tbuckley/cabot-search huggingface dataset:
Adjuvant sunitinib following chemoradiotherapy (CRT) and surgery for esophageal cancer: A phase II trial
Authors: A. M. Horgan, G. Darling, R. Wong, A. Visbal, M. Guindi, D. Jonker, G. Liu, J. Hornby, W. Xu, J. J. Knox
Journal: Journal of Clinical Oncology (2009)

e15550 Background: Locally advanced esophageal cancer (LAEC) has a 5-year survival of &lt; 30 %. Most patients (pts) fail after curative intent tri-modality treatment with distant metastatic disease. This phase II trial aims to determine if adjuvant targeted therapy, after neoadjuvant CRT plus surgery for resectable LAEC, may impact on systemic disease without significant toxicity. Methods: Pts with LAEC of the thoracic esophagus or gastroesophageal junction, ECOG PS 0,1 and surgical candidates treated with: preoperative Irinotecan (65mg/m 2 initially, ammended to 50mg/m 2 ) + Cisplatin (30mg/m 2 ) on weeks 1,2,4,5,7,8 + concurrent conformal radiotherapy (50Gy/25 fractions) on weeks 4–8. Esophagectomy during weeks 15–18. Sunitinib 37.5mg daily (escalating to 50mg daily if tolerated) commenced 4–12 weeks post surgery, for 1 year. Primary endpoint is feasibility and efficacy of adjuvant sunitinib. Planned sample size 36pts. Results: 30pts enrolled from 11/06 to 12/08. Median age 64 yr (43–71), male: 22, adenocarcinoma: squamous 22:6; 10 pts stage IIA, 5 IIB and 13 III. 2 pts excluded with positive PET scan. 28 pts completed CRT - 18 pts (64%) received ≥80% of planned chemotherapy dose, 23 pts (82%) received full radiation dose. Grade 3/4 toxicity included: neutropenia (17/28), diarrhea (7/28), dehydration (4/28), febrile neutropenia (FN) (3/28) and nausea (2/28). 2 deaths on chemotherapy (1 bacterial meningitis, 1 FN) leading to irinotecan dose- reduction. Dysphagia improved in 14/23 pts during CRT. 18 pts have undergone esophagectomy. Complete pathological response in 4 (22%), downstaging in 3 (17%), stable disease in 11 (61%). 2 pts unresectable (metastases at laparotomy). 1 post-operative death due to pulmonary embolus. 9 pts have commenced sunitinib, 6 maintained at starting dose of 37.5mg; 2 dose reductions; 1 discontinued with poor wound healing. Grade 3 toxicity included: leukopenia (2/9), hand-foot reaction (1/9) and depression (1/9). Conclusions: In LAEC, induction Irinotecan/Cisplatin and radiotherapy followed by esophagectomy is associated with a significant but manageable toxicity profile. Early initiation of sunitinib is feasible and well-tolerated. Updated results to be presented. No significant financial relationships to disclose.
Abstract 246: Transendocardial Injections of Allogeneic Mesenchymal Stem Cells Demonstrate Reversal of Left Ventricular Remodeling to Baseline
Authors: Frederic C McCall, Adam R Williams, Viky Y Suncion, Vasileios Karantalis, Juan P Zambrano, Alan W Heldman, Joshua M Hare
Journal: Circulation Research (2012)

