Hemopathologic consequences of protracted gamma irradiation: alterations in granulocyte reserves and granutocyte mobilization

Blood ◽  
1980 ◽  
Vol 56 (1) ◽  
pp. 42-51 ◽  
Author(s):  
TM Seed ◽  
SM Cullen ◽  
LV Kaspar ◽  
DV Tolle ◽  
TE Fritz
Keyword(s):  
Phase I ◽  
Gamma Irradiation ◽  
Aplastic Anemia ◽  
Low Dose ◽  
Intermediate Phase ◽  
Myelogenous Leukemia ◽  
Time Dependent ◽  
Phase Iii ◽  
Simple Pattern ◽  
Radiation Induced

Abstract Aplastic anemia and myelogenous leukemia are prominent pathologic effects in beagles exposed to continuous, daily, low-dose gamma irradiation. In the present work, granulocyte reserves and related mobilization functions have been sequentially assessed by the endotoxin stress assay during the preclinical and clinical phases of these hemopoietic disorders. Characteristic patterns of granulocyte reserve mobilization are described that reflect given stages of pathologic progression. For radiation-induced leukemia, a five stage pattern has been proposed. In contrast, a simple pattern of progressive, time- dependent contraction of granulocyte reserves and mobilization capacity was noted in the development of terminal aplastic anemia. Early preclinical phases of radiation-induced leukemia appear to involve an extensive depletion of the granulocyte reserves ((phase I) during the first approximately 200 days of exposure followed by a partial renewal of the reserves and associated mobilization functions approximately 200 and 400 days (phase II). Sustained, subnormal granulocyte mobilizations (phase III) following endotoxin stress typify the responses of dogs during the intermediate phase, whereas late preclinical, preleukemic stages (phase IV) are characterized by a further expansion of the reserves and in the mobilization capacities, particularly of the less mature granulocytes. Such late alterations in the pattern of granulocyte mobilization, together with other noted cellular aberrancies in the peripheral blood and marrow, appear to indicate leukemia (phase V) onset.

scholarly journals Hemopathologic consequences of protracted gamma irradiation: alterations in granulocyte reserves and granutocyte mobilization

Blood ◽  
1980 ◽  
Vol 56 (1) ◽  
pp. 42-51 ◽  
Author(s):  
TM Seed ◽  
SM Cullen ◽  
LV Kaspar ◽  
DV Tolle ◽  
TE Fritz
Keyword(s):  
Phase I ◽  
Gamma Irradiation ◽  
Aplastic Anemia ◽  
Low Dose ◽  
Intermediate Phase ◽  
Myelogenous Leukemia ◽  
Time Dependent ◽  
Phase Iii ◽  
Simple Pattern ◽  
Radiation Induced

Aplastic anemia and myelogenous leukemia are prominent pathologic effects in beagles exposed to continuous, daily, low-dose gamma irradiation. In the present work, granulocyte reserves and related mobilization functions have been sequentially assessed by the endotoxin stress assay during the preclinical and clinical phases of these hemopoietic disorders. Characteristic patterns of granulocyte reserve mobilization are described that reflect given stages of pathologic progression. For radiation-induced leukemia, a five stage pattern has been proposed. In contrast, a simple pattern of progressive, time- dependent contraction of granulocyte reserves and mobilization capacity was noted in the development of terminal aplastic anemia. Early preclinical phases of radiation-induced leukemia appear to involve an extensive depletion of the granulocyte reserves ((phase I) during the first approximately 200 days of exposure followed by a partial renewal of the reserves and associated mobilization functions approximately 200 and 400 days (phase II). Sustained, subnormal granulocyte mobilizations (phase III) following endotoxin stress typify the responses of dogs during the intermediate phase, whereas late preclinical, preleukemic stages (phase IV) are characterized by a further expansion of the reserves and in the mobilization capacities, particularly of the less mature granulocytes. Such late alterations in the pattern of granulocyte mobilization, together with other noted cellular aberrancies in the peripheral blood and marrow, appear to indicate leukemia (phase V) onset.

