tbuckley/cabot-search huggingface dataset:
Pharmacokinetics of intra-arterial applied liposomal encapsulated doxorubicin in liver metastases or hepatocellular carcinoma: A phase I study
Authors: R. A. Hilger, H. Richly, M. Grubert, M. Libicher, D. Strumberg, J. Ebert, D. Hecker, M. Zähringer
Journal: Journal of Clinical Oncology (2008)

13523 Background: Doxorubicin has been one of the most widely used anti-neoplastic agents as a single-agent systemic therapy for HCC. Doxorubicin is also used in locoregional therapy approaches. Caelyx (Doxil) is a doxorubicin formulation of polyethylene glycol-coated liposomes. For this new form of doxorubicin, a superior pharmacokinetic profile over that of free doxorubicin is postulated. Blood flow reduction by micro embolization with degradable starch microspheres (DSM; e.g. Spherex, EmboCept) is effective in HCC and liver metastasis. Purpose: Evaluation of the pharmacokinetics (PK) of the encapsulated as well as the released fraction of doxorubicin in addition to the determination of the maximum tolerated dose of intra-arterially applied liposomal encapsulated doxorubicin (Caelyx) in HCC and liver metastases in combination with DSM. Methods: All patients with histologically proven HCC or liver metastases had shown progressive disease when previously treated with systemic chemotherapy. Six dose escalation steps from 15 mg/m2 to 100 mg/m2 were performed with two or three patients in each dose group. Each patient received one single application of Caelyx/DSM. The distribution of Caelyx depended on the tumor size in the left and right liver lobe. For the quantification of Caelyx, doxorubicin, and doxorubicinol, a validated RP-HPLC method with fluorometric detection (excitation wavelength: 470 nm, emission wavelength: 550 nm) was used. Results: PK was calculated for 13 out of 14 treated patients. The mean (terminal) half life for Caelyx was calculated as 3 days, mean residence time about 5 days, the Vss 1.5 l, clearance was determined to be less than 1 ml/min. The increase in peak plasma concentration as well as AUC was linear between 15 and 100 mg/m2 Caelyx. The MTD was reached at a single dose of 100 mg/m2 due to WHO- grade 3 myelosuppression in two patients without further SAE. Conclusions: These first results indicate that hepatic intra arterial chemotherapy with Caelyx in combination with DSM is well tolerated and achieved encouraging responses in patients with liver metastases or HCC. The main PK parameter for Caelyx in combination with DSM did not significantly differ from those obtained after systemic intravenous infusion. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Essex Pharma GmbH, PharmaCept GmbH
Factors associated with aerobic fitness in adolescents with asthma
Authors: Sveinung Berntsen, Karin C. Lødrup Carlsen, Sigmund Alfred Anderssen, Petter Mowinckel, Kai-Håkon Calrsen
Journal: European Respiratory Journal (2012)

Background : In adolescents with asthma, information on factors associated with aerobic fitness levels is limited. The present study  aimed  to determine if physical activity as well as skin fold thickness, asthma exacerbations, use of inhaled corticosteroids or lung function influences direct measurements of peak oxygen uptake (VO 2 peak) in adolescents with asthma.   Methods : From the general population based birth cohort, Environment and Childhood Asthma study in Oslo, Norway, in a nested case-control study 86 13-years old adolescents with and 76 without asthma performed maximal running on a treadmill with VO 2 peak measured. The sum of four skin fold thicknesses was recorded, followed by wearing an activity monitor for four consecutive days. Lung function was measured by maximum forced expiratory flow-volume curves and body plethysmography. Asthma exacerbations and use of medication were registered by parental structured interview. Data were analyzed using multiple regression analysis.   Results : Vigorous physical activity (coefficients with 95% confidence intervals; 1.73 (0.32, 3.14)) and body fat -0.35 (-0.41, -0.28)) were significantly associated with VO 2 peak in adolescents with asthma. Neither use of inhaled corticosteroids, lung function nor number of asthma exacerbations was associated with VO 2 peak when taking physical activity and skin fold thickness into account. In the adolescents without asthma only skin fold thicknesses was associated with VO 2 peak.   Conclusions : VO 2 peak appears to be determined by vigorous physical activity level and skin fold thickness in Norwegian adolescents with asthma and not by asthma-related factors such as use of inhaled corticosteroids, lung function nor number of asthma exacerbations.
Analysis of 430 chest trauma patients in Kashan trauma center: 2003-2011
Authors: Abdoulhossein Davoodabadi
Journal: European Respiratory Journal (2012)

