tbuckley/cabot-search huggingface dataset:
Prognostic significance of initial clinical and molecular genetic features of acute promyelocytic leukemia (APL): Results from the North American Intergroup Trial, C9710
Authors: W. Stock, B. Moser, B. L. Powell, F. R. Appelbaum, M. S. Tallman, R. A. Larson, J. H. Feusner, C. D. Bloomfield, C. Willman, R. E. Gallagher
Journal: Journal of Clinical Oncology (2007)

7016 Background: The impact of previously defined prognostic variables can change with advances in treatment. Thus, the significance of initial clinical and molecular genetic features of APL were explored in the context of the first randomized trial designed to evaluate the potential benefit of adding As 2 O 3 consolidation into front-line all-trans retinoic acid (ATRA)-based therapy of APL (Powell et al, ASCO 2007). Methods: We evaluated pre-treatment white blood cell (WBC) and platelet count, age, PML-RARA transcript level and isoform type in the first 180 untreated APL patients (pts) who underwent molecular analysis on C9710 and explored their relationship to disease- free (DFS) and overall survival (S). PML-RARA transcripts were measured using real-time quantitative RT-PCR and expressed as a normalized quotient (NQ) of PML-RARA/GAPDH. Results: Using a multivariate proportional hazard model, pre-treatment PML-RARA level and WBC count were independently associated with DFS; p = 0.0073 and p = 0.05, respectively. Pre-treatment WBC count was the only feature significantly associated with S; p&lt;0.0001. With a median follow-up of 29 months, neither median DFS nor S have been reached and only 30 DFS events have been reported among these 180 pts. Pts with higher presenting WBC &gt; 10K/μl had both shorter DFS and S with hazard ratios (HR) of 2.3 and 5.5, respectively. The relationships between treatment arm and pre-treatment WBC and PML-RARA transcript level were explored by categorical analyses. For non-As 2 O 3 -treated pts, a striking difference was observed in DFS at 2.5 years between those above or below cut-off values: WBC &lt;10K, 78%; WBC &gt;10K, 50%; NQ &lt;median, 87%; NQ &gt;median, 60%. For As 2 O 3 -treated pts smaller and the reverse differences were observed: WBC &lt;10K, 94%; WBC &gt;10K, no DFS events reported; NQ &lt; median, 93%; NQ &gt;median, no DFS events reported. Conclusion: These preliminary results (based on analysis of 31% of total C9710 pts) indicate that pre-treatment PML-RARA transcript level and WBC are prognostic variables for newly diagnosed APL pts in first remission treated with standard ATRA-based chemotherapy but suggest that they may not apply in pts receiving two 25-day courses of As 2 O 3 as first consolidation. No significant financial relationships to disclose.
Effect of baseline FVC on preservation of lung function with BIBF 1120: Results from the TOMORROW trial
Authors: Luca Richeldi, Ulrich Costabel, Moises Selman, Dong Soon Kim, Kevin R. Flaherty, Paul W. Noble, Ganesh Raghu, Arata Azuma, Michèle Brun, Abhya Gupta, Matthias Klueglich, Nolwenn Juhel, Roland M. du Bois
Journal: European Respiratory Journal (2011)

Background: BIBF 1120 is an inhibitor of tyrosine kinase receptors involved in the progression of lung fibrosis.

Methods: The efficacy and safety of 50 mg, 100 mg, 200 mg and 300 mg daily doses of BIBF 1120 were evaluated in 428 patients diagnosed with IPF in a Phase 2 randomized, double-blind placebo (PBO)-controlled trial. Subgroup analyses of the annual rate of decline in forced vital capacity (FVC) by baseline lung function were carried out to evaluate the impact of stage of disease on the effect of BIBF 1120.

