E-selectin ligands recognised by HECA452 induce drug resistance in myeloma, which is overcome by the E-selectin antagonist, GMI-1271.

Multiple myeloma (MM) is characterized by the clonal expansion and metastatic spread of malignant plasma cells to multiple sites in the bone marrow (BM). Recently, we implicated the sialyltransferase ST3Gal-6, an enzyme critical to the generation of E-selectin ligands, in MM BM homing and resistance to therapy. Since E-selectin is constitutively expressed in the BM microvasculature, we wished to establish the contribution of E-selectin ligands to MM biology. We report that functional E-selectin ligands are restricted to a minor subpopulation of MM cell lines which, upon expansion, demonstrate specific and robust interaction with recombinant E-selectin in vitro. Moreover, an increase in the mRNA levels of genes involved in the generation of E-selectin ligands was associated with inferior progression-free survival in the CoMMpass study. In vivo, E-selectin ligand-enriched cells induced a more aggressive disease and were completely insensitive to Bortezomib. Importantly, this resistance could be reverted by co-administration of GMI-1271, a specific glycomimetic antagonist of E-selectin. Finally, we report that E-selectin ligand-bearing cells are present in primary MM samples from BM and peripheral blood with a higher proportion seen in relapsed patients. This study provides a rationale for targeting E-selectin receptor/ligand interactions to overcome MM metastasis and chemoresistance.

Proteomic characterization of human multiple myeloma bone marrow extracellular matrix.

The extracellular matrix (ECM) is a major component of the tumor microenvironment, contributing to the regulation of cell survival, proliferation, differentiation and metastasis. In multiple myeloma (MM), interactions between MM cells and the bone marrow (BM) microenvironment, including the BM ECM, are critical to the pathogenesis of the disease and the development of drug resistance. Nevertheless, composition of the ECM in MM and its role in supporting MM pathogenesis has not been reported. We have applied a novel proteomic-based strategy and defined the BM ECM composition in patients with monoclonal gammopathy of undetermined significance (MGUS), newly diagnosed and relapsed MM compared with healthy donor-derived BM ECM. In this study, we show that the tumor ECM is remodeled at the mRNA and protein levels in MGUS and MM to allow development of a permissive microenvironment. We further demonstrate that two ECM-affiliated proteins, ANXA2 and LGALS1, are more abundant in MM and high expression is associated with a decreased overall survival. This study points to the importance of ECM remodeling in MM and provides a novel proteomic pipeline for interrogating the role of the ECM in cancers with BM tropism.

Prospective Assessment of Radiation in Pediatric Urology: The Pediatric Urology Radiation Safety Evaluation Study.

PURPOSE: Pediatric tissues are exquisitely sensitive to ionizing radiation from diagnostic studies and therapies involving fluoroscopy. We prospectively monitored radiation exposure in our pediatric urology patients during fluoroscopy guided operative procedures with single point dosimeters to quantify radiation dose. MATERIALS AND METHODS: Children undergoing fluoroscopy guided urological procedures were prospectively enrolled in the study from 2013 to 2015. Single point dosimeters were affixed to skin overlying the procedural site for the durations of the procedures to record dosimetry data. Patient demographics, procedural variables and fluoroscopic settings were recorded. RESULTS: A total of 78 patients underwent 96 procedures, including retrograde pyelography, ureteral stent insertion, ureteroscopy and percutaneous nephrolithotomy. Median patient age was 12 years (range 0.3 to 17) and median body mass index percentile for age was 70.7 (1.0 to 99.1). Median skin entrance radiation dose for all procedures performed was 0.56 mGy. Median dosages associated with the 29 diagnostic procedures and 49 definitive interventions were 0.6 mGy (mean 0.8, range 0.1 to 2.2) and 0.7 mGy (1.1, 0.0 to 5.5), respectively. The dose associated with the 18 procedures of temporization was significantly higher by comparison (median 1.0 mGy, mean 2.6, range 0.1 to 10.7, p = 0.02). CONCLUSIONS: Pediatric radiation exposure is not insignificant during urological procedures. Further multi-institutional work would provide context for our findings. Protocols to optimize fluoroscopic settings and minimize patient exposure, and guidelines for radiation based imaging should have a key role in all pediatric radiation safety initiatives.

Tracking of radiation exposure in pediatric stone patients: The time is now.

