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  1. Article ; Online: Influence of Individual Surgeon Volume on Oncological Outcome of Colorectal Cancer Surgery.

    Buurma, Marleen / Kroon, Hidde M / Reimers, Marlies S / Neijenhuis, Peter A

    International journal of surgical oncology

    2015  Volume 2015, Page(s) 464570

    Abstract: Background: Surgery performed by a high-volume surgeon improves short-term outcomes. However, not much is known about long-term effects. Therefore we performed the current study to evaluate the impact of high-volume colorectal surgeons on survival.: ... ...

    Abstract Background: Surgery performed by a high-volume surgeon improves short-term outcomes. However, not much is known about long-term effects. Therefore we performed the current study to evaluate the impact of high-volume colorectal surgeons on survival.
    Methods: We conducted a retrospective analysis of our prospectively collected colorectal cancer database between 2004 and 2011. Patients were divided into two groups: operated on by a high-volume surgeon (>25 cases/year) or by a low-volume surgeon (<25 cases/year). Perioperative data were collected as well as follow-up, recurrence rates, and survival data.
    Results: 774 patients underwent resection for colorectal malignancies. Thirteen low-volume surgeons operated on 453 patients and 4 high-volume surgeons operated on 321 patients. Groups showed an equal distribution for preoperative characteristics, except a higher ASA-classification in the low-volume group. A high-volume surgeon proved to be an independent prognostic factor for disease-free survival in the multivariate analysis (P = 0.04). Although overall survival did show a significant difference in the univariate analysis (P < 0.001) it failed to reach statistical significance in the multivariate analysis (P = 0.09).
    Conclusions: In our study, a higher number of colorectal cases performed per surgeon were associated with longer disease-free survival. Implementing high-volume surgery results in improved long-term outcome following colorectal cancer.
    MeSH term(s) Aged ; Aged, 80 and over ; Colorectal Neoplasms/radiotherapy ; Colorectal Neoplasms/surgery ; Digestive System Surgical Procedures/statistics & numerical data ; Disease-Free Survival ; Female ; Humans ; Male ; Middle Aged ; Neoplasm Recurrence, Local/epidemiology ; Netherlands/epidemiology ; Retrospective Studies ; Risk Factors ; Surgeons/statistics & numerical data ; Treatment Outcome
    Language English
    Publishing date 2015
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2584964-5
    ISSN 2090-1410 ; 2090-1402
    ISSN (online) 2090-1410
    ISSN 2090-1402
    DOI 10.1155/2015/464570
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  2. Article ; Online: The Prognostic Value of Microsatellite Instability,

    Vogelaar, F Jeroen / Erning, Felice N van / Reimers, Marlies S / Linden, Hans van der / Pruijt, Hans / Brule, Adriaan J C van den / Bosscha, Koop

    Molecular medicine (Cambridge, Mass.)

    2016  Volume 21, Issue 1, Page(s) 1038–1046

    Abstract: In the era of personalized cancer medicine, identifying mutations within patient tumors plays an important role in defining high-risk stage II colon cancer patients. The prognostic role ... ...

    Abstract In the era of personalized cancer medicine, identifying mutations within patient tumors plays an important role in defining high-risk stage II colon cancer patients. The prognostic role of
    Language English
    Publishing date 2016-05-09
    Publishing country England
    Document type Journal Article
    ZDB-ID 1283676-x
    ISSN 1528-3658 ; 1076-1551
    ISSN (online) 1528-3658
    ISSN 1076-1551
    DOI 10.2119/molmed.2015.00220
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  3. Article ; Online: Tumour budding is associated with the mesenchymal colon cancer subtype and RAS/RAF mutations: a study of 1320 colorectal cancers with Consensus Molecular Subgroup (CMS) data.

