tbuckley/cabot-search huggingface dataset:
A loss of microRNA expression as a characterization of synchronous peritoneal secondary localizations of epithelial ovarian cancer as compared to primary tumors.
Authors: Delia Mezzanzanica, Loris De Cecco, Daniela Califano, Simona Losito, Marina Bagnoli, Renato Franco, Giosuè Scognamiglio, Gennaro Chiappetta, Domenica Lorusso, Francesco Raspagliesi, Silvana Canevari, Sandro Pignata
Journal: Journal of Clinical Oncology (2013)

11037 Background: Epithelial ovarian cancer (EOC) is the most lethal gynecological malignancy and one of the most challenging areas of cancer research being a highly heterogeneous disease difficult to diagnose and treat. EOC has a peculiar dissemination process due to the sloughing-off of cells from primary tumors and their spread throughout the peritoneal cavity. A better characterization of the mechanism involved in tumor spreading might help in design new therapeutic intervention. Methods: Forty-four couples of chemo naïf primary tumors and synchronous secondary peritoneal localizations, obtained at primary surgery from MITO2 clinical trial, have been profiled for microRNA (miRNA) expression on an Agilent Platform. Total RNA was extracted from formalin-fixed paraffin embedded tissues. An independent validation set of samples with similar characteristics, has been collected at INT Milan. Results: By class comparison analysis, imposing a false discovery rate &lt;10%,45 miRNAs were identified as differentially expressed: 32 down-modulated and 13 up-modulated in secondary localizations compared to primary tumors. Among the miRNAs down-modulated in the secondary localizations we detected most of the miRNA belonging to the Xq27.3 cluster, whose low expression we previously described to be associated with EOC early relapse, and a number of miRNAs related to epithelial/mesenchimal transition (EMT) whose modulation could be related to dissemination of the disease and response to drug treatment. In particularly loss of has-miR-506 resulted associated to platinum resistance since its ectopic expression in EOC cell lines increased their sensitivity to the drug. Furthermore preliminary data indicated that has-miR-506 regulated N-cadherin linking its modulation to EMT. Conclusions: To our knowledge, the present study is the first attempt to characterize a miRNA signature differentially expressed between EOC primary tumors and synchronous secondary peritoneal localizations. The validation of the miRNA profile as well as of target genes might help in elucidating EOC dissemination mechanisms and in defining possible new therapeutic targets.
Trends in Disease Presentation, Management, Cost of Care and Outcomes: A Comprehensive Look at Racial Disparities in Multiple Myeloma (MM)
Authors: Sikander Ailawadhi, Ryan D Frank, Mayank Sharma, Richa Menghani, M'hamed Temkit, Shumail M. Paulus, Nandita Khera, Shahrukh K. Hashmi, Pooja Advani, Abhisek Swaika, Aneel Paulus, Nabeel Aslam, Vivek Roy, Gerardo Colon-Otero, Asher A. Chanan-Khan
Journal: Blood (2016)
A phase I/II trial of multiple dose VB-111 and weekly paclitaxel in recurrent platinum-resistant Müllerian cancer.
Authors: Richard T. Penson, Suzanne T. Berlin, Panagiotis Konstantinopoulos, Carolyn N. Krasner, Ursula Matulonis, Allison Ambrosio, Daphne Suzin, Siobhan A Collins, Michael J. Birrer, Yael Chava Cohen
Journal: Journal of Clinical Oncology (2015)

