    Oslo Univ Hosp, Div Paediat & Adolescent Med, Oslo, Norway.
    Skog, Oskar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Univ Gothenburg, Inst Biomed, Dept Clin Chem & Transfus Med, Gothenburg, Sweden.
    Characterisation of the endocrine pancreas in type 1 diabetes: islet size is maintained but islet number is markedly reduced2019In: The journal of pathology. Clinical research, ISSN 2056-4538, Vol. 5, no 4, p. 248-255Article in journal (Refereed)
    Abstract [en]

    Insulin deficiency in type 1 diabetes (T1D) is generally considered a consequence of immune-mediated specific beta-cell loss. Since healthy pancreatic islets consist of similar to 65% beta cells, this would lead to reduced islet size, while the number of islets per pancreas volume (islet density) would not be affected. In this study, we compared the islet density, size, and size distribution in biopsies from subjects with recent-onset or long-standing T1D, with that in matched non-diabetic subjects. The results presented show preserved islet size and islet size distribution, but a marked reduction in islet density in subjects with recent onset T1D compared with non-diabetic subjects. No further reduction in islet density occurred with increased disease duration. Insulin-negative islets in T1D subjects were dominated by glucagon-positive cells that often had lost the alpha-cell transcription factor ARX while instead expressing PDX1, normally only expressed in beta cells within the islets. Based on our findings, we propose that failure to establish a sufficient islet number to reach the beta-cell mass needed to cope with episodes of increased insulin demand contributes to T1D susceptibility. Exhaustion induced by relative lack of beta cells could then potentially drive beta-cell dedifferentiation to alpha-cells, explaining the preserved islet size observed in T1D compared to controls.

  • 5.
    Sgaramella, Niccola
    et al.
    Univ Naples Federico II, Dept Neurosci Reprod & Dent Sci, Naples, Italy.
    Lindell Jonsson, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Boldrup, Linda
    Califano, Luigi
    Univ Naples Federico II, Dept Neurosci Reprod & Dent Sci, Naples, Italy.
    Coates, Philip
    Tartaro, Gianpaolo
    Lo Muzio, Lorenzio
    Fåhraeus, Robin
    Colella, Giuseppe
    Dell'Aversana Orabona, Giovanni
    Loljung, Lotta
    Santagata, Mario
    Rosiello, Riccardo
    Wilms, Torben
    Danielsson, Karin
    Laurell, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Nylander, Karin
    High expression of podoplanin in squamous cell carcinoma of the tongue occurs predominantly in patients≤ 40 years but does not correlate with tumour spread2016In: The journal of pathology. Clinical research, ISSN 2056-4538, no 1, p. 3-8Article in journal (Refereed)
    Abstract [en]

    More than 30% of patients with squamous cell carcinoma (SCC) of the mobile tongue have clinically undetectable lymph node metastasis. Tumour cells can spread as single cells or collectively. A protein known to play a role in both processes is podoplanin, which is expressed in endothelial cells not only in lymph vessels but also in some aggressive tumours with high invasive and metastatic potential. Here we studied samples from 129 patients with primary SCC of the tongue for expression of podoplanin using immunohistochemistry. mRNA levels were analysed in another 27 cases of tongue SCC with adjacent clinically tumour-free tongue tissue and 14 tongue samples from healthy donors. Higher levels of podoplanin were seen in tumours compared to both normal tongue and clinically normal tongue in the tumour vicinity. No association was found between levels of podoplanin, presence of lymph node metastases or other clinical factors. Patients aged 40 or less were more likely to express high levels of podoplanin protein compared to older patients (p = 0.027). We conclude that levels of podoplanin in primary tongue SCCs are not associated with lymph node metastases. However, tongue SCCs arising in young patients (< 40 years of age) are more likely to express high levels of podoplanin than tongue SCCs that arise in the more elderly. The data suggest that podoplanin has a distinctive role in young patients, who are known to have a poor prognosis: these patients may, therefore, benefit from podoplanin inhibitory therapies.

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