    Trinh, Anne / Lädrach, Claudia / Dawson, Heather E / Ten Hoorn, Sanne / Kuppen, Peter J K / Reimers, Marlies S / Koopman, Miriam / Punt, Cornelis J A / Lugli, Alessandro / Vermeulen, Louis / Zlobec, Inti

    British journal of cancer

    2018  Volume 119, Issue 10, Page(s) 1244–1251

    Abstract: Background: Tumour budding is an important prognostic factor in colorectal cancer (CRC). Molecular profiling of tumour buds suggests (partial) epithelial-mesenchymal transition and cancer stem-cell phenotype, similarly described in the "mesenchymal" ... ...

    Abstract Background: Tumour budding is an important prognostic factor in colorectal cancer (CRC). Molecular profiling of tumour buds suggests (partial) epithelial-mesenchymal transition and cancer stem-cell phenotype, similarly described in the "mesenchymal" Consensus Molecular Subtype 4 (CMS4), which identifies a particularly poor prognostic subgroup. Here, we determine the association of tumour budding with CMS classification, prognosis, and response to therapy.
    Methods: AMC-AJCCII-90 cohort (n = 76, stage II) was evaluated for peritumoural budding on H&E slides. LUMC (n = 270, stage I-IV), CAIRO (n = 504, metastatic CRC) and CAIRO2 (n = 472, metastatic CRC) cohorts were investigated for intratumoural budding using pan-cytokeratin-stained tissue microarrays. Budding was scored as count/area, then classified as <5 or ≥5 buds. For all cohorts, CMS classifications were available (gene-expression/immunohistochemistry-based classifiers).
    Results: High (≥5) budding predicted a worse outcome in multivariate analysis in AMC-AJCCII-90 (p = 0.018), LUMC (p < 0.0001), and CAIRO (p = 0.03), and in CAIRO2 (continuous variable, p = 0.02). Tumour budding counts were higher in CMS4 compared to epithelial CMS2/3 cancers (p < 0.01, all), and associated with KRAS/BRAF mutations (p < 0.01, AMC-AJCCII-90, CAIRO, CAIRO2).
    Conclusion: Tumour budding is an adverse prognostic factor across all CRC stages and is associated with the mesenchymal CMS4 phenotype. KRAS/BRAF mutations are strongly correlated with tumour budding suggesting their involvement in the regulation of this process.
    MeSH term(s) Adult ; Aged ; Aged, 80 and over ; Biomarkers, Tumor/metabolism ; Cohort Studies ; Colorectal Neoplasms/classification ; Colorectal Neoplasms/metabolism ; Colorectal Neoplasms/pathology ; Epithelial-Mesenchymal Transition ; Female ; Genes, ras ; Humans ; Male ; Mesoderm/pathology ; Middle Aged ; Mutation ; Prognosis ; Randomized Controlled Trials as Topic ; raf Kinases/genetics
    Chemical Substances Biomarkers, Tumor ; raf Kinases (EC 2.7.11.1)
    Language English
    Publishing date 2018-11-02
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 80075-2
    ISSN 1532-1827 ; 0007-0920
    ISSN (online) 1532-1827
    ISSN 0007-0920
    DOI 10.1038/s41416-018-0230-7
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  4. Article ; Online: How does genome sequencing impact surgery?

    Reimers, Marlies S / Engels, Charla C / Kuppen, Peter J K / van de Velde, Cornelis J H / Liefers, Gerrit J

    Nature reviews. Clinical oncology

    2014  Volume 11, Issue 10, Page(s) 610–618

    Abstract: Cancer is a leading cause of death worldwide. Great efforts are dedicated to the development of prognostic and predictive biomarkers to improve diagnosis and achieve optimal treatment selection, thereby, introducing precision medicine in the ... ...

