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  • 1
    In: Metabolites, MDPI AG, Vol. 9, No. 9 ( 2019-09-06), p. 178-
    Abstract: Cachexia is a multifactorial syndrome that is characterized by loss of skeletal muscle mass in cancer patients. The biological pathways involved remain poorly characterized. Here, we compare urinary metabolic profiles in newly diagnosed colorectal cancer patients (stage I–IV) from the ColoCare Study in Heidelberg, Germany. Patients were classified as cachectic (n = 16), pre-cachectic (n = 13), or non-cachectic (n = 23) based on standard criteria on weight loss over time at two time points. Urine samples were collected pre-surgery, and 6 and 12 months thereafter. Fat and muscle mass area were assessed utilizing computed tomography scans at the time of surgery. N = 152 compounds were detected using untargeted metabolomics with gas chromatography–mass spectrometry and n = 154 features with proton nuclear magnetic resonance spectroscopy. Thirty-four metabolites were overlapping across platforms. We calculated differences across groups and performed discriminant and overrepresentation enrichment analysis. We observed a trend for 32 compounds that were nominally significantly different across groups, although not statistically significant after adjustment for multiple testing. Nineteen compounds could be identified, including acetone, hydroquinone, and glycine. Comparing cachectic to non-cachectic patients, higher levels of metabolites such as acetone (Fold change (FC) = 3.17; p = 0.02) and arginine (FC = 0.33; p = 0.04) were observed. The two top pathways identified were glycerol phosphate shuttle metabolism and glycine and serine metabolism pathways. Larger subsequent studies are needed to replicate and validate these results.
    Type of Medium: Online Resource
    ISSN: 2218-1989
    Language: English
    Publisher: MDPI AG
    Publication Date: 2019
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  • 2
    In: Cancer Prevention Research, American Association for Cancer Research (AACR), Vol. 13, No. 10 ( 2020-10-01), p. 817-828
    Abstract: Obesity and obesity-driven cancer rates are continuing to rise worldwide. We hypothesize that adipocyte–colonocyte interactions are a key driver of obesity-associated cancers. To understand the clinical relevance of visceral adipose tissue in advancing tumor growth, we analyzed paired tumor-adjacent visceral adipose, normal mucosa, and colorectal tumor tissues as well as presurgery blood samples from patients with sporadic colorectal cancer. We report that high peroxisome proliferator-activated receptor gamma (PPARG) visceral adipose tissue expression is associated with glycoprotein VI (GPVI) signaling—the major signaling receptor for collagen—as well as fibrosis and adipogenesis pathway signaling in colorectal tumors. These associations were supported by correlations between PPARG visceral adipose tissue expression and circulating levels of plasma 4-hydroxyproline and serum intercellular adhesion molecule 1 (ICAM1), as well as gene set enrichment analysis and joint gene-metabolite pathway results integration that yielded significant enrichment of genes defining epithelial-to-mesenchymal transition—as in fibrosis and metastasis—and genes involved in glycolytic metabolism, confirmed this association. We also reveal that elevated prostaglandin-endoperoxide synthase 2 (PTGS2) colorectal tumor expression is associated with a fibrotic signature in adipose–tumor crosstalk via GPVI signaling and dendritic cell maturation in visceral adipose tissue. Systemic metabolite and biomarker profiling confirmed that high PTGS2 expression in colorectal tumors is significantly associated with higher concentrations of serum amyloid A and glycine, and lower concentrations of sphingomyelin, in patients with colorectal cancer. This multi-omics study suggests that adipose–tumor crosstalk in patients with colorectal cancer is a critical microenvironment interaction that could be therapeutically targeted. See related spotlight by Colacino et al., p. 803
    Type of Medium: Online Resource
    ISSN: 1940-6207 , 1940-6215
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
    detail.hit.zdb_id: 2422346-3
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  • 3
    In: Metabolomics, Springer Science and Business Media LLC, Vol. 14, No. 3 ( 2018-3)
    Type of Medium: Online Resource
    ISSN: 1573-3882 , 1573-3890
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2018
    detail.hit.zdb_id: 2182289-X
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  • 4
    In: Cancer Epidemiology, Biomarkers & Prevention, American Association for Cancer Research (AACR), Vol. 28, No. 1 ( 2019-01-01), p. 76-82
