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1. Clinical Performance of the Consensus Immunoscore in Colon Cancer in the Asian Population from the Multicenter International SITC Study

Author

Mlecnik, B., Torigoe, T., Bindea, G., Popivanova, B., Xu, M., Fujita, T., Hazama, S., Suzuki, N., Nagano, H., Okuno, K., Hirohashi, Y., Furuhata, T., Takemasa, I., Patel, P., Vora, H., Shah, B., Patel, J.B., Rajvik, K.N., Pandya, S.J., Shukla, S.N., Wang, Yili, Zhang, G., Yoshino, T., Taniguchi, H., Bifulco, C., Lugli, A., Lee, J.J., Zlobec, I., Rau, T.T., Berger, M.D., Nagtegaal, I.D., Vink-Borger, Elisa, Hartmann, A., Geppert, C.I., Kolwelter, J., Merkel, S., Grützmann, R., Eynde, M. Van den, Jouret-Mourin, A., Kartheuser, A., Léonard, D., Remue, C., Wang, J., Bavi, P., Roehrl, M.H.A., Ohashi, P.S., Nguyen, L.T., Han, S., MacGregor, H.L., Hafezi-Bakhtiari, S., Wouters, B.G., Masucci, G.V., Andersson, E., Zavadova, E., Vocka, M., Spacek, J., Petruzelka, L., Konopasek, B., Dundr, P., Skalova, H., Nemejcova, K., Botti, G., Tatangelo, F., Delrio, P., Ciliberto, G., Maio, M, Laghi, L., Grizzi, F., Marliot, F., Fredriksen, T., Buttard, B., Lafontaine, L., Maby, P., Majdi, A., Hijazi, A., Sissy, C. El, Kirilovsky, A., Berger, A., Lagorce, C., Paustian, C., Ballesteros-Merino, C., Dijkstra, J.R., Water, C. van de, Lent-van Vliet, S. van, Knijn, N., Mușină, A.M., Scripcariu, D.V., Marincola, F.M., Ascierto, P.A., Fox, B.A., Pagès, F., Kawakami, Y., Galon, J., Mlecnik, B., Torigoe, T., Bindea, G., Popivanova, B., Xu, M., Fujita, T., Hazama, S., Suzuki, N., Nagano, H., Okuno, K., Hirohashi, Y., Furuhata, T., Takemasa, I., Patel, P., Vora, H., Shah, B., Patel, J.B., Rajvik, K.N., Pandya, S.J., Shukla, S.N., Wang, Yili, Zhang, G., Yoshino, T., Taniguchi, H., Bifulco, C., Lugli, A., Lee, J.J., Zlobec, I., Rau, T.T., Berger, M.D., Nagtegaal, I.D., Vink-Borger, Elisa, Hartmann, A., Geppert, C.I., Kolwelter, J., Merkel, S., Grützmann, R., Eynde, M. Van den, Jouret-Mourin, A., Kartheuser, A., Léonard, D., Remue, C., Wang, J., Bavi, P., Roehrl, M.H.A., Ohashi, P.S., Nguyen, L.T., Han, S., MacGregor, H.L., Hafezi-Bakhtiari, S., Wouters, B.G., Masucci, G.V., Andersson, E., Zavadova, E., Vocka, M., Spacek, J., Petruzelka, L., Konopasek, B., Dundr, P., Skalova, H., Nemejcova, K., Botti, G., Tatangelo, F., Delrio, P., Ciliberto, G., Maio, M, Laghi, L., Grizzi, F., Marliot, F., Fredriksen, T., Buttard, B., Lafontaine, L., Maby, P., Majdi, A., Hijazi, A., Sissy, C. El, Kirilovsky, A., Berger, A., Lagorce, C., Paustian, C., Ballesteros-Merino, C., Dijkstra, J.R., Water, C. van de, Lent-van Vliet, S. van, Knijn, N., Mușină, A.M., Scripcariu, D.V., Marincola, F.M., Ascierto, P.A., Fox, B.A., Pagès, F., Kawakami, Y., and Galon, J.

Abstract

Contains fulltext : 283495.pdf (Publisher’s version ) (Open Access), BACKGROUND: In this study, we evaluated the prognostic value of Immunoscore in patients with stage I-III colon cancer (CC) in the Asian population. These patients were originally included in an international study led by the Society for Immunotherapy of Cancer (SITC) on 2681 patients with AJCC/UICC-TNM stages I-III CC. METHODS: CD3+ and cytotoxic CD8+ T-lymphocyte densities were quantified in the tumor and invasive margin by digital pathology. The association of Immunoscore with prognosis was evaluated for time to recurrence (TTR), disease-free survival (DFS), and overall survival (OS). RESULTS: Immunoscore stratified Asian patients (n = 423) into different risk categories and was not impacted by age. Recurrence-free rates at 3 years were 78.5%, 85.2%, and 98.3% for a Low, Intermediate, and High Immunoscore, respectively (HR[Low-vs-High] = 7.26 (95% CI 1.75-30.19); p = 0.0064). A High Immunoscore showed a significant association with prolonged TTR, OS, and DFS (p < 0.05). In Cox multivariable analysis stratified by center, Immunoscore association with TTR was independent (HR[Low-vs-Int+High] = 2.22 (95% CI 1.10-4.55) p = 0.0269) of the patient's gender, T-stage, N-stage, sidedness, and MSI status. A significant association of a High Immunoscore with prolonged TTR was also found among MSS (HR[Low-vs-Int+High] = 4.58 (95% CI 2.27-9.23); p ≤ 0.0001), stage II (HR[Low-vs-Int+High] = 2.72 (95% CI 1.35-5.51); p = 0.0052), low-risk stage-II (HR[Low-vs-Int+High] = 2.62 (95% CI 1.21-5.68); p = 0.0146), and high-risk stage II patients (HR[Low-vs-Int+High] = 3.11 (95% CI 1.39-6.91); p = 0.0055). CONCLUSION: A High Immunoscore is significantly associated with the prolonged survival of CC patients within the Asian population.