    Abstract Cancer is a leading cause of death worldwide. Great efforts are dedicated to the development of prognostic and predictive biomarkers to improve diagnosis and achieve optimal treatment selection, thereby, introducing precision medicine in the multimodality treatment of cancer. Genomic aberrations are the basis of tumour development, representing excellent candidates for the development of promising clinical biomarkers. Over the past decade, single-gene mutations and genomic profiling have been increasingly used in multidisciplinary consultations for risk-assessment and treatment planning for patients with cancer. We discuss the impact of such genetic-based information on surgical decision-making. Single-gene mutations have already influenced surgical decision-making in breast, colorectal and thyroid cancer. However, the direct impact of genomic profiling on surgical care has not yet been fully established. We discuss the direct and indirect influences of genomic profiling on surgery, and analyse the limitations and unresolved issues of a genotypic-approach to the surgical management of cancer.
    MeSH term(s) Genetic Variation ; Genome, Human ; Genomics/methods ; Humans ; Mutation ; Neoplasms/diagnosis ; Neoplasms/genetics ; Neoplasms/surgery ; Patient Selection ; Precision Medicine/methods ; Prognosis ; Sequence Analysis, DNA
    Language English
    Publishing date 2014-06-24
    Publishing country England
    Document type Review
    ZDB-ID 2491410-1
    ISSN 1759-4782 ; 1759-4774
    ISSN (online) 1759-4782
    ISSN 1759-4774
    DOI 10.1038/nrclinonc.2014.101
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  5. Article ; Online: Prognostic value of HLA class I, HLA-E, HLA-G and Tregs in rectal cancer: a retrospective cohort study.

    Reimers, Marlies S / Engels, Charla C / Putter, Hein / Morreau, Hans / Liefers, Gerrit Jan / van de Velde, Cornelis J H / Kuppen, Peter J K

    BMC cancer

    2014  Volume 14, Page(s) 486

    Abstract: Background: Evasion of immune surveillance and suppression of the immune system are important hallmarks of tumorigenesis. The goal of this study was to establish distinct patterns that reflect a rectal tumors' immune-phenotype and to determine their ... ...

    Abstract Background: Evasion of immune surveillance and suppression of the immune system are important hallmarks of tumorigenesis. The goal of this study was to establish distinct patterns that reflect a rectal tumors' immune-phenotype and to determine their relation to patient outcome.
    Methods: The study population consisted of 495 Stage I-IV non-preoperatively treated rectal cancer patients of which a tissue micro array (TMA) was available. Sections of this TMA were immunohistochemically stained and quantified for presence of Foxp3+ cells (Tregs) and tumor expression of HLA Class I and non-classical HLA-E and HLA-G. All markers were, separate and combined, analyzed for clinical prognostic value.
    Results: Expression of HLA class I (DFS HR 0.637 (0.458-0.886), p = 0.013), Foxp3+ infiltration above median (OS HR 0.637 (0.500-0.813), p < 0.001 and DFS HR 0.624 (0.491-0.793), p < 0.001) and expression of HLA-G (DFS HR 0.753 (0.574-0.989), p = 0.042) were related to a better clinical prognosis. When these markers were combined, patients with 2 or 3 markers associated with poor prognosis (loss of HLA Class I, Foxp3+ below median, and weak HLA-G expression), showed a significantly worse survival (OS and DFS p < 0.001). This immune-phenotype was an independent predictor for DFS (HR 1.56 (1.14-2.14), p = 0.019).
    Conclusions: In conclusion, rectal tumors showing loss of HLA class I expression, Foxp3+ infiltration below median and weak HLA-G expression were related to a worse OS and DFS. Combining these immune markers lead to the creation of tumor immune-phenotypes , which related to patient outcome and were significant independent clinical prognostic markers in rectal cancer.
    MeSH term(s) Aged ; Biomarkers/metabolism ; Female ; HLA-G Antigens/immunology ; Histocompatibility Antigens Class I/immunology ; Humans ; Immunohistochemistry ; Lymphocytes, Tumor-Infiltrating/immunology ; Male ; Middle Aged ; Neoplasm Grading ; Neoplasm Staging ; Patient Outcome Assessment ; Phenotype ; Prognosis ; Rectal Neoplasms/diagnosis ; Rectal Neoplasms/immunology ; Rectal Neoplasms/mortality ; Rectal Neoplasms/therapy ; Retrospective Studies ; T-Lymphocytes, Regulatory/immunology ; T-Lymphocytes, Regulatory/metabolism ; HLA-E Antigens
    Chemical Substances Biomarkers ; HLA-G Antigens ; Histocompatibility Antigens Class I
    Language English
    Publishing date 2014-07-05
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2041352-X
    ISSN 1471-2407 ; 1471-2407
    ISSN (online) 1471-2407
    ISSN 1471-2407
    DOI 10.1186/1471-2407-14-486
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  6. Article: Biomarkers in precision therapy in colorectal cancer.

