Willem J. van Heeckeren

Hypertension, Proteinuria, and Antagonism of Vascular Endothelial Growth Factor Signaling: Clinical Toxicity, Therapeutic Target, or Novel Biomarker?

There are three US Food and Drug Administration–approved angiogenesis inhibitors for the treatment of cancer that specifically target vascular endothelial growth factor (VEGF) signaling. Bevacizumab (monoclonal antibody to VEGF) has been shown to confer a survival advantage when used in combination with cytotoxic chemotherapy in patients with colorectal cancer and non– small-cell lung cancer. 1,2 Sorafenib and sunitinib are orally bioavailable, small-molecule tyrosine kinase inhibitors that target the intracellular tyrosine kinase domain of the VEGF receptor (VEGFR) among other tyrosine kinase targets. Sorafenib has been shown to increase progression-free survival in patients with renal cell carcinoma. 3 Sunitinib has been shown to increase progressionfree survival in patients with renal cell carcinoma and GI stromal tumors. 4-6 A plethora of new small-molecule tyrosine kinase inhibitors are in preclinical development and early-phase clinical trials that target VEGFR with varying degrees of specificity, including AZD2171, which is the subject of a published report by Drevs et al

Evidence for Splice Site Pairing via Intron Definition in Schizosaccharomyces pombe

ABSTRACT Schizosaccharomyces pombe pre-mRNAs are generally multi-intronic and share certain features with pre-mRNAs fromDrosophila melanogaster, in which initial splice site pairing can occur via either exon or intron definition. Here, we present three lines of evidence suggesting that, despite these similarities, fission yeast splicing is most likely restricted to intron definition. First, mutating either or both splice sites flanking an internal exon in the S. pombe cdc2 gene produced almost exclusively intron retention, in contrast to the exon skipping observed in vertebrates. Second, we were unable to induce skipping of the internal microexon in fission yeast cgs2, whereas the default splicing pathway excludes extremely small exons in mammals. Because nearly quantitative removal of the downstream intron incgs2 could be achieved by expanding the microexon, we propose that its retention is due to steric occlusion. Third, several cryptic 5′ junctions in the second intron of fission yeastcdc2 are located within the intron, in contrast to their generally exonic locations in metazoa. The effects of expanding and contracting this intron are as predicted by intron definition; in fact, even highly deviant 5′ junctions can compete effectively with the standard 5′ splice site if they are closer to the 3′ splicing signals. Taken together, our data suggest that pairing of splice sites inS. pombe most likely occurs exclusively across introns in a manner that favors excision of the smallest segment possible.

Promise of New Vascular-Disrupting Agents Balanced With Cardiac Toxicity: Is It Time for Oncologists to Get to Know Their Cardiologists?

Willem J. van Heeckeren, Division of Hematology/Oncology, Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH Shyam Bhakta and Jose Ortiz, Division of Cardiology, Department of Medicine, CASE School of Medicine, Cleveland, OH Jeff Duerk, Departments of Radiology and Biomedical Engineering, CASE School of Medicine, Cleveland, OH Matthew M. Cooney, Afshin Dowlati, Keith McCrae, and Scot C. Remick, Division of Hematology/Oncology, Department of Medicine, Case Western Reserve University School of Medicine, Developmental Therapeutics Program, CASE Comprehensive Cancer Center, University Hospitals of Cleveland, Cleveland, OH

Complications from vascular disrupting agents and angiogenesis inhibitors : aberrant control of hemostasis and thrombosis