Background:  Chest trauma as a potentially life threatening injury is increasing with increased number of high-speed accidents in Iran.   Methods:  430 patients were treated for chest trauma (Mar 2003 and Dec 2011)patients9 age and gender, blood pressure, respiratory rate on admission, Glasgow Coma Scale (GCS) scores, types of trauma, the extent of intra thoracic injury, types of associated injuries, length of hospital and ICU stay, morbid conditions, and deaths were analyzed.   Results:  343 pt were male (80%).Mean age was 37.67±19.14 .305 patients (70.9%) had blunt and the rest (29.1%) penetrating chest trauma. (83patients (19%) had hemothorax 53patients (12%) pneumothorax and the rest were, cardiac, (10pt), great vessel (12pt) and tracheal injuries (8pt).  Rib fracture was the most common thoracic injury with 270pt (63%), were treated with closed thoracostomy drainage.65 patients (15%) had hemothorax and lung contusion, whoever 42patients (11%) of penetrative injury and lung contusion leads to empyema, who need thoracotomy with decortications and diaphragmatic repair Motorcycles and car accidents were the most common etiologic causes in 331 (76%).  The most frequent extra-thoracic injury with (33%) was pelvic and limb injuries. while (25%) needed surgical intervention during the first 24 hours. The most common operation was laparotomy. Mean duration of hospital stay was 7± 9.6 (range: 1-70) and ICU stay 1.9days. overall mortality was (11.7%)   Conclusion:  Chest trauma is a major preventable cause of mortality and morbidity in our country. Systolic blood pressure ≤90, pulse rate ≥120, respiratory rate >29, GCS
Updated Follow-Up In The CLL2007FMP Trial Supports The Non Superiority Of The Association Fludarabine-Cyclophosphamide (FC) Plus Campath Compared To FC Plus Rituximab and Points Out The Importance Of Minimal Residual Disease, By 6-Color Flow Cytometry Technique, On Progression Free Survival
Authors: Pierre Feugier, Remi Letestu, Sylvie Chevret, Thérèse Aurran, Beatrice Mahe, Bruno Cazin, Olivier Tournilhac, Hervé Maisonneuve, Olivier Casasnovas, Alain Delmer, Véronique Leblond, Bruno Royer, Brigitte Corront, Roselyne Delepine, Sandrine Vaudaux, Eric Van Den Neste, Marie C Béné, PharmSciD, Florence Cymbalista, Stéphane Leprêtre
Journal: Blood (2013)
A simple practical method to partition lung peripheral and airway nitric oxide
Authors: Paolo Paredi, Sergei A. Kharitonov, Peter J. Barnes, Omar Usmani
Journal: European Respiratory Journal (2012)

Background: By measuring FeNO at multiple flows and applying mathematical models of FeNO exchange dynamics, the signal can be partitioned into its proximal airway [Jno (nl/sec)] and distal airway/alveolar contributions [Calv (ppb)] using a linear regression. This method is time consuming, requires at least 3 exhalations and is affected by a number of limitations such as axial diffusion and turbulent flow. We developed a more practical method.  Methods: In a group of 29 normal subjects (38±2 yr; 20 male), 13 asthmatic patients (48±8 yr; 8 male, FEV1 90±4 % predicted), 14 patients with chronic obstructive pulmonary disease (COPD) (63±2 yr; 10 male, FEV1 59±3 %), and 12 patients with cystic fibrosis (21±4 yr; 8 male, FEV1 60±3 %) we compared Calv and Jno with the variation of total NO production at 50 and 200 ml/s [Vno50-200 (nl/s)]. Vno was measured by calculating the average area under the curve (NO concentration/time) of two successive exhalations at each flow rate.  Results: Vno50-200 was strongly correlated with Jno in normal subjects (r=0.94, p
Correlation of Surface Markers of Cells of Human Lymphatic Leukemias With Disease Type2
Authors: T. Tsubota, J. Minowada, S. Nakazawa, L. F. Sinks, T. Han, R. J. Higby, D. Pressman
Journal: JNCI Journal of the National Cancer Institute (1977)

