tbuckley/cabot-search huggingface dataset:
Use of whole genome expression analysis of pancreatic adenocarcinoma to predict prognosis after OXi4503 surgery
Authors: E. A. Collisson, D. Das, R. Mori, A. C. Hoffmann, G. E. Kim, R. Hajnal, P. V. Danenberg, J. Cooc, K. D. Danenberg, M. A. Tempero
Journal: Journal of Clinical Oncology (2008)

4503 Background: Surgery is the first line treatment for patients with resectable pancreatic ductal adenocarcinoma (PDA). However pancreaticoduodenectomy is challenging and some patients recur quickly, negating the benefit of aggressive resection. To assess for prognostic information in resected tissues, we compared gene expression profiles associated with long and short-survival derived from microdissected FFPE pancreatic cancer specimens. Methods: We selected pathologically confirmed PDAfrom archival FFPE specimens from a single center. Among 29 specimens, 19 were from long (> 300d) and 10 from short (< 300d) survivors. Samples from pancreaticoduodenectomy for non-neoplastic diagnoses (n=8) were handled similarly. Multiple slide sections taken from each paraffin block were microdissected to isolate tumor cells. Following isolation, RNA was amplified, labeled, and hybridized to Affymetrix U133 Plus 2.0 GeneChips. Differentially expressed gene lists were determined between long and short survivors by T-Test and hierarchical clustering (method 1) as well as adaptive linear splines (method 2). Leave one out cross validation (LOOCV) with weighted voting was performed for validation of the data. Results: Between the groups, adenocarcinoma samples were clearly distinguishable from normal specimens using unsupervised analysis. In the microdissected samples, gene clusters created with supervised analyses based on outcome identified ∼300 differentially expressed genes between the long and the short survivor groups (p=0.005). Adaptive linear splines identified multiple genes, the expression levels of which were strongly correlated with survival duration (top gene p-value = 2e-8, FDR = 0.03%). LOOCV analysis confirmed both methods. Conclusion: Gene profiling of microdissected PDA FFPE tissue is feasible and yields data indicative of prognosis after surgery, suggesting that the disparity in outcomes seen after intended curative resection for PDA is largely tumor-intrinsic (rather than due to host factors or surgical technique). Further, these results demonstrate the potential to derive preoperative recurrence risk profiles with ramifications for patient management in this challenging disease. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Response Genetics Inc. Response Genetics Inc. Response Genetics Inc. Response Genetics Inc. Response Genetics Inc.
Urokinase plasminogen activator receptor (uPAR) as a novel biomarker in prostate cancer.
Authors: Solvej Lippert, Kasper Drimer Berg, Peter Iversen, Gunilla Høyer-Hansen, Ib Jarle Christensen, Klaus Brasso, M. Andreas Røder
Journal: Journal of Clinical Oncology (2015)

183 Background: New biomarkers are warranted to distinguish between indolent and aggressive prostate cancer (PCa). The urokinase plasminogen activator receptor (uPAR) plays an important role in pericellular proteolysis by binding urokinase plasminogen activator (uPA). This is required for degradation of the extracellular matrix and for cancer invasion. In addition to binding uPAR, uPA cleaves uPAR liberating uPAR(I) and uPAR(II-III). Intact, uPAR(I-III), and uPAR(II-III) can be liberated from the cell surface resulting in three different uPAR forms in circulation. The different uPAR forms are strong prognostic markers in several cancers. We measured the uPAR forms in plasma from patients with different stages of PCa. Methods: Between February 1, 2012 and October 1, 2014, 400 patients with PCa (se table) had plasma samples obtained. The levels of intact uPAR [uPAR(I-III)], intact uPAR + cleaved uPAR domains II+III [uPAR(I-III) + uPAR(II-III)], and cleaved uPAR domain I [uPAR(I)] were determined in citrated plasma samples with two-site sandwich time-resolved fluorescence immunoassays (TR-FIAs). Results: Plasma uPAR(I-III) + uPAR(II-III) and uPAR(I) were significantly higher in hormone naïve patients and CRPC patients compared to patients with localized disease (see table). Quantification of intact uPAR(I-III) revealed no significant differences between the three groups. Conclusions: Our findings suggest that uPAR(I-III) + uPAR(II-III) and uPAR(I) are associated with higher tumor stage as well as advanced PCa disease. These associations suggest that uPAR domains in plasma harbour prognostic value for PCa patients. Further studies are warranted to validate the use of uPAR forms as biomarkers for PCa. [Table: see text]
Correlating cellular imaging of a p65-fusion reporter with protein interactions using the HaloTag technology
Authors: Randall Learish, Georgyi Los, Natasha Karassina, Chad Zimprich, Marjeta Uhr, Mark McDougall, Dieter Klaubert, Robert Bulleit, Keith Wood
Journal: Cancer Research (2007)