Results: Baseline FVC was similar in all groups (mean: 2.8 L; 81.3% predicted). The annual rate of decline in FVC was -0.060 L/year with BIBF 1120 300 mg vs -0.190 L/year with PBO (p=0.014; closed-testing multiplicity-corrected: p=0.064). Patients with baseline FVC ≥70% of predicted value showed almost no FVC decline with BIBF 1120 300 mg (-0.010 L/year [n=57] compared with -0.186 L/year in the PBO group [n=61]; p=0.004). However, there were no significant differences in FVC decline in patients with baseline FVC <70% of predicted value (-0.176 L/year with 300 mg [n=27] vs -0.203 L/year with PBO [n=22]; p=0.794). Similarly, lower rates of FVC decline were observed with 300 mg vs PBO in patients with baseline FVC ≥85% (-0.027 L/year [n=30] vs -0.160 [n=31]; p=0.112) and ≥90% (-0.019 L/year [n=23] vs -0.186 [n=25]; p=0.088) of predicted value; however, these findings were based on small sample sizes and the differences did not reach significance.

Conclusion: The effects of IPF treatment may be more easily demonstrable in patients with FVC values closer to predicted values.
NEMO: A phase 3 trial of binimetinib (MEK162) versus dacarbazine in patients with untreated or progressed after first-line immunotherapy unresectable or metastatic <i>NRAS</i>-mutant cutaneous melanoma.
Authors: Keith Flaherty, Petr Arenberger, Paolo Antonio Ascierto, Jan Willem De Groot, Sigrun Hallmeyer, Georgina V. Long, Michal Lotem, Maria Marples, Dirk Schadendorf, Alexander Starodub, Matthew Hiram Taylor, Pascal Wolter, Naoya Yamazaki, Ernesto Wasserman, James Ford, Marine Weill, Reinhard Dummer
Journal: Journal of Clinical Oncology (2014)

TPS9102 Background: Melanoma tumors often harbor mutations in the mitogen-activated protein kinase-signaling pathway family members BRAF or NRAS. NRAS mutations, observed in about 15% of patients with melanoma, are associated with higher tumor proliferation and poorer prognoses. A large retrospective analysis (n = 677) demonstrated that NRAS mutations are independently predictive of poor survival in patients with cutaneous melanoma (Jakob et al., 2011). With no approved targeted therapies for melanoma patients with NRAS-mutant tumors, treatments are currently limited to chemotherapy and/or immunotherapy. Binimetinib (MEK162), a potent and selective inhibitor of MEK1/2, has demonstrated promising phase 2 clinical activity in this patient subset. Here we describe the “NRAS mElanoma and MEK inhibitOr” (NEMO) trial, an ongoing phase 3 study designed to compare the efficacy of binimetinib vs dacarbazine in patients with metastatic NRAS-mutant cutaneous melanoma (NCT01763164). Methods: NEMO is a 2-arm, open-label, 2:1 randomized trial of binimetinib vs dacarbazine. Eligible patients must have advanced unresectable or metastatic cutaneous melanoma with a documented NRAS Q61 mutation (by central molecular screening) that was previously untreated or has progressed after 1 line of immunotherapy. Patients are stratified by stage, performance status, and prior immunotherapy. The primary endpoint of the study is progression-free survival, and secondary endpoints include overall survival, overall response, disease control rate, safety, and quality of life. Binimetinib is administered orally at 45 mg twice daily and dacarbazine is dosed intravenously at 1000 mg/m2 once every 3 weeks, until disease progression or unacceptable toxicity. Patient crossover from the dacarbazine arm to the binimetinib arm is not permitted. This phase 3 trial is designed to enroll 393 patients and is currently recruiting patients at more than 150 centers worldwide. Clinical trial information: NCT01763164.
Court-mandated treatment: dilemmas for hospital psychiatry
Authors: R Liss, A Frances
Journal: American Journal of Psychiatry (1975)

The authors present clinical material to illustrate the special treatment and management problems posed by different types of mentally ill offenders; they suggest that court-mandated hospital treatment is often destructive and unrelated to the needs of the patient, the community, and the mental institution. The failure to create new kinds of institutions, combining modalities derived from the hospital and correctional systems, is traced to poor communication among the disciplines involved. The "mentally ill offender" is caught in the interplay of these systems and is consequently both their victim and victimizer.
Cigarette smoke induces β2-integrin-dependent neutrophil migration across human umbilical vein endothelium
Authors: Saskia Overbeek, Saskia Braber, Paul Henricks, Marije Kleinjan, Vera Kamp, Niki Georgiou, Johan Garssen, Aletta Kraneveld, Gert Folkerts
Journal: European Respiratory Journal (2011)

