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  • 1. Arkestal, Kurt
    et al.
    Mints, Michael
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Enocson, Anders
    Linton, Ludvig
    Marits, Per
    Glise, Hans
    Andersson, John
    Winqvist, Ola
    CCR2 upregulated on peripheral T cells in osteoarthritis but not in bone marrow2018In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 88, no 6, article id e12722Article in journal (Refereed)
    Abstract [en]

    Osteoarthritis (OA) is a condition affecting millions of patients around the world, causing pain and disability and often resulting in joint replacement surgery. The aetiology of OA has long been attributed to mechanical wear mainly due to the increased prevalence of OA in load bearing joints among older patients. However, recent studies reveal a complex molecular disease causality in which inflammation, nutritional deficit and angiogenesis lead to the destruction of the joint structure. The aim of this study was to examine chemokine receptor expression in peripheral blood and bone marrow in OA patients. We devised a protocol for extracting healthy bone marrow from patients undergoing hip arthroplasty due to coxarthrosis. Flow cytometry was used to determine the expression of 18 chemokine receptors on CD4 and CD8 T cells from bone marrow and blood from 7 osteoarthritis patients and peripheral blood from 9 healthy controls. We found a significantly increased fraction of CCR2 expressing CD4 and CD8 T cell in peripheral blood compared to healthy controls. Also, there was a significant decrease in CXCR3 (Th1) (P < 0.01) expressing T cells in peripheral blood from OA patients. Finally, multivariate analysis was used to separate T cell profiles from healthy controls and OA patients and demonstrate that the divergence of chemokine receptor expression occurs in the mature T cell subsets. In conclusion, we find increased CCR2 expression in peripheral blood from OA patients that possibly may be targeted in future clinical studies.

  • 2. Bersani, Cinzia
    et al.
    Mints, Michael
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Tertipis, Nikolaos
    Haeggblom, Linnea
    Näsman, Anders
    Romanitan, Mircea
    Dalianis, Tina
    Ramqvist, Torbjörn
    MicroRNA-155,-185 and-193b as biomarkers in human papillomavirus positive and negative tonsillar and base of tongue squamous cell carcinoma2018In: Oral Oncology, ISSN 1368-8375, E-ISSN 1879-0593, Vol. 82, p. 8-16Article in journal (Refereed)
    Abstract [en]

    Objective: Three-year disease-free survival (DFS) is 80% for human papillomavirus (HPV) positive tonsillar and base of tongue cancer (TSCC/BOTSCC) treated with radiotherapy alone, and today's intensified therapy does not improve prognosis. More markers are therefore needed to more accurately identify patients with good prognosis or in need of alternative therapy. Here, microRNAs (miRs) 155, 185 and 193b were examined as potential prognostic markers in TSCC/BOTSCC.

    Material and methods: 168 TSCC/BOTSCC patients diagnosed 2000-2013, with known data on HPV-status, CD8(+) tumour infiltrating lymphocytes, tumour staging and survival were examined for expression of miR-155, -185 and -193b using Real-Time PCR. Associations between miR expression and patient and tumour characteristics were analysed using univariate testing and multivariate regression.

    Results: Tumours compared to normal tonsils showed decreased miR-155 and increased miR-193b expression. miR-155 expression was associated with HPV-positivity, low T-stage, high CD8(+) TIL counts and improved survival. miR-185 expression was associated with HPV-negativity and a tendency towards decreased survival, while miR-193b expression was associated with higher T-stage, male gender and lower CD8(+) TIL counts, but not with outcome. Upon Cox regression, miR-185 was the only miR significantly associated with survival. Combining miR-155 and miR-185 to predict outcome in HPV+ patients yielded an area under curve (AUC) of 71%.

    Conclusion: Increased miR-155 expression was found as a positive predictor of survival, with the effect mainly due to its association with high CD8(+) TIL numbers, while miR-185 independently associated with decreased survival. Addition of these miRs to previously validated prognostic biomarkers could improve patient stratification accuracy.

