Randomized use of cyclosporin A (CsA) to modulate P-glycoprotein in children with AML in remission: Pediatric Oncology Group Study 9421

Relapse is a major obstacle in the cure of acute myeloid leukemia (AML). The Pediatric Oncology Group AML Study 9421 tested 2 different strategies to improve event-free survival (EFS) and overall survival (OS). Patients were randomized to receive standard-dose DAT (daunorubicin, cytarabine, and thioguanine) or high-dose DAT during induction. To interfere with P-glycoprotein (P-gp)-dependent drug efflux, the second randomization tested the benefit of cyclosporine (CsA) added to consolidation chemotherapy. Of the 282 children randomly assigned to receive standard DAT induction, 248 (87.9%) achieved remission compared to 253 (91%) of the 278 receiving high-dose DAT (P = ns). Children with HLA-identical sibling donors who achieved a complete remission received an allogeneic bone marrow transplant as consolidation. For the 83 patients receiving a matched related donor bone marrow transplantation (BMT), the 3-year disease-free survival (DFS) is 67%. Of the 418 children who achieved remission and went on to consolidation with and without CsA, the DFS was 40.6% and 33.9%, respectively (P = .24). Overexpression of P-gp was infrequent (14%) in this pediatric population. In this study, intensifying induction with high-dose DAT and the addition of CsA to consolidation chemotherapy did not prolong the durations of remission or improve overall survival for children with AML.     

Is the prevalence of arterial hypertension in rheumatoid arthritis and osteoarthritis associated with disease?

In this study, we compare the prevalence of arterial hypertension (HT) in rheumatoid arthritis (RA) and osteoarthritis (OA) patients, exposed to high- and low-grade chronic inflammation, respectively, to assess the possible association between chronic inflammation and HT. A total of consecutive 627 RA and 352 OA patients were enrolled in this multicentric study. HT was defined as a systolic blood pressure (BP) ≥ 140 and/or diastolic BP ≥ 90 mmHg or current use of any antihypertensive drug. Overweight/obesity was defined as body mass index (BMI) ≥ 25, and patients ≥65 years were considered elderly. The prevalence of HT was higher in the OA group than in the RA group [73.3 % (95 % CI, 68.4, 77.7) and 59.5 % (95 % CI, 55.6, 68.4) P < 0.001, respectively]. When the results were adjusted for age and BMI, the HT prevalence was similar in both groups [RA 59 % (95 % CI, 55.1, 63.8) OA 60 % (95 % CI, 58.4, 65.0)]. In both groups, the prevalence of HT was higher in the elderly and those who were overweight than in the younger patients and those with a BMI < 25. Overweight (BMI ≥ 25) and age ≥65 were independent predictors of HT in multivariate logistic regression model, which showed no association between HT and the disease (RA or OA). The results indicate a robust association of age and BMI with HT prevalence in both RA and OA. The difference in HT prevalence between RA and OA is due rather to age and BMI than to the features of the disease, putting into question specific association of HT with RA.     

Esophagogastric anastomosis in rats: Improved healing by BPC 157 and L-arginine,aggravated by L-NAME

