实体瘤患者腹水表现出明显的炎症模式。

IF 24.9 1区 医学 Q1 ONCOLOGY
Julia M. Berger, Martin Korpan, Carina Zierfuss, Katharina Syböck, Erwin Tomasich, Andreas Kienzle, Maria Koenig, Markus Kleinberger, Lynn Gottmann, Birgit Fendl, Cihan Ay, Johannes Pammer, Catharina Müller, Rudolf Oehler, Lorenz Balcar, Thomas Reiberger, Elisabeth S. Bergen, Barbara Niederdorfer, Matthias Preusser, Anna S. Berghoff
{"title":"实体瘤患者腹水表现出明显的炎症模式。","authors":"Julia M. Berger,&nbsp;Martin Korpan,&nbsp;Carina Zierfuss,&nbsp;Katharina Syböck,&nbsp;Erwin Tomasich,&nbsp;Andreas Kienzle,&nbsp;Maria Koenig,&nbsp;Markus Kleinberger,&nbsp;Lynn Gottmann,&nbsp;Birgit Fendl,&nbsp;Cihan Ay,&nbsp;Johannes Pammer,&nbsp;Catharina Müller,&nbsp;Rudolf Oehler,&nbsp;Lorenz Balcar,&nbsp;Thomas Reiberger,&nbsp;Elisabeth S. Bergen,&nbsp;Barbara Niederdorfer,&nbsp;Matthias Preusser,&nbsp;Anna S. Berghoff","doi":"10.1002/cac2.70031","DOIUrl":null,"url":null,"abstract":"<p>Ascites formation in solid tumor patients is associated with an increased risk of death [<span>1, 2</span>]. The lack of pathophysiological insight limited the development of targeted treatment so far. With advances in immune modulating therapies, the inflammatory component of ascites moved into focus. Experimental approaches targeting immunologic dysregulation have shown only limited success [<span>3, 4</span>]. Therefore, we investigated inflammatory processes of ascites, taking the presence of tumor cells into account, while focusing on gastrointestinal tract malignancies due to their underrepresentation in literature.</p><p>A total of 63 patients were included in this study. Among these patients, 55 (87.3%) underwent paracentesis for ascites caused by advanced solid tumors, of which 30/63 (47.6%) patients had negative tumor cell cytology (paramalignant ascites) and 25/63 (39.7%) had positive tumor cell cytology (malignant ascites). Additionally, 8/63 (12.7%) patients with non-malignant ascites due to liver cirrhosis were included. Patients’ characteristics are displayed in Supplementary Table S1.</p><p>To study differences in the inflammatory profiles based on tumor cells within ascites, nine cytokines (interleukin-6 [IL-6], IL-8, IL-10, IL-17, tumor necrosis factor-alpha [TNF-α], C-reactive protein [CRP], Eotaxin, vascular endothelial growth factor [VEGF], and the soluble programmed death ligand-1 [sPD-L1]) were measured in ascitic supernatant. Malignant ascites showed increased levels of IL-6, IL-8, VEGF, and sPD-L1, compared to paramalignant and non-malignant ascites, respectively (Figure 1A-D). In contrast, no differences in cytokine levels were observed between non-malignant and paramalignant ascites in all measured cytokines, indicating that the inflammatory composition of ascites correlates with the presence of tumor cells.</p><p>To correlate systemic inflammatory processes with local inflammation in ascites supernatant in patients with advanced solid tumors, we measured cytokine levels in serum samples obtained at the timepoint of paracentesis. Strong correlations between ascitic and serum cytokine levels were evident for IL-8 and IL-17 (Figure 1E-F). Additionally, strong correlation was evident for CRP levels (Figure 1G), while no or weak correlations were detected in other cytokines. CRP as well as levels sPD-L1were decreased in ascites compared to serum (Supplementary Table S2). Compared to serum, ascitic IL-6 was significantly elevated (Supplementary Table S2) without a correlation to systemic IL-6 levels (<i>ρ</i> = 0.16, <i>P &gt; 0.05</i>), suggesting IL-6 signaling may be important for local inflammation.</p><p>To tie the link between soluble inflammatory markers and the cellular inflammatory compartment, we investigated correlations between cytokine levels and leukocyte as well as cell count for 19 overlapping samples. While no associations between leukocyte count and cytokine levels were observed, strong correlations between overall cell count in ascites and VEGF as well as sPD-L1 (Figure 1H-I) were evident.</p><p>DNA methylation analyses of 32 cellular samples of ascites by Infinium Methylation EPIC V2.0 microarray were performed to obtain further insight on cellular composition and inflammatory pathways of interest (Supplementary Materials and Methods). No difference in the methylation profile of samples according to TNF-α (<i>n</i> = 19) or IL-6 (<i>n</i> = 17) were observed. Methylation variation seemed to be driven by cytology, with tumor cell cytology positive and negative samples separating along the first dimension of the multidimensional scaling plot (Figure 1J). 37,494 CpG sites were differentially methylated between malignant and paramalignant ascites (FDR <i>&lt; 0.05</i>). An enrichment of KEGG pathways for differentially methylated CpGs located on promotor revealed that hypermethylated probes were associated with Neuroactive ligand-receptor interaction (hsa04080) while hypomethylated CpGs were associated with Olfactory transduction (hsa04740, Supplementary Figure S1). Clustering of cellular ascites samples based on the top 20,000 differentially methylated CpGs, revealed three main clusters (cluster A-C, Figure 1K). Cluster B and C show a similar signature of hypermethylated CpGs in CpG Islands and consist of malignant ascites samples. Cluster A represents paramalignant ascites samples, with some cytology positive samples showing a similar signature.</p><p>As immune cell-type proportions may influence observed differences in DNA methylation, we inferred the cellular compositions by deconvolution. However, no deconvolution tools are optimized for ascites analysis, so results should be interpreted cautiously. In line with this, only weak to medium correlation of the estimated cell fraction by deconvolution with cell counts from cytology analysis was observed for overlapping samples (<i>n</i> = 21, neutrophils [Pearson R = 0.55, <i>P =</i> 0.01], T and B cell [Pearson R = 0.67, <i>P &lt;</i> 0.001], monocytes [Pearson R = 0.27, <i>P &gt;</i> 0.05). In alignment with cytology, we observed a higher cancer cell fraction according to the deconvolution in malignant versus paramalignant ascites samples (FDR adjusted <i>P &lt;</i> 0.001). Next, we compared estimated cell fractions between methylation clusters based on differentially methylated CpGs between malignant and paramalignant ascites (Figure 1K). No significant differences for immune cell types were observed, while a significantly higher cancer cell fraction was found in samples present in cluster B+C compared to cluster A (FDR adjusted <i>P &lt;</i> 0.001). When correlating estimated immune cell fractions with cytokine levels for overlapping samples (<i>n</i> = 17-19), we observed significant, albeit weak correlations (NK cells and IL-8, Pearson R = 0.44, <i>P =</i> 0.047; NK cells and IL-6, Pearson R = -0.48, <i>P</i> = 0.036; CD4 cells and IL-8, Pearson R = 0.46, <i>P =</i> 0.036; CD4 cells and TNF-a, R = 0.46, <i>P =</i> 0.046; CD8 cells and IL8, Pearson R = 0.52, <i>P =</i> 0.016).