  • 3. Bersani, Cinzia
    et al.
    Mints, Michael
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences. Dept. of Medicine, Karolinska Institutet, Stockholm, Sweden.
    Tertipis, Nikolaos
    Haeggblom, Linnea
    Sivars, Lars
    Ährlund-Richter, Andreas
    Vlastos, Andrea
    Smedberg, Cecilia
    Grün, Nathalie
    Munck-Wikland, Eva
    Näsman, Anders
    Ramqvist, Torbjörn
    Dalianis, Tina
    A model using concomitant markers for predicting outcome in human papillomavirus positive oropharyngeal cancer2017In: Oral Oncology, ISSN 1368-8375, E-ISSN 1879-0593, Vol. 68, p. 53-59Article in journal (Refereed)
    Abstract [en]

    Objective: Head-neck cancer therapy has become intensified. With radiotherapy alone, 3-year disease-free survival (DFS) is 80% for HPV-positive TSCC/BOTSCC and better for patients with favorable characteristics, suggesting therapy could be tapered for some, decreasing side-effects. Therefore, we built a model to predict progression-free survival for patients with HPV-positive TSCC and BOTSCC. Material and methods: TSCC/BOTSCC patients treated curatively between 2000 and 2011, with HPV16 DNA/E7 mRNA positive tumors examined for CD8(+) TILs, HPV16 mRNA and HLA class I expression were included. Patients were split randomly 65/35 into training and validation sets, and LASSO regression was used to select a model in the training set, the performance of which was evaluated in the validation set. Results: 258 patients with HPV DNA/E7 mRNA positive tumors could be included, 168 and 90 patients in the respective sets. No treatment improved prognosis compared to radiotherapy alone. CD8(+) TIL counts and young age were the strongest predictors of survival, followed by T-stage <3 and presence of HPV16 E2 mRNA. The model had an area under curve (AUC) of 76%. A model where the presence of three of four of these markers defined good prognosis captured 56% of non-relapsing patients with a positive predictive value of 98% in the validation set. Furthermore, the model identified 35% of our cohort that was over-treated and could safely have received de-escalated therapy. Conclusion: CD8(+) TIL counts, age, T-stage and E2 expression could predict progression-free survival, identifying patients eligible for randomized trials with milder treatment, potentially reducing side effects without worsening prognosis.

  • 4. Bersani, Cinzia
    et al.
    Sivars, Lars
    Haeggblom, Linnea
    DiLorenzo, Sebastian
    Mints, Michael
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences. Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
    Ahrlund-Richter, Andreas
    Tertipis, Nikolaos
    Munck-Wikland, Eva
    Nasman, Anders
    Ramqvist, Torbjorn
    Dalianis, Tina
    Targeted sequencing of tonsillar and base of tongue cancer and human papillomavirus positive unknown primary of the head and neck reveals prognostic effects of mutated FGFR32017In: Oncotarget, E-ISSN 1949-2553, Vol. 8, no 21, p. 35339-35350Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Human papillomavirus positive (HPV+) tonsillar cancer (TSCC), base of tongue cancer (BOTSCC) and unknown primary cancer of the head and neck (HNCUP) have better outcome than corresponding HPV- cancers. To find predictive markers for response to treatment, and correlations and differences in mutated oncogenes and suppressor genes between HPV+TSCC/BOTSSCC and HPV+ HNCUP and HPV- TSCC/BOTSCC targeted next-generation sequencing was performed of frequently mutated regions in 50 cancer related genes.

    PATIENTS AND METHODS: DNA from 348 TSCC/BOTSCC and 20 HNCUP from patients diagnosed 2000-2011, was sequenced by the Ion Proton sequencing platform using the Ion AmpliSeq Cancer Hotspot Panel v2 to identify frequently mutated regions in 50 cancer related genes. Ion Torrent Variant Caller software was used to call variants.

