tbuckley/cabot-search huggingface dataset:
Hormone receptor discordance between local and central pathology with RT-PCR analysis: Results from multicenter Phase III WSG-PlanB trial.
Authors: Raquel Von Schumann, Oleg Gluz, Ulrike Nitz, Michael Clemens, Kristina Luebbe, Bahriye Aktas, Marianne Just, Thomas Noesselt, Stephan Henschen, John Hackmann, Fatemeh Lorenz-Salehi, Kristin Freese, Christer Svedman, Ronald E. Kates, Hans Heinrich Kreipe, Nadia Harbeck, Cornelia Liedtke
Journal: Journal of Clinical Oncology (2015)

e11555 Background: Discordances between local and central pathology regarding ER, PR, and HER2 status may occur at varying frequencies, which may be attributable to technical factors (tissue handling, inter-observer variability) or to underlying disease heterogeneity. Our aim was to analyze local and central ER/PR status among samples acquired in a randomized clinical trial for associations with clinical and pathological parameters. Methods: PlanB accrued 3,198 patients with primary HER2- breast cancer to (i) optimize prognostication using Recurrence Score (RS) and (ii) compare adjuvant anthracycline-free (docetaxel/cyclophosphamide) to anthracycline-containing chemotherapy (EC-Doc). Recently, WSG-Plan B provided first prospective phase III survival data for Oncotype DX with 98% 3y EFS for low and intermediate risk RS. Patients were entered based on local immunohistochemistry (IHC) but also centrally tested (ER/PR, grade, Ki67). Here, discordant cases were identified, rechecked, and analyzed regarding clinical/pathological parameters including quantitative ER/PR (Oncotype DX). Results: RS and both local and central ER / PR were available in n = 2170 patients; 58 (median age 50.5y) had discordant local vs. central ER and/or PR status. Receptor discordant cases more often presented with > 3 lymph nodes (15.5% vs. 5.4%, p = 0.001), local G3 (53.4% vs. 21.8%, p < 0.001), central G3 (50.0% vs. 31.4%, 0.013), high Ki67 (81.8% vs. 50.5%, p < 0.001) and RS > 11 (94.7% vs. 81.6%, p = 0.004). Discordant cases were less frequently positive for quantitative ER (52.6% vs. 98.9%, p < 0.001) and PR (42.1% vs. 86.2%, p < 0.001) and had lower mean % central ER (7.5% vs. 91.8%, p < 0.001) and PR (21.0% vs. 62.7%, p < 0.001). Concordance between quantitative HR (Oncotype DX)and central IHC was higher than with local HR. Conclusions: Overall, excellent concordance (97.3%) was found for ER and PR between local and central pathology. Cases with discordant HR status between local and central pathology present with more aggressive biology and lower quantitative HR measurements compared to concordant HR positive disease. The clinical consequences will become apparent as follow up matures in this study. Clinical trial information: NCT01049425.
Abstract P6-09-51: The REQUITE-AB study: Validating predictive models and biomarkers of radiotherapy toxicity to reduce side-effects and improve quality of life in breast cancer patients
Authors: T Rattay, K Johnson, D Azria, J Chang-Claude, S Davidson, A Dunning, D de Ruyscher, S Guiterrez-Enriquez, P Lambin, T Rancati, B Rosenstein, P Seibold, RP Symonds, H Thierens, R Valdagni, A Vega, A Webb, F Wenz, C West, C Talbot
Journal: Cancer Research (2017)

Abstract Clinically significant side-effects from radiotherapy affect around a quarter of breast cancer patients and may impact considerably on outcomes from treatment. An increasing number of replicated genetic associations for radiotherapy toxicity are being reported[1],[2]. The international REQUITE consortium aims to validate genetic markers and clinical factors implicated in radiotoxicity. The purpose of the REQUITE-AB project is to develop an integrated set of predictors for acute radiotherapy side-effects in breast cancer patients to be used as a clinical decision-making tool. As part of the REQUITE prospective cohort study, 2,000 patients eligible for adjuvant breast radiotherapy will be recruited in nine centres across Europe and North America between April 2014 and August 2016, with centralised data management, biobanking and two years' follow-up using a standardised data collection protocol. Patient characteristics and treatment details being captured also include dose-volume histograms and DICOM files. Genotyping will take place in fall 2016. Primary endpoints are acute skin toxicity (CTC-AE v4.0) and quality-of-life (QoL) on completion of radiotherapy and at 3 months from start of radiotherapy. Secondary endpoints are late side-effects including change in breast appearance. 