tbuckley/cabot-search huggingface dataset:
Dual effects of metformin on breast cancer proliferation in a randomized trial.
Authors: Andrea De Censi, Michael N. Pollak, Matteo Puntoni, Sara Gandini, Massimiliano Cazzaniga, Giancarlo Pruneri, Davide Serrano, Aliana Guerrieri-Gonzaga, Serena Mora, Alessandra Gennari, Harriet Ann Johansson, Valentina Aristarco, Debora Macis, Fabio Bassi, Alberto Luini, Matteo Lazzeroni, Bernardo Bonanni
Journal: Journal of Clinical Oncology (2012)

519 Background: Metformin lowers breast cancer risk in observational studies in diabetics, but evidence for its clinical activity is scanty. We studied the metformin antiproliferative effect in a pre-surgical study. Since the antidiabetic effect of metformin is heterogeneous according to obesity and insulin resistance (IR), we also determined whether its antiproliferative effect was modified by risk biomarkers. Methods: After tumor biopsy, we randomly allocated 200 non-diabetic women with breast cancer to either metformin, 850 mg/bid (n=100) or placebo (n=100) for 4 wks. The primary endpoint was the post-pretreatment change in Ki-67 between arms. We explored effect modifications by STEPP and tested biomarker thresholds that showed an interaction with treatment on Ki-67. Results: Overall, median (IQR) Ki-67 was 19 (14-31) at baseline and 21 (14-32) after 4 wks and 18 (12-29) at baseline and 20 (13-31) after 4 wks in the metformin and placebo arm, respectively with mean increase of 4.0% (95%CI, -5.6 to 14.4) on metformin versus placebo. Multivariate analyses showed an increase of Ki-67 after 4 wks placebo in the following subgroups: HOMA&gt; IR threshold, IGFBP3&gt; highest quartile, IGFBP1&lt; lowest quintile, IGFratio (IGF1/IGFBP3)&lt; median, CRP&gt; inflection point at STEPP analysis, HER2+ve tumors (versus –ve). Metformin blunted the increase of Ki-67 noted on placebo in these subgroups. Conclusions: Overall, metformin did not affect Ki-67 in most subjects with breast cancer. However, in exploratory analysis we identified subgroups of patients where metformin showed antiproliferative effect. Further studies to a personalized approach are warranted with selection of study populations. [Table: see text]
mRNA expression patterns of growth and survival related genes for identification of distinct prognostic groups in advanced pancreatic cancer patients treated with chemotherapy and an EGFR inhibitor.
Authors: George Papaxoinis, Paris A. Kosmidis, Zoi Alexopoulou, Christos Dervenis, Christos Agalianos, Epaminondas Samantas, Elpida Charalambous, Chrysoula Gkakou, Konstantine T. Kalogeras, Vassiliki Kotoula, George E. Pentheroudakis, Dimitrios G. Pectasides, George Fountzilas
Journal: Journal of Clinical Oncology (2014)

e15259 Background: The aim of the study was to examine the mRNA expression pattern of growth and survival related genes and their prognostic significance in patients with advanced pancreatic cancer by means of unsupervised hierarchical clustering. Methods: In total, 98 patients with available tumor tissue samples were included in this retrospective translational research study and were evaluated for KRAS mutational status. CCND1, AKT1, AKT2, AKT3, EGFR, MAPK1, MET, MYC, NFKB1, PTEN and FRAP1 mRNA expression was assessed in 73 patients treated with first-line gemcitabine in combination with erlotinib (N=57) or gefitinib (N=16) for advanced disease by reverse transcription-polymerase chain reaction (RT-PCR). Twenty-five patients received adjuvant gemcitabine or fluorouracil and were included in order to enrich our molecular epidemiology data. Results: At a median follow-up of 6.1 months, median progression-free and overall survival was 5 and 7 months, respectively. KRAS mutations were detected in 56 of the 80 patients examined for KRAS status and did not correlate with mRNA expression of the genes assessed by RT-PCR or significantly influenced prognosis. Clustering according to mRNA gene expression successfully distinguished tumors in four prognostically distinct groups, only in the KRAS wild-type subset. Global overexpression of the 11 genes evaluated in the present study appeared to be associated with the best prognosis, while global suppression or heterogeneous expression patterns were associated with worse survival. Conclusions: Unsupervised hierarchical clustering seems to classify tumors into prognostically distinct groups, but only in the KRAS wild-type subset. Our results need to be independently validated in larger cohorts.
Retrospective analysis of cardiac tolerability of concurrent administration of trastuzumab- and anthracycline-based regimen for breast cancer, to address one-year-term issues in LVEF.
Authors: Naoki Watanabe, Shoko Otsuka, Yoko Sasaki, Takeshi Yuasa, Ken Shimada
Journal: Journal of Clinical Oncology (2015)