Background: Cigarette smoking induces peripheral inflammatory responses in all smokers and is the major risk factor for neutrophilic lung diseases such as chronic obstructive pulmonary disease. The aim of this study was to investigate the effect of cigarette smoke on neutrophil chemotaxis and on β2-integrin activation and function in neutrophilic transmigration through endothelium.

Methods and results: Utilizing freshly isolated human neutrophils, the effect of cigarette smoke on chemotaxis and β2-integrin activation was studied. We demonstrate that cigarette smoke extract (CSE) dose dependently induced chemotaxis of neutrophils in vitro. Moreover, CSE promoted neutrophil adherence to fibrinogen. Using functional blocking antibodies against CD11b and CD18, it was shown that Mac-1 (CD11b/CD18) was responsible for the cigarette smoke-induced firm adhesion of neutrophils to fibrinogen. Furthermore, neutrophils transmigrated through endothelium by cigarette smoke due to the activation of β2-integrins, since pre-incubation of neutrophils with functional blocking antibodies against CD11b and CD18 attenuated this transmigration.

Conclusion: This is the first study to describe that cigarette smoke extract is a direct chemo-attractant for neutrophils and an activator of β2-integrins on the cell surface. Blocking this activation of β2-integrins might be an important target in cigarette smoke induced neutrophilic diseases.
Effects of atrasentan on disease progression and biological markers in men with metastatic hormone-refractory prostate cancer: Phase 3 study
Authors: M. Carducci, J. B. Nelson, F. Saad, C. C. Schulman, D. P. Dearnaley, D. J. Sleep, S. M. Hulting, J. D. Isaacson, A. R. Allen, P. Nisen
Journal: Journal of Clinical Oncology (2004)

4508 Background: In earlier trials, atrasentan, a potent, selective, oral endothelin A receptor antagonist, significantly delays time to disease progression (TTP) in a per-protocol group of hormone-refractory prostate cancer (HRPC) patients identified pre–blind break. We report the results from a phase 3 trial. Methods: 809 subjects with metastatic HRPC enrolled into a phase 3, randomized, double-blind, placebo-controlled study of 10 mg atrasentan were analyzed (401 placebo, 408 atrasentan). Kaplan-Meier and Cox proportional hazard methodologies were used to compare TTP (a composite of radiographic and clinical measures) between treatments. Analysis of covariance compared change from baseline to final value in PSA and bone and total alkaline phosphatase (BAP and ALP). Data from a protocol-compliant subset identified prior to blind break were analyzed as well. Results: Atrasentan exhibited a nonsignificant trend in delayed TTP (log-rank p=0.091; hazard ratio [HR] = 1.14, 95% CI = 0.98–1.34) and significantly delayed time to BAP progression (TTBAP, >50% increase from nadir) versus placebo (median: 254 vs 505 days; log-rank p<0.001; HR = 1.78, 95% CI = 1.34–2.37). The atrasentan group showed smaller mean increases than the placebo group in PSA (p=0.025), BAP (p=0.001), and ALP (p<0.001). In the protocol-compliant subset (329 placebo, 342 atrasentan), atrasentan significantly delayed TTP (log-rank p=0.007; HR = 1.26, 95% CI = 1.06–1.50) and TTBAP (log-rank p<0.001) and resulted in smaller mean changes from baseline to final in the 3 biological markers. Atrasentan was well tolerated. The most common associated adverse events, peripheral edema, rhinitis, and headache, resulted in few discontinuations. Conclusions: Atrasentan demonstrated a significant delay in TTP and attenuated increase in relevant bone and tumor markers in metastatic HRPC patients representative of the intended target population. The accumulating and consistent data for atrasentan demonstrates biologic and clinical activity of endothelin receptor blockade in metastatic HRPC. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Abbott Laboratories Abbott Laboratories Abbott Laboratories Aventis Abbott Laboratories
Postoperative gemcitabine alone and concurrent with radiation therapy in locally advanced pancreatic carcinoma.
Authors: S. Demirci, S. Ozkok, D. Yalman, M. Zeytunlu, D. Nart, Y. Yuzer, A. Coker, R. Uslu, E. Goker
Journal: Journal of Clinical Oncology (2010)

