tbuckley/cabot-search huggingface dataset:
Anthracycline-induced cardiotoxicity in patients with early stage breast cancer: The Canadian cancer trials group (NCIC CTG) MA.21 experience.
Authors: Susan Faye Dent, Olexiy Aseyev, Mark Norman Levine, Kathleen I. Pritchard, Wendy R. Parulekar, Bingshu E. Chen, Patti O'Brien, Margot J. Burnell, Lois E. Shepherd
Journal: Journal of Clinical Oncology (2016)

1016 Background: Anthracycline containing chemotherapy (An-CT) has led to improved clinical outcomes in women with early breast cancer (EBC); however cardiotoxicity (CTox) can occur acutely or years later. We report the incidence of CTox in women with EBC who participated in a large randomized phase III trial of 3 different An-CT regimens: cyclophosphamide (C) epirubicin (E) fluorouracil (F); dose dense EC followed by paclitaxel (T); and Adriamycin (A) and C followed by T. Methods: Women (≤60 years) were randomized to one of: Arm A – CEF (E: 60mg/m2 and F days 1 and 8 x 6); Arm B - EC/T (E: 120mg/m2 q2 weeks x 6 followed by T q 3 weeks x 4); Arm C - AC/T (A: 60mg/m2q3 weeks x 4 followed by T q3 weeks x 4). Left ventricular ejection fraction (LVEF) was measured at baseline by echocardiogram (ECHO) (19%) or MUGA (81%), then yearly x 5. CTox was defined as at least 10% decline in LVEF to below 50%. Left ventricular dysfunction (LVD) was defined as: mild (LVEF 40-50%); moderate/severe (LVEF < 40%). Congestive heart failure (CHF) was reported using the NCI Common Toxicity Criteria V.2.0 - cardiac LVF Grades 3 or 4. Results: 2104 women were accrued from 12/2000-04/2005. Mean change in LVEF (0 to 5 years): Arm A (63 to 57%;p<0.0001); Arm B: (63 to 59%: P< 0.0001); Arm C: (63 to 61%; p<0.0001). Conclusions: Pts treated with An-CT remain at risk of CTox up to 5 years after completing treatment. Higher rates of An-CT-induced LVD, CHF, and CTox were observed in the dose intense E treatment arms. While the use of An-CT in BC has been declining, large numbers of women previously treated with An-CT remain at risk for late CTox. Surveillance strategies are needed to guide appropriate identification and monitoring of this patient population. Clinical trial information: NCT00014222.Cardiotoxicity in patients with EBC at 5 years after treatment. Treatment Arm A (CEF) B (EC/T) C (AC/T) No. % No % No. % No. of women 701 33.3 701 33.3 702 33.3 Compliance with LVEF monitoring 575 82.0 589 84.0 548 78.0 Cardiotoxicity (p<0.0001) 38 6.6 24 4.1 7 1.3 Left Ventricular Dysfunction (LVD) Mild LVD (p<0.0001) 48 11.9 31 7.6 13 3. 4 Moderate/severe LVD(p=0.60) 4 0.9 2 0.5 2 0.6 Congestive Heart Failure (CHF) During treatment (p=0.87) 3 0.4 2 0.3 2 0.3 Delayed (p=0.0005) 21 3.0 5 0.7 6 0.9
C/EBPβ Is Upregulated Through STAT5 and Accelerates Exhaustion of Leukemic Stem Cells During BCR-ABL-Mediated Myeloid Expansion
Authors: Yoshihiro Hayashi, Hideyo Hirai, Hisayuki Yao, Satoshi Yoshioka, Akihiro Tamura, Yasuo Miura, Eishi Ashihara, Yoshihide Fujiyama, Daniel G. Tenen, Taira Maekawa
Journal: Blood (2012)
Abstract 220: SR4 uncouples mitochondrial oxidative-phosphorylation, modulates AMPK-mTOR signaling, and inhibits proliferation of HepG2 hepatocarcinoma cells
Authors: Sharad S. Singhal, James Figarola, Jyotsana Singhal, Joshua Tompkins, David Horne, Sanjay Awasthi, Arthur Riggs
Journal: Cancer Research (2016)

