tbuckley/cabot-search huggingface dataset:
DUX study: A phase II study of evaluating dual targeting of the EGFR using the combination of cetuximab and erlotinib in patients with chemotherapy refractory metastatic colorectal cancer.
Authors: A. J. Weickhardt, T. J. Price, N. Pavlakis, E. Skrinos, A. Dobrovic, R. Salemi, A. M. Scott, J. Mariadason, G. Chong, N. C. Tebbutt
Journal: Journal of Clinical Oncology (2010)

3533 Background: Cetuximab has proven efficacy in advanced CRC. However,the activity of cetuximab monotherapy is modest,hence further approaches are required. The combination of cetuximab (C) and erlotinib (E) has shown synergistic activity in preclinical models. This phase II study evaluated the combination of C and E in patients with advanced CRC. Methods: Eligibility included:metastatic CRC, PS 0-1, failure of prior fluoropyrimidine, oxaliplatin and irinotecan, but no previous EGFR targeted therapy, measurable disease, adequate organ function and informed consent. Treatment was: C (400 mg/m2 iv wk1 then 250 mg/m2 iv qw and E (100 mg/day po). Patients continued treatment until disease progression with CT scans q6w. Primary endpoint was response rate (RECIST) evaluated separately in KRAS wild-type versus KRAS mutant tumours. Secondary endpoints included toxicity, PFS and OS and correlation of tumour genotype (KRAS/BRAF/PI3K) with efficacy parameters. The planned sample size was 50 patients, with a 1 stage design. Results: Between October 2008 and September 2009,50 pts were enrolled. Median age was 62.7 years, males 68%. 48 patients were evaluable for response (2 withdrew from study due to rash before 6 week scan). The RR was 41% (95% CI 26-57%) in KRAS wt tumours. There were no responses in 11 patients with KRAS mutations, after which the TMC ceased recruitment of KRAS mutant tumours. No responses occurred in the 8 BRAF mutant tumours and patients who were both KRAS/BRAF wt had a RR of 52% (95% CI 34–69%). Frequent grade 3/4 toxicities were: rash 44%, hypomagnesemia 16%, fatigue 11%, and diarrhea 4%. There were no toxic deaths and 60d all cause mortality was 4% (95 CI 0–9%). PFS and OS data will be presented at the meeting. Conclusions: The combination of C and E achieves a promising RR in patients with chemotherapy refractory CRC, which is confined to patients with KRAS/BRAF wild-type tumours. EGFR related toxicity also appears somewhat higher than observed with monotherapy. This data suggests that EGFR targeted monotherapy may not completely inhibit EGFR signalling and that dual targeting of EGFR may be a valid therapeutic strategy in CRC. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Amgen, Lilly, Merck, Merck Serono, Roche ImClone Systems, Lilly, Merck, Pfizer, Roche Merck Serono, Roche Amgen, Roche
Abstract P222: Serum fibroblast growth factor-23 and risk of incident stroke: The Atherosclerosis Risk in Communities Study (ARIC)
Authors: Pamela L Lutsey, Elizabeth Selvin, Jeffrey R Misialek, Erin D Michos, Casey M Rebholz, Rebecca F Gottesman, John H Eckfeldt, Alvaro Alonso
Journal: Circulation (2014)

Background: Fibroblast growth factor-23 (FGF23), a hormone involved in phosphorous regulation and vitamin D metabolism, has been associated with risk of coronary heart disease and heart failure and is a potential target for intervention. FGF23 may influence stroke risk through several pathways: suboptimal vitamin D levels, impaired kidney function, endothelial dysfunction, and/or inflammation. We tested whether elevated FGF23 is associated with increased risk of incident stroke, independent of traditional stroke risk factors and kidney function. Methods: Biologically active intact FGF23 was measured in stored samples collected at baseline, in 1990-1992, from 12,432 stroke-free ARIC participants. Participants were followed through 2010. Incident stroke events (both ischemic and hemorrhagic) were identified during follow-up and adjudicated using medical chart review. Multivariable Cox proportional hazards regression models were used to evaluate the independent association of baseline serum FGF23 with risk of incident stroke. Results: Over a median follow-up of 19 years, 766 participants (median age 56, 24% black) developed incident stroke. A significant association of baseline FGF23 with incident stroke was only observed in the highest quintile of serum FGF23. Compared to those in the lowest quintile of FGF23, those in the highest quintile were at 37% greater risk of incident stroke (Table), after adjustment for demographics, behaviors, and body mass index. Additional adjustment for cardiovascular risk factors and eGFR categories completely attenuated the association. There was no evidence of interaction by age, sex, race, or eGFR category. Conclusions: Elevated levels of serum FGF23 were associated with modestly increased risk of incident stroke in this large, biracial, community-based cohort in minimally-adjusted models, however this association was not independent of cardiovascular risk factors and kidney function.
The synthesis and coupling of photoreactive collagen-based peptides to restore integrin reactivity to an inert substrate, chemically-crosslinked collagen
Authors: Jean-Daniel Malcor, Daniel Bax, Samir W. Hamaia, Natalia Davidenko, Serena M. Best, Ruth E. Cameron, Richard W. Farndale, Dominique Bihan
Journal: Biomaterials (2016)