Background: Mesenchymal stem cells (MSCs) improve ventricular function post MI Hypothesis: Transendocardial stem cell injections (TESI) reverse remodeling in a swine model of chronic ischemic cardiomyopathy (CIC). Methods: Gottingen swine (n=12), underwent a closed-chest, LAD occlusion-reperfusion model to create chronic ischemic cardiomyopathy. Three months post-MI, transendocardial injections of allogeneic MSCs (n=6) or sham injection (control group, n=6) were administered to the infarct and border zones. Cardiac MRI and pressure volume loops were obtained at baseline, during injection, and 6 months post injection. The three dimensional sphericity index (SI) was determined using the formula, SI= (π x LVLA3)/6, where LVLA is the left ventricle long axis length as measured in a 4-chamber long axis cardiac MRI end diastolic frame perpendicular to the line from the annulus of the mitral valve to the apex. Results: The sphericity index increased in both groups 3 months after MI, from 0.268 ± 0.054 to 0.348 ± 0.050 in the sham injection group and 0.277 ± 0.051 to 0.380 ± 0.059 in the TESI group. In the sham injection group, SI remained stable 9 months post sham injections indicative of irreversible remodeling post MI. In contrast, the injection group SI continued to decrease from 0.380 ± 0.059 to 0.346 ± 0.064 and 0.280 ± 0.50 at 3 and 6 months post TESI, respectively. Conclusions: Measurements of SI show that transendocardial stem cell injections of allogeneic MSCs demonstrate the potential to reverse left ventricular remodeling in CIC patients to geometric configurations comparable to their pre-MI shapes.
Abstract A2-35: Discovery of differentiation therapeutics using a systems biology approach
Authors: Yulin Li, Jun Seita, Dean Felsher, David Dill
Journal: Cancer Research (2015)

Abstract Accurately assessing the changes in cellular differentiation status in response to drug treatments or genetic manipulations is crucial for understanding the tumorigenesis process and developing novel therapeutics for human cancer. Here we have developed a novel systems biology approach, called the Lineage Maturation Index (LMI), to define the changes in differentiation state of cancer cells based on their gene expression profiles. We have been focusing on hematopoietic malignancies, but this approach is applicable to many human cancer types. We define the expression profile of N genes within a cell to be a point in an N-dimensional space. A lineage vector is derived from a progenitor cell (such as a hematopoietic stem cell) to a mature cell (such as a granulocyte) based on the expression of these N genes. By projecting the expression profile of an unknown cell onto the lineage vector, an LMI can be computed for the differentiation state of this specific cell. Upon drug treatments or genetic manipulations, a shift in LMI from stem cells towards mature cell types indicates differentiation. We have confirmed that the LMI approach can track the differentiation of normal hematopoietic cells. We have further shown that differentiation is a major consequence of various targeted therapies against leukemia irrespective of the driving oncogenes. Most importantly, we have used this approach to analyze the Connectivity Map HL60 leukemia data set for drugs that can induce leukemia cells to differentiate. In addition to drugs known to have differentiation activities (such as all-trans retinoic acid and etoposide), we discovered that several novel drugs (such as dihydroergotamine, mebendazole, and clonidine) have potent differentiation activities in leukemia cells. Currently, we are expanding our study into multiple types of solid tumors, such as breast, prostate, and colon cancers. Our LMI approach is highly robust in characterizing differentiation of the cancer cells and discovering novel differentiation therapies for human cancer. Citation Format: Yulin Li, Jun Seita, Dean Felsher, David Dill. Discovery of differentiation therapeutics using a systems biology approach. [abstract]. In: Proceedings of the AACR Special Conference on Translation of the Cancer Genome; Feb 7-9, 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 1):Abstract nr A2-35.
Abstract 18956: Loss of Gelsolin Attenuates Pressure Overload Induced Heart Failure: Novel Role of Gelsolin in Cardiac Biomechanical Stress Induced Cytoskeletal Remodeling
Authors: Vaibhav B Patel, Pavel Zhabyeyev, Ratnadeep Basu, Zamaneh Kassiri, Gavin Y Oudit
Journal: Circulation (2014)