Published
2022

4. International validation of the consensus Immunoscore for the classification of colon cancer: a prognostic and accuracy study

Author

Pages, F., Mlecnik, B., Marliot, F., Bindea, G., Ou, F.S., Bifulco, C., Lugli, A., Zlobec, I., Rau, T.T., Berger, M.D., Nagtegaal, I.D., Vink-Borger, E., Hartmann, A., Geppert, C., Kolwelter, J., Merkel, S., Grutzmann, R., Eynde, M. Van den, Jouret-Mourin, A., Kartheuser, A., Leonard, D., Remue, C., Wang, J.Y., Bavi, P., Roehrl, M.H.A., Ohashi, P.S., Nguyen, L.T., Han, S., MacGregor, H.L., Hafezi-Bakhtiari, S., Wouters, B.G., Masucci, G.V., Andersson, E.K., Zavadova, E., Vocka, M., Spacek, J., Petruzelka, L., Konopasek, B., Dundr, P., Skalova, H., Nemejcova, K., Botti, G., Tatangelo, F., Delrio, P., Ciliberto, G., Maio, M, Laghi, L., Grizzi, F., Fredriksen, T., Buttard, B., Angelova, M., Vasaturo, A., Maby, P., Church, S.E., Angell, H.K., Lafontaine, L., Bruni, D., Sissy, C. El, Haicheur, N., Kirilovsky, A., Berger, A., Lagorce, C., Meyers, J.P., Paustian, C., Feng, Z., Ballesteros-Merino, C., Dijkstra, J., Water, C. van de, Vliet, S. van, Knijn, N., Musina, A.M., Scripcariu, D.V., Popivanova, B., Xu, M., Fujita, T., Hazama, S., Suzuki, N., Nagano, H., Okuno, K., Torigoe, T., Sato, N., Furuhata, T., Takemasa, I., Itoh, K., Patel, P.S., Vora, H.H., Shah, B., Patel, J.B., Rajvik, K.N., Pandya, S.J., Shukla, S.N., Wang, Y., Zhang, G., Kawakami, Y., Marincola, F.M., Ascierto, P.A., Sargent, D.J., Fox, B.A., Galon, J., Pages, F., Mlecnik, B., Marliot, F., Bindea, G., Ou, F.S., Bifulco, C., Lugli, A., Zlobec, I., Rau, T.T., Berger, M.D., Nagtegaal, I.D., Vink-Borger, E., Hartmann, A., Geppert, C., Kolwelter, J., Merkel, S., Grutzmann, R., Eynde, M. Van den, Jouret-Mourin, A., Kartheuser, A., Leonard, D., Remue, C., Wang, J.Y., Bavi, P., Roehrl, M.H.A., Ohashi, P.S., Nguyen, L.T., Han, S., MacGregor, H.L., Hafezi-Bakhtiari, S., Wouters, B.G., Masucci, G.V., Andersson, E.K., Zavadova, E., Vocka, M., Spacek, J., Petruzelka, L., Konopasek, B., Dundr, P., Skalova, H., Nemejcova, K., Botti, G., Tatangelo, F., Delrio, P., Ciliberto, G., Maio, M, Laghi, L., Grizzi, F., Fredriksen, T., Buttard, B., Angelova, M., Vasaturo, A., Maby, P., Church, S.E., Angell, H.K., Lafontaine, L., Bruni, D., Sissy, C. El, Haicheur, N., Kirilovsky, A., Berger, A., Lagorce, C., Meyers, J.P., Paustian, C., Feng, Z., Ballesteros-Merino, C., Dijkstra, J., Water, C. van de, Vliet, S. van, Knijn, N., Musina, A.M., Scripcariu, D.V., Popivanova, B., Xu, M., Fujita, T., Hazama, S., Suzuki, N., Nagano, H., Okuno, K., Torigoe, T., Sato, N., Furuhata, T., Takemasa, I., Itoh, K., Patel, P.S., Vora, H.H., Shah, B., Patel, J.B., Rajvik, K.N., Pandya, S.J., Shukla, S.N., Wang, Y., Zhang, G., Kawakami, Y., Marincola, F.M., Ascierto, P.A., Sargent, D.J., Fox, B.A., and Galon, J.

Abstract

Contains fulltext : 193579.pdf (publisher's version ) (Closed access), BACKGROUND: The estimation of risk of recurrence for patients with colon carcinoma must be improved. A robust immune score quantification is needed to introduce immune parameters into cancer classification. The aim of the study was to assess the prognostic value of total tumour-infiltrating T-cell counts and cytotoxic tumour-infiltrating T-cells counts with the consensus Immunoscore assay in patients with stage I-III colon cancer. METHODS: An international consortium of 14 centres in 13 countries, led by the Society for Immunotherapy of Cancer, assessed the Immunoscore assay in patients with TNM stage I-III colon cancer. Patients were randomly assigned to a training set, an internal validation set, or an external validation set. Paraffin sections of the colon tumour and invasive margin from each patient were processed by immunohistochemistry, and the densities of CD3+ and cytotoxic CD8+ T cells in the tumour and in the invasive margin were quantified by digital pathology. An Immunoscore for each patient was derived from the mean of four density percentiles. The primary endpoint was to evaluate the prognostic value of the Immunoscore for time to recurrence, defined as time from surgery to disease recurrence. Stratified multivariable Cox models were used to assess the associations between Immunoscore and outcomes, adjusting for potential confounders. Harrell's C-statistics was used to assess model performance. FINDINGS: Tissue samples from 3539 patients were processed, and samples from 2681 patients were included in the analyses after quality controls (700 patients in the training set, 636 patients in the internal validation set, and 1345 patients in the external validation set). The Immunoscore assay showed a high level of reproducibility between observers and centres (r=0.97 for colon tumour; r=0.97 for invasive margin; p<0.0001). In the training set, patients with a high Immunoscore had the lowest risk of recurrence at 5 years (14 [8%] patients with a high Immunosc

Published
2018

10. Competition among native and invasive Phragmites australis populations: An experimental test of the effects of invasion status, genome size, and ploidy level

Author

Hana Ryšavá, Magdalena Lučanová, Carla Lambertini, Pavel Trávníček, Zuzana Chumová, Petr Šmilauer, Kristýna Šemberová, Petr Pyšek, Jan Čuda, Hana Skálová, Laura A. Meyerson, Pysek P., Cuda J., Smilauer P., Skalova H., Chumova Z., Lambertini C., Lucanova M., Rysava H., Travnicek P., Semberova K., and Meyerson L.A.

Subjects
0106 biological sciences, media_common.quotation_subject, intraspecific competition, native population, Zoology, Biology, 010603 evolutionary biology, 01 natural sciences, Genome, Competition (biology), Intraspecific competition, Phragmites, 03 medical and health sciences, lcsh:QH540-549.5, Genome size, Ecology, Evolution, Behavior and Systematics, 030304 developmental biology, Nature and Landscape Conservation, media_common, plant invasion, 0303 health sciences, Ecology, food and beverages, ploidy level, Nuclear DNA, Europe, Shoot, genome size, North America, lcsh:Ecology, Ploidy, native populations, common reed
Abstract

Among the traits whose relevance for plant invasions has recently been suggested are genome size (the amount of nuclear DNA) and ploidy level. So far, research on the role of genome size in invasiveness has been mostly based on indirect evidence by comparing species with different genome sizes, but how karyological traits influence competition at the intraspecific level remains unknown. We addressed these questions in a common‐garden experiment evaluating the outcome of direct intraspecific competition among 20 populations of Phragmites australis, represented by clones collected in North America and Europe, and differing in their status (native and invasive), genome size (small and large), and ploidy levels (tetraploid, hexaploid, or octoploid). Each clone was planted in competition with one of the others in all possible combinations with three replicates in 45‐L pots. Upon harvest, the identity of 21 shoots sampled per pot was revealed by flow cytometry and DNA analysis. Differences in performance were examined using relative proportions of shoots of each clone, ratios of their aboveground biomass, and relative yield total (RYT). The performance of the clones in competition primarily depended on the clone status (native vs. invasive). Measured in terms of shoot number or aboveground biomass, the strongest signal observed was that North American native clones always lost in competition to the other two groups. In addition, North American native clones were suppressed by European natives to a similar degree as by North American invasives. North American invasive clones had the largest average shoot biomass, but only by a limited, nonsignificant difference due to genome size. There was no effect of ploidy on competition. Since the North American invaders of European origin are able to outcompete the native North American clones, we suggest that their high competitiveness acts as an important driver in the early stages of their invasion.

