tbuckley/cabot-search huggingface dataset:
Analysis of biomarkers during early phase clinical development of AMG 479, an investigational fully human monoclonal antibody antagonist of type 1 insulin-like growth factor receptor (IGF-1R)
Authors: I. McCaffery, A. Tolcher, I. Puzanov, J. Sarantopoulos, L. Rosen, H. Deng, K. Paweletz, G. Friberg
Journal: Journal of Clinical Oncology (2009)

3545 Background: AMG 479 showed anti-tumor activity in a phase 1 (P1) and phase 1b (P1b) trial (Tolcher, J Clin Oncol. 2007;25:3002; Sarantopoulos, J Clin Oncol. 2008;26:3583). We sought to identify predictive markers of response to AMG 479 in these trials by analyzing pharmacodynamic (PD) markers in serum, and expression and mutations of regulators of the IGF-1R pathway in tumors. Methods: Patients (pts) had advanced solid tumors and received AMG 479 (1–20 mg/kg Q2W) in the P1 trial or AMG 479 (6 or 12 mg/kg Q2W) + panitumumab (6 mg/kg Q2W) or gemcitabine (1,000 mg/m 2 QW) in the P1b trial. Serum levels of IGF-1 and IGFBP-3 were measured pre dose on Day -1 and post dose at various time points. In the P1 trial, we examined relationships between tumor response (by RECIST) and: 1) levels of IGF-1 and IGFBP-3 (at baseline or PD change from baseline); 2) somatic mutations in key genes (including K-ras, and PTEN) of the IGF-1R pathway (in archival tumors); and 3) expression of PTEN (measured by immunohistochemistry in archival tumors). Results: Serum IGF-1 and IGFBP-3 increased in a concentration-dependent manner between 1 and 12 mg/kg AMG 479, with an apparent plateau between 12 and 20 mg/kg AMG 479. Baseline and PD changes in IGF-1 and IGFBP-3 were not substantially different in pts with a tumor response compared with those without a tumor response. A partial response to AMG 479 was observed in a pt with an activating K-ras mutation. No responses have been observed in tumors that lack expression of PTEN. Conclusions: The PD results suggest near complete biochemical coverage at 12-mg/kg AMG 479. Our hypothesis-generating analyses suggest that: 1) pre and postdose levels of IGF-1 and IGFBP-3 do not predict response to single-agent AMG 479; 2) activating K-ras mutations do not appear to preclude responsiveness to single-agent AMG 479 (in contrast to EGFR inhibitors); 3) expression and mutations of regulators of the PI3K/Akt pathway downstream of IGF-1R activation may be useful in predicting response to AMG 479. [Table: see text]
Identification of novel candidate genes for ependymoma progression in chromosomal regions over-represented at recurrence and detected by CGH array
Authors: S. Puget, A. Valent, I. Bieche, P. Dessen, A. Kauffmann, M. Peyre, C. Dirven, C. Sainte-Rose, G. Vassal, J. Grill
Journal: Journal of Clinical Oncology (2007)

2008 Background: The biology and genetics of ependymomas remain poorly understood. As opposed to other pediatric tumors, few recurrent chromosomal abnormalities or relevant pathways have been identified. Method: In order to gain new insight into the molecular mechanisms involved in ependymoma progression, we performed BAC array-based comparative genomic hybridization (aCGH) in a series of 59 tumors at diagnosis and at relapse (42 posterior fossa and 17 supratentorial). Specific chromosomal imbalances were confirmed by FISH. Expression of candidate genes was evaluated by RT-PCR and immunohistochemistry. Results: As compared to CGH (Cancer Genet Cytogenet 2002), aCGH detected more abnormalities since 18/33 samples at diagnosis and 22/26 at recurrence showed chromosomal imbalances. Three distinct patterns were observed : no imbalance (15 at diagnosis, 4 at relapse), large and numerous imbalances (7 at diagnosis, 12 at relapse) and small and rare imbalances (11 at diagnosis, 10 at relapse). At diagnosis, absence of chromosomal imbalance was correlated with young age (p=0.034) and shorter progression-free survival (p=0.014). At relapse, patients with large and numerous imbalances had a shorter survival (p=0.026). Specific chromosomal imbalances were significantly more frequent at recurrence: 9 qter gain (54% vs 21%), 1q gain (12% vs 0%) and 6q loss (27% vs 6%). Samples were available both at diagnosis and relapse for 16 patients. Whole genome changes were towards increase of genomic abnormalities (n=10) but also simplification (n=6), the former being associated with a higher risk of death from disease (Fisher exact, p=0.03). A candidate gene strategy was focussed on the frequently gained 9qter locus. Significant overexpression compared to normal brain was identified for Tenascin-C (median 35 fold, max 220 fold, p&lt;0.0001) and Notch1 (median 6 fold, max 45 fold, p&lt;0.0001). Notch pathway analysis by RT-PCR revealed potential regulatory loops between JAG1/2 or DLL1/3 and Notch1/2. Conclusion: aCGH pattern may identify subgroups of ependymomas with respect to prognosis. Notch pathway and Tenascin-C are important regulatory genes in ependymoma progression and may represent interesting new targets for therapy. No significant financial relationships to disclose.
Breast MRI screening of women at average risk of breast cancer: An observational cohort study.
Authors: Christiane K. Kuhl, Heribert Bieling, Kevin Strobel, Claudia Leutner, Hans H Schild, Simone Schrading
Journal: Journal of Clinical Oncology (2015)