e14664 Background: To evaluate the treatment results of gemcitabine (GEM) alone and concurrent with radiotherapy (RT) after R0/R1 resection of locally advanced pancreatic cancer. Methods: From 1999 to 2005, 55 patients with stage II resected pancreatic cancer whom were treated with GEM based radiochemotherapy (RCT) were retrospectively evaluated. Treatment schema consist of 1 cycle of induction GEM 1,000 mg/m2 on D1,D8, D15 followed by GEM 300 mg/m2 weekly concurrent with radiotherapy (50.4-54 Gy in 180 cGy daily fractions). After the completion of radiochemotherapy, patients received 3 additional courses of GEM 1,000 mg/m2 on D1, D8, D15. Results: Thirteen patients were stage IIA and 42 were stage IIB. Forty-six patients (83.6%) had R0 and 9 patients (16.4%) had R1 resection. All of the patients received induction chemotherapy and RT, all but 3 received concurrent RCT, and 46 (84%) patients received maintanence chemotherapy. 11 %, 13.5%, 19.5 % of the patients had at least one ≥ grade 3 toxicity during induction, concurrent, and maintanence phases of the treatment schema. Within a median 47 months of (34-105) follow-up, 4 (7.3%) patients had isolated local recurrence, 5 (9%) patients had both local recurrence and distant metastases, and 27 (49 %) had only distant metastases. Median disease-free survival (DFS) and overall-survival (OS) were 13 (4-105), and 19 months (6-105) respectively. In multivariate analysis, statistically significant prognostic factors were nodal stage (p = 0.05), AJCC stage (p = 0.05) and number of lymph nodes dissected (p = 0.006) for DFS and Karnofsky Performance Status (p = 0.03) was for OS. Conclusions: Pancreatic cancer prognosis still remains poor despite adjuvant RCT. More aggressive treatments should be considered in patients with unfavorable prognostic factors. No significant financial relationships to disclose.
Phase II randomized study of FOLFIRI vs FOLFIRI + celecoxib in first line treatment of advanced colorectal cancer (ACRC)
Authors: E. Maiello, F. Giuliani, S. Romito, G. Pezzella, R. Mallamaci, N. Di Renzo, M. Di Bisceglie, V. Gebbia, M. Lopez, G. Colucci
Journal: Journal of Clinical Oncology (2005)

