ONJ appears to be time-dependent with higher risk after long-term use of bisphosphonates in older MM patients often after dental extractions. No satisfactory therapy is currently available. Trials addressing the benefits/risks of continuing bisphosphonate therapy are needed.

IntroductionMultiple myeloma (MM) is a B-cell malignancy characterized by the accumulation of plasma cells with a low proliferation index and an extended life span. 1,2 Despite improvements in event-free and long-term survival resulting from autologous stem cell transplantation, MM remains an incurable disease in the majority of patients. 3,4 In the initial phases of this disease, the malignant plasma cells are dependent on the supportive environment of the bone marrow, which is at least partly responsible for the up-regulation of antiapoptotic factors in the tumor cells. 5,6 Translocations and aneuploidy are detected in the earliest stage of the disease (monoclonal gammopathy of undetermined significance), 7-9 and karyotypic abnormalities accumulate as the disease progresses. 2,10 In the later stages of disease, genetic lesions result in the activation of oncogenes that promote cell growth (Ras) and the loss of tumor suppressors (p16 Ink4a , p53), and the disease becomes bone marrow stroma-independent. 2 The molecular basis for the poor prognosis conferred by other genetic lesions, especially deletions of chromosome 13q, remains to be elucidated. 11 Interleukin-6 (IL-6) is important for the growth and survival 12-14 of myeloma cells and increases resistance to a variety of therapeutic interventions. [15][16][17] Bone marrow (BM) stromal cells provide IL-6 in a paracrine fashion, leading to activation of the Ras/mitogen-activated protein kinase (MAPK) and Jak/signal transducers and activators of transcription (STAT) pathways. 2,18,19 The Ras/MAPK pathway is considered more important for MM cell proliferation 20 ; however, it is likely that downstream effectors of Ras also play a role in cell survival. 21 In some experimental systems, STAT3 has been shown to activate genes that promote MM cell survival, including Bcl-XL and myeloid cell factor-1(Mcl-1). 22,23 Constitutive expression of STAT3 has been demonstrated in freshly isolated MM cells and may confer an important survival advantage in vivo. 22 Expression of antiapoptotic members of the Bcl-2 family appears to be an important factor for the clinical resistance of MM. Five antiapoptotic Bcl-2 family members (Bcl-2, Bcl-XL, A1, Mcl-1, and Bcl-w) have been identified in mammalian cells. [24][25][26] Bcl-2 has been found to be highly expressed in malignant plasma cells. [27][28][29] Bcl-XL expression was detected more frequently in patients at relapse and was shown to correlate with resistance to chemotherapy. 30,31 Mcl-1 is distinct from Bcl-2 and Bcl-XL in that it lacks a BH4 domain and is a large protein (40 kd as compared with 26 kd for Bcl-2) that encodes additional domains with Pro-Glu-Ser-Thr-like sequences (PEST) that could account for its short half-life (although recent data question the importance of the putative Pro-Glu-Ser-Thr sequences in regulating Mcl-1 turnover). [32][33][34] Mcl-1 levels in MM cells were reported to be induced by IL-6 in a STAT3-dependent mechanism. 23 The roles of A1 and Bcl-W in MM remain to be determined. Thus, MM cells expr...

BACKGROUND. Bortezomib is active in heavily pretreated multiple myeloma patients; the dose‐limiting toxicity is peripheral neuropathy (PN). METHODS. The authors retrospectively reviewed the incidence, severity, and risk factors for PN in 78 patients who received bortezomib. The median age was 57 years (range, 33–80 years), 62% of patients were men, and 37% of patients were African Americans. Seventeen patients (22%) had diabetes mellitus (DM), and 66 patients (85%) had received thalidomide. Before bortezomib treatment, 37% of the patients reported subjective, grade 1 or 2 PN. Patients received bortezomib alone (n = 10 patients) plus dexamethasone (n = 36 patients) and thalidomide (n = 20 patients) or chemotherapy (n = 12 patients). PN affected 52% of patients, including grade 3 and 4 PN in 15% and 7%, respectively. RESULTS. Twelve patients stopped bortezomib because of side effects that included PN (n = 9 patients), diarrhea (n = 2 patients) and cytomegalovirus pneumonia (n = 1 patient); 11 patients had dose reductions because of PN. Grade 4 PN affected 6 patients (sensory, n = 4 patients; motor/sensory, n = 2 patients). The onset of grade 4 PN was sudden rather than cumulative. Factors that were predictive of PN grade were baseline PN (P = .002), prior thalidomide use (P = .03), and the presence of DM (P = .03). Multiple myeloma responses included complete, near complete, and partial responses in 5% of patients, 10% of patients, and 27% of patients, respectively. Responses were independent of PN and of whether bortezomib was combined with chemotherapy or thalidomide. Patients remained on therapy longer for a median of 5 cycles (range, 2–36 cycles) when they received bortezomib plus thalidomide versus 3 cycles (range, 1–19 cycles) for the other combinations. PN therapy was mostly supportive. It was noteworthy that 6 of 9 patients with PN who received lenalidomide as salvage therapy after bortezomib had significant improvement in their symptoms. CONCLUSIONS. The risk of bortezomib‐related PN was greater in patients who had PN and DM at baseline. The authors concluded that an unexpected, symptomatic improvement of PN on lenalidomide is worth further investigation. Cancer 2007. © 2007 American Cancer Society.

This paper discusses the research conducted to achieve an accurate bubble-growth model and simulation scheme to describe precisely the bubble-growth phenomena that occur in polymeric foaming. Using the accurately measured thermophysical and rheological properties of polymer/gas mixtures (i.e., the solubility, the diffusivity, the surface tension, the viscosity, and the relaxation time) as the inputs for computer simulation, the growth profiles for bubbles nucleated at different times were predicted and carefully compared to experimentally observed data obtained from batch foaming simulation with online visualization. A polystyrene/carbon dioxide (PS/CO2) system is used herein as a case example. It was verified that the cell-growth model is capable of thoroughly depicting the growth behaviors of bubble nuclei nucleated under varying processing conditions without using any fitting parameter. These results indicate that the established model accounts for most of the physics behind the bubble-growth phenomena. Furthermore, the effects of the aforementioned thermophysical and rheological parameters on the cell-growth dynamics were demonstrated by a series of sensitivity studies.