e11590 Background: Patients with HER2-rich breast cancer who receive weekly paclitaxel (P) followed by q3w epirubicin at 75 mg/m2, fluorouracil, and cyclophosphamide (FEC75) and concurrent q1w trastuzumab show good cardiac tolerability. We assessed the left ventricular ejection fraction (LVEF) of these patients regularly, compared it with that of HER2-negative breast cancer patients administered P followed by FEC100, and followed these patients for one year more in order to address the longer-term issues in LVEF. Methods: From 2010 to 2014, we administered P followed by FEC75 with concurrent q1w trastuzumab to 49 patients with HER2-rich breast cancer (with H group), and P followed by FEC100 without trastuzumab to 45 patients who were HER2-negative (without H group). We routinely assessed LVEF by echocardiography at the time of initiation, after P, after FEC, and 1 year after the end of FEC, and compared them between these two groups. Results: In the with H group, LVEF was significantly reduced from the initial level (63.1%) to 60.4% at the time point “after FEC” (p = 0.007), and in the without H group, LVEF was reduced from 63.1% to 61.5%, but the difference was not significant (p = 0.376). In the with H group, LVEF had recovered to 60.9% “after 1 year”, at which time there was no significant difference between these data (vs. 61.413, p = 0.095). Two-way repeated-measures ANOVA demonstrated a significant decline in LVEF level over time (p < 0.002), but no interaction was revealed between the time course of LVEF and treatment with or without trastuzumab (p = 0.834). In addition, there was no significant difference between groups (p = 0.386). Conclusions: Weekly paclitaxel followed by FEC75 with concurrent trastuzumab is still useful and evidence of its sufficient cardiac safety is provided.
Genetic variants associated with mosaic Y chromosome loss highlight cell cycle genes and overlap with cancer susceptibility
Authors: Daniel J Wright, Felix R Day, Nicola D Kerrison, Florian Zink, Alexia Cardona, Patrick Sulem, Deborah J Thompson, Svanhvit Sigurjonsdottir, Daniel F Gudbjartsson, Agnar Helgason, J Ross Chapman, Steve P Jackson, Claudia Langenberg, Nicholas J Wareham, Robert A Scott, Unnur Thorsteindottir, Ken K Ong, Kari Stefansson, John R B Perry
Journal: Nature Genetics (2017)
Characterization of cancer family history among patients with PCa cancer.
Authors: Emma M. Ernst, Elisa M. Ledet, Joshua Schiff, Shuwen Lin, Cathryn E. Garvey, Oliver Sartor
Journal: Journal of Clinical Oncology (2017)

272 Background: Family history (FH) is a well-documented risk factor for prostate cancer (PCa). Certain cancers (Ca) are also shown to co-segregate in families. This study evaluated Ca FH in PCa patients (pts) and the impact of FH on clinical covariates. Methods: FHs were collected from 535 PCa pts at Tulane Hospital between 2015 and 2016. Incidence rates of familial Cas were analyzed. Age at diagnosis (dx), Gleason score, and the presence of metastases at any time were documented. Chi-square and the Mann-Whitney U tests were performed to identify correlations between clinical parameters and FH. Results: 435 pts (81.3%) had a Ca FH. 281 pts (52.5%) had ≥2 relatives with Ca. Rates of breast, lung, colorectal, pancreatic Ca, and leukemia FH did not vary between pts diagnosed at ≤55 and those diagnosed over 55. Pts with PCa FH were more likely than pts with no PCa FH to have an age of dx ≤55 (p= 0.0169). Median age at dx was 59 for pts with PCa FH and 64 for pts with no PCa FH. PCa FH did not affect Gleason score or the presence of metastases. Conclusions: PCa, breast, lung, and colorectal were the most common familial Cas reported. Pts with PCa FH were younger at dx than those without PCa FH. Further studies are needed to understand the co-segregation of PCa with other Cas and genetic studies are needed to clarify the mechanisms of these trends. [Table: see text]
Humanisation of a claudin-1-specific monoclonal antibody for clinical prevention and cure of HCV infection without escape
Authors: Che C Colpitts, Rajiv G Tawar, Laurent Mailly, Christine Thumann, Laura Heydmann, Sarah C Durand, Fei Xiao, Eric Robinet, Patrick Pessaux, Mirjam B Zeisel, Thomas F Baumert
Journal: Gut (2017)

