tbuckley/cabot-search huggingface dataset:
Abstract 1827: Inhibition of Src, HER2, and EGFR by the multi-kinase inhibitor KD019 overcomes trastuzumab resistance in breast cancer
Authors: Rigen Mo, Nishta Rao, James Tonra, Samuel Waksal, Masha Poyurovsky
Journal: Cancer Research (2014)

Abstract KD019 (previously EXEL-7647) is an orally bioavailable spectrum selective small molecule kinase inhibitor of Src family nonreceptor tyrosine kinases (Src) as well as HER2, EGFR, and VEGFR2/KDR. Because of its complement of targets KD019 is able to disrupt multiple components of tumor pathology and, in earlier studies, KD019 demonstrated robust activity in multiple in vivo tumor models. In recent years Src has emerged as a critical convergent node downstream of multiple signaling cascades initiated by transmembrane receptor tyrosine kinases (RTKs), most notably HER2, EGFR and IGF-1R. Crosstalk between Src and RTKs facilitates RTK-dependent tumor growth and, in patients with HER2-amplified (HER2+) breast cancer, where Src is upregulated, may confer resistance to anti-HER2 therapies. Based on the target specificity of KD019, including Src, we hypothesized that KD019 may prove to be an effective treatment in overcoming trastuzumab resistance in HER2+ breast cancer. Here we present data showing that KD019 effectively inhibited growth of several trastuzumab resistant cell lines with IC50 of 0.3 uM in vitro. Not only did KD019 potently inhibit HER2 and EGFR phosphorylation in these cells, but it also efficiently inhibited the phosphorylation of c-Met through receptor hetero-oligomerization mechanism, thus downregulating another pathway by which tumors may escape HER2 targeted therapies. Further, we demonstrate that once daily dosing of KD019 strongly inhibited tumor growth in xenograft models of trastuzumab resistance and that Src activity was inhibited in KD019 treated tumors even 24 hrs after drug administration. The significance of inhibiting the specific combination of targets is underscored by the fact that KD019 was 10 fold more potent when compared to saracatinib (a selective Src inhibitor) in inhibiting growth of trastuzumab resistant cells, which are also insensitive to blockade of individual RTKs. Together, these results provide a rational for clinical investigation of KD019 in patients whose tumors are resistant to anti-HER2 therapies. Citation Format: Rigen Mo, Nishta Rao, James Tonra, Samuel Waksal, Masha Poyurovsky. Inhibition of Src, HER2, and EGFR by the multi-kinase inhibitor KD019 overcomes trastuzumab resistance in breast cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1827. doi:10.1158/1538-7445.AM2014-1827
Provider Type and Quality of Outpatient Cardiovascular Disease Care
Authors: Salim S. Virani, Thomas M. Maddox, Paul S. Chan, Fengming Tang, Julia M. Akeroyd, Samantha A. Risch, William J. Oetgen, Anita Deswal, Biykem Bozkurt, Christie M. Ballantyne, Laura A. Petersen
Journal: Journal of the American College of Cardiology (2015)
The Ring Total Knee Replacement — A Comparison of Survivorship
Authors: M J Curtis, J M Bland, P A Ring
Journal: Journal of the Royal Society of Medicine (1992)

Long term results of joint replacement are frequently expressed as survivorship; it therefore becomes increasingly important to have the ability to make valid comparisons between survivorship tables in order to determine accurately the statistical significance of published differences. We present a statistical method for direct comparison of survivorship tables. We have applied this technique to evaluate the survivorship of the unconstrained, uncemented Ring total knee replacement first implanted in 1975 and compare this to contemporaneous constrained prostheses. There is a significant improvement in survival, which suggests a beneficial long-term effect on the bone/implant interface of this changing design concept.
Valvular 18F-Fluoride and 18F-Fluorodeoxyglucose Uptake Predict Disease Progression and Clinical Outcome in Patients With Aortic Stenosis
Authors: William S.A. Jenkins, Alex T. Vesey, Anoop S.V. Shah, Tania A. Pawade, Calvin W.L. Chin, Audrey C. White, Alison Fletcher, Timothy R.G. Cartlidge, Andrew J. Mitchell, Mark A.H. Pringle, Oliver S. Brown, Renzo Pessotto, Graham McKillop, Edwin J.R. Van Beek, Nicholas A. Boon, James H.F. Rudd, David E. Newby, Marc R. Dweck
Journal: Journal of the American College of Cardiology (2015)
Characteristics of 10-Year Survivors of Pancreatic Ductal Adenocarcinoma
Authors: Alessandro Paniccia, Patrick Hosokawa, William Henderson, Richard D. Schulick, Barish H. Edil, Martin D. McCarter, Csaba Gajdos
Journal: JAMA Surgery (2015)