Collagen is frequently advocated as a scaffold for use in regenerative medicine. Increasing the mechanical stability of a collagen scaffold is widely achieved by cross-linking using 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) and N-hydroxysuccinimide (NHS). However, this treatment consumes the carboxylate-containing amino acid sidechains that are crucial for recognition by the cell-surface integrins, abolishing cell adhesion. Here, we restore cell reactivity to a cross-linked type I collagen film by covalently linking synthetic triple-helical peptides (THPs), mimicking the structure of collagen. These THPs are ligands containing an active cell-recognition motif, GFOGER, a high-affinity binding site for the collagen-binding integrins. We end-stapled peptide strands containing GFOGER by coupling a short diglutamate-containing peptide to their N-terminus, improving the thermal stability of the resulting THP. A photoreactive Diazirine group was grafted onto the end-stapled THP to allow covalent linkage to the collagen film upon UV activation. Such GFOGER-derivatized collagen films showed restored affinity for the ligand-binding I domain of integrin α2β1, and increased integrin-dependent cell attachment and spreading of HT1080 and Rugli cell lines, expressing integrins α2β1 and α1β1, respectively. The method we describe has wide application, beyond collagen films or scaffolds, since the photoreactive diazirine will react with many organic carbon skeletons.
Randomized Phase 2 Study of Investigational, Selective Aurora a Kinase Inhibitor Alisertib (Mln8237) with Weekly Paclitaxel Vs Paclitaxel Alone in Patients (Pts) with Recurrent Ovarian Cancer (Oc)
Authors: R. Coleman, A. Roszak, K. Behbakht, I.L. Ray-Coquard, U. Matulonis, H. Liu, C. Schusterbauer, C. Dansky Ullmann
Journal: Annals of Oncology (2014)
Association between ColDx assay result and recurrence-free interval in stage II colon cancer patients on CALGB (Alliance) 9581.
Authors: Donna Niedzwiecki, Wendy Frankel, Alan Paul Venook, Xing Ye, Paula N. Friedman, Richard M. Goldberg, Robert J. Mayer, Thomas Anthony Colacchio, Richard D. Kennedy, Timothy Davison, Eamonn J. O'Brien, Jude Mulligan, Patrick G. Johnston, D. Paul Harkin, Richard L. Schilsky, Monica M. Bertagnolli, Federico Innocenti
Journal: Journal of Clinical Oncology (2014)

455 Background: Only 15-25% of pts with stage II colon cancer (CC) experience recurrence and conventional staging methods neither allow accurate identification of low (L) and high-risk (H) subgroups nor predict benefit of adjuvant chemotherapy. The ColDx assay (Almac Diagnostics) is a 634-probeset gene expression signature shown to be independently prognostic for recurrence-free interval (RFI). The objective of this study was to assess the ability of ColDx to classify stage II CC pts at L- and H-risk of relapse. Methods: This validation study was conducted using formalin fixed paraffin embedded biospecimens and clinical data from CALGB 9581, a phase III trial of edrecolomab v. observation in pts with normal risk, stage II CC. 1,454 CALGB 9,581 pts met eligibility criteria. A case-cohort sampling design was used to randomly select (RS) 514 pts from 901 eligible pts with available tissue; supplemented by 49 non-RS recurrent pts (total 563). Risk status for each pt was based on a positive or negative ColDx score using a pre-specified cutpoint, 0.4377. The Self Prentice method was used to test the association between ColDx categories and RFI (distant recurrence or death due to primary disease). Results: Initial results in 563 pts were erroneous due to a quality failure in a batch of reagent. 524 samples were re-labeled, re-ordered, and re-assayed using reagents that passed quality control (36 samples had insufficient material; 95 failed ColDx QC). Final analysis comprised 393 pts, 360 RS (58 events; 16%); 33 non-RS events. 216 pts (55%) were predicted H (62 events); 177 (45%) pts were predicted L (29 events). H pts exhibited significantly worse RFI (univariable hazard ratio (HR), 2.0; 95% CI, 1.3-3.3; p &lt; 0.01). ColDx remained significant after adjustment for prognostic factors; HR, 2.1 (95% CI, 1.3-3.4; p &lt; 0.01). Conclusions: The ColDx assay result is associated with RFI in the CALGB 9,581 sub-sample and is independent from other prognostic factors, including MSI. Further investigation is needed to establish the role of this classifier in guiding treatment decisions in this patient population.
Cancer Risk-Assessment Models: Anticipated Contributions From Biochemical Epidemiology
Authors: M Alavanja, J Aron, C Brown, J Chandler
Journal: JNCI Journal of the National Cancer Institute (1987)