3656 Background: The combination of Irinotecan (CPT-11) at 180 mg/mq combined with LV5FU2 (FOLFIRI - Douillard regimen), represents a standard first-line therapy for ACRC pts. Celecoxib is a selective anti-Cox2 compound with antineoplastic properties such as angiogenic inhibition and apoptosis induction. Experimental data demonstrated the synegistic interaction of Celecoxib with CPT-11 and Fluorouracil (FU). Taking into account these data the Gruppo Oncologico dell’Italia Meridionale (GOIM), started a phase II randomized study to compare the activity and toxicity of FOLFIRI regimen alone (arm A) or with the addition of Celecoxib (arm B) in ACRC pts. Methods: Pts with hystological/cytological diagnosis of colorectal cancer, measurable disease, ECOG PS ≤ 2, age ≥ 18 and ≤ 75 years, entered into this trial. Pts were randomized to receive: Arm A: CPT-11 180 mg/mq on day 1 and LV5FU2 regimen (Folinic acid 100 mg/mq in 2-hr iv infusion, FU 400 mg/mq iv bolus, and FU 600 mg/mq in 22-hr iv infusion on day 1 and 2); or Arm B: as arm A with the addition of Celecoxib (400 mg bid continously).Both regimen were repeated every 2 weeks. Recist and NCI-NCTG criteria were employed to evaluate the activity and toxicity, respectively. Results: Up to now 71 pts have been enrolled (A/B: 35/36) and 56 are evaluable for activity and toxicity (A/B: 29/27). The main characteristics of the evaluable pts were (A/B): median age 64/65; median PS: 0/0; sites of disease: liver 23/21, lung 11/11, lymphnodes 5/5, primary tumor 3/3. Multiple sites of disease were present in 22 and 27 pts, respectively. Among the 29 evaluable pts in arm A we observed: 11 PR (38%), 11 SD (38%) and 7 PD (24%) with an objective response rate (ORR) of 38%; in arm B we observed 1 CR (4%), 9 PR (33%), 12 SD (44%) and 5 PD (19%) for an ORR of 37%. The main toxicities (% grade III-IV, A/B) were: neutropenia 3/7, anemia 3/7, nausea/vomiting 3/7, diarrea 3/7, mucositis 3/3, alopecia 0/7. Conclusions: These preliminary data indicate that the addition of Celecoxib to FOLFIRI regimen is is an efficacious and well tolerated treatment in ACRC pts. The study is ongoing. No significant financial relationships to disclose.
The mechanisms of anti-inflammatory action of bronchodilators
Authors: Usman Farkhutdinov, Shamil Farkhutdinov, Guzel Yakupova, Yulia Kharisova
Journal: European Respiratory Journal (2013)

Tiotropium (T) is one of the basic medications in the treatment of chronic obstructive pulmonary disease (COPD). Apart from high bronchodilator activity the efficacy of T may be attributed to its potential influence on the production of active oxygen forms (AOF) by inflammatory cells.  The aim was to study the effect of T on the production of AOF in the blood of patients with COPD.   Methods:  In in-vitro experiments the method of chemiluminescence (ChL) registration was used to study the production of AOF in the blood of patients with COPD exacerbations and the effect of T on this process. To determine a dose dependence of AOF generation in blood the concentration of T was changed. The preparation was added into the whole blood of patients in various doses (0.005 mkg/ml, 0.01 mkg/ml, 0.05 mkg/ml).   Results:  In comparison with normal findings ChL intensity of blood in patients with COPD exacerbations was higher by 1.4-times. At a dose of 0.005 mkg/ml T decreased ChL intensity of blood of patients by 15.1%±0.3 (p   Conclusion:  The study demonstrated that T possesses a dose-dependent antioxidant activity. The ability of T to suppress production of AOF underlies the mechanism of its anti-inflammatory effect in patients with COPD.
Freeze-Etching, Scanning, and Thin-Section Electron Microscopic Studies of the “Hairy” Leukocytes in Leukemic Reticuloendotheliosis2
Authors: C. Patrick Burns, John C. Hoak
Journal: JNCI Journal of the National Cancer Institute (1973)

We used 3 techniques—freeze-etching, scanning, and thin-section electron microscopy—to study the ultrastructure of abnormal mononuclear leukocytes from 3 patients with leukemic reticuloendotheliosis. Freeze-etching minimized artifactual distortion of the cytoplasmic “hairs,” while allowing α three-dimensional-like view of the cell cleaved through membrane planes. Cleavage planes revealed no membrane abnormalities. Multishaped, tentacle-like projections of the cytoplasm contained few organelles. Cytoplasm contained mitochondria, endoplasmic reticulum, microfilaments, and granules. Nuclear pores were present in a high density similar to that in activated lymphocytes. Scanning electron microscopy, after critical point drying to decrease distortion, revealed abnormal cells with an extensive series of membrane outpouchings in these leukocytes but not in control preparations of cells from normal individuals and patients with chronic lymphocytic leukemia. Examination of thin sections revealed many cytoplasmic projections into redundant but apparently normal tri laminar membrane. Observation of these unique neoplastic cells by specialized ultrastructural techniques suggested that their major feature was the redundant membrane without unique morphologic membrane defects. The freezeetch studies confirmed that the hairlike projections of the leukocytes were not artifacts.
Preliminary results from the laboratory phase of ECRHSIII in Melbourne
Authors: Michael Abramson, Sonia Kaushik, Geza Benke, Bruce Thompson, Shyamali Dharmage
Journal: European Respiratory Journal (2013)