AIM To cure typically life-threatening esophagogastric anastomosis in rats, lacking anastomosis healing and sphincter function rescue, in particular. METHODS Because we assume esophagogastric fistulas represent a particular NO-system disability, we attempt to identify the benefits of anti-ulcer stable gastric pentadecapeptide BPC 157, which was in trials for ulcerative colitis and currently for multiple sclerosis, in rats with esophagocutaneous fistulas. Previously, BPC 157 therapies have promoted the healing of intestinal anastomosis and fistulas, and esophagitis and gastric lesions, along with rescued sphincter function. Additionally, BPC 157 particularly interacts with the NOsystem. In the 4 d after esophagogastric anastomosis creation, rats received medication(/kg intraperitoneallyonce daily: BPC 157(10 μg, 10 ng), L-NAME(5 mg), or L-arginine(100 mg) alone and/or combined or BPC 157(10 μg, 10 ng) in drinking water). For rats underwent esophagogastric anastomosis, daily assessment included progressive stomach damage(sum of the longest diameters, mm), esophagitis(scored 0-5), weak anastomosis(m L H2 O before leak), low pressure in esophagus at anastomosis and in the pyloric sphincter(cm H2O), progressive weight loss(g) and mortality. Immediate effect assessed blood vessels disappearance(scored 0-5) at the stomach surface immediately after anastomosis creation. RESULTS BPC 157(all regimens) fully counteracted the perilous disease course from the very beginning(i.e., with the BPC 157 bath, blood vessels remained present at the gastric surface after anastomosis creation) and eliminated mortality. Additionally, BPC 157 treatment in combination with L-NAME nullified any effect of L-NAME that otherwise intensified the regular course. Consistently, with worsening(with L-NAME administration) and amelioration(with L-arginine), either L-arginine amelioration prevails(attenuated esophageal and gastric lesions) or they counteract each other(L-NAME + L-arginine); with the addition of BPC 157(L-NAME + L-arginine + BPC 157), there was a marked beneficial effect. BPC 157 treatment for esophagogastric anastomosis, along with NOS-blocker L-NAME and/or NOS substrate L-arginine, demonstrated an innate NO-system disability(as observed with L-arginine effectiveness). BPC 157 distinctively affected corresponding events: worsening(obtained with L-NAME administration that was counteracted); or amelioration(L-arginine + BPC 157-rats correspond to BPC 157-rats).CONCLUSION Innate NO-system disability for esophagogastric anastomoses, including L-NAME-worsening, suggests that these effects could be corrected by L-arginine and almost completely eliminated by BPC 157 therapy.     

Validation of a Limited Sampling Model to Determine Etoposide Area Under the Curve

Study Objective . To validate the utility of a previously reported 3-point limited sampling model (LSM) for determining etoposide area under the curve to infinity (AUC_∞). Design . Secondary analysis of data from two clinical trials of etoposide. Setting . University medical center clinical research center. Patients . Thirty-four patients with different malignancies. Interventions . Etoposide was administered as a 2-hour infusion to 34 patients. Serial plasma samples were drawn over 24 hours after the infusion and analyzed for etoposide by high-performance liquid chromatography. Measurements and Main Results . The 3-point LSM AUC was compared with a 14-point actual AUC calculated by the linear trapezoidal rule. Actual and predicted AUC_∞ by the LSM were highly correlated (r=0.97, p<0.0001). The LSM predictions had a mean absolute error of 10.9% (95% CI −14.1, −5.3) and a mean error of −9.7% (95% CI 6.9, 14.9). Nine patients with poor AUC_∞ estimations by the LSM (error > 12%) tended to have abnormally low or high peak concentrations. Conclusion . Our findings suggest the development of more robust LSM using other techniques, such as pharmacostatistical models, that can accommodate a greater degree of pharmacokinetic variability. (Pharmacotherapy 1997;17(5):887–890)     

Image quality of mammography in Croatian nationwide screening program: comparison between various types of facilities

Purpose

The study was aimed to provide objective evidence about the mammographic image quality in Croatia, to compare it between different types of MG facilities and to identify the most common deficiencies and possible reasons as well as the steps needed to improve image quality.

Materials and methods

A total of 420 mammographic examinations collected from 84 mammographic units participating in the Croatian nationwide breast cancer screening program were reviewed in terms of four image quality categories: identification of patient and examination, breast positioning and compression, exposure and contrast, and artifacts. Those were rated using image evaluating system based on American College of Radiology and European Commission proposals. The results were compared among different types of mammographic units, and common image quality deficiencies were identified.

Results

Total image quality scores of 12.8, 16.1, 13.0 and 13.7 were found for general hospitals, university hospitals, private clinics and public healthcare centres, respectively. Average score for all mammographic units was 13.5 (out of 25 points). University hospitals were significantly better than all other mammography units in overall image quality, which was mostly contributed by better breast positioning practices. Private clinics showed the worst results in identification, exposure, contrast and artifacts.

Conclusions

Serious deficiencies in identification and breast positioning, which might compromise breast cancer screening outcome, were detected in our material. They occur mainly due to subjective reasons and could be corrected through additional staff training and improvement of working discipline.