tbuckley/cabot-search huggingface dataset:
EGFR mutation and intron 1 CA repeat polymorphism as predictive markers of gefitinib responsiveness in non-small cell lung cancer (NSCLC)
Authors: S. W. Han, T. Y. Kim, K. W. Lee, D. Y. Oh, S. H. Lee, D. W. Kim, D. H. Chung, S. A. Im, D. S. Heo, Y. J. Bang
Journal: Journal of Clinical Oncology (2006)

7173 Background: EGFR mutation is significantly associated with objective response and prolonged survival in NSCLC patients treated with gefitinib. However, presence of mutant nonresponses and nonmutant responses mandates investigation of other molecular markers for more effective prediction of gefitinib sensitivity in NSCLC. It is unclear whether low CA repeat number in EGFR intron 1 has such a predictive role. Methods: Advanced NSCLC patients received gefitinib 250mg/day. EGFR mutation in exons 18 - 21 were identified by direct sequencing of PCR products of DNA extracted from archival paraffin embedded tissue. Number of CA repeat in intron 1 of EGFR was determined by GeneScan with tumoral DNA. Baseline characteristics, mutational status, CA repeat number and efficacy of gefitinib were analyzed in respect to each other. Results: To date, 73 patients were evaluable for EGFR mutation, CA repeat and gefitinib responsiveness. 14 patients (19.2%) harbored EGFR mutation (7 deletion in exon 19, 4 L858R, 1 L861Q, 1 G719A, and 1 insertion in exon 20). Most common CA repeat genotype was 20/20 repeat (31 patients) followed by 16/20 repeat (15 patients). Patients were classified as having either low CA repeat (sum of both allele ≤ 37 repeats) or high CA repeat (≥ 38 repeats). 34 patients (46.6%) had low repeat, whereas 39 patients (53.4%) had high repeat. Patients with EGFR mutation showed better objective response (response rate [RR] 57.1% vs. 10.2% in wild type [WT], p &lt; 0.001), time-to-progression (TTP) (p = 0.031, median 5.1 vs. 1.9 months in WT), and overall survival (OS) (p = 0.051, median14.5 vs. 7.4 months in WT). In the whole study population, low CA repeat was not associated with RR (p = 0.38), TTP (p = 0.15), or OS (p = 0.51). However, in the 59 patients without an EGFR mutation, patients with low CA repeat tended to have better objective response (RR 17.2% [5/29] in low repeat vs. 3.3% [1/30] in high repeat, p = 0.10) and significantly better TTP (p = 0.019, median 2.2 months in low repeat vs. 1.2 months in high repeat). Conclusions: Our results suggest that low number of CA repeats in EGFR intron 1 may have possible role in prediction of gefitinib responsiveness when analyzed together with EGFR mutational status. [Table: see text]
Bronchiectasis: how to be an orphan with many parents?
Authors: Pieter C. Goeminne, Anthony De Soyza
Journal: European Respiratory Journal (2015)

When René Laennec first described bronchiectatic lesions, he wrote: " Je me contenterai donc de donner deux exemples propres à faire connaître plus amplement l'altération organique assez rare dont il s'agit " [1]. Loosely translated, it shows us that during his discovery he had the conviction that bronchiectatic lesions were a rather rare phenomenon. However, at that time, Laennec was the first and only person to characterise these lesions, suggesting that his contemporaries had completely overlooked their existence. What is unsought will go undetected. Bronchiectasis, an orphan disease in the spotlight: more common than previously thought yet lots still to discover <http://ow.ly/Ut1eT>
GFI1 as a novel prognostic and therapeutic factor for AML/MDS
Authors: J M Hönes, L Botezatu, A Helness, C Vadnais, L Vassen, F Robert, S M Hergenhan, A Thivakaran, J Schütte, Y S Al-Matary, R F Lams, J Fraszscak, H Makishima, T Radivoyevitch, B Przychodzen, S V da Conceição Castro, A Görgens, B Giebel, L Klein-Hitpass, K Lennartz, M Heuser, C Thiede, G Ehninger, U Dührsen, J P Maciejewski, T Möröy, C Khandanpour
Journal: Leukemia (2016)
A pilot study comparing a patient-centered symptom-reporting follow-up program to standard care in patients who have completed the acute phase of treatment for early breast cancer.
Authors: M. E. Melisko, E. Mihalis, M. Ernest, H. S. Rugo, J. W. Park, M. M. Moasser, P. N. Munster, L. Esserman
Journal: Journal of Clinical Oncology (2010)