    Abstract: Adiposity has been linked to both risk and prognosis of colorectal cancer; however, the impact of different fat areas [visceral (VFA) vs. subcutaneous fat area (SFA)] is unclear. We investigated associations between adiposity and biomarkers of inflammation and angiogenesis among patients with colorectal cancer. Methods: Preoperative serum samples and computed tomography scans were obtained from 188 patients diagnosed with primary invasive stage I–IV colorectal cancer enrolled in the ColoCare Study. Adiposity was assessed by area-based quantification of VFA, SFA, and VFA:SFA ratio on spinal levels L3/L4 and L4/L5. Circulating levels of inflammation (CRP, SAA, sICAM-1, and sVCAM-1) and angiogenesis (VEGF-A and VEGF-D) were assessed from patient sera on the Meso Scale Discovery platform. Partial correlations and regression analyses, adjusted for age, sex, and tumor stage, were performed. Results: VFA was moderately correlated with CRP and SAA (CRP: L3/L4 and L4/L5:r = 0.21, P = 0.01; SAA: L3/L4:r = 0.17, P = 0.04). The correlation between SFA and the measured biomarkers were weak (r ≤ 0.13, not significant). The ratio of VFA:SFA at L3/L4 was moderately correlated with VEGF-A (r = 0.28, P = 0.0008) and SAA (r = 0.24, P = 0.006), and less so with CRP (r = 0.18, P = 0.04) and sICAM-1 (r = 0.18, P = 0.04). Similar correlations were found for the VFA:SFA ratio at L4/L5. Conclusions: We observed an association between visceral adiposity and biomarkers of inflammation and angiogenesis in colorectal cancer. In particular, the VFA:SFA ratio was correlated with circulating levels of the proangiogenic biomarker VEGF-A. Impact: Our findings support a direct association of visceral adipose tissue with inflammatory and angiogenic processes, which play fundamental roles in the development and progression of colorectal cancer.
    Type of Medium: Online Resource
    ISSN: 1055-9965 , 1538-7755
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
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  • 5
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 77, No. 13_Supplement ( 2017-07-01), p. 5325-5325
    Abstract: BACKGROUND Obesity is associated with colorectal cancer (CRC) risk and prognosis. We investigated associations between plasma metabolites and multiple dimensions of body fatness in early- and late-stage CRC patients enrolled in the ColoCare Study, a multicenter international cohort. METHODS Pre-operatively collected plasma samples of newly diagnosed CRC patients [n=212; (stage I-IV)] from the ColoCare Study were utilized to perform targeted metabolomics by mass spectrometry using the AbsoluteIDQ p180 Kit assay (Biocrates; intra-plate CVs & lt;20%, inter-plate CVs & lt;20%) as part of the MetaboCCC consortium. Abdominal adipose tissue (AT) was assessed by area-based quantification of visceral (VAT), and subcutaneous AT (SAT), as well as their ratio (VAT:SAT) on levels L3/L4 and L4/L5. Body mass index (BMI) was calculated (kg/m2). Demographic and clinical data were abstracted from medical records. Partial correlations and regression analyses were used, adjusting for age, sex, batch, stage overall and in stratified analyses by early- (I/II; n=111) and late-stage (III/IV; n=101) and corrected for multiple hypotheses testing (FDR). We used Cox proportional hazard models to investigate overall survival (OS) after 24 months of follow-up. RESULTS A total of 127 metabolites from 5 different compound classes (i.e., amino acids, biogenic amines, glycerophospholipids, sphingomyelins, acylcarnitines) were included for statistical analysis. Overall obesity (BMI) and VAT were not associated with any metabolites in early-stage or late-stage tumors. SAT (L3/L4 and L4/L5) was inversely associated with 3 glycerophospholipids in analyses restricted to late-stage, but not early-stage tumors: PC-ae-C34_0 (pFDR=0.02), PC-ae-C36_0 (pFDR=0.03), PC-ae-C36_1 (pFDR=0.03). A doubling of concentration in selected glycerophospholipids was associated with a significant increase in risk for death in late-stage (III and IV) CRC. CONCLUSIONS We observed a negative association between subcutaneous abdominal adiposity and glycerophospholipids in late-stage CRC. Glycerophospholipids are major components of cellular membranes and are pertinent to cancer cells that undergo progression and metastasis. Our results suggest that a metabolic shift in glycerophospholipid metabolism in late-stage tumors may take place and have potential impact on survival. Note: This abstract was not presented at the meeting. Citation Format: Jennifer Ose, Tengda Lin, Nina Habermann, David Achaintre, Pekka Keski-Rahkonen, Augustin Scalbert, Juergen Boehm, Biljana Gigic, Dominique Scherer, Johanna Nattenmueller, Mariam Salou, Lin Zielske, Alexis Ulrich, Jewel Samadder, Hanno Glimm, Stephen Hursting, Hans-Ulrich Kauczor, Cornelia M. Ulrich. Associations between adipose tissue compartments and the plasma metabolome in colorectal cancer patients: Results from the ColoCare Study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5325. doi:10.1158/1538-7445.AM2017-5325
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2017
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  • 6
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 78, No. 13_Supplement ( 2018-07-01), p. 5249-5249