</p><p>Ascites formation in patients with solid tumors remains a clinical challenge. Existing clinical trials were designed without biomarkers and potential biological subtypes in ascites were not acknowledged [<span>5, 6</span>]. Our data suggests that distinct inflammatory subtypes of ascites in cancer patients exist on cellular and cytokine levels, as inflammatory profiles of patients with negative tumor cytology resembled non-malignant ascites. Given their low inflammation levels, cancer patients without tumor cells within ascites might profit from treatment established in non-malignant ascites patients like diuretic treatment [<span>7</span>]. Importantly, malignant ascites, defined by the presence of tumor cells within ascites, presented with increased inflammation compared to paramalignant and non-malignant ascites. We certainly have to acknowledge the limitation, that only one liter of ascites was processed per patient, leaving the theoretical possibility of single tumor cells in patients with paramalignant ascites. However, given the differing inflammatory profiles according to the observed tumor cell cytology, local inflammatory processes differ according to the amount /presence of tumor cells and serve as a potential therapeutic target particular in patients with positive cancer cytology. As the inflammatory profile of ascites was mainly independent of the systemic profile, the immunological effects might be locally specific. Local IL-6 was directly linked to paradox immunosuppressive effects in malignant ascites [<span>8</span>]. Adding to the heterogeneity of soluble inflammatory profiles, DNA methylation of cellular ascites samples revealed distinct profiles according to cytology. Three distinct methylation clusters were identified, where clustering seemed to be driven by the local presence of tumor cells. Pathway analysis suggested differences in Olfactory transduction and Neuroactive ligand-receptor interaction, both linked to immunosuppression [<span>9</span>]. Although the heterogeneity of our cohort needs to be acknowledged, previous studies in other entities as ovarian cancer are rare. Given the impaired clinical efficacy of bevacizumab in ascites treatment of patients with other primary tumors than ovarian cancer, the identified inflammatory targets are of interest for further investigation. Given the particular inflammatory profile of malignant ascites in our study, future research should focus on IL-6, IL-8 and immune checkpoints. Still, these first findings need to be evaluated in subsequent studies with bigger subgroups, to further assess their pathophysiologic relevance in ascites formation and potential clinical implications.</p><p><i>Conceptualization</i>: Julia M. Berger, Birgit Fendl, Barbara Niederdorfer, and Anna S. Berghoff. <i>Data curation</i>: Julia M. Berger, Martin Korpan, Carina Zierfuss, Katharina Syböck, Erwin Tomasich, Andreas Kienzle, Maria Koenig, Markus Kleinberger, Lynn Gottmann, Birgit Fendl, Cihan Ay, Johannes Pammer, Catharina Müller, Rudolf Öhler, Lorenz Balcar, Thomas Reiberger, Elisabeth S. Bergen, and Barbara Niederdorfer.Formal analysis: Julia M. Berger, Barbara Niederdorfer, and Anna S. Berghoff. <i>Funding acquisition</i>: Julia M. Berger, Matthias Preusser, and Anna S. Berghoff. Investigation: Julia M. Berger, Barbara Niederdorfer, and Anna S. Berghoff. <i>Methodology</i>: Julia M. Berger, Carina Zierfuss, Barbara Niederdorfer, and Anna S. Berghoff. <i>Project administration</i>: Julia M. Berger and Martin Korpan. <i>Resources</i>: Thomas Reiberger, Matthias Preusser, and Anna S. Berghoff. <i>Software</i>: Julia M. Berger and Barbara Niederdorfer. <i>Supervision</i>: Anna S. Berghoff. <i>Validation</i>: Julia M. Berger, Barbara Niederdorfer, and Anna S. Berghoff. <i>Visualization</i>: Julia M. Berger and Barbara Niederdorfer. <i>Writing: original draft</i>: Julia M. Berger, Barbara Niederdorfer, and Anna S. Berghoff. <i>Writing: review &amp; editing</i>: Julia M. Berger, Martin Korpan, Carina Zierfuss, Katharina Syböck, Erwin Tomasich, Andreas Kienzle, Maria Koenig, Markus Kleinberger, Lynn Gottmann, Birgit Fendl, Cihan Ay, Johannes Pammer, Catharina Müller, Rudolf Öhler, Lorenz Balcar, Thomas Reiberger, Elisabeth S. Bergen, Barbara Niederdorfer, Matthias Preusser, and Anna S. Berghoff.</p><p>Thomas Reiberger received grant support from Abbvie, Boehringer Ingelheim, Gilead, Intercept/Advanz Pharma, MSD, Myr Pharmaceuticals, Philips Healthcare, Pliant, Siemens and W. L. Gore &amp; Associates; speaking honoraria from Abbvie, Gilead, Intercept/Advanz Pharma, Roche, MSD, W. L. Gore &amp; Associates; consulting/advisory board fee from Abbvie, Astra Zeneca, Bayer, Boehringer Ingelheim, Gilead, Intercept/Advanz Pharma, MSD, Resolution Therapeutics, Siemens; and travel support from Abbvie, Boehringer Ingelheim, Dr. Falk Pharma, Gilead and Roche.</p><p>Matthias Preusser has received honoraria for lectures, consultation or advisory board participation from the following for-profit companies: Bayer, Bristol-Myers Squibb, Novartis, Gerson Lehrman Group (GLG), CMC Contrast, GlaxoSmithKline, Mundipharma, Roche, BMJ Journals, MedMedia, Astra Zeneca, AbbVie, Lilly, Medahead, Daiichi Sankyo, Sanofi, Merck Sharp &amp; Dome, Tocagen, Servier.</p><p>Anna S. Berghoff has received research support from Daiichi Sankyo (≤ 10000 €), Roche (&gt; 10000 €) and honoraria for lectures, consultation or advisory board participation from Roche Bristol-Meyers Squibb, Merck, Daiichi Sankyo (all &lt; 5000 €) as well as travel support from Roche, Amgen and AbbVie.</p><p>All other authors report not conflict of interest concerning this specific publication.</p><p>The financial support by the Margaretha Hehberger-Cancer Research Fund, the Austrian Federal Ministry for Digital and Economic Affairs, the National Foundation for Research, Technology and Development and the Christian Doppler Research Association is gratefully acknowledged.</p><p>All patients were treated according to best clinical practice and to current treatment guidelines throughout their whole clinical course of disease at our tertiary care center. This study was approved by the Ethics Committee of the Medical University of Vienna (vote number 2100 of 2022) and performed according to the Declaration of Helsinki and its Amendments. Consent to participate in this study was waived.