| 51. |
- Hafström, Anna, et al.
(författare)
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Patients with cutaneous head and neck melanoma, particularly elderly with more advanced primary tumors, seem to benefit from initial CT staging before considering a sentinel lymph node biopsy
- 2020
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Ingår i: Acta Oto-Laryngologica. - : Informa UK Limited. - 0001-6489 .- 1651-2251. ; 140:9, s. 795-802
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Tidskriftsartikel (refereegranskat)abstract
- Background: The role of CT scanning at the time of diagnosis for patients with primary cutaneous head and neck melanoma (cHNM) clinically asymptomatic for metastatic disease remains unclear. Aim: To determine the positive yield of initial CT scanning before considering sentinel lymph node biopsy (SLNB) staging. Materials and methods: A retrospective review was performed on 170 consecutive patients with cHNM referred to a tertiary head and neck academic center for SLNBs from 2014 through 2018. Results: Initial CTs identified occult melanoma metastases in 7.1% and other advanced malignancies in 4.7%. The overall CT yield for patients >65 years (n = 115) was 13.9%, and 5.5% for patients <65 (only occult melanoma metastases). The SLNB yield did not differ between older (11.5%) and younger patients (10.2%). Patients with more advanced primary tumors were upstaged more often by both staging procedures. Multivariate analysis indicated a true-positive CT finding as the strongest prognostic factor for OS (p<.001). Conclusions and significance: The CT yield was >11% and higher for older than for younger patients. The findings suggest that CT imaging may be considered before SLNB staging, potentially identifying metastatic melanoma disease as well as other occult malignancies, enabling especially older patients to bypass the SLNB procedure.
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| 52. |
- Hafström, Anna, et al.
(författare)
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Predictors of survival in advanced oral cancers after salvage surgery with free tissue flap reconstruction
- 2023
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Ingår i: European Archives of Oto-Rhino-Laryngology. - : Springer Science and Business Media LLC. - 0937-4477 .- 1434-4726. ; 280:6, s. 2953-2964
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To identify prognostic factors for patients with advanced persistent, recurrent, or 2nd primary oral cavity squamous cell carcinoma (OCSCC) potentially unsuitable for salvage surgery with free tissue flap (FTF) reconstruction. Materials and methods: A population-based cohort of 83 consecutive patients with advanced OCSCC who underwent salvage surgery with FTF reconstruction at a tertiary referral centre between 1990 and 2017. Retrospective uni- and multivariable analyses were performed to identify factors affecting all-cause mortality (ACM), i.e., overall survival (OS), as well as disease-specific mortality (DSM), i.e., disease-specific survival (DSS) after salvage surgery. Results: Median disease-free interval until recurrence was 15 months with recurrent stage I/II in 31% and III/IV in 69%. Median age at salvage surgery was 67 years (range 31–87) and the median follow-up (alive patients) 126 months. At 2, 5, and 10 years after salvage surgery, respectively, DSS rates were 61%, 44%, and 37% and OS rates 52%, 30%, and 22%. Median DSS was 26 and OS 43 months. Multivariable analysis identified recurrent clinical regional (cN-plus) disease [HR 3.57; p <.001] and elevated gamma-glutamyl transferase (GGT) [HR 3.30; p =.003] as independent pre-salvage predictors for poor OS after salvage, whereas initial cN-plus [HR 2.07; p =.039] and recurrent cN-plus disease [HR 5.14; p <.001] predicted poor DSS. Among post-salvage factors, extranodal extension according to histopathology [HR ACM 6.11; HR DSM 9.99; p <.001] as well as positive [HR ACM 4.98; DSM 7.51; p < 0.001] and narrow surgical margins [HR ACM 2.12; DSM HR 2.80; p < 0.01] emerged as independent factors for poor survival. Conclusion: While salvage surgery with FTF reconstruction is the primary curative option for patients with advanced recurrent OCSCC, the present findings may help guide discussions with patients who have advanced recurrent regional disease and high GGT preoperatively, especially if there is a small chance of reaching surgical radicality.
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| 53. |
- Hafström, Anna, et al.
(författare)
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Sentinel lymph node biopsy staging for cutaneous malignant melanoma of the head and neck.