1,766 breast cancer patients have been recruited to date with standardized documentation of toxicity and QoL. Among patients who completed radiotherapy so far, 21.6% of patients developed grade 2 skin toxicity (brisk erythema) and 1.3% grade 3 (moist desquamation). The ability of patient, treatment and genetic variables to predict clinical outcomes and QoL will be examined. The REQUITE study includes the largest radiogenomics cohort of breast cancer patients to date recruited under a single standardised protocol. Findings of the REQUITE-AB project are likely to inform the development of interventional biomarker trials and personalise breast cancer care in the future. [1] Talbot et al, Br J Cancer, 2012; 107: 748-53. [2] Seibold et al, Int J Radiat Oncol Biol Phys, 2015; 92: 1084-92. Citation Format: Rattay T, Johnson K, Azria D, Chang-Claude J, Davidson S, Dunning A, de Ruyscher D, Guiterrez-Enriquez S, Lambin P, Rancati T, Rosenstein B, Seibold P, Symonds RP, Thierens H, Valdagni R, Vega A, Webb A, Wenz F, West C, Talbot C. The REQUITE-AB study: Validating predictive models and biomarkers of radiotherapy toxicity to reduce side-effects and improve quality of life in breast cancer patients [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-09-51.
Long-term pulmonary complications in perinatally HIV-infected youth
Authors: William T. Shearer, Denise L. Jacobson, Wendy Yu, George K. Siberry, Murli Purswani, Suzanne Siminski, Laurie Butler, Erin Leister, Gwendolyn Scott, Russell B. Van Dyke, Ram Yogev, Mary E. Paul, Ana Puga, Andrew A. Colin, Meyer Kattan
Journal: Journal of Allergy and Clinical Immunology (2017)
Direct Comparison of 4 Very Early Rule-Out Strategies for Acute Myocardial Infarction Using High-Sensitivity Cardiac Troponin I
Authors: Jasper Boeddinghaus, Thomas Nestelberger, Raphael Twerenbold, Karin Wildi, Patrick Badertscher, Janosch Cupa, Tobias Bürge, Patrick Mächler, Sydney Corbière, Karin Grimm, Maria Rubini Giménez, Christian Puelacher, Samyut Shrestha, Dayana Flores Widmer, Jakob Fuhrmann, Petra Hillinger, Zaid Sabti, Ursina Honegger, Nicolas Schaerli, Nikola Kozhuharov, Katharina Rentsch, Òscar Miró, Beatriz López, F. Javier Martin-Sanchez, Esther Rodriguez-Adrada, Beata Morawiec, Damian Kawecki, Eva Ganovská, Jiri Parenica, Jens Lohrmann, Wanda Kloos, Andreas Buser, Nicolas Geigy, Dagmar I. Keller, Stefan Osswald, Tobias Reichlin, Christian Mueller
Journal: Circulation (2017)

Background: Four strategies for very early rule-out of acute myocardial infarction using high-sensitivity cardiac troponin I (hs-cTnI) have been identified. It remains unclear which strategy is most attractive for clinical application. Methods: We prospectively enrolled unselected patients presenting to the emergency department with symptoms suggestive of acute myocardial infarction. The final diagnosis was adjudicated by 2 independent cardiologists. Hs-cTnI levels were measured at presentation and after 1 hour in a blinded fashion. We directly compared all 4 hs-cTnI–based rule-out strategies: limit of detection (LOD, hs-cTnI&lt;2 ng/L), single cutoff (hs-cTnI&lt;5 ng/L), 1-hour algorithm (hs-cTnI&lt;5 ng/L and 1-hour change&lt;2 ng/L), and the 0/1-hour algorithm recommended in the European Society of Cardiology guideline combining LOD and 1-hour algorithm. Results: Among 2828 enrolled patients, acute myocardial infarction was the final diagnosis in 451 (16%) patients. The LOD approach ruled out 453 patients (16%) with a sensitivity of 100% (95% confidence interval [CI], 99.2%–100%), the single cutoff 1516 patients (54%) with a sensitivity of 97.1% (95% CI, 95.1%–98.3%), the 1-hour algorithm 1459 patients (52%) with a sensitivity of 98.4% (95% CI, 96.8%–99.2%), and the 0/1-hour algorithm 1463 patients (52%) with a sensitivity of 98.4% (95% CI, 96.8%–99.2%). Predefined subgroup analysis in early presenters (≤2 hours) revealed significantly lower sensitivity (94.2%, interaction P =0.03) of the single cutoff, but not the other strategies. Two-year survival was 100% with LOD and 98.1% with the other strategies ( P &lt;0.01 for LOD versus each of the other strategies). Conclusions: All 4 rule-out strategies balance effectiveness and safety equally well. The single cutoff should not be applied in early presenters, whereas the 3 other strategies seem to perform well in this challenging subgroup. Clinical Trial Registration: URL: http://www.clinicaltrials.gov . Unique identifier: NCT00470587.