5542 Background: VB-111 is a gene therapy agent consisting of a non-replicating adenovirus vector (Ad-5) with a modified murine pre-proendothelin promoter leading to apoptosis of tumor vasculature by expressing a fas-chimera transgene in angiogenic endothelial cells. One hundred and sixty five patients have been treated so far with VB-111 across different cancer indications including Recurrent GBM, advanced well differentiated thyroid carcinoma with preliminary evidence of anti-tumor activity with no significant safety issues. Safety of VB-111 in combination with paclitaxel was evaluated for patients with recurrent Müllerian cancers in a phase I/II dose-escalation study. Methods: VB-111 was administered as a single intravenous infusion at escalating doses from 3x1012 (DL1&2) to 1x1013 viral particles (VPs) (DL3), followed by repeat doses every 2 months. Paclitaxel was given at 40 mg/m2 (DL1), and 80mg/m2 weekly (DL2-3), with a planned dose expansion at DL3. Assessments included safety, pharmacokinetics, pharmacodynamics, tumor response (CA125 and RECIST criteria) and progression free survival (PFS). Results: Fourteen patients at 2 US centers received up to 6 repeat doses of VB-111. Of these 10 received the higher dose (1x1013 VPs). Patients were relatively older (Median age 65 (41-74)) with poor prognosis disease. No DLTs were observed. VB-111 was associated with flu-like symptoms and mild infusion reactions. CTCAE grade ≥ 3 toxicity included infection (1), proteinuria (1), GI (2), and thrombosis (2) including a fatal MI, anaphylaxis (1), neutropenia (2), hypophosphatemia (2). 57% (8 /14) of the patients had a CA125 response (defined as 50% reduction), 62% (8/13) had clinical benefit (RECIST stable disease) on study. Median progression free survival was 2.0 months (1.6 to 12.0). Conclusions: The expansion cohort was defined as VB-111 1x1013 VPs in combination with weekly paclitaxel 80 mg/m2. VB-111 was safe and well tolerated in combination with paclitaxel in ovarian cancer patients. Anticipated toxicities and clinical benefit were observed. Clinical trial information: NCT01711970.
Effects of Hydroxyurea (HU) On Lymphocyte Subsets and the Immune Response to Pneumococcal, Measles, Mumps and Rubella Vaccination in the Pediatric Hydroxyurea Phase III Clinical Trial - BABY HUG - (ClinicalTrials.gov Identifier: NCT00006400)
Authors: Howard M. Lederman, Margaret A. Connolly, Ram Kalpatthi, Russell E. Ware, Winfred C. Wang, Lori Luchtman-Jones, Myron Waclawiw, Jonathan C. Goldsmith, James F. Casella
Journal: Blood (2012)
Clinical Competence in Electrocardiography
Authors: Charles Fisch, Thomas J. Ryan, Sankey V. Williams, James L. Achord, Masood Akhtar, Michael H. Crawford, Gottlieb C. Friesinger, Elmer J. Holzinger, Francis J. Klocke, Peter R. Kowey, Risa J. Lavizzo-Mourey, James Leonard, John B. O’Connell, Robert A. O’Rourke, William A. Reynolds, Patrick J. Scanlon, Robert C. Schlant, Donald E. Ware
Journal: Circulation (1995)
Dissecting Signal Transduction Pathways In vivo with Dynamic Real-time Molecular Imaging
Authors: David Piwnica-Worms
Journal: Clinical Cancer Research (2007)

PL03-05   Genetically-encoded imaging reporters introduced into cells and transgenic animals enable noninvasive, longitudinal studies of dynamic biological processes in intact cells and living animals. The most common reporters include firefly luciferase (bioluminescence imaging), green fluorescence protein (fluorescence imaging), Herpes Simplex Virus-1 thymidine kinase (positron emission tomography) and variants with enhanced spectral and kinetic properties optimized for use  in vivo . When cloned into promoter/enhancer sequences or engineered into fusion proteins, molecular imaging reporters enable fundamental processes such as transcriptional regulation, signal transduction cascades, protein-protein interactions, oncogenic transformation, cell trafficking and targeted drug action to be temporally and spatially registered  in vivo . Dynamic analysis of cancer with genetically-encoded imaging reporters provides new insight into cancer-specific molecular and regulatory machinery within the contextual environment of the whole animal.
Features of prognosis, genetics and drug sensitivity of very elderly lung cancer patients.
Authors: Yoichi Ohtaki, Arito Yamane, Kimihiro Shimizu, Susumu Rokudai, Toshiteru Nagashima, Kai Obayashi, Yoshinori Yamashita, Kiyomi Taniyama, Tetsuya Mitsudomi, Yasushi Yatabe, Izumi Takeyoshi, Masahiko Nishiyama
Journal: Journal of Clinical Oncology (2015)