</p>","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 8","pages":"936-940"},"PeriodicalIF":24.9000,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.70031","citationCount":"0","resultStr":"{\"title\":\"Ascites of patients with solid tumors shows distinct inflammatory patterns\",\"authors\":\"Julia M. Berger,&nbsp;Martin Korpan,&nbsp;Carina Zierfuss,&nbsp;Katharina Syböck,&nbsp;Erwin Tomasich,&nbsp;Andreas Kienzle,&nbsp;Maria Koenig,&nbsp;Markus Kleinberger,&nbsp;Lynn Gottmann,&nbsp;Birgit Fendl,&nbsp;Cihan Ay,&nbsp;Johannes Pammer,&nbsp;Catharina Müller,&nbsp;Rudolf Oehler,&nbsp;Lorenz Balcar,&nbsp;Thomas Reiberger,&nbsp;Elisabeth S. Bergen,&nbsp;Barbara Niederdorfer,&nbsp;Matthias Preusser,&nbsp;Anna S. Berghoff\",\"doi\":\"10.1002/cac2.70031\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p>Ascites formation in solid tumor patients is associated with an increased risk of death [<span>1, 2</span>]. The lack of pathophysiological insight limited the development of targeted treatment so far. With advances in immune modulating therapies, the inflammatory component of ascites moved into focus. Experimental approaches targeting immunologic dysregulation have shown only limited success [<span>3, 4</span>]. Therefore, we investigated inflammatory processes of ascites, taking the presence of tumor cells into account, while focusing on gastrointestinal tract malignancies due to their underrepresentation in literature.</p><p>A total of 63 patients were included in this study. Among these patients, 55 (87.3%) underwent paracentesis for ascites caused by advanced solid tumors, of which 30/63 (47.6%) patients had negative tumor cell cytology (paramalignant ascites) and 25/63 (39.7%) had positive tumor cell cytology (malignant ascites). Additionally, 8/63 (12.7%) patients with non-malignant ascites due to liver cirrhosis were included. Patients’ characteristics are displayed in Supplementary Table S1.</p><p>To study differences in the inflammatory profiles based on tumor cells within ascites, nine cytokines (interleukin-6 [IL-6], IL-8, IL-10, IL-17, tumor necrosis factor-alpha [TNF-α], C-reactive protein [CRP], Eotaxin, vascular endothelial growth factor [VEGF], and the soluble programmed death ligand-1 [sPD-L1]) were measured in ascitic supernatant. Malignant ascites showed increased levels of IL-6, IL-8, VEGF, and sPD-L1, compared to paramalignant and non-malignant ascites, respectively (Figure 1A-D). In contrast, no differences in cytokine levels were observed between non-malignant and paramalignant ascites in all measured cytokines, indicating that the inflammatory composition of ascites correlates with the presence of tumor cells.</p><p>To correlate systemic inflammatory processes with local inflammation in ascites supernatant in patients with advanced solid tumors, we measured cytokine levels in serum samples obtained at the timepoint of paracentesis. Strong correlations between ascitic and serum cytokine levels were evident for IL-8 and IL-17 (Figure 1E-F). Additionally, strong correlation was evident for CRP levels (Figure 1G), while no or weak correlations were detected in other cytokines. CRP as well as levels sPD-L1were decreased in ascites compared to serum (Supplementary Table S2). Compared to serum, ascitic IL-6 was significantly elevated (Supplementary Table S2) without a correlation to systemic IL-6 levels (<i>ρ</i> = 0.16, <i>P &gt; 0.05</i>), suggesting IL-6 signaling may be important for local inflammation.</p><p>To tie the link between soluble inflammatory markers and the cellular inflammatory compartment, we investigated correlations between cytokine levels and leukocyte as well as cell count for 19 overlapping samples. While no associations between leukocyte count and cytokine levels were observed, strong correlations between overall cell count in ascites and VEGF as well as sPD-L1 (Figure 1H-I) were evident.</p><p>DNA methylation analyses of 32 cellular samples of ascites by Infinium Methylation EPIC V2.0 microarray were performed to obtain further insight on cellular composition and inflammatory pathways of interest (Supplementary Materials and Methods). No difference in the methylation profile of samples according to TNF-α (<i>n</i> = 19) or IL-6 (<i>n</i> = 17) were observed. Methylation variation seemed to be driven by cytology, with tumor cell cytology positive and negative samples separating along the first dimension of the multidimensional scaling plot (Figure 1J). 37,494 CpG sites were differentially methylated between malignant and paramalignant ascites (FDR <i>&lt; 0.05</i>). An enrichment of KEGG pathways for differentially methylated CpGs located on promotor revealed that hypermethylated probes were associated with Neuroactive ligand-receptor interaction (hsa04080) while hypomethylated CpGs were associated with Olfactory transduction (hsa04740, Supplementary Figure S1). Clustering of cellular ascites samples based on the top 20,000 differentially methylated CpGs, revealed three main clusters (cluster A-C, Figure 1K). Cluster B and C show a similar signature of hypermethylated CpGs in CpG Islands and consist of malignant ascites samples. Cluster A represents paramalignant ascites samples, with some cytology positive samples showing a similar signature.</p><p>As immune cell-type proportions may influence observed differences in DNA methylation, we inferred the cellular compositions by deconvolution. However, no deconvolution tools are optimized for ascites analysis, so results should be interpreted cautiously. In line with this, only weak to medium correlation of the estimated cell fraction by deconvolution with cell counts from cytology analysis was observed for overlapping samples (<i>n</i> = 21, neutrophils [Pearson R = 0.55, <i>P =</i> 0.01], T and B cell [Pearson R = 0.67, <i>P &lt;</i> 0.001], monocytes [Pearson R = 0.27, <i>P &gt;</i> 0.05). In alignment with cytology, we observed a higher cancer cell fraction according to the deconvolution in malignant versus paramalignant ascites samples (FDR adjusted <i>P &lt;</i> 0.001). Next, we compared estimated cell fractions between methylation clusters based on differentially methylated CpGs between malignant and paramalignant ascites (Figure 1K). No significant differences for immune cell types were observed, while a significantly higher cancer cell fraction was found in samples present in cluster B+C compared to cluster A (FDR adjusted <i>P &lt;</i> 0.001). When correlating estimated immune cell fractions with cytokine levels for overlapping samples (<i>n</i> = 17-19), we observed significant, albeit weak correlations (NK cells and IL-8, Pearson R = 0.44, <i>P =</i> 0.047; NK cells and IL-6, Pearson R = -0.48, <i>P</i> = 0.036; CD4 cells and IL-8, Pearson R = 0.46, <i>P =</i> 0.036; CD4 cells and TNF-a, R = 0.46, <i>P =</i> 0.046; CD8 cells and IL8, Pearson R = 0.52, <i>P =</i> 0.016).