Allogeneic Hematopoietic Cell Transplantation in the Treatment of Chronic Lymphocytic Leukemia: Why and When?

Chronic lymphocytic leukemia (CLL) is the most common hematologic malignancy in adults with an incidence rate of 4.2 per 100,000 per year. CLL frequently takes an indolent course, with some patients not requiring treatment for years, yet is incurable by currently available chemo- and immuno-therapeutic modalities. Despite high initial response rates, particularly to purine analogues, patients invariably relapse and subsequently develop resistance to therapy. The traditional “watchful waiting” approach to CLL is being challenged by data showing that treatments used early in the disease course impact long-term overall and progression-free survivals . The only curative treatment for CLL currently, is allogeneic hematopoeietic cell transplantation (alloHCT). In contrast to autologous transplant, myeloablative alloHCT for CLL patients generates durable remissions with promising survival plateaus; however, significant transplant related mortality (TRM) is also observed (25-50%) . At present the fact remains that for poor-risk CLL, alloHCT is the only treatment with the potential of providing long-term disease control. Future combinations with emerging low-toxicity therapies may further enhance the curative potential of allogeniec hematopoietic cell transplant. New drugs can also potentially enable refractory patients to attain response as a bridge to more effective stem cell transplantation

SpectralNET – an application for spectral graph analysis and visualization

BACKGROUND: Graph theory provides a computational framework for modeling a variety of datasets including those emerging from genomics, proteomics, and chemical genetics. Networks of genes, proteins, small molecules, or other objects of study can be represented as graphs of nodes (vertices) and interactions (edges) that can carry different weights. SpectralNET is a flexible application for analyzing and visualizing these biological and chemical networks. RESULTS: Available both as a standalone .NET executable and as an ASP.NET web application, SpectralNET was designed specifically with the analysis of graph-theoretic metrics in mind, a computational task not easily accessible using currently available applications. Users can choose either to upload a network for analysis using a variety of input formats, or to have SpectralNET generate an idealized random network for comparison to a real-world dataset. Whichever graph-generation method is used, SpectralNET displays detailed information about each connected component of the graph, including graphs of degree distribution, clustering coefficient by degree, and average distance by degree. In addition, extensive information about the selected vertex is shown, including degree, clustering coefficient, various distance metrics, and the corresponding components of the adjacency, Laplacian, and normalized Laplacian eigenvectors. SpectralNET also displays several graph visualizations, including a linear dimensionality reduction for uploaded datasets (Principal Components Analysis) and a non-linear dimensionality reduction that provides an elegant view of global graph structure (Laplacian eigenvectors). CONCLUSION: SpectralNET provides an easily accessible means of analyzing graph-theoretic metrics for data modeling and dimensionality reduction. SpectralNET is publicly available as both a .NET application and an ASP.NET web application from . Source code is available upon request

Preclinical Results of Camptothecin-Polymer Conjugate (IT-101) in Multiple Human Lymphoma Xenograft Models

Purpose: Camptothecin (CPT) has potent broad-spectrum antitumor activity by inhibiting type I DNA topoisomerase (DNA topo I). It has not been used clinically because it is water-insoluble and highly toxic. As a result, irinotecan (CPT-11), a water-soluble analogue of CPT, has been developed and used as salvage chemotherapy in patients with relapsed/refractory lymphoma, but with only modest activity. Recently, we have developed a cyclodextrin-based polymer conjugate of 20-(S)-CPT (IT-101). In this study, we evaluated the preclinical antilymphoma efficacy of IT-101 as compared with CPT-11. Experimental Design: We determined an in vitro cytotoxicity of IT-101, CPT-11, and their metabolites against multiple human lymphoma cell lines. In human lymphoma xenografts, the pharmacokinetics, inhibitions of tumor DNA topo I catalytic activity, and antilymphoma activities of these compounds were evaluated. Results: IT-101 and CPT had very high in vitro cytotoxicity against all lymphoma cell lines tested. As compared with CPT-11 and SN-38, IT-101 and CPT had longer release kinetics and significantly inhibit higher tumor DNA topo I catalytic activities. Furthermore, IT-101 showed significantly prolonged the survival of animals bearing s.c. and disseminated human xenografts when compared with CPT-11 at its maximum tolerated dose in mice. Conclusions: The promising present results provide the basis for a phase I clinical trial in patients with relapsed/refractory lymphoma

HIV Status Does Not Affect the Outcome of Autologous Stem Cell Transplantation (ASCT) for Non-Hodgkin Lymphoma (NHL)