    RESULTS: 279 HPV+ TSCC/BOTSCC, 46 HPV- TSCC/BOTSCC and 19 HPV+ HNCUP samples qualified for further analysis. Mutations/tumor were fewer in HPV+ TSCC/BOTSCC and HNCUP, compared to HPV- tumors (0.92 vs. 1.32 vs. 1.68). Differences in mutation frequency of TP53 and PIK3CA were found between HPV+ TSCC/BOTSCC and HNCUP and HPV- TSCC/BOTSCC. In HPV+TSCC/BOTSCC presence of FGFR3 mutations correlated to worse prognosis. Other correlations to survival within the groups were not disclosed.

    CONCLUSIONS: In HPV+ TSCC/BOTSCC mutation of PIK3CA was most frequently observed, while TP53 mutations dominated in HPV- TSCC/BOTSCC. In HPV+ TSCC/BOTSCC and HNCUP, mutations/tumor were similar in frequency and fewer compared to that in HPV- TSCC/BOTSCC. Notably, FGFR3 mutations in HPV+ TSCC/BOTSCC indicated worse prognosis.

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  • 5.
    Eldh, Maria
    et al.
    Division of Immunology and Allergy, Department of Medicine Solna, Karolinska Institute, Stockholm, Sweden.
    Mints, Michael
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. Division of Immunology and Allergy, Department of Medicine Solna, Karolinska Institute, Stockholm, Sweden.
    Hiltbrunner, Stefanie
    Division of Immunology and Allergy, Department of Medicine Solna, Karolinska Institute, Stockholm, Sweden.
    Ladjevardi, Sam
    Department of Urology, Akademiska University Hospital, Uppsala, Sweden.
    Alamdari, Farhood
    Department of Urology, Västmanland Hospital, Västerås, Sweden.
    Johansson, Markus
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Jakubczyk, Tomasz
    Department of Urology, Länssjukhuset Ryhov, Jönköping, Sweden.
    Veerman, Rosanne E.
    Division of Immunology and Allergy, Department of Medicine Solna, Karolinska Institute, Stockholm, Sweden.
    Winqvist, Ola
    Department of Clinical Immunology and Transfusion Medicine, Karolinska University Hospital, Solna, Sweden.
    Sherif, Amir
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Gabrielsson, Susanne
    Division of Immunology and Allergy, Department of Medicine Solna, Karolinska Institute, Stockholm, Sweden.
    Proteomic profiling of tissue exosomes indicates continuous release of malignant exosomes in urinary bladder cancer patients, even with pathologically undetectable tumour2021In: Cancers, ISSN 2072-6694, Vol. 13, no 13, article id 3242Article in journal (Refereed)
    Abstract [en]

    Invasive urothelial bladder cancer (UBC) has high recurrence rates even after radical cystectomy (RC). Exosomes are membrane-bound nanovesicles, which have been shown to contribute to carcinogenesis and metastasis. We previously showed that urinary exosomes display a malignant profile in UBC patients despite the absence of detectable tumour. Here, we investigated exosomes from sampling sites close to or distant from the former tumour, aiming to understand the effect of the tumour on the local milieu. Ten patients scheduled for cystectomy after transurethral bladder resection (TUR-B), without remaining detectable tumour, were included. Exosomes were isolated from tissue explants of both the previous tumour site and distant bladder tissue. Proteins were quantified by mass spectrometry in seven patients. Exosomes from the previous tumour site were enriched in inflammatory but not cancer-related pathways compared to distant tissue. However, the 69 most abundant proteins in tissue-derived exosomes regardless of site, 20 of which were also found in urinary exosomes from our previous study, were enriched for cancer-related metabolic pathways and associated with poor prognosis in an external mRNA dataset. The enrichment of cancer-related pathways in the most abundant proteins, regardless of sampling site, confirms our hypothesis that despite the absence of detectable tumour, the entire bladder releases exosomes that contribute to metastasis and highlights the need for early RC.

