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Article ; Online: An Autologous Dendritic Cell Vaccine Promotes Anticancer Immunity in Patients with Ovarian Cancer with Low Mutational Burden and Cold Tumors.

Fucikova, Jitka / Hensler, Michal / Kasikova, Lenka / Lanickova, Tereza / Pasulka, Josef / Rakova, Jana / Drozenova, Jana / Fredriksen, Tessa / Hraska, Marek / Hrnciarova, Tereza / Sochorova, Klara / Rozkova, Daniela / Sojka, Ludek / Dundr, Pavel / Laco, Jan / Brtnicky, Tomas / Praznovec, Ivan / Halaska, Michael J / Rob, Lukas /

Ryska, Ales / Coosemans, An / Vergote, Ignace / Cibula, David / Bartunkova, Jirina / Galon, Jérôme / Galluzzi, Lorenzo / Spisek, Radek

Clinical cancer research : an official journal of the American Association for Cancer Research

2022 Volume 28, Issue 14, Page(s) 3053–3065

Abstract: Purpose: The successful implementation of immune checkpoint inhibitors (ICI) in the clinical management of various solid tumors has raised considerable expectations for patients with epithelial ovarian carcinoma (EOC). However, EOC is poorly responsive ... ...

Abstract	Purpose: The successful implementation of immune checkpoint inhibitors (ICI) in the clinical management of various solid tumors has raised considerable expectations for patients with epithelial ovarian carcinoma (EOC). However, EOC is poorly responsive to ICIs due to immunologic features including limited tumor mutational burden (TMB) and poor lymphocytic infiltration. An autologous dendritic cell (DC)-based vaccine (DCVAC) has recently been shown to be safe and to significantly improve progression-free survival (PFS) in a randomized phase II clinical trial enrolling patients with EOC (SOV01, NCT02107937). Patients and methods: We harnessed sequencing, flow cytometry, multispectral immunofluorescence microscopy, and IHC to analyze (pretreatment) tumor and (pretreatment and posttreatment) peripheral blood samples from 82 patients enrolled in SOV01, with the aim of identifying immunologic biomarkers that would improve the clinical management of patients with EOC treated with DCVAC. Results: Although higher-than-median TMB and abundant CD8+ T-cell infiltration were associated with superior clinical benefits in patients with EOC receiving standard-of-care chemotherapy, the same did not hold true in women receiving DCVAC. Conversely, superior clinical responses to DCVAC were observed in patients with lower-than-median TMB and scarce CD8+ T-cell infiltration. Such responses were accompanied by signs of improved effector functions and tumor-specific cytotoxicity in the peripheral blood. Conclusions: Our findings suggest that while patients with highly infiltrated, "hot" EOCs benefit from chemotherapy, women with "cold" EOCs may instead require DC-based vaccination to jumpstart clinically relevant anticancer immune responses.
MeSH term(s)	Biomarkers, Tumor ; Cancer Vaccines/therapeutic use ; Carcinoma, Ovarian Epithelial/genetics ; Carcinoma, Ovarian Epithelial/therapy ; Dendritic Cells ; Female ; Humans ; Mutation ; Ovarian Neoplasms/genetics ; Ovarian Neoplasms/therapy
Chemical Substances	Biomarkers, Tumor ; Cancer Vaccines
Language	English
Publishing date	2022-05-10
Publishing country	United States
Document type	Clinical Trial, Phase II ; Journal Article ; Randomized Controlled Trial ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	1225457-5
ISSN	1557-3265 ; 1078-0432
ISSN (online)	1557-3265
ISSN	1078-0432
DOI	10.1158/1078-0432.CCR-21-4413
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Article: Multi-Institutional Evaluation of Pathologists' Assessment Compared to Immunoscore.