1 Background: Breast-MRI is currently recommended for screening women at high-risk of breast-cancer only. However, despite decades of mammographic-screening, breast-cancer continues to represent a major cause of cancer-death also for women at average-risk – suggesting a need for improved methods for early diagnosis also for these women. Therefore, we investigated the utility of supplemental MRI-screening of women who carry an average-risk of breast-cancer. Methods: Prospective observational cohort-study conducted in two academic breast-centers on asymptomatic women at average-risk in the usual age range for screening-mammography (40 to 70). Women underwent DCE-breast-MRI in addition to mammography every 12, 24, or 36 months, plus follow-up of 2 years to establish a standard-of-reference. We report on the supplemental-cancer-yield, interval-cancer-rate, diagnostic accuracy of screening-MRI, and biologic profiles of additional, MRI-detected breast-cancers. Results: 2120 women underwent a total 3861 MRI-studies covering 7007 women-years. Breast-cancer was diagnosed in 61/2120 women (DCIS: 20, invasive: 41), and ADH/LIN in another 21. Interval-cancer-rate was 0%, irrespective of screening interval. Forty-eight women were diagnosed with breast-cancer at prevalence-screening by MRI alone (supplemental cancer-detection-rate: 22.6 per 1000); 13 women were diagnosed with breast-cancer in 1741 incidence-screening-rounds collected over 4887 women-years. A total 12 of these 13 incident cancers were diagnosed by screening-MRI alone (supplemental-cancer-detection-rate: 6.9 per 1000), one by MRI and mammography, none by mammography alone. Supplemental-cancer-detection-rate was independent of mammographic breast-density. Invasive cancers were small (mean size: 8mm), node-negative in 93.4%, ER/PR-negative in 32.8%, and de-differentiated in 41.7% at prevalence, and 46.0% at incidence-screening. Specificity of MRI-screening was 97.1%, False-Positive-Rate 2.9%. Conclusions: MRI-screening improves detection of biologically relevant breast-cancer in women at average-risk, and reduces the interval-cancer-rate down to 0%, at a low false-positive rate.
Abstract 13123: Noncoding RNAs in Early Mouse Embryonic Stem Cell Commitment to Cardiovascular Precursors
Authors: Chiara Cencioni, Matteo Savoia, Francesco Spallotta, Carsten Kuenne, Stefan Guenther, Andreas M Zeiher, Carlo Gaetano
Journal: Circulation (2014)