Published
2020

11. LOTVS: A global collection of permanent vegetation plots

Author

Marta Gaia Sperandii, Francesco de Bello, Enrique Valencia, Lars Götzenberger, Manuele Bazzichetto, Thomas Galland, Anna E‐Vojtkó, Luisa Conti, Peter B. Adler, Hannah Buckley, Jiří Danihelka, Nicola J. Day, Jürgen Dengler, David J. Eldridge, Marc Estiarte, Ricardo García‐González, Eric Garnier, Daniel Gómez‐García, Lauren Hallett, Susan Harrison, Tomas Herben, Ricardo Ibáñez, Anke Jentsch, Norbert Juergens, Miklós Kertész, Duncan M. Kimuyu, Katja Klumpp, Mike Le Duc, Frédérique Louault, Rob H. Marrs, Gábor Ónodi, Robin J. Pakeman, Meelis Pärtel, Begoña Peco, Josep Peñuelas, Marta Rueda, Wolfgang Schmidt, Ute Schmiedel, Martin Schuetz, Hana Skalova, Petr Šmilauer, Marie Šmilauerová, Christian Smit, Ming‐Hua Song, Martin Stock, James Val, Vigdis Vandvik, Karsten Wesche, Susan K. Wiser, Ben A. Woodcock, Truman P. Young, Fei‐Hai Yu, Amelia A. Wolf, Martin Zobel, Jan Lepš, Centro de Investigaciones sobre Desertificacion (CIDE), Consejo Superior de Investigaciones Científicas [Madrid] (CSIC), Universidad Rey Juan Carlos [Madrid] (URJC), Institute of Botany of the Czech Academy of Sciences (IB / CAS), Czech Academy of Sciences [Prague] (CAS), UNIVERSITY OF SOUTH BOHEMIA CESKE BUDEJOVICE CZE, Partenaires IRSTEA, Institut national de recherche en sciences et technologies pour l'environnement et l'agriculture (IRSTEA)-Institut national de recherche en sciences et technologies pour l'environnement et l'agriculture (IRSTEA), Czech University of Life Sciences Prague (CZU), Utah State University (USU), Auckland University of Technology (AUT), Masaryk University [Brno] (MUNI), Victoria University of Wellington, Zürich University of Applied Sciences (ZHAW), University of New South Wales [Kensington], CREAF - Centre for Ecological Research and Applied Forestries, Instituto Pirenaico de Ecologìa = Pyrenean Institute of Ecology [Zaragoza] (IPE - CSIC), Centre d’Ecologie Fonctionnelle et Evolutive (CEFE), Université Paul-Valéry - Montpellier 3 (UPVM)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud])-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut Agro Montpellier, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Université de Montpellier (UM), University of Oregon, Eugene, OR 97403, United States, University of California (UC), Department of Zoology, Charles University in Prague, Faculty of Science, Viniicna 7, 128 43 Praha 2, Universidad Pública de Navarra [Espagne] = Public University of Navarra (UPNA), University of Hamburg, Hungarian Academy of Sciences (MTA), University of Liverpool, Unité Mixte de Recherche sur l'Ecosystème Prairial - UMR (UREP), VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), The James Hutton Institute, University of Tartu, Autonomous University of Madrid, Faculty of Sciences, Department of Ecology, 28049 Madrid, Spain, Universidad de Sevilla / University of Sevilla, Centre for Biodiversity and Sustainable Land-use [University of Göttingen] (CBL), Georg-August-University = Georg-August-Universität Göttingen, Hamburg University of Applied Sciences [Hamburg], Swiss Federal Institute for Forest, Snow and Landscape Research WSL, University of South Bohemia, Groningen Institute for Evolutionary Life Sciences [Groningen] (GELIFES), University of Groningen [Groningen], Chinese Academy of Agricultural Sciences (CAAS), Wadden Sea National Park of Schleswig-Holstein, University of Bergen (UiB), Senckenberg Museum of Natural History Görlitz, Senckenberg – Leibniz Institution for Biodiversity and Earth System Research - Senckenberg Gesellschaft für Naturforschung, Leibniz Association-Leibniz Association, Manaaki Whenua – Landcare Research [Lincoln], Center for Ecology and Hydrology, Taizhou University, University of Texas-Pan, Smit group, Royal Society of New Zealand, Czech Science Foundation, Academy of Sciences of the Czech Republic, Ministerio de Ciencia e Innovación (España), Agencia Estatal de Investigación (España), Institut National de la Recherche Agronomique (France), Federal Ministry of Education and Research (Germany), Oberfranken Stiftung, Agence Nationale de la Recherche (France), Scottish Government's Rural and Environment Science and Analytical Services, Estonian Research Council, European Commission, Fundación Ramón Areces, Generalitat de Catalunya, European Research Council, Dresden University of Technology, Ministry of Business, Innovation, and Employment (New Zealand), Natural Environment Research Council (UK), Biotechnology and Biological Sciences Research Council (UK), Comunidad de Madrid, Universidad Rey Juan Carlos, National Science Foundation (US), South Bohemian Research Center of Aquaculture and Biodiversity of Hydrocenoses [University of South Bohemia] (CENAKVA), Faculty of Fisheries and Protection of Waters [University of South Bohemia], University of South Bohemia -University of South Bohemia, Desertification Research Centre (CIDE), Consejo Superior de Investigaciones Científicas [Madrid] (CSIC)-Universitat de València (UV), University of Bayreuth, German Centre for Integrative Biodiversity Research (iDiv), University of New South Wales [Sydney] (UNSW), Centre for Ecological Research and Forestry Applications (CREAF), Unit CREAF-CSIC-UABB, Global Ecology Unit (CREAF-CSIC-UAB), Université de Montpellier (UM), Institut de Recherche pour le Développement (IRD), Department of Mathematics, University of Oregon [Eugene], University of Oregon [Eugene], Department of Computer Science [Univ California Davis] (CS - UC Davis), University of California [Davis] (UC Davis), University of California (UC)-University of California (UC), Charles University [Prague] (CU), Distributed Events Analysis Research Group (MTA SZTAKI Hungarian Academy of Sciences), Mpala Research Centre, Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS), Université Clermont Auvergne (UCA), Institute of Computer Science [University of Tartu, Estonie], Centre de Recerca Ecològica i Aplicacions Forestals - Centre for Ecological Research and Forestry Applications, Partenaires INRAE, University of Chinese Academy of Sciences [Beijing] (UCAS), Lake Ecosystems Group [Lancaster, U.K.] (Centre for Ecology & Hydrology), Lancaster Environment Centre [Lancaster, U.K.], Zhejiang Provincial Key Laboratory of Plant Evolutionary Ecology and Conservation, Taizhou University, Taizhou, China, Department of Electrical and Computer Engineering - University of Texas (ECE), University of Texas at Austin [Austin], ANR-11-INBS-0001,ANAEE-FR,ANAEE-Services(2011), Sperandii, M. G., de Bello, F., Valencia, E., Gotzenberger, L., Bazzichetto, M., Galland, T., E-Vojtko, A., Conti, L., Adler, P. B., Buckley, H., Danihelka, J., Day, N. J., Dengler, J., Eldridge, D. J., Estiarte, M., Garcia-Gonzalez, R., Garnier, E., Gomez-Garcia, D., Hallett, L., Harrison, S., Herben, T., Ibanez, R., Jentsch, A., Juergens, N., Kertesz, M., Kimuyu, D. M., Klumpp, K., Le Duc, M., Louault, F., Marrs, R. H., Onodi, G., Pakeman, R. J., Partel, M., Peco, B., Penuelas, J., Rueda, M., Schmidt, W., Schmiedel, U., Schuetz, M., Skalova, H., Smilauer, P., Smilauerova, M., Smit, C., Song, M. -H., Stock, M., Val, J., Vandvik, V., Wesche, K., Wiser, S. K., Woodcock, B. A., Young, T. P., Yu, F. -H., Wolf, A. A., Zobel, M., and Leps, J.