Uncertainties in quantitative assessment of cancer risk limit the scientific role of this activity in the policy and regulatory debate on cancer control. Risk-assessment strategies and models are highly dependent on the nature and quality of the data available. However, accumulating laboratory and epidemiologic studies that are shedding new light on mechanisms of carcinogenesis have not yet been integrated into current risk-assessment models. Future developments in risk assessment may, therefore, be anticipated by considering the type of epidemiologic data that may soon be generated. Three important areas of epidemiologic and biochemical research should reduce some of the uncertainty in quantitative risk assessment by making it possible to: a) identify stages of the disease process through precursor lesions, biochemical markers, and to determine at which stage the carcinogen acts; b) identify subpopulations that are at enhanced or reduced susceptibility to carcinogenic influences; and c) obtain additional and refined indices of dose. Much of this research is being called “biochemical epidemiology.” Strategies for incorporating these newly generated data into regulatory decisions vary from developing new mechanistically based mathematical models to applying existing models to biologically distinct subpopulations.
Effectiveness of capecitabine plus oxaliplatin for advanced colon cancer: A public hospital experience.
Authors: Carrie Luu, Johnathan Velasquez, Amy Kaji, Bruce E. Stabile, Beverley A Petrie, Ravin Kumar, Amy Caton, Joseph Kim, Steven L. Chen, Byrne Lee
Journal: Journal of Clinical Oncology (2013)

570 Background: Adjuvant chemotherapy has been shown to improve disease-free survival (DFS) and overall survival (OS) in advanced colon cancer (CC). 5-fluorouracil (5-FU)/leucovorin and oxaliplatin is the first line therapy for stage II and III CC. Due to systematic and financial constraints imposed by administering infusional 5-FU, this agent is not available at our institution. Capecitabine plus oxaliplatin (CAPOX) has been studied by others as a possible alternative. We report our experience with CAPOX in the adjuvant treatment of CC patients in a large, public hospital. Methods: A retrospective study of 142 patients with CC who received CAPOX from 2005 to 2011 was performed. Data on patient demographics, treatment, disease recurrence, and survival were analyzed. Survival was assessed by the Kaplan-Meier method. The Cox regression model was used for multivariate analysis. Results: There were 60 female and 82 male patients with a mean age of 54 years (range 21-80). 57 patients were diagnosed with stage II CC and 85 with stage III CC. All patients with stage II and stage III disease underwent curative-intent surgical resection, except for one patient, who refused surgery. 14/141 operations (10%) were performed emergently. Mean follow-up was 36 months (range 2-85 months). The 3-year OS rates were 91% and 81% for stages II and III, respectively. The 3-year DFS rate was 74% for stage II and 66% for stage III. By multivariate analysis, only cancer stage was predictive of overall survival. Conclusions: CAPOX is an effective treatment for stage II and III CC in the adjuvant setting. Our study supports recent evidence demonstrating the efficacy of CAPOX in CC. Ease of administration and improved utilization of resources make it an ideal regimen for public hospital facilities.
HER-2/neu in tissue and serum at time of primary diagnosis of breast cancer
Authors: M. Dresse, D. Mayr, V. Heinemann, S. Kahlert, I. Bauerfeind, D. Nagel, D. Seidel, P. Stieber
Journal: Journal of Clinical Oncology (2009)