Willis, Joseph / Anders, Robert A / Torigoe, Toshihiko / Hirohashi, Yoshihiko / Bifulco, Carlo / Zlobec, Inti / Mlecnik, Bernhard / Demaria, Sandra / Choi, Won-Tak / Dundr, Pavel / Tatangelo, Fabiana / Di Mauro, Annabella / Baldin, Pamela / Bindea, Gabriela / Marliot, Florence / Haicheur, Nacilla / Fredriksen, Tessa / Kirilovsky, Amos / Buttard, Bénédicte /

Vasaturo, Angela / Lafontaine, Lucie / Maby, Pauline / El Sissy, Carine / Hijazi, Assia / Majdi, Amine / Lagorce, Christine / Berger, Anne / Van den Eynde, Marc / Pagès, Franck / Lugli, Alessandro / Galon, Jérôme

Cancers

2023 Volume 15, Issue 16

Abstract: Background: The Immunoscore (IS) is a quantitative digital pathology assay that evaluates the immune response in cancer patients. This study reports on the reproducibility of pathologists' visual assessment of CD3+- and CD8+-stained colon tumors, ... ...

Abstract	Background: The Immunoscore (IS) is a quantitative digital pathology assay that evaluates the immune response in cancer patients. This study reports on the reproducibility of pathologists' visual assessment of CD3+- and CD8+-stained colon tumors, compared to IS quantification. Methods: An international group of expert pathologists evaluated 540 images from 270 randomly selected colon cancer (CC) cases. Concordance between pathologists' T-score, corresponding hematoxylin-eosin (H&E) slides, and the digital IS was evaluated for two- and three-category IS. Results: Non-concordant T-scores were reported in more than 92% of cases. Disagreement between semi-quantitative visual assessment of T-score and the reference IS was observed in 91% and 96% of cases before and after training, respectively. Statistical analyses showed that the concordance index between pathologists and the digital IS was weak in two- and three-category IS, respectively. After training, 42% of cases had a change in T-score, but no improvement was observed with a Kappa of 0.465 and 0.374. For the 20% of patients around the cut points, no concordance was observed between pathologists and digital pathology analysis in both two- and three-category IS, before or after training (all Kappa < 0.12). Conclusions: The standardized IS assay outperformed expert pathologists' T-score evaluation in the clinical setting. This study demonstrates that digital pathology, in particular digital IS, represents a novel generation of immune pathology tools for reproducible and quantitative assessment of tumor-infiltrated immune cell subtypes.
Language	English
Publishing date	2023-08-10
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers15164045
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Article ; Online: Prognostic assessment of resected colorectal liver metastases integrating pathological features, RAS mutation and Immunoscore.

Baldin, Pamela / Van den Eynde, Marc / Mlecnik, Bernhard / Bindea, Gabriela / Beniuga, Gabriela / Carrasco, Javier / Haicheur, Nacilla / Marliot, Florence / Lafontaine, Lucie / Fredriksen, Tessa / Lanthier, Nicolas / Hubert, Catherine / Navez, Benoît / Huyghe, Nicolas / Pagès, Franck / Jouret-Mourin, Anne / Galon, Jérôme / Komuta, Mina

The journal of pathology. Clinical research

2020 Volume 7, Issue 1, Page(s) 27–41

Abstract: Surgical resection of colorectal liver metastases combined with systemic treatment aims to maximize patient survival. However, recurrence rates are very high postsurgery. In order to assess patient prognosis after metastasis resection, we evaluated the ... ...