TPS272 Background: There are over 2.5 million breast cancer survivors in the United States. With outcomes improving, the number of survivors in follow-up care continues to increase and will eventually result in an unmanageable load on medical and surgical oncologists. Many patients (pts) continue to see an oncology specialist for years after their diagnosis, which may not be necessary or optimal. A Swedish study demonstrated that follow- up care provided by advanced practice nurses was equivalent to physician led care. Online health tools have proven successful in engaging breast cancer survivors. We sought to combine these strategies to test a patient-oriented approach that aims to decrease unnecessary clinic visits while providing support for pts in managing breast cancer and treatment-related symptoms. Methods: Breast cancer pts who have completed the acute phase of treatment are randomized to 1 of 2 follow up care plans: 1. SIS.NET - One or two oncology related clinic visits a year with additional access to oncology care driven by ongoing nurse practitioner review of pt-reported symptoms through web-based questionnaires (WBQ); or 2. Routine follow-up care with appointment frequency determined by the treating oncologist and WBQ only before clinic visits. Pts in the SIS.NET arm are assigned a limited number of clinic visits over the 18 month trial period but receive a WBQ every 3 months (and more frequently upon request), allowing them to report symptoms at regular intervals between clinic appointments. Based on a predefined algorithm, the nurse practitioner contacts patients within 24-72 business hours to address new or worsening symptoms that may have clinical significance. The trial's primary aim is to compare time to evaluation of breast cancer or treatment-related symptoms between pts enrolled in SIS.NET care and standard care. The trial will also compare pt satisfaction, frequency of doctors' visits, and number and type of diagnostic tests between the methods of care. Current enrollment is 69 patients, and the planned accrual is 150 patients. There have been 7 refusals to participate. No significant financial relationships to disclose.
The renin-angiotensin system in the type II diabetic obese Zucker rat.
Authors: C T Harker, M P O'Donnell, B L Kasiske, W F Keane, S A Katz
Journal: Journal of the American Society of Nephrology (1993)

Recently, the obese Zucker rat (OZR), an animal model of non-insulin-dependent (type II) diabetes, was shown to respond to converting enzyme inhibition with decreased albuminuria and a marked attenuation of glomerular injury. It was hypothesized that the OZR would possess low plasma renin values and an increased vascular responsiveness to angiotensin II, and therefore, the renin-angiotensin system (PRA, active renin, inactive renin, renal renin content, and plasma angiotensinogen) and vascular reactivity in OZR at 10 and 24 wk of age were investigated. PRA and renin concentration, inactive plasma renin, and renal renin content were all significantly (P < 0.05) reduced in OZR when compared with age-matched lean controls. The ratio of inactive to total renin was significantly increased in the OZR. OZR aortic ring vascular reactivity to KCl, norepinephrine, and angiotensin II was assessed. Despite essentially equal or increased contractile responses to KCl and norepinephrine at both 10 and 24 wk of age, the OZR was not more sensitive to angiotensin II and displayed a significantly reduced contractile response to angiotensin II at 24 wk of age, when compared with lean age-matched controls. It was concluded that the renal protective effect of converting enzyme inhibition in OZR, despite significantly reduced PRA and concentration, inactive plasma renin, and renal renin content, may not be due to a diabetes-induced increased vascular reactivity to angiotensin II.
Effect of serum proteins on sodium-linked transport processes in cultured kidney cells.
Authors: S S Blumenthal, D L Lewand, P A Tipnis, J G Kleinman
Journal: Journal of the American Society of Nephrology (1995)