To our knowledge, this study reports on the largest cohort of long-term survivors (LTSs) (≥10 years) following a diagnosis of pancreatic ductal adenocarcinoma (PADC) and identifies the characteristics associated with LTS.To determine patient, tumor, surgical, and sociodemographic characteristics associated with LTS.A nationwide retrospective cohort study of patients with invasive PADC (International Classification of Diseases for Oncology, Third Edition codes 8140/3, 8500/3, 8021/3, and 8035/3) was conducted using data collected in the National Cancer Database (NCDB). A multivariable logistic regression model of factors significantly associated with LTS was developed and used to generate a nomogram predicting the likelihood of surviving at least 10 years from initial diagnosis. Data collected from more than 1500 academic centers and community hospitals in the United States and Puerto Rico were assessed. Patients included were those with histologically proven PADC who underwent pancreatic surgical resection aimed at removal of the primary tumor between January 1, 1998, and December 31, 2002 (n = 11,917). The initial cohort (n = 70,915) excluded noninvasive tumors or tumors with unknown histology (n = 11,696) and was limited to patients who underwent surgical resection (n = 47,302 excluded). Analysis was conducted from January 1, 1998, to December 31, 2011.Pancreatic ductal adenocarcinoma.Long-term survival, defined as surviving at least 10 years from initial diagnosis.Of the 11,081 patients with complete survival information, 431 individuals (3.9%) were LTSs. Significant predictors of LTS included (determined using odds ratio [OR]; 95% CI), in order of importance, lymph node positivity ratio (0%: 4.6; 3.4-6.4), adjuvant chemotherapy (2.4; 2.0-3.0), pathologic T stage (T1: 3.1; 1.8-5.6), patient age (50-60 years: 3.4; 1.8-6.7), tumor grade (well differentiated: 2.2; 1.5-3.0), surgical margin (negative: 1.9; 1.4-2.6), pathologic M stage (M = X: 5.6; 2.1-22.8), tumor size (<2 cm: 1.7; 1.2-2.5), educational level (>86% high school graduates: 1.7; 1.2-2.4), and insurance status according to the patient's zip code (private: 2.0; 95% CI, 0.9-5.1). The model C index was 0.768. Based on our nomogram, patients with the most favorable characteristics had an 18.1% chance of LTS. Furthermore, survival curves demonstrated that the probability of dying following initial diagnosis of PADC reached a plateau of approximately 10% per year after 7 years of survival.Although PADC remains a deadly disease, long-term survival is possible, even beyond the 10-year mark. Our adjusted analysis identified lymph node ratio, administration of adjuvant chemotherapy, and pathologic T stage as being the top 3 variables associated with LTS of PADC. In addition, our easy-to-use nomogram may be able to identify potential LTS among patients with resected PADC.
Levamisole: known effects on the immune system, clinical results, and future applications to the treatment of cancer.
Authors: H C Stevenson, I Green, J M Hamilton, B A Calabro, D R Parkinson
Journal: Journal of Clinical Oncology (1991)

Levamisole has been used in a wide array of clinical research and treatment settings over the past two decades, ranging from such diseases as helminthic infestations to various autoimmune diseases. Numerous preclinical evaluations and clinical trials with levamisole in the cancer arena have been sponsored by the National Cancer Institute and other agencies worldwide with the hopes of demonstrating anticancer activity. Trials in advanced breast cancer, lung cancer, colorectal cancer, melanoma, and lymphoproliferative diseases have generally been negative or inconclusive. However, there is some indication that levamisole may be useful by itself as an adjuvant therapy for resected melanoma; recently it has been shown to be effective in combination with fluorouracil (5-FU) as adjuvant therapy for tumor-node-metastasis (TNM) stage III (Dukes' C) colon carcinoma. In the aggregate, the past 20 years of clinical experience with levamisole has resulted in as many questions as answers. However, further testing of the anticancer activity of levamisole can be expected in clinical research trials over the next few years. Hopefully, these future trials will include studies of the mechanisms of action of this agent.
Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Treatment Response in Advanced Non-Small Cell Lung Cancer with G719X/L861Q/S768I Mutations
Authors: C. Chiu, C. Yang, J. Shih, M. Huang, W. Su, R. Lai, C. Wang, S. Hsiao, Y. Lin, C. Ho, M. Wu, T. Hsia, C. Lai, K. Lee, C. Lin, F. Chang, C. Chuang, D.Y. Yeh, R. Perng
Journal: Annals of Oncology (2014)
The Consult Guys - Proceed to Surgery: Are You Kidding Me?
Authors: Geno J. Merli, Howard H. Weitz
Journal: Annals of Internal Medicine (2015)