Background: Biomechanical stress and cytoskeletal remodeling are key determinants in pressure-overload induced heart failure. Gelsolin (GSN) is a Ca2+ and polyphosphoinositide 4,5-biphosphate (PIP2)-regulated actin filament severing and capping protein, and is upregulated in failing human hearts and animal models of heart failure (HF). Hypothesis: We hypothesize that loss of gelsolin will attenuate the adverse cytoskeletal remodeling and will lead to increased resistance to the development of HF in response to pressure-overload. Methods and Results: Eight-week old male GSN null (GSNKO) mice and wildtype (WT) littermate control mice were subjected to transverse aortic constriction (TAC) induced pressure-overload. GSN expression was increased in response to 9 wks of pressure-overload in WT mice, which was associated with heart failure with reduced ejection fraction (EF). Loss of gelsolin resulted in preserved systolic function (EF: 54.6±2.07 in GSNKO-TAC vs 39.4±3.04 in WT-TAC; p0.05). Cardiomyocytes from W...
Rare loss-of-function variants in SETD1A are associated with schizophrenia and developmental disorders
Authors: Tarjinder Singh, Mitja I Kurki, David Curtis, Shaun M Purcell, Lucy Crooks, Jeremy McRae, Jaana Suvisaari, Himanshu Chheda, Douglas Blackwood, Gerome Breen, Olli Pietiläinen, Sebastian S Gerety, Muhammad Ayub, Moira Blyth, Trevor Cole, David Collier, Eve L Coomber, Nick Craddock, Mark J Daly, John Danesh, Marta DiForti, Alison Foster, Nelson B Freimer, Daniel Geschwind, Mandy Johnstone, Shelagh Joss, Georg Kirov, Jarmo Körkkö, Outi Kuismin, Peter Holmans, Christina M Hultman, Conrad Iyegbe, Jouko Lönnqvist, Minna Männikkö, Steve A McCarroll, Peter McGuffin, Andrew M McIntosh, Andrew McQuillin, Jukka S Moilanen, Carmel Moore, Robin M Murray, Ruth Newbury-Ecob, Willem Ouwehand, Tiina Paunio, Elena Prigmore, Elliott Rees, David Roberts, Jennifer Sambrook, Pamela Sklar, David St Clair, Juha Veijola, James T R Walters, Hywel Williams, Patrick F Sullivan, Matthew E Hurles, Michael C O'Donovan, Aarno Palotie, Michael J Owen, Jeffrey C Barrett
Journal: Nature Neuroscience (2016)
Assessment of tumour size and its relationship to nodal involvement in multifocal and multicentric breast cancer
Authors: A. Rezo, K. Rodins, A. J. Davis, B. Shadbolt, Y. Zhang, F. Huynh, J. Dahlstrom
Journal: Journal of Clinical Oncology (2007)

10602 Background: The AJCC/UICC staging system categorises tumour size in multifocal and multicentric breast cancer (MMBC) using the largest dimension of the largest focus of tumour. This under-estimates the total tumour burden and therefore may under-estimate the potential of these tumours to metastasise. This study tests the hypothesis that an aggregate measurement of tumour size in MMBC is more closely related to nodal status than the size of the largest focus. Methods: This prospective cohort study involved women with ipsilateral invasive breast cancer with known nodal status using data from the ACT &amp; SENSW BCTG database from July 1997 to June 2004. Pathology reports were reviewed to obtain tumour size in the unifocal group and nodal status in all women. The histopathology of MMBC cases were reviewed measuring all tumour foci that were recorded as: (1) the diameter of the largest deposit (LD), (2) the aggregate diameter (AD) of all deposits, and (3) a calculation of the aggregate volume (AV) using the largest dimension of each focus. The MMBC dimensions were compared with unifocal cancers and against nodal status using a multivariate logistic regression analysis and compared against each other using a stepwise method to determine which method is most predictive of nodal involvement. Results: 795 women met the criteria for study entry: 139 (17.5%) had MMBC and 656 (82.5%) had unifocal disease. When adjusting for tumour size method of measurement in MMBC, there was strong agreement between the AD MMBC and unifocal groups in terms of nodal status (p=0.7). Conversely, there were statistically significant differences in nodal status using LD (p=0.008) and AV (p=0.02) measurements in MMBC when compared to the unifocal group. Within the MMBC group the aggregated diameter measure was most significantly related to nodal status (p=0.001). Conclusions: The results of this study confirm that the current tumour staging system in MMBC under-estimates the potential for nodal spread and that aggregate diameter is more clinically useful. Nodal status is used in this study as a surrogate for tumour behaviour. Further studies are underway to assess relationship of aggregate size of MMBC to relapse and survival. No significant financial relationships to disclose.
Modulation of the sleep–wake cycle by changes in energy balance
Authors: Tinh-Hai Collet, Agatha A van der Klaauw, Elana Henning, Julia M Keogh, Diane Suddaby, Sekesai V Dachi, Síle Dunbar, Sarah Kelway, Suzanne L Dickson, I Sadaf Farooqi, Sebastian M Schmid
Journal: The Lancet (2016)
Analysis of the rate of non-target disease progression in patients with stable or responding target disease by the Response Evaluation Criteria in Solid Tumors (RECIST)
Authors: K. Borradaile, R. Ford
Journal: Journal of Clinical Oncology (2009)