<h3>Objective</h3> HCV infection is a leading cause of chronic liver disease and a major indication for liver transplantation. Although direct-acting antivirals (DAAs) have much improved the treatment of chronic HCV infection, alternative strategies are needed for patients with treatment failure. As an essential HCV entry factor, the tight junction protein claudin-1 (CLDN1) is a promising antiviral target. However, genotype-dependent escape via CLDN6 and CLDN9 has been described in some cell lines as a possible limitation facing CLDN1-targeted therapies. Here, we evaluated the clinical potential of therapeutic strategies targeting CLDN1. <h3>Design</h3> We generated a humanised anti-CLDN1 monoclonal antibody (mAb) (H3L3) suitable for clinical development and characterised its anti-HCV activity using cell culture models, a large panel of primary human hepatocytes (PHH) from 12 different donors, and human liver chimeric mice. <h3>Results</h3> H3L3 pan-genotypically inhibited HCV pseudoparticle entry into PHH, irrespective of donor. Escape was likely precluded by low surface expression of CLDN6 and CLDN9 on PHH. Co-treatment of a panel of PHH with a CLDN6-specific mAb did not enhance the antiviral effect of H3L3, confirming that CLDN6 does not function as an entry factor in PHH from multiple donors. H3L3 also inhibited DAA-resistant strains of HCV and synergised with current DAAs. Finally, H3L3 cured persistent HCV infection in human-liver chimeric uPA-SCID mice in monotherapy. <h3>Conclusions</h3> Overall, these findings underscore the clinical potential of CLDN1-targeted therapies and describe the functional characterisation of a humanised anti-CLDN1 antibody suitable for further clinical development to complement existing therapeutic strategies for HCV.
Preclinical study of c-Met inhibitor as an adjuvant treatment for hepatocellular carcinoma with macroscopic portal vein invasion.
Authors: Takashi Kokudo, Yoshinori Inagaki, Kiyoshi Hasegawa, Chikara Shirata, Katsumi Amikura, Amane Takahashi, Junichi Kaneko, Nobuhisa Akamatsu, Junichi Arita, Yoshihiro Sakamoto, Hirohiko Sakamoto, Norihiro Kokudo
Journal: Journal of Clinical Oncology (2017)

301 Background: Patients with advanced hepatocellular carcinoma (HCC) demonstrating a macroscopic portal vein tumor thrombus (PVTT) have been reported to have an extremely poor prognosis. Palliative sorafenib is the only recommended treatment option. Methods: We statistically compared the patient characteristics and surgical outcomes in HCC patients with PVTT. Among 1,611 hepatic resections, 105 cases of PVTT were identified. Microarray analysis was performed in three patients to identify gene expression changes in PVTT compared with those in the principal tumor, and the changes were validated in 20 human HCC tissues with PVTT. The human HCC cell lines HuH-7 and SKHep-1 were used for this experimental study. A subcutaneously transplanted xenograft model was employed for the in vivo study. The c-Met inhibitor SU11274 was used in both in vitro and in vivoanalyses. Results: The median survival time in patients with PVTT was 2.01 years, while that in patients without PVTT was 6.43 years; the median time to recurrence was 0.31 and 1.61 years, respectively. Microarray analysis revealed 36 genes related to PVTT. Immunohistochemistry analysis revealed that compared with the principal tumor, E-cadherin (a key regulator of cancer metastatic potential) significantly decreased in PVTT in all 20 patients. The c-Met inhibitor elevated the E-cadherin expression level in HCC cells both in vitro and in vivo. This inhibitor induced sheet formation and attenuated the migration of HCC cells. Conclusions: Although liver resection provides acceptable overall survival for patients with PVTT, the recurrence rate remains high. The c-Met inhibitor exhibits an anti-metastatic effect in vitro and in vivo and may be useful as an adjuvant treatment for PVTT.
Secretogranin III as a disease-associated ligand for antiangiogenic therapy of diabetic retinopathy
Authors: Michelle E. LeBlanc, Weiwen Wang, Xiuping Chen, Nora B. Caberoy, Feiye Guo, Chen Shen, Yanli Ji, Hong Tian, Hui Wang, Rui Chen, Wei Li
Journal: The Journal of Experimental Medicine (2017)