The mechanism for increased Na+ retention in the nephrotic syndrome is unknown. To determine if Na+ transport systems in the proximal tubule might be affected by filtered proteins, mouse cortical tubule cells grown in defined medium were exposed to concentrations of bovine serum albumin (BSA) ranging from 0.01 to 0.5%. Activity of the Na(+)-glucose cotransporter, measured as Na(+)-dependent uptake of alpha-methylglucoside, increased progressively to a maximum of 2.3-fold above baseline (P < 0.001; N = 10). The increase in transporter activity was due to an increased Vmax, and the magnitude of the increase was inversely related to the basal cotransporter activity of the cultures. Increased cotransporter activity was detectable 6 h after exposure, was sustained for 24 h after cells were removed from an albumin-free medium, and was prevented by cycloheximide. Heat-treated BSA, fatty-acid and globulin-free BSA, and gamma-globulins were as effective at increasing Na(+)-glucose cotransporter activity as untreated Fraction V BSA. Dextran, dextran-sulfate, and amino acid supplements were ineffective. Neither protease inhibitors nor chloroquine added to an albumin-containing medium prevented increased alpha-methylglucoside uptake. Albumin did not change the rate of fluid-phase endocytosis in the cultured cells. Na(+)-amino acid cotransport and Na(+)-H+ exchange were either decreased or unchanged after BSA exposure. Exposing apical surfaces of cells grown on permeable membranes to BSA led to a greater increase in activity of the Na(+)-glucose cotransporter relative to controls than did exposing the basolateral surface (145 versus 89%; P < 0.05; N = 5).(ABSTRACT TRUNCATED AT 250 WORDS)
Cost-utility of darbepoetin alfa (DARBE) on an every-2 week (QOW) schedule in anemic non-myeloid hematologic malignancies: A positive overall impact on the healthcare system (HCS)
Authors: S. L. Scarpace, K. Miller, A. Elefante, M. S. Czuczman, P. McCarthy, A. Chanan-Khan
Journal: Journal of Clinical Oncology (2004)

8278 Background: DARBE is a long-acting erythropoietin approved for chemotherapy-induced anemia. It is preferentially prescribed at 200 mcg subcutaneously QOW. This administration has shown equal efficacy and appears to be cost effective and convenient to patients (pts) in comparison to recombinant human erythropoietin (EPO). The actual cost-utility benenfit of this schedule has not been reported. We conducted a cost analysis at our institution in patients with non-myeloid hematological cancers to assess the projected cost savings by using DARBE and to determine its potential overall impact on the HCS. Methods: This is a single institution study. All pts with multiple myeloma and lymphomas, treated with EPO between 1/1/02–12/31/02 were captured by a report generated through the pharmacy computer system. We projected that the number of pts treated with EPO 40,000 units QW would receive DARBE 200 mcg QOW. HCS cost was calculated based on acquisition cost of drug, travel costs based on IRS reimbursement rates, wages lost by patient and caretaker conservatively estimated based on national minimum wage, and nursing (RN), pharmacy (RPh), physician (MD) wages from the US Dept of Labor. Data was also collected for administration of each growth factor injection from the clinic including RN, RPh, MD time, wait time, appointment time, infusion chair time and drive time (see Table 1). Results: 300 doses of EPO were administered between 1/1/02 - 12/31/02. A summary of the financial and time costs is presented in Table 1. Conclusion: DARBE QOW is both more cost-effective and convenient for pts and clinical staff compared to EPO QW. Our limited analysis is suggestive of a global potential benefit to the HCS by use of longer acting HGF agents. No significant financial relationships to disclose.
Circuits of cancer drivers revealed by convergent misregulation of transcription factor targets across tumor types
Authors: Abel Gonzalez-Perez
Journal: Genome Medicine (2016)

Background: Large tumor genome sequencing projects have now uncovered a few hundred genes involved in the onset of tumorigenesis, or drivers, in some two dozen malignancies.One of the main challenges emerging from this catalog of drivers is how to make sense of their heterogeneity in most cancer types.This is key not only to understand how carcinogenesis appears and develops in these malignancies to be able to early diagnose them, but also to open up the possibility to employ therapeutic strategies targeting a driver protein to counteract the alteration of another connected driver.Methods: Here, I focus on driver transcription factors and their connection to tumorigensis in several tumor types through the alteration of the expression of their targets.First, I explore their involvement in tumorigenesis as mutational drivers in 28 different tumor types.Then, I collect a list of downstream targets of the all driver transcription factors (TFs), and identify which of them exhibit a differential expression upon alterations of driver transcription factors.Results: I identify the subset of targets of each TF most likely mediating the tumorigenic effect of their driver alterations in each tumor type, and explore their overlap.Furthermore, I am able to identify other driver genes that cause tumorigenesis through the alteration of very similar sets of targets.Conclusions: I thus uncover these circuits of connected drivers which cause tumorigenesis through the perturbation of overlapping cellular pathways in a pan-cancer manner across 15 malignancies.The systematic detection of these circuits may be key to propose novel therapeutic strategies indirectly targeting driver alterations in tumors.
Has NHS reorganisation saved lives? A CuSum study using 65 years of data
Authors: Alice S Lale, Jonathan MF Temple
Journal: Journal of the Royal Society of Medicine (2015)