CME論文: 世界保健機関-本態性血小板血症における血栓症の国際予後スコア(IPSET-血栓症)の開発および検証
Authors: Barbui Tiziano, Finazzi Guido, Carobbio Alessandra, Thiele Juergen, Passamonti Francesco, Rumi Elisa, Ruggeri Marco, Rodeghiero Francesco, Randi Maria Luigia, Bertozzi Irene, Gisslinger Heinz, Buxhofer-Ausch Veronika, DE Stefano Valerio, Betti Silvia, Rambaldi Alessandro, M Vannucchi Alessandro, Tefferi Ayalew
Journal: Blood (2012)
Added Value of Serum Hormone Measurements in Risk Prediction Models for Breast Cancer for Women Not Using Exogenous Hormones: Results from the EPIC Cohort
Authors: Anika Hüsing, Renée T. Fortner, Tilman Kühn, Kim Overvad, Anne Tjønneland, Anja Olsen, Marie-Christine Boutron-Ruault, Gianluca Severi, Agnes Fournier, Heiner Boeing, Antonia Trichopoulou, Vassiliki Benetou, Philippos Orfanos, Giovanna Masala, Valeria Pala, Rosario Tumino, Francesca Fasanelli, Salvatore Panico, H. Bas Bueno de Mesquita, Petra H. Peeters, Carla H. van Gills, J. Ramón Quirós, Antonio Agudo, Maria-Jose Sánchez, Maria-Dolores Chirlaque, Aurelio Barricarte, Pilar Amiano, Kay-Tee Khaw, Ruth C. Travis, Laure Dossus, Kuanrong Li, Pietro Ferrari, Melissa A. Merritt, Ioanna Tzoulaki, Elio Riboli, Rudolf Kaaks
Journal: Clinical Cancer Research (2017)

Abstract Purpose: Circulating hormone concentrations are associated with breast cancer risk, with well-established associations for postmenopausal women. Biomarkers may represent minimally invasive measures to improve risk prediction models. Experimental Design: We evaluated improvements in discrimination gained by adding serum biomarker concentrations to risk estimates derived from risk prediction models developed by Gail and colleagues and Pfeiffer and colleagues using a nested case–control study within the EPIC cohort, including 1,217 breast cancer cases and 1,976 matched controls. Participants were pre- or postmenopausal at blood collection. Circulating sex steroids, prolactin, insulin-like growth factor (IGF) I, IGF-binding protein 3, and sex hormone–binding globulin (SHBG) were evaluated using backward elimination separately in women pre- and postmenopausal at blood collection. Improvement in discrimination was evaluated as the change in concordance statistic (C-statistic) from a modified Gail or Pfeiffer risk score alone versus models, including the biomarkers and risk score. Internal validation with bootstrapping (1,000-fold) was used to adjust for overfitting. Results: Among women postmenopausal at blood collection, estradiol, testosterone, and SHBG were selected into the prediction models. For breast cancer overall, model discrimination after including biomarkers was 5.3 percentage points higher than the modified Gail model alone, and 3.4 percentage points higher than the Pfeiffer model alone, after accounting for overfitting. Discrimination was more markedly improved for estrogen receptor–positive disease (percentage point change in C-statistic: 7.2, Gail; 4.8, Pfeiffer). We observed no improvement in discrimination among women premenopausal at blood collection. Conclusions: Integration of hormone measurements in clinical risk prediction models may represent a strategy to improve breast cancer risk stratification. Clin Cancer Res; 23(15); 4181–9. ©2017 AACR.