Abstract Mitochondrial oxidative phosphorylation produces most of the energy in aerobic cells by coupling respiration with the production of ATP. Mitochondrial uncouplers, which reduce the proton gradient across the mitochondrial inner membrane, create a futile cycle of nutrient oxidation without generating ATP. Regulation of mitochondrial dysfunction and associated cellular bioenergetics has been recently identified as promising targets for anticancer therapy. Here, we show that SR4 is a novel mitochondrial uncoupler that causes dose-dependent increase in mitochondrial respiration and dissipation of mitochondrial membrane potential (MMP) in HepG2 hepatocarcinoma cells. These effects were reversed by the recoupling agent 6-ketocholestanol, but not cyclosporin A, and were non-existent in mitochondria-DNA depleted HepG2 (po) cells. In isolated mouse liver mitochondria, SR4 similarly increased oxygen consumption independent of adenine nucleotide translocase (ANT) and uncoupling proteins, decreases MMP, and promotes swelling of valinomycin-treated mitochondria in potassium acetate media. Mitochondrial uncoupling in HepG2 cells by SR4 results in the reduction of cellular ATP production, increased ROS production, activation of the energy-sensing enzyme AMPK, and inhibition of acetyl-CoA carboxylase and mammalian target of rapamycin (mTOR) signaling pathways, leading to cell cycle arrest and apoptosis. Global analysis of SR4-associated differential gene expression confirms these observations, including significant induction of apoptotic genes and down regulation of cell cycle, mitochondrial and oxidative-phosphorylation pathway transcripts at 24 h post treatment. Collectively, our studies demonstrate that SR4's previously reported indirect activation of AMPK and in-vitro anticancer properties, as well as its beneficial effects in both animal xenograft and obese mice models could be a direct consequence of its mitochondrial uncoupling activity (Supported by NIH grant CA 77495 and Beckman Research Institute of the City of Hope). Citation Format: Sharad S. Singhal, James Figarola, Jyotsana Singhal, Joshua Tompkins, David Horne, Sanjay Awasthi, Arthur Riggs. SR4 uncouples mitochondrial oxidative-phosphorylation, modulates AMPK-mTOR signaling, and inhibits proliferation of HepG2 hepatocarcinoma cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 220.
Abstract 5110: The role of autophagy in the tumor microenvironment
Authors: Christopher M. Dower, Hong-Gang Wang
Journal: Cancer Research (2016)

Abstract The tumor microenvironment (TME) is a complex and dynamic breeding ground for the selection of aggressive tumor cells with an advantage of survival and metastatic potential. Autophagy has emerged as a powerful cellular process that can greatly influence how cancer cells respond to nutrient deprivation and hypoxic stress, the hallmarks of the TME. However, the physiological importance of hypoxia-regulated autophagy remains unknown. Here, we used a novel hypoxia-dependent reversible dominant-negative strategy, which allowed for physiological regulation of autophagy at the cellular level during tumor growth and metastasis and creates a heterogeneous population comprised of autophagy-competent and autophagy-deficient tumor cells. We demonstrate that the suppression of autophagy by HIF1-α dependent ULK1 inhibition within the hypoxic tumor microenvironment enhances the metastatic potential of breast cancer cells both in vitro and in vivo. Functional proteomic and transcriptome analysis indicated that the loss of hypoxia-regulated autophagy promotes metastasis through extracellular remodeling pathways, primarily through induction of the fibronectin-integrin signaling axis, along with LOX-mediated extracellular remodeling and pre-metastatic niche formation. In this way, the role of physiological hypoxia regulated autophagy was assessed for the first time in a triple negative breast cancer model. Currently, we are exploring the interplay between autophagy-competent and autophagy-deficient tumor cells within the TME, and how it relates to metastasis. Although the importance of autophagy in tumor-stromal interactions has recently become appreciated, the role autophagy plays in tumor cell-tumor cell interactions remains unknown. Through investigation of these intra-tumor cell networks, we can elucidate the precise mechanism of how physiologically-regulated autophagy in tumor cells influences the surrounding TME and tumor progression. Citation Format: Christopher M. Dower, Hong-Gang Wang. The role of autophagy in the tumor microenvironment. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5110.
Abstract 3394: Bevacizumab enhances the antitumor effect of BRAFV600E inhibition in colorectal and melanoma xenograft models
Authors: Valentina Comunanza, Davide Corà, Emanuele Middonti, Federica Di Nicolantonio, Enzo Medico, Dario Sangiolo, Federico Bussolino
Journal: Cancer Research (2016)