Subjects
Plant communities, temporal analysis, Plant community, Plant Science, ecological succession, Permanent plot, ecoinformatic, plant communitie, Ecology and Environment, ecoinformatics, vegetation, Ecological succession, Ecoinformatics, Global scale, 577: Ökologie, time-serie, Vegetation, ecosystem stability, Ecology, time-series, Temporal analysis, permanent plot, plant diversity, plant communities, temporal analysi, 580: Pflanzen (Botanik), Plant diversity, global scale, Ecosystem stability, Permanent plots, Time-series, permanent plots, [SDE.BE]Environmental Sciences/Biodiversity and Ecology
Abstract

Analysing temporal patterns in plant communities is extremely important to quantify the extent and the consequences of ecological changes, especially considering the current biodiversity crisis. Long-term data collected through the regular sampling of permanent plots represent the most accurate resource to study ecological succession, analyse the stability of a community over time and understand the mechanisms driving vegetation change. We hereby present the LOng-Term Vegetation Sampling (LOTVS) initiative, a global collection of vegetation time-series derived from the regular monitoring of plant species in permanent plots. With 79 data sets from five continents and 7,789 vegetation time-series monitored for at least 6 years and mostly on an annual basis, LOTVS possibly represents the largest collection of temporally fine-grained vegetation time-series derived from permanent plots and made accessible to the research community. As such, it has an outstanding potential to support innovative research in the fields of vegetation science, plant ecology and temporal ecology., The authors acknowledge institutional support as follows. Nicola J. Day: Te Apārangi Royal Society of New Zealand (Rutherford Postdoctoral Fellowship). Jiří Danihelka: Czech Science Foundation (project no. 19-28491X) and Czech Academy of Sciences (project no. RVO 67985939). Francesco de Bello: Spanish Plan Nacional de I+D+i (project PGC2018-099027-B-I00). Eric Garnier: La Fage INRA experimental station. Tomáš Herben: GAČR grant 20-02901S. Anke Jentsch: German Federal Ministry of Education and Research (grant 031B0516C - SUSALPS) and Oberfrankenstiftung (grant OFS FP00237). Norbert Juergens: German Federal Ministry of Education and Research (grant 01LG1201N - SASSCAL ABC). Frédérique Louault and Katja Klumpp: AnaEE-France (ANR-11-INBS-0001). Robin J. Pakeman: Strategic Research Programme of the Scottish Government's Rural and Environment Science and Analytical Services Division. Meelis Pärtel: Estonian Research Council (PRG609) and European Regional Development Fund (Centre of Excellence EcolChange). Josep Peñuelas: Spanish Government (grant PID2019-110521GB-I00), Fundación Ramon Areces (grant ELEMENTAL-CLIMATE), Catalan Government (grant SGR 2017-1005), and European Research Council (Synergy grant ERC-SyG-2013-610028, IMBALANCE-P). Ute Schmiedel: German Federal Ministry of Education and Research (Promotion numbers 01LC0024, 01LC0024A, 01LC0624A2, 01LG1201A, 01LG1201N). Hana Skálová: GAČR grant 20-02901S. Karsten Wesche: International Institute Zittau, Technische Universität Dresden. Susan K. Wiser: New Zealand Ministry for Business, Innovation and Employment’s Strategic Science Investment Fund. Ben A. Woodcock: NERC and BBSRC (NE/N018125/1 LTS-M ASSIST - Achieving Sustainable Agricultural Systems). Enrique Valencia: Program for attracting and retaining talent of Comunidad de Madrid (no. 2017-T2/AMB-5406) and Community of Madrid and Rey Juan Carlos University (Young Researchers R&D Project. Ref. M2165 – INTRANESTI). Truman P. Young: National Science Foundation (LTREB DEB 19-31224).

Published
2022
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12. Physiology of a plant invasion

Author

Jan Doležal, Jan Čuda, Klára Pyšková, Ondřej Kauzál, Carla Lambertini, Petr Pyšek, Wen-Yong Guo, Hans Brix, Laura A. Meyerson, Hana Skálová, Pysek P., Skalova H., Cuda J., Guo W.-Y., Dolezal J., Kauzal O., Lambertini C., Pyskova K., Brix H., and Meyerson L.A.