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  • 6. Hiltbrunner, Stefanie
    et al.
    Mints, Michael
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. Division of Immunology and Allergy, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
    Eldh, Maria
    Rosenblatt, Robert
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. Department of Urology, Södersjukhuset, Stockholm, Sweden.
    Holmström, Benny
    Alamdari, Farhood
    Johansson, Markus
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. Department of Urology, Sundsvall Hospital, Sundsvall, Umeå University, Umeå, Sweden.
    Veerman, Rosanne E.
    Winqvist, Ola
    Sherif, Amir
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Gabrielsson, Susanne
    Urinary Exosomes from Bladder Cancer Patients Show a Residual Cancer Phenotype despite Complete Pathological Downstaging2020In: Scientific Reports, E-ISSN 2045-2322, Vol. 10, no 1, article id 5960Article in journal (Refereed)
    Abstract [en]

    Invasive urinary bladder cancer shows high recurrence rates after cystectomy even with apparent complete downstaging at cystectomy. Exosomes are nano-sized vesicles important in cell-cell communication, which have been hypothesized to contribute to cancer dissemination and recurrence. The aim of this study was to investigate if pro-carcinogenic exosomes could be detected in urine from histologically downstaged bladder cancer patients. 13 Patients were included in this study. Paired ureter and urine samples from nine patients underwent mass spectrometry, while samples from the remaining patients were used for exosome characterization. At cystectomy, exosomes were isolated from bladder and ureter urine, whereafter quantitative proteome profiling was performed. Urinary exosomes clustered based on whether they came from the bladder, with tumour contact, or the ureters, without tumour contact, even though all came from completely downstaged patients. Proteins overexpressed in exosomes derived from bladder urine contained several oncogenes and were mainly associated with tumour metabolism pathways. Although patients were histologically tumour-free at cystectomy, the bladder urine contained exosomes with a carcinogenic metabolic profile. This suggests a continuous release of exosomes from the bladder, which may promote recurrence at distant sites through metabolic rewiring, even after apparent complete downstaging. These exosomes, coming from either undetected cancer cells or partly transformed cells, are likely to increase the risk of metastasis and encourages cystectomy even in completely downstaged patients.

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  • 7. Korsnes, Lars
    et al.
    Gottvall, Andreas
    Buttazzoni, Christian
    Mints, Michael
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Undersizing the Exeter stem in hip hemiarthroplasty increases the risk of periprosthetic fracture2020In: HIP International, ISSN 1120-7000, E-ISSN 1724-6067, Vol. 30, no 4, p. 469-473Article in journal (Refereed)
    Abstract [en]

    Introduction:: Whether under- or oversizing of the femoral component of cemented hip hemiarthroplasties impacts the risk of periprosthetic fractures (PPF) has only been examined experimentally. This study was carried out to add more knowledge about the risks of PPF in cemented polished tapered hemiarthroplasties.

    Methods: 20 patients with PPF following hip hemiarthroplasty with cemented Exeter V40 stems were compared to 50 controls who never suffered PPF having received the same type of Exeter hemiprosthesis for the same indication. The difference between stem size and post-hoc radiographic ideal templated size was investigated as a predictor of PPF.

    Results: Cases had a median size difference to post-hoc templating of –2, while controls had a median size difference of –1 (p = 0.09). An ROC curve constructed to find an optimal cutoff point in size difference between cases and controls arrived at an area under curve of 63%, with –1.5 as the cutoff. Patients with size differences exceeding –1.5 had a statistically significant increased PPF risk (odds ratio = 3.8, 95% confidence interval, 1.1–13.3, p < 0.05). This group covered 55% of all cases.

    Conclusion: An implanted femoral component that is 2 or more sizes smaller than the template that is shown to be appropriate will increase the risk of PPF in Exeter hip hemiarthroplasties.

