Citations

Monoclonal gammopathy of undetermined significance (MGUS) is a premalignant plasma-cell proliferative disorder associated with a life-long risk of progression to multiple myeloma (MM). It is not known whether MM is always preceded by a premalignant asymptomatic MGUS stage. Among 77 469 healthy adults enrolled in the nationwide population-based prospective Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial, we identified 71 subjects who developed MM during the course of the study in whom serially collected (up to 6) prediagnostic serum samples obtained 2 to 9.8 years prior to MM diagnosis were available. Using assays for monoclonal (M)–proteins (electrophoresis/immunofixation) and kappa-lambda free light chains (FLCs), we determined longitudinally the prevalence of MGUS and characterized patterns of monoclonal immunoglobulin abnormalities prior to MM diagnosis. MGUS was present in 100.0% (87.2%-100.0%), 98.3% (90.8%-100.0%), 97.9% (88.9%-100.0%), 94.6% (81.8%-99.3%), 100.0% (86.3%-100.0%), 93.3% (68.1%-99.8%), and 82.4% (56.6%-96.2%) at 2, 3, 4, 5, 6, 7, and 8+ years prior to MM diagnosis, respectively. In approximately half the study population, the M-protein concentration and involved FLC-ratio levels showed a yearly increase prior to MM diagnosis. In the present study, an asymptomatic MGUS stage consistently preceded MM. Novel molecular markers are needed to better predict progression to MM in patients with MGUS.

Abstract We examined whether monoclonal gammopathy of undetermined significance (MGUS) is increased in first-degree relatives of multiple myeloma (MM) or MGUS patients. Probands were recruited from a population-based prevalence study (MGUS) and the Mayo Clinic (MM). Serum samples were collected from first-degree relatives older than 40 years and subjected to electrophoresis and immunofixation. The prevalence of MGUS in relatives was compared with population-based rates. Nine-hundred eleven relatives of 232 MM and 97 MGUS probands were studied. By electrophoresis, MGUS was detected in 55 (6%) relatives, and immunofixation identified 28 additional relatives for an age- and sex-adjusted prevalence of 8.1% (95% CI, 6.3 to 9.8). The prevalence of MGUS in relatives increased with age (1.9%, 6.9%, 11.6%, 14.6%, 21.0% for ages 40-49, 50-59, 60-69, 70-79, ≥ 80 years, respectively; P < .001). Using similar MGUS detection methods, there was a higher risk of MGUS in relatives (age-adjusted risk ratio [RR], 2.6; 95% CI, 1.9 to 3.4) compared with the reference population. The increased risk was seen among relatives of MM (RR, 2.0; 95% CI, 1.4 to 2.8) and MGUS probands (RR, 3.3; 95% CI, 2.1 to 4.8). The increased risk of MGUS in first-degree relatives of MGUS or MM patients implies shared environment and/or genetics.

Abstract Resistance to temozolomide and radiotherapy is a major problem for patients with glioblastoma but may be overcome using the poly(ADP-ribose) polymerase inhibitor ABT-888. Using two primary glioblastoma xenografts, the efficacy of ABT-888 combined with radiotherapy and/or temozolomide was evaluated. Treatment with ABT-888 combined with temozolomide resulted in significant survival prolongation (GBM12: 55.1%, P = 0.005; GBM22: 54.4%, P = 0.043). ABT-888 had no effect with radiotherapy alone but significantly enhanced survival in GBM12 when combined with concurrent radiotherapy/temozolomide. With multicycle therapy, ABT-888 further extended the survival benefit of temozolomide in the inherently sensitive GBM12 and GBM22 xenograft lines. However, after in vivo selection for temozolomide resistance, the derivative GBM12TMZ and GBM22TMZ lines were no longer sensitized by ABT-888 in combination with temozolomide, and a similar lack of efficacy was observed in two other temozolomide-resistant tumor lines. Thus, the sensitizing effects of ABT-888 were limited to tumor lines that have not been previously exposed to temozolomide, and these results suggest that patients with newly diagnosed glioblastoma may be more likely to respond to combined temozolomide/poly(ADP-ribose) polymerase inhibitor therapy than patients with recurrent disease. [Mol Cancer Ther 2009;8(2):OF407–8]

Among young normotensive men, a reciprocal balance between cardiac output and sympathetic nerve activity is important in the regulation of arterial pressure. In young women, the balance among cardiac output, peripheral resistance, and sympathetic nerve activity is unknown. Consequently, the aim of this study was to examine the relationship of cardiac output and total peripheral resistance to muscle sympathetic nerve activity in young women. Multiunit peroneal recordings of muscle sympathetic nerve activity were obtained in 17 women (mean±SEM: age 24±3 years) and 21 men (mean±SEM: age 25±5 years). Mean resting muscle sympathetic nerve activity was lower in women compared with men (19±3 versus 25±1 bursts minute −1 ; P <0.05), as was mean arterial pressure (89±1 versus 94±2 mm Hg; P <0.05). Mean arterial pressure was not related to muscle sympathetic nerve activity in men ( P =0.80) or women ( P =0.62). There was a positive relationship between total peripheral resistance and muscle sympathetic nerve activity ( r =0.62; P <0.05) and an inverse relationship between cardiac output and muscle sympathetic nerve activity ( r =−0.69; P <0.05) in men. Unexpectedly, muscle sympathetic nerve activity had no relationship to either total peripheral resistance ( r =−0.27; P >0.05) or cardiac output ( r =0.23; P >0.05) in women. Our results demonstrate that men and women rely on different integrated physiological mechanisms to maintain a normal arterial pressure despite widely varying sympathetic nerve activity among individuals. These findings may have important implications for understanding how hypertension and other disorders of blood pressure regulation occur in men and women.

Dendritic cells (DCs) play a pivotal role in the control of innate and adaptive immune responses. They are a heterogeneous cell population, where plasmacytoid dendritic cells (pDCs) are a unique subset capable of secreting high levels of type I IFNs. It has been demonstrated that pDCs can coordinate events during the course of viral infection, atopy, autoimmune diseases, and cancer. Therefore, pDC, as a main source of type I IFN, is an attractive target for therapeutic manipulations of the immune system to elicit a powerful immune response against tumor antigens in combination with other therapies. The therapeutic vaccination with antigen-pulsed DCs has shown a limited efficacy to generate an effective long-lasting immune response against tumor cells. A rational manipulation and design of vaccines which could include DC subsets outside “Langerhans cell paradigm” might allow us to improve the therapeutic approaches for cancer patients.