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ABT-263: a potent and orally bioavailable Bcl-2 family inhibitor.
Tse C, Shoemaker AR, Adickes J, Anderson MG, Chen J, Jin S, Johnson EF, Marsh KC, Mitten MJ, Nimmer P, Roberts L, Tahir SK, Xiao Y, Yang X, Zhang H, Fesik S, Rosenberg SH, Elmore SW
(2008) Cancer Res 68: 3421-8
MeSH Terms: Administration, Oral, Aniline Compounds, Animals, Antibodies, Monoclonal, Antibodies, Monoclonal, Murine-Derived, Antineoplastic Agents, Carcinoma, Small Cell, Cells, Cultured, Drug Synergism, Humans, Lung Neoplasms, Lymphoma, Mantle-Cell, Mice, Mice, Knockout, Mice, SCID, Models, Biological, Neoplasms, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Proto-Oncogene Proteins c-bcl-2, Rituximab, Sulfonamides, Thrombocytopenia, Treatment Outcome, Tumor Burden, Xenograft Model Antitumor Assays
Show Abstract · Added March 5, 2014
Overexpression of the prosurvival Bcl-2 family members (Bcl-2, Bcl-xL, and Mcl-1) is commonly associated with tumor maintenance, progression, and chemoresistance. We previously reported the discovery of ABT-737, a potent, small-molecule Bcl-2 family protein inhibitor. A major limitation of ABT-737 is that it is not orally bioavailable, which would limit chronic single agent therapy and flexibility to dose in combination regimens. Here we report the biological properties of ABT-263, a potent, orally bioavailable Bad-like BH3 mimetic (K(i)'s of <1 nmol/L for Bcl-2, Bcl-xL, and Bcl-w). The oral bioavailability of ABT-263 in preclinical animal models is 20% to 50%, depending on formulation. ABT-263 disrupts Bcl-2/Bcl-xL interactions with pro-death proteins (e.g., Bim), leading to the initiation of apoptosis within 2 hours posttreatment. In human tumor cells, ABT-263 induces Bax translocation, cytochrome c release, and subsequent apoptosis. Oral administration of ABT-263 alone induces complete tumor regressions in xenograft models of small-cell lung cancer and acute lymphoblastic leukemia. In xenograft models of aggressive B-cell lymphoma and multiple myeloma where ABT-263 exhibits modest or no single agent activity, it significantly enhances the efficacy of clinically relevant therapeutic regimens. These data provide the rationale for clinical trials evaluating ABT-263 in small-cell lung cancer and B-cell malignancies. The oral efficacy of ABT-263 should provide dosing flexibility to maximize clinical utility both as a single agent and in combination regimens.
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25 MeSH Terms
Impact of aspirin therapy in cancer patients with thrombocytopenia and acute coronary syndromes.
Sarkiss MG, Yusuf SW, Warneke CL, Botz G, Lakkis N, Hirch-Ginsburg C, Champion JC, Swafford J, Shaw AD, Lenihan DJ, Durand JB
(2007) Cancer 109: 621-7
MeSH Terms: Acute Disease, Aged, Anti-Inflammatory Agents, Non-Steroidal, Aspirin, Coronary Disease, Female, Hemorrhage, Humans, Male, Medical Records, Myocardial Infarction, Neoplasms, Outcome Assessment, Health Care, Platelet Count, Retrospective Studies, Survival Rate, Thrombocytopenia
Show Abstract · Added October 20, 2015
BACKGROUND - Patients with cancer who have thrombocytopenia may experience acute coronary syndromes (ACS), and the use of aspirin (ASA) poses an increased risk of bleeding. The purpose of this study was to test the hypothesis that the benefit of ASA therapy in the treatment of ACS would extend to cancer patients with thrombocytopenia and outweigh the risks of severe bleeding.
METHODS - The records of all cancer patients diagnosed with an ACS in 2001 and referred for cardiology consultation were reviewed. Patients were divided into 2 groups on the basis of platelet count, >100 cells k/microL and < or = 100 cells k/microL. Data were collected on the use of ASA therapy, bleeding complications, and survival rates. The authors assessed group differences by using the Wilcoxon rank sum test or 2-tailed Fisher exact test, as appropriate. Univariate and multivariate logistic regression models were used to assess factors potentially associated with 7-day survival.
RESULTS - In cancer patients with ACS and thrombocytopenia, those who did not receive ASA had a 7-day survival rate of 6% compared with 90% in those who did receive ASA (P < .0001). There were no severe bleeding complications. Patients with a platelet count (>100 cells k/microL) who received ASA had a 7-day survival rate of 88% compared with 45% in those who did not receive ASA (P = .0096).