- 2016
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Ingår i: Acta Oto-Laryngologica. - : Informa UK Limited. - 1651-2251 .- 0001-6489. ; 136:3
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Tidskriftsartikel (refereegranskat)abstract
- Conclusion Sentinel lymph node biopsies (SLNBs) can be performed safely and with reasonable accuracy in HNM patients. The outcome provides important prognostic information concerning DFS and further treatment. However, one must recognize that SLNB is a multidisciplinary procedure with a learning curve for all. Objectives To evaluate efficacy of performing SLNBs in a series of consecutive patients with cutaneous head and neck melanoma (HNM) ≥ T1b from introduction of the procedure and 10 years onward. Method End-points comprised of SLNB outcome, disease-free survival (DFS), and overall survival (OS). Results SNs were harvested in 128 of 160 patients (median Breslow = 2.0 mm, 29% ulcerated); success rate = 80.0%, or 92.1% if excluding patients where SLNBs were omitted due to non-localization on pre-operative imaging or because of SN-location in the parotid basin. Ten patients (7.8%) had positive SLNBs and were offered early completion neck dissections. Of the 146 patients available for follow-up (median = 27 months), 15.8% had recurrent disease. The risk of a regional nodal recurrence after a negative SLNB was 7.5%. SN-negative patients had improved DFS c.f. SN-positive patients (p < 0.001). A positive SLNB was the most important prognostic predictor of decreased DFS (hazard ratio = 5.70; p < 0.005), but had no significant impact on OS.
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| 54. |
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| 55. |
- Hoh, Ramona A., et al.
(författare)
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Clonal evolution and stereotyped sequences of human IgE lineages in aeroallergen-specific immunotherapy
- 2023
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Ingår i: Journal of Allergy and Clinical Immunology. - : Elsevier BV. - 0091-6749. ; 152:1, s. 214-229
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Tidskriftsartikel (refereegranskat)abstract
- Background: Allergic disease reflects specific inflammatory processes initiated by interaction between allergen and allergen-specific IgE. Specific immunotherapy (SIT) is an effective long-term treatment option, but the mechanisms by which SIT provides desensitization are not well understood. Objective: Our aim was to characterize IgE sequences expressed by allergen-specific B cells over a 3-year longitudinal study of patients with aeroallergies who were undergoing SIT. Methods: Allergen-specific IgE–expressing clones were identified by using combinatorial single-chain variable fragment libraries and tracked in PBMCs and nasal biopsy samples over a 3-year period with antibody gene repertoire sequencing. The characteristics of private IgE-expressing clones were compared with those of stereotyped or “public” IgE responses to the grass pollen allergen Phleum pratense (Phl p) 2. Result: Members of the same allergen-specific IgE lineages were observed in nasal biopsy samples and blood, and lineages detected at baseline persisted in blood and nasal biopsy samples after 3 years of SIT, including B cells that express IgE. Evidence of progressive class switch recombination to IgG subclasses was observed after 3 years of SIT. A common stereotyped Phl p 2–specific antibody heavy chain sequence was detected in multiple donors. The amino acid residues enriched in IgE-stereotyped sequences from seropositive donors were analyzed with machine learning and k-mer motif discovery. Stereotyped IgE sequences had lower overall rates of somatic hypermutation and antigen selection than did single-chain variable fragment–derived allergen-specific sequences or IgE sequences of unknown specificity. Conclusion: Longitudinal tracking of rare circulating and tissue-resident allergen-specific IgE+ clones demonstrates persistence of allergen-specific IgE+ clones, progressive class switch recombination to IgG subtypes, and distinct maturation of a stereotyped Phl p 2 clonotype.
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| 56. |
- Hägerbrand, Karin, et al.