Abstract BRAF inhibitors (BRAFi) have shown improved response rate and overall survival (OS) compared to standard chemotherapy in metastatic melanoma. Combinations of BRAF and MEK targeted agents further improve progression-free survival (PFS) and OS when compared with single-agent BRAFi, but the development of resistance remains a major obstacle to long-term disease control. Thus, additional strategies must be exploited to increase the efficacy of BRAF-MEK blockade in metastatic melanoma and circumvent or delay the onset of resistance. We have previously demonstrated in murine xenograft models of BRAF mutant melanomas and colorectal cancers (CRC) that the vemurafenib analog, PLX4720, has cytostatic activity and induces vascular normalization by changing the pro-angiogenic program triggered by the oncogenic mutation (Bottos A et al., 2012;109(6):E353-9). We hypothesized that BRAF-targeted inhibitors could cooperate with anti-angiogenic regimens in the treatment of BRAF-mutant melanoma and colorectal tumors. Here, we demonstrated that when associated with the VEGFA neutralizing antibody bevacizumab (COMBO), PLX4720 shows enhanced anti-cancer effects and induces a de novo transcriptional signature in BRAF mutant melanoma and colorectal xenografts. Interestingly, in the COMBO, bevacizumab does not alter the improvement in blood perfusion and tumor vessel normalization observed with PLX4720 alone. Although targeted inhibition of either BRAF or VEGFA initially suppresses the tumor growth, only combined inhibition of both pathways results in an evident apoptotic effect. Furthermore, bevacizumab delays the onset of resistance to PLX4720 by recruiting macrophages with a M1-like phenotype and inducing a remodeling of the extracellular matrix. The latter is characterized by a reduction in collagen deposition and of cancer-associated fibroblasts (CAFs), known to sustain cancer progression. The effect of bevacizumab on acquired resistance to PLX4720 is transient and depends on the presence of M1 macrophages. Indeed, 3/6 xenografts treated with COMBO start re-growing after 6 weeks with a dramatic reduction of infiltrating macrophages and an increase of CAFs. Collectively, our findings offer a new perspective for the management of clinical resistance to BRAF inhibitors and offer a rationale to combine BRAFV600E inhibitors with anti-angiogenic regimens. Citation Format: Valentina Comunanza, Davide Corà, Emanuele Middonti, Federica Di Nicolantonio, Enzo Medico, Dario Sangiolo, Federico Bussolino. Bevacizumab enhances the antitumor effect of BRAFV600E inhibition in colorectal and melanoma xenograft models. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3394.
Modified FOLFOX6 With or Without Radiation Versus Fluorouracil and Leucovorin With Radiation in Neoadjuvant Treatment of Locally Advanced Rectal Cancer: Initial Results of the Chinese FOWARC Multicenter, Open-Label, Randomized Three-Arm Phase III Trial
Authors: Yanhong Deng, Pan Chi, Ping Lan, Lei Wang, Weiqing Chen, Long Cui, Daoda Chen, Jie Cao, Hongbo Wei, Xiang Peng, Zonghai Huang, Guanfu Cai, Ren Zhao, Zhongcheng Huang, Lin Xu, Hongfeng Zhou, Yisheng Wei, Hao Zhang, Jian Zheng, Yan Huang, Zhiyang Zhou, Yue Cai, Liang Kang, Meijin Huang, Junsheng Peng, Donglin Ren, Jianping Wang
Journal: Journal of Clinical Oncology (2016)

Total mesorectal excision with fluorouracil-based preoperative chemoradiotherapy and postoperative chemotherapy is a standard treatment of locally advanced rectal cancer. This study investigated the addition of oxaliplatin with and without preoperative radiotherapy.In this multicenter, open-label, phase III trial, we randomly assigned (1:1:1) Chinese adults (age 18 to 75 years) with locally advanced stage II/III rectal cancer to three treatments: five 2-week cycles of infusional fluorouracil (leucovorin 400 mg/m(2), fluorouracil 400 mg/m(2), and fluorouracil 2.4 g/m(2) over 48 h) plus radiotherapy (46.0 to 50.4 Gy delivered in 23 to 25 fractions during cycles 2 through 4) followed by surgery and seven cycles of infusional fluorouracil, the same treatment plus intravenous oxaliplatin 85 mg/m(2) on day 1 of each cycle (modified FOLFOX6 [mFOLFOX6]), or four to six cycles of mFOLFOX6 followed by surgery and six to eight cycles of mFOLFOX6. Random assignment was performed by using computer-generated block randomization codes. The primary end point was 3-year disease-free survival. Secondary end points of histopathologic response and toxicity are reported.A total of 495 patients were enrolled from June 2010 to February 2015; 475 were evaluable (fluorouracil-radiotherapy, n = 155; mFOLFOX6-radiotherapy, n = 157; mFOLFOX6, n = 163). In the fluorouracil-radiotherapy, mFOLFOX6-radiotherapy, and mFOLFOX6 groups, the rate of pathologic complete response (pCR) was 14.0%, 27.5%, and 6.6%, and downstaging (ypStage 0 to 1) was achieved by 37.1%, 56.4%, and 35.5% of patients, respectively. Higher toxicity and more postoperative complications were observed in patients who received radiotherapy.mFOLFOX6-based preoperative chemoradiotherapy results in a higher pCR rate than fluorouracil-based treatment. Perioperative mFOLFOX6 alone had inferior results and a lower pCR rate than chemoradiotherapy but led to a similar downstaging rate as fluorouracil-radiotherapy, with less toxicity and fewer postoperative complications.
Newborn Bilirubin Screening for Biliary Atresia
Authors: Sanjiv Harpavat, Joseph A Garcia-Prats, Benjamin L Shneider
Journal: New England Journal of Medicine (2016)

