We investigated the anti-asparaginase antibody (Ab) and asparaginase enzymatic activity in the sera of 1,001 patients (CCG-1961) with high-risk acute lymphoblastic leukemia (HR-ALL). Patients received nine doses of native Escherichia coli asparaginase during induction. Half of rapid early responders (RER) were randomly assigned to standard intensity arms and continued to receive native asparaginase. The other RER patients and all slow early responders received 6 or 10 doses of PEG-asparaginase. Serum samples (n = 3,193) were assayed for determination of asparaginase Ab titers and enzymatic activity. Three hundred ninety of 1,001 patients (39%) had no elevation of Ab among multiple evaluations-that is, were Ab-negative (<1.1 over negative control)-and 611 patients (61%) had an elevated Ab titer (>1.1). Among these 611 patients, 447 had no measurable asparaginase activity during therapy. Patients who were Ab-positive but had no clinical allergies continued to receive E. coli asparaginase, the activity of which declined precipitately. No detectable asparaginase activity was found in 81 of 88 Ab-positive patients shortly after asparaginase injections (94% neutralizing Ab). The Ab-positive patients with clinical allergies subsequently were given Erwinase and achieved substantial activity (0.1-0.4 IU/ml). An interim analysis of 280 patients who were followed for 30 months from induction demonstrated that the Ab-positive titers during interim maintenance-1 and in delayed intensification-1 were associated with an increased rate of events. The CCG-1961 treatment schedule was very immunogenic, plausibly due to initially administrated native asparaginase. Anti-asparaginase Ab was associated with undetectable asparaginase activity and may be correlated with adverse outcomes in HR ALL.

Purpose To assess the incidence of clinical allergy and end-Induction anti-asparaginase antibodies in children with high-risk acute lymphoblastic leukemia treated with pegylated E. coli asparaginase (PEG ASNase) and determine if they carry any prognostic significance. Patients and Methods Of 2057 eligible patients, 1155 patients were allocated to “augmented” arms where PEG ASNase replaced native ASNase post-Induction. Erwinia ASNase could replace native ASNase after allergy, if available. Allergy and survival data were complete for 990 patients. End-Induction antibody titers were available for 600 patients. Results During Consolidation, 29.2% (289/990 patients) had an allergic reaction. There were less allergic reactions to Erwinia ASNase than native ASNase (OR=4.33; p<0.0001) or PEG ASNase (OR=3.08; p<0.0001) during Interim Maintenance #1 only. There was no significant difference in 5-year EFS between patients who received PEG ASNase throughout the entire study post-Induction versus those who developed an allergic reaction to PEG ASNase during Consolidation and received Erwinia ASNase subsequently (80.8 ± 2.8% and 81.6 ± 3.8% (p=0.66), respectively). Patients with positive antibody titers post-Induction were more likely to have an allergic reaction to PEG ASNase (OR=2.4; p<0.001). Neither the 5-year EFS between patients with a negative versus positive antibody titer (80 ± 2.6% and 77.7 ± 4.3%, respectively, p=0.68) nor patients who did not receive any asparaginase post-Consolidation and patients who received PEG ASNase throughout the study (p=0.22) were significantly different. Conclusion We demonstrate differences in the incidence rates of toxicity between asparaginase preparations, but not in EFS. The presence of anti-asparaginase antibodies did not affect EFS.

These studies demonstrate that the tyrosine kinase inhibitor NSC 680410 has significant antileukemic activity in p53-null, drug-resistant human leukemia cell lines, as well as significant antitumor activity in combination with Flt-1/Fc chimera against U87 MG glioblastoma brain tumors implanted in situ in athymic mice.