(författare)
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Bispecific antibodies targeting CD40 and tumor-associated antigens promote cross-priming of T cells resulting in an antitumor response superior to monospecific antibodies
- 2022
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Ingår i: Journal for ImmunoTherapy of Cancer. - : BMJ. - 2051-1426. ; 10:11
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Tidskriftsartikel (refereegranskat)abstract
- Background Indications with poor T-cell infiltration or deficiencies in T-cell priming and associated unresponsiveness to established immunotherapies represent an unmet medical need in oncology. CD40-targeting therapies designed to enhance antigen presentation, generate new tumor-specific T cells, and activate tumor-infiltrating myeloid cells to remodel the tumor microenvironment, represent a promising opportunity to meet this need. In this study, we present the first in vivo data supporting a role for tumor-associated antigen (TAA)-mediated uptake and cross-presentation of tumor antigens to enhance tumor-specific T-cell priming using CD40×TAA bispecific antibodies, a concept we named Neo-X-Prime. Methods Bispecific antibodies targeting CD40 and either of two cell-surface expressed TAA, carcinoembryonic antigen-related cell adhesion molecule 5 (CEA) or epithelial cell adhesion molecule (EpCAM), were developed in a tetravalent format. TAA-conditional CD40 agonism, activation of tumor-infiltrating immune cells, antitumor efficacy and the role of delivery of tumor-derived material such as extracellular vesicles, tumor debris and exosomes by the CD40×TAA bispecific antibodies were demonstrated in vitro using primary human and murine cells and in vivo using human CD40 transgenic mice with different tumor models. Results The results showed that the CD40×TAA bispecific antibodies induced TAA-conditional CD40 activation both in vitro and in vivo. Further, it was demonstrated in vitro that they induced clustering of tumor debris and CD40-expressing cells in a dose-dependent manner and superior T-cell priming when added to dendritic cells (DC), ovalbumin (OVA)-specific T cells and OVA-containing tumor debris or exosomes. The antitumor activity of the Neo-X-Prime bispecific antibodies was demonstrated to be significantly superior to the monospecific CD40 antibody, and the resulting T-cell dependent antitumor immunity was directed to tumor antigens other than the TAA used for targeting (EpCAM). Conclusions The data presented herein support the hypothesis that CD40×TAA bispecific antibodies can engage tumor-derived vesicles containing tumor neoantigens to myeloid cells such as DCs resulting in an improved DC-mediated cross-priming of tumor-specific CD8 + T cells. Thus, this principle may offer therapeutics strategies to enhance tumor-specific T-cell immunity and associated clinical benefit in indications characterized by poor T-cell infiltration or deficiencies in T-cell priming.
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| 57. |
- Jimenez, David Gomez, et al.
(författare)
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Single-cell analysis of myeloid cells in HPV+ tonsillar cancer
- 2023
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Ingår i: Frontiers in Immunology. - : Frontiers Media SA. - 1664-3224. ; 13
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Tidskriftsartikel (refereegranskat)abstract
- The incidence of human papillomavirus-positive (HPV+) tonsillar cancer has been sharply rising during the last decades. Myeloid cells represent an appropriate therapeutic target due to their proximity to virus-infected tumor cells, and their ability to orchestrate antigen-specific immunity, within the tonsil. However, the interrelationship of steady-state and inflammatory myeloid cell subsets, and their impact on patient survival remains unexplored. Here, we used single-cell RNA-sequencing to map the myeloid compartment in HPV+ tonsillar cancer. We observed an expansion of the myeloid compartment in HPV+ tonsillar cancer, accompanied by interferon-induced cellular responses both in dendritic cells (DCs) and monocyte-macrophages. Our analysis unveiled the existence of four DC lineages, two macrophage polarization processes, and their sequential maturation profiles. Within the DC lineages, we described a balance shift in the frequency of progenitor and mature cDC favoring the cDC1 lineage in detriment of cDC2s. Furthermore, we observed that all DC lineages apart from DC5s matured into a common activated DC transcriptional program involving upregulation of interferon-inducible genes. In turn, the monocyte-macrophage lineage was subjected to early monocyte polarization events, which give rise to either interferon-activated or CXCL-producing macrophages, the latter enriched in advanced tumor stages. We validated the existence of most of the single-cell RNA-seq clusters using 26-plex flow cytometry, and described a positive impact of cDC1 and interferon-activated DCs and macrophages on patient survival using gene signature scoring. The current study contributes to the understanding of myeloid ontogeny and dynamics in HPV-driven tonsillar cancer, and highlights myeloid biomarkers that can be used to assess patient prognosis.
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| 58. |
- Jimenez, David Gomez, et al.