6603 Background: RECIST suggests progression of non-target disease is rare in patients with stable or responding target disease. We reviewed outcomes by RECIST to determine the rate of non-target (NT) progressive disease (PD). Methods: Outcomes of RECIST-based blinded independent central review (BICR) of 962 breast and colon cancer patients were used to identify 514 patients that had a progression event in order to determine the incidence of NT-PD. The radiographs of the 55 patients that had NT-PD were further reviewed by the authors (KB, RF) to confirm the NT-PD was “unequivocal.” To be considered unequivocal, there had to be a definite, substantial increase in the size of one or more metastatic NT lesions that was clearly not related to differences in imaging technique. To confirm the subjective nature of the “unequivocal progression,” the lesion(s) upon which PD was assessed was measured and a 20% increase in the lesion(s) since nadir was required. Results: Of the patients with PD, 11% (55/514) progressed only on worsening of NT disease. In 82% (45/55) of cases where the NT-PD was unequivocal, either the target disease was increasing but had not met the quantitative requirement for progression or the increase in NT disease would have resulted in target progression had the NT site(s) of disease been included with the baseline target lesions. Of the remaining 18% (10/55) where the two criteria described above did not apply, and an additional evaluation was performed, the next evaluation confirmed PD. Conclusions: Progression on the basis of NT disease can be reliably assessed if the target disease has started to increase from the nadir or if the increase in NT disease is significant enough to have resulted in target disease progression if classified as such. If one of the above criteria is not met, it is recommended that treatment continue until progression can be confirmed at the next evaluation. No significant financial relationships to disclose.
A phase I trial of a novel mTOR inhibitor AP23573 administered weekly (wkly) in patients (pts) with refractory or advanced malignancies: A pharmacokinetic (PK) and pharmacodynamic (PD) analysis
Authors: A. A. Desai, L. Janisch, L. R. Berk, H. L. Knowles, V. M. Rivera, C. L. Bedrosian, M. J. Ratain
Journal: Journal of Clinical Oncology (2004)

3150 Background:AP23573 is a non-prodrug rapamycin analog that potently inhibits mTOR, a downstream effector of the PI3K/Akt and nutrient pathways. AP23573 demonstrated powerful antiproliferative activity in vitroand antitumor activity in mouse xenograft studies. Methods: This trial is utilizing an accelerated dose escalation scheme to determine safety and tolerability, establish a maximum tolerated dose, and characterize the PK and PD of AP23573. AP23573 is administered as 30-minute IV infusion wkly on 4-week cycles, and tumor responses are evaluated every 2 cycles. Potential PD markers are being assessed using western blot analysis of peripheral blood mononuclear cells. Results: As of 12/01/03: 9 pts (4M/5F), median age 55 yrs (range 27–79 yrs), have received doses ranging from 6.25 to 25 mg in 3 dose level cohorts (total cycles, 15; median cycles, 2/pt). No dose limiting toxicities or AP23573-related serious adverse events have been observed. Common reversible side effects for first cycle have been grade 1 chills, diarrhea, fatigue, rash, anorexia, mucositis, and one pt had grade 2 anemia. PK analyses (doses 6.25 and 12.5 mg) suggest a mean AP23573 half-life of 46–52 hours, with AP23573 concentration levels generally remaining above in vitro antiproliferation IC50 levels until the next wkly dose. PD analyses (doses 12.5 and 25 mg) show inhibition of mTOR activity until the next wkly dose as measured by decrease in phosphorylated 4EBP1 levels. One of 5 evaluable pts has stable medullary thyroid cancer for > 2 months. Conclusions: AP23573 can be administered safely using this schedule. There is evidence of a substantial PD effect at dose levels associated with minimal toxicity, and early evidence of antitumor activity. Given the promising PD findings, further dose escalation and new pt enrollment will include evaluation of maximum effective dose of AP23573 based on PK/PD relationship. If substantial interindividual PK variability is observed, the trial also is prospectively designed to evaluate the relevance of genetic variants in candidate drug metabolism genes. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration ARIAD Pharmaceuticals, Inc. ARIAD Pharmaceuticals, Inc. ARIAD Pharmaceuticals, Inc.
Abstract 17698: Plasma C-reactive Protein Elevation and Coronary Plaque Instability in Patients with Stable Angina Pectoris
Authors: eisuke miura, Hironori Kneko, Mikihiro Kijima, Yukio Maruyama
Journal: Circulation (2010)