Abstract	Surgical resection of colorectal liver metastases combined with systemic treatment aims to maximize patient survival. However, recurrence rates are very high postsurgery. In order to assess patient prognosis after metastasis resection, we evaluated the main patho-molecular and immune parameters of all surgical specimens. Two hundred twenty-one patients who underwent, after different preoperative treatment, curative resection of 582 metastases were analyzed. Clinicopathological parameters, RAS tumor mutation, and the consensus Immunoscore (I) were assessed for all patients. Overall survival (OS) and time to relapse (TTR) were estimated using the Kaplan-Meier method and compared by log-rank tests. Cox proportional hazard models were used for uni- and multivariate analysis. Immunoscore and clinicopathological parameters (number of metastases, surgical margin, histopathological growth pattern, and steatohepatitis) were associated with relapse in multivariate analysis. Overall, pathological score (PS) that combines relevant clinicopathological factors for relapse, and I, were prognostic for TTR (2-year TTR rate PS 0-1: 49.8.% (95% CI: 42.2-58.8) versus PS 2-4: 20.9% (95% CI: 13.4-32.8), hazard ratio (HR) = 2.54 (95% CI: 1.82-3.53), p < 0.0000; and 2-year TTR rate I 0: 25.7% (95% CI: 16.3-40.5) versus I 3-4: 60% (95% CI: 47.2-76.3), HR = 2.87 (95% CI: 1.73-4.75), p = 0.0000). Immunoscore was also prognostic for OS (HR [I 3-4 versus I 0] = 4.25, 95% CI: 1.95-9.23; p = 0.0001). Immunoscore (HR [I 3-4 versus I 0] = 0.27, 95% CI: 0.12-0.58; p = 0.0009) and RAS mutation (HR [mutated versus WT] = 1.66, 95% CI: 1.06-2.58; p = 0.0265) were significant for OS. In conclusion, PS including relevant clinicopathological parameters and Immunoscore permit stratification of stage IV colorectal cancer patient prognosis in terms of TTR and identify patients with higher risk of recurrence. Immunoscore remains the major prognostic factor for OS.
MeSH term(s)	Adult ; Aged ; Aged, 80 and over ; Biomarkers, Tumor/genetics ; Colorectal Neoplasms/pathology ; Decision Support Techniques ; Female ; Genes, ras ; Genetic Predisposition to Disease ; Hepatectomy ; Humans ; Liver Neoplasms/diagnosis ; Liver Neoplasms/genetics ; Liver Neoplasms/immunology ; Liver Neoplasms/secondary ; Male ; Metastasectomy ; Middle Aged ; Mutation ; Phenotype ; Predictive Value of Tests ; Retrospective Studies ; Risk Assessment ; Risk Factors ; Treatment Outcome ; Tumor Microenvironment/immunology
Chemical Substances	Biomarkers, Tumor
Language	English
Publishing date	2020-09-09
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2814357-7
ISSN	2056-4538 ; 2056-4538
ISSN (online)	2056-4538
ISSN	2056-4538
DOI	10.1002/cjp2.178
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Article ; Online: Evolution of Metastases in Space and Time under Immune Selection.

Angelova, Mihaela / Mlecnik, Bernhard / Vasaturo, Angela / Bindea, Gabriela / Fredriksen, Tessa / Lafontaine, Lucie / Buttard, Bénédicte / Morgand, Erwan / Bruni, Daniela / Jouret-Mourin, Anne / Hubert, Catherine / Kartheuser, Alex / Humblet, Yves / Ceccarelli, Michele / Syed, Najeeb / Marincola, Francesco M / Bedognetti, Davide / Van den Eynde, Marc / Galon, Jérôme

Cell

2018 Volume 175, Issue 3, Page(s) 751–765.e16

Abstract: We examined how the immune microenvironment molds tumor evolution at different metastatic organs in a longitudinal dataset of colorectal cancer. Through multiplexed analyses, we showed that clonal evolution patterns during metastatic progression depend ... ...

Abstract	We examined how the immune microenvironment molds tumor evolution at different metastatic organs in a longitudinal dataset of colorectal cancer. Through multiplexed analyses, we showed that clonal evolution patterns during metastatic progression depend on the immune contexture at the metastatic site. Genetic evidence of neoantigen depletion was observed in the sites with high Immunoscore and spatial proximity between Ki67
MeSH term(s)	Humans ; Leukemic Infiltration/immunology ; Lymphocytes, Tumor-Infiltrating/immunology ; Models, Statistical ; Neoplasm Metastasis ; Neoplasms/genetics ; Neoplasms/immunology ; Neoplasms/pathology ; Tumor Burden/immunology ; Tumor Microenvironment/immunology
Language	English
Publishing date	2018-10-11
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	187009-9
ISSN	1097-4172 ; 0092-8674
ISSN (online)	1097-4172
ISSN	0092-8674
DOI	10.1016/j.cell.2018.09.018
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Zs.A 1167: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: A Diagnostic Biopsy-Adapted Immunoscore Predicts Response to Neoadjuvant Treatment and Selects Patients with Rectal Cancer Eligible for a Watch-and-Wait Strategy.