Journal Article Correlation of Surface Markers of Cells of Human Lymphatic Leukemias With Disease Type Get access T. Tsubota, T. Tsubota Search for other works by this author on: Oxford Academic PubMed Google Scholar J. Minowada, J. Minowada Search for other works by this author on: Oxford Academic PubMed Google Scholar S. Nakazawa, S. Nakazawa Search for other works by this author on: Oxford Academic PubMed Google Scholar L. F. Sinks, L. F. Sinks Search for other works by this author on: Oxford Academic PubMed Google Scholar T. Han, T. Han Search for other works by this author on: Oxford Academic PubMed Google Scholar R. J. Higby, R. J. Higby Search for other works by this author on: Oxford Academic PubMed Google Scholar D. Pressman D. Pressman Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 59, Issue 3, September 1977, Pages 845–850, https://doi.org/10.1093/jnci/59.3.845 Published: 01 September 1977 Article history Received: 14 February 1977 Accepted: 11 April 1977 Published: 01 September 1977
Abstract 2977: Coronary Small Vessel Disease is the Main Mechanism of Myocardial Ischemia in Fabry Cardiomyopathy
Authors: Cristina Chimenti, Gaetano Tanzilli, Emanuele Morgante, Romina Verardo, Mangieri Enrico, Carlo Gaudio, Matteo A Russo, Andrea Frustaci
Journal: Circulation (2006)
Fas gets protective
Authors: Nicole Johnston
Journal: The Journal of Experimental Medicine (2005)

A deadly receptor reveals a benevolent side in a study on page 575. Landau and colleagues show that the cell death–inducing receptor Fas is required for protection against neurodegeneration in a mouse model of Parkinson's disease (PD).






Figure 

Loss of dopamine-containing neurons (red) is accelerated in the brains of Fas-deficient mice (bottom).




The Fas receptor (Fas), best known for its apoptotic role in the immune system, is widely expressed in nonimmune tissues, including the central nervous system. In the brains of patients with PD, the expression of both Fas and Fas ligand (FasL) is reduced, whereas the expression of soluble Fas is elevated. Soluble Fas is a decoy receptor that impairs Fas signaling by competing for free ligand. Apoptosis has been implicated in PD neurodegeneration, but this occurs independently of caspase-8, an upstream activator in Fas-mediated apoptosis, suggesting that Fas may not be the predominant death inducer in PD.Using mice with Fas/FasL mutations, the authors showed that decreased Fas expression increased susceptibility to a PD-causing neurotoxin. Neuronal cell loss was markedly increased in Fas-deficient mice, and these mice developed severe PD symptoms within days of toxin exposure. In contrast, two strains of mice that express Fas but have mutations in the Fas death domain, a region responsible for apoptotic signaling, were resistant to PD.

Fas defects might also underlie PD in humans, as circulating T cells from patients with PD failed to up-regulate Fas expression in response to mitogenic stimulation. Although the Fas-induced signals that protect the brain have yet to be identified, these findings suggest that, in this model of PD, Fas-induced neuroprotection trumps Fas-induced cell death.
Prognosis after androgen deprivation therapy in men with a rising PSA after prostatectomy
Authors: F. J. Bianco, M. W. Kattan, K. W. Beekman, H. I. Scher, P. T. Scardino
Journal: Journal of Clinical Oncology (2005)

4552 Introduction: PSA levels decline after androgen deprivation therapy (ADT) by cessation of gene expression, decreased cell proliferation and apoptosis. The median duration of response to ADT in men with a rising PSA after radical prostatectomy (RP) is ∼11yrs. We analyzed a large cohort to identify prognostic factors which would predict the duration of response to ADT, including the nadir level of PSA within a defined time after initiation of ADT. Methods: Of 4,035 men treated with RP, 346 received ADT, 81% and 19% for a rising PSA (rPSA) or metastases (M+). They were followed prospectively for a median of 8.4 (interquartile, 5.6 - 11.5) years after RP and 63 died from disease. We incorporated the pathologic stage,Gleason grade, time to rising PSA, PSA doubling time (PSA DT), pre-ADT PSA, and PSA nadir (<0.2ng/ml) within 8 months of ADT (8mPSA0) in our prognostic models aiming at duration of response and cancer specific survival (CSS) from 8 months after ADT Results:Within 8 months of ADT, PSA nadir was <0.2 in 224 (80%) and 44 (66%) patients with rPSA and M+, respectively (p=0.01). There was no difference in CSS rates at 10 years between men treated continuously (61%) or intermittently (68%). The median CSS rate for those who failed to reach an undetectable PSA was 4.8 (95%CI, 2.6–7.1) years. For those with 8mPSA0, the CSS rate at 10 years was 71%, and not significantly affected by the presence or absence of M+. The only independent predictor of 8mPSA0 was the pre-ADT serum PSA level. Independent predictors of duration of response and CSS were 8mPSA0, pre-ADT PSA and PSA DT. Conclusions: For men with a rising PSA after RP, the duration of response to ADT is prolonged. Independent prognostic factors for duration of response to ADT include PSA level at ADT, PSA DT, and PSA nadir at undetectable levels within 8 months of ADT. Predictive models can be developed from this data to identify patients at high risk for early relapse after ADT who may benefit from alternative approaches No significant financial relationships to disclose.
Right ventricular lymphatic insufficiency is associated with increased edema in pulmonary hypertension
Authors: Kelley Colvin, Kurt Stenmark, Michael Yeager
Journal: European Respiratory Journal (2013)