Inducible Loss of the Fanconi Anemia Pathway in iPSC Causes Rapid Cell Cycle Arrest and Apoptosis through ATM/ATR and p53 Signaling
Authors: Timothy M Chlon, Elizabeth E Hoskins, Sonya Ruiz-Torres, Christopher N Mayhew, Kathryn A Wikenheiser-Brokamp, Stella M. Davies, Parinda A. Mehta, Kasiani C. Myers, James M Wells, Susanne I Wells
Journal: Blood (2014)
Inter and Intra-Clonal Heterogeneity in Multiple Myeloma and Waldenstrom Macroglobulinemia
Authors: Jana Jakubikova, Danka Cholujova, Teru Hideshima, Jacob P. Laubach, Nikhil C. Munshi, Steven P. Treon, Paul Richardson, Efstathios Kastritis, David M Dorfman, Kenneth C. Anderson
Journal: Blood (2014)
Short Term Signalling Responses of the Most Primitive Subsets of Human Hematopoietic Cells Stimulated in Vitro Correlate with Their Subsequent Self-Renewal Behaviour.
Authors: David J.H.F. Knapp, Sean C. Bendall, Paul H. Miller, Alice M.S. Cheung, Suzan Imren, R. Keith Humphries, Ryan R. Brinkman, Robert A.J. Oostendorp, Garry P. Nolan, Connie J. Eaves
Journal: Blood (2012)
Low-Density Lipoprotein Receptor-Related Protein 1 (LRP1) Polymorphism 663 C&gt;T Affects Clotting Factor VIII Activity and Increases the Risk of Venous Thromboembolism.
Authors: Rainer Vormittag, Peter Bencur, Cihan Ay, Theres Tengler, Thomas Vukovich, Peter Quehenberger, Ingrid Pabinger, Christine Mannhalter
Journal: Blood (2006)
BRCA1 immunohistochemistry in high-grade serous ovarian cancers (HGS-OC) characterized for BRCA1 germ-line mutations.
Authors: David Michael Hyman, Karuna Garg, Rachel Nicole Grisham, Jasmine Bhatia, Angela G. Arnold, Carol Aghajanian, Noah D. Kauff, Douglas A. Levine, Robert A Soslow, David R. Spriggs
Journal: Journal of Clinical Oncology (2012)

5043 Background: The optimal use of BRCA1 germline testing in patients with HGS-OC is unclear. Moreover, BRCA1 germline testing does not provide information on non-germline mechanisms of BRCA1 loss. We investigated the performance of BRCA1 immunohistochemistry (IHC) testing in HGS-OC with known BRCA1 mutation status. Methods: Eligible patients had HGS-OC, underwent surgery at a single institution between 1997 and 2010, and were tested for germline BRCA1 mutations under IRB-approved protocols. FFPE tumor tissue was used in triplicate to construct a tissue microarray (TMA). Two pathologists, blinded to BRCA1 status, independently scored each sample as BRCA1 IHC present (normal) or absent (abnormal). Whole sections were stained for all samples with absent BRCA1 staining on TMA. A commercially available monoclonal antibody against BRCA1, clone MS110 from Calbiochem (OP92) was used with previously optimized conditions. Results: 123 samples (30 BRCA1 +; 93 BRCA1 wild-type) were analyzed and 47 (38%) had abnormal BRCA1 IHC. Inter-observer agreement on BRCA IHC was high (kappa=0.87). BRCA IHC had a sensitivity of 83.3% (CI: 70.0-96.7%), specificity of 76.3% (CI: 67.7-85.0%), PPV of 53.2% (CI: 38.9-67.5%), and NPV of 93.4% (CI: 87.9-99.0%) for BRCA1 germline mutation. There was a trend towards improved overall survival in the BRCA IHC abnormal vs. normal patients (median survival 82 vs 61 wks, HR 0.70, p=0.12). Conclusions: BRCA1 IHC is a reproducible and inexpensive test with a high NPV for absence of a BRCA1 germline mutation. The 22 (17.7%) cases with abnormal BRCA1 IHC and wild-type BRCA1 germline status may have other mechanisms of protein loss such as promoter hypermethylation or somatic mutation and are currently being tested for these changes. This rate of non-germline BRCA1 loss in HGS-OC is consistent with data generated by the Tumor Cancer Genome Atlas Network. BRCA1 IHC may be useful as a reliable biomarker for risk stratification in HGS-OC. [Table: see text]
Good Pregnancy Outcome in a Patient Affected by Paroxysmal Nocturnal Hemoglobinuria Treated with Eculizumab.