    Reimers, Marlies S / Zeestraten, Eliane C M / Kuppen, Peter J K / Liefers, Gerrit Jan / van de Velde, Cornelis J H

    Gastroenterology report

    2013  Volume 1, Issue 3, Page(s) 166–183

    Abstract: Colorectal cancer (CRC) is the most commonly diagnosed cancer in Europe. Because CRC is also a major cause of cancer-related deaths worldwide, a lot of research has been focused on the discovery and development of biomarkers to improve the diagnostic ... ...

    Abstract Colorectal cancer (CRC) is the most commonly diagnosed cancer in Europe. Because CRC is also a major cause of cancer-related deaths worldwide, a lot of research has been focused on the discovery and development of biomarkers to improve the diagnostic process and to predict treatment outcomes. Up till now only a few biomarkers are recommended by expert panels. Current TNM criteria, however, cause substantial under- and overtreatment of CRC patients. Consequently, there is a growing need for new and efficient biomarkers to ensure optimal treatment allocation. An ideal biomarker should be easily translated into clinical practice, to identify patients who can be spared from treatment or benefit from therapy, ultimately resulting in precision medicine in the future. In this review we aim to provide an overview of a number of frequently studied biomarkers in CRC and, at the same time, we will emphasize the challenges and controversies that withhold the clinical introduction of these biomarkers. We will discuss both prognostic and predictive markers of chemotherapy, aspirin therapy as well as overall therapy toxicity. Currently, only mutant KRAS, mutant BRAF, MSI and the Oncotype DX® Colon Cancer Assay are used in clinical practice. Other biomarker studies showed insufficient evidence to be introduced into clinical practice. Divergent patient selection criteria, absence of validation studies and a large number of single biomarker studies are possibly responsible. We therefore recommend that future studies focus on combining key markers, rather than analysing single markers, standardizing study protocols, and validate the results in independent study cohorts, followed by prospective clinical trials.
    Language English
    Publishing date 2013-08-23
    Publishing country England
    Document type Journal Article
    ZDB-ID 2710871-5
    ISSN 2052-0034
    ISSN 2052-0034
    DOI 10.1093/gastro/got022
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  7. Article ; Online: The Influence of BRAF and KRAS Mutation Status on the Association between Aspirin Use and Survival after Colon Cancer Diagnosis.

    Frouws, Martine A / Reimers, Marlies S / Swets, Marloes / Bastiaannet, Esther / Prinse, Bianca / van Eijk, Ronald / Lemmens, Valery E P P / van Herk-Sukel, Myrthe P P / van Wezel, Tom / Kuppen, Peter J K / Morreau, Hans / van de Velde, Cornelis J H / Liefers, Gerrit-Jan

    PloS one

    2017  Volume 12, Issue 1, Page(s) e0170775

    Abstract: Background: Use of aspirin after diagnosis of colon cancer has been associated with improved survival. Identification of cancer subtypes that respond to aspirin treatment may help develop personalized treatment regimens. The aim of this study was to ... ...