The European Community Respiratory Health Survey (ECRHS) was the largest international study of lung health in young adults.   Aim:  to describe changes in chronic respiratory diseases and symptom prevalence in adults as they age.   Methods:  876 young adults participated in ECRHS in Melbourne in 1992. Of 722 eligible subjects, 543 (75.2%) completed postal or telephone screening questionnaires in 2012. 451 were invited for clinical testing including a more extensive interviewer administered questionnaire.   Results:  Of the first 48 subjects to attend the laboratory, 29 (60.4%) were female. The mean age was 57.0 (SD 4.5) years. The most common respiratory symptoms reported were shortness of breath after exertion 20 (41.7%), wheezing / chest tightness each reported by 10 (20.8%) participants, nocturnal cough 16 (33.3%), daytime cough 8 (16.7%), productive cough 4 (8.3%), nocturnal shortness of breath 3 (6.3%), shortness of breath at rest 2 (4.2%) and morning cough 2 (4.2%). Males were more likely to report nocturnal chest tightness than females (p=0.03), but there no were no other significant differences between genders. Dr diagnosed asthma was reported by 15 (31.3%); 5 (10.4%) reported an attack within the last 12 months and 8 (16.7%) were taking medication. Chronic bronchitis was reported by 8 (16.7%), but none reported a diagnosis of emphysema or COPD. Short acting beta agonists were used by 9 (18.8%) and combination LABA / steroid inhalers by 8 (16.7%).   Conclusions:  The cohort remains highly symptomatic, although most have not been diagnosed or treated. Longitudinal analysis of the complete data will be conducted to determine whether there have been changes in prevalence over 20 years.
Abstract P350: Short-Term Ginger Consumption Does Not Affect Metabolic Profile and Inflammatory Markers in Overweight Men
Authors: Yu-Ming Ni, Muhammad Mansour, Marie-Pierre St-Onge
Journal: Circulation (2012)

Introduction: Functional foods are foods that exhibit beneficial health effects beyond their inherent nutritional value. Spices, in particular, have been targeted for their apparent thermogenic and anti-inflammatory properties. Ginger has been used in ancient medicine to treat a variety of conditions, including hypertension, hyperlipidemia, hyperglycemia, and hypercholesterolemia. However, while several studies have examined the effects of ginger in animal or in vitro models, few studies have verified the health effects of ginger consumption in humans. The purpose of this study was to determine the metabolic, inflammatory, and gut hormone effects of ginger consumption in overweight men. Hypothesis: We hypothesize that acute ginger consumption would improve metabolic profile and inflammatory markers compared to a no-ginger condition. Methods: Ten men completed this 2-arm randomized pilot crossover study in which they consumed a standard breakfast with either 2 g ginger powder dissolved in hot water (treatment phase) or hot water only (control phase). Blood samples were drawn before and at 0, 30, 45, 60, 120, 180 min after breakfast consumption and analyzed for glucose, insulin, leptin, adiponectin, triglycerides, inflammatory markers (interleukin-6, C-reactive protein, and tumor necrosis factor alpha) and gut hormones (ghrelin, peptide YY, glucagon-like peptide 1). Regression analysis was done to test the effects of ginger intake on hormones and metabolites after adjusting for age, body weight, and race. Results: There was no significant ginger x time interaction on any of the hormones and metabolites assayed. Total ghrelin levels tended to be higher in the ginger compared to the control condition (P = 0.096), and removing the data from a diabetic subject led to a significant difference (P = 0.0416). Active ghrelin levels were not significantly different between test conditions (P = 0.15). Conclusions: This study provides preliminary information on the effects of ginger consumption on metabolic risk factors in humans. Future research should examine the long-term effects of regular ginger consumption as prolonged consumption may be necessary to observe changes in metabolic risk factors.