Phase I trial of gemtuzumab ozogamicin in intensive combination chemotherapy for relapsed or refractory adult acute myeloid leukemia (AML): Japan Adult Leukemia Study Group (JALSG)-AML206 study

In order to investigate better molecular-target therapy for acute myeloid leukemia (AML), we conducted a phase I trial of a combination of gemtuzumab ozogamicin (GO) with conventional chemotherapy. Between January 2007 and December 2009, a total of 19 adult Japanese patients with relapsed or refractory CD33-positive AML (excluding acute promyelocytic leukemia) were enrolled. All registered patients received a standard dose of cytarabine (Ara-C) (100 mg/m(2) × 7 days), combined with either idarubicin (IDR) (10-12 mg/m(2) × 3 days) or daunorubicin (DNR) (50 mg/m(2) × 3-5 days), and then GO (3-5 mg/m(2) ), which was administered 1 day after the last infusion of IDR (IAG regimen) or DNR (DAG regimen). While doses of both GO and IDR and the administration period of only DNR were increased, the dose-limiting toxicity (DLT) was assessed. Among 19 patients (nine in the IAG regimen, 10 in the DAG regimen), the median age was 59 years (range 33-64), and the relapsed/refractory ratio was 13/6. In the therapy using 3 mg/m(2) GO in the IAG or DAG regimen, grade 3/4 leukopenia and neutropenia were observed in all patients, but none had grade 3/4 non-hematological toxicities, except febrile neutropenia. Three patients in the IAG regimen who were administered 5 mg/m(2) GO showed DLT. No patients had veno-occlusive disease or sinusoidal obstructive syndrome. In conclusion, 3 mg/m(2) GO combined with Ara-C and IDR or DNR can be safely administered, and phase II trials should be conducted to investigate the clinical efficacy of the combination therapy.     

Pulmonary Artery Leiomyosarcoma Diagnosed without Delay

A 63-year-old female presented with abnormal lung shadows but had, apart from this, few symptoms. Computed tomography (CT) revealed multiple nodules and blockage of the pulmonary artery. She was immediately diagnosed with pulmonary artery sarcoma based on a careful differential diagnosis and underwent surgery. Her tumor was pathologically diagnosed as leiomyosarcoma (i.e. intimal sarcoma). Pulmonary artery sarcoma can be easily confounded with thromboembolism in a clinical setting and some cases are diagnosed post mortem only. In our case, clinical prediction scores (Wells score, Geneva score, and revised Geneva score) for the pulmonary embolism showed low probability. Moreover, chest CT showed uncommon findings for pulmonary thromboembolism, as the nodules were too big for thrombi. Because surgical resection can provide the only hope of long-term survival in cases of pulmonary artery sarcoma, clinicians should consider this possibility in the differential diagnosis of pulmonary embolism. Clinical prediction scores and CT findings might help to reach the correct diagnosis of pulmonary artery sarcoma.     

Changes of D-dimer after total hip arthroplasty in patients with and without intraoperative heparin

Introduction Marked activation of thrombosis is common in patients undergoing total hip arthroplasty, especially during reaming of the femur and after insertion of the femoral prosthesis. This suggests that management designed to minimize deep vein thrombosis and fatal pulmonary embolism after total hip arthroplasty should be focused on the period during insertion of the femoral component. In some previous studies, a low dose of heparin administered intraoperatively was shown to suppress the formation of fibrin. Objective The present study was performed to evaluate the influence of intraoperative heparin administration on the D-dimer level and on the prevention of pulmonary embolism after total hip arthroplasty. Material/methods A total of 22 and 26 consecutive patients respectively underwent total hip arthroplasty with and without intraoperative administration of unfractionated heparin. Postoperatively, all patients wore knee-high elastic stockings and were fitted with calf-to-thigh intermittent pneumatic compression devices. Active ankle flexion and extension exercises were commenced as soon as motor function recovered. None of the 48 patients received prophylactic anticoagulants postoperatively. Results There was a significant difference of the mean D-dimer level on the 1st day between the patients with and without intraoperative administration of heparin (8.9 ± 6.6 vs. 15.7 ± 12.7, P < 0.05). Although there were no patients with symptomatic deep venous thrombosis and pulmonary embolism, asymptomatic pulmonary embolism was detected by pulmonary perfusion scintigraphy in three patients who did not receive intraoperative heparin. The operative blood loss and postoperative drainage were similar in both groups and no bleeding complications were observed. In conclusion, we recommend a safe and inexpensive regimen comprising 1,000 U of intravenous unfractionated heparin intraoperatively, postoperative pneumatic compression, and early active mobilization for prevention of thoromboembolic complications after total hip arthroplasty.     