Web Exclusives15 September 2015The Consult Guys - Proceed to Surgery: Are You Kidding Me?FREEGeno J. Merli, MD and Howard H. Weitz, MDGeno J. Merli, MDSearch for more papers by this author and Howard H. Weitz, MDSearch for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/G15-3009 SectionsSupplemental MaterialAboutVisual Abstract ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail The Consult Guys bring a new perspective to the art and science of medicine with lively discussion and analysis of real-world cases and situations.For more videos from and information on The Consult Guys, visit www.annals.org/ConsultGuys. Comments0 CommentsSign In to Submit A Comment Author, Article, and Disclosure InformationAffiliations: Disclosures: Geno J. Merli, MD, reports the following: Research grants/contracts: Bristol-Myers Squibb, Janssen, Portola; Consultancies: Bristol-Myers Squibb, Janssen. Howard H. Weitz, MD, reports that he has no financial relationships or interests to disclose.Editors' Disclosures: Christine Laine, MD, MPH, Editor in Chief, reports that she has no financial relationships or interests to disclose. Darren B. Taichman, MD, PhD, Executive Deputy Editor, reports that he has no financial relationships or interests to disclose. Cynthia D. Mulrow, MD, MSc, Senior Deputy Editor, reports that she has no relationships or interests to disclose. Deborah Cotton, MD, MPH, Deputy Editor, reports that she has no financial relationships or interest to disclose. Jaya K. Rao, MD, MHS, Deputy Editor, reports that she has stock holdings/options in Eli Lilly and Pfizer. Sankey V. Williams, MD, Deputy Editor, reports that he has no financial relationships or interests to disclose. Catharine B. Stack, PhD, MS, Deputy Editor for Statistics, reports that she has stock holdings in Pfizer. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics 15 September 2015Volume 163, Issue 6Page: CG1KeywordsDisclosureResearch grantsResearch reporting guidelinesSurgery ePublished: 15 September 2015 Issue Published: 15 September 2015 Copyright & PermissionsCopyright © 2015 by American College of Physicians. All Rights Reserved.Loading ...
Functional disorders in patients with COPD assessed by spirometry DLCO transfer characteristics, and plethysmography
Authors: Richard Kraemer, Jörg Salomon, Magdalen Gürtler, Stefan Minder
Journal: European Respiratory Journal (2014)

Rational.  Post-bronchodilator fixed ratio of FEV 1 /FVC and FEV 1  are widely accepted as primary parameter representing airflow limitation and,CO-transfer characteristics serves as additional severity parameters in COPD. Less is known to what extend plethysmography additionally offers information regarding obstruction, pulmonary hyperinflation (PH) and trapped gases (V TG ).   Aim.  Assessment of functional disorders by body plethysmography in addition to spirometry and single-breath DLCO in COPD patients.   Methods.  We evaluated 174 patients (84 males; 90 females; aged 29.4 to 89.4 ys) with COPD, (GOLD I to IV). All lung function data were expressed as gender- age- and height-specific standard deviations scores (SDS) obtained by z-transformation from newest prediction equations, taking also into consideration lower and upper limits of normal, defined as ±1.645*SDS. Target parameters were FEV 1 /FVC, FEV 1 , TLC He , FRC He , RV He , TLC, FRC pleth , RV, V TG =FRC pleth -FRC He , sG eff , sG tot .   Results.  Post-bronchodilator fixed ratio of FEV 1 /FVC was lower than LLN in 66.1%, FEV 1  in 75.3% (combined in 90.2%) of cases. In contrast, bronchial obstruction was recognized by sG eff  in 98.9%. Gas transfer disturbances were recognised by DL CO  in 73.6% of cases. In 14.9% PH, in 39.7% V TG  and in 29.3% PH and V TG  were found. Moreover, DL CO  transfer characteristics significantly correlated with the amount of V TG  (p   Conclusion.  The patter of different functional derangements in patients with COPD can comprehensively only be assessed by plethysmography, feathering together with DL CO  and K CO  insights into the interacting processes of lung physiology in COPD.
Vascular Endothelial Growth Factor C for Polycystic Kidney Diseases
Authors: Jennifer L. Huang, Adrian S. Woolf, Maria Kolatsi-Joannou, Peter Baluk, Richard N. Sandford, Dorien J.M. Peters, Donald M. McDonald, Karen L. Price, Paul J.D. Winyard, David A. Long
Journal: Journal of the American Society of Nephrology (2015)