</p><p>Ascites formation in patients with solid tumors remains a clinical challenge. Existing clinical trials were designed without biomarkers and potential biological subtypes in ascites were not acknowledged [<span>5, 6</span>]. Our data suggests that distinct inflammatory subtypes of ascites in cancer patients exist on cellular and cytokine levels, as inflammatory profiles of patients with negative tumor cytology resembled non-malignant ascites. Given their low inflammation levels, cancer patients without tumor cells within ascites might profit from treatment established in non-malignant ascites patients like diuretic treatment [<span>7</span>]. Importantly, malignant ascites, defined by the presence of tumor cells within ascites, presented with increased inflammation compared to paramalignant and non-malignant ascites. We certainly have to acknowledge the limitation, that only one liter of ascites was processed per patient, leaving the theoretical possibility of single tumor cells in patients with paramalignant ascites. However, given the differing inflammatory profiles according to the observed tumor cell cytology, local inflammatory processes differ according to the amount /presence of tumor cells and serve as a potential therapeutic target particular in patients with positive cancer cytology. As the inflammatory profile of ascites was mainly independent of the systemic profile, the immunological effects might be locally specific. Local IL-6 was directly linked to paradox immunosuppressive effects in malignant ascites [<span>8</span>]. Adding to the heterogeneity of soluble inflammatory profiles, DNA methylation of cellular ascites samples revealed distinct profiles according to cytology. Three distinct methylation clusters were identified, where clustering seemed to be driven by the local presence of tumor cells. Pathway analysis suggested differences in Olfactory transduction and Neuroactive ligand-receptor interaction, both linked to immunosuppression [<span>9</span>]. Although the heterogeneity of our cohort needs to be acknowledged, previous studies in other entities as ovarian cancer are rare. Given the impaired clinical efficacy of bevacizumab in ascites treatment of patients with other primary tumors than ovarian cancer, the identified inflammatory targets are of interest for further investigation. Given the particular inflammatory profile of malignant ascites in our study, future research should focus on IL-6, IL-8 and immune checkpoints. Still, these first findings need to be evaluated in subsequent studies with bigger subgroups, to further assess their pathophysiologic relevance in ascites formation and potential clinical implications.</p><p><i>Conceptualization</i>: Julia M. Berger, Birgit Fendl, Barbara Niederdorfer, and Anna S. Berghoff. <i>Data curation</i>: Julia M. Berger, Martin Korpan, Carina Zierfuss, Katharina Syböck, Erwin Tomasich, Andreas Kienzle, Maria Koenig, Markus Kleinberger, Lynn Gottmann, Birgit Fendl, Cihan Ay, Johannes Pammer, Catharina Müller, Rudolf Öhler, Lorenz Balcar, Thomas Reiberger, Elisabeth S. Bergen, and Barbara Niederdorfer.Formal analysis: Julia M. Berger, Barbara Niederdorfer, and Anna S. Berghoff. <i>Funding acquisition</i>: Julia M. Berger, Matthias Preusser, and Anna S. Berghoff. Investigation: Julia M. Berger, Barbara Niederdorfer, and Anna S. Berghoff. <i>Methodology</i>: Julia M. Berger, Carina Zierfuss, Barbara Niederdorfer, and Anna S. Berghoff. <i>Project administration</i>: Julia M. Berger and Martin Korpan. <i>Resources</i>: Thomas Reiberger, Matthias Preusser, and Anna S. Berghoff. <i>Software</i>: Julia M. Berger and Barbara Niederdorfer. <i>Supervision</i>: Anna S. Berghoff. <i>Validation</i>: Julia M. Berger, Barbara Niederdorfer, and Anna S. Berghoff. <i>Visualization</i>: Julia M. Berger and Barbara Niederdorfer. <i>Writing: original draft</i>: Julia M. Berger, Barbara Niederdorfer, and Anna S. Berghoff. <i>Writing: review &amp; editing</i>: Julia M. Berger, Martin Korpan, Carina Zierfuss, Katharina Syböck, Erwin Tomasich, Andreas Kienzle, Maria Koenig, Markus Kleinberger, Lynn Gottmann, Birgit Fendl, Cihan Ay, Johannes Pammer, Catharina Müller, Rudolf Öhler, Lorenz Balcar, Thomas Reiberger, Elisabeth S. Bergen, Barbara Niederdorfer, Matthias Preusser, and Anna S. Berghoff.</p><p>Thomas Reiberger received grant support from Abbvie, Boehringer Ingelheim, Gilead, Intercept/Advanz Pharma, MSD, Myr Pharmaceuticals, Philips Healthcare, Pliant, Siemens and W. L. Gore &amp; Associates; speaking honoraria from Abbvie, Gilead, Intercept/Advanz Pharma, Roche, MSD, W. L. Gore &amp; Associates; consulting/advisory board fee from Abbvie, Astra Zeneca, Bayer, Boehringer Ingelheim, Gilead, Intercept/Advanz Pharma, MSD, Resolution Therapeutics, Siemens; and travel support from Abbvie, Boehringer Ingelheim, Dr. Falk Pharma, Gilead and Roche.</p><p>Matthias Preusser has received honoraria for lectures, consultation or advisory board participation from the following for-profit companies: Bayer, Bristol-Myers Squibb, Novartis, Gerson Lehrman Group (GLG), CMC Contrast, GlaxoSmithKline, Mundipharma, Roche, BMJ Journals, MedMedia, Astra Zeneca, AbbVie, Lilly, Medahead, Daiichi Sankyo, Sanofi, Merck Sharp &amp; Dome, Tocagen, Servier.</p><p>Anna S. Berghoff has received research support from Daiichi Sankyo (≤ 10000 €), Roche (&gt; 10000 €) and honoraria for lectures, consultation or advisory board participation from Roche Bristol-Meyers Squibb, Merck, Daiichi Sankyo (all &lt; 5000 €) as well as travel support from Roche, Amgen and AbbVie.</p><p>All other authors report not conflict of interest concerning this specific publication.</p><p>The financial support by the Margaretha Hehberger-Cancer Research Fund, the Austrian Federal Ministry for Digital and Economic Affairs, the National Foundation for Research, Technology and Development and the Christian Doppler Research Association is gratefully acknowledged.</p><p>All patients were treated according to best clinical practice and to current treatment guidelines throughout their whole clinical course of disease at our tertiary care center. This study was approved by the Ethics Committee of the Medical University of Vienna (vote number 2100 of 2022) and performed according to the Declaration of Helsinki and its Amendments. Consent to participate in this study was waived.</p>\",\"PeriodicalId\":9495,\"journal\":{\"name\":\"Cancer Communications\",\"volume\":\"45 8\",\"pages\":\"936-940\"},\"PeriodicalIF\":24.9000,\"publicationDate\":\"2025-05-08\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.70031\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Cancer Communications\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://onlinelibrary.wiley.com/doi/10.1002/cac2.70031\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"ONCOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cancer Communications","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1002/cac2.70031","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ONCOLOGY","Score":null,"Total":0}
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摘要

