Biophysical technologies for understanding circulating tumor cell biology and metastasis.

An understanding of cancer evolution in lung cancer with its associated resistance to therapy can only be achieved with repeated sampling and analysis of the cancer. Given the high risks and costs associated with repeat physical biopsy, alternative technologies must be applied. Several modalities exist for analysis and re-analysis of cancer biology. Among them are the CellSearch platform, the CTC chip, and the high-definition CTC platform. While the former is primarily able to provide prognosticating information in the form of CTC enumeration, the latter two have the advantage of serving as a platform to study tumor biology. Techniques for analysis of single cell genomics, as well as protein expression on a single cell basis provide scientists with the capacity to understand cancer cell populations as a collection of individual cells, rather than as an average of all cells. A multimodal combination of circulating tumor DNAs (ctDNAs), CTCs, proteomics, and CTC-derived xenografts (CDXs) to create computational models useful in diagnosis, prognostication, and predictiveness to treatment is likely the future of tailoring individualized cancer care.

Asian-variant intravascular large B-cell lymphoma.

Intravascular large B-cell lymphoma (IVLBCL) is a rare and deadly malignancy involving the growth of lymphoma cells within vessel lumina of all organ types. IVLBCL is further divided into the hemophagocytic Asian variant and a classical Western variant. Both variants are difficult to diagnose by imaging, and although diagnostic criteria have been developed to guide workup, histopathological examination remains imperative. Treatment of IVLBCL remains difficult given the high mortality of the disease, but rituximab has emerged as a promising therapeutic option when combined with various cytotoxic regimens. The two main variants of IVLBCL generally manifest in their respective Asian or Western populations, and crossover between ethnicities is rare. We present the second described case of Asian-variant IVLBCL in an African American individual.

Chronic lymphocytic leukemia and B and T cells differ in their response to cyclic nucleotide phosphodiesterase inhibitors.

Phosphodiesterase (PDE)4 inhibitors, which activate cAMP signaling by reducing cAMP catabolism, are known to induce apoptosis in B lineage chronic lymphocytic leukemia (CLL) cells but not normal human T cells. The explanation for such differential sensitivity remains unknown. In this study, we report studies contrasting the response to PDE4 inhibitor treatment in CLL cells and normal human T and B cells. Affymetrix gene chip analysis in the three cell populations following treatment with the PDE4 inhibitor rolipram identified a set of up-regulated transcripts with unusually high fold changes in the CLL samples, several of which are likely part of compensatory negative feedback loops. The high fold changes were due to low basal transcript levels in CLL cells, suggesting that cAMP-mediated signaling may be unusually tightly regulated in this cell type. Rolipram treatment augmented cAMP levels and induced ATF-1/CREB serine 63/133 phosphorylation in both B lineage cell types but not T cells. As treatment with the broad-spectrum PDE inhibitor 3-isobutyl-1-methylxanthine induced T cell CREB phosphorylation, we tested a series of family-specific PDE inhibitors for their ability to mimic 3-isobutyl-1-methylxanthine-induced ATF-1/CREB phosphorylation. Whereas PDE3 inhibitors alone had no effect, the combination of PDE3 and PDE4 inhibitors induced ATF-1/CREB serine 63/133 phosphorylation in T cells. Consistent with this observation, PDE3B transcript and protein levels were low in CLL cells but easily detectable in T cells. Combined PDE3/4 inhibition did not induce T cell apoptosis, suggesting that cAMP-mediated signal transduction that leads to robust ATF-1/CREB serine 63/133 phosphorylation is not sufficient to induce apoptosis in this lymphoid lineage.