    Abstract Background: Use of aspirin after diagnosis of colon cancer has been associated with improved survival. Identification of cancer subtypes that respond to aspirin treatment may help develop personalized treatment regimens. The aim of this study was to investigate the influence of BRAF and KRAS mutation status on the association between aspirin use and overall survival after colon cancer diagnosis.
    Methods: A random selection of 599 patients with colon cancer were analyzed, selected from the Eindhoven Cancer Registry, and BRAF and KRAS mutation status was determined. Data on aspirin use (80 mg) were obtained from the PHARMO Database Network. Parametric survival models with exponential (Poisson) distribution were used.
    Results: Aspirin use after colon cancer diagnosis was associated with improved overall survival in wild-type BRAF tumors, adjusted rate ratio (RR) of 0.60 (95% CI 0.44-0.83). In contrast, aspirin use in BRAF mutated tumors was not associated with an improved survival (RR 1.11, 95% CI 0.57-2.16). P-value for interaction was non-significant. KRAS mutational status did not differentiate in the association between aspirin use and survival.
    Conclusion: Low-dose aspirin use after colon cancer diagnosis was associated with improved survival in BRAF wild-type tumors only. However, the large confidence interval of the rate ratio for the use of aspirin in patients with BRAF mutation does not rule out a possible benefit. These results preclude BRAF and KRAS mutation status to be used as a marker for individualized treatment with aspirin, if aspirin becomes regular adjuvant treatment for colon cancer patients in the future.
    MeSH term(s) Aged ; Aged, 80 and over ; Aspirin/therapeutic use ; Colon/drug effects ; Colon/metabolism ; Colon/pathology ; Colonic Neoplasms/diagnosis ; Colonic Neoplasms/drug therapy ; Colonic Neoplasms/genetics ; Colonic Neoplasms/mortality ; Female ; Gene Expression ; Humans ; Male ; Middle Aged ; Mutation ; Prognosis ; Proto-Oncogene Proteins B-raf/genetics ; Proto-Oncogene Proteins p21(ras)/genetics ; Registries ; Retrospective Studies ; Survival Analysis
    Chemical Substances KRAS protein, human ; BRAF protein, human (EC 2.7.11.1) ; Proto-Oncogene Proteins B-raf (EC 2.7.11.1) ; Proto-Oncogene Proteins p21(ras) (EC 3.6.5.2) ; Aspirin (R16CO5Y76E)
    Language English
    Publishing date 2017
    Publishing country United States
    Document type Journal Article
    ISSN 1932-6203
    ISSN (online) 1932-6203
    DOI 10.1371/journal.pone.0170775
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  8. Article ; Online: The Prognostic Value of the Apoptosis Pathway in Colorectal Cancer

    Eliane C.M. Zeestraten / Anne Benard / Marlies S. Reimers / Philip C. Schouten / Gerrit J. Liefers / Cornelis J.H. van de Velde / Peter J.K. Kuppen

    Biomarkers in Cancer, Vol 2013, Iss 5, Pp 13-

    A Review of the Literature on Biomarkers Identified by Immunohistochemistry

    2013  Volume 29

    Keywords Neoplasms. Tumors. Oncology. Including cancer and carcinogens ; RC254-282 ; Internal medicine ; RC31-1245 ; Medicine ; R ; DOAJ:Oncology ; DOAJ:Medicine (General) ; DOAJ:Health Sciences
    Language English
    Publishing date 2013-07-01T00:00:00Z
    Publisher Libertas Academica
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  9. Article: The prognostic value of the apoptosis pathway in colorectal cancer: a review of the literature on biomarkers identified by immunohistochemistry.

    Zeestraten, Eliane C M / Benard, Anne / Reimers, Marlies S / Schouten, Philip C / Liefers, Gerrit J / van de Velde, Cornelis J H / Kuppen, Peter J K

    Biomarkers in cancer

    2013  Volume 5, Page(s) 13–29

    Abstract: Research towards biomarkers that predict patient outcome in colorectal cancer (CRC) is rapidly expanding. However, none of these biomarkers have been recommended by the American Association of Clinical Oncology or the European Group on Tumor Markers. ... ...