  • 8. Krantz, David
    et al.
    Mints, Michael
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Winerdal, Malin
    Riklund, Katrine
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Rutishauser, Dorothea
    Zubarev, Roman
    Zirakzadeh, Amir Ali
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Alamdari, Farhood
    Johansson, Markus
    Sherif, Amir
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Winqvist, Ola
    IL-16 processing in sentinel node regulatory T cells is a factor in bladder cancer immunity2020In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 92, no 6, article id e12926Article in journal (Refereed)
    Abstract [en]

    In the effort of developing new immunotherapies, the sentinel node (SN) has proven a promising source from which to harness an effective antitumour T cell response. However, tumour immune escape, a process in which regulatory T cells (Tregs) play a central role, remains a major limiting factor. Therefore, there is a clear need to increase the knowledge of Treg function and signalling in sentinel nodes. Here, we set out to explore whether the proteome in SN-resident T cells is altered by the tumour and to identify key proteins in SN T cell signalling, focusing on Tregs. Five patients with muscle-invasive urothelial bladder cancer were prospectively included. Mass spectrometry was performed on two patients, with validation and functional studies being performed on three additional patients and four healthy donors. At cystectomy, SN, non-SN lymph nodes and peripheral blood samples were collected from the patients and T cell subsets isolated through flow cytometry before downstream experiments. Proteomic analysis indicated that growth and immune signalling pathways are upregulated in SN-resident Tregs. Furthermore, centrality analysis identified the cytokine IL-16 to be central in the SN-Treg signalling network. We show that tumour-released factors, through activating caspase-3, increase Treg IL-16 processing into bioactive forms, reinforcing Treg suppressive capacity. In conclusion, we provide evidence that Tregs exposed to secreted factors from bladder tumours show increased immune and growth signalling and altered IL-16 processing which translates to enhanced Treg suppressive function, indicating altered IL-16 signalling as a novel tumour immune escape mechanism.

  • 9. Landin, David
    et al.
    Ahrlund-Richter, Andreas
    Mirzaie, Leila
    Mints, Michael
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. Departement of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel.
    Nasman, Anders
    Kolev, Aeneas
    Marklund, Linda
    Dalianis, Tina
    Munck-Wikland, Eva
    Ramqvist, Torbjorn
    Immune related proteins and tumor infiltratingCD8+ lymphocytes in hypopharyngeal cancer in relation to human papillomavirus (HPV) and clinical outcome2020In: Head and Neck, ISSN 1043-3074, E-ISSN 1097-0347, Vol. 42, no 11, p. 3206-3217Article in journal (Refereed)
    Abstract [en]

    Background: Hypopharyngeal cancer (HPSCC) shows a poor clinical outcome, while HPSCC, caused by human papillomavirus (HPV), presents a better outcome. Here, HPCC, immune proteins, and tumor infiltrating CD8+ lymphocytes (CD8+ TILs) were evaluated in relation to HPV and outcome.

    Methods: Fresh frozen tissue from four HPV-positive HPSCC, 39 HPV-negative HPSCC, and normal samples were analyzed for protein expression by the Proseek immuno-oncology immunoassay. CD8+ TIL numbers evaluated by immunohistochemistry on 144 formalin-fixed biopsies were analyzed in relation to clinical outcome.

    Results: Proteins differing between HPV-positive and negative HPSCC included CD8A, PD-L1, Fas ligand, and chemokines. High CD8+ TIL numbers were correlated to improve clinical outcome in HPV-negative HPSCC.

    Conclusions: High expression of immune proteins in HPV-positive HPSCC may explain the better clinical outcome. CD8+ TILs are of relevance for outcome of HPV-negative HPSCC, while tumors with high immune activity but poor patient survival suggest a role for immune therapy.