El Sissy, Carine / Kirilovsky, Amos / Van den Eynde, Marc / Muşină, Ana-Maria / Anitei, Maria-Gabriela / Romero, Alfredo / Marliot, Florence / Junca, Audelaure / Doyen, Jérôme / Mlecnik, Bernhard / Haicheur, Nacilla / Fredriksen, Tessa / Lagorce, Christine / Jouret-Mourin, Anne / Leonard, Daniel / Bibeau, Frédéric / Iseas, Soledad / Roca, Enrique L / Cabanne, Ana M /

Vaccaro, Carlos A / Santino, Juan P / Huertas, Eduardo / Tougeron, David / Carvalho, Carlos / Figueiredo, Nuno / Perez, Rodrigo O / Habr-Gama, Angelita / Scripcariu, Viorel / Gerard, Jean-Pierre / Galon, Jérôme / Zeitoun, Guy / Pagès, Franck

Clinical cancer research : an official journal of the American Association for Cancer Research

2020 Volume 26, Issue 19, Page(s) 5198–5207

Abstract: Purpose: No biomarker to personalize treatment in locally advanced rectal cancer (LARC) is currently available. We assessed in LARC whether a diagnostic biopsy-adapted immunoscore (IS: Experimental design: Biopsies from two independent cohorts (: ... ...

Abstract	Purpose: No biomarker to personalize treatment in locally advanced rectal cancer (LARC) is currently available. We assessed in LARC whether a diagnostic biopsy-adapted immunoscore (IS Experimental design: Biopsies from two independent cohorts ( Results: IS Conclusions: IS
MeSH term(s)	Aged ; Biopsy ; CD3 Complex/immunology ; CD8-Positive T-Lymphocytes/immunology ; Cell Lineage/immunology ; Cell Proliferation/drug effects ; Disease-Free Survival ; Female ; Fluorouracil/administration & dosage ; Fluorouracil/adverse effects ; Humans ; Immunity/drug effects ; Immunity/immunology ; Male ; Middle Aged ; Neoadjuvant Therapy/adverse effects ; Neoplasm Recurrence, Local/diagnostic imaging ; Neoplasm Recurrence, Local/drug therapy ; Neoplasm Recurrence, Local/immunology ; Neoplasm Recurrence, Local/surgery ; Patient Selection ; Rectal Neoplasms/diagnostic imaging ; Rectal Neoplasms/drug therapy ; Rectal Neoplasms/immunology ; Rectal Neoplasms/surgery
Chemical Substances	CD3 Complex ; Fluorouracil (U3P01618RT)
Language	English
Publishing date	2020-07-15
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1225457-5
ISSN	1557-3265 ; 1078-0432
ISSN (online)	1557-3265
ISSN	1078-0432
DOI	10.1158/1078-0432.CCR-20-0337
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Article ; Online: The tumor microenvironment and Immunoscore are critical determinants of dissemination to distant metastasis.

Mlecnik, Bernhard / Bindea, Gabriela / Kirilovsky, Amos / Angell, Helen K / Obenauf, Anna C / Tosolini, Marie / Church, Sarah E / Maby, Pauline / Vasaturo, Angela / Angelova, Mihaela / Fredriksen, Tessa / Mauger, Stéphanie / Waldner, Maximilian / Berger, Anne / Speicher, Michael R / Pagès, Franck / Valge-Archer, Viia / Galon, Jérôme

Science translational medicine

2016 Volume 8, Issue 327, Page(s) 327ra26

Abstract: Although distant metastases account for most of the deaths in cancer patients, fundamental questions regarding mechanisms that promote or inhibit metastasis remain unanswered. We show the impact of mutations, genomic instability, lymphatic and blood ... ...