    Abstract: Adipose tissue has recently emerged as a driver of tumorigenesis, as adipose-associated factors enhance tumor growth and development. Here we investigated for the first time direct crosstalk between visceral adipose tissue (VAT) and tumor tissues in colorectal cancer (CRC) patients. We analyzed paired transcriptomic profiles of tissues and systemic inflammatory biomarkers among CRC patients to elucidate potential mechanisms and molecular signals driving the host-tumor interaction. Paired presurgery blood and tumor adjacent VAT, colorectal tumor and mucosa tissue samples collected during surgery were obtained from 47 Caucasian patients diagnosed with microsatellite-stable primary CRC enrolled in the ColoCare Study. Clinical/demographic information, and lifestyle-related risk factors, were reported. VAT was quantified by computed tomography. RNA was extracted from VAT, colorectal tumor and mucosa tissues, analyzed using HumanHT-12 Expression BeadChips, processed, and validated. Serum-based assays were conducted in 46 of 47 patients for systemic inflammatory markers with the Mesoscale Discovery Platform. High PTGS2 tumor expression was associated with 131 significantly altered VAT genes, of which 85.5% were upregulated. A significant upstream regulator of dysregulated VAT genes was SAA1. Investigation of circulating inflammatory biomarkers corroborated these transcriptomic findings, as patients with high PTGS2 tumor expression were also significantly more likely to have higher serum-based SAA levels. The differential expression of PPAR-γ in VAT identified 284 significantly altered tumor genes. 71.8% of tumor genes were upregulated in association with higher PPAR-γ VAT expression. Differentially expressed tumor genes were enriched in functional cellular movement. Inflammatory biomarkers in patient sera showed marginally significant differences for soluble ICAM-1 in association with differential PPAR-γ VAT expression. Overlap of the 131 altered VAT genes associated with differential PTGS2 tumor expression with the 284 dysregulated tumor genes associated with differential PPAR-γ VAT expression identified 15 common genes. Gene set enrichment analysis demonstrated that phenotypes associated with these genes in humans included cancer invasiveness signatures from tumor microenvironment interactions. Our multi-omics profiling of paired tissue transcriptomics and systemic inflammatory biomarkers from CRC patients established a bidirectional link between VAT and colorectal tumor tissue. We have demonstrated that this direct crosstalk activates signaling cascades to promote proinflammatory interactions and metabolic reprogramming. Future efforts to develop mechanism-based interventions that disrupt these molecular signals at the nexus of VAT-tumor crosstalk may improve obesity-driven CRC prevention and control. Citation Format: Andreana N. Holowatyj, Mariam Haffa, Tengda Lin, Biljana Gigic, Jennifer Ose, Christy Warby, Caroline Himbert, Clare Abbenhardt, Juergen Boehm, Magnus von Knebel Doeberitz, Nina Habermann, Esther Herpel, Hans-Ulrich Kauczor, Matthias Kloor, Johanna Nattenmüller, Peter Schirmacher, Martin Schneider, Petra Schrotz-King, Thomas Simon, Alexis Ulrich, Laura Bowers, Stephen D. Hursting, Cornelia M. Ulrich. Crosstalk between visceral adipose and tumor tissue in colorectal cancer patients: Molecular signals driving host-tumor interaction [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5249.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
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  • 7
    In: Nutrients, MDPI AG, Vol. 12, No. 5 ( 2020-04-28), p. 1247-
    Abstract: Background: Obesity, defined by body mass index (BMI), measured at colorectal cancer (CRC) diagnosis has been associated with postoperative complications and survival outcomes. However, BMI does not allow for a differentiation between fat and muscle mass. Computed tomography (CT)-defined body composition more accurately reflects different types of tissue and their associations with health-related quality of life (HRQoL) during the first year of disease, but this has not been investigated yet. We studied the role of visceral and subcutaneous fat area (VFA and SFA) and skeletal muscle mass (SMM) on longitudinally assessed HRQoL in CRC patients. Methods: A total of 138 newly diagnosed CRC patients underwent CT scans at diagnosis and completed questionnaires prior to and six and twelve months post-surgery. We investigated the associations of VFA, SFA, and SMM with HRQoL at multiple time points. Results: A higher VFA was associated with increased pain six and twelve months post-surgery (β = 0.06, p = 0.04 and β = 0.07, p = 0.01) and with worse social functioning six months post-surgery (β = −0.08, p = 0.01). Higher SMM was associated with increased pain twelve months post-surgery (β = 1.03, p 〈 0.01). Conclusions: CT-quantified body composition is associated with HRQoL scales post-surgery. Intervention strategies targeting a reduction in VFA and maintaining SMM might improve HRQoL in CRC patients during the first year post-surgery.