BACKGROUND: Despite the increasing incidence of pediatric nephrolithiasis, there is little data quantifying the radiation exposure associated with treatment of this disease. In this study, pediatric patients with nephrolithiasis who were managed at a single institution were identified, and the average fluoroscopy time and estimated radiation exposure associated with their procedures were reported. METHODS: Stone procedures performed on pediatric patients between 2005 and 2012 were retrospectively identified. Procedures were classified as primary ureteroscopy (URS), stent placement prior to ureteroscopy (SURS), percutaneous nephrolithotomy (PCNL), and bilateral ureteroscopy (BLURS). Patient demographic information, stone size, stone location, number of radiographic images, and fluoroscopy times were analyzed. RESULTS: A total of 152 stone procedures were included in the final analysis (92 URS, 38 SURS, eight BLURS and 14 PCNL). Mean patient age at time of stone treatment was 15.94 ± 4.1 years. Median fluoroscopy times were 1.6 (IQR 0.8-2.4), 2.1 (IQR 1.6-3.0), 2.5 (IQR 2.0-2.9), and 11.7 (IQR 5.0-18.5) minutes for URS, SURS, BLURS and PCNL, respectively. There was a moderate correlation between stone size and fluoroscopy time (r = 0.33). When compared with ureteroscopic procedures, PCNL was associated with a significantly higher fluoroscopy time (11.7 vs 2.1 min, P < 0.001). The estimated median effective dose was 3 mSv for ureteroscopic procedures and 16.8 mSv for PCNL. In addition to radiation exposure during treatment, patients in this cohort were exposed to an average of one (IQR1-3) CT scan and three (IQR 1-8) abdominal X-rays. No new malignancies were identified during the limited follow-up period. CONCLUSIONS: Radiation exposure during treatment of pediatric stone disease is not trivial, and is significantly greater when PCNL is performed. Given the recommended maximum effective dose of 50 mSv in any one year, urologists should closely monitor the amount of fluoroscopy used, and consider the potential for radiation exposure when choosing the operative approach. Prospective studies are currently underway to elucidate precise dose measurements and localize sites of radiation exposure in children during stone treatment.

Demonstration of Philadelphia chromosome negative abnormal clones in patients with chronic myelogenous leukemia during major cytogenetic responses induced by imatinib mesylate.

Imatinib mesylate, an Abl-specific kinase inhibitor, produces sustained complete hematologic responses (CHR) and major cytogenetic responses (MCR) in chronic myeloid leukemia (CML) patients, but long-term outcomes in these patients are not yet known. This article reports the identification of clonal abnormalities in cells lacking detectable Philadelphia (Ph) chromosome/BCR-ABL rearrangements from seven patients with chronic- or accelerated-phase CML, who were treated with imatinib. All seven patients were refractory or intolerant to interferon therapy. Six of seven patients demonstrated MCR and one patient, who had a cryptic translocation, achieved low-level positivity (2.5%) for BCR-ABL by fluorescence in situ hybridization. The median duration of imatinib treatment before the identification of cytogenetic abnormalities in BCR-ABL-negative cells was 13 months. The most common cytogenetic abnormality was trisomy 8, documented in three patients. All patients had varying degrees of dysplastic morphologic abnormalities. One patient exhibited increased numbers of marrow blasts, yet consistently demonstrated no Ph-positive metaphases and the absence of morphologic features of CML. The presence of clonal abnormalities in Ph-negative cells of imatinib-treated CML patients with MCR and CHR highlights the importance of routine metaphase cytogenetic testing and long-term follow-up of all imatinib-treated patients.

Insights from pre-clinical studies for new combination treatment regimens with the Bcr-Abl kinase inhibitor imatinib mesylate (Gleevec/Glivec) in chronic myelogenous leukemia: a translational perspective.

Clinical phase I/II studies with the Abl kinase inhibitor imatinib mesylate (Gleevec/Glivec, formerly STI571) for the treatment for chronic myelogenous leukemia (CML) demonstrated the safety and the remarkable efficacy of this molecularly targeted agent. However, a significant proportion of patients treated in the chronic phase of the disease after having failed interferon alpha (IFN) remain predominantly Philadelphia chromosome positive (Ph(+)), suggesting a risk of later relapses. Furthermore, results in blast crisis patients revealed a high frequency of relapses or resistance to imatinib. To circumvent resistance, improve response rates, or prolong survival, pre-clinical evaluations of combinations of imatinib with other agents have been pursued. Some of these have already been translated into clinical studies. Here, we first summarize evidence from pre-clinical studies on new combination regimens with imatinib in the treatment of CML. Second, we analyze preliminary clinical data of ongoing combination studies. Finally, we provide a summary of approaches that use novel antileukemic agents with molecularly characterized modes of action.