2822  The study of complex protein networks in living cells is facilitated by the use of technologies which offer multiple applications. Here we study a cell-based model of the NFκB signaling pathway using a reporter-fusion protein technology to both functionally label, and immobilize and capture, p65 and its binding partners.  p65 fusion constructs were made using the HaloTag™ Interchangeable Labeling Technology and expressed by in vitro translation, or in vivo by transient or stable transfection. Following expression in rabbit reticulocyte lysates or mammalian cell lines, the fusion protein was directly immobilized onto HaloLink™ agarose beads without prior purification steps. This approach achieved successful capture of the p65 fusion protein as well as co-capture of its binding partner IκB, as demonstrated by western blotting. Fusion proteins were also captured using streptavidin-coated beads following labeling of the p65-fusion with a biotinylated HaloTag ligand. The p65-fusion was visualized in living cells following transfection and labeling with fluorescent ligands. In both transiently and stably transfected cells, the signal was localized to the cytoplasm. Following fluorescent labeling and treatment with TNFα in vivo, nuclear translocation of the p65-fusion construct was visualized by time lapse confocal imaging. At intervals after treatment, cell lysates were obtained, fractionated into nuclear and cytoplasmic pools, and probed with IκB or p65 antibodies. Western blot analysis revealed a time-dependant degradation and reappearance of IκB in the cytoplasm, as well as correlative evidence for translocation of the p65-fusion protein into the nucleus. Finally, this technology was applied to study the DNA promoter binding activity of the p65-fusion protein by cross-linking TNFα treated samples with paraformaldehyde and then capturing DNA fragments using HaloLink.  The covalent attachment and rapid binding rate of the HaloTag ligands to the reporter protein has made possible a large set of applications that span the areas of imaging, high content analysis and proteomics. Here the versatility of the technology permitted the generation of a broad set of data using a single fusion construct to study NFκB signaling in vitro and in vivo.
A multicenter phase II study of epirubicin (E) with low-dose herceptin (LD-H) as a first-line treatment in HER2 overexpressing metastatic breast cancer (MBC)
Authors: M. De Tursi, C. Carella, E. Ricevuto, A. Gennari, C. Orlandini, A. Frassoldati, P. F. Conte, S. Iacobelli
Journal: Journal of Clinical Oncology (2007)

1060 Background: The combination of doxorubicin and herceptin (H) has been proven to be an effective regimen in metastatic breast cancer (MBC), although it was associated with an increased risk of cardiotoxicity. Methods: The aim of this study was to evaluate cardiac safety and efficacy of epirubicin (E) in combination with low-dose herceptin (LD-H) as first-line chemotherapy for women with HER-2 positive MBC. Forty-five patients were enrolled in a two-step, multicenter phase II study. In the first step, H was given at 2 mg/Kg loading dose on day 1, followed by 1 mg/Kg weekly; in the second step (≥ 12 objective responses/21pts), H dose was maintained at 1 mg/kg weekly. E was administered at 90 mg/m 2 on day 1 every 3 weeks. After 6–8 courses, H was continued as a single agent for a maximum of 52 weeks. To assess cardiotoxicity, patients were evaluated for the left ventricular ejection fraction (LVEF) at baseline, every two cycles during E and LD-H, and every three months during LD-H alone. Cardiotoxicity was defined as signs or symptoms of congestive heart failure in = 10% of patients at an E dose of 720 mg/ m 2 or in = 20% of patients at an E dose &gt; 720 &lt; 1,000 mg/m 2 . Results: Eight episodes of cardiotoxicity were observed (an asymptomatic decrease in LVEF =15% in 6 patients and an asymptomatic decline of LVEF at = 50% in 2 patients). Grade 3–4 neutropenia, alopecia and thrombocytopenia occurred in 25%, 45.5% and 6.8% of patients, respectively. Complete and partial responses were 2.4 and 61.9%, respectively, for an overall response rate of 64.3%. The median time to progression was 8.2 months (95% CI, 5.2–9.2 months) and the median overall survival was 32.8 months (95% CI, 17.1–48.6 months). Conclusions: E plus LD-H is an active treatment regimen for HER-2 positive MBC and demonstrates a very favourable safety profile, with manageable cardiotoxicity. No significant financial relationships to disclose.
Phase II multicentric study of concurrent chemoradiation (CCR) with biweekly gemcitabine after induction chemotherapy with cisplatin and gemcitabine in unresectable stage III non small cell lung cancer (NSCLC)
Authors: R. Blanco, J. Solé, M. Nogué, J. Montesinos, E. Gallardo, C. Vadell, C. Mesía, M. Algara, J. Terrassa
Journal: Journal of Clinical Oncology (2004)