Background: There is still no reliable clinical bio-marker to predict plaque instability in the early stage before presenting cardiac events. Plasma C-reactive protein(CRP), the prototypic marker o...
Phase I study of belinostat (PXD101) plus azacitidine (AZC) in patients with advanced myeloid neoplasms
Authors: O. Odenike, M. Green, R. A. Larson, E. S. Rich, J. Ott, M. J. Ratain, W. Stock
Journal: Journal of Clinical Oncology (2008)

7057 Background: Belinostat (BEL) is a potent inhibitor of histone deacetylase activity. The MTD of single agent BEL in Phase I studies was 1000 mg/m2; DLTs were diarrhea, fatigue and atrial fibrillation. We hypothesized that simultaneously targeting 2 pathways of epigenetic silencing using BEL and the DNA hypomethylating agent AZC would lead to an additive or synergistic effect, in patients (pts) with advanced myeloid neoplasms. Methods: The primary objective of this segment of the study was to determine the MTD of BEL when given with a fixed dose of AZC. 3 to 6 pts were enrolled per dose level in the absence of a DLT or until the 1000 mg/m2 dose level of BEL was attained. Pts had relapsed or refractory AML, intermediate or high risk MDS or advanced MPD. AZC, 75 mg/m2/d, was given SC on days 1–5 followed by escalating doses of BEL given IV over 30 minutes on the same days in a 28 day cycle. Results: BEL dose levels were 150 mg/m2 (n=6), 300 mg/m2 (n=5), 600 mg/m2 (n=6) and 1000 mg/m2 (n=6). Patient characteristics-M/F: 17/6, median age 70 (range 49–79), AML de novo=52%, t-AML/MDS= 18%, MDS/CMML=26%, primary myelofibrosis=4%. 78% had primary refractory or relapsed disease; 43% had poor risk cytogenetics. Non-hematologic grade 1–2 toxicities included fatigue (43%), nausea and vomiting (39%), diarrhea (17%) and phlebitis (13%). One DLT (grade 3 myalgia) was observed in cycle 2 at the 1000 mg/m2 dose level. 21 patients received at least 1 cycle (median-4; range 1–17) and are evaluable for response: 2 CRs, 1 PR and 4 with hematologic improvement; 3 occurred at the 1000 mg/m2 dose level. Median time to response was 2 cycles (range, 1–4). Increased platelets (mean 150%; range 58% to 224%) at 4 weeks were observed in one-third of pts, and at all dose levels studied. Conclusions: The combination of BEL with AZC is feasible and clinical activity was observed. A randomized study would be required to assess the relative contribution of BEL to this combination. That phase of the study will evaluate the 1000 mg/m2 dose level of PXD101 and include pharmacodynamic endpoints. Sponsored by NCI grant 5U01-CA69852–12 No significant financial relationships to disclose.
Immunophenotypic and Genotypic Features,Clinical Characteristics,and Treatment Outcome of Adult Pro-B acute Lymphoblastic Leukemia:Results of the German Multicenter Trials GMALL 03/87 and 04/89
Authors: Wolf-Dieter Ludwig, Harald Rieder, Claus R. Bartram, Barbara Heinze, Stefan Schwartz, Winfried Gassmann, Helmut Löffler, Dieter Hossfeld, Gerhard Heil, Susanne Handt, Axel Heyll, Helmut Diedrich, Konstanze Fischer, Adelheid Weiss, Bernd Völkers, Ülker Aydemir, Christa Fonatsch, Nicola Gökbuget, Eckhard Thiel, Dieter Hoelzer
Journal: Blood (1998)
A planned comparison of menopausal symptoms during the first year in 1,000 patients receiving either exemestane or tamoxifen in a double-blind adjuvant hormonal study
Authors: L. Asmar, J. Cantrell, S. J. Vukelja, J. E. Pippen, J. O'Shaughnessy, J. L. Blum, R. J. Brooks, S. Mull, H. Guo, S. Jones
Journal: Journal of Clinical Oncology (2004)