Abstract	Although distant metastases account for most of the deaths in cancer patients, fundamental questions regarding mechanisms that promote or inhibit metastasis remain unanswered. We show the impact of mutations, genomic instability, lymphatic and blood vascularization, and the immune contexture of the tumor microenvironment on synchronous metastases in large cohorts of colorectal cancer patients. We observed large genetic heterogeneity among primary tumors, but no major differences in chromosomal instability or key cancer-associated mutations. Similar patterns of cancer-related gene expression levels were observed between patients. No cancer-associated genes or pathways were associated with M stage. Instead, mutations of FBXW7 were associated with the absence of metastasis and correlated with increased expression of T cell proliferation and antigen presentation functions. Analyzing the tumor microenvironment, we observed two hallmarks of the metastatic process: decreased presence of lymphatic vessels and reduced immune cytotoxicity. These events could be the initiating factors driving both synchronous and metachronous metastases. Our data demonstrate the protective impact of the Immunoscore, a cytotoxic immune signature, and increased marginal lymphatic vessels, against the generation of distant metastases, regardless of genomic instability.
MeSH term(s)	Blood Vessels/pathology ; Cell Count ; Cell Death ; Colorectal Neoplasms/genetics ; Colorectal Neoplasms/immunology ; Colorectal Neoplasms/pathology ; Disease Progression ; Gene Expression Regulation, Neoplastic ; Genome, Human ; Humans ; Lymphatic System/pathology ; Lymphocytes/metabolism ; Mutation/genetics ; Neoplasm Metastasis ; Tumor Microenvironment/genetics ; Tumor Microenvironment/immunology
Language	English
Publishing date	2016-02-24
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2518854-9
ISSN	1946-6242 ; 1946-6234
ISSN (online)	1946-6242
ISSN	1946-6234
DOI	10.1126/scitranslmed.aad6352
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Article: Multicenter International Study of the Consensus Immunoscore for the Prediction of Relapse and Survival in Early-Stage Colon Cancer.

Mlecnik, Bernhard / Lugli, Alessandro / Bindea, Gabriela / Marliot, Florence / Bifulco, Carlo / Lee, Jiun-Kae Jack / Zlobec, Inti / Rau, Tilman T / Berger, Martin D / Nagtegaal, Iris D / Vink-Börger, Elisa / Hartmann, Arndt / Geppert, Carol I / Kolwelter, Julie / Merkel, Susanne / Grützmann, Robert / Van den Eynde, Marc / Jouret-Mourin, Anne / Kartheuser, Alex /

Léonard, Daniel / Remue, Christophe / Wang, Julia / Bavi, Prashant / Roehrl, Michael H A / Ohashi, Pamela S / Nguyen, Linh T / Han, SeongJun / MacGregor, Heather L / Hafezi-Bakhtiari, Sara / Wouters, Bradly G / Masucci, Giuseppe V / Andersson, Emilia K / Zavadova, Eva / Vocka, Michal / Spacek, Jan / Petruzelka, Lubos / Konopasek, Bohuslav / Dundr, Pavel / Skalova, Helena / Nemejcova, Kristyna / Botti, Gerardo / Tatangelo, Fabiana / Delrio, Paolo / Ciliberto, Gennaro / Maio, Michele / Laghi, Luigi / Grizzi, Fabio / Fredriksen, Tessa / Buttard, Bénédicte / Lafontaine, Lucie / Maby, Pauline / Majdi, Amine / Hijazi, Assia / El Sissy, Carine / Kirilovsky, Amos / Berger, Anne / Lagorce, Christine / Paustian, Christopher / Ballesteros-Merino, Carmen / Dijkstra, Jeroen / van de Water, Carlijn / Vliet, Shannon van Lent-van / Knijn, Nikki / Mușină, Ana-Maria / Scripcariu, Dragos-Viorel / Popivanova, Boryana / Xu, Mingli / Fujita, Tomonobu / Hazama, Shoichi / Suzuki, Nobuaki / Nagano, Hiroaki / Okuno, Kiyotaka / Torigoe, Toshihiko / Sato, Noriyuki / Furuhata, Tomohisa / Takemasa, Ichiro / Patel, Prabhu / Vora, Hemangini H / Shah, Birva / Patel, Jayendrakumar B / Rajvik, Kruti N / Pandya, Shashank J / Shukla, Shilin N / Wang, Yili / Zhang, Guanjun / Kawakami, Yutaka / Marincola, Francesco M / Ascierto, Paolo A / Fox, Bernard A / Pagès, Franck / Galon, Jérôme

