Targeting NF-kappaB in Waldenstrom macroglobulinemia

The nuclear factor-B (NF-B) path-way has been implicated in tumor B-cell survival, growth, and resistance to therapy. Because tumor cells overcome single-agent antitumor activity, we hypothesized that combination of agents that target differentially NF-B pathway will induce significant cytotoxicity. Therapeutic agents that target proteasome and Akt pathways should induce significant activity in B-cell malignancies as both pathways impact NF-B activity. We demonstrated that perifosine and bortezomib both targeted NF-B through its recruitment to the promoter of its target gene IB using chromatin immunoprecipitation assay. This combination led to synergistic cytotoxicity in Waldenstrom macroglobulinemia (WM) cells that was mediated through a combined reduction of the PI3K/Akt and ERK signaling pathways, found to be critical for survival of WM cells. Moreover, a combination of these drugs with the CD20 monoclonal antibody rituximab further increased their cytotoxic activity. Thus, effective WM therapy may require combination regimens targeting the NF-B pathway.      

Soluble receptor activator of nuclear factor kappaB ligand-osteoprotegerin ratio predicts survival in multiple myeloma: proposal for a novel prognostic index

Interaction between receptor activator of nuclear factor kappaB ligand (RANKL) and RANK/osteoprotegerin (OPG) plays a dominant role in osteoclast activation and possibly in plasma cell survival in multiple myeloma (MM). We measured soluble RANKL (sRANKL), OPG, and bone remodeling markers in 121 patients with newly diagnosed MM to evaluate their role in bone disease and survival. Serum levels of sRANKL were elevated in patients with MM and correlated with bone disease. The sRANKL/OPG ratio was also increased and correlated with markers of bone resorption, osteolytic lesions, and markers of disease activity. The sRANKL/OPG ratio, C-reactive protein (CRP), and beta2-microglobulin were the only independent prognostic factors predicting survival in multivariate analysis. We generated a prognostic index based on these factors that divided our patients into 3 risk groups. The low-risk group had a 96% probability of survival at 5 years, whereas the intermediate-risk and the high-risk groups had probabilities of survival of 52% and 0%, respectively. Not only do these results confirm for the first time in humans the importance of sRANKL/OPG in the development of bone disease, they also highlight the role of this pathway in the biology of plasma cell growth as reflected by its influence on survival.     

Incidence of posterior vitreous detachment after laser in situ keratomileusis

Background Vitreoretinal complications are rare in laser in situ keratomileusis (LASIK). Increase in intraocular pressure caused by intraoperative suction with subsequent deforming of the ocular globe and excimer laser shock during the ablation have been discussed as possible causes. The purpose of this study was to determine the effect of LASIK on the vitreous body. Patients and methods In a prospective study we performed ocular ultrasonography (B scan) immediately before and 1 week after LASIK procedure in 103 myopic or myopic–astigmatic eyes (53 patients, mean age 36.3 years, 32 women, 21 men). In particular, the prevalence, localization, and extent of posterior vitreous detachment (PVD) were determined. Results The mean spherical equivalent was −4.85 D (range −1.25 to −8.38) and the mean anteroposterior ocular globe length was 25.13 mm (range 23.31–27.65). Ninety-five eyes (92.2%) had no PVD preoperatively. Nine eyes out of this group (seven patients, 9.5%) developed incomplete PVD as assessed 1 week postoperatively. Eight eyes (7.8%) had a partial PVD preoperatively and in only one eye was an extension of vitreous detachment observed after the surgery. None of the preoperatively measured parameters could predict the occurrence of PVD by LASIK. Conclusions LASIK may in rare cases lead to new occurrence of PVD or extension of a previously existing partial PVD. Thomas Kohnen is a consultant for scientific advice to Bausch & Lomb, Inc., but neither author has a financial proprietary in any of the instrumentation or devices used in this study. This paper was presented in part at the German Ophthalmic Society (DOG) 2003 annual meeting, Berlin, with the title “LASIK-induced posterior vitreous detachment.”     

Measuring contrast sensitivity under different lighting conditions: comparison of three tests.

PURPOSE: The purpose of this study was to evaluate three psychophysical tests for the measurement of contrast sensitivity (CS) and disability glare (DG) at different luminance levels. METHODS: In 60 eyes of 60 individuals (group 1: 20 healthy eyes of young individuals; group 2: 20 healthy eyes of elderly subjects; group 3: 20 eyes with nuclear cataract), CS with best correction was measured twice with the Frankfurt-Freiburg Contrast and Acuity Test System (FF-CATS) and the Functional Acuity Contrast Test (FACT, 1.5 cycles per degree [cpd]) at 167 cd/m2 and 0.167 cd/m2, and with the Pelli-Robson Chart (PRC) at 100 cd/m2 with and without glare. Repeatability of test and retest, and discriminative ability between the different subgroups, were assessed for CS values. RESULTS: Maximum CS values varied across tests. In all groups, highest CS values were obtained with the photopic FF-CATS. For FACT scores at 1.5 cpd, there was a ceiling effect for young subjects. CS scores obtained with the PRC were the lowest. The PRC had the best test-retest repeatability of all tests. Under mesopic conditions with glare, reliability was generally lower; the FF-CATS had the highest repeatability of the mesopic tests. The FF-CATS discriminated best between the different groups for all conditions. CONCLUSIONS: There are large discrepancies in the test results between CS testing methods, especially under different lighting conditions. Results from different CS tests are not interchangeable.     