实体瘤患者腹水形成与死亡风险增加相关[1,2]。迄今为止,缺乏病理生理学的认识限制了靶向治疗的发展。随着免疫调节疗法的进步,腹水的炎症成分成为焦点。针对免疫失调的实验方法仅显示出有限的成功[3,4]。因此,我们研究腹水的炎症过程,考虑到肿瘤细胞的存在,同时关注胃肠道恶性肿瘤,因为它们在文献中代表性不足。本研究共纳入63例患者。其中55例(87.3%)因晚期实体瘤所致腹水行穿刺,其中30/63例(47.6%)为肿瘤细胞学阴性(副恶性腹水),25/63例(39.7%)为肿瘤细胞学阳性(恶性腹水)。此外,8/63(12.7%)肝硬化非恶性腹水患者被纳入研究。患者特征见补充表S1。为了研究腹水内肿瘤细胞炎症谱的差异,我们在腹水上清中检测了9种细胞因子(白介素-6 [IL-6]、IL-8、IL-10、IL-17、肿瘤坏死因子-α [TNF-α]、c反应蛋白[CRP]、Eotaxin、血管内皮生长因子[VEGF]和可溶性程序性死亡配体-1 [sPD-L1])。与准恶性和非恶性腹水相比,恶性腹水中IL-6、IL-8、VEGF和sPD-L1水平分别升高(图1A-D)。相反,在所有测量的细胞因子中,在非恶性和副恶性腹水之间没有观察到细胞因子水平的差异,表明腹水的炎症成分与肿瘤细胞的存在相关。为了将晚期实体瘤患者腹水上清中的全身炎症过程与局部炎症联系起来,我们测量了在穿刺时间点获得的血清样本中的细胞因子水平。腹水和血清细胞因子IL-8和IL-17水平之间明显存在强相关性(图1E-F)。此外,CRP水平之间存在明显的强相关性(图1G),而其他细胞因子之间没有或只有弱相关性。与血清相比,腹水中CRP和spd - l1水平降低(补充表S2)。与血清相比,腹水IL-6显著升高(补充表S2),与全身IL-6水平无相关性(ρ = 0.16, P &gt; 0.05),提示IL-6信号可能对局部炎症很重要。为了将可溶性炎症标志物与细胞炎症室之间的联系联系起来,我们研究了19个重叠样本中细胞因子水平与白细胞以及细胞计数之间的相关性。虽然白细胞计数和细胞因子水平之间没有相关性,但腹水中总细胞计数与VEGF和sPD-L1之间存在明显的相关性(图1h - 1)。利用Infinium methylation EPIC V2.0微阵列对32个腹水细胞样本进行DNA甲基化分析,以进一步了解细胞组成和炎症途径(补充材料和方法)。根据TNF-α (n = 19)或IL-6 (n = 17)观察样品的甲基化谱无差异。甲基化变异似乎是由细胞学驱动的,肿瘤细胞细胞学阳性和阴性样本沿着多维标度图的第一维分离(图1J)。37,494个CpG位点在恶性和副恶性腹水之间存在甲基化差异(FDR &lt; 0.05)。对启动子上差异甲基化CpGs的KEGG通路的富集表明,高甲基化探针与神经活性配体-受体相互作用(hsa04080)有关,而低甲基化的CpGs与嗅觉转导有关(hsa04740, Supplementary Figure S1)。基于前20,000个差异甲基化CpGs的细胞腹水样本聚类,揭示了三个主要聚类(聚类A-C,图1K)。聚类B和C在CpG岛显示出类似的高甲基化CpGs特征,由恶性腹水样本组成。集群A代表副恶性腹水样本,与一些细胞学阳性样本显示类似的特征。由于免疫细胞类型比例可能影响观察到的DNA甲基化差异,我们通过反褶积推断细胞组成。然而,没有优化的反褶积工具用于腹水分析,因此结果应谨慎解释。与此相一致的是,在重叠样本(n = 21,中性粒细胞[Pearson R = 0.55, P = 0.01], T细胞和B细胞[Pearson R = 0.67, P &lt; 0.001],单核细胞[Pearson R = 0.27, P &gt; 0.05)中,通过反卷积估计的细胞分数与细胞学分析的细胞计数只有弱至中等的相关性。 与细胞学一致,根据反褶积,我们观察到恶性腹水样本与副恶性腹水样本的癌细胞比例更高(FDR调整P &lt; 0.001)。接下来,我们比较了基于恶性和副恶性腹水之间甲基化CpGs差异的甲基化簇之间的估计细胞分数(图1K)。在免疫细胞类型上没有观察到显著差异,而在B+C组的样本中发现的癌细胞比例明显高于a组(FDR调整P &lt; 0.001)。当将重叠样本(n = 17-19)的估计免疫细胞分数与细胞因子水平相关联时,我们观察到显著但微弱的相关性(NK细胞和IL-8, Pearson R = 0.44, P = 0.047; NK细胞和IL-6, Pearson R = -0.48, P = 0.036; CD4细胞和IL-8, Pearson R = 0.46, P = 0.036; CD4细胞和TNF-a, R = 0.46, P = 0.046;腹水形成的病人的实体瘤仍然是一个临床挑战。现有的临床试验设计中没有生物标志物,腹水中潜在的生物学亚型也没有得到确认[5,6]。我们的数据表明,癌症患者腹水的不同炎症亚型在细胞和细胞因子水平上存在,因为肿瘤细胞学阴性患者的炎症谱与非恶性腹水相似。鉴于癌症患者的炎症水平较低,腹水内无肿瘤细胞的癌症患者可能受益于非恶性腹水患者的治疗方法,如利尿剂治疗[7]。重要的是,恶性腹水,由腹水内存在肿瘤细胞定义,与副恶性和非恶性腹水相比,表现为炎症增加。我们当然必须承认其局限性,每个病人只有一升腹水被处理,理论上留下了副恶性腹水病人单个肿瘤细胞的可能性。然而,鉴于根据观察到的肿瘤细胞细胞学不同的炎症特征,局部炎症过程根据肿瘤细胞的数量/存在而不同,并且在癌症细胞学阳性的患者中作为潜在的治疗靶点。由于腹水的炎症特征主要独立于全身特征,免疫效应可能是局部特异性的。局部IL-6与恶性腹水[8]的悖论免疫抑制作用直接相关。增加可溶性炎症谱的异质性,细胞腹水样本的DNA甲基化根据细胞学显示出不同的谱。鉴定出三个不同的甲基化簇,其中聚类似乎是由肿瘤细胞的局部存在驱动的。通路分析表明嗅觉转导和神经活性配体-受体相互作用的差异都与免疫抑制[9]有关。