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  • 10. Magalhaes, Isabelle
    et al.
    Carvalho-Queiroz, Claudia
    Hartana, Ciputra Adijaya
    Kaiser, Andreas
    Lukic, Ana
    Mints, Michael
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Nilsson, Ola
    Grönlund, Hans
    Mattsson, Jonas
    Berglund, Sofia
    Facing the future: challenges and opportunities in adoptive T cell therapy in cancer2019In: Expert Opinion on Biological Therapy, ISSN 1471-2598, E-ISSN 1744-7682, Vol. 19, no 8, p. 811-827Article in journal (Refereed)
    Abstract [en]

    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.

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  • 11.
    Mints, Michael
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    Hiltbrunner, Stefanie
    Eldh, Maria
    Rosenblatt, Robert
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    Holmström, Benny
    Alamdari, Farhood
    Johansson, Markus
    Hansson, Johan
    Vasko, Jonas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Winqvist, Ola
    Sherif, Amir
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    Gabrielsson, Susanne
    Exosomes in urine retain a malignant protein profile after primary tumour ablation in patients with invasive urinary bladder cancer2017In: Scandinavian journal of urology, ISSN 2168-1805, E-ISSN 2168-1813, Vol. 51, p. 38-39Article in journal (Other academic)
  • 12.
    Mints, Michael
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    Krantz, David
    Johansson, Markus
    Hansson, Johan
    Vasko, Jonas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Winerdal, Malin
    Zirakzadeh, Ali
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Riklund, Katrin
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Zubarev, Roman
    Rutishauser, Dorothea
    Sherif, Amir
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    Winqvist, Ola
    Individual immunoproteomics identifies il-16 processing in tregs as a factor in bladder cancer tumour immunity2017In: Scandinavian journal of urology, ISSN 2168-1805, E-ISSN 2168-1813, Vol. 51, p. 36-37Article in journal (Other academic)
  • 13.
    Mints, Michael
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel.
    Landin, David
    Näsman, Anders
    Mirzaie, Leila
    Ursu, Ramona Gabriela
    Zupancic, Mark
    Marklund, Linda
    Dalianis, Tina
    Munck-Wikland, Eva
    Ramqvist, Torbjörn
    Tumour inflammation signature and expression of S100A12 and HLA class I improve survival in HPV-negative hypopharyngeal cancer2021In: Scientific Reports, E-ISSN 2045-2322, Vol. 11, no 1, article id 1782Article in journal (Refereed)
    Abstract [en]

    Hypopharyngeal squamous cell carcinoma (HPSCC) has a very poor prognosis. Local surgery may increase survival, but is often avoided due to significant post-op co-morbidities. Since prognostic markers are lacking, the aim was to find predictive biomarkers that identify patients whose response to oncological treatment is poor and who may benefit from primary surgery to increase survival. Pretreatment biopsies from 23 HPSCC patients, 3 human papillomavirus (HPV) positive and 20 HPV-negative, were analyzed for expression of 750 mRNAs using the Nanostring nCounter IO360 panel in relation to 3-year survival. Validation was performed through immunohistochemistry (IHC) for HLA class I and S100A12 in 74 HPV-negative HPSCC samples. Clustering identified a subset of HPV-negative HPSCC with favorable prognosis and a gene expression signature overexpressing calgranulins and immune genes, distinct from that of HPV-positive HPSCC. Enrichment analysis showed immune signaling, including the tumor inflammation signature, to be enriched in surviving patients. IHC validation confirmed high S100A12 and HLA class I expression to correlate with survival in HPV-negative HPSCC. This shows that immune activity is strongly related to survival in HPV-negative HPSCC. Enrichment of the tumor inflammation signature indicates a potential benefit of immunotherapy. Low expression of both HLA class I and S100A12 could be used to select patients for local surgery.