Diabetic retinopathy (DR) is a leading cause of vision loss with retinal vascular leakage and/or neovascularization. Current antiangiogenic therapy against vascular endothelial growth factor (VEGF) has limited efficacy. In this study, we applied a new technology of comparative ligandomics to diabetic and control mice for the differential mapping of disease-related endothelial ligands. Secretogranin III (Scg3) was discovered as a novel disease-associated ligand with selective binding and angiogenic activity in diabetic but not healthy vessels. In contrast, VEGF bound to and induced angiogenesis in both diabetic and normal vasculature. Scg3 and VEGF signal through distinct receptor pathways. Importantly, Scg3-neutralizing antibodies alleviated retinal vascular leakage in diabetic mice with high efficacy. Furthermore, anti-Scg3 prevented retinal neovascularization in oxygen-induced retinopathy mice, a surrogate model for retinopathy of prematurity (ROP). ROP is the most common cause of vision impairment in children, with no approved drug therapy. These results suggest that Scg3 is a promising target for novel antiangiogenic therapy of DR and ROP.
Predicting outcomes in patients with advanced malignancies treated on Phase 1 clinical trials.
Authors: Kit Man Wong, Dexiang Gao, Heather McCoy, Amanda Brock, Rebecca W Powell, Cindy L. O'Bryant, D. Ross Camidge, Lia Gore, Antonio Jimeno, Jennifer Robinson Diamond, Wells A. Messersmith, S. Gail Eckhardt, Stephen Leong
Journal: Journal of Clinical Oncology (2015)

2543 Background: Appropriate selection of patients fit for Phase 1 trials is critical to avoid harm and maximize the potential for benefit, yet this can be challenging. Previous studies of prognostic factors demonstrated mixed results and many were limited by small cohorts. There is no consensus on the optimal prognostication strategy. We analyzed outcomes and prognostic factors of a large cohort of Phase 1 patients treated at an academic center. Methods: 779 patients with advanced solid malignancies enrolled on Phase 1 trials from 2001-2009 at the University of Colorado were included. Baseline patient, disease and lab parameters, trial characteristics and outcomes were extracted from a prospective IRB-approved database. Associations between clinical factors and 90-day mortality (90DM), overall survival (OS), progression-free survival (PFS) and response rate (RR: CR+PR) were analyzed by multivariate Cox or logistic regression. Results: The study population had a median age of 59 (18-87) years and 49% males. Gastrointestinal (GI) cancers were most common (30%). 151 (19%) patients had ≥ 3 metastatic sites, mainly lungs (37%) and liver (33%), while 350 (45%) had > 2 prior lines of therapy. The experimental regimen consisted of: 88% targeted, 1% cytotoxic, 11% both. Median PFS and OS were 8.0 (95% CI 7.6-8.4) and 31 (95% CI 27-34) weeks, respectively. The 90DM rate was 31% and RR was 3.1%. The likelihood of 90DM was associated with high LDH ( > 2.5x upper limit of normal (ULN) vs. < ULN: adjusted odds ratio (aOR) 4.6, 95% CI 1.7-12.2) and low albumin ( < 30 vs. > 35g/L: aOR 5.1, 95% CI 3.0-8.7). Independent factors for poor OS included breast, gynecologic and GI tumors, LDH > ULN, ALP > ULN, albumin < 35g/L, and Hb < 80g/L. Shorter PFS was also predicted by these factors (except ALP), as well as > 2 prior treatments, use of targeted therapy alone and ≥ 2 agents. Addition of cytotoxics to a targeted agent significantly increased response (aOR 6.5, 95% CI 2.5-16.8). Conclusions: This single-center cohort of Phase 1 patients is characterized by a unique set of prognostic factors, some of which are consistent with prior studies. Tumor type, LDH, ALP, albumin and Hb are potential determinants of OS. Further validation of these prognostic factors is warranted.
Prediction of Allogeneic Stem Cell Transplantation Mortality in Patients with Acute Leukemia (AL) Using the AL- European Society for Blood and Marrow Transplantation (EBMT) Risk Score in the Gruppo Italiano Trapianto Di Midollo Osseo (GITMO) Data Set: A Study on Behalf of the AL Working Party (ALWP) of the EBMT and GITMO
Authors: Roni Shouval, Francesca Bonifazi, Joshua Fein, Cristina Boschini, Elena Oldani, Myriam Labopin, Roberto Raimondi, Osamah Dabash, Ron Unger, Mohamad Mohty, Alessandro Rambaldi, Arnon Nagler
Journal: Blood (2016)
Patterns of chemotherapy and survival in elderly patients with advanced bladder cancer: A large Medicare database study.
Authors: Guoqing J. Chen, Matt D. Galsky, David M. Latini, Guru Sonpavde
Journal: Journal of Clinical Oncology (2013)