Authors: Valeria Coluccio, Roberto Marasca, Rita Santachiara, Giovanna Leonardi, Alessandro Ghiddi, Elisabetta Colaci, Giuseppe Torelli, Lucio Luzzatto
Journal: Blood (2009)
Abstract P6-04-01: Engineering mesenchymal stem cells(MSCs) to secrete tumour-suppressing exosomes for breast cancer therapy
Authors: KP O'Brien, S Khan, K Thompson, D Joyce, P Lalor, P Dockery, H Ingoldsby, MJ Kerin, RM Dwyer
Journal: Cancer Research (2017)

Abstract Introduction: Mesenchymal Stem Cells(MSCs) are multipotent stromal cells that are known to engraft into tumours, raising their potential as tumour-targeted delivery vehicles. MSCs secrete tiny vesicles known as exosomes, which contain genetic material including microRNAs, and are effectively taken up by recipient cells. This study aimed to characterise a tumour-suppressing microRNA, miR-379, and engineer MSCs to secrete exosomes enriched with the microRNA. Methods: The mechanism of action of miR-379 In Vivo was determined through lentivirus-mediated upregulation of miR-379 in breast tumours, and analysis of changes in tumour angiogenesis, proliferation and progression. Subsequently, MSCs were engineered with lenti-379 and any impact on MSC migration, proliferation and morphology was assessed. MSC-secreted exosomes were isolated and characterised using Transmission Electron Microscopy(TEM) and Western Blot. The exosomal microRNA content was analysed by RQ-PCR, and transfer between cell populations visualised using confocal microscopy. Results: While elevated miR-379 expression did not impact tumour size In Vivo, an increase in tumour necrosis and decrease in invasion was observed. MSCs were successfully transduced with miR-379, resulting in a distinct change in cell morphology. Despite this, MSC-379 cells maintained inherent tumour-targeted migratory capacity, with no impact on proliferation observed. MSC-379 derived exosomes were 30-120nm in size and expressed the exosome-associated protein CD63. A 5-fold increase in miR-379 was observed in engineered exosomes. Successful transfer of RFP-labelled MSC-derived exosomes to breast cancer cells was visualised using confocal microscopy. Conclusion: Engineering tumour-targeted MSCs to secrete exosomes enriched with miR-379 holds exciting potential as a novel therapy for breast cancer. Citation Format: O'Brien KP, Khan S, Thompson K, Joyce D, Lalor P, Dockery P, Ingoldsby H, Kerin MJ, Dwyer RM. Engineering mesenchymal stem cells(MSCs) to secrete tumour-suppressing exosomes for breast cancer therapy [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-04-01.