虽然我们的队列的异质性需要承认,以前的研究在其他实体如卵巢癌是罕见的。鉴于贝伐单抗在治疗除卵巢癌以外的其他原发肿瘤患者腹水中的临床疗效受损,确定的炎症靶点值得进一步研究。鉴于本研究中恶性腹水的特殊炎症特征,未来的研究应重点关注IL-6、IL-8和免疫检查点。尽管如此,这些初步发现需要在后续更大的亚组研究中进行评估,以进一步评估其在腹水形成中的病理生理学相关性和潜在的临床意义。概念化:Julia M. Berger, Birgit Fendl, Barbara Niederdorfer和Anna S. Berghoff。数据策展:Julia M. Berger、Martin Korpan、Carina Zierfuss、Katharina Syböck、Erwin Tomasich、Andreas Kienzle、Maria Koenig、Markus Kleinberger、Lynn Gottmann、Birgit Fendl、Cihan Ay、Johannes Pammer、Catharina mller、Rudolf Öhler、Lorenz Balcar、Thomas Reiberger、Elisabeth S. Bergen和Barbara Niederdorfer。形式分析:Julia M. Berger, Barbara Niederdorfer和Anna S. Berghoff。融资收购:Julia M. Berger, Matthias Preusser, Anna S. Berghoff。调查:Julia M. Berger, Barbara Niederdorfer和Anna S. Berghoff。方法:Julia M. Berger, Carina Zierfuss, Barbara Niederdorfer和Anna S. Berghoff。项目管理:Julia M. Berger和Martin Korpan。资料来源:Thomas Reiberger, Matthias Preusser和Anna S. Berghoff。软件:Julia M. Berger和Barbara Niederdorfer。监督:Anna S. Berghoff。验证:Julia M. Berger, Barbara Niederdorfer和Anna S. Berghoff。可视化:Julia M. Berger和Barbara Niederdorfer。编剧:原稿:Julia M. Berger, Barbara Niederdorfer, Anna S. Berghoff。写作:评论&编辑:Julia M。 Berger, Martin Korpan, Carina Zierfuss, Katharina Syböck, Erwin Tomasich, Andreas Kienzle, Maria Koenig, Markus Kleinberger, Lynn Gottmann, Birgit Fendl, Cihan Ay, Johannes Pammer, Catharina mller, Rudolf Öhler, Lorenz Balcar, Thomas Reiberger, Elisabeth S. Bergen, Barbara Niederdorfer, Matthias Preusser和Anna S. Berghoff。Thomas Reiberger获得了Abbvie、Boehringer Ingelheim、Gilead、Intercept/Advanz Pharma、MSD、Myr Pharmaceuticals、Philips Healthcare、Pliant、Siemens和w.l. Gore &amp; Associates的资助;来自艾伯维(Abbvie)、吉利德(Gilead)、Intercept/Advanz Pharma、罗氏(Roche)、默沙杜公司(MSD)、W. L. Gore & Associates的荣誉致辞;Abbvie、Astra Zeneca、Bayer、Boehringer Ingelheim、Gilead、Intercept/Advanz Pharma、MSD、Resolution Therapeutics、Siemens的咨询/顾问委员会费用;以及艾伯维、勃林格殷格翰、福克制药、吉利德和罗氏的差旅支持。Matthias Preusser曾获得以下营利性公司的讲座、咨询或顾问委员会参与荣誉:拜耳、百时美施贵宝、诺华、格森-莱尔集团(GLG)、CMC Contrast、葛兰素史克、蒙迪制药、罗氏、BMJ期刊、MedMedia、阿斯特拉-利康、艾伯维、礼来、Medahead、Daiichi Sankyo、赛诺菲、默克夏普Dome、Tocagen、施维雅。Anna S. Berghoff获得了第一三共(≤10000欧元)、罗氏(10000欧元)的研究支持,以及罗氏百时美施贵宝、默克、第一三共(均为5000欧元)的讲座、咨询或顾问委员会参与酬金,以及罗氏、安进和艾伯维的差旅支持。所有其他作者报告与此特定出版物没有利益冲突。感谢Margaretha hehberger癌症研究基金、奥地利联邦数字和经济事务部、国家研究、技术和发展基金会以及基督教多普勒研究协会的财政支持。所有患者在我们三级护理中心的整个临床病程中均按照最佳临床实践和现行治疗指南进行治疗。本研究经维也纳医科大学伦理委员会批准(2022年投票号2100),并根据《赫尔辛基宣言》及其修正案进行。同意参加这项研究被放弃。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Ascites of patients with solid tumors shows distinct inflammatory patterns

