Günther Eibl

High expression of the chemokine receptor CXCR4 predicts extramedullary organ infiltration in childhood acute lymphoblastic leukaemia

Childhood acute lymphoblastic leukaemia (ALL) is a malignancy with the potential to infiltrate the liver, spleen, lymph nodes and brain. Such extramedullary presentation is important for understanding the biology of childhood ALL and also for developing new prognostic parameters. A potential mechanism in the trafficking of leukaemia cells is the interaction of the chemokine receptor CXCR4, which is expressed on ALL cells, and its ligand stromal cell‐derived factor‐1 (SDF‐1), produced by stromal cells in bone marrow and extramedullary organs. Functionality of CXCR4 was demonstrated by a high correlation between cell surface density of CXCR4 and transendothelial migration of leukaemia blasts towards a gradient of SDF‐1 (r = 0·73, P = 0·001). Inhibition of SDF‐1‐induced migration by an anti‐CXCR4 monoclonal antibody (78·33 ± 23·86% inhibition) evidenced the specificity of CXCR4 to SDF‐1. In order to evaluate clinical significance of CXCR4 expression, lymphoblasts from the bone marrow of 73 patients with and without extramedullary organ infiltration were compared. Multiparameter flow cytometry revealed that lymphoblasts from patients with high extramedullary organ infiltration, defined as ultrasonographically measured enlargement of liver or spleen, expressed the CXCR4 receptor at higher fluorescence intensity (median 66·12 ± 66·17) than patients without extramedullary organ infiltration (median 17·56 ± 19·29; P < 0·001). Consequently, high expression of CXCR4 was strongly predictive for extramedullary organ involvement, independently of the peripheral lymphoblast count. Highest CXCR4 expression was seen in mature B ALL (median 102·74 ± 92·13; P < 0·003), a disease characterized by a high incidence of extramedullary bulky disease. As high expression of the chemokine receptor CXCR4 predicts extramedullary organ infiltration in childhood ALL, we suggest that CXCR4 and its ligand play an essential role in extramedullary invasion.

Prognostic significance of Ep-CAM AND Her-2/neu overexpression in invasive breast cancer.

To assess the frequency and prognostic impact of Ep‐CAM and Her‐2/neu overexpression in patients with breast cancer and to determine its relationship with other prognostic markers, 205 breast cancer patients with a median follow‐up of 10.8 years were enrolled in this retrospective study. Overexpression of Ep‐CAM and Her‐2/neu in tumor tissue samples was assessed by immunohistochemistry. Tumors presenting a Her‐2/neu 2+ staining were additionally analyzed by FISH to exclude false positive results. Ep‐CAM and Her‐2/neu overexpression was found in 35.6% and 19.5% of the tumor samples, respectively. Both Ep‐CAM and Her‐2/neu overexpression were predictive for poor disease‐free (DFS) and disease‐related overall survival (DROS). Concurrent Ep‐CAM and Her‐2/neu overexpression was present in 13.2% of tumor specimens and had an additive negative impact on DFS and DROS. This minority of patients had a median time to relapse of only 34 months, whereas the median time to relapse was not reached in the patient population without Her‐2/neu and Ep‐CAM overexpression. By multivariate analysis Ep‐CAM overexpression proved to be an indicator of poor prognosis, independent of tumor size, histologic grade, hormone receptor expression and Her‐2/neu overexpression. In conclusion, overexpression of Ep‐CAM and Her‐2/neu complement each other as predictors for poor prognosis in patients with invasive breast cancer. Determination of these tumor markers should help in assigning breast cancer patients to 1 of 3 distinct risk categories.

Increased frequency of thorax injuries with ACD-CPR ☆

A prospective, randomised out-of-hospital study in a two-tiered system with active compression-decompression (ACD) cardiopulmonary resuscitation (CPR) versus standard (STD) CPR in patients following non-traumatic cardiac arrest was planned to test the hypothesis that ACD-CPR by the first tier may increase the occurrence of ventricular fibrillation as compared with STD-CPR. Furthermore, in a later phase of the study, sternal and rib fractures induced by both CPR methods were determined by extensive autopsy. After enrolling 90 patients the study was terminated because of a high frequency of chest injuries found at autopsy. Forty-two patients received STD-CPR from the first tier and ACD-CPR from the second tier. Thirty-three patients received ACD-CPR only by the first and the second tier, while 15 patients received STD-CPR only from the first and second tiers. In order to obtain a sufficiently large control group for autopsy findings after STD-CPR, STD-CPR was performed in an additional 33 patients within a second period of 4 months. There was no improvement in the number of patients found in ventricular fibrillation after ACD-CPR as compared to STD-CPR performed by the first tier. In patients undergoing autopsy (n = 35) there were significantly more sternal fractures with ACD-CPR versus STD-CPR (14/15 vs. 6/20; P <0.005) and rib fractures (13/15 vs. 11/20; P < 0.05) In conclusion, ACD-CPR appears to cause more CPR-related injuries than does standard CPR, but as a result of a number of limitations on this study, this fact cannot be proven beyond doubt.