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  • 14.
    Puram, Sidharth V.
    et al.
    Department of Otolaryngology—Head and Neck Surgery, Washington University School of Medicine, MO, St. Louis, United States; Department of Genetics, Washington University School of Medicine, MO, St. Louis, United States; Siteman Cancer Center, Washington University in St. Louis, MO, St. Louis, United States.
    Mints, Michael
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel; Department of Oncology–Pathology, Karolinska Institute, Stockholm, Sweden.
    Pal, Ananya
    Department of Otolaryngology—Head and Neck Surgery, Washington University School of Medicine, MO, St. Louis, United States.
    Qi, Zongtai
    Department of Otolaryngology—Head and Neck Surgery, Washington University School of Medicine, MO, St. Louis, United States.
    Reeb, Ashley
    Department of Otolaryngology—Head and Neck Surgery, Washington University School of Medicine, MO, St. Louis, United States.
    Gelev, Kyla
    Department of Internal Medicine, Washington University School of Medicine, MO, St. Louis, United States.
    Barrett, Thomas F.
    Department of Otolaryngology—Head and Neck Surgery, Washington University School of Medicine, MO, St. Louis, United States.
    Gerndt, Sophie
    Department of Otolaryngology—Head and Neck Surgery, Washington University School of Medicine, MO, St. Louis, United States.
    Liu, Ping
    Department of Internal Medicine, Washington University School of Medicine, MO, St. Louis, United States; Department of Radiation Oncology, Washington University School of Medicine, MO, St. Louis, United States.
    Parikh, Anuraag S.
    Department of Otolaryngology–Head and Neck Surgery, Columbia University Irving Medical Center, NY, New York, United States.
    Ramadan, Salma
    Department of Otolaryngology—Head and Neck Surgery, Washington University School of Medicine, MO, St. Louis, United States.
    Law, Travis
    Department of Otolaryngology—Head and Neck Surgery, Washington University School of Medicine, MO, St. Louis, United States.
    Mroz, Edmund A.
    Department of Otolaryngology–Head and Neck Surgery, Ohio State University, OH, Columbus, United States.
    Rocco, James W.
    Department of Otolaryngology–Head and Neck Surgery, Ohio State University, OH, Columbus, United States.
    Adkins, Doug
    Siteman Cancer Center, Washington University in St. Louis, MO, St. Louis, United States; Department of Medicine, Washington University School of Medicine, MO, St. Louis, United States.
    Thorstad, Wade L.
    Siteman Cancer Center, Washington University in St. Louis, MO, St. Louis, United States; Department of Radiation Oncology, Washington University School of Medicine, MO, St. Louis, United States.
    Gay, Hiram A.
    Siteman Cancer Center, Washington University in St. Louis, MO, St. Louis, United States; Department of Radiation Oncology, Washington University School of Medicine, MO, St. Louis, United States.
    Ding, Li
    Department of Medicine, Washington University School of Medicine, MO, St. Louis, United States; McDonnell Genome Institute, Washington University in St. Louis, MO, St. Louis, United States.
    Paniello, Randal C.
    Department of Otolaryngology—Head and Neck Surgery, Washington University School of Medicine, MO, St. Louis, United States; Siteman Cancer Center, Washington University in St. Louis, MO, St. Louis, United States.
    Pipkorn, Patrik
    Department of Otolaryngology—Head and Neck Surgery, Washington University School of Medicine, MO, St. Louis, United States; Siteman Cancer Center, Washington University in St. Louis, MO, St. Louis, United States.
    Jackson, Ryan S.
    Department of Otolaryngology—Head and Neck Surgery, Washington University School of Medicine, MO, St. Louis, United States; Siteman Cancer Center, Washington University in St. Louis, MO, St. Louis, United States.
    Wang, Xiaowei
    Department of Internal Medicine, Washington University School of Medicine, MO, St. Louis, United States; Department of Pharmacology and Regenerative Medicine, University of Illinois at Chicago, IL, Chicago, United States.
    Mazul, Angela
    Department of Otolaryngology—Head and Neck Surgery, Washington University School of Medicine, MO, St. Louis, United States.
    Chernock, Rebecca
    Department of Pathology and Immunology, Washington University School of Medicine, MO, St. Louis, United States.
    Zevallos, Jose P.
    Department of Otolaryngology—Head and Neck Surgery, Washington University School of Medicine, MO, St. Louis, United States; Siteman Cancer Center, Washington University in St. Louis, MO, St. Louis, United States.
    Silva-Fisher, Jessica
    Siteman Cancer Center, Washington University in St. Louis, MO, St. Louis, United States; Department of Internal Medicine, Washington University School of Medicine, MO, St. Louis, United States.
    Tirosh, Itay
    Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel.
    Cellular states are coupled to genomic and viral heterogeneity in HPV-related oropharyngeal carcinoma2023In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 55, no 4, p. 640-650Article in journal (Refereed)
    Abstract [en]

