Faculty Bibliography

Using a data set of 1217 patients with multiple myeloma enrolled in Total Therapies, we have examined the impact of novel therapies on molecular and risk subgroups and the clinical value of molecular classification. Bortezomib significantly improved the progression-free survival (PFS) and overall survival (OS) of the MMSET (MS) subgroup. Thalidomide and bortezomib positively impacted the PFS of low-risk (LoR) cases defined by the GEP70 signature, whereas high-risk (HiR) cases showed no significant changes in outcome. We show that molecular classification is important if response rates are to be used to predict outcomes. The t(11;14)-containing CD-1 and CD-2 subgroups showed clear differences in time to response and cumulative response rates but similar PFS and OS. Furthermore, complete remission was not significantly associated with the outcome of the MAF/MAFB (MF) subgroup or HiR cases. HiR cases were enriched in the MF, MS and proliferation subgroups, but the poor outcome of these groups was not linked to subgroup-specific characteristics such as MAF overexpression per se. It is especially important to define risk status if HiR cases are to be managed appropriately because of their aggressive clinical course, high rates of early relapse and the need to maintain therapeutic pressure on the clone.

As part of Total Therapy (TT) 3b, baseline marrow aspirates were subjected to two-color flow cytometry of nuclear DNA content and cytoplasmic immunoglobulin (DNA/CIG) as well as plasma cell gene expression profiling (GEP). DNA/CIG-derived parameters, GEP and standard clinical variables were examined for their effects on overall survival (OS) and progression-free survival (PFS). Among DNA/CIG parameters, the percentage of the light chain-restricted (LCR) cells and their cytoplasmic immunoglobulin index (CIg) were linked to poor outcome. In the absence of GEP data, low CIg <2.8, albumin <3.5 g/dl and age ⩾65 years were significantly associated with inferior OS and PFS. When GEP information was included, low CIg survived the model along with GEP70-defined high risk and low albumin. Low CIg was linked to beta-2-microglobulin >5.5 mg/l, a percentage of LCR cells exceeding 50%, C-reactive protein ⩾8 mg/l and GEP-derived high centrosome index. Further analysis revealed an association of low CIg with 12 gene probes implicated in cell cycle regulation, differentiation and drug transportation from which a risk score was developed in TT3b that held prognostic significance also in TT3a, TT2 and HOVON trials, thus validating its general applicability. Low CIg is a powerful new prognostic variable and has identified potentially drug-able targets.

Nerve growth factor (NGF), which has long been considered to be a trophic factor for peripheral sensory and sympathetic neurons, has been found recently to influence cholinergic neurons in the basal forebrain and neostriatum. In the present study, we provide evidence that brainstem neurons in the perihypoglossal area that relay information from the inner ear and vestibular apparatus to the cerebellum and tectum are responsive to NGF. These neurons, which are located in the nucleus prepositus hypoglossi (NPH), spinal vestibular nucleus, cochlear complex, and gigantocellular and paragigantocellular nuclei of the reticular formation, express functional receptors for NGF and up-regulate the expression of trkA receptors after injection of NGF into targets. In addition, the developmental up-regulation of NGF in the cerebellum coincides with the differentiation of the perihypoglossal nuclei. These results suggest that neurons representing the principal brain relays for auditory and vestibular pathways and perihypoglossal neurons involved in gaze coordination are a novel group of central neurons (besides cholinergic neurons in the basal forebrain and neostriatum) that respond to NGF.

A rapid quantitative in vitro assay measured the effects of antiplaque agents and antiserum on growth and sucrose-mediated adherence of radio-labeled S. mutans 6715. Acid production was measured by change in pH. In this assay the primary effect of chlorhexidine and fluoride was bacteriostasis and inhibition of acid production, respectively; the primary effect of dextran, dextranase, and specific antiserum was inhibition of sucrose-mediated adherence