e20540 Background: In anticipation of the increasing aging of the population, we need to clarify the characteristics of elderly patients and the survival benefit of treating elderly patients. We investigated the clinical and prognostic features of elderly lung cancer patients, and analyzed driver gene mutations and expression data related to anticancer drug sensitivity to validate the personalized therapy for elderly patients. Methods: A total of 519 patients, who underwent surgical resection of primary lung cancer, were enrolled. Clinicopathological factors, status of driver mutations, survival differences including overall survival (OS), disease specific survival (DSS) were compared retrospectively stratified with aging. Of those, 60 tumor RNA sample available were assessed for mRNA levels related to anticancer drug sensitivity as follow; TYMS, DPYD, MFTHR, UMPS, ERCC1, ABCB1, GSTP1, TUBB3, BRCA1, RRM1. Results: The numbers of the patients in each group were middle-aged (age 40-64): 168, elderly (age 65-74): 217, and very elderly (age ≥ 75): 134. Pathological stages were IA: 219, IB: 97, II: 87, and III-IV: 116. Although adenocarcinoma histology was more frequent in young group (P = 0.001), significant differences of the frequency of driver gene mutation including EGFR, KRAS, HER2, BRAF were not observed. The OS of middle-aged group was significantly better than the other groups, but there were no difference between those of elderly and very elderly group. In terms of DSS, no significant survival differences among all three groups were observed. Multivariate analysis revealed that only elderly group was an independent unfavorable prognostic factor for OS, but very elderly group was not. For the mRNA expressional levels of anticancer drug sensitivity, lower expressions of ERCC1, GSTP1, DPYD, and ABCB1 in very elderly group than younger groups were observed. Conclusions: The prognosis and the frequencies of driver mutations of very elderly lung cancer patients were comparable to those of younger patients. Expression levels of anticancer drug sensitivity genes in elderly suggest better response to the chemotherapy, especially to platinums. Cytotoxic chemotherapy could be beneficial to the elderly lung cancer patients.
Risk-adjusted adverse outcomes in complex abdominal wall hernia repair with biologic mesh: A case series of 140 patients
Authors: Rifat Latifi, David Samson, Ansab Haider, Asad Azim, Hajira Iftikhar, Bellal Joseph, Elizabeth Tilley, Jorge Con, Saranda Gashi, Ayman El-Menyar
Journal: International Journal of Surgery (2017)
Chromosomal domains of transcriptional activation by PI3K/AKT pathway alterations in glioblastomas
Authors: Bruno Costa, Justin Smith, Ying Chen, Kenneth Aldape, Giuseppe Zardo, Janice Nigro, Heidi Phillips, C. David James, Jane Fridlyand, Joseph Costello
Journal: Cancer Research (2007)

AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA

242 

Glioblastoma (GBM) is the most common and aggressive primary brain tumor and existing therapy regimens are often ineffective. The methylation status of MGMT promoter region is currently the best molecular marker of overall survival in GBM patients treated with radiation and Temozolomide. However, MGMT is not the sole prognostic determinant and does not completely define patient outcome. HOX genes encode transcription factors that play crucial roles in normal development, and have been shown to be altered in different tumor types. Considering the very limited number of studies characterizing the importance of HOXA genes in gliomagenesis, we investigated the relevance of HOXA genes in GBM and their potential as prognostic molecular markers.

A cluster of HOXA genes was aberrantly expressed in GBM cell lines and primary tumors, but not in lower grade gliomas. Notably, expression of HOXA9 was associated with shorter overall and progression-free survival for GBM patients, in two independent sets of tumors. Furthermore, univariate and multivariate survival analyses showed that combined assessment of HOXA9 expression and MGMT methylation provides a better prognostication tool for GBMs than MGMT alone. In primary GBMs, aberrant overexpression of HOXA9 was associated with PTEN gene inactivation. Indeed, pharmacological manipulations of the PI3K/AKT pathway suggested that the mechanism of aberrant HOXA gene activation involves epigenetic alterations of this locus that are dependent on genetic alterations of the PI3K/AKT pathway. In conclusion, we found that a subset of the most highly malignant GBMs show a chromosomal domain of gene activation encompassing the HOXA gene cluster, where aberrant HOXA9 activation seems to be a novel molecular marker of prognosis for GBM that could improve MGMT -based predictions. These findings may help to stratify GBM patients for specific therapies. Overall, our data support the hypothesis that whole gene clusters along a chromosomal region may be activated in human tumors, and that epigenetic alterations, namely modifications at the histone tails as a result of PI3K/AKT dysfunction, may be one of the underlying mechanisms affecting these aberrant expression profiles.
Fulminant brain lymphoid infiltration in a patient with chronic lymphocytic leukemia
Authors: Venancio Conesa, Angela Mompel, Jos� Ruiz, Amparo G�mez, Pascual Fernandez, Javier Lucas, Ignacio Aranda
Journal: American Journal of Hematology (1999)