In this preliminary study at four hospitals, newborn screening for biliary atresia with a two-stage measurement of serum bilirubin levels had very high sensitivity and specificity but a low positive predictive value.
Vinflunine (VFL) in patients (pts) with metastatic transitional cell carcinoma of the urothelial tract (mTCCU): Clinical outcome and prognostic factors in a nationwide, real-life setting (MOVIE trial).
Authors: Rodolfo Passalacqua, Silvia Lazzarelli, Rodolfo Montironi, Rosa Tambaro, Ugo De Giorgi, Antonio Bernardo, Giovanni Luca Ceresoli, Gianluca Del Conte, Maddalena Donini, Elisa Iezzi, Franco Morelli, Franco Nole, Stefano Panni, Bruno Perrucci, Ermanno Rondini, Roberto Sabbatini, Manuel Sequino, Giuseppe Tonini, Paolo Andrea Zucali, Caterina Caminiti
Journal: Journal of Clinical Oncology (2016)

e16031 Background: To assess the clinical impact of VFL in pts with mTCCU and verify the prognostic factors in a large, unselected population treated according to routine clinical practice (CP). Methods: This is a retrospective, observational multicenter trial. According to the Italian Regulatory Agency Registry (AIFA), all oncological centers that treated with VFL at least 4 pts from Feb 2011 to June 2014, were invited to take part to this study. Pts must have received a previous platinum therapy and were treated with VFL according to CP. Primary objective is to test whether efficacy in terms of overall survival (OS) obtained in the registration study are confirmed in the real life setting. Sample size has been determined considering the OS obtained in the registration study, with α=0.05 and 1-β=80%, 197 pts have to be enrolled. Results: 217 pts were registered in 24 centers across all Italy. Median age was 69 yrs; 84% males; ECOG was 0,1,2 in 47%, 46%, and 7%; 21% had liver metastasis. 77% received VFL as second-line and 23% as third-line. The median number of VFL cycles was 4; 29% received an initial dose of 320 mg/m, 35% 280 mg/m and 36% a lower dose. Toxicity was manageable, 21% had a grade 3-4: neutropenia 9%, asthenia/fatigue 7%, leucopenia 2%, constipation 5%. Conclusions:The good efficacy of VFL was confirmed in this large unselected cohort treated according to routine CP. In our multivariate model ECOG PS, liver involvement and the number of involved organs were the main risk factors affecting OS. Hemoglobin level was not significant. No CR (%) PR (%) Median PFS (95% CI) Median OS (95% CI) Registration study 253 0 (0%) 16 (6%) 3.0 (2.1- 4.0) 6.9 (5.7- 8.0) Current study 217 6 (3%) 21 (10%) 3.2 (2.6- 3.7) 8.1 (6.3- 8.9) Univariate and multivariate analysis for overall survival No Median OS (95% CI) Log rank (p) HR (95% CI) p ECOG PS 0 101 9.7 (8.1-11.0) 15.3 (<0.001) 0.61 (0.45- 0.81) 0.001 N. of organs in volved =1 127 9.5 (8.0-10.6) 15.2 (<0.001) 0.66 (0.48- 0.89) 0.008 No liver involvement 171 8.6 (6.3-9.7) 11.2 (<0.001) 0.68 (0.47- 0.99) 0.045
P1335 : A randomized, controlled phase III trial of sorafenib with or without conventional transarterial chemoembolization in patients with advanced hepatocellular carcinoma (STAH)
Authors: J.-W. Park, Y.J. Kim, D.Y. Kim, S.H. Bae, J.E. Yeon, S.Y. Han, J.S. Hwang, Y.-J. Lee, J.Y. Cheong, O.S. Kwon, H.Y. Kim, H.C. Lee, J. Heo, B.H. Kim, S.W. Paik
Journal: Journal of Hepatology (2015)
Use of fresh assessment of tumor-initiating cells in pleural fluid of breast cancer patients to predict overall survival.
Authors: W. A. Woodward, E. N. Cohen, H. Gao, L. Li, C. Jimenez, S. Krishnamurthy, S. L. Tucker, M. Cristofanilli, T. A. Buchholz, J. M. Reuben
Journal: Journal of Clinical Oncology (2010)