Ascites of patients with solid tumors shows distinct inflammatory patterns

Ascites formation in solid tumor patients is associated with an increased risk of death [1, 2]. The lack of pathophysiological insight limited the development of targeted treatment so far. With advances in immune modulating therapies, the inflammatory component of ascites moved into focus. Experimental approaches targeting immunologic dysregulation have shown only limited success [3, 4]. Therefore, we investigated inflammatory processes of ascites, taking the presence of tumor cells into account, while focusing on gastrointestinal tract malignancies due to their underrepresentation in literature.

A total of 63 patients were included in this study. Among these patients, 55 (87.3%) underwent paracentesis for ascites caused by advanced solid tumors, of which 30/63 (47.6%) patients had negative tumor cell cytology (paramalignant ascites) and 25/63 (39.7%) had positive tumor cell cytology (malignant ascites). Additionally, 8/63 (12.7%) patients with non-malignant ascites due to liver cirrhosis were included. Patients’ characteristics are displayed in Supplementary Table S1.

To study differences in the inflammatory profiles based on tumor cells within ascites, nine cytokines (interleukin-6 [IL-6], IL-8, IL-10, IL-17, tumor necrosis factor-alpha [TNF-α], C-reactive protein [CRP], Eotaxin, vascular endothelial growth factor [VEGF], and the soluble programmed death ligand-1 [sPD-L1]) were measured in ascitic supernatant. Malignant ascites showed increased levels of IL-6, IL-8, VEGF, and sPD-L1, compared to paramalignant and non-malignant ascites, respectively (Figure 1A-D). In contrast, no differences in cytokine levels were observed between non-malignant and paramalignant ascites in all measured cytokines, indicating that the inflammatory composition of ascites correlates with the presence of tumor cells.

To correlate systemic inflammatory processes with local inflammation in ascites supernatant in patients with advanced solid tumors, we measured cytokine levels in serum samples obtained at the timepoint of paracentesis. Strong correlations between ascitic and serum cytokine levels were evident for IL-8 and IL-17 (Figure 1E-F). Additionally, strong correlation was evident for CRP levels (Figure 1G), while no or weak correlations were detected in other cytokines. CRP as well as levels sPD-L1were decreased in ascites compared to serum (Supplementary Table S2). Compared to serum, ascitic IL-6 was significantly elevated (Supplementary Table S2) without a correlation to systemic IL-6 levels (ρ = 0.16, P > 0.05), suggesting IL-6 signaling may be important for local inflammation.

To tie the link between soluble inflammatory markers and the cellular inflammatory compartment, we investigated correlations between cytokine levels and leukocyte as well as cell count for 19 overlapping samples. While no associations between leukocyte count and cytokine levels were observed, strong correlations between overall cell count in ascites and VEGF as well as sPD-L1 (Figure 1H-I) were evident.

DNA methylation analyses of 32 cellular samples of ascites by Infinium Methylation EPIC V2.0 microarray were performed to obtain further insight on cellular composition and inflammatory pathways of interest (Supplementary Materials and Methods). No difference in the methylation profile of samples according to TNF-α (n = 19) or IL-6 (n = 17) were observed. Methylation variation seemed to be driven by cytology, with tumor cell cytology positive and negative samples separating along the first dimension of the multidimensional scaling plot (Figure 1J). 37,494 CpG sites were differentially methylated between malignant and paramalignant ascites (FDR < 0.05). An enrichment of KEGG pathways for differentially methylated CpGs located on promotor revealed that hypermethylated probes were associated with Neuroactive ligand-receptor interaction (hsa04080) while hypomethylated CpGs were associated with Olfactory transduction (hsa04740, Supplementary Figure S1). Clustering of cellular ascites samples based on the top 20,000 differentially methylated CpGs, revealed three main clusters (cluster A-C, Figure 1K). Cluster B and C show a similar signature of hypermethylated CpGs in CpG Islands and consist of malignant ascites samples. Cluster A represents paramalignant ascites samples, with some cytology positive samples showing a similar signature.

As immune cell-type proportions may influence observed differences in DNA methylation, we inferred the cellular compositions by deconvolution. However, no deconvolution tools are optimized for ascites analysis, so results should be interpreted cautiously. In line with this, only weak to medium correlation of the estimated cell fraction by deconvolution with cell counts from cytology analysis was observed for overlapping samples (n = 21, neutrophils [Pearson R = 0.55, P = 0.01], T and B cell [Pearson R = 0.67, P < 0.001], monocytes [Pearson R = 0.27, P > 0.05). In alignment with cytology, we observed a higher cancer cell fraction according to the deconvolution in malignant versus paramalignant ascites samples (FDR adjusted P < 0.001). Next, we compared estimated cell fractions between methylation clusters based on differentially methylated CpGs between malignant and paramalignant ascites (Figure 1K). No significant differences for immune cell types were observed, while a significantly higher cancer cell fraction was found in samples present in cluster B+C compared to cluster A (FDR adjusted P < 0.001). When correlating estimated immune cell fractions with cytokine levels for overlapping samples (n = 17-19), we observed significant, albeit weak correlations (NK cells and IL-8, Pearson R = 0.44, P = 0.047; NK cells and IL-6, Pearson R = -0.48, P = 0.036; CD4 cells and IL-8, Pearson R = 0.46, P = 0.036; CD4 cells and TNF-a, R = 0.46, P = 0.046; CD8 cells and IL8, Pearson R = 0.52, P = 0.016).