(författare)
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Subpopulations of organoid-forming cells have different motility
- 2020
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Ingår i: Applied Sciences (Switzerland). - : MDPI AG. - 2076-3417. ; 10:13
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Tidskriftsartikel (refereegranskat)abstract
- Cancer stem cells from oropharyngeal squamous cell carcinoma (OPSCC) have the ability to self-renew and differentiate into heterogeneous three-dimensional structures carrying features of tumor cells. Here, we describe a simple and label-free method for generating tumor organoids, and imaging them using live digital holographic microscopy (DHM) on the basis of the phase shift caused by light passing through the cells. We show early events of cell aggregation during tumor-organoid formation, and display their heterogeneity in terms of optical parameters up to an optical volume of 105 μm3. Lastly, by sorting OPSCC epithelial cells, we demonstrate that CD44+ cells displayed greater motility and tumor-forming capacity than those of CD44- cells. These results were in line with previous reports highlighting increased invasive and tumorigenic potential in tumor cells expressing high levels of CD44. Our method provides insight into the formation of tumor organoids, and could be used to assess stemness-associated biomarkers and drug screenings on the basis of tumor organoids.
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| 59. |
- Jimenez, David Gomez, et al.
(författare)
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Tonsillar cancer with high cd8+ t‐cell infiltration features increased levels of dendritic cells and transcriptional regulation associated with an inflamed tumor microenvironment
- 2021
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Ingår i: Cancers. - : MDPI AG. - 2072-6694. ; 13:21
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Tidskriftsartikel (refereegranskat)abstract
- Human papillomavirus (HPV) is the main causal agent of tonsillar cancer (TC) and HPV+ TC has a favorable prognosis compared to HPV– disease. In this study, we examined aspects of the tumor microenvironment of TC, focusing on T‐cells, dendritic cells (DC), and macrophages. Fresh biopsies of TC and the contralateral healthy tonsil (HT) were obtained from 20 patients, analyzed by multiparameter flow cytometry, and assessed against a detailed HPV‐status. Additionally, RNA-sequencing data from 38 TC samples available in the public database, The Cancer Genome Atlas (TCGA), were explored, focusing on the same leukocyte populations. HPV+ TC featured increased levels of CD8+ T‐cells and antigen‐presenting cells (cf. HPV– TC and HT, respectively). In HPV+ TC, CD8+ T‐cell frequencies correlated to DC levels independently of tumor stage, HPV 16 copy number, and E7 oncogene expression as well as frequencies of other leukocytes. Similarly, RNA sequencing data were explored by dividing the HPV+ TCs according to predefined CD8+ T‐cell scores in silico. Higher levels of genes expressed by antigen‐presenting cells and effector T‐cells, such as immune checkpoints and cytokines, were detected in the CD8HIGH HPV+ TC samples (cf. CD8LOW HPV+ TC). In conclusion, CD8HIGH HPV+ TC displays a unique inflammatory profile associated with increased effector T‐cell functions and the presence of antigen‐presenting cells in the tumor microenviron-ment. Further studies are warranted to assess if this information can be used on an individual basis to aid in prognosis and treatment decisions.
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| 60. |
- Kirik, Ufuk, et al.
(författare)
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Antibody heavy chain variable domains of different germline gene origins diversify through different paths
- 2017
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Ingår i: Frontiers in Immunology. - : Frontiers Media SA. - 1664-3224. ; 8:NOV
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Tidskriftsartikel (refereegranskat)abstract
- B cells produce antibodies, key effector molecules in health and disease. They mature their properties, including their affinity for antigen, through hypermutation events; processes that involve, e.g., base substitution, codon insertion and deletion, often in association with an isotype switch. Investigations of antibody evolution define modes whereby particular antibody responses are able to form, and such studies provide insight important for instance for development of efficient vaccines. Antibody evolution is also used in vitro for the design of antibodies with improved properties. To better understand the basic concepts of antibody evolution, we analyzed the mutational paths, both in terms of amino acid substitution and insertions and deletions, taken by antibodies of the IgG isotype. The analysis focused on the evolution of the heavy chain variable domain of sets of antibodies, each with an origin in 1 of 11 different germline genes representing six human heavy chain germline gene subgroups. Investigated genes were isolated from cells of human bone marrow, a major site of antibody production, and characterized by next-generation sequencing and an in-house bioinformatics pipeline. Apart from substitutions within the complementarity determining regions, multiple framework residues including those in protein cores were targets of extensive diversification. Diversity, both in terms of substitutions, and insertions and deletions, in antibodies is focused to different positions in the sequence in a germline gene-unique manner. Altogether, our findings create a framework for understanding patterns of evolution of antibodies from defined germline genes.
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