Purpose of reviewTo discuss thrombotic and hemorrhagic complications from angiogenesis inhibitors and vascular disrupting agents, pathogenesis, and recommendations for prophylaxis and management of those complications. Recent findingsVenous thromboembolism has been a significant complication of the angiogenesis inhibitors thalidomide and lenalidomide. Prophylaxis with aspirin, low-molecular-weight heparin, or warfarin has been shown to decrease rates of venous thromboembolism in patients treated with these agents. Life-threatening hemorrhage and arterial thromboembolism have been observed in patients using treatments that inhibit the vascular endothelial growth factor signaling pathway. Patients should be screened for arterial thromboembolism and hemorrhage risk prior to using vascular endothelial growth factor signal inhibitors. It is not known how angiogenesis inhibitors and vascular disrupting agents upset normal hemostasis. It is likely that disruption of the function and/or integrity of vascular endothelium leads to an increased risk for thrombosis and/or hemorrhage. SummaryNew angiogenesis inhibitors and vascular disrupting agents have been developed that have significant activity against neoplasms. Potentially life-threatening side effects of hemorrhage and thrombosis have been observed with many of these new agents. As new treatments that disrupt angiogenesis or existing tumor vasculature are developed, attention should be given to these toxicities in clinical practice and clinical trials.

Randomised comparison of two B-cell purging protocols for patients with B-cell non-Hodgkin lymphoma: in vivo purging with rituximab versus ex vivo purging with CliniMACS CD34+ cell enrichment device

We investigated the feasibility, safety and efficacy of two B‐cell purging methods in patients with CD20+ non‐Hodgkin lymphoma (NHL) receiving autologous stsem cell transplantation. Myeloid and immune recoveries between the methods were compared. Twenty‐seven patients were randomised to either in vivo purging with rituximab or ex vivo purging by CD34+ cell selection. Both purging methods were efficient at eliminating B‐cells in infusates. When compared with in vivo purging, ex vivo purging was associated with CD34+ cell loss and delayed median neutrophil (10 d vs. 11 d) and platelet (12·5 d vs. 17 d) count recoveries. Lymphocyte recovery was similar in both groups, but immunoglobulin recovery was delayed after in vivo purging. Late‐infectious complications were few in both arms. At a median follow‐up of 27 months, 2‐year probabilities of event‐free survival (EFS) rates were 81% for in vivo purging and 76% for ex vivo purging (P = 0·66). When compared with 53 unpurged patients, all 27 purged patients had improved 3‐year probabilities of overall survival (89% vs. 70%, P = 0·014) and a trend for improved EFS (78% vs. 57%, P = 0·075). In conclusion, although both purging methods were feasible and safe, rituximab purging was superior as it did not impair CD34+ cell mobilisation and was associated with faster myeloid recovery. Further studies are needed to determine whether rituximab purging is more effective than the use of unpurged autografts.

Influence of human leucocyte antigen disparity and graft lymphocytes on allogeneic engraftment and survival after umbilical cord blood transplant in adults

The dose of graft‐nucleated cells and CD34+ haematopoietic progenitor cells are predictors of allogeneic engraftment and survival in umbilical cord blood (UCB) recipients. In this single institution prospective phase II trial, flow cytometric analyses of CD34+ progenitor and lymphocyte populations in unmodified single unit human leucocyte antigen (HLA)‐disparate UCB grafts infused into 31 consecutive adults (median age 41 years, range 20–64) receiving myeloablative conditioning were compared with clinical outcomes. Median infused UCB graft‐nucleated cells and CD34+ dose was 2·2 × 107/kg and 1·2 × 105/kg respectively. Day to absolute neutrophil count ≥0·5 × 109/l with full donor chimerism averaged 27 d (range 12–41). Univariate analyses demonstrated that UCB graft‐infused cell doses of CD34+ (P = 0·015), CD3+ (P = 0·024) and CD34+HLADR+CD38+ progenitors (P = 0·043) correlated with neutrophil engraftment. This same analysis did not demonstrate a correlation between CD34+ (P = 0·11), CD3+ (P = 0·28) or CD34+HLADR+CD38+ (P = 0·108) cell dose and event‐free survival (EFS). High‐resolution matching for HLA‐class II (DRB1) resulted in improved EFS (P = 0·02) and decreased risk for acute graft‐versus‐host disease (GVHD) (P = 0·004). Early mortality (prior to post‐transplant day +28) occurred in three patients, while 26 patients achieved myeloid engraftment. These results suggest that UCB graft matching at DRB1 is an important risk factor for acute GVHD and survival, while higher UCB graft cell doses of CD34+, committed CD34+ progenitors and CD3+ T cells favourably influence UCB allogeneic engraftment.