Subjects
Plant invasion, Growth trait, Climate, Intraspecific differentiation, Biomass, Below- and aboveground bioma, Plant Science, phylogeography, Phragmites, Photosynthesi, Specific leaf area, PLOIDY LEVEL, Botany, Phragmites australi, Phragmites australis, physiological traits, climate, plant invasion, Physiological trait, N and P concentrations, photosynthesis, Ecology, COMMON REED, R-PACKAGE, intraspecific differentiation, below- and aboveground biomass, NITROGEN, Phylogeography, SELECT, Common reed, LONG-DISTANCE DISPERSAL, GENETIC DIVERSITY, N and P concentration, SPREAD, growth traits, ELEVATED CO2, specific leaf area
Abstract

Differentiation within Phragmites australis, one of the world's most cosmopolitan and globally important wild plants, and invasions by individual lineages outside of their native ranges is attracting the interest of scientists worldwide. We compared the physiological performance of 89 populations representing distinct genotypes from six phylogcographic groups from Australia. Europe, North America (two groups including native and invasive populations introduced from Europe), South Africa and Far East in a common garden experiment. We show that the populations cluster into two distinct groups: one that includes populations from Europe and Far East together with the North American invasive, and the second the North American native populations with those from Australia and South Africa. Populations within the former group exhibited superior performance in the following traits: they were more vigorous in terms of higher shoot number per pot, greater belowground biomass, longer rhizomes, had greater specific leaf area (SLA), higher N and P concentrations in tissues, and greater investment into generative reproduction. Pooled across phylogcographic groups, P. australis has higher values of maximal photosynthesis (A(max)), higher N and P concentrations in tissues, and greater SLA than most vascular plants, represented by the GLOPNET dataset. Whether due to a weak environmental match or genetic differences, the results indicate that invasion by Australian and African populations in the Northern Hemisphere seems unlikely at present. However, it is not possible to exclude the invasion of genotypes of European origin into Southern Hemisphere or other temperate regions.

Published
2019
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13. Functional trait trade-offs define plant population stability across different biomes.

Author

Conti L, Valencia E, Galland T, Götzenberger L, Lepš J, E-Vojtkó A, Carmona CP, Májeková M, Danihelka J, Dengler J, Eldridge DJ, Estiarte M, García-González R, Garnier E, Gómez D, Hadincová V, Harrison SP, Herben T, Ibáñez R, Jentsch A, Juergens N, Kertész M, Klumpp K, Krahulec F, Louault F, Marrs RH, Ónodi G, Pakeman RJ, Pärtel M, Peco B, Peñuelas J, Rueda M, Schmidt W, Schmiedel U, Schuetz M, Skalova H, Šmilauer P, Šmilauerová M, Smit C, Song M, Stock M, Val J, Vandvik V, Ward D, Wesche K, Wiser SK, Woodcock BA, Young TP, Yu FH, Zobel M, and de Bello F

Subjects
Phylogeny, Seeds, Phenotype, Plant Leaves, Ecosystem, Plants
Abstract

Ecological theory posits that temporal stability patterns in plant populations are associated with differences in species' ecological strategies. However, empirical evidence is lacking about which traits, or trade-offs, underlie species stability, especially across different biomes. We compiled a worldwide collection of long-term permanent vegetation records (greater than 7000 plots from 78 datasets) from a large range of habitats which we combined with existing trait databases. We tested whether the observed inter-annual variability in species abundance (coefficient of variation) was related to multiple individual traits. We found that populations with greater leaf dry matter content and seed mass were more stable over time. Despite the variability explained by these traits being low, their effect was consistent across different datasets. Other traits played a significant, albeit weaker, role in species stability, and the inclusion of multi-variate axes or phylogeny did not substantially modify nor improve predictions. These results provide empirical evidence and highlight the relevance of specific ecological trade-offs, i.e. in different resource-use and dispersal strategies, for plant populations stability across multiple biomes. Further research is, however, necessary to integrate and evaluate the role of other specific traits, often not available in databases, and intraspecific trait variability in modulating species stability.

Published
2023
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14. Human centenarian-associated SIRT6 mutants modulate hepatocyte metabolism and collagen deposition in multilineage hepatic 3D spheroids.

Author

Frohlich J, Raffaele M, Skalova H, Leire E, Pata I, Pata P, Gorbunova V, and Vinciguerra M

Subjects
Humans, Aged, 80 and over, Centenarians, Hepatocytes metabolism, Hepatocytes pathology, Collagen metabolism, Non-alcoholic Fatty Liver Disease genetics, Non-alcoholic Fatty Liver Disease metabolism, Non-alcoholic Fatty Liver Disease pathology, Carcinoma, Hepatocellular metabolism, Carcinoma, Hepatocellular pathology, Liver Neoplasms metabolism, Liver Neoplasms pathology, Sirtuins genetics, Sirtuins metabolism
Abstract

Non-alcoholic fatty liver disease (NAFLD), encompassing fatty liver and its progression into nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and hepatocellular carcinoma (HCC), is one of the rapidly rising health concerns worldwide. SIRT6 is an essential nuclear sirtuin that regulates numerous pathological processes including insulin resistance and inflammation, and recently it has been implicated in the amelioration of NAFLD progression. SIRT6 overexpression protects from formation of fibrotic lesions. However, the underlying molecular mechanisms are not fully delineated. Moreover, new allelic variants of SIRT6 (N308K/A313S) were recently associated with the longevity in Ashkenazi Jews by improving genome maintenance and DNA repair, suppressing transposons and killing cancer cells. Whether these new SIRT6 variants play different or enhanced roles in liver diseases is currently unknown. In this study, we aimed to clarify how these new centenarian-associated SIRT6 genetic variants affect liver metabolism and associated diseases. We present evidence that overexpression of centenarian-associated SIRT6 variants dramatically altered the metabolomic and secretomic profiles of unchallenged immortalized human hepatocytes (IHH). Most amino acids were increased in the SIRT6 N308K/A313S overexpressing IHH when compared to IHH transfected with the SIRT6 wild-type sequence. Several unsaturated fatty acids and glycerophospholipids were increased, and ceramide tended to be decreased upon SIRT6 N308K/A313S overexpression. Furthermore, we found that overexpression of SIRT6 N308K/A313S in a 3D hepatic spheroid model formed by the co-culture of human immortalized hepatocytes (IHH) and hepatic stellate cells (LX2) inhibited collagen deposition and fibrotic gene expression in absence of metabolic or dietary challenges. Hence, our findings suggest that novel longevity associated SIRT6 N308K/A313S variants could favor the prevention of NASH by altering hepatocyte proteome and lipidome., (© 2022. The Author(s), under exclusive licence to American Aging Association.)

Published
2023
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15. Multicenter International Study of the Consensus Immunoscore for the Prediction of Relapse and Survival in Early-Stage Colon Cancer.