The primary growth factor receptors involved in angiogenesis and lymphomagenesis can be grouped into the vascular endothelial growth factor (VEGF) receptors and related families. Inhibition of VEGF and other growth factors, including c-Abl, c-Kit, platelet-derived growth factor (PDGF), epidermal growth factor (EGF) and insulin-like growth factor (IGF), or their receptors containing tyrosine kinase domains by antiangiogenesis drugs disrupts cell survival signal transduction pathways and may contribute to the proapoptotic pathways in malignant cells. However, clinical trials suggest that signal transduction inhibitors have considerable antitumor activity when used as single agents only for a short time, most likely due to the development of drug resistance by the host or by the tumor cells. In order to prevent this problem and to augment their antitumor efficacy, these agents could be administered in combination with cytotoxic antineoplastic drugs. We hypothesized that the combination of the antiangiogenesis tyrosine kinase inhibitors with cytotoxic drugs would produce synergistic drug regimens. Two human T-lymphoblastic leukemia cell lines that express VEGF-R1, CEM/0 (wild-type, WT) and the drug-resistant clone CEM/ara-C/I/ASNase-0.5-2, were utilized in the drug combination studies. NSC 680410, a tyrosine kinase inhibitor given at 0.1 to 1 microM for 72 h, inhibited VEGF secretion and leukemic cell growth at 90% of vehicle-treated control cultures with an IC50 value of less than 1 microM. The cytotoxic drugs idarubicin (IDA), fludarabine (Fludara), and cytosine arabinoside (ara-C) were used for the various drug combinations. One-, two-, three-, and four-drug treatments were tested. Cell viability was documented by the MTT assay and photomicrographic estimation of apoptotic cells. Both the combination index (CI) and isobologram evaluations demonstrated strong synergism between these drugs and the tyrosine kinase inhibitor. NSC 680410 was highly synergistic with IDA, IDA + ara-C, and IDA + Fludara + ara-C, over the respective cytotoxic drug regimens at concentrations easily achieved in patient plasma. NSC 680410 potentiated the activity of IDA in both leukemia cell lines by 17.8- and 221.4-fold in the WT and drug-resistant line, respectively. The activity of NSC 680410 + IDA + ara-C was also potentiated by 58.8-fold in the WT line, and the activity of NSC 680410 + IDA + Fludara + ara-C by 2.4- and 6.47x10(6)-fold in the WT and drug-resistant lines, respectively. The results suggest that IDA was not needed for optimal synergistic activity in the CEM/0 cells, but IDA was a necessary component to obtain drug synergism in the drug-resistant clone. Similarly, STI571 (imatinib mesylate, Gleevec), the p210(bcr/abl) tyrosine kinase inhibitor, demonstrated synergism with Fludara + ara-C or IDA + ara-C. Most importantly STI571 showed synergism with NSC 680410, suggesting that these drugs inhibit different tyrosine kinase domains in human leukemia cells. Lastly, pretreatment of leukemic cells with NSC 680410 showed additivity ...

Purpose: Many molecular pathways, including cell cycle control, angiogenesis, and drug resistance, mediate tumor growth and survival. Vascular endothelial growth factor-A (VEGF-A) serum levels &lt;40 and &gt;100 pg/mL have been associated with good and poor prognoses, respectively. Experimental Design: The hypothesis was that serum VEGF-A levels in standard-risk acute lymphoblastic leukemia pediatric patients at induction are predictive of event-free survival (EFS). One hundred seventeen patients were entered in CCG-1962 study and randomized into the native and polyethylene glycolated asparaginase arms. VEGF-A levels were quantified by an ELISA assay. Results: All patients had a decrease in VEGF-A levels by day 14 of induction, but they later dichotomized; EFS group levels remained low and event group levels increased. A correlation exists between high VEGF-A levels at entry to induction and time to event. Moreover, 6-year EFS patients have lower end of induction VEGF-A levels (28 ± 6 pg/mL) than event patients (&gt;100 pg/mL; P &lt; 0.01). Kaplan-Meier curves using various VEGF-A values were produced; with ≤30 at entry into induction (day 0) and ≤60 pg/mL at the end of induction (day 28), patients with low VEGF-A levels had superior EFS (P &lt; 1e−4). Furthermore, patients who had an increase in VEGF-A during induction (ΔVEGF-positive, days 0-28) were more likely to have an event (P &lt; 1e−4). Bifurcation by asparaginase treatment arm did not alter these results. Conclusions: These observations strongly support that high VEGF-A levels in induction are an asparaginase treatment–independent predictive marker for EFS. Hence, an anti-VEGF-A therapy should be tested in acute lymphoblastic leukemia.

Background:Rotator cuff pathology occurs commonly and its cause is likely multifocal in origin. The development and progression of rotator cuff injury, especially in relation to extrinsic shoulder compression, remain unclear. Traditionally, certain acromial morphologies have been thought to contribute to rotator cuff injury by physically decreasing the subacromial space. The relationship between subacromial space volume and rotator cuff tears (RCT) has, however, never been experimentally confirmed. In this study, we retrospectively compared a control patient population to patients with partial or complete RCTs in an attempt to quantify the relationship between subacromial volume and tear type.Materials and Methods:We retrospectively identified a total of 46 eligible patients who each had shoulder magnetic resonance imaging (MRI) performed from January to December of 2008. These patients were stratified into control, partial RCT, and full-thickness RCT groups. Subacromial volume was estimated for each patient by averaging five sequential MRI measurements of subacromial cross-sectional areas. These volumes were compared between control and experimental groups using the Student's t-test.Results:With the numbers available, there was no statistically significant difference in subacromial volume measured between: the control group and patients diagnosed partial RCT (P > 0.339), the control group and patients with complete RCTs (P > 0.431).Conclusion:We conclude that subacromial volumes cannot be reliably used to predict RCT type.

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Intra-articular sacral facet fractures may be an underrecognized and misdiagnosed career-ending injury in elite athletes. In patients who have localized pain with back extension, a computed tomographic scan, and not a magnetic resonance image, diagnosed this injury. Although this series is small, it seems that early recognition and treatment of sacral facet fractures maximize chances of pain resolution and return to sport.