Polycystic kidney diseases (PKD) are genetic disorders characterized by progressive epithelial cyst growth leading to destruction of normally functioning renal tissue. Current therapies have focused on the cyst epithelium, and little is known about how the blood and lymphatic microvasculature modulates cystogenesis. Hypomorphic Pkd1nl/nl mice were examined, showing that cystogenesis was associated with a disorganized pericystic network of vessels expressing platelet/endothelial cell adhesion molecule 1 and vascular endothelial growth factor receptor 3 (VEGFR3). The major ligand for VEGFR3 is VEGFC, and there were lower levels of Vegfc mRNA within the kidneys during the early stages of cystogenesis in 7-day-old Pkd1nl/nl mice. Seven-day-old mice were treated with exogenous VEGFC for 2 weeks on the premise that this would remodel both the VEGFR3+ pericystic vascular network and larger renal lymphatics that may also affect the severity of PKD. Treatment with VEGFC enhanced VEGFR3 phosphorylation in the kidney, normalized the pattern of the pericystic network of vessels, and widened the large lymphatics in Pkd1nl/nl mice. These effects were associated with significant reductions in cystic disease, BUN and serum creatinine levels. Furthermore, VEGFC administration reduced M2 macrophage pericystic infiltrate, which has been implicated in the progression of PKD. VEGFC administration also improved cystic disease in Cys1cpk/cpk mice, a model of autosomal recessive PKD, leading to a modest but significant increase in lifespan. Overall, this study highlights VEGFC as a potential new treatment for some aspects of PKD, with the possibility for synergy with current epithelially targeted approaches.
Usefulness of NT-proBNP dosage during the follow-up of PAH: Comparison with 6MWD
Authors: Giuseppe Paciocco, Silvia Gamberini, Luca Novelli, Ausiliatrice Lucenti, Antonella Vincenzi, Alberto Pesci
Journal: European Respiratory Journal (2014)

INTRODUCTION: Pulmonary Arterial Hypertension (PAH) is a rare disease with poor prognosis that needs early diagnosis and aggressive therapy. 6-min walk distance (6MWD) has been diffusely used for clinical follow-up and therapy response. Serum NT-proBNP has been recently used to assess right ventricular dysfunction.

PURPOSE: To analyze association between NT-proBNP and 6MWD and their distribution in different World Health Organization (WHO) functional class.

METHODS: We followed 34 patients (pts) affected by group 1 PAH with a median follow-up of 31 months (m) (min. 1 – max 69 m) for a total of 431 visits. At each visit, all pts were clinically evaluated into WHO status and prospectively performed at same daily-time 6MWD, preceded by NT-proBNP dosage not more than 10 minutes before walking.

RESULTS: Pearson correlation index between NT-proBNP and 6MWD resulted -0.60 (p 1400pg/mL, 93% of the 6MWT were ≤380m; only 56% of pts with NT-proBNP≤1400pg/mL walked >380m, probably due to physical confounding factors (age, sex weight, etc). During follow-up period, no pts in WHO I-II had NT-proBNP>1400pg/mL, while 15% of pts in WHO class I-II walked <380 m.

CONCLUSION: If performed together, NT-proBNP and 6MWT had an inverse correlation. These results may suggest low clinical utility of follow-up 6MWT in pts with NT-proBNP>1400pg/mL, highlighted by their compromised functional class (WHO III-IV). A cut-off of 380m at 6MWT was not able to define a correct WHO status, whereas NT-proBNP>1400pg/mL may exclude pts in WHO I-II.
Endobronchial identification of persistent peripheral bronchopleural fistula with digital chest tube monitoring followed by treatment with endobronchial one-way valve implantation
Authors: Irene Firlinger, Elisabeth Stubenberger, Michael Müller, Otto Burghuber, Arschang Valipour
Journal: European Respiratory Journal (2011)

Introduction: Bronchopleural fistula (BPF) is associated with high morbidity and mortality and causes prolonged hospital stay and costs. Surgery remains the treatment of choice, however, many patients are at high risk or unwilling to undergo thoracotomy.

Objectives: To present a standardized approach of endoscopic diagnosis and treatment of persistent peripheral BPF.

Methods: 10 patients with persistent air leaks (presence of chest tube >7 days) underwent bronchoscopy with balloon occlusion technique and digital monitoring of airflow in order to identify the peripheral source of bronchopleural fistula. Endobronchial one-way valve implantation (Spiration Inc., Olympus) was performed on a segmental or subsegmental level to block ventilation to the BPF.