Cancers

2023 Volume 15, Issue 2

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 ... ...

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.
Language	English
Publishing date	2023-01-08
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers15020418
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Article ; Online: Comprehensive Intrametastatic Immune Quantification and Major Impact of Immunoscore on Survival.

Mlecnik, Bernhard / Van den Eynde, Marc / Bindea, Gabriela / Church, Sarah E / Vasaturo, Angela / Fredriksen, Tessa / Lafontaine, Lucie / Haicheur, Nacilla / Marliot, Florence / Debetancourt, Daphné / Pairet, Géraldine / Jouret-Mourin, Anne / Gigot, Jean-Francois / Hubert, Catherine / Danse, Etienne / Dragean, Cristina / Carrasco, Javier / Humblet, Yves / Valge-Archer, Viia /

Berger, Anne / Pagès, Franck / Machiels, Jean-Pascal / Galon, Jérôme

Journal of the National Cancer Institute

2017 Volume 110, Issue 1

Abstract: Background: This study assesses how the metastatic immune landscape is impacting the response to treatment and the outcome of colorectal cancer (CRC) patients.: Methods: Complete curative resection of metastases (n = 441) was performed for two ... ...

Abstract	Background: This study assesses how the metastatic immune landscape is impacting the response to treatment and the outcome of colorectal cancer (CRC) patients. Methods: Complete curative resection of metastases (n = 441) was performed for two patient cohorts (n = 153). Immune densities were quantified in the center and invasive margin of all metastases. Immunoscore and T and B cell (TB) score were analyzed in relation to radiological and pathological responses and patient's disease-free (DFS) and overall survival (OS) using multivariable Cox proportional hazards models. All statistical tests were two-sided. Results: The spatial distribution of immune cells within metastases was nonuniform. Patients, as well as metastases of the same patient, had variable immune infiltrates and response to therapy. A beneficial response was statistically significantly associated with increased immune densities. Among all metastases, Immunoscore (I) and TB score evaluated in the least immune-infiltrated metastases were the strongest predictors for DFS and OS (five-year follow-up, Immunoscore: I 3-4: DFS rate = 27.9%, 95% CI = 15.2 to 51.3; vs I 0-1-2: DFS rate = 12.3%, 95% CI = 4.9 to 30.6; HR = 0.45, 95% CI = 0.28 to 0.70, P = .02; I 3-4: OS rate = 64.6%, 95% CI = 46.6 to 89.6; vs I 0-1-2: OS rate = 32.5%, 95% CI = 17.2 to 61.4; HR = 0.32, 95% CI = 0.15 to 0.66, P = .001, C-index = 65.9%; five-year follow-up, TB score: TB 3-4: DFS rate = 25.7%, 95% CI = 14.2 to 46.6; vs TB 0-1-2: DFS rate = 5.0%, 95% CI = 0.8 to 32.4; HR = 0.36, 95% CI = 0.22 to 0.57, P < .001; TB 3-4: OS rate = 63.7%, 95% CI = 46.4 to 87.5; vs TB 0-1-2: OS rate: 21.4%, 95% CI = 9.2 to 49.8; HR = 0.25, 95% CI = 0.12 to 0.51, P < .001, C-index = 67.8%). High TB score and Immunoscore patients had a median survival of 70.5 months, while low patients survived only 25.1 to 38.3 months. Nonresponding patients with high-immune infiltrates had prolonged DFS (HR = 0.28, 95% CI = 0.15 to 0.52, P = .001) and OS (HR = 0.25, 95% CI = 0.1 to 0.62, P = .001). The immune parameters remained the only statistically significant prognostic factor associated with DFS and OS in multivariable analysis (P < .001), while response to treatment was not. Conclusions: Response to treatment and prolonged survival of metastatic CRC patients were statistically significantly associated with high-immune densities quantified into the least immune-infiltrated metastasis.