7322 Background: CCR in unresectable NSCLC has been superior to sequential approach in several studies. However, concurrence often precludes administration of full-dose chemotherapy. So, induction chemotherapy followed by CCR seems a promising alternative. A phase I study confirmed the feasibility of CCR with biweekly, low-dose, gemcitabine in NSCLC patients (Blackstock, ASTRO99). Methods: Inclusion criteria: unresectable stage III NSCLC, Karnofsky >70,adequate pulmonary, hematologic, renal and liver functions, and planned treated volume <2200cc. Treatment: 3 cycles of cisplatin (100 mg/m2, d1) and gemcitabine (1250 mg/m2, d1&8) q3w followed by CCR (gemcitabine 50 mg/m2 Monday & Thursday and radiotherapy 68.4 Gy, 1.8 Gy qd). After 22 patients included (Group A), unacceptable toxicity was detected and we reduced induction cisplatin dose (70 mg/m2) and CCR gemcitabine dose (35 mg/m2). Another 34 patients (33 eligible, Group B) were included. Results: Toxicity: Non-hematological toxicity of chemo-radiation was similar in both groups (see Table). However, 40.9% of patients in Group A vs. 66.6% in Group B completed treatment. Responses (intent to treat): In Group A, 40.9% PR, 18.1% CR. In group B, 54.5% PR, 12.1% CR. Survival: For group A, median survival was modest (11.8 months), but 6 (27 %) of patients are alive at a minimum follow-up of 35 months. For Group B, survival data are not yet available. Conclusions: This treatment is feasible in patients with unresectable stage III NSCLC. Non-hematological toxicity of chemo-radiation is substantial, but long-term results suggest that selected patients could benefit from this approach. No significant financial relationships to disclose.
Abstract 2525: Cardiovascular Effects of Unilateral Adrenalectomy are Superior to Those of Aldosterone Antagonist Treatment in Primary Aldosteronism
Authors: Michael Stowasser, Diane Cowley, Richard Gordon, James Sharman, Thomas Marwick
Journal: Circulation (2007)

Primary aldosteronism (PAL) is the commonest specifically treatable form of hypertension. Adrenal venous sampling (AVS) is the most reliable means of differentiating unilateral forms (1/3 of patients) correctable by unilateral laparoscopic adrenalectomy (ADX) from bilateral forms (2/3) usually treated with aldosterone antagonist medications (MED RX). Because AVS is technically difficult and invasive, some physicians have suggested avoiding AVS and instead treating most/all patients with PAL medically on the assumption that ADX and MED RX have similar beneficial effects. We tested that premise by prospectively comparing cardiovascular (CV) effects of ADX with those of MED RX (spironolactone 12.5–50 mg/d and/or amiloride 2.5–10 mg/d). We studied 19 ADX pts (9 F; mean age 51 ± 10y SD) found by AVS to have unilateral PAL and 43 MED RX pts (25 F; age 52 ± 13y) with bilateral PAL. At baseline, patients with unilateral PAL had similar mean 24h ambulatory BP (149/87 ± 15/20 vs 145/86 ± 20/10 mm/Hg), number of antihypertensive drugs required (2.2 ±1.1 vs 1.9 ± 1.0), LV mass index (LVMI, 146 ± 29 vs 131 ± 36 g/m2), and ejection fraction (EF, 62 ± 7 vs 63 ± 5 %) but higher upright plasma aldosterone (30 ± 17 vs 20 ± 11 ng/dL; P<0.01), end-diastolic volume (EDV, 119 ± 25 vs 98 ± 32 mL; P<0.05) and end-systolic volume (ESV, 44 ± 13 vs 37 ±14 mL; P<0.05) than those with bilateral PAL. After 7–31 (median 17) mths following ADX or commencement of MED RX, both groups showed significant falls in 24h DBP, ESV, EDV and LVMI but no change in EF; only the ADX group showed falls in 24h SBP and number of drugs; and ADX was associated with greater falls in EDV, ESV, LVED and LVMI than MED RX (Table). The greater fall in LVMI was independent of baseline LVMI or fall in BP. Beneficial CV effects of ADX for unilateral PAL are superior to those of MED RX for bilateral PAL. We therefore advocate AVS as an important part of the diagnostic workup of PAL, permitting identification of patients with unilateral forms who are candidates for ADX. (Table available in original abstract)
Gene expression: the key to treatment decisions in early-stage adenocarcinoma?
Authors: T Hillman
Journal: Thorax (2009)

Recent evidence shows that adjuvant chemotherapy significantly improves the survival of patients with early-stage lung cancers. There are, however, groups of patients who do not fit neatly into prognostic categories according to stage, and tumour biology is likely to play an important role. This retrospective blinded validation study aimed to identify predictors of survival (classifiers) using gene expression profiling.