1044 Background: The purpose of this study was to examine the association of percentage of tumor initiating cells (TICs) in malignant pleural effusions (MPE) with survival. Methods: Fresh MPE samples from 29 pts with breast cancer and MPE were analyzed for TIC markers-CD326+/EpCAM (epithelial marker), CD44+, and CD24lo (tumor-initiating markers), and CD45- (leukocyte marker)- using multicolor flow cytometry on an IRB approved protocol. Overall survival (OS) was measured from time of MPE. Univariate analyses of survival were performed using the log-rank test, and the method of Kaplan-Meier. Multivariate analyses were performed using the Cox proportional hazards model. Results: Median follow-up was 4.2 months (range 0.1-26). Eighteen patients have died of disease. Median age was 54 years (range: 32-74). Median percentage of CD326+ cells was 1.24% which contained a median TIC component of 9.5%. TIChi (> median) did not correlate with hormone receptor status, T4d disease, or pretreatment on chi-squared analysis, however mean percentage of TIC was higher in estrogen receptor (ER) negative patients (33% vs. 11%, p=0.045, t- test). On univariate analysis, actuarial 1-yr OS was 24% for TIChi vs. 77% TIClo, p=0.01. Longer time to MPE from diagnosis (56% vs. 34%, p=0.06), ER or progesterone receptor positivity (70% vs. 22% and 74% vs. 22% both p=0.01), and no prior chemotherapy (80% vs. 33%, p=0.03) were also significantly associated with differences in OS at 1 yr. Increasing percentages of TICs remained a significant predictor for worse OS on multivariate analysis. Exploratory recursive partitioning analysis using multiple gating strategies for the TIC variables (CD44+CD24lo markers on any CD326+ cells, vs. CD326 bright or dim cells as well as variables for CD326 staining independent of CD44 and CD24) leaves CD45-CD326 brightCD44+CD24lo as the only factor selected. Conclusions: Increased percentage of TICs predicted for decreased OS among patients with MPE consistent with the hypothesis that these cells mediate recurrence and death from breast cancer. A larger study is needed to validate these data and further examine correlation between the percentage of TICs and known prognostic variables. No significant financial relationships to disclose.
Abstract 1523: Cross-disciplinary methods for personalizing screening modalities for early gastric cancer intervention
Authors: Rachel Walker, Jaime Mejia, Heiko Enderling, Jose M. Pimiento, Domenico Coppola
Journal: Cancer Research (2016)

Abstract Background. Up to 80% of patients in the early stages of gastric cancer are asymptomatic, making early diagnosis and hence effective treatment challenging. The poor prognosis of patients with late diagnoses clearly necessitates the identification of markers for early detection and the development of streamlined screening protocols. This is particularly crucial in high-risk populations, for example regions in which Helicobacter Pylori infection and associated chronic inflammation, responsible for over 70% of gastric cancers worldwide, is prevalent. At present, an efficient and personalized program for early detection does not exist. Methods. Specific biomarkers for the progression of gastric cancer have been identified in preliminary studies, including CD44, Lgr5 and CD133. In retrospective tissue samples incremental increases in expression of these markers was observed during the progression from normal gastric tissue to precancerous histologic lesions such as intestinal metaplasia and ultimately dysplasia and carcinoma. We developed a mechanistic mathematical model capable of simulating these marker-positive population dynamics, calibrated using the existing clinical data. The predictive capability of the model is validated by comparison of simulated to actual marker expression patterns in an independent test cohort of endoscopic gastric biopsies taken at sequential points during individual patients’ disease progression. Results. Based on clinically obtainable, patient-specific tissue conditions, the computational model can simulate the dynamics of marker-positive cells and, when calibrated and validated with clinical data from specific patient populations, may forecast disease progression and suggest optimal screening schedules for individual patients. Conclusions. The tools of mathematical oncology have the potential to directly inform clinical screening protocols. Verified prognostic factors for disease progression can be incorporated into mathematical models to improve diagnostic accuracy and allow clinically-actionable screening optimization. This can guide personalized screening schedules according to current marker expression on a case-by-case basis to achieve more efficient prognosis and reduced healthcare costs. Citation Format: Rachel Walker, Jaime Mejia, Heiko Enderling, Jose M. Pimiento, Domenico Coppola. Cross-disciplinary methods for personalizing screening modalities for early gastric cancer intervention. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1523.