e11500 Aim: HER2 in breast cancer tissue is a marker of high prognostic and predictive relevance. Soluble HER-2, the extracellular domain of the HER-2/neu receptor which is shed into the blood, has been suggested to be a helpful tumor marker. We investigated whether there exists a relationship between the concentration of HER-2/neu Shed Antigen in serum (s-HER-2/neu) and HER- 2/neu in breast cancer tissue and whether this relationship could be used for diagnostic purposes. Patients and Methods: s-HER- 2/neu was measured at time of primary diagnosis in the pretherapeutical (presurgical) sera of 525 breast cancer patients with known HER- 2/neu-status in breast cancer tissue. 33 of the patients (6,3%) revealed to have distant metastases (M1). The HER-2/neu- status in tumor tissue was determined by immunhistochemistry, followed by subsequent FISH analysis in case of score 2+. Dako-Score 3+ or 2+ and geneamplification in FISH analysis were regarded as HER-2/neu-positive. HER-2/neu shed antigen was analysed by Immunoassay. Results: For patients without distant metastases (M0) as well as patients with distant metastases (M1) we observed a correlation of s-HER-2/neu with HER-2/neu-status. The median s-HER-2/neu-concentrations were 11.7 ng/ml (13.2 ng/ml) for the HER-2/neu-negative resp. -positive patients in the M0 group (p&lt;0,001) and 11.9 ng/ml (16,0 ng/ml) in the M1 group (p=0,01). In 492 M0-patients we performed a ROC-analysis in order to investigate the diagnostic capacity of s-HER-2/neu concerning its predictive value for the HER-2/neu-status: using a cut off value of 30 ng/ml the HER-2/neu-status was always positive, corresponding to a specificity of 100% and a sensitivity of 7.7 %. Conclusions: There is a correlation between high s-HER-2/neu-values and a positive HER-2/neu-status. Pretherapeutical s-HER- 2/neu-values ≥30 ng/ml were only observed in HER-2/neu-positive patients. HER-2/neu shed antigen in serum can add up to the HER-2/neu-status and might reveal false-negative tissue findings. [Table: see text]
Correlation of positron emission tomography (PET)-avidity in esophageal and cardiac adenocarcinomas with hypoxia-related biomarkers
Authors: A. Driessen, H. Alaerts, J. Van Riet, P. Flamen, L. Plessers, P. Nafteux, K. Haustermans, T. Lerut, L. Mortelmans, N. Ectors
Journal: Journal of Clinical Oncology (2004)

4045 Background: PET is a non-invasive diagnostic tool in oncology that reflects tissue metabolism by a variable uptake of 18F-fluoro-deoxy-D-glucose (FDG). Glucose metabolism and neovascularization are activated by hypoxia. Hypoxic tumors have a poor prognosis and poor response to radiotherapy. We aimed at correlating the avidity of PET in esophageal and cardiac carcinomas with hypoxia-related markers: glut-1 and glut-3 (glucose transporters); vascular-endothelial growth factor (VEGF), a pro-angiogenic factor; carbonic anhydrase IX (CA IX), a marker for chronic hypoxia. Methods: Our retrospective study comprised 89 patients (65 yr, 32–83 yr, M/F=4.5) treated with primary surgery. Exclusion criteria were neo-adjuvant therapy and a tumor < 1 cm on ultrasound. PET before surgery was scored: PET1 = intense hot spot (n=47), PET2 = limited positivity (n=10), PET3 = inhomogeneous labeling (n=11), PET4 = no hot spot (n=21). Immunohistochemistry was performed on formol-fixed paraffin-embedded samples of resection specimens. Antibodies used: glut-1 (Chemicon, 1/1000), glut-3 (Chemicon, 1/500), CA IX (clone M75, 1/20), VEGF (SantaCruz, 1/100). The expression of these antibodies was evaluated semi-quantitatively. Statistical analysis: Chi2-test. Results: The overall prevalence of the antibodies was: glut-1 47%, glut-3 28%, VEGF 66% and CA IX 45%. The expression varied in function of the avidity in PET. Compared to non-avide tumors (PET4), PET1-tumors showed a significantly higher prevalence of glut-1-positivity (62 % vs. 24 %, p=0.009). These tumors also expressed more frequently VEGF (72% vs. 48%), CA IX (59% vs. 33%) and glut-3 (35% vs. 19%) than non-avide tumors. PET-positive tumors show a higher expression of glut-1 (p=0.01) and VEGF (p=0.003) than non-avide tumors. Conclusions: Our study shows that there is a relationship between the FDG avidity of a tumor on PET and different hypoxic markers. Avide tumors express more frequently these biomarkers. Hence PET may be used to select patients with a more hypoxic tumor, which is associated with a poor prognosis and a poor response to radiotherapy. No significant financial relationships to disclose.
Fungi communities detected by metagenomic tools in sputum in patients with cystic fibrosis
Authors: Laura Carrasco Hernadez, Maria Abad Arranz, Carmen De la Horra Padilla, Esther Quintana Gallego, Elena Campano Cuevas, Enrique Calderon Sandubete, Jose Manuel Varela Aguilar
Journal: European Respiratory Journal (2013)