Introduction:  It has been demonstrated that nitric oxide (NO) induces chromatin remodeling and, in mouse embryonic stem cells (mES), it is responsible for a decreased expression of stemness-associated genes including Oct4, Nanog, Sox2 and KLF4. During this process, NO negatively regulates the zinc-finger E-box binding homeobox 1 and 2 (ZEBs) transcription repression factors via miR-200 family members.   Hypothesis:  Objective of the present work is to understand the molecular mechanism by which NO, ZEB factors and miR-200 family cooperated to maintain stemness in mES.   Methods and Results:  In these experiments mES were cultured in 3 different conditions: 1) stem condition, achieved by “ground state” medium (DMEM + 10% FBS + 3 inhibitors: leukemia inhibitory factor (LIF); ERK inhibitor; and GSK3 inhibitor); 2) spontaneous differentiation (DMEM + 10% FBS); 3) NO-dependent mesendodermal differentiation (DMEM + 10% FBS + 250 μM NO donor DETA/NO). In the presence of NO, the combination of RNA-Seq experiments by next generation sequencing as well as targeted real time PCR expression analyses showed the presence of lineage specific mesendodermal markers and concurrent down modulation of neuroectodermal markers in mES. In addition to the up regulation of the miR-200 family that inhibited expression of mesendodermal markers, this analysis identified 4 long non-coding RNAs (LncRNAs) highly expressed in undifferentiated mES and 6 different LncRNAs up-regulated after inhibition withdrawal. One of the candidates, the LncRNA Gtl2-as, which has been recently reported to interact with the Polycomb complex, was significantly increased after exposure to NO. Moreover, a RNA-protein interaction prediction analysis identified potential binding elements for ZEB factors, suggesting a new molecular regulation pathway for control of stem cell function.   Conclusions:  Our data provide the first indication of a molecular interplay between factors ZEB1 and 2 and selected LncRNAs during mES stemness maintenance and early commitment to the mesoderm.
Abstract 9396: A Genetic Fate-Mapping Study Showing That Leukemia Inhibitory Factor Stimulates Cardiac Stem Cell-Derived Cardiomyocyte Renewal After Myocardial Infarction
Authors: Masato Kanda, Toshio Nagai, Toshinao Takahashi, Mei Lan Liu, Masakuni Tokunaga, Atsuhiko Naito, Hiroshi Akazawa, Yoshio Kobayashi, Issei Komuro
Journal: Circulation (2011)

Introduction: Recent studies have contradicted the notion that the adult heart is a terminally differentiated organ. The source of cardiac regeneration and its relation with cardio-protective drugs remain controversial. Using a genetic fate-mapping model, we examined the rate of stem cell-derived cardiomyocyte renewal, focusing on the effect of leukemia inhibitory factor (LIF) on cardiac stem cells. Methods and Results: We generated MerCreMer-LacZ mice, in which more than 99.9% of the cardiomyocytes in the left ventricular field showed positive 5-bromo-4-chloro-3-indolyl-β-D-galactoside (Xgal) staining just after tamoxifen injection. Thus, every Xgal-negative cardiomyocyte was derived from a stem or precursor cell after tamoxifen administration. During normal aging spanning 1 year, the number of Xgal-negative cardiomyocytes in the mice did not change significantly: 2 weeks, 9.8 ± 3.8 cells per section; 1 year, 9.8 ± 5.2 cells per section. In contrast, at 6 months after myocardial infarction (MI), the MI mice had more Xgal-negative cells (41.0 ± 9.3 cells per section) than the control mice (8.0 ± 2.6 cells per section; P &lt; 0.001) did. We injected the LIF plasmid or phosphate-buffered saline (PBS) at the time of MI. At 1 month after MI, the MI + LIF group (118.6 ± 51.5 cells per section) had a greater number of Xgal-negative cells than the MI + PBS group (37.0 ± 5.5 cells per section; P &lt; 0.05) did. Echocardiography showed significant recovery of functional shortening in the LIF-treated group only. To detect the source of LIF-induced cardiomyocyte renewal, we studied cardiac side population (SP) cells. SP cells were found to have LIF receptors, and the percentage of phosphorylated signal transducers and activators of transcription 3-positive and cyclin D1-positive SP cells increased after LIF stimulation in vitro. In addition, continuous 5-bromodeoxyuridine (BrdU) administration during the first week after MI resulted in 68.9% BrdU-positive SP cells in LIF-treated mice, but only 30.5% in PBS-treated mice, suggesting that LIF influenced SP cell proliferation. Conclusion: LIF may stimulate stem cell-derived cardiomyocyte regeneration in part by activating SP cells. Our findings should help provide a novel strategy for therapeutic cardiogenesis.
Germline single nucleotide polymorphisms (SNPs) in XRCC3, XRCC1, and XPD, and survival outcomes after adjuvant chemotherapy (CT) in early breast cancer (EBC) patients (pts).
Authors: E. Castro, V. Reguero, A. Garcia, R. Leno, S. Ciria, L. Mezquita, E. Sanchez, C. A. Rodriguez, R. Gonzalez, J. J. Cruz
Journal: Journal of Clinical Oncology (2010)