Phase I Study of 30-Minute Infusion of Carfilzomib As Single Agent or in Combination With Low-Dose Dexamethasone in Patients With Relapsed and/or Refractory Multiple Myeloma

2015 ◽  
Vol 33 (7) ◽  
pp. 732-739 ◽  
Author(s):  
Kyriakos P. Papadopoulos ◽  
David S. Siegel ◽  
David H. Vesole ◽  
Peter Lee ◽  
Steven T. Rosen ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Plasma Concentration ◽  
Phase I ◽  
Phase I Study ◽  
Low Dose ◽  
Single Agent ◽  
Phase Iii ◽  
Maximum Plasma ◽  
Irreversible Inhibitor ◽  
Refractory Multiple Myeloma

Purpose Carfilzomib is an irreversible inhibitor of the constitutive proteasome and immunoproteasome. This phase I study evaluated the maximum-tolerated dose (MTD), pharmacokinetics, and pharmacodynamics of carfilzomib administered as a 30-minute intravenous (IV) infusion. Safety and efficacy of carfilzomib as a single agent or in combination with low-dose dexamethasone were assessed. Patients and Methods Patients with relapsed and/or refractory multiple myeloma (MM) were administered single-agent carfilzomib on days 1, 2, 8, 9, 15, and 16 of a 28-day cycle. Cycle one day 1 and 2 doses were 20 mg/m2, followed thereafter by dose escalation to 36, 45, 56, or 70 mg/m2. Additionally, carfilzomib was combined with low-dose dexamethasone (40 mg/wk). Results Thirty-three patients were treated with single-agent carfilzomib. Dose-limiting toxicities in two patients at 70 mg/m2 were renal tubular necrosis and proteinuria (both grade 3). The MTD was 56 mg/m2. Nausea (51.5%), fatigue (51.5%), pyrexia (42.4%), and dyspnea and thrombocytopenia (each 39.4%) were the most common treatment-related toxicities. Overall response rate (ORR) was 50% (56-mg/m2 cohort). Increasing carfilzomib dosing from 20 to 56 mg/m2 resulted in higher area under the plasma concentration-time curve from time zero to last sampling and maximum plasma concentration exposure with short half-life (range, 0.837 to 1.21 hours) and dose-dependent inhibition of proteasome chymotrypsin-like activity. In 22 patients treated with 45 or 56 mg/m2 of carfilzomib plus low-dose dexamethasone, the ORR was 55% with a safety profile comparable to that of single-agent carfilzomib. Conclusion Carfilzomib administered as a 30-minute IV infusion at 56 mg/m2 (as single agent or with low-dose dexamethasone) was generally well tolerated and highly active in patients with relapsed and/or refractory MM. These data have provided the basis for the phase III randomized, multicenter trial ENDEAVOR.

LBH589 (panobinostat): A Potential Novel Anti-Switching Therapy.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2568-2568 ◽  
Author(s):  
Abdullah Kutlar ◽  
Niren Patel ◽  
Celalettin Ustun ◽  
Kavita Natarajan ◽  
Anand Jillella ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Phase I ◽  
Research Funding ◽  
Hdac Inhibitors ◽  
Primary Myelofibrosis ◽  
Hematologic Malignancies ◽  
Myelogenous Leukemia ◽  
Phase Iii ◽  
Maximal Response ◽  
Globin Synthesis