    Head and neck squamous cell carcinoma (HNSCC) includes a subset of cancers driven by human papillomavirus (HPV). Here we use single-cell RNA-seq to profile both HPV-positive and HPV-negative oropharyngeal tumors, uncovering a high level of cellular diversity within and between tumors. First, we detect diverse chromosomal aberrations within individual tumors, suggesting genomic instability and enabling the identification of malignant cells even at pathologically negative margins. Second, we uncover diversity with respect to HNSCC subtypes and other cellular states such as the cell cycle, senescence and epithelial-mesenchymal transitions. Third, we find heterogeneity in viral gene expression within HPV-positive tumors. HPV expression is lost or repressed in a subset of cells, which are associated with a decrease in HPV-associated cell cycle phenotypes, decreased response to treatment, increased invasion and poor prognosis. These findings suggest that HPV expression diversity must be considered during diagnosis and treatment of HPV-positive tumors, with important prognostic ramifications.

  • 15.
    Ährlund-Richter, Andreas
    et al.
    Department of Oncology-Pathology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
    Holzhauser, Stefan
    Department of Oncology-Pathology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
    Dalianis, Tina
    Department of Oncology-Pathology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
    Näsman, Anders
    Department of Oncology-Pathology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden; Department of Clinical Pathology, CCK R8:02, Karolinska University Hospital, Stockholm, Sweden.
    Mints, Michael
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. Department of Oncology-Pathology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden; Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden; Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel.
    Whole-exome sequencing of HPV positive tonsillar and base of tongue squamous cell carcinomas reveals a global mutational pattern along with relapse-specific somatic variants2022In: Cancers, ISSN 2072-6694, Vol. 14, no 1, article id 77Article in journal (Refereed)
    Abstract [en]

    To identify predictive/targetable markers in human papillomavirus positive (HPV+) ton-sillar and base of tongue cancer (TSCC/BOTSCC), whole-exome sequencing (WES) of tumours of patients with/without recurrence was performed. Forty primary tumours and adjacent normal tissue were separated by micro-dissection from formalin-fixed paraffin-embedded tissue from patients treated with curative intent 2000–2014 at Karolinska University Hospital. Successful sequencing was obtained in primary tumours of 18 patients without and primaries of 17 with local or distant recurrence, as well as in 10 corresponding recurrences (i.e., five local relapses and five distant metas-tases) from these 17 patients. One variant—a high-impact deletion in the CDC27 gene—was observed only in primaries of 5/17 patients that had a recurrence after full treatment but in none of those without recurrence. In addition, 3 variants and 26 mutated genes, including CDC27, BCLAF1 and AQP7, were present in at least 30% of all primary tumours independent of prognosis. To conclude, a CDC27 deletion was specific and found in ~30% of samples from patients with a local relapse/distant metastasis and could, therefore, potentially be a prospective marker to predict prognosis. Commonly mutated genes, such as BCLAF1, should be further studied in the context of targeted therapy.

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