In Children With Nonalcoholic Fatty Liver Disease, Zone 1 Steatosis Is Associated With Advanced Fibrosis
Authors: Jonathan A. Africa, Cynthia A. Behling, Elizabeth M. Brunt, Nan Zhang, Yunjun Luo, Alan Wells, Jiayi Hou, Patricia H. Belt, Rohit Kohil, Joel E. Lavine, Jean P. Molleston, Kimberly P. Newton, Peter F. Whitington, Jeffrey B. Schwimmer, Stephanie H. Abrams, Sarah Barlow, Ryan Himes, Rajesh Krisnamurthy, Leanel Maldonado, Rory Mahabir, April Carr, Kimberlee Bernstein, Kristin Bramlage, Kim Cecil, Stephanie DeVore, Rohit Kohli, Kathleen Lake, Daniel Podberesky, Alex Towbin, Stavra Xanthakos, Gerald Behr, Joel E. Lavine, Jay H. Lefkowitch, Ali Mencin, Elena Reynoso, Adina Alazraki, Rebecca Cleeton, Maria Cordero, Albert Hernandez, Saul Karpen, Jessica Cruz Munos, Nicholas Raviele, Miriam Vos, Molly Bozic, Oscar W. Cummings, Ann Klipsch, Jean P. Molleston, Emily Ragozzino, Kumar Sandrasegaran, Girish Subbarao, Laura Walker, Kimberly Kafka, Ann Scheimann, Joy Ito, Mark H. Fishbein, Saeed Mohammad, Cynthia Rigsby, Lisa Sharda, Peter F. Whitington, Sarah Barlow, Theresa Cattoor, Jose Derdoy, Janet Freebersyser, Ajay Jain, Debra King, Jinping Lai, Pat Osmack, Joan Siegner, Susan Stewart, Susan Torretta, Kristina Wriston, Susan S. Baker, Diana Lopez–Graham, Sonja Williams, Lixin Zhu, Jonathan Africa, Hannah Awai, Cynthia Behling, Craig Bross, Jennifer Collins, Janis Durelle, Kathryn Harlow, Michael Middleton, Kimberly Newton, Melissa Paiz, Jeffrey B. Schwimmer, Claude Sirlin, Patricia Ugalde-Nicalo, Mariana Dominguez Villarreal, Bradley Aouizerat, Jesse Courtier, Linda D. Ferrell, Natasha Feier, Ryan Gill, Camille Langlois, Emily Rothbaum Perito, Philip Rosenthal, Patrika Tsai, Kara Cooper, Simon Horslen, Evelyn Hsu, Karen Murray, Randolph Otto, Matthew Yeh, Melissa Young, Elizabeth M. Brunt, Kathryn Fowler
Journal: Clinical Gastroenterology and Hepatology (2017)
Improved early prediction of individual prognosis for patients with mCRC: Joint modeling of tumor shrinkage with volume data for PFS and OS.
Authors: Ulrich Robert Mansmann, Ruediger Paul Laubender, Ute Sartorius, Clemens Albrecht Giessen, Anno Graser, Volker Heinemann
Journal: Journal of Clinical Oncology (2012)

3603 Background: Piessevaux et al. (ESMO 2010) proposed a decrease in RECIST-based tumor size of 20% at week 8 following 1st-line therapy for mCRC as a predictor of clinical outcome (PFS and OS). We expanded upon this idea (ASCO GI 2012). A tumor volume algorithm was developed providing a better approximation to true tumor volume by using both the longest and the longest orthogonal diameters of a target lesion. In this study we compare the quality of early prediction-based individual patient prognosis based on tumor change according to either RECIST or the tumor volume algorithm. Methods: The prognostic method is combined with the volume algorithm and applied to the data from 2 studies (OPUS, n=337; CRYSTAL, n=1198) and 4 treatment regimens (FOLFOX4 +/- cetuximab and FOLFIRI +/- cetuximab), in patients with mCRC. The influence of the treatment regimen on early PFS and OS prognosis is studied by joint modeling. The quality of early prognosis depending on the tumor size assessment used is compared by the logarithmic scoring rule. Results: Individual volume shrinkage and baseline volume are considered prognostic factors. Individual predictions depend on the chemotherapy administered and whether cetuximab is added. Equivalent tumor baseline volumes and early volume changes, predict an up to 20% higher 1 year (y) PFS and 2y OS rate for FOLFIRI than for FOLFOX. The addition of cetuximab to standard chemotherapy (CT) translates into a mean increase in shrinkage of 10% resulting in an improvement in 1y PFS rates of 23% and in 2y OS rates of 18%. The quality of individual prediction over the 4 regimens is combined in one logarithmic (log) score. The log score for the RECIST-based prediction is 2.45 which is significantly higher than that for the volume-based prediction of 1.97 (p&lt;0.0001). Lower scores correspond to a better prediction. Conclusions: The tumor volume algorithm enables a more precise prediction of individual patient PFS and OS than RECIST-based tumor assessments. Based on early tumor changes for CT, +/- cetuximab, it is possible to calculate quantitative information on a patient’s prognosis. The model has high potential to guide individual clinical decision making for mCRC patients.