Author

Mlecnik B, Lugli A, Bindea G, Marliot F, Bifulco C, Lee JJ, Zlobec I, Rau TT, Berger MD, Nagtegaal ID, Vink-Börger E, Hartmann A, Geppert CI, Kolwelter J, Merkel S, Grützmann R, Van den Eynde M, Jouret-Mourin A, Kartheuser A, Léonard D, Remue C, Wang J, Bavi P, Roehrl MHA, Ohashi PS, Nguyen LT, Han S, MacGregor HL, Hafezi-Bakhtiari S, Wouters BG, Masucci GV, Andersson EK, Zavadova E, Vocka M, Spacek J, Petruzelka L, Konopasek B, Dundr P, Skalova H, Nemejcova K, Botti G, Tatangelo F, Delrio P, Ciliberto G, Maio M, Laghi L, Grizzi F, Fredriksen T, Buttard B, Lafontaine L, Maby P, Majdi A, Hijazi A, El Sissy C, Kirilovsky A, Berger A, Lagorce C, Paustian C, Ballesteros-Merino C, Dijkstra J, van de Water C, Vliet SVL, Knijn N, Mușină AM, Scripcariu DV, Popivanova B, Xu M, Fujita T, Hazama S, Suzuki N, Nagano H, Okuno K, Torigoe T, Sato N, Furuhata T, Takemasa I, Patel P, Vora HH, Shah B, Patel JB, Rajvik KN, Pandya SJ, Shukla SN, Wang Y, Zhang G, Kawakami Y, Marincola FM, Ascierto PA, Fox BA, Pagès F, and Galon J

Abstract

Background: The prognostic value of Immunoscore was evaluated in Stage II/III colon cancer (CC) patients, but it remains unclear in Stage I/II, and in early-stage subgroups at risk. An international Society for Immunotherapy of Cancer (SITC) study evaluated the pre-defined consensus Immunoscore in tumors from 1885 AJCC/UICC-TNM Stage I/II CC patients from Canada/USA (Cohort 1) and Europe/Asia (Cohort 2). METHODS: Digital-pathology is used to quantify the densities of CD3+ and CD8+ T-lymphocyte in the center of tumor (CT) and the invasive margin (IM). The time to recurrence (TTR) was the primary endpoint. Secondary endpoints were disease-free survival (DFS), overall survival (OS), prognosis in Stage I, Stage II, Stage II-high-risk, and microsatellite-stable (MSS) patients. RESULTS: High-Immunoscore presented with the lowest risk of recurrence in both cohorts. In Stage I/II, recurrence-free rates at 5 years were 78.4% (95%-CI, 74.4−82.6), 88.1% (95%-CI, 85.7−90.4), 93.4% (95%-CI, 91.1−95.8) in low, intermediate and high Immunoscore, respectively (HR (Hi vs. Lo) = 0.27 (95%-CI, 0.18−0.41); p < 0.0001). In Cox multivariable analysis, the association of Immunoscore to outcome was independent (TTR: HR (Hi vs. Lo) = 0.29, (95%-CI, 0.17−0.50); p < 0.0001) of the patient’s gender, T-stage, sidedness, and microsatellite instability-status (MSI). A significant association of Immunoscore with survival was found for Stage II, high-risk Stage II, T4N0 and MSS patients. The Immunoscore also showed significant association with TTR in Stage-I (HR (Hi vs. Lo) = 0.07 (95%-CI, 0.01−0.61); P = 0.016). The Immunoscore had the strongest (69.5%) contribution χ2 for influencing survival. Patients with a high Immunoscore had prolonged TTR in T4N0 tumors even for patients not receiving chemotherapy, and the Immunoscore remained the only significant parameter in multivariable analysis. CONCLUSION: In early CC, low Immunoscore reliably identifies patients at risk of relapse for whom a more intensive surveillance program or adjuvant treatment should be considered.

Published
2023
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16. Clinical Performance of the Consensus Immunoscore in Colon Cancer in the Asian Population from the Multicenter International SITC Study.

Author

Mlecnik B, Torigoe T, Bindea G, Popivanova B, Xu M, Fujita T, Hazama S, Suzuki N, Nagano H, Okuno K, Hirohashi Y, Furuhata T, Takemasa I, Patel P, Vora H, Shah B, Patel JB, Rajvik KN, Pandya SJ, Shukla SN, Wang Y, Zhang G, Yoshino T, Taniguchi H, Bifulco C, Lugli A, Lee JJ, Zlobec I, Rau TT, Berger MD, Nagtegaal ID, Vink-Börger E, Hartmann A, Geppert CI, Kolwelter J, Merkel S, Grützmann R, Van den Eynde M, Jouret-Mourin A, Kartheuser A, Léonard D, Remue C, Wang J, Bavi P, Roehrl MHA, Ohashi PS, Nguyen LT, Han S, MacGregor HL, Hafezi-Bakhtiari S, Wouters BG, Masucci GV, Andersson E, Zavadova E, Vocka M, Spacek J, Petruzelka L, Konopasek B, Dundr P, Skalova H, Nemejcova K, Botti G, Tatangelo F, Delrio P, Ciliberto G, Maio M, Laghi L, Grizzi F, Marliot F, Fredriksen T, Buttard B, Lafontaine L, Maby P, Majdi A, Hijazi A, El Sissy C, Kirilovsky A, Berger A, Lagorce C, Paustian C, Ballesteros-Merino C, Dijkstra J, Van de Water C, van Lent-van Vliet S, Knijn N, Mușină AM, Scripcariu DV, Marincola FM, Ascierto PA, Fox BA, Pagès F, Kawakami Y, and Galon J

Abstract

BACKGROUND: In this study, we evaluated the prognostic value of Immunoscore in patients with stage I−III colon cancer (CC) in the Asian population. These patients were originally included in an international study led by the Society for Immunotherapy of Cancer (SITC) on 2681 patients with AJCC/UICC-TNM stages I−III CC. METHODS: CD3+ and cytotoxic CD8+ T-lymphocyte densities were quantified in the tumor and invasive margin by digital pathology. The association of Immunoscore with prognosis was evaluated for time to recurrence (TTR), disease-free survival (DFS), and overall survival (OS). RESULTS: Immunoscore stratified Asian patients (n = 423) into different risk categories and was not impacted by age. Recurrence-free rates at 3 years were 78.5%, 85.2%, and 98.3% for a Low, Intermediate, and High Immunoscore, respectively (HR[Low-vs-High] = 7.26 (95% CI 1.75−30.19); p = 0.0064). A High Immunoscore showed a significant association with prolonged TTR, OS, and DFS (p < 0.05). In Cox multivariable analysis stratified by center, Immunoscore association with TTR was independent (HR[Low-vs-Int+High] = 2.22 (95% CI 1.10−4.55) p = 0.0269) of the patient’s gender, T-stage, N-stage, sidedness, and MSI status. A significant association of a High Immunoscore with prolonged TTR was also found among MSS (HR[Low-vs-Int+High] = 4.58 (95% CI 2.27−9.23); p ≤ 0.0001), stage II (HR[Low-vs-Int+High] = 2.72 (95% CI 1.35−5.51); p = 0.0052), low-risk stage-II (HR[Low-vs-Int+High] = 2.62 (95% CI 1.21−5.68); p = 0.0146), and high-risk stage II patients (HR[Low-vs-Int+High] = 3.11 (95% CI 1.39−6.91); p = 0.0055). CONCLUSION: A High Immunoscore is significantly associated with the prolonged survival of CC patients within the Asian population.