    Abstract Research towards biomarkers that predict patient outcome in colorectal cancer (CRC) is rapidly expanding. However, none of these biomarkers have been recommended by the American Association of Clinical Oncology or the European Group on Tumor Markers. Current staging criteria result in substantial under-and over-treatment of CRC patients. Evasion of apoptosis, a characteristic feature of tumorigenesis, is known to correlate with patient outcome. We reviewed the literature on immunohistochemistry-based studies between 1998 and 2011 describing biomarkers in this pathway in CRC and identified 26 markers. Most frequently described were p53, Bcl-2, survivin, and the Fas and TRAILR1 receptors and their ligands. None of the studies reviewed provided sufficient support for implementing a single marker into current clinical practice. This is likely due to the complex biology of this pathway. We suggest focusing on the combination of key markers within the apoptosis pathway that together represent an 'apoptotic tumor profile', which better reflects the status of this pathway in a tumor.
    Language English
    Publishing date 2013-07-04
    Publishing country United States
    Document type Journal Article ; Review
    ZDB-ID 2592049-2
    ISSN 1179-299X
    ISSN 1179-299X
    DOI 10.4137/BIC.S11475
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  10. Article ; Online: Validation of the 12-gene colon cancer recurrence score as a predictor of recurrence risk in stage II and III rectal cancer patients.

    Reimers, Marlies S / Kuppen, Peter J K / Lee, Mark / Lopatin, Margarita / Tezcan, Haluk / Putter, Hein / Clark-Langone, Kim / Liefers, Gerrit Jan / Shak, Steve / van de Velde, Cornelis J H

    Journal of the National Cancer Institute

    2014  Volume 106, Issue 11

    Abstract: Background: The 12-gene Recurrence Score assay is a validated predictor of recurrence risk in stage II and III colon cancer patients. We conducted a prospectively designed study to validate this assay for prediction of recurrence risk in stage II and ... ...

    Abstract Background: The 12-gene Recurrence Score assay is a validated predictor of recurrence risk in stage II and III colon cancer patients. We conducted a prospectively designed study to validate this assay for prediction of recurrence risk in stage II and III rectal cancer patients from the Dutch Total Mesorectal Excision (TME) trial.
    Methods: RNA was extracted from fixed paraffin-embedded primary rectal tumor tissue from stage II and III patients randomized to TME surgery alone, without (neo)adjuvant treatment. Recurrence Score was assessed by quantitative real time-polymerase chain reaction using previously validated colon cancer genes and algorithm. Data were analysed by Cox proportional hazards regression, adjusting for stage and resection margin status. All statistical tests were two-sided.
    Results: Recurrence Score predicted risk of recurrence (hazard ratio [HR] = 1.57, 95% confidence interval [CI] = 1.11 to 2.21, P = .01), risk of distant recurrence (HR = 1.50, 95% CI = 1.04 to 2.17, P = .03), and rectal cancer-specific survival (HR = 1.64, 95% CI = 1.15 to 2.34, P = .007). The effect of Recurrence Score was most prominent in stage II patients and attenuated with more advanced stage (P(interaction) ≤ .007 for each endpoint). In stage II, five-year cumulative incidence of recurrence ranged from 11.1% in the predefined low Recurrence Score group (48.5% of patients) to 43.3% in the high Recurrence Score group (23.1% of patients).
    Conclusion: The 12-gene Recurrence Score is a predictor of recurrence risk and cancer-specific survival in rectal cancer patients treated with surgery alone, suggesting a similar underlying biology in colon and rectal cancers.
    MeSH term(s) Aged ; Aged, 80 and over ; Colonic Neoplasms/epidemiology ; Colonic Neoplasms/genetics ; Colonic Neoplasms/pathology ; Female ; Gene Expression Profiling ; Gene Expression Regulation, Neoplastic ; Genetic Testing ; Humans ; Incidence ; Kaplan-Meier Estimate ; Male ; Middle Aged ; Neoplasm Recurrence, Local/epidemiology ; Neoplasm Recurrence, Local/genetics ; Neoplasm Staging ; Netherlands/epidemiology ; Odds Ratio ; Predictive Value of Tests ; Prognosis ; Proportional Hazards Models ; Prospective Studies ; Randomized Controlled Trials as Topic ; Real-Time Polymerase Chain Reaction ; Rectal Neoplasms/genetics ; Rectal Neoplasms/pathology
    Language English
    Publishing date 2014-11
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Validation Studies
    ZDB-ID 2992-0
    ISSN 1460-2105 ; 0027-8874 ; 0198-0157
    ISSN (online) 1460-2105
    ISSN 0027-8874 ; 0198-0157
    DOI 10.1093/jnci/dju269
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