Fulminant Brain Lymphoid Infiltration in a Patient With Chronic Lymphocytic LeukemiaTo the Editor: Symptomatic involvement of the central nervous system (CNS) in chronic lymphocytic leukemia (CLL) is very rare.We present a TABLE I. Drugs Associated With Lymphadenopathy* Phenytoin Carbamazepine Para-amino salicylic
Prognostic Significance of Corrected QT and Corrected JT Interval for Incident Coronary Heart Disease in a General Population Sample Stratified by Presence or Absence of Wide QRS Complex
Authors: Richard S. Crow, Peter J. Hannan, Aaron R. Folsom
Journal: Circulation (2003)

Heart rate-corrected QT interval (QTc) is the traditional method of assessing the duration of repolarization. Prolonged heart rate-corrected QT interval is associated with higher risk of mortality in patients with coronary heart disease (CHD) and in the general population. However, the QTc is typically not evaluated when QRS duration is > or =120 ms, because increased QRS duration (QRSd) contributes to QT interval prolongation. In these circumstances, the JT interval has been proposed as a more valid way to assess ventricular repolarization.To allow for variation in heart rate, corrected JT interval (JTc) was defined as QTc-QRSd. Using data from the Atherosclerosis Risk in Communities Study, JTc and QTc were compared for their prognostic associations with incident CHD events among 14 696 men and women who were CHD-free at baseline, having either normal conduction or wide QRS complex. Among individuals with normal QRS duration, logistic regression adjusted for age, hypertensive status, diabetes, race, systolic blood pressure, smoking, HDL and LDL cholesterol, R-R interval, and menopausal status in women showed QTc and JTc were nonpredictive of future coronary events in men but significant in women. In individuals with wide QRS complex (QRSd > or =120 ms), similar analyses showed JTc had a significant prognostic advantage compared with QTc in men but not in women, among whom only 11 events occurred.The JTc is a simple measurement that is a significant independent predictor of incident CHD events in men with wide QRS complex.
Polycystic Kidney Disease without an Apparent Family History
Authors: Ioan-Andrei Iliuta, Vinusha Kalatharan, Kairong Wang, Emilie Cornec-Le Gall, John Conklin, Marina Pourafkari, Ryan Ting, Chen Chen, Alessia C. Borgo, Ning He, Xuewen Song, Christina M. Heyer, Sarah R. Senum, Young-Hwan Hwang, Andrew D. Paterson, Peter C. Harris, Korosh Khalili, York Pei
Journal: Journal of the American Society of Nephrology (2017)

The absence of a positive family history (PFH) in 10%–25% of patients poses a diagnostic challenge for autosomal dominant polycystic kidney disease (ADPKD). In the Toronto Genetic Epidemiology Study of Polycystic Kidney Disease, 210 affected probands underwent renal function testing, abdominal imaging, and comprehensive PKD1 and PKD2 mutation screening. From this cohort, we reviewed all patients with and without an apparent family history, examined their parental medical records, and performed renal imaging in all available parents of unknown disease status. Subsequent reclassification of 209 analyzed patients revealed 72.2% (151 of 209) with a PFH, 15.3% (32 of 209) with de novo disease, 10.5% (22 of 209) with an indeterminate family history, and 1.9% (four of 209) with PFH in retrospect. Among the patients with de novo cases, we found two families with germline mosaicism and one family with somatic mosaicism. Additionally, analysis of renal imaging revealed that 16.3% (34 of 209) of patients displayed atypical PKD, most of which followed one of three patterns: asymmetric or focal PKD with PFH and an identified PKD1 or PKD2 mutation (15 of 34), asymmetric and de novo PKD with proven or suspected somatic mosaicism (seven of 34), or focal PKD without any identifiable PKD1 or PKD2 mutation (eight of 34). In conclusion, PKD without an apparent family history may be due to de novo disease, missing parental medical records, germline or somatic mosaicism, or mild disease from hypomorphic PKD1 and PKD2 mutations. Furthermore, mutations of a newly identified gene for ADPKD, GANAB , and somatic mosaicism need to be considered in the mutation-negative patients with focal disease.
Localization of erythropoietin receptor mRNA in primary breast tumors by laser capture microdissection
Authors: C. P. Miller, K. Loeb, K. Edlefsen, N. Urban, C. A. Blau
Journal: Journal of Clinical Oncology (2009)