619 Background: Specific DNA repair pathways are responsible for the different types of DNA damage, including those caused by CT. XRCC1, XRCC3, and XPD are involved in base-excision repair, double-strand break repair, and nucleotide excision repair, respectively. Certain SNPs in these genes are common in the general population and may result in different abilities to repair CT-related DNA insults. Methods: Peripheral blood samples for DNA extraction were collected from women considered for adjuvant CT for EBC between January 1990 and February 2004. XRCC1Arg399Gln, XRCC3Thr241Met and XPDLys751Gln SNPs were studied by RT-PCR genotyping using TaqMan probes. Demographics, clinical and treatment characteristics, disease free survival (DFS) and overall survival (OS) times were collected. Associations between these SNPs and survival outcomes were analysed using Kaplan-Meier method and Cox regression model. Results: 150 women (73% postmenopausal) were included, with a median age of 62 years (range 35-91). The commonest clinico-pathological characteristics were: ductal carcinoma (84%), grade 3 (44%), luminal subtype 64% (triple-negative 16%, HER2 11%), pT2 (54%), pN+ 56% (pN1 50%). 64% of pts received adjuvant anthracyclines, 15% taxanes, and 63% hormonotherapy. Median follow-up was 62 months (range 11-228). 5-years DFS and OS rates were 70% (CI95% 63-78) and 84% (CI95% 78-90), respectively. Overall, no SNP was associated with DFS. XRCC3Met241Met was associated with longer OS (p = 0.02) in the univariate analysis. In the pts subgroup receiving anthracylines (which induce single- and double-strand DNA breaks) XRCC1Arg399Arg was associated with longer DFS (HR 0.4, CI95% 0.2-0.9) and XRCC3Met241Met with improved OS (HR 0.15, CI95% 0.02-0.99). Conclusions: Germline SNPs in XRCC3 and XRCC1 genes are associated with different outcomes in our series, likely attributable to the differential abilities to repair anthracycline-induced DNA damage. These promising findings have pharmacogenomics implications in matching particular adjuvant CT for specific EBC pts. Prospective studies to validate the impact of these SNPs are awaited. No significant financial relationships to disclose.
Randomized Phase 3 Trial of Regorafenib in Patients (Patients) with Metastatic and/or Unresectable Gastrointestinal Stromal Tumor (GIST) Progressing Despite Prior Treatment with at Least Imatinib (IM) and Sunitinib (SU) : Grid Trial
Authors: T. Nishida, P.G. Casali, P. Reichardt, Y.-K. Kang, J.-Y. Blay, H. Joensuu, R.G. Maki, P. Rutkowski, P. Hohenberger, H. Gelderblom, M.G. Leahy, M. von Mehren, P. Schoffski, M.E. Blackstein, A.L. Cesne, G. Badalamenti, J.-M. Xu, D. Laurent, I. Kuss, G.D. Demetri
Journal: Annals of Oncology (2012)
A randomized phase II study of concurrent cisplatin-radiotherapy (RT) with or without neoadjuvant chemotherapy using docetaxel and cisplatin in advanced nasopharyngeal carcinoma (NPC)
Authors: A. T. Chan, E. P. Hui, B. Ma, S. F. Leung, A. King, F. Mo, M. Lai, K. H. Yu, W. H. Kwan, B. Zee
Journal: Journal of Clinical Oncology (2005)

5544 Background: Our previous study of neoadjuvant chemotherapy followed by concurrent cisplatin-RT showed encouraging toxicity profile and disease control in advanced NPC (JCO 2004: 22: 3053–3060). This study aimed to compare the toxicities and tumor response of advanced NPC patients treated with concurrent cisplatin-RT +/− neoadjuvant docetaxel (Taxotere) and cisplatin. Methods: Previously untreated NPC of UICC 1997 stage III/IVA/IVB. Randomized (stratified by stage 3 vs 4) to (1) Neoadjuvant chemotherapy: docetaxel 75 mg/m2 and cisplatin 75 mg/m2 D1 q 3 wks x 2, followed by cisplatin 40mg/m2 weekly x 6–8 concurrent with RT (66 Gy in 2-Gy fractions), or (2) Control arm : concurrent cisplatin-RT as arm 1 without neoadjuvant chemotherapy. Planned accrual was 30 patients (pts) per arm to detect 20% difference of toxicity on one side of a 95% confidence interval. Results: From 11/2002 to 11/2004, 60 pts were randomized. Toxicity and response data of the first 53 pts are available for this analysis. Median age 48 (range 32–70). M:F=37:16. Stages: III (30), IVA (11), IVB (12). CTC grade 3/4 toxicity: (a) During neoadjuvant chemotherapy: neutropenia G3=21%, G4=75%, febrile neutropenia 14%, fatigue G3=7%, vomiting G3=7%. (b) During concurrent cisplatin-RT: (Table). Response rate to neoadjuvant chemotherapy: NP 86% (CR 22%, PR 64%), nodal 80% (CR 50%, PR 30%). Response after cisplatin-RT: (a) neoadjuvant arm: NP 100% (CR 96%, PR 4%), nodal 95% (CR 80%, PR 15%); (b) control arm: NP 100% (CR 84%, PR 16%), nodal 100% (CR 65%, PR 35%). Conclusions: Neoadjuvant docetaxel and cisplatin followed by cisplatin-RT is well tolerated although haematological toxicities were higher compared to patients who only received cisplatin-RT. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Aventis
Increased incidence of disease transformation and development of MDS/AML in Waldenstrom's macroglobulinemia (WM) patients treated with nucleoside analogues
Authors: X. P. Leleu, R. Manning, J. Soumerai, Z. R. Hunter, A. Moreau, E. Hatjiharissi, A. Roccaro, S. Adamia, C. J. Patterson, I. M. Ghobrial, S. P. Treon
Journal: Journal of Clinical Oncology (2007)