    Type of Medium: Online Resource
    ISSN: 2072-6643
    Language: English
    Publisher: MDPI AG
    Publication Date: 2020
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  • 8
    In: The Journal of Clinical Endocrinology & Metabolism, The Endocrine Society, Vol. 104, No. 11 ( 2019-11-01), p. 5225-5237
    Abstract: Adipose tissue inflammation and dysregulated energy homeostasis are key mechanisms linking obesity and cancer. Distinct adipose tissue depots strongly differ in their metabolic profiles; however, comprehensive studies of depot-specific perturbations among patients with cancer are lacking. Objective We compared transcriptome profiles of visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) from patients with colorectal cancer and assessed the associations of different anthropometric measures with depot-specific gene expression. Design Whole transcriptomes of VAT and SAT were measured in 233 patients from the ColoCare Study, and visceral and subcutaneous fat area were quantified via CT. Results VAT compared with SAT showed elevated gene expression of cytokines, cell adhesion molecules, and key regulators of metabolic homeostasis. Increased fat area was associated with downregulated lipid and small molecule metabolism and upregulated inflammatory pathways in both compartments. Comparing these patterns between depots proved specific and more pronounced gene expression alterations in SAT and identified unique associations of integrins and lipid metabolism–related enzymes. VAT gene expression patterns that were associated with visceral fat area poorly overlapped with patterns associated with self-reported body mass index (BMI). However, subcutaneous fat area and BMI showed similar associations with SAT gene expression. Conclusions This large-scale human study demonstrates pronounced disparities between distinct adipose tissue depots and reveals that BMI poorly correlates with fat mass–associated changes in VAT. Taken together, these results provide crucial evidence for the necessity to differentiate between distinct adipose tissue depots for a correct characterization of gene expression profiles that may affect metabolic health of patients with colorectal cancer.
    Type of Medium: Online Resource
    ISSN: 0021-972X , 1945-7197
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    Language: English
    Publisher: The Endocrine Society
    Publication Date: 2019
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  • 9
    In: Cancer Epidemiology, Biomarkers & Prevention, American Association for Cancer Research (AACR), Vol. 26, No. 5_Supplement ( 2017-05-01), p. A26-A26
    Abstract: Background: Adiposity has been linked to both risk and prognosis of colorectal cancer; however, the impact of different compartments of adipose tissue (visceral vs. subcutaneous) is unclear. In healthy individuals, adiposity is associated with elevated biomarkers of inflammation, which provides a mechanistic link between adiposity and cancer risk. For prognosis, the downstream effects of inflammation on angiogenesis may be central. We investigated associations between adiposity and biomarkers of inflammation, as well as angiogenesis, in colorectal cancer patients enrolled in the ColoCare Study, an international multicenter patient cohort. Methods: We utilized preoperatively obtained serum samples of patients with newly diagnosed colorectal cancer [n=164; (stage I-IV)] from the ColoCare Study in Heidelberg, Germany, with available diagnostic multi-detector-CT images for adipose tissue quantification. Abdominal adipose tissue was assessed by area-based quantification of visceral (VAT), and subcutaneous adipose tissue (SAT), as well as their ratio (VAT/SAT) on levels L3/L4 and L4/L5. Body mass index (BMI) was calculated (kg/m2) and demographic and clinical-surgical data were abstracted from medical records. Circulating CRP, SAA, VEGF-A, VEGF-D, sICAM-1 and sVCAM-1 levels were assessed on the Meso Scale Discoveries platform with V-plex assays at the Huntsman Cancer Institute (average intra-plate CVs 2.9%, inter-plate CVs 7.9%). Partial correlations and regression analyses, adjusting for age, sex and tumor stage were performed. Results: While overall obesity (BMI) was only significantly associated with sVCAM (r=0.23, p=0.006), visceral adiposity (VAT) was associated with both CRP and SAA (r=0.21, p=0.01 and r=0.17, p=0.04, respectively). There was no association between SAT and the measured biomarkers. Most predictive was the ratio of VAT/SAT on level L3/L4, which was associated with CRP (r=0.18, p=0.04), SAA (r=0.24, p=0.006), sICAM-1 (r=0.18, p=0.04), and particularly VEGF-A (r=0.28, p=0.0008). Similar associations were observed for the VAT/SAT ratio on level L4/5. Conclusions: We demonstrated a link between specifically visceral adiposity and biomarkers of inflammation in colorectal cancer patients. In addition, we showed that visceral adiposity also affects circulating VEGF-A levels. This protein has various effects, including the induction of angiogenesis, vasculogenesis and endothelial cell growth, as well as the promotion of cell migration, and the inhibition of apoptosis. Our findings support a mechanistic role of visceral adipose tissue in colorectal cancer risk and potentially prognosis. Citation Format: Cornelia M. Ulrich, Jürgen Böhm, Christy Warby, Tengda Lin, Mariam Salou, Biljana Gigic, Dominique Scherer, Johanna Nattenmueller, Jennifer Ose, Lin Zielske, Petra Schrotz-King, Torsten Kölsch, Erin Siegel, Christopher Li, Alexis Ulrich, Hanno Glimm, Jewel Samadder, Stephen Hursting, Hans-Ulrich Kauczor. Body fatness and adipose tissue subtypes are associated with circulating biomarkers of inflammation and angiogenesis in colorectal cancer patients: The ColoCare Study. [abstract]. In: Proceedings of the AACR Speci al Conference: Improving Cancer Risk Prediction for Prevention and Early Detection; Nov 16-19, 2016; Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2017;26(5 Suppl):Abstract nr A26.