Data were collected about 442 …
New feasibility study design with hepatocellular carcinoma: A phase I/II study of TSU-68, an oral angiogenesis inhibitor
Authors: F. Kanai, H. Yoshida, T. Teratani, S. Sato, R. Tateishi, S. Obi, M. Yamashita, T. Kawabe, S. Shiina, M. Omata
Journal: Journal of Clinical Oncology (2006)

4145 Background: Hepatocellular carcinoma (HCC) is a devastating disease with limited treatment options at advanced stages. HCC is a highly vascular tumor in which angiogenesis contributes to its pathogenesis. TSU-68 is an oral anti-angiogenesis compound that blocks VEGFR-2, PDGFR, and FGFR. Methods: This is an open-label phase I/II study to characterize the safety, tolerability, pharmacokinetic (PK) profile and efficacy of TSU-68 at 800mg/po daily in adults with unresectable HCC. Patients (Pts) previously treated with surgery, radiofrequency ablation, transcatheter arterial embolization, chemotherapy, or radiotherapy were eligible. Pts were stratified into three groups based on hepatic function: level 1 (no cirrhosis), level 2 (Childs-Pugh A) or level 3 (Childs-Pugh B). The safety, tolerability and PK of TSU-68 were assessed sequentially from level 1 by enrolling 3 pts in each level. The response was evaluated based on RECIST. Results: 15 pts were enrolled: median age = 67 years (range 53–74 years), male/female = 11/4, cirrhosis/no cirrhosis = 12/3, HCV/HBV/alcohol = 12/2/1. 2 pts at level 3 who received 800 mg/d experienced DLTs (CTC grade 3 abdominal pain and ascites). The dose was reduced to 400 mg/d in an additional 3 pts at level 3 (no DLT observed). The most common adverse events were: hypoalbuminemia, diarrhea, abdominal pain, fever, and AST/ALT elevation. PK data from 12 pts (3 at level 1; 3 at level 2; 6 at level 3) indicated that the area under the curve (AUC) of TSU-68 was similar from level 1 to 3, and biologically active levels of TSU-68 could be reached at a dose of 400 mg/d. One pt had a partial response, 7 pts had stable disease (2 pts for over 12 months) and 7 pts had progressive disease. Tumor necrosis was observed in 8 pts. Conclusions: The study design based on hepatic function is useful to assess the safety of anti-tumor agent in pts with impaired liver function. A dose of 400 mg/d TSU-68 is well tolerated in pts with HCC. While the study is still on going, the preliminary results suggest that TSU-68 has anti-tumor activity against HCC. No significant financial relationships to disclose.
Phase I study of pemetrexed plus paclitaxel in patients with solid tumor
Authors: T. Graefe, C. Lubbing, C. Bolling, S. Muller-Hagen, B. Leisner, J. Fleet, F. E. Ludtke, J. Blatter, A. Suri, A.-R. Hanauske
Journal: Journal of Clinical Oncology (2004)

2103 Background: Pemetrexed (Pe) and paclitaxel (Pa) are clinically active in various solid tumors. The primary objective of this Phase I study was to determine maximum tolerated dose (MTD) of the Pe-Pa combination; secondary objectives included determination of dose-limiting toxicities (DLTs), recommended phase II dose, and pharmacokinetic assessment. Methods: Patients (pts) were given escalating dose levels of Pa (30–100 mg/m2, 3h infusion, d1 and d8) and Pe (400–500 mg/m2, 10 min infusion, d8 prior to Pa) q21d. Standard taxane premedications, folic acid, and vitamin B12 were given to reduce toxicities. Results: 45 pts [31 M, 14 F; median age 59 (range 31–77); WHO performance status 0–1 (86.7%); prior chemotherapy (53.3%)] were enrolled. See table for DLTs (cycle 1) and other toxicities experienced. Three drug-related discontinuations were anorexia, thrombocytopenia, and pancytopenia. Four pts died while on study (1 nondrug-related; 1 gastric ulcer hemorrhage, 1 sepsis, and 1 tumor lysis). Stable disease occurred in pts with mesothelioma (3) and esophagus (2) cancers, and 1 pt each with thyroid, head and neck, lung, liver, pancreas, prostate, renal, and stomach cancers. Of special note, this regimen has clinical activity in follicular/papillary thyroid cancer with 4/6 pts showing long-lasting partial responses (16+, 7+, 4+, 3+ months). Conclusions: Pemetrexed can be combined with paclitaxel and demonstrates broad clinical activity. At present, there is no evidence of pharmacokinetic interactions. MTD has not been reached, and study enrollment is ongoing at the 500/120-dose level. This combination warrants further investigation in thyroid cancer. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Eli Lilly & Co. Eli Lilly & Co.
Needs assessment: Cancer genetics knowledge, attitudes, beliefs among Puerto Rican islander women with breast cancer
Authors: B. Lozada-Cruz, L. Baez-Diaz, W. Caceres, S. E. Simonsen, A. Kinney
Journal: Journal of Clinical Oncology (2005)