Abstract Abstract 2568 Poster Board II-545 Reversing the perinatal switch from fetal to adult hemoglobin synthesis has been an attractive therapeutic goal for β-hemoglobinopathies such as sickle cell disease (SCD) and β-thalassemia. Fetal hemoglobin (Hb F) inhibits the polymerization of deoxy Hb S (anti-sickling effect) in SCD and ameliorates the globin chain imbalance by compensating for severely diminished or absent β-globin synthesis in β-thalassemia. Different classes of compounds have been used for this purpose; only hydroxyurea (HU), an S-phase specific chemotherapeutic agent, an inhibitor of ribonucleotide reductase, has been FDA approved for use in adults with SCD and is currently in phase III trials for infants and children. Despite the established efficacy of HU in many patients with SCD, there is a need for alternative Hb F inducing agents and therapies; an estimated 30% of patients do not respond to HU therapy. In addition, some patients are intolerant of HU due to a number of side effects. The development of novel, more effective anti-switching agents is hampered by a lack of a clear and complete understanding of the molecular mechanism(s) underlying the perinatal switch from fetal (γ-globin) to adult (β-globin) synthesis despite three decades of intensive research. Nevertheless, it has been established that epigenetic mechanisms such as histone deacetylation and DNA methylation do play an important role in the silencing of the γ-globin genes during the perinatal period. In vitro studies and early phase clinical trials in a small number of patients have provided the proof-of-principle for the efficacy of a number of histone deacetylase (HDAC) inhibitors and hypomethylating agents (DNA methyl transferase I inhibitors). Butyrate derivatives are an example of HDAC inhibitors whose efficacy in inducing Hb F has been proven in both SCD and β-thalassemia. More recently, other HDAC inhibitors (SAHA, Depsipeptide, Trichostatin A) have been shown to induce Hb F synthesis in erythroid cultures. DNMT-1 inhibitors, 5-Azacytidine and decitabine, have also been used in small clinical trials to enhance Hb F production and ameliorate the course of severe SCD. LBH589 (panobinostat, Novartis Pharma) is a pan-HDAC inhibitor that belongs to the hydroxamic acid class of HDAC inhibitors that is currently being investigated in Phase I/II trials in hematologic malignancies and a number of solid tumors. We monitored the Hb composition of 21 patients with relapsed/refractory hematologic malignancies enrolled into a Phase I/b trial of panobinostat conducted at the MCG Cancer Center. Hb quantification was done by a cation exchange HPLC procedure. Eight patients were on panobinostat for 2 months or longer with a starting dose of 40–60 mg PO administered thrice weekly (MWF). Three patients carried a diagnosis of Primary Myelofibrosis and one each had Chronic Lymphocytic Leukemia, Mantle Cell Lymphoma, Multiple Myeloma, Refractory Non-Hodgkins Lymphoma, and Chronic Myelogenous Leukemia-accelerated phase. Of these, 4 patients displayed an increase in Hb F over baseline values. None of the patients had an inherited hemoglobinopathy (SCD or β-thalassemia). The median Hb F was 0.33% at entry (range: 0–2.3) and increased to 1.1% (range 0–17%) at the end of the study period. The maximal response was seen in a patient with Primary Myelofibrosis whose Hb F increased from a pretreatment value of 0.2% to 17.0% over a period of 16 months. Overall, patients who were on panobinostat for longer periods of time (≥ 2 months) had a more pronounced increase in Hb F. The remaining 13 patients were on study drug for <2 months. In studies of other Hb F inducing agents, optimal response is not generally reached in less than 6 months. The slight but significant increase in Hb F in this small group of patients without an underlying hemoglobinopathy is encouraging and provides the rationale for a trial of panobinostat as an anti-switching agent in clinically significant hemoglobinopathies such as SCD and β-thalassemia. This effect will likely be enhanced in patients with hemoglobinopathies given the erythropoietic stress and the selection of RBCs containing Hb F. Studies in transgenic mouse models of SCD and a phase I study in patients with SCD who have failed or intolerant of HU are underway. Disclosures: Kutlar: Novartis Pharmaceuticals, Inc.: Research Funding; Celgene Corporation: Research Funding; HemaQuest Pharmaceuticals, Inc.: Research Funding. Meiler:Celgene Corporation: Research Funding; Novartis Pharmaceuticals, Inc.: Research Funding. Bhalla:Novartis: Honoraria, Research Funding; Merck: Honoraria.

Value of Low Dose IL-2 as Maintenance Following Consolidation Treatment or Autologous Transplantation in Acute Myelogenous Leukemia (AML) Patients Aged 15-60 Years Who Reached CR After High Dose (HD-AraC) Vs Standard Dose (SD-AraC) Cytosine Arabinoside During Induction: Results of the AML-12 Trial of EORTC and GIMEMA Leukemia Groups.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 791-791 ◽  
Author(s):  
Roelof Willemze ◽  
Stefan Suciu ◽  
Franco Mandelli ◽  
Stijn J.M. Halkes ◽  
Jean-Pierre Marie ◽  
...  
Keyword(s):  
Overall Survival ◽  
Low Dose ◽  
Hazard Ratio ◽  
Myelogenous Leukemia ◽  
Phase Iii ◽  
Medical Decision ◽  
Induction Treatment ◽  
High Dose ◽  
Observation Period