To determine if NHS reforms affect population mortality.Retrospective study using routinely published data.Resident population of England and Wales 1948 to 2012 MAIN OUTCOME MEASURE: All cause age sex directly standardised mortality England and Wales 1948 to 2012.Using the CuSum technique and Change-Point Analysis to identify sustained changes in the improving age-standardised mortality rates for the period 1948-2012, and comparing the time of these changes with periods of NHS reform. Where observed changes did not fit with NHS reform, changes external to the NHS were sought as a possible explanation of changes observed.CuSum plotting and CPA showed no significant changes in female mortality trend between 1948 and 2012. However, this analysis identified a sustained improvement in the male mortality trend, occurring in the mid-1970s. A further change in the rate of male mortality decline was found around the Millennium.The 1974 NHS reorganisation, changing service arrangements predominantly for women and children, is considered an unlikely explanation of the improved rate of male mortality decline. Thus, centrally led NHS reorganisation has never had any detectable effect on either male or female mortality and must be considered ineffective for this purpose. But some evidence supporting the view that increased funding improves outcomes is found.
Interferon lambda 4 genotypes and resistance‐associated variants in patients infected with hepatitis C virus genotypes 1 and 3
Authors: Kai‐Henrik Peiffer, Lisa Sommer, Simone Susser, Johannes Vermehren, Eva Herrmann, Matthias Döring, Julia Dietz, Dany Perner, Caterina Berkowski, Stefan Zeuzem, Christoph Sarrazin
Journal: Hepatology (2015)

Single‐nucleotide polymorphisms (SNPs) in the interferon lambda 4 ( IFNL4 ) gene are predictors for treatment success in patients with hepatitis C virus (HCV) infection. For direct‐acting antiviral combinations only weak association with IFNL4 SNPs was observed. Little is known about potential selections of resistance‐associated variants (RAVs) by the IFNL4 genotype. This study analyzed the prevalence of RAVs to currently approved direct‐acting antivirals in a large European population in correlation to SNPs in IFNL4 . Samples of 633 patients chronically infected with HCV genotypes 1a (n = 259), 1b (n = 323), and 3 (n = 51) were genotyped for rs12979860 (formerly known as IL28B ) and rs368234815. RAVs in NS3 , NS5A , and NS5B were detected by population‐based sequencing. In addition, IFNL4 SNPs and NS5A RAVs were analyzed including deep sequencing (n = 109) in an independent replication cohort of HCV genotype 1‐infected patients (n = 201). No significant correlation was found between IFNL4 SNPs and rare and common RAVs within NS3 and NS5B . In contrast, the NS5A RAV Y93H was detected frequently in HCV genotype 1b (14%) and significantly associated with the beneficial IFNL4 SNPs ( P &lt; 0.001 and P = 0.002, respectively). Moreover, the presence of Y93H in HCV genotype 1b patients was significantly associated with the second site variant T83M ( P &lt; 0.001). Independent factors significantly associated with the presence of Y93H were IFNL4 genotype and high baseline viral load. Conclusion: The NS5A RAV Y93H is significantly associated with the presence of beneficial IFNL4 SNPs and a high baseline viral load in HCV genotype 1‐infected patients, which may explain a lack of correlation or even an inverse correlation of treatment response with IFNL4 genotype in some NS5A inhibitor containing IFN‐free regimens. (H epatology 2016;63:63–73)
Abstract 059: Long-term Exposure to Oxides of Nitrogen and Left Ventricular Mass in the Multi-Ethnic Study of Atherosclerosis and Air Pollution
Authors: Victor C Van Hee, Assaf P Oron, David A Bluemke, Adam A Szpiro, Ana V Diez-Roux, David Siscovick, Joel D Kaufman
Journal: Circulation (2012)