9706 Background: Cancer susceptibility genes and clinical genetic testing have become subjects of intense research during the last few decades. Although there are numerous studies examining the interest in and outcomes of genetic testing among non-Latino white populations, there is a death of research focusing on U.S. Latino subpopulations. There are not studies focusing on Puerto Rican Islanders. This study examined Puerto Rican breast cancer patients’ attitudes about genetic testing for familial breast-ovarian cancer susceptibility. Methods: We conducted a cross-sectional observational cohort study in the island of Puerto Rico. A convenience sample of women participating in the San Juan Clinical Community Oncology Program was surveyed. Eligible persons included females between 18 and 80 years of age who were diagnosed with breast and/or ovarian cancer. The main purpose of the survey was to assess attitudes, beliefs, knowledge, and health care practices among Puerto Rican islanders who have an increased risk for carrying a hereditary breast/ovarian cancer susceptibility gene. Results: Sixty-four of the participants reported that they have never heard about genetic testing for familial breast-ovarian cancer susceptibility. However, when informed about the availability of testing, 67% expressed interest in testing. Factors associated with interest in genetic testing included family history of breast and/or ovarian cancer (p <0.05), young age (p <0.05), and higher levels of education and income (p <0.05). Breast cancer genetics and general breast cancer control knowledge was low; mean knowledge scores for the genetics and general breast items were 53 (22.7) and 72 (34.2), respectively. One quarter of the sample recognized early detection as a method to reduce disease-related deaths. With regard to informational preferences about genetic information, the most preferred source was pamphlets/booklets and the second most common was discussions with health care providers. Conclusions: Our data indicate a need for genetic education and a high level of interest in genetic testing for familial breast-ovarian cancer in Puerto Rican Islander breast cancer patients. No significant financial relationships to disclose.
The Lovely Day
Authors: Lawrence J. Hergott
Journal: Annals of Internal Medicine (2016)

Ad Libitum5 January 2016The Lovely DayLawrence J. Hergott, MDLawrence J. Hergott, MDFrom the Center for Bioethics and Humanities, University of Colorado School of Medicine, Denver, Colorado.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/M15-1817 Audio Reading - “The Lovely Day” Audio. Michael A. LaCombe, MD, Annals Associate Editor, reads "The Lovely Day," by L.J. Hergott. Your browser does not support the audio element. Audio player progress bar Step backward in current audio track Play current audio trackPause current audio track Step forward in current audio track Mute current audio trackUnmute current audio track 00:00/ SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Leaning out in piercing windsOn darkened afternoons,When solstice souls can't comprehendThe thought of future JunesOr caught up in an inner stormWhich blunts the noble effort made,And dulls the sense of others' forms,All seeming muted shadesIn press of vital burdens due—A pause—I smiling say,While feeling them yet sensing you,"It's such a lovely day." Author, Article, and Disclosure InformationAffiliations: From the Center for Bioethics and Humanities, University of Colorado School of Medicine, Denver, Colorado.Current Author Address: Lawrence J. Hergott, MD; e-mail, [email protected]net. PreviousarticleNextarticle Advertisement Audio Reading - “The Lovely Day” Audio. Michael A. LaCombe, MD, Annals Associate Editor, reads "The Lovely Day," by L.J. Hergott. Your browser does not support the audio element. Audio player progress bar Step backward in current audio track Play current audio trackPause current audio track Step forward in current audio track Mute current audio trackUnmute current audio track 00:00/ FiguresReferencesRelatedDetails Metrics 5 January 2016Volume 164, Issue 1Page: 58KeywordsEmotionsForecastingStorms ePublished: 5 January 2016 Issue Published: 5 January 2016 Copyright & PermissionsCopyright © 2016 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...