Rationale: Pulmonary hypertension (PH) is associated with right ventricular hypertrophy, decreased cardiac output, and failure. There are no data available on cardiac lymphatic vascularity in PH. We hypothesized that experimental PH with right ventricular failure would be associated with decreased cardiac lymphatic vessel density.  Methods: We evaluated expression of podoplanin, prox-1, aquaporin-1 (AQP-1), LYVE-1, lectins, CD31, and von Willebrand Factor- (vWF) to distinguish lymphatic and blood vessels in the right ventricles (RV) and left ventricles (LV) of rats with PH induced by hypoxia or monocrotaline (MCT). Heart performance was measured using catheterization and echocardiography.  Results: We found decreased AQP-1+/vWF- vessels in RVs of rats with PH compared to controls. These vessels were negative for CD31 expression and alpha-actinin. Lymphatic vessel density appeared unchanged in the LV of PH rats compared to controls. Flow cytometry confirmed the decreased lymphatics in RVs of PH rats. PCR and immunoblot studies confirmed decreased lymphatics in RVs of PH rats vs. controls and LVs of all rats. We performed wet weight (-) dry weight : dry weight ratios on RVs and LVs and found significant increases in edema in RVs and LVs of MCT PH rats vs. hypoxic rats and controls.  Conclusion: These data suggest that experimental PH is associated with RV lymphatic insufficiency and cardiac edema. This may be insufficient to drain the edematous RV, leading to reduced cardiac output and failure. Given the importance of RV failure in PH, our data regarding cardiac lymphatics in PH may have profound therapeutic significance.
Operating characteristics of two independent sample design in phase I trials in pediatric oncology
Authors: M. Raphael, M. Le Deley, G. Vassal, X. Paoletti
Journal: Journal of Clinical Oncology (2007)

9555 Background: The European Medicine Agency (EMEA) stated that the degree of pre-treatments can modify the patient's tolerance to new treatments in pediatrics oncology, and then suggested that exploration of this potential difference should be considered. It is current practice to split a phase I trial in two groups to identify the Maximum Tolerated Dose (MTD) in each group. Yet how relevant such approach is, has not been investigated. In particular, role of baseline characteristics has not been explored. Methods: We reanalyze a large phase I trial of CPT11 in which 80 children had been included (32 heavily pre-treated pts and 48 less heavily pre-treated) to determine if baseline characteristics were associated with the heaviness of pre-treatment and could predict serious adverse events. To investigate robustness of conclusions in the context of small sample sizes, we performed an extended simulation study. We explored dose recommendations in scenarios with group difference, as measured by Odds Ratio (OR), ranging from 1 (absence of difference) to 8 (large difference) and sample size increasing from 2 * 20 to 2*40. Results: We did not find any relation between the degree and pre- treatment and neither the risk of DLT nor the baseline characteristics in this pediatric trial. However robustness appeared to be critical with high risk of misidentification of MTD in each of the two groups, whatever the prognostic value. With a group difference corresponding to OR=8 and balanced sample sizes (2*20 pts), the same MTD was identified in 10% of the simulations. Even with larger sample sizes (2*40pts), this figure reached 24% for OR=3. There is also a very high risk of identifying two different MTD although the risk is similar in the two groups (52% for 40 × 2 patients). Conclusions: Two independent sample designs in pediatric phase I trials should be avoided or reserved to limited situations when there is a strong rationale possibly based on adult data. No significant financial relationships to disclose.
Estrogen and Adenosine Triphosphate–Sensitive Potassium Channels
Authors: Carolyn Webb, Peter Collins
Journal: Circulation (2003)