Objective: To determine whether long-term exposure to oxides of nitrogen (NO x ) is associated with left ventricular mass index (LVMI) in adults without known cardiovascular disease (CVD). Background: An association between very close (&lt;50 meter) residential proximity to major roadways and LVMI, an important predictor of heart failure, has been previously described. To date, the relationship between LVMI and NO x , a specific, gaseous traffic related pollutant and more reliable surrogate for traffic-related pollution, has not been examined. Methods: This study included 4125 participants free of clinical cardiovascular disease in the Multi-Ethnic Study of Atherosclerosis (MESA) who underwent cardiac MRI, cardiac computed tomography (CT), and an extensive air pollution exposure assessment campaign to determine long-term individual residential exposure to NO x . This study used year 2000 average exposure to estimate long term exposure to NO x . LVMI was calculated by indexing cardiac MRI measures of left ventricular mass to body surface area measured at the exam. Agatston score was calculated based on cardiac CT. Multiple linear regression was used to examine the association between long-term exposure to NO x and LVMI, adjusted for multiple potential confounders including study site. To examine whether such relationships may be mediated by atherosclerosis or blood pressure, additional adjustment for Agatston score and blood pressure was performed. Results: An interquartile range (44 ppb) increase in estimated residential NO x was associated with significantly higher LVMI (1.6 g/m 2 , 95% CI: 0.1 to 3.1, p=0.03). Such estimates were comparable to prior associations observed for the relationship between close residential proximity to major roadways and LVMI (comparing individuals living 150m away). Additional adjustment for Agatston score and blood pressure had no effect on estimates of association. Stratified analyses suggested interactions with age, with younger individuals demonstrating larger associations than older individuals (p for interaction = 0.05). No significant evidence of effect modification by race, gender, other cardiovascular risk factors, or study site was observed. Conclusions: This study further supports the observation that long-term exposure to traffic-related air pollution is associated with higher left ventricular mass, and suggests that such associations may be independent of effects on blood pressure or atherosclerotic disease.
Karnofsky Memorial Lecture. Natural history of small breast cancers.
Authors: S Hellman
Journal: Journal of Clinical Oncology (1994)

Article Tools Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/JCO.1994.12.10.2229 Journal of Clinical Oncology - published online before print September 21, 2016 PMID: 7931493 Karnofsky Memorial Lecture. Natural history of small breast cancers. S HellmanxS HellmanSearch for articles by this author Show More Department of Radiation and Cellular Oncology, University of Chicago, IL 60637-1470. https://doi.org/10.1200/JCO.1994.12.10.2229 First Page PDF © 1994 by American Society of Clinical Oncology
Clinical pattern and outcome of gastric cancer patients with skeletal metastases.
Authors: H. Park, S. Y. Rha, W. Hyung, H. C. Chung, J. K. Roh, S. Noh, H. Jeung
Journal: Journal of Clinical Oncology (2010)

e14561 Background: Gastric cancer (GC) with skeletal metastases has adverse prognosis, pursuing rapidly deteriorating clinical course and quality of life. To date, only limited information about skeletal metastasis from GC is available. Here we investigated clinic-pathologic features, treatment outcome, and prognostic factors in the GC patients who developed skeletal metastases on diagnosis or during treatment. Methods: We retrospectively reviewed 8,373 patients with GC (not gastro-esophageal junction cancer) treated from January 1998 to May 2008. Skeletal metastasis was defined if there is radiographically positive finding or no benign radiographic explanation could be found after 99mTc-labeled bone scan. Results: There were 203 (2.4%) patients identified to have skeletal metastases, and majority had poorly differentiated carcinoma (n = 152, 75%). We found that 117 (58%) patients had synchronous metastases. For 86 metachronous patients, the median time to skeletal metastasis was 14 (range, 1 to 86) months. Most patients (n = 180, 89%) involved multiple sites and spine (86%) was most frequently involved. Eighty-three patients (41%) developed skeletal-related events (SRE); 80 patients received radiotherapy or operation, three suffered pathologic fracture, two developed hypercalcemia. As for treatment, 120 (59%) patients received chemotherapy ± radiotherapy, and remaining 83 received local therapy or supportive care only. Median survival after skeletal metastases was 103 (95% CI, 80-126) days. Multivariate analysis revealed initial alkaline phosphatase (> 158 mg/mL) (relative risk [RR] 1.72, p = 0.006), bone marrow involvement (RR 3.30; p = 0.026), and poor performance status (ECOG 3-4) (RR 1.95, p = 0.009) comprised poor prognosis for survival. Conclusions: This study indicates that better understanding of metastatic behavior is helpful for diagnosis, treatment strategy, and method of follow up for patients with skeletal metastasis from GC. We suggest that GC patients with skeletal metastases should receive more tailored therapies according to different risk factors in order to enhance survival. No significant financial relationships to disclose.