Randomized trials comparing autologous stem cell transplant (ASCT) to conventional chemotherapy have demonstrated superior survival among HIV-negative ASCT patients with relapsed non-Hodgkin lymphoma (NHL). Recent trials explored the feasibility of ASCT in the HIV setting. Although these studies have shown that ASCT in HIV-positive NHL patients (HIVpos-NHL) is well tolerated, the impact of HIV infection on long-term transplant outcome is not well characterized. Ongoing comparison of long-term survival following ASCT in HIVpos-NHL patients and HIVneg-NHL patients will allow investigators to explore whether there should be inclusion of HIVpos-NHL patients in ASCT trials. To study long-term outcome we conducted a single-institution matched case-controlled study in HIVpos-NHL patients (cases) and HIVneg-NHL patients (controls). Twenty-nine patients with HIVpos-NHL were matched with HIVneg-NHL controls on sex, time to ASCT, year of transplant, histology, age, disease status, number prior regimens, and conditioning regimen. Nonrelapse mortality (NRM) was similar: 11% (95% confidence interval [CI]: 4%-28%) in HIVpos-NHL patients and 4% (95% CI: 1%-25%) in HIVneg-NHL controls (P = .18). Two-year disease-free survival (DFS) for the HIVpos-NHL patients was 76% (95% CI: 62%-85%) and 56% (95% CI: 45%-66%) for the HIVneg-NHL controls (P = .33). Overall survival was also similar; the 2-year point estimates were 75% (95% CI: 61%-85%) and 75% (95% CI: 60%-85%), respectively (P = .93), despite inclusion of more poor risk HIVpos-NHL patients. These results provide further evidence that HIV status does not affect the long-term outcome of ASCT for NHL, and therefore HIV status alone should no longer exclude these patients from transplant clinical trials

Adenovirus 36 DNA in Adipose Tissue of Patient with Unusual Visceral Obesity

Massive adipose tissue depositions in the abdomen and thorax sufficient to interfere with respiration developed in a patient with multiple medical problems. Biopsy of adipose tissue identified human adenovirus 36 (Adv 36) DNA. Adv 36 causes adipogenesis in animals and humans. Development of massive lipomatosis may be caused by Adv 36

Deep Chandra Observations of Abell 2199: the Interplay between Merger-Induced Gas Motions and Nuclear Outbursts in a Cool Core Cluster

We present new Chandra observations of Abell 2199 that show evidence of gas sloshing due to a minor merger, as well as impacts of the radio source, 3C 338, hosted by the central galaxy, NGC 6166, on the intracluster gas. The new data are consistent with previous evidence of a Mach 1.46 shock 100" from the cluster center, although there is still no convincing evidence for the expected temperature jump. Other interpretations of this feature are possible, but none is fully satisfactory. Large scale asymmetries, including enhanced X-ray emission 200" southwest of the cluster center and a plume of low entropy, enriched gas reaching 50" to the north of the center, are signatures of gas sloshing induced by core passage of a merging subcluster about 400 Myr ago. An association between the unusual radio ridge and low entropy gas are consistent with this feature being the remnant of a former radio jet that was swept away from the AGN by gas sloshing. A large discrepancy between the energy required to produce the 100" shock and the enthalpy of the outer radio lobes of 3C 338 suggests that the lobes were formed by a more recent, less powerful radio outburst. Lack of evidence for shocks in the central 10" indicates that the power of the jet now is some two orders of magnitude smaller than when the 100" shock was formed.Comment: 17 pages, 20 figures, accepted for publication in Ap

Globular Clusters and X-ray Point Sources in Centaurus A (NGC 5128)

We detect 353 X-ray point sources, mostly low-mass X-ray binaries (LMXBs), in four Chandra observations of Centaurus A (NGC 5128), the nearest giant early-type galaxy, and correlate this point source population with the largest available ensemble of confirmed and likely globular clusters associated with this galaxy. Of the X-ray sources, 31 are coincident with 30 globular clusters that are confirmed members of the galaxy by radial velocity measurement (2 X-ray sources match one globular cluster within our search radius), while 1 X-ray source coincides with a globular cluster resolved by HST images. Another 36 X-ray point sources match probable, but spectroscopically unconfirmed, globular cluster candidates. The color distribution of globular clusters and cluster candidates in Cen A is bimodal, and the probability that a red, metal rich GC candidate contains an LMXB is at least 1.7 times that of a blue, metal poor one. If we consider only spectroscopically confirmed GCs, this ratio increases to ~3. We find that LMXBs appear preferentially in more luminous (massive) GCs. These two effects are independent, and the latter is likely a consequence of enhanced dynamical encounter rates in more massive clusters which have on average denser cores. The X-ray luminosity functions of the LMXBs found in GCs and of those that are unmatched with GCs reveal similar underlying populations, though there is some indication that fewer X-ray faint LMXBs are found in globular clusters than X-ray bright ones. Our results agree with previous observations of the connection of GCs and LMXBs in early-type galaxies and extend previous work on Centaurus A.Comment: 34 pages, 10 figures, 2 tables, Accepted for Publication in The Astrophysical Journa