Abstract Abstract 791 The AML-12 randomized phase III trial of the EORTC and GIMEMA Leukemia Groups assessed the efficacy and toxicity of HD-AraC (3 g/m2/12 hrs for 4 days) combined with daunorubicin (50 mg/sqm for 3 days) and etoposide (50 mg/sqm for 5 days) vs SD-AraC (100 mg/sqm for 10 days) combined with the same drugs. Patients (pts) in complete remission (CR) received consolidation consisting of AraC (500 mg/sqm/12 hrs for 6 days) and daunorubicin (50 mg/sqm for 3 days). Subsequently an allogeneic (allo-SCT) or autologous stem cell transplantation (auto-SCT) was planned according to donor availability, cytogenetics and age. A 2nd randomization was performed after consolidation in pts without a donor: auto-SCT followed or not by low dose IL-2 (4-8 × 106 IU s.c. for 5 days per month) during one year. A total of 577 patients were required to be randomized for the 2nd question in order to reach 255 events (relapses or deaths) which would allow to detect a 11.5% increase in the 3-year disease-free survival (DFS) from 50% to 61.5% corresponding to hazard ratio (HR) = 0.70 (2-sided alpha=5%, statistical power=80%). Randomization was performed centrally; the 2nd randomization was stratified for induction treatment, cytogenetic/molecular genetic group, number of courses to reach CR, auto-SCT planned (No/Yes) and center. Intent-to-treat analysis was done. From 9/1999 till 1/2008, 2005 previously untreated AML pts (APL excluded), age<61 years, were randomized (891 by EORTC-LG and 1114 by GIMEMA) and 104 (GIMEMA) were registered to receive SD-AraC (+etoposide+daunorubicine) in induction. After 1 or 2 courses of induction, CR was achieved in 1377 patients. Between 4/2000 and 5/2008 550 (230 EORTC, 320 GIMEMA) were randomized for the IL-2 question: 276 in IL-2, 274 Observation (Obs) arm; the remaining patients were not randomized due to prolonged hypoplasia after consolidation or after auto-SCT, or refusal of the patient or a planned allo-SCT. The 2 groups were well balanced with respect to the stratification factors, age, sex, WBC counts and history of the disease. Currently, maintenance/observation period has been documented for 144 IL-2 and 144 Obs patients. The patients received a median of 30 s.c. injections (range 3-60) of IL-2. In more than 75% of patients, the mean dose was 6 × 106 IU per injection. Grade 3-4 toxicity was more frequent in the IL-2 compared to Obs arm and consisted of hypersensitivity (4.2% vs 0%), fatigue (9% vs 1.4%), rigor/chills (4.2% vs 0%), arthralgia/myalgia (3.5% vs 0%). A total of 32 patients (22.2%) out of 144 stopped IL-2 prematurely based on patient refusal or medical decision due to toxicity. In the Obs arm, 4 (2.8%) patients out of 144 went off study due to toxicity. Maintenance/observation period has not yet been documented for 132 IL-2 and 130 Obs patients. Among them 28 (21.2%) vs 13 (10%) respectively went off-study due to toxicity of the previous treatment (autoSCT or consolidation), 41 vs 45 due to early relapse, 9 vs 11 due to protocol violation, 9 vs 5 due to other reason. For the total of 550 patients, the median follow-up from the 2nd randomization was 3.6 years. As of July 2009, a total of 269 DFS events were reported: 132 (IL-2 arm) vs 137 (Obs arm); among them 242 relapses (121 vs 121) and 27 deaths without relapses (11 vs 16). The DFS from 2nd randomization was similar in the 2 groups: the 3-yr DFS rate was 44.1% (IL-2) vs 42.0% (Obs), hazard ratio (HR)=0.93 (95% CI 0.74-1.19), p=0.57. A total of 106 patients died in each treatment group. The 3-yr overall survival rate was 54.1% (IL-2) vs 55.9% (Obs), HR=1.01 (95% CI 0.77-1.32), p=0.94. The initial treatment received/randomized did not impact the treatment outcome after the 2nd randomization. This evaluation of the second randomization (IL-2 vs Obs) of the EORTC-GIMEMA AML-12 trial shows that, with a median follow-up of 3.6 years, low dose IL-2 maintenance does not lead to a higher DFS and overall survival. Disclosures: Muus: Alexion Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Bewegungstherapie und körperliche Aktivität bei Patienten mit Herzinsuffizienz

Praxis ◽  
2018 ◽  
Vol 107 (17-18) ◽  
pp. 951-958 ◽  
Author(s):  
Matthias Wilhelm
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Körperliche Aktivität ◽  
Phase Iii

Zusammenfassung. Herzinsuffizienz ist ein klinisches Syndrom mit unterschiedlichen Ätiologien und Phänotypen. Die überwachte Bewegungstherapie und individuelle körperliche Aktivität ist bei allen Formen eine Klasse-IA-Empfehlung in aktuellen Leitlinien. Eine Bewegungstherapie kann unmittelbar nach Stabilisierung einer akuten Herzinsuffizienz im Spital begonnen werden (Phase I). Sie kann nach Entlassung in einem stationären oder ambulanten Präventions- und Rehabilitationsprogramm fortgesetzt werden (Phase II). Typische Elemente sind Ausdauer-, Kraft- und Atemtraining. Die Kosten werden von der Krankenversicherung für drei bis sechs Monate übernommen. In erfahrenen Zentren können auch Patienten mit implantierten Defibrillatoren oder linksventrikulären Unterstützungssystemen trainieren. Wichtiges Ziel der Phase II ist neben muskulärer Rekonditionierung auch die Steigerung der Gesundheitskompetenz, um die Langzeit-Adhärenz bezüglich körperlicher Aktivität zu verbessern. In Phase III bieten Herzgruppen Unterstützung.