CONCLUSIONS - Therapy with ASA was associated with a significantly improved 7-day survival after ACS in cancer patients, with or without thrombocytopenia, and not associated with more severe bleeding.
(c) 2007 American Cancer Society.
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17 MeSH Terms
TITAN: modifying an innovative American program for use with a European audience.
Ahlberg K, Dielenseger P, Dolan S, Foubert J, Munoz M, Ouwerkerk J, Uhlenhopp M, Wujcik D, Training Initiatives in Thrombocytopenia, Anemia, and Neutropenia Working Group, Appropriate Treatment Assures Quality (ATAQ)
(2005) J Support Oncol 3: 34-5
MeSH Terms: Anemia, Antineoplastic Agents, Education, Nursing, Europe, Health Education, Humans, Neoplasms, Neutropenia, Thrombocytopenia, Training Support, United States
Added March 27, 2014
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11 MeSH Terms
Acute lung injury after blood transfusion in mechanically ventilated patients.
Gajic O, Rana R, Mendez JL, Rickman OB, Lymp JF, Hubmayr RD, Moore SB
(2004) Transfusion 44: 1468-74
MeSH Terms: Aged, Blood Component Transfusion, Blood Preservation, Blood Specimen Collection, Erythrocytes, Female, Humans, Male, Middle Aged, Plasma, Respiration, Artificial, Respiratory Distress Syndrome, Retrospective Studies, Risk Factors, Thrombocytopenia
Show Abstract · Added March 5, 2014
BACKGROUND - Liberal transfusion strategy increases the risk of acute lung injury (ALI), but specific transfusion-related factors have not been characterized. We tested the hypotheses that storage age and specific type of blood products are associated with increased risk of ALI in mechanically ventilated patients.
STUDY DESIGN AND METHODS - From a database of mechanically ventilated patients, we identified those who received blood products during the first 48 hours of intensive care. We extracted information about underlying ALI risk factors as well as the type, amount, and shelf age of administered blood products. Outcome was assessed by an independent, blind review of chest radiographs and clinical findings.
RESULTS - Of 181 patients transfused during the first 48 hours of mechanical ventilation, 60 (33%) developed ALI. There was no difference in average duration of red blood cells storage between patients who did and did not develop ALI (median, 18.5 vs. 17.5 days; p = 0.22). In a multivariable logistic regression analysis, important risk factors associated with the development of ALI were thrombocytopenia (odds ratio, 5.9; p = 0.004) and transfusion of fresh frozen plasma (odds ratio, 3.2; p = 0.023).
CONCLUSION - Thrombocytopenia and transfusion of fresh frozen plasma, but not storage age of red blood cells, were associated with the development of ALI in this cohort of mechanically ventilated patients.
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15 MeSH Terms
Kasabach-merritt phenomenon: a retrospective study of treatment with vincristine.
Haisley-Royster C, Enjolras O, Frieden IJ, Garzon M, Lee M, Oranje A, de Laat PC, Madern GC, Gonzalez F, Frangoul H, Le Moine P, Prose NS, Adams DM
(2002) J Pediatr Hematol Oncol 24: 459-62
MeSH Terms: Antineoplastic Agents, Phytogenic, Female, Fibrinogen, Hemangioendothelioma, Hemangioma, Capillary, Humans, Infant, Infant, Newborn, Male, Platelet Count, Retrospective Studies, Thrombocytopenia, Vincristine
Show Abstract · Added March 27, 2014
PURPOSE - Kasabach-Merritt phenomenon (KMP) is characterized by profound thrombocytopenia, microangiopathic hemolytic anemia, a consumptive coagulopathy, and an enlarging vascular lesion. The syndrome develops in infancy and is associated with a high morbidity and mortality rate. The purpose of this study was to assess the effectiveness of vincristine in the treatment of KMP.
METHODS - We retrospectively reviewed the clinical and laboratory data of 15 patients with KMP treated with vincristine at 9 institutions across the United States, South America, and Europe.
RESULTS - All 15 patients had profound thrombocytopenia and consumption of fibrinogen at presentation. Ten patients had biopsies of their lesions, and results included five (33.3%) kaposiform hemangioendotheliomas, three (20%) tufted angiomas, one lesion (6.7%) with features of both kaposiform hemangioendothelioma and tufted angioma, and one (6.7%) unclassified vascular tumor. All 15 patients had an increase in platelet count of at least 20,000 with an average response time of 4.0 weeks after initiation of vincristine therapy. Thirteen patients had an increase in fibrinogen level of 50 mg/dL with an average response time of 3.4 weeks. In 13 patients there was a significant decrease in the size of the vascular lesion. The average duration of treatment was 21.5 (+/-12.6) weeks. Four patients (26%) relapsed. All four were successfully treated with a second course of vincristine. Complications included one patient with abdominal pain, one patient with transient loss of deep tendon reflexes, and one patient with irritability.
