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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.
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.
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.
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.
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.
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.
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.
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.