ST1571, a tyrosine kinase inhibitor for the treatment of chronic myelogenous leukemia: validating the promise of molecularly targeted therapy.

The deregulated tyrosine kinase activity of the Bcr-Abl fusion protein has been established as the causative molecular event in chronic myelogenous leukemia (CML). Thus the Bcr-Abl tyrosine kinase is an ideal target for pharmacologic inhibition. ST1571 (formerly CGP57148B), is an Abl-specific tyrosine kinase inhibitor that in preclinical studies selectively kills Bcr-Abl-containing cells in vitro and in vivo. The results of clinical studies have demonstrated the potential of molecularly targeted therapies, and ST1571 is emerging as a new therapeutic agent for CML.

Chronic myelogenous leukaemia--new therapeutic principles.

The deregulated tyrosine kinase activity of the BCR-ABL fusion protein is the cause of malignant transformation in almost all cases of chronic myelogenous leukaemia (CML), making BCR-ABL an ideal target for pharmacological inhibition. Signal transduction inhibitor (STI571) (formerly CGP57 148B), is an ABL specific, tyrosine kinase inhibitor. In preclinical studies, it has been shown to selectively kill BCR-ABL expressing cells, both in-vitro and in vivo. The results of clinical studies to date are highly encouraging and STI571 promises to be an important addition to the therapy of CML.

The role of the tyrosine kinase inhibitor STI571 in the treatment of cancer.

The tyrosine kinase inhibitor STI571 exemplifies the successful development of a rationally designed, molecularly targeted therapy for the treatment of cancer. This review details the steps in the development of this agent and highlights why this drug has been so successful in the treatment of chronic myelogenous leukaemia. Future directions including the mechanisms and management of resistance and new therapeutic strategies are discussed. Finally, the literature supporting the use of STI571 in other malignancies, including solid tumors is briefly reviewed.

Status of bcr-abl tyrosine kinase inhibitors in chronic myelogenous leukemia.

The bcr-abl fusion protein is present in the vast majority of cases of chronic myelogenous leukemia, and the deregulated tyrosine kinase activity of this protein is essential for leukemic transformation. Thus, bcr-abl is an ideal target for pharmacologic inhibition. In preclinical studies, ST1571 (formerly CGP57148B), an abl-specific, tyrosine kinase inhibitor, selectively killed bcr-abl-expressing cells both in vitro and in vivo. In early clinical trials of ST1571, encouraging results have been obtained, and there is already a suggestion that ST1571 may soon need to be incorporated into treatment algorithms for chronic myelogenous leukemia.

Pulmonary hemorrhage in a hemophiliac simulating a lung neoplasm.

We report an elderly, male smoker with moderate hemophilia B who presented with hemoptysis. Chest imaging revealed a well-circumscribed, pulmonary, mass lesion. Repeated bronchoscopy failed to make a diagnosis, and the patient ultimately underwent open thoracotomy with resection of the mass. Pathologic examination revealed hemorrhagic changes in association with bullous lung disease. This is the first report of symptomatic pulmonary hemorrhage in a patient with hemophilia B. Hemorrhage into a pre-existing bulla can simulate a primary lung neoplasm.

Successful treatment of aggressive post transplant lymphoproliferative disorder using rituximab.

A 52 year -old female developed a histologically aggressive, Epstein-Barr virus positive, lymphoproliferative disorder involving the brain and liver 4 months following a combined kidney/pancreas transplant. Following a brief trial of reduced immunosuppression, she was treated with rituximab. Despite subsequent re-intensification of immunosuppression, the lesions showed continued regression with almost complete disappearance by 5 months. Rituximab appears to be a safe, effective treatment for post transplant lymphoproliferative disorder.

STI571: an inhibitor of the BCR-ABL tyrosine kinase for the treatment of chronic myelogenous leukaemia.

The deregulated tyrosine kinase activity of the BCR-ABL fusion protein has been established as the causative molecular event in chronic myelogenous leukaemia. Thus, the BCR-ABL tyrosine kinase is an ideal target for pharmacological inhibition. STI571 (formerly CGP57148B), is an ABL-specific inhibitor of tyrosine kinase that, in preclinical studies, selectively killed BCR-ABL-containing cells in vitro and in vivo. Clinical studies have shown the potential of this specifically targeted therapy, and STI571 is emerging as an important new therapeutic agent for chronic myelogenous leukaemia.