Ascites formation in patients with solid tumors remains a clinical challenge. Existing clinical trials were designed without biomarkers and potential biological subtypes in ascites were not acknowledged [5, 6]. Our data suggests that distinct inflammatory subtypes of ascites in cancer patients exist on cellular and cytokine levels, as inflammatory profiles of patients with negative tumor cytology resembled non-malignant ascites. Given their low inflammation levels, cancer patients without tumor cells within ascites might profit from treatment established in non-malignant ascites patients like diuretic treatment [7]. Importantly, malignant ascites, defined by the presence of tumor cells within ascites, presented with increased inflammation compared to paramalignant and non-malignant ascites. We certainly have to acknowledge the limitation, that only one liter of ascites was processed per patient, leaving the theoretical possibility of single tumor cells in patients with paramalignant ascites. However, given the differing inflammatory profiles according to the observed tumor cell cytology, local inflammatory processes differ according to the amount /presence of tumor cells and serve as a potential therapeutic target particular in patients with positive cancer cytology. As the inflammatory profile of ascites was mainly independent of the systemic profile, the immunological effects might be locally specific. Local IL-6 was directly linked to paradox immunosuppressive effects in malignant ascites [8]. Adding to the heterogeneity of soluble inflammatory profiles, DNA methylation of cellular ascites samples revealed distinct profiles according to cytology. Three distinct methylation clusters were identified, where clustering seemed to be driven by the local presence of tumor cells. Pathway analysis suggested differences in Olfactory transduction and Neuroactive ligand-receptor interaction, both linked to immunosuppression [9]. Although the heterogeneity of our cohort needs to be acknowledged, previous studies in other entities as ovarian cancer are rare. Given the impaired clinical efficacy of bevacizumab in ascites treatment of patients with other primary tumors than ovarian cancer, the identified inflammatory targets are of interest for further investigation. Given the particular inflammatory profile of malignant ascites in our study, future research should focus on IL-6, IL-8 and immune checkpoints. Still, these first findings need to be evaluated in subsequent studies with bigger subgroups, to further assess their pathophysiologic relevance in ascites formation and potential clinical implications.

Conceptualization: Julia M. Berger, Birgit Fendl, Barbara Niederdorfer, and Anna S. Berghoff. Data curation: Julia M. Berger, Martin Korpan, Carina Zierfuss, Katharina Syböck, Erwin Tomasich, Andreas Kienzle, Maria Koenig, Markus Kleinberger, Lynn Gottmann, Birgit Fendl, Cihan Ay, Johannes Pammer, Catharina Müller, Rudolf Öhler, Lorenz Balcar, Thomas Reiberger, Elisabeth S. Bergen, and Barbara Niederdorfer.Formal analysis: Julia M. Berger, Barbara Niederdorfer, and Anna S. Berghoff. Funding acquisition: Julia M. Berger, Matthias Preusser, and Anna S. Berghoff. Investigation: Julia M. Berger, Barbara Niederdorfer, and Anna S. Berghoff. Methodology: Julia M. Berger, Carina Zierfuss, Barbara Niederdorfer, and Anna S. Berghoff. Project administration: Julia M. Berger and Martin Korpan. Resources: Thomas Reiberger, Matthias Preusser, and Anna S. Berghoff. Software: Julia M. Berger and Barbara Niederdorfer. Supervision: Anna S. Berghoff. Validation: Julia M. Berger, Barbara Niederdorfer, and Anna S. Berghoff. Visualization: Julia M. Berger and Barbara Niederdorfer. Writing: original draft: Julia M. Berger, Barbara Niederdorfer, and Anna S. Berghoff. Writing: review & editing: Julia M. Berger, Martin Korpan, Carina Zierfuss, Katharina Syböck, Erwin Tomasich, Andreas Kienzle, Maria Koenig, Markus Kleinberger, Lynn Gottmann, Birgit Fendl, Cihan Ay, Johannes Pammer, Catharina Müller, Rudolf Öhler, Lorenz Balcar, Thomas Reiberger, Elisabeth S. Bergen, Barbara Niederdorfer, Matthias Preusser, and Anna S. Berghoff.

Thomas Reiberger received grant support from Abbvie, Boehringer Ingelheim, Gilead, Intercept/Advanz Pharma, MSD, Myr Pharmaceuticals, Philips Healthcare, Pliant, Siemens and W. L. Gore & Associates; speaking honoraria from Abbvie, Gilead, Intercept/Advanz Pharma, Roche, MSD, W. L. Gore & Associates; consulting/advisory board fee from Abbvie, Astra Zeneca, Bayer, Boehringer Ingelheim, Gilead, Intercept/Advanz Pharma, MSD, Resolution Therapeutics, Siemens; and travel support from Abbvie, Boehringer Ingelheim, Dr. Falk Pharma, Gilead and Roche.

Matthias Preusser has received honoraria for lectures, consultation or advisory board participation from the following for-profit companies: Bayer, Bristol-Myers Squibb, Novartis, Gerson Lehrman Group (GLG), CMC Contrast, GlaxoSmithKline, Mundipharma, Roche, BMJ Journals, MedMedia, Astra Zeneca, AbbVie, Lilly, Medahead, Daiichi Sankyo, Sanofi, Merck Sharp & Dome, Tocagen, Servier.

Anna S. Berghoff has received research support from Daiichi Sankyo (≤ 10000 €), Roche (> 10000 €) and honoraria for lectures, consultation or advisory board participation from Roche Bristol-Meyers Squibb, Merck, Daiichi Sankyo (all < 5000 €) as well as travel support from Roche, Amgen and AbbVie.

All other authors report not conflict of interest concerning this specific publication.

The financial support by the Margaretha Hehberger-Cancer Research Fund, the Austrian Federal Ministry for Digital and Economic Affairs, the National Foundation for Research, Technology and Development and the Christian Doppler Research Association is gratefully acknowledged.

All patients were treated according to best clinical practice and to current treatment guidelines throughout their whole clinical course of disease at our tertiary care center. This study was approved by the Ethics Committee of the Medical University of Vienna (vote number 2100 of 2022) and performed according to the Declaration of Helsinki and its Amendments. Consent to participate in this study was waived.

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来源期刊
Cancer Communications
Cancer Communications Biochemistry, Genetics and Molecular Biology-Cancer Research
CiteScore
25.50
自引率
4.30%
发文量
153
审稿时长
4 weeks
期刊介绍: Cancer Communications is an open access, peer-reviewed online journal that encompasses basic, clinical, and translational cancer research. The journal welcomes submissions concerning clinical trials, epidemiology, molecular and cellular biology, and genetics.
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