Introducction: Cystic fibrosis (CF) is the disease in which respiratory infections are the main cause of morbidity and mortality. Although bacterias are important microorganisms which usually colonize the respiratory tract, recently has been described that some uncultivable fungi may appear in these patients without knowing the long-term impact on disease progression.  Aim. Describe the fungal microbiota in CF and assess the clinical aspects related with this microbiota.  Method. 50 CF patients were incluyed. Clinical, functional data and sputum sample to study the microbiota were collected in all cases. The microbiological study was performed with a metagenomic approach that allows us to amplify the specific gene by fungal ITS polymerase chain reaction nested type and subsequent direct sequencing for isolated populations or cloning in case of obtaining more than one fungus.  Results. Metagenomics techniques detected 37 cases with some isolation of fungi, while by conventional cultivation were only 10 cases. Most were Candida sp. (64.9%) followed by Aspergillus sp. (13.5%). The use of inhaled corticosteroids was associated with the presence of fungi in sputum (51,4% vs 19,4%; p=0,011), without differences between fluticasone and budesonide. There were no differences obstruction degree, and the degree of radiographic involvement by TAC, or with chronic or intermittent colonization of various germs.  Conclusions. The colonization of fungi in the airway measured by metagenomic techniques provides information on the prevalence and factors associated with this colonization. This technique enables the detection of unknown fungi and uncultivable which currently play an unknown pathophysiological role.
Correlation between immunohistochemical biomarker expression and in vitro drug response factors in stage III-IV ovarian cancer
Authors: O. Tawfik, L. Peterson, R. Parker, E. Mechetner, M. Davis, J. Chapman, Q. Khan, J. Ma
Journal: Journal of Clinical Oncology (2007)

16055 Background: The reliability of molecular biomarkers as predictors of treatment outcome remains unclear and, in relation to drug resistance even less is known. Immunohistochemical (IHC) expression of biomarkers and in vitro drug resistance (IVDR) relative to clinical outcome were evaluated in patients with stage III-IV epithelial ovarian cancer (OC) who received combination carboplatin (CAR) plus paclitaxel (TAX) chemotherapy. Methods: We correlated clinical outcome with histopathology and biomarker expression of MIB-1, p53, BCL2, EGFR, ER and PR in 98 OC patients with tumors tested for IVDR by extreme drug resistance (EDR) assay. IVDR was determined following exposures to single agents CAR, cisplatin (CP), TAX, taxotere (TXT), gemcitabine (GCB), topotecan (TP), liposomil doxorubicin, and cytoxan (CT). Percentage cell growth inhibition (PCI) for each drug was compared with PCI from untreated control cultures. Results: Tumors with prior chemotherapy (n=29) were more resistant to CAR (unpaired t-test, p=0.046), and CT (p=0.038), and more sensitive to liposomil doxorubicin (p=0.009), compared to treatment naive tumors (n=53). For 65 tumors, there was a positive relationship between MIB-1 vs p53 (r=0.419; p=0.001), and between ER vs PR (r=0.339; p=0.011). Correlation between biomarkers and drug response showed a significantly inverse relationship between MIB-1 vs liposomil doxorubicin, p53 vs liposomil doxorubicin, EGFR vs CAR, CP, GCB and TAX; and between ER vs TXT and CT, and PR vs CT and TP. With a 53% (33/61) response rate to CAR+TAX, time to progression (TTP) for responders (R) with EGFR+ tumors was longer (median TTP 15.6 mo); and shorter for R with EGFR- tumors (p=0.008). For R and non-R, BCL2+ tumors had longer overall survival (OS) (median OS 23.3 mo; p=0.006). No other significant correlations were seen. Conclusion: Prior chemotherapy increased IVDR to CAR and CT, and increased sensitivity to liposomil doxorubicin. Increased expression of proliferation biomarkers, particularly EGFR, correlated with resistance to several chemotherapeutic agents. EGFR expression in responders was associated with longer TTP. The significance of in vitro correlates of prognostic biomarker expression and IVDR for predicting chemoresistance warrants prospective studies to assess its value in clinical settings. [Table: see text]