Results: Mean chest tube drainage time prior to the intervention was 22±13 days. The source of the BPF was endoscopically identified in all cases. Bronchoscopic valve implantation (1.6±0.8 valves per patient) was performed successfully in all patients. Using digital chest tube monitoring air flow immediately decreased from 1026±695ml/min to 56±71ml/min (p < 0,001), indicating successful cessation of the leakage. 2 patients underwent additional chemical pleurodesis. The chest tube was removed 8±5 days after bronchoscopy. There was no evidence of recurrence during a mean follow-up time of 2 months.

Conclusion: Using a standardized approach in endobronchial diagnosis followed by endobronchial one-way valve implantation results in a high responder rate in patients with peripheral BPF.
Endotoxin Up-regulates Interleukin-18
Authors: Deirdre M. Kelly, Catherine M. Greene, Gerard Meachery, Michael O'Mahony, Paula M. Gallagher, Clifford C. Taggart, Shane J. O'Neill, Noel G. McElvaney
Journal: American Journal of Respiratory and Critical Care Medicine (2005)

Sarcoidosis is a granulomatous disease of unknown etiology characterized by a helper T-cell type 1-mediated process. Previously we demonstrated a role for interleukin-18 in sarcoidosis. Here we examine the regulation of interleukin-18 in this condition.Cytokine levels in sarcoid epithelial lining fluid were measured by ELISA. We examined interleukin-18 promoter activity and mRNA and protein levels in the epithelial lining fluid of individuals with active sarcoidosis, and of individuals recovered from sarcoidosis, in response to purified protein derivative of Mycobacterium tuberculosis, beryllium sulfate, zirconium sulfate, aluminum sulfate, and lipopolysaccharide. Endotoxin levels in the epithelial lining fluid of individuals with sarcoidosis, individuals recovered from sarcoidosis, and control subjects were assessed by Limulus amebocyte lysate analysis. Allele-specific polymerase chain reaction was used to genotype 94 patients with sarcoidosis and 97 control subjects for the interleukin-18 -607(A/C) polymorphism. Species-specific polymerase chain reaction identified bacterial DNA in fluid samples.Epithelial lining fluid from active sarcoids contained elevated levels of interleukin-18, interferon-gamma, and interleukin-12 compared with recovered patients and also contained significantly higher levels of endotoxin. Depletion of endotoxin from this epithelial lining fluid reduced its effect on the human interleukin-18 promoter in vitro. There was a higher frequency of the -607C allele and -607(C/C) genotype in the sarcoidosis population compared with control subjects; however, this was not associated with a functional response to endotoxin treatment. Finally, bacterial 16S rRNA from Haemophilus influenzae and Moraxella catarrhalis was detected in sarcoid fluid samples.The pathogenesis of sarcoidosis is propagated through the actions of a helper T-cell type 1-driven response. This study shows that gram-negative bacteria may contribute to this effect by upregulating interleukin-18 expression.
Studies of a Melanoma Tumor-Associated Antigen Detected in the Spent Culture Medium of a Human Melanoma Cell Line by Allogeneic Antibody. II. Immunobiologic Characterization23
Authors: Rishab K. Gupta, Donald L. Morton
Journal: JNCI Journal of the National Cancer Institute (1984)

A tumor-associated antigen (TAA) was isolated from spent culture medium of human melanoma cell line UCLA-SO-M14 (M14). After radioiodination and further purification, it was used in a radioimmunoassay (RIA). When tested in RIA for anti-TAA activity, 56% (111/200) of sera from melanoma patients, 21% (21/100) of sera from sarcoma patients, and 19% (19/100) of sera from carcinoma patients, as well as 12% (6/50) sera from pregnant women and 10% (10/100) apparently normal sera, were positive. The variations (0.25–3.8 μg/mg total protein) in specific TAA activity in 20 different batches of spent media collected for 18 months exhibited patterns of gradual increases and decreases, suggesting a cell growth cycle-related phenomenon. Binding between the allogeneic antibody and 125 I-labeled TAA was inhibited by 70% (32/47) of melanoma spent media and cells (from culture or biopsy). Conversely, only 7% (3/33) spent medium or membrane extracts of other tumor cells and 0% (1/69) of human normal, fetal, or placental cells were positive in competitive RIA. The TAA was immunologically different from normal tissue antigens, blood-group antigens, human leukocyte antigens, and microbial antigens. These immunobiologic properties of the TAA isolated from M14 spent culture medium and used in the RIA suggested that such TAA was melanoma associated.