Risk for cytomegalovirus infection following reduced intensity allogeneic stem cell transplantation

Preliminary data suggest a faster immune recovery following non-myeloablative stem cell transplantation because of the persistence of recipient T cells, but the real impact on post-transplant infectious complications remains unknown. We retrospectively analysed the incidence of cytomegalovirus (CMV) infection in twenty patients following reduced intensity conditioning with busulfan/fludarabine±thiotepa and post-transplant immunosuppression with cyclosporine A/mycophenolate mofetil. Results were compared with 20 patients receiving myeloablative transplants during the same time period and who were matched for CMV risk group and for donor origin. The cumulative incidence of CMV infection following reduced intensity vs. myeloablative transplants was 60.4% vs. 40.0%, respectively (p value 0.1, log rank test). The risk for CMV infection in both cohorts was increased after in vivo T cell depletion with antithymocyte globulin (75% and 60%, respectively). Acute GVHD preceded the diagnosis of CMV infection by a median of 25 (range, 9–61) days following reduced intensity transplants and a median of 14 (range, 10–34) days in myeloablative transplants. Recurrent CMV infections were observed only in patients receiving reduced intensity transplants. Using multivariate analysis only reduced intensity transplantation and in vivo T cell depletion had a significant impact on the risk of CMV infection. In our series the incidence for CMV infection following reduced intensity transplants seems to be increased as compared with risk-matched myeloablative transplants. When adding anti-T cell antibodies to the conditioning regimen, the risk for CMV infection increases by up to 75%. Thorough studies of the risk of post-transplant viral infection are necessary to optimize surveillance as well as pre-emptive and/or prophylactic treatment strategies in the non-myeloablative transplantation setting.

Prolonged iron depletion after allogeneic 2-unit RBC apheresis.

BACKGROUND: Allogeneic 2‐unit RBC apheresis is a safe procedure offering many advantages for donors and blood banks. A controlled study was performed to determine whether the recommended minimum interval of 4 months between 2‐unit RBC apheresis donations is appropriate in terms of the recovery of RBCs and the regeneration of iron stores.

Perinatal Bone Turnover in Term Human Neonates and the Influence of Maternal Smoking

Bone turnover in neonates appears independently of the comparably low maternal bone turnover, but there is only sparse information on the effect of the in utero environment on fetal bone turnover. Postnatally, the resuming growth velocity and alterations in mineral homeostasis affect neonatal bone turnover. This study evaluated the relationship of bone marker concentrations to maternal and fetal auxological variables as well as maternal smoking and assessed the short-term change in bone markers during the first days of life. Serum markers of bone formation [osteocalcin and bone-specific alkaline phosphatase (BALP)] and bone resorption (C-terminal telopeptide of type I collagen) were measured in cord blood and at discharge (median d 3) in 69 healthy term neonates. Concentrations of BALP were significantly lower in neonates of smokers (n = 16) compared with nonsmokers (n = 53), both at birth (p = 0.013) and at discharge (p = 0.036). Both cord osteocalcin and BALP were negatively related to maternal weight and maternal body mass index. Maternal smoking and pregnancy weight gain were the predictors of cord BALP (r2 = 0.24;p < 0.001), whereas the mode of delivery best predicted cord C-terminal telopeptide of type I collagen levels (r2 = 0.19;p < 0.001). C-terminal telopeptide of type I collagen and osteocalcin increased significantly (p < 0.001) from birth to discharge, whereas BALP levels did not change significantly during the same period. Our results suggest that maternal smoking during pregnancy and maternal obesity may have a negative impact on fetal bone formation. The significant increase of osteocalcin and C-terminal telopeptide of type I collagen may result either from an increase in bone turnover or altered renal clearance.

Analysis of the performance of AdaBoost.M2 for the simulated digit-recognition-example

In simulation studies boosting algorithms seem to be susceptible to noise. This article applies Ada.Boost.M2 used with decision stumps to the digit recognition example, a simulated data set with attribute noise. Although the final model is both simple and complex enough, boosting fails to reach the Bayes error. A detailed analysis shows some characteristics of the boosting trials which influence the lack of fit.