We read with interest the publication by Lee et al 1 describing the potential mechanisms and effects of intracoronary conjugated estrogens on coronary vasomotion and myocardial ischemia in patients undergoing percutaneous coronary angioplasty.We were surprised at the very high bolus dose of intracoronary Premarin (Wyeth-Ayerst) given-5 mg into the left coronary system (postmenopausal replacement doses, given orally, range from 0.625 to 1.25 mg daily).The initial exposure dose to the coronary circulation would have been enormous; however, the local concentrations of estrogens are not discussed.It is important and relevant to the interpretation of this study to distinguish between acute, pharmacological effects and long-term replacement effects.How can the authors state that physiological levels of estrogen were achieved?They report that "end-study" coronary sinus 17␤-estradiol levels were raised in their subjects (mostly male) receiving Premarin, but the levels exceed that reported in women taking oral replacement. 2The authors state that the levels achieved were similar to those of premenopausal women and were, therefore, physiological.The other point to note is that Premarin is a mixture of several conjugated equine estrogens and is not known to contain 17␤estradiol.It is metabolized mainly to estrone, which then is converted to other estrogens, including 17␤-estradiol. 2 The authors, therefore, were wrong in measuring estradiol without also measuring estrone.Blood sampling for measurement of estradiol levels was performed "at the end of the study," but no time period after administration of Premarin is given.This is vital information for determining whether conversion of Premarin would have occurred.We, therefore, feel that the clinical relevance of this study must be interpreted with caution.
Circulating tumor DNA reflects therapy response in colorectal cancer
Authors: Kerstin Schmidt, Frank Diehl, Michael Choti, Kathy Romans, Kenneth Kinzler, Luis Diaz, Bert Vogelstein
Journal: Clinical Cancer Research (2008)

B40   Somatic mutations are known to drive human tumorigenesis and are suited as highly specific markers of neoplasia. Therefore, a potential approach is to measure mutant DNA fragments released by tumor cells into the circulation to determine tumor burden and to monitor therapy response. In our study the sensitive BEAMing (Beads, Emulsion, Amplification and Magnetics) assay was used to not only detect but also quantify mutant as well as wild-type DNA fragments in plasma. In a prospective study, 162 blood samples of 18 patients with primary and metastatic colorectal cancer who underwent multimodality treatment were longitudinally collected and analyzed. The number of mutant DNA fragments was compared to radiologic findings and values of carcinoembryonic antigen during therapy. We could identify circulating tumor DNA in all patients prior to treatment. Circulating tumor DNA levels dropped rapidly after surgical resection of the tumor but were still detectable in all patients who relapsed later. Furthermore, we were able to detect recurrence before any radiological or biochemical evidence of disease. We could identify circulating tumor DNA in all patients and reliably monitor tumor burden during the course of therapy. We see this approach as a powerful and promising tool for monitoring therapy response and disease progression which could be easily extended to other cancer types in the future.
A retrospective cohort study of interstitial lung diseases in Denmark
Authors: Charlotte Hyldgaard, Elisabeth Bendstrup, Ole Hilberg
Journal: European Respiratory Journal (2012)

Introduction   Interstitial lung diseases are a heterogeneous group of diseases with varying degrees of inflammation and fibrosis. Epidemiological data based on the current diagnostic criteria are sparse.   Objectives   The aim of this study was to characterize the distribution of ILD subtypes in a cohort of Danish patients referred to a tertiary referral hospital.   Methods   We included 431 patients diagnosed with interstitial lung disease (sarcoidosis excluded) and first visit at our department between April 1. 2003 and April 1. 2009. All diagnoses were re-evaluated according to current diagnostic criteria including the 2011 ATS/ERS IPF-guidelines. Details on diagnostics, lung function, comorbidity and treatment were recorded at baseline and throughout the follow-up period.   Results   A total of 186 patients were diagnosed with idiopathic interstitial lung diseases. In this group IPF (n=121) was the most common diagnosis (108 definite and 13 probable IPF) followed by NSIP (n=30), and DIP (n=20). Other large groups were unclassifiable fibrosis (n=62), end stage fibrosis (n=43), extrinsic allergic alveolitis (n=32) and ILD in collagen vascular disease (n=54). Of patients with CVD-ILD 14 showed a UIP pattern, 22 a NSIP pattern and 18 an unclassifiable fibrosis pattern.  The remaining 54 patients in the cohort had 15 different diagnoses.  Mean age at diagnosis was 61 years (SD=14), and mean symptom duration before referral was 2.5 years. Thoracoscopic biopsy was performed in 39%. The estimated incidence rate is 4.1 per 100,000/year.   Conclusion   The preliminary results of the study of this well-characterised cohort show that IPF is the most common diagnosis, and that a definite IPF-diagnosis can be made in the majority of these cases.
Cancer Metastasis: Perivascular Macrophages Under Watch
Authors: Ece Kadioglu, Michele De Palma
Journal: Cancer Discovery (2015)

Abstract Summary: TIE2-expressing macrophages cluster around blood vessels and sustain tumor angiogenesis. Harney and colleagues now use live imaging of mouse mammary tumors to show that these perivascular macrophages also promote the transient opening of tumor blood vessels to facilitate hematogenous cancer cell dissemination and metastasis. Cancer Discov; 5(9); 906–8. ©2015 AACR. See related article by Harney et al., p. 932.