MeSH term(s)	Aged ; Antigens, CD20/analysis ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; B-Lymphocytes/chemistry ; CD3 Complex/analysis ; CD8-Positive T-Lymphocytes ; Chemotherapy, Adjuvant ; Colorectal Neoplasms/immunology ; Colorectal Neoplasms/pathology ; Colorectal Neoplasms/therapy ; Disease-Free Survival ; Follow-Up Studies ; Forkhead Transcription Factors/analysis ; Hepatectomy ; Humans ; Leukocyte Common Antigens/analysis ; Liver Neoplasms/immunology ; Liver Neoplasms/secondary ; Liver Neoplasms/therapy ; Lung Neoplasms/immunology ; Lung Neoplasms/secondary ; Lung Neoplasms/therapy ; Lymphocyte Count ; Lymphocytes, Tumor-Infiltrating ; Metastasectomy ; Middle Aged ; Neoplasm Metastasis ; Pneumonectomy ; Preoperative Period ; Response Evaluation Criteria in Solid Tumors ; Survival Rate ; T-Lymphocytes/chemistry ; Tumor Microenvironment/immunology
Chemical Substances	Antigens, CD20 ; CD3 Complex ; FOXP3 protein, human ; Forkhead Transcription Factors ; Leukocyte Common Antigens (EC 3.1.3.48)
Language	English
Publishing date	2017-09-27
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2992-0
ISSN	1460-2105 ; 0027-8874 ; 0198-0157
ISSN (online)	1460-2105
ISSN	0027-8874 ; 0198-0157
DOI	10.1093/jnci/djx123
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Article ; Online: Functional network pipeline reveals genetic determinants associated with in situ lymphocyte proliferation and survival of cancer patients.

Mlecnik, Bernhard / Bindea, Gabriela / Angell, Helen K / Sasso, Maria Stella / Obenauf, Anna C / Fredriksen, Tessa / Lafontaine, Lucie / Bilocq, Amelie M / Kirilovsky, Amos / Tosolini, Marie / Waldner, Maximilian / Berger, Anne / Fridman, Wolf Herman / Rafii, Arash / Valge-Archer, Viia / Pagès, Franck / Speicher, Michael R / Galon, Jérôme

Science translational medicine

2014 Volume 6, Issue 228, Page(s) 228ra37

Abstract: The tumor microenvironment is host to a complex network of cytokines that contribute to shaping the intratumoral immune reaction. Chromosomal gains and losses, coupled with expression analysis, of 59 cytokines and receptors and their functional networks ... ...

Abstract	The tumor microenvironment is host to a complex network of cytokines that contribute to shaping the intratumoral immune reaction. Chromosomal gains and losses, coupled with expression analysis, of 59 cytokines and receptors and their functional networks were investigated in colorectal cancers. Changes in local expression for 13 cytokines were shown. Metastatic patients exhibited an increased frequency of deletions of cytokines from chromosome 4. Interleukin 15 (IL15) deletion corresponded with decreased IL15 expression, a higher risk of tumor recurrence, and reduced patient survival. Decreased IL15 expression affected the local proliferation of B and T lymphocytes. Patients with proliferating B and T cells at the invasive margin and within the tumor center had significantly prolonged disease-free survival. These results delineate chromosomal instability as a mechanism of modulating local cytokine expression in human tumors and underline the major role of IL15. Our data provide further mechanisms resulting in changes of specific immune cell densities within the tumor, and the importance of local active lymphocyte proliferation for patient survival.
MeSH term(s)	Cell Proliferation ; Cytokines/genetics ; Humans ; Lymphocytes/pathology ; Neoplasm Recurrence, Local ; Neoplasms/genetics ; Neoplasms/pathology ; Survival Rate ; Tumor Microenvironment
Chemical Substances	Cytokines
Language	English
Publishing date	2014-03-19
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2518854-9
ISSN	1946-6242 ; 1946-6234
ISSN (online)	1946-6242
ISSN	1946-6234
DOI	10.1126/scitranslmed.3007240
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Article ; Online: The Link between the Multiverse of Immune Microenvironments in Metastases and the Survival of Colorectal Cancer Patients.