Serum CA 125 combined with transvaginal ultrasonography for ovarian cancer screening

BACKGROUND: The aim of this study was to evaluate the combination of serum CA125 and Transvaginal Ultra Sonography (TVUS) score, as a screening procedure for ovarian cancer in premenopausal and postmenopausal women. PATIENTS AND METHODS: A retrospective case-control pilot study was conducted. The files of 120 women with ovarian neoplasia detected by TVUS and increased CA125 level, within the framework of a prevention program, were reviewed. The relationship between the above tests and epithelial malignancy was investigated using the SPSS-12 program for Windows. RESULTS: The combination of CA125 value exceeding 30U/ml and a TVUS score > or = 35 had a sensitivity of 81.7% and specificity of 100% in predicting ovarian cancer. Mathematical analysis of the logistic model of our variables revealed a mathematical model that can calculate the likelihood of ovarian cancer detection, by using a combination of CA125 > or = 30U/ml and TVUS score > or = 35. CONCLUSION: By combining TVUS and CA125, an accurate prediction for the presence of ovarian cancer may be achieved. Further investigation in a larger population is warranted.     

Comparison of a digital and a handheld infrared pupillometer for determining scotopic pupil diameter

To compare a digital infrared pupillometer with a handheld infrared pupillometer for determining scotopic pupil size.Department of Ophthalmology, Johann Wolfgang Goethe-University, Frankfurt am Main, Germany.In 100 eyes of 50 healthy individuals (mean age 38.8 years +/- 10.7 [SD]), the scotopic pupil size was measured with a digital (Procyon) and a handheld (Colvard) infrared pupillometer. After dark adaptation of 1 minute, measurements were performed with both devices by 2 examiners (E1 and E2). Agreement and repeatability were analyzed using a comparison method described by Bland and Altman.The mean scotopic pupil diameter was 5.90 +/- 0.97 mm (range 3.24 to 7.91 mm) with the Procyon and 5.78 +/- 0.98 mm (range 3.00 to 7.30 mm) with the Colvard pupillometer. The mean difference between the 2 devices was -0.01 mm (E1) and -0.24 mm (E2). The limits of agreement ranged from 2.84 (E1) to 3.24 (E2). The coefficients of repeatability were 0.64 (Procyon) and 1.16 (Colvard). The mean difference between E1 and E2 was -0.10 for the Procyon and 0.13 for the Colvard pupillometer. The limits of agreement ranged from 1.28 (Procyon) to 2.32 (Colvard).The digital infrared pupillometer (Procyon) demonstrated better repeatability and agreement in measuring scotopic pupil size than a handheld device (Colvard).     

Association between the plasminogen activator inhibitor-1 4G/5G polymorphism and venous thrombosis. A meta-analysis

The effect of the 675 insertion/deletion (4G/5G) polymorphism of plasminogen activator inhibitor-1 (PAI-1) gene on the risk of venous thromboembolism (VTE) remains controversial. In this study, we performed a meta-analysis of published data regarding this issue. A comprehensive electronic search was carried out up until September 2006. A total of 22 articles were included in the analysis that was performed using random effects models. Eighteen papers, concerning patients without another known risk factor, comprised 2,644 cases and 3,739 controls. The alleles contrast (4G vs. 5G allele) yielded a statistically significant odds ratio (OR) of 1.153 (95% confidence interval [CI]: 1.068-1.246). In a sub-analysis of five studies that included 256 cases with another genetic risk factor and 147 controls, the combined per-allele OR was still significant (OR: 1.833,95% CI: 1.325-2.536). On the contrary, the analysis of five studies regarding cases with a non-genetic risk factor for VTE (antiphospholipid antibody syndrome, Behcet disease) provided insignificant results in all aspects. There was no evidence for heterogeneity and publication bias in all analyses. Based on our findings, the 4G allele appears to increase the risk of venous thrombosis, particularly in subjects with other genetic thrombophilic defects. Recommendation for detection of this polymorphism in evaluating thrombophilia in such patients might be considered.     

Prognostication of the high-risk WM patient

Waldenström's macroglobulinemia is characterized by a protracted course in most patients and the median survival may be long. However, a subset of patients may present with more aggressive disease that is associated with short survival. In order to better characterize these “poor-risk” patients, we identified patients who died within 2 years from the initiation of front-line treatment. These patients were older and had more often features of aggressive disease, such as elevated LDH and low serum albumin than the standard-risk population. Furthermore, only a minority of poor-risk patient had a response to initial therapy. However, conventional clinical factors or even the lack on response could not adequately identify poor-risk patients, indicating the need for novel molecular or other markers that would be able to effectively recognize patients at greatest need for aggressive therapies.     

Novel therapeutic avenues in myeloma: changing the treatment paradigm

Our better understanding of the complex interaction of multiple myeloma (MM) cells with their bone marrow microenvironment and the signaling pathways that are dysregulated in this process has resulted in a dramatic increase in the therapeutic agents available for this disease. A number of these new agents have demonstrated significant activity in patients with MM. Over the past 5 years, three drugs have received approval from the US Food and Drug Administration for therapy in MM--bortezomib, thalidomide, and lenalidomide. To date, the choice of therapy for MM is not individualized according to the biologic characteristics of the disease, but future studies should enable us to identify patients who may benefit most from certain therapeutic interventions, and thus develop individualized therapy for MM. In this review, we will present some of the treatment algorithms currently developed for patients with MM and focus on established advances in therapy, specifically with thalidomide, bortezomib, and lenalidomide. We will also discuss some of the emerging novel therapeutic agents showing promise in phase I/II clinical trials in MM.