e22036 Background: Adverse effects of erythropoiesis stimulating agents on tumor progression and/or survival were observed in recent Phase III clinical trials, however, mechanisms are not understood. Whether tumor erythropoietin receptor (EpoR) expression is associated with erythropoietin-dependent tumor progression remains unclear, owing in part to the lack of specificity of commercial antibodies for protein detection. To overcome issues of protein detection, we previously optimized a quantitative RTPCR approach for reliable measurements of low level EpoR mRNA in primary tumor samples, and observed a 30-fold range of EpoR expression among panels of both breast and head and neck cancer samples. Methods: To test whether EpoR mRNA is expressed in tumor epithelial cells, we performed laser capture microdissection to fractionate 3 breast tumors into tumor epithelial enriched vs. depleted fractions. In each fraction, lineage marker and EpoR mRNA expression was normalized to 3 endogenous control genes. Results: Vascular endothelial markers in tumor epithelial-enriched fractions were reduced by an average of 15.3-fold (vascular endothelial cadherin) and 18.5-fold (platelet cell adhesion molecule 1) while the stromal marker vimentin was reduced by 14.7-fold. EpoR expression was enriched by 4.9-, 7.2-, and 1.1-fold in epithelial enriched fractions. Conclusions: Despite the depletion of endothelial cells, EpoR mRNA was at the same level or enriched in tumor epithelial fractions. These results demonstrate that malignant epithelial cells are a major source of EpoR mRNA in primary tumors. Applying this approach to additional breast cancer specimens as well as other cancer types will improve our understanding of erythropoietin-associated tumor progression. [Table: see text]
A phase 1b, dose-finding study of ruxolitinib plus panobinostat in patients with myelofibrosis.
Authors: Florian Heidel, Vincent Ribrag, Alessandro M. Vannucchi, Jean-Jacques Kiladjian, Francesco Passamonti, Amjad Hayat, Eibhlin Conneally, Thomas Kindler, Bruno Martino, Daniel B Lipka, Suddhasatta Acharyya, Florence Binlich, Tracy Liu, Song Mu, Claire N. Harrison
Journal: Journal of Clinical Oncology (2014)

7022^ Background: Myelofibrosis (MF) is a myeloproliferative neoplasm characterized by dysregulation of the Janus kinase (JAK) pathway resulting in bone marrow fibrosis, splenomegaly, and debilitating symptoms. Ruxolitinib (RUX) is a potent JAK1/JAK2 inhibitor that decreased spleen volume, improved symptoms, and prolonged survival in phase 3 studies. Panobinostat (PAN) is a potent pan-deacetylase inhibitor (DACi) that has shown splenomegaly reduction and improvement of marrow fibrosis in phase 1/2 studies. RUX and PAN demonstrated synergistic anti-MF activity in preclinical studies. Here, we present the updated results of a phase 1b study of the combination of RUX and PAN in MF patients (pts). Methods: Eligible pts had intermediate-1, -2, or high-risk MF by International Prognostic Scoring System criteria with palpable splenomegaly. Pts received RUX (5-15 mg) twice daily, every day (BID) and PAN (10-25 mg) once daily, 3 times a week (TIW; days 2, 4, and 6), every other week (QOW) in a 28-day cycle. The primary objective was determination of the recommended phase 2 dose (RP2D) and/or maximum tolerated dose (MTD). Dose escalation was guided by a Bayesian logistic regression model with overdose control based on cycle 1 dose-limiting toxicities (DLTs) and other safety results. Additional pts were enrolled and treated at the RP2D in the expansion phase. Results: A total of 48 pts were enrolled (38 escalation phase and 10 expansion phase). Preliminary RP2D was identified at RUX 15 mg BID/PAN 25 mg TIW/QOW. Grade 3/4 adverse events (AEs) included anemia (42%), thrombocytopenia (21%), abdominal pain (8%), and diarrhea (8%) in the escalation phase and anemia (20%) and asthenia (10%) in the expansion phase. Preliminary activity in the dose escalation phase was demonstrated by a ≥ 50% decrease in palpable spleen length at any time in 76% of pts and 50% of patients demonstrating a 100% (non-palpable spleen) response. In the expansion phase, all 4 evaluable pts demonstrated a best spleen response of 100% (non-palpable spleen). Conclusions: The combination of RUX and PAN has a tolerable safety profile and encouraging efficacy as demonstrated by spleen responses. Additional safety and efficacy data from the expansion phase will be presented. Clinical trial information: NCT01433445.