    Type of Medium: Online Resource
    ISSN: 1055-9965 , 1538-7755
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2017
    detail.hit.zdb_id: 2036781-8
    detail.hit.zdb_id: 1153420-5
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  • 10
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 75, No. 15_Supplement ( 2015-08-01), p. 3437-3437
    Abstract: Introduction: Abdominal surgery for tumor removal is essential in the treatment of colorectal cancer (CRC). Incisional hernias (IH) are a common long-term complication after abdominal surgery with an incidence of 9-20%. Several risk factors for developing IH have been identified, including a higher body mass index (BMI). However, it is unknown whether specific abdominal fat compartments, such as subcutaneous or visceral fat, are associated with IH occurrence. Thus, the aim of this study was to explore whether subcutaneous or visceral fat compartments might be predictors of IH occurrence in CRC patients after oncologic surgery. Methods: This study was conducted on 139 newly-diagnosed colorectal cancer patients of the prospective cohort study ColoCare (NCT, Heidelberg, Germany) who underwent oncologic surgery at the surgical clinics of the University Hospital Heidelberg. Self-administered questionnaires were used to assess hernia occurrence at 3, 6, 12 and 24 months post-surgery. BMI was calculated (kg/m^2) and abdominal fat compartments were assessed by routine computed tomography (CT) scans. The total (TFA), subcutaneous (SFA) and visceral fat area (VFA) was quantified as area (cm^2) on level L3/L4 and L4/L5. Before analyses, fat data were grouped into two categories (high vs. low) by the median. Logistic regression was used to measure the association between BMI, TFA, SFA or VFA and IH occurrence. Results: Patients were on average 61.3 (±12.5) years old with 37% being female and 63% being male. Patients were diagnosed with either colon/rectosigmoid (53%) or rectal (47%) primary cancer. CT data on abdominal fat compartments were available for 56% (n = 80) of patients as CT scans were not performed on every subject during clinical routine. BMI was a statistically significant predictor of IH occurrence after adjusting for gender and age (Wald p-value & lt;0.001, OR = 1.19). Of all fat values, only VFA on level L3/L4 was statistically significant associated with IH occurrence after adjusting for gender and age (Wald p-value & lt;0.05, OR = 2.36), while TFA and SFA on level L3/L4 and all level L4/L5 fat values were not associated with IH occurrence. Conclusion: Our findings underline BMI as a known predictive risk factor for IH. In addition, our study newly identified visceral, but not total or subcutaneous fat, as risk factors for IH. Further studies with an increased sample size are needed to test these associations in subgroups of patients, e.g. by gender or surgical procedures. In the future, these findings may help to preoperatively decide on prophylactic interventions, such as intraoperative mesh implantations, to reduce hernia occurrence. Citation Format: Jürgen Böhm, Johanna Nattenmüller, Frank Pianka, Biljana Gigic, Yesilda Balavarca, Nina Stüttgen, Petra Schrotz-King, Dominique Scherer, Alexis Ulrich, Markus K. Diener, Hans-Ulrich Kauczor, Cornelia M. Ulrich. Visceral abdominal fat is associated with incisional hernia occurrence after colorectal cancer surgery - the ColoCare Study. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3437. doi:10.1158/1538-7445.AM2015-3437
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2015
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    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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