CONCLUSION - Vincristine presents a safe and sometimes effective treatment option in the management of KMP.
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13 MeSH Terms
Angiographic follow-up after suture-mediated femoral artery closure.
Brown DB, Crawford ST, Norton PL, Hovsepian DM
(2002) J Vasc Interv Radiol 13: 677-80
MeSH Terms: Angiography, Embolization, Therapeutic, Female, Femoral Artery, Follow-Up Studies, Hemostatic Techniques, Humans, Male, Middle Aged, Sutures, Thrombocytopenia
Show Abstract · Added March 5, 2014
PURPOSE - Percutaneous closure devices are used in as many as 30% of all endovascular studies. Despite widespread use of these devices, only limited imaging has been performed after percutaneous closure. In this study, arteriograms of patients who had undergone suture-mediated closure with the Perclose device were reviewed.
MATERIALS AND METHODS - Between June 1998 and November 2001, 31 patients who had previously undergone closure with use of the Perclose device at our institution returned for additional angiographic procedures. Twenty-one patients underwent closure with use of the Perclose device after embolization, including hepatic artery chemoembolization (n = 18), treatment of hypervascular sacral metastases (n = 2), and bronchial artery embolization (n = 1). Nineteen of these patients had thrombocytopenia. Ten patients underwent closure with use of the Perclose device after diagnosis and treatment of peripheral vascular disease.
RESULTS - Of 31 patients, 28 had normal follow-up studies, including one patient who underwent four previous closures. These 28 patients all had normal femoral artery caliber at initial angiography and a platelet count of more than 18,000/mm(3). Two patients with preexisting atherosclerotic change had progression of disease at the puncture site and a third with severe thrombocytopenia developed a small asymptomatic posterolateral pseudoaneurysm.
CONCLUSION - In patients with normal femoral arteries, the long-term effects of closure with use of the Perclose device, even performed multiple times, appears to be minimal.
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11 MeSH Terms
Interleukin 10-induced thrombocytopenia in normal healthy adult volunteers: evidence for decreased platelet production.
Sosman JA, Verma A, Moss S, Sorokin P, Blend M, Bradlow B, Chachlani N, Cutler D, Sabo R, Nelson M, Bruno E, Gustin D, Viana M, Hoffman R
(2000) Br J Haematol 111: 104-11
MeSH Terms: Adult, Blood Platelets, Cell Count, Double-Blind Method, Female, Hemoglobins, Humans, Interleukin-10, Male, Megakaryocytes, Platelet Count, Recombinant Proteins, Spleen, Statistics, Nonparametric, Thrombocytopenia
Show Abstract · Added March 5, 2014
Recombinant human interleukin 10 (rhuIL-10) inhibits the production of proinflammatory cytokines and has shown promise in the treatment of inflammatory bowel disease. Clinical trials have been accompanied by a reversible decline in platelet counts. We conducted a randomized, double-blinded, placebo-controlled, parallel group trial in 12 healthy volunteers to investigate the aetiology of rhuIL-10-induced thrombocytopenia. Eight volunteers received 8 microg/kg/d of rhuIL-10 subcutaneously, while four subjects received a placebo alone for 10 d. A reversible decline in the platelet counts from a mean of 275 x 10(9)/l to 164 x 10(9)/l was observed in the IL-10-treated cohort (P = 0.012). A fall in the haemoglobin mean levels was also observed in the IL-10-treated cohort from 13.7 to 11.7 g/dl (P = 0.011). No significant change was observed in the bone marrow cellularity or myeloid/erythroid ratio or in the number of megakaryocytes per high-powered field (HPF). A fall was observed in the number of megakaryocyte colony-forming units (CFU-MKs) after the administration of IL-10 compared with those receiving the placebo (P = 0.068). No difference in the change in granulocyte-macrophage CFUs (CFU-GMs), mixed lineage CFUs (CFU-GEMMs) or erythroid burst-forming units (BFU-Es) was observed when comparing the IL-10- vs. placebo-treated groups (P > 0.465). Serum cytokine levels of thrombopoietin (TPO). IL-6 and granulocyte-macrophage colony stimulating factor (GM-CSF) were not decreased following IL-10 administration. In fact, both TPO and GM-CSF appeared to be slightly increased in the serum. All subjects underwent In111-labelled platelet survival studies with liver/spleen scans to assess splenic sequestration prior to and then on day 7 of treatment. A significant reduction in splenic sequestration of platelets (P =0.012) was observed in the IL-10-treated group, but not in the placebo-treated subjects.