Improving Coded Data Entry by an Electronic Patient Record System

1996 ◽  
Vol 35 (02) ◽  
pp. 108-111 ◽  
Author(s):  
F. Puerner ◽  
H. Soltanian ◽  
J. H. Hohnloser
Keyword(s):  
Phase I ◽  
Electronic Patient Record ◽  
Data Entry ◽  
Discharge Summary ◽  
Patient Record ◽  
Phase Iii ◽  
Electronic Patient Record System ◽  
Record System ◽  
Data Encoding ◽  
Discharge Summaries

AbstractData are presented on the use of a browsing and encoding utility to improve coded data entry for an electronic patient record system. Traditional and computerized discharge summaries were compared: during three phases of coding ICD-9 diagnoses phase I, no coding; phase II, manual coding, and phase III, computerized semiautomatic coding. Our data indicate that (1) only 50% of all diagnoses in a discharge summary are encoded manually; (2) using a computerized browsing and encoding utility this percentage may increase by 64%; (3) when forced to encode manually, users may “shift” as much as 84% of relevant diagnoses from the appropriate coding section to other sections thereby “bypassing” the need to encode, this was reduced by up to 41 % with the computerized approach, and (4) computerized encoding can improve completeness of data encoding, from 46 to 100%. We conclude that the use of a computerized browsing and encoding tool can increase data quality and the percentage of documented data. Mechanisms bypassing the need to code can be avoided.

Inhibition kinetics for propionate degradation using propionate-enriched mixed cultures

1998 ◽  
Vol 38 (8-9) ◽  
pp. 443-451 ◽  
Author(s):  
S. H. Hyun ◽  
J. C. Young ◽  
I. S. Kim
Keyword(s):  
Phase I ◽  
Competitive Inhibition ◽  
Gas Production ◽  
Phase Iii ◽  
Utilization Rate ◽  
Inhibition Kinetics ◽  
Wide Range ◽  
Propionate Degradation ◽  
Acetate Utilization ◽  
Velocity Coefficient

To study propionate inhibition kinetics, seed cultures for the experiment were obtained from a propionate-enriched steady-state anaerobic Master Culture Reactor (MCR) operated under a semi-continuous mode for over six months. The MCR received a loading of 1.0 g propionate COD/l-day and was maintained at a temperature of 35±1°C. Tests using serum bottle reactors consisted of four phases. Phase I tests were conducted for measurement of anaerobic gas production as a screening step for a wide range of propionate concentrations. Phase II was a repeat of phase I but with more frequent sampling and detailed analysis of components in the liquid sample using gas chromatography. In phase III, different concentrations of acetate were added along with 1.0 g propionate COD/l to observe acetate inhibition of propionate degradation. Finally in phase IV, different concentrations of propionate were added along with 100 and 200 mg acetate/l to confirm the effect of mutual inhibition. Biokinetic and inhibition coefficients were obtained using models of Monod, Haldane, and Han and Levenspiel through the use of non-linear curve fitting technique. Results showed that the values of kp, maximum propionate utilization rate, and Ksp, half-velocity coefficient for propionate conversion, were 0.257 mg HPr/mg VSS-hr and 200 mg HPr/l, respectively. The values of kA, maximum acetate utilization rate, and KsA, half-velocity coefficient for acetate conversion, were 0.216 mg HAc/mg VSS-hr and 58 mg HAc/l, respectively. The results of phase III and IV tests indicated there was non-competitive inhibition when the acetate concentration in the reactor exceeded 200 mg/l.

Time-Dependent Effects of Low-Dose Aspirin Administration on Blood Pressure in Pregnant Women

Hypertension ◽  
1997 ◽  
Vol 30 (3) ◽  
pp. 589-595 ◽  
Author(s):  
Ramón C. Hermida ◽  
Diana E. Ayala ◽  
Manuel Iglesias ◽  
Artemio Mojón ◽  
Inés Silva ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Pregnant Women ◽  
Low Dose ◽  
Time Dependent ◽  
Dose Aspirin ◽  
Low Dose Aspirin
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