Published
2022
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17. Multicenter International Society for Immunotherapy of Cancer Study of the Consensus Immunoscore for the Prediction of Survival and Response to Chemotherapy in Stage III Colon Cancer.

Author

Mlecnik B, Bifulco C, Bindea G, Marliot F, Lugli A, Lee JJ, Zlobec I, Rau TT, Berger MD, Nagtegaal ID, Vink-Börger E, Hartmann A, Geppert C, Kolwelter J, Merkel S, Grützmann R, Van den Eynde M, Jouret-Mourin A, Kartheuser A, Léonard D, Remue C, Wang JY, Bavi P, Roehrl MHA, Ohashi PS, Nguyen LT, Han S, MacGregor HL, Hafezi-Bakhtiari S, Wouters BG, Masucci GV, Andersson EK, Zavadova E, Vocka M, Spacek J, Petruzelka L, Konopasek B, Dundr P, Skalova H, Nemejcova K, Botti G, Tatangelo F, Delrio P, Ciliberto G, Maio M, Laghi L, Grizzi F, Fredriksen T, Buttard B, Lafontaine L, Bruni D, Lanzi A, El Sissy C, Haicheur N, Kirilovsky A, Berger A, Lagorce C, Paustian C, Ballesteros-Merino C, Dijkstra J, van de Water C, van Lent-van Vliet S, Knijn N, Muşină AM, Scripcariu DV, Popivanova B, Xu M, Fujita T, Hazama S, Suzuki N, Nagano H, Okuno K, Torigoe T, Sato N, Furuhata T, Takemasa I, Itoh K, Patel PS, Vora HH, Shah B, Patel JB, Rajvik KN, Pandya SJ, Shukla SN, Wang Y, Zhang G, Kawakami Y, Marincola FM, Ascierto PA, Fox BA, Pagès F, and Galon J

Subjects
Aged, Aged, 80 and over, CD3 Complex metabolism, Chemotherapy, Adjuvant, Colonic Neoplasms genetics, Colonic Neoplasms pathology, Disease-Free Survival, Female, Humans, Lymphocyte Count, Lymphocytes, Tumor-Infiltrating, Male, Microsatellite Instability, Middle Aged, Mutation, Neoplasm Staging, Predictive Value of Tests, Survival Rate, Time Factors, Antineoplastic Agents therapeutic use, CD8-Positive T-Lymphocytes metabolism, Colonic Neoplasms drug therapy, Colonic Neoplasms immunology, Neoplasm Recurrence, Local immunology
Abstract

Purpose: The purpose of this study was to evaluate the prognostic value of Immunoscore in patients with stage III colon cancer (CC) and to analyze its association with the effect of chemotherapy on time to recurrence (TTR)., Methods: An international study led by the Society for Immunotherapy of Cancer evaluated the predefined consensus Immunoscore in 763 patients with American Joint Committee on Cancer/Union for International Cancer Control TNM stage III CC from cohort 1 (Canada/United States) and cohort 2 (Europe/Asia). CD3+ and cytotoxic CD8+ T lymphocyte densities were quantified in the tumor and invasive margin by digital pathology. The primary end point was TTR. Secondary end points were overall survival (OS), disease-free survival (DFS), prognosis in microsatellite stable (MSS) status, and predictive value of efficacy of chemotherapy., Results: Patients with a high Immunoscore presented with the lowest risk of recurrence, in both cohorts. Recurrence-free rates at 3 years were 56.9% (95% CI, 50.3% to 64.4%), 65.9% (95% CI, 60.8% to 71.4%), and 76.4% (95% CI, 69.3% to 84.3%) in patients with low, intermediate, and high immunoscores, respectively (hazard ratio [HR; high v low], 0.48; 95% CI, 0.32 to 0.71; P = .0003). Patients with high Immunoscore showed significant association with prolonged TTR, OS, and DFS (all P < .001). In Cox multivariable analysis stratified by participating center, Immunoscore association with TTR was independent (HR [high v low], 0.41; 95% CI, 0.25 to 0.67; P = .0003) of patient's sex, T stage, N stage, sidedness, and microsatellite instability status. Significant association of a high Immunoscore with prolonged TTR was also found among MSS patients (HR [high v low], 0.36; 95% CI, 0.21 to 0.62; P = .0003). Immunoscore had the strongest contribution χ2 proportion for influencing survival (TTR and OS). Chemotherapy was significantly associated with survival in the high-Immunoscore group for both low-risk (HR [chemotherapy v no chemotherapy], 0.42; 95% CI, 0.25 to 0.71; P = .0011) and high-risk (HR [chemotherapy v no chemotherapy], 0.5; 95% CI, 0.33 to 0.77; P = .0015) patients, in contrast to the low-Immunoscore group ( P > .12)., Conclusion: This study shows that a high Immunoscore significantly associated with prolonged survival in stage III CC. Our findings suggest that patients with a high Immunoscore will benefit the most from chemotherapy in terms of recurrence risk.

Published
2020
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18. Immunological examination of peripheral blood in patients with colorectal cancer compared to healthy controls.

Author

Spacek J, Vocka M, Netikova I, Skalova H, Dundr P, Konopasek B, Zavadova E, and Lubos P

Subjects
Blood Circulation, Female, Humans, Immunity, Cellular, Lymphocyte Count, Male, Middle Aged, Neoplasm Staging, Adenocarcinoma immunology, B-Lymphocytes immunology, CD4-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes immunology, Colorectal Neoplasms immunology, Killer Cells, Natural immunology, Transforming Growth Factor beta1 blood, Vascular Endothelial Growth Factor A blood
Abstract

Background: The objective of this study was to investigate serum levels of immunosuppressive cytokines TGF beta 1 and VEGF and count of immune cells in peripheral blood in stage II and III colorectal cancer patients., Methods: Blood samples were collected from 22 colorectal patients and 25 healthy controls before the start of treatment. All patients were examined by a clinical immunologist to exclude patients with immune disorders and autoimmune diseases. TGF beta 1 and VEGF were measured by ELISA, and anti-tumor cellular immunity cells (CD4, CD8, B cells, NK cells) were measured by flow cytometry., Results: TGF beta 1 and VEGF plasma levels were significantly increased in stage II and III colorectal patients compared with control group (both p < 0.0001). A decrease in the cellular immunity was shown in the absolute numbers of cytotoxic T lymphocytes (CD8+ ; p = 0.0240), helper T lymphocytes (CD4+ ; p = 0.0019), and natural killer cells (CD16 + CD56+; p < 0.0001) in both stage II and stage III patients. On the contrary, B lymphocyte (CD19+) serum levels were increased in colon cancer patients (p < 0.0001) compared to the control group., Conclusions: Our results show peripheral blood levels of TGF beta and VEGF were significantly increased in colorectal patients and changes in cellular anticancer immunity in comparison to control group. These results will be compared with results from Immunoscore.