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15 MeSH Terms
Fever, thrombocytopenia, anasarca, and acute renal failure in a 50-year-old woman.
Goral S, Horn R, Brouillette J, Fogo A
(1998) Am J Kidney Dis 31: 890-5
MeSH Terms: Acute Kidney Injury, Diagnosis, Differential, Edema, Female, Fever, Hemolytic-Uremic Syndrome, Humans, Kidney, Middle Aged, Pleural Effusion, Thrombocytopenia
Added January 20, 2012
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11 MeSH Terms
Paclitaxel plus carboplatin in the treatment of patients with advanced lung cancer: a Vanderbilt University Cancer Center phase II trial (LUN-46).
Johnson DH, Paul DM, Hande KR, DeVore R
(1996) Semin Oncol 23: 42-6
MeSH Terms: Adult, Aged, Agranulocytosis, Antineoplastic Agents, Phytogenic, Antineoplastic Combined Chemotherapy Protocols, Arthralgia, Carboplatin, Carcinoma, Non-Small-Cell Lung, Drug Administration Schedule, Female, Humans, Infusions, Intravenous, Lung Neoplasms, Male, Middle Aged, Nausea, Neuralgia, Paclitaxel, Peripheral Nervous System Diseases, Survival Rate, Thrombocytopenia, Treatment Outcome, Vomiting
Show Abstract · Added March 5, 2014
In studies conducted by the Eastern Cooperative Oncology Group, treatment with either paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) or carboplatin was associated with an improvement in 1-year survival in patients with stage IV non-small cell lung cancer (NSCLC). Based on these findings, a phase II trial of carboplatin plus paclitaxel was conducted in patients with advanced NSCLC to determine the activity and toxicity of this regimen. Eligibility requirements included stage IIIB or IV histologically confirmed NSCLC, Eastern Cooperative Oncology Group performance status of 0 to 2, no prior chemotherapy, and adequate hematologic, renal, hepatic, and cardiac functions. Paclitaxel was administered intravenously over 24 hours at a dose of 135 mg/m2 (28 patients) or 175 mg/m2 (23 patients), followed by a 1-hour infusion of carboplatin on day 2. Carboplatin was administered at a dose of 300 mg/m2 (16 patients) or, using the Calvert formula, a dose calculated to achieve an area under the concentration-time curve of 6 mg/mL x min (35 patients). Treatment was repeated every 28 days for a total of six cycles. Among the 51 eligible patients, 34 were men and 17 were women; their median age was 60 years and their median Eastern Cooperative Oncology Group performance status was 1. Six patients had stage IIIB and 45 had stage IV disease. Grade 3 or 4 granulocytopenia and thrombocytopenia were observed in 47% and 3% of treatment cycles, respectively. The most common nonhematologic toxicities noted included nausea and emesis, neuropathy, and arthralgia and myalgia. There were no complete responses and 14 partial responses, for an overall response rate of 27% (95% confidence interval, 17% to 41%). Median survival was 38 weeks and the survival rate at 1 year was 32%. Paclitaxel plus carboplatin, as given in this study, was found to be a moderately active regimen in patients with advanced NSCLC. This regimen warrants comparison with existing cisplatin-based regimens in a prospective randomized trial.
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23 MeSH Terms
Successful treatment of fetal cardiac arrest by left ventricular exchange transfusion.
Rodeck CH, Roberts LJ
(1994) Fetal Diagn Ther 9: 213-7
MeSH Terms: Adult, Antigens, Human Platelet, Blood Platelets, Blood Transfusion, Intrauterine, Blood Viscosity, Exchange Transfusion, Whole Blood, Female, Fetal Diseases, Heart Arrest, Heart Ventricles, Humans, Isoantibodies, Male, Maternal-Fetal Exchange, Platelet Transfusion, Pregnancy, Pregnancy Complications, Thrombocytopenia
Show Abstract · Added December 10, 2013
A 36-year-old pregnant woman with anti-HPA1a antibodies underwent six fetal platelet concentrate transfusions. During the second, at 28 weeks' gestation, fetal asystole occurred in association with a post-transfusion platelet count of 813 x 10(9)/l. Asystole was reversed by an intracardiac partial exchange transfusion of normal saline for fetal blood, simultaneously reducing fetal plasma viscosity and enabling re-commencement of the fetal circulation.
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18 MeSH Terms