Van den Eynde, Marc / Mlecnik, Bernhard / Bindea, Gabriela / Fredriksen, Tessa / Church, Sarah E / Lafontaine, Lucie / Haicheur, Nacilla / Marliot, Florence / Angelova, Mihaela / Vasaturo, Angela / Bruni, Daniela / Jouret-Mourin, Anne / Baldin, Pamela / Huyghe, Nicolas / Haustermans, Karin / Debucquoy, Annelies / Van Cutsem, Eric / Gigot, Jean-Francois / Hubert, Catherine /

Kartheuser, Alex / Remue, Christophe / Léonard, Daniel / Valge-Archer, Viia / Pagès, Franck / Machiels, Jean-Pascal / Galon, Jérôme

Cancer cell

2018 Volume 34, Issue 6, Page(s) 1012–1026.e3

Abstract: Treatment of metastatic colorectal cancer is based upon the assumption that metastases are homogeneous within a patient. We quantified immune cell types of 603 whole-slide metastases and primary colorectal tumors from 222 patients. Primary lesions, and ... ...

Abstract	Treatment of metastatic colorectal cancer is based upon the assumption that metastases are homogeneous within a patient. We quantified immune cell types of 603 whole-slide metastases and primary colorectal tumors from 222 patients. Primary lesions, and synchronous and metachronous metastases, had a heterogeneous immune infiltrate and mutational diversity. Small metastases had frequently a low Immunoscore and T and B cell score, while a high Immunoscore was associated with a lower number of metastases. Anti-epidermal growth factor receptor treatment modified immune gene expression and significantly increased T cell densities in the metastasis core. The predictive accuracy of the Immunoscore from a single biopsy was superior to the one of programmed cell death ligand 1 (PD-L1). The immune phenotype of the least-infiltrated metastasis had a stronger association with patient outcome than other metastases.
MeSH term(s)	Adult ; Aged ; Aged, 80 and over ; Antineoplastic Agents/pharmacology ; B7-H1 Antigen/genetics ; B7-H1 Antigen/immunology ; B7-H1 Antigen/metabolism ; Cohort Studies ; Colorectal Neoplasms/drug therapy ; Colorectal Neoplasms/genetics ; Colorectal Neoplasms/immunology ; ErbB Receptors/antagonists & inhibitors ; ErbB Receptors/immunology ; ErbB Receptors/metabolism ; Female ; Gene Expression Regulation, Neoplastic/drug effects ; Gene Expression Regulation, Neoplastic/immunology ; Gene Ontology ; Gene Regulatory Networks ; Humans ; Kaplan-Meier Estimate ; Lymphocytes, Tumor-Infiltrating/drug effects ; Lymphocytes, Tumor-Infiltrating/immunology ; Lymphocytes, Tumor-Infiltrating/metabolism ; Male ; Middle Aged ; Neoplasm Metastasis ; Tumor Microenvironment/drug effects ; Tumor Microenvironment/genetics ; Tumor Microenvironment/immunology
Chemical Substances	Antineoplastic Agents ; B7-H1 Antigen ; CD274 protein, human ; ErbB Receptors (EC 2.7.10.1)
Language	English
Publishing date	2018-12-07
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2078448-X
ISSN	1878-3686 ; 1535-6108
ISSN (online)	1878-3686
ISSN	1535-6108
DOI	10.1016/j.ccell.2018.11.003
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