Published
2018
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19. International validation of the consensus Immunoscore for the classification of colon cancer: a prognostic and accuracy study.

Author

Pagès F, Mlecnik B, Marliot F, Bindea G, Ou FS, Bifulco C, Lugli A, Zlobec I, Rau TT, Berger MD, Nagtegaal ID, Vink-Börger E, Hartmann A, Geppert C, Kolwelter J, Merkel S, Grützmann R, Van den Eynde M, Jouret-Mourin A, Kartheuser A, Léonard D, Remue C, Wang JY, Bavi P, Roehrl MHA, Ohashi PS, Nguyen LT, Han S, MacGregor HL, Hafezi-Bakhtiari S, Wouters BG, Masucci GV, Andersson EK, Zavadova E, Vocka M, Spacek J, Petruzelka L, Konopasek B, Dundr P, Skalova H, Nemejcova K, Botti G, Tatangelo F, Delrio P, Ciliberto G, Maio M, Laghi L, Grizzi F, Fredriksen T, Buttard B, Angelova M, Vasaturo A, Maby P, Church SE, Angell HK, Lafontaine L, Bruni D, El Sissy C, Haicheur N, Kirilovsky A, Berger A, Lagorce C, Meyers JP, Paustian C, Feng Z, Ballesteros-Merino C, Dijkstra J, van de Water C, van Lent-van Vliet S, Knijn N, Mușină AM, Scripcariu DV, Popivanova B, Xu M, Fujita T, Hazama S, Suzuki N, Nagano H, Okuno K, Torigoe T, Sato N, Furuhata T, Takemasa I, Itoh K, Patel PS, Vora HH, Shah B, Patel JB, Rajvik KN, Pandya SJ, Shukla SN, Wang Y, Zhang G, Kawakami Y, Marincola FM, Ascierto PA, Sargent DJ, Fox BA, and Galon J

Subjects
Adult, Aged, Colonic Neoplasms immunology, Female, Humans, Lymphocytes, Tumor-Infiltrating, Male, Middle Aged, Neoplasm Staging, Prognosis, Proportional Hazards Models, Reproducibility of Results, Colonic Neoplasms classification, Colonic Neoplasms diagnosis, Neoplasm Recurrence, Local etiology
Abstract

Background: The estimation of risk of recurrence for patients with colon carcinoma must be improved. A robust immune score quantification is needed to introduce immune parameters into cancer classification. The aim of the study was to assess the prognostic value of total tumour-infiltrating T-cell counts and cytotoxic tumour-infiltrating T-cells counts with the consensus Immunoscore assay in patients with stage I-III colon cancer., Methods: An international consortium of 14 centres in 13 countries, led by the Society for Immunotherapy of Cancer, assessed the Immunoscore assay in patients with TNM stage I-III colon cancer. Patients were randomly assigned to a training set, an internal validation set, or an external validation set. Paraffin sections of the colon tumour and invasive margin from each patient were processed by immunohistochemistry, and the densities of CD3+ and cytotoxic CD8+ T cells in the tumour and in the invasive margin were quantified by digital pathology. An Immunoscore for each patient was derived from the mean of four density percentiles. The primary endpoint was to evaluate the prognostic value of the Immunoscore for time to recurrence, defined as time from surgery to disease recurrence. Stratified multivariable Cox models were used to assess the associations between Immunoscore and outcomes, adjusting for potential confounders. Harrell's C-statistics was used to assess model performance., Findings: Tissue samples from 3539 patients were processed, and samples from 2681 patients were included in the analyses after quality controls (700 patients in the training set, 636 patients in the internal validation set, and 1345 patients in the external validation set). The Immunoscore assay showed a high level of reproducibility between observers and centres (r=0·97 for colon tumour; r=0·97 for invasive margin; p<0·0001). In the training set, patients with a high Immunoscore had the lowest risk of recurrence at 5 years (14 [8%] patients with a high Immunoscore vs 65 (19%) patients with an intermediate Immunoscore vs 51 (32%) patients with a low Immunoscore; hazard ratio [HR] for high vs low Immunoscore 0·20, 95% CI 0·10-0·38; p<0·0001). The findings were confirmed in the two validation sets (n=1981). In the stratified Cox multivariable analysis, the Immunoscore association with time to recurrence was independent of patient age, sex, T stage, N stage, microsatellite instability, and existing prognostic factors (p<0·0001). Of 1434 patients with stage II cancer, the difference in risk of recurrence at 5 years was significant (HR for high vs low Immunoscore 0·33, 95% CI 0·21-0·52; p<0·0001), including in Cox multivariable analysis (p<0·0001). Immunoscore had the highest relative contribution to the risk of all clinical parameters, including the American Joint Committee on Cancer and Union for International Cancer Control TNM classification system., Interpretation: The Immunoscore provides a reliable estimate of the risk of recurrence in patients with colon cancer. These results support the implementation of the consensus Immunoscore as a new component of a TNM-Immune classification of cancer., Funding: French National Institute of Health and Medical Research, the LabEx Immuno-oncology, the Transcan ERAnet Immunoscore European project, Association pour la Recherche contre le Cancer, CARPEM, AP-HP, Institut National du Cancer, Italian Association for Cancer Research, national grants and the Society for Immunotherapy of Cancer., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Published
2018
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20. Premalignant and malignant lesions of the heterotopic pancreas in the esophagus: a case report and review of the literature.

Author

Ulrych J, Fryba V, Skalova H, Krska Z, Krechler T, and Zogala D

Subjects
Adult, Biopsy, Choristoma surgery, Esophageal Neoplasms surgery, Esophagectomy, Humans, Male, Multimodal Imaging methods, Pancreas, Positron-Emission Tomography, Precancerous Conditions surgery, Predictive Value of Tests, Tomography, X-Ray Computed, Choristoma diagnosis, Esophageal Neoplasms diagnosis, Pancreatic Neoplasms, Precancerous Conditions diagnosis
Abstract

Heterotopic pancreas is a congenital pathology of the gastrointestinal tract, particularly rare in the esophagus. Both symptomatology and findings during preoperative examinations are non-specific and therefore do not often lead to an accurate diagnosis, which is usually revealed only by histopathological assessment of a resected specimen. We report an unusual case of a patient suffering from severe dysphagia caused by heterotopic pancreas in the distal esophagus with chronic inflammation and foci of premalignant changes. This article also reviews 14 adult cases of heterotopic pancreas in the esophagus previously reported in the literature, with the aim of determining the clinical features of this disease and possible complications including rare premalignant lesions and malignant transformation. Especially with regard to those complications, we suggest that both symptomatic and incidentally found asymptomatic lesions should be resected.

Published
2015
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