4551 Background: The frequency of employment of cisplatin-based chemotherapy in elderly patients (≥66 years) presenting with advanced (unresectable or metastatic) bladder cancer is unclear. We examined the use of and overall survival (OS) with chemotherapy regimens employed in elderly patients with newly diagnosed advanced bladder cancer (ABC). Methods: SEER-Medicare linked data were used to identify incident ABC patients presenting with the following stages of bladder cancer: T4bN0M0; Any TN1–N3M0; Any T, Any N, M1 between 2004 and 2007, with claims data until 2009. Outpatient and inpatient Medicare claims data were queried for receipt and type of chemotherapy used. The descriptive analyses were performed to examine associations between chemotherapy regimen, clinical characteristics and OS. Results: A total of 1,031 patients with ABC met inclusion criteria. The median age was 74 years, 69.8% were men. 4.6% (n=47) were T4bN0M0, 55.3% (n=570) were anyT,N1-3M0 and 40.1% (n=414) were any T, any N, M1. Overall, 20.5% (n=211) received cisplatin, 26.1% (n=269) received carboplatin, 5% (n=52) received no platinum and 48.4% (n=499) received no chemotherapy. There were no differences in regimen according to gender, race, stage and age. The median OS for cisplatin, carboplatin, no platinum and no chemotherapy groups were 1.67, 1.41, 1.5 and 1.41 years, respectively (F=5.36, p&lt;0.001). Patients with Any TN1–N3M0; Any T, Any N, M1 receiving cisplatin had better OS compared to carboplatin. T4bN0M0 patients receiving carboplatin exhibited better OS relative to those receiving cisplatin, but this finding is limited by the small number of patients. Conclusions: Among patients presenting with ABC in the Medicare database aged ≥66 years, only 20.5% received cisplatin and 48.4% received no chemotherapy. Those with distant and nodal metastasis displayed better OS with cisplatin. Further analysis will control for baseline prognostic factors and comorbidities. Drug development in the ABC population, especially the elderly, should focus on chemotherapy-ineligible and cisplatin-ineligible patients.
Epirubicin/cyclophosphamide followed by docetaxel as the primary systemic therapy for locally advanced breast cancer: The final analysis of a phase II study.
Authors: Akira Hirano, Mari Kamimura, Kaoru Ogura, Akinori Hattori, Fumie Okubo, Hiroaki Inoue, Jun Kinoshita, Mariko Fujibayashi, Tadao Shimizu
Journal: Journal of Clinical Oncology (2013)

e12026 Background: The aim of this study was to evaluate the efficacy and safety of epirubicin/cyclophosphamide (EC) followed by docetaxel as the primary systemic therapy for locally advanced breast cancer. We previously reported pathological and objective response of patients receiving this treatment (Anticancer Res 28:4137-42, 2008). Another follow-up period of 5 years (5y) has since passed, and 5y overall survival (OS) and relapse-free survival (RFS) rates were determined. Methods: The primary endpoints were pathological and objective response in the breast and axilla, and toxicities. The secondary endpoints were the rate of breast-conserving surgery and the 5y OS and RFS rates. Patients with histologically diagnosed invasive breast cancer of T2-4 (&gt;3 cm) or N1-3 were included in this study. The expected rate of pCR was 25%, and the sample size was calculated using the Simon method, with a type I error of 5% and a study power of 80%. The target enrollment was estimated to be 40 evaluable patients. pCR was defined as no evidence of residual invasive cancer, either in the breast or axilla. Patients received E (90 mg/m 2 ) and C (600 mg/m 2 ) every 3 weeks for 4 cycles followed by docetaxel (70 mg/m 2 ) every 3 weeks for 4 cycles. Trastuzumab was not added to the regimen. Results: Forty-six patients were enrolled in this study. pCR were observed in 6 patients and the pCR rate was 13.0% (95% confidence interval, 3.4-22.7%). In particular, patients with HER2 positive tumor had a significantly higher rate of pCR than others (40.0% vs. 5.6%; p=0.0096). Overall, 5y OS was 93.2% and 5y RFS was 72.9%. According to ER, PgR, HER2 status, the following 4 subtypes were classified: luminal (ER and/or PgR+, HER2-; n=28), luminal-HER2 (ER and/or PgR+, HER2+; n=3), HER2 (ER and PgR-, HER2+; n=7) and triple negative (ER, PgR and HER2-; n=8). 5y OS and RFS were 96.4% and 70.6% in luminal type, 100% and 50% in luminal-HER2, 71.4% and 57.1% in HER2, 100% and 100% in triple negative, respectively. Conclusions: EC followed by docetaxel was an effective and well-tolerated treatment, and it is suggested that this treatment provides survival benefit especially for patients with triple-negative breast cancer.