8018 Background: WM is an indolent B-cell lymphoma. NA are widely used in the treatment of WM, and are considered as appropriate first line agents for the treatment of WM (Gertz et al, Semin Oncol 2003; Treon et al, Blood 2006). Increased incidences of disease transformation and development of MDS/AML have been observed among patients with indolent B-cell malignancies receiving NA. We therefore sought to delineate the incidence for these events in a large population of WM patients treated at our institution. Methods: 326 previously treated patients with the consensus panel definition of WM, who received treatment with (n=173) or without (n=153) a NA were included in this analysis. Baseline characteristics between NA and non-NA treated patients were not significantly different and were as follows: median age 59 years; male/female ratio 1.4; median B 2 M 2.9 mg/L; serum IgM 3,000 mg/dL; BM involvement 40%; Hct 34%; WBC 5,100/ul, and PLT count 243,000/ul. For patients receiving NA, treatment consisted of either fludarabine (n=117; 68%), cladribine (n=48; 27%) or both (n=8; 5%). For non-NA treated patients, therapy included chlorambucil, rituximab, CVP, CHOP, thalidomide, and cyclophosphamide alone or in combination with rituximab, and alemtuzumab. Median follow-up of patients was 64 (range 10–270) months. Results: Among NA treated patients, 10 (5.7%) patients had transformation to an aggressive NHL (to DLBCL) (n=7; 4%) or developed MDS/AML (n=3; 1.7%). Disease transformation and development of MDS/AML occurred at a median time of 48 (range 7–114), and 48 (range 38–52) months following NA treatment, respectively. In contrast, among non-NA treated patients, only 1 patient demonstrated disease transformation (to DLBCL) at 10 months and no patients developed AML/MDS (p=0.025). Conclusions: These data demonstrate an increased incidence of disease transformation and development of MDS/AML among WM patients treated with NA. No significant financial relationships to disclose.
Analysis of palliative care studies with joint models for quality-of-life measures and survival.
Authors: Tor D Tosteson, Zhigang Li, Qian Yang, H. Robert Frost, Marie Bakitas
Journal: Journal of Clinical Oncology (2014)

41 Background: In palliative care studies, the primary outcomes are often health related quality of life measures (HRLQ). Randomized trials and prospective cohorts typically recruit patients with advanced stage of disease and follow them until death or end of the study. During this time, HRLQ measures are collected at regular intervals. The typical analysis involves comparing the means of two or more intervention or exposure groups at specific times from entry into the study. An important feature of such studies is that, by design, some patients, but not all, are likely to die during the course of the study. For instance, in the Dartmouth ENABLE II study (Bakitas et al., 2009), 60% of patients died during the study. This feature affects the interpretation of the conventional analysis of palliative care trials and suggests the need for specialized methods of analysis. Methods: We have developed a “terminal decline model” for palliative care trials that, by jointly modeling the time until death and the HRQL measures, leads to flexible interpretation and efficient analysis of the trial data (Li, Tosteson, Bakitas, 2012). Importantly, it allows the estimation of the quality of life in the months preceding death, and specifically incorporates data for patients not dying during the study. At the same time, it permits the efficient estimation and interpretation of HRQL effects as measured in the conventional analysis as the difference in HRQL at specified times from enrollment conditional on being alive. Finally, it allows the estimation of the HRQL weighted survival or quality adjusted life years (QALY). Results: Based on the terminal decline model, survival distributions are shown affect the conventional estimates of HRQL trends in palliative care trials. A direct estimate for quality of life at specified times prior to death is provided. The methods are illustrated with ENABLE II data as an approach for improving the conduct of palliative care studies. Conclusions: Proper interpretation of palliative care studies requires consideration of the joint distribution of quality of life measures and survival as in the terminal decline model.