In vitro evaluation of dose-response curve for paclitaxel in breast cancer

Background  The dose-response curve for anticancer agents cannot be evaluated by studying patients directly. To investigate individual differences in the dose-response curve for paclitaxel in breast cancer, we utilized the histoculture drug response assay (HDRA) technique. as]Materials and Methods: Twenty specimens obtained from breast cancer patients who underwent surgical resection were used in this study. The inhibition rates of paclitaxel at several concentrations were measured and fitted to a sigmoid dose-response curve, using non-linear least squares analysis with the fitting equation y=A(l-l/(l+exp(B(x-log(C))))), where A denotes maximal response; B, slope factor; and C, ED50. Results  A dose-response curve was obtained in all tumors. The mean value (±SD) of maximum response, slope factor, and ED50 were 90.2±5.5 %, 9.4 ± 4.3, and 36.8 ± 17.2 μg/g/ml, respectively. The slope factor was higher in nuclear grade 3 tumors compared with nuclear grade 1 and 2 tumors. Conclusion  An individual dose-response curve for paclitaxel in breast cancer can be obtained using the HDRA technique. Nuclear grade 3 tumors appeared to have more uniform chemosensitivity to paclitaxel compared with nuclear grade 1 and 2 tumors.     

Pharmacological characterization of the β-adrenoceptor that mediates the relaxant response to noradrenaline in guinea-pig tracheal smooth muscle

Pharmacological characteristics of beta-adrenoceptors (beta-ARs) mediating noradrenaline-induced relaxation were investigated in guinea-pig tracheal smooth muscle. The inhibitory effects of several types of beta-AR antagonists on noradrenaline-induced relaxation against histamine contraction were scrutinized with Schild plot analysis. The concentration-response curve for noradrenaline obtained in the absence of phentolamine and uptake inhibitors was competitively antagonized by all of the beta-AR antagonists used in this study (propranolol, bupranolol, atenolol, butoxamine and ICI-118,551). However, their pA2 values were markedly less than the expected values for beta1-AR and beta2-AR. On the other hand, pA2 values of ICI-118,551 (6.85) determined in the presence of phentolamine suggested a contribution of a beta1 -AR rather than beta2 -AR. In the presence of phentolamine and uptake inhibitors (desipramine and deoxycorticosterone), the Schild plot for atenolol was a better fit, with two distinct straight lines. The pA2 values of atenolol provided by the regression were: approximately 7.0, which corresponds to the expected beta1-AR value, and approximately 6.5, which was 3 times less than the expected value for beta1 -AR, and thus the possible presence of two classes of beta1 -AR (beta1(Low) and beta1(High)) was suggested. This view was also supported by Schild plot analysis for propranolol, which fit two straight lines each with a slope of 1.0. The present findings indicate that beta1 -ARs contributing to noradrenaline-elicited relaxation in guinea-pig tracheal smooth muscle exhibit diverse pharmacological characteristics and may be subdivided into at least two classes with distinct affinities for atenolol. Under physiological conditions, beta1(Low) rather than beta1(High) seems to play a more significant role in noradrenaline-regulated airway smooth muscle tone.     

Longitudinal study of procedural memory in patients with Alzheimer-type dementia]

We never forget how to ride a bicycle, and it is thought that procedural memories are retained for a long time. Recently, it was reported that patients with dementia of the Alzheimer type(DAT) could not only acquire, but also retain, long-lasting procedural memories. Previous group studies had shown procedural memory retention times of only 1 month in DAT patients, while amnesic patients and healthy people could retain such memories for 12 months. The relationship between the ability to retain procedural memory and the stage of the disease is not clear, as to date there has been no longitudinal study of procedural memory retention in DAT patients. Thus, we examined DAT patients' ability to retain long-term procedural memories (after 1, 5 and 20 months), and analyzed the relationship between procedural memory ability and the progress of disease. Motor-type procedural memory was examined using the mirror tracing task and the bi-manual coordinated tracing task. All three of the DAT patients showed improvement in their performance. The time required for the tracing was reduced between trials, and the improvement did not disappear between sessions, or rather, their times further decreased in subsequent sessions. Even the most severe DAT patient (Mini Mental State Examination(MMSE) score of 4) was able to acquire the procedural memory and retain it for at least 3 months. Furthermore, one of the subjects showed retention of the procedural memory at 20 months. Our results suggest that DAT patients can retain procedural memories for extended periods, with no relationship between retention ability and disease progression. It is possible for even severely demented patients to acquire and retain motor-type procedural memories. Cognitive rehabilitation in DAT appears to be effective, and it is possible for DAT patients to learn new things. It may be that DAT patients can ameliorate their quality of life by using retained procedural memory.     

Increased alveolar fluid clearance following thoracotomy: Report of a case and results of an analysis

Alveolar fluid clearance was studied in the resected lung of a 58-year-old man who had undergone exploratory thoracotomy 9 days earlier. An isosmolar albumin solution was instilled into the distal air spaces, and the albumin and electrolyte concentrations were measured over 4h. Alveolar sodium and fluid clearance had increased by nearly 200% from the control values in the resected lungs of patients without prior thoracotomy (n=5), and histological examination showed that the number of alveolar type II epithelial cells was markedly elevated. These results suggest that an increase in the number of alveolar type II cells may accelerate alveolar fluid clearance under certain clinical conditions.