516 Background: We assessed 10 menopausal symptoms at baseline and every 3 months during the first year of an ongoing randomized Phase III trial comparing relapse-free survival of postmenopausal women with receptor positive, early breast cancer treated with exemestane (an aromatase inactivator) or tamoxifen for 5 years. Methods: Symptoms were assessed by each patient as none, mild, moderate, or severe with more detail used to establish a “hot flash score”. The median age of 997 evaluable pts was 65 years (range, 40–90). The symptoms were examined statistically by analysis of variance with repeated measurement design. Results: Vaginal dryness (p=0.0021) and bone/muscle aches (p<0.001) were worse in pts receiving exemestane while vaginal discharge was more common (p<0.001) in pts receiving tamoxifen. Most symptoms were mild or moderate and many pts recorded symptoms prior to the start of treatment (e.g. only 27% of pts recorded “none” for “low energy”). Based on the current sample size of 997 pts, there are no significant differences between the 2 treatments with respect to vaginal bleeding, mood alteration, impaired word finding, low energy, and hot flashes. Conclusion: This analysis is based on review of 3740 forms and by the time of the ASCO meeting, an analysis based on >4500 forms will be presented. Supported by Pfizer, New York, NY, USA Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Pfizer Pfizer Pfizer
The multifactorial nature of microRNAs in vascular remodelling
Authors: S.M.J. Welten, E.A.C. Goossens, P.H.A. Quax, A.Y. Nossent
Journal: Cardiovascular Research (2016)

Vascular remodelling is a multifactorial process that involves both adaptive and maladaptive changes of the vessel wall through, among others, cell proliferation and migration, but also apoptosis and necrosis of the various cell types in the vessel wall. Vascular remodelling can be beneficial, e.g. during neovascularization after ischaemia, as well as pathological, e.g. during atherosclerosis and aneurysm formation. In recent years, it has become clear that microRNAs are able to target many genes that are involved in vascular remodelling processes and either can promote or inhibit structural changes of the vessel wall. Since many different processes of vascular remodelling are regulated by similar mechanisms and factors, both positive and negative vascular remodelling can be affected by the same microRNAs. A large number of microRNAs has been linked to various aspects of vascular remodelling and indeed, several of these microRNAs regulate multiple vascular remodelling processes, including both the adaptive processes angiogenesis and arteriogenesis as well as maladaptive processes of atherosclerosis, restenosis and aneurysm formation. Here, we discuss the multifactorial role of microRNAs and microRNA clusters that were reported to play a role in multiple forms of vascular remodelling and are clearly linked to cardiovascular disease (CVD). The microRNAs reviewed are miR-126, miR-155 and the microRNA gene clusters 17-92, 23/24/27, 143/145 and 14q32. Understanding the contribution of these microRNAs to the entire spectrum of vascular remodelling processes is important, especially as these microRNAs may have great potential as therapeutic targets for treatment of various CVDs.