Efficacy and safety of tabalumab plus standard of care in Japanese patients with active systemic lupus erythematosus: Subgroup analyses of the ILLUMINATE-1 study

Objective: To assess the efficacy and safety of tabalumab, an anti-B cell activating factor (BAFF) antibody, in combination with standard of care (SoC) therapy in Japanese patients with active systemic lupus erythematosus (SLE).

Methods: A subgroup analysis was conducted in Japanese patients (n?=?45) enrolled in ILLUMINATE-1, a phase III global trial in SLE patients (N?=?1164). Patients received SoC plus tabalumab or placebo, starting with a loading dose (240?mg) at week 0, followed by 120?mg every 4 weeks (120 Q4W, n?=?15), 120?mg every 2 weeks (120 Q2W, n?=?15), or placebo Q2W (n?=?15). The primary endpoint was proportion achieving SLE Responder Index-5 (SRI-5) improvement at week 52.

Results: A numerically greater SRI-5 response rate was achieved with 120 Q2W (46.7%; p?=?0.059 vs. placebo) compared with 120 Q4W (20.0%) and placebo Q2W (13.3%). The proportion of patients with severe SLE flare was lower for 120 Q2W (0%) and 120 Q4W (6.7%) than for placebo (26.7%). The rates of serious adverse events (AEs) and treatment-emergent AEs were similar across treatments.

Conclusion: In Japanese SLE patients, tabalumab 120 Q2W improved SRI-5 response rate and reduced the frequency of severe flares compared with placebo. Safety profiles were similar with tabalumab and placebo.     

Evaluation of computer-aided detection of lesions in mammograms obtained with a digital phase-contrast mammography system

A computer-aided detection (CAD) system was evaluated for its ability to detect microcalcifications and masses on images obtained with a digital phase-contrast mammography (PCM) system, a system characterised by the sharp images provided by phase contrast and by the high resolution of 25-μm-pixel mammograms. Fifty abnormal and 50 normal mammograms were collected from about 3,500 mammograms and printed on film for reading on a light box. Seven qualified radiologists participated in an observer study based on receiver operating characteristic (ROC) analysis. The average of the areas under ROC curve (AUC) values for the ROC analysis with and without CAD were 0.927 and 0.897 respectively (P?=?0.015). The AUC values improved from 0.840 to 0.888 for microcalcifications (P?=?0.034) and from 0.947 to 0.962 for masses (P?=?0.025) respectively. The application of CAD to the PCM system is a promising approach for the detection of breast cancer in its early stages.     

Patterns of failure and influence of potential prognostic factors after surgery in transitional cell carcinoma of the upper urinary tract

Background  We investigated the long-term outcome of upper urinary tract transitional cell carcinoma (TCC) after surgery. Methods  The study population comprised 114 surgically treated patients with upper urinary tract TCC treated at Jikei University Hospital between March 1990 and December 2004. All these patients underwent radical surgery without any type of neoadjuvant therapy. Patterns of failure and patient survival were compared with clinicopathological parameters. Results  The 5- and 10-year overall survival (OAS) rates for the patients were 85% (95% confidence interval [CI], 81%–89%) and 76% (95% CI, 69%–83%). To date, 19 patients (16.7%) have experienced distant or lymph node metastasis at a mean of 13.3 months following surgery (range, 1 to 50 months). The site of the primary tumor did not affect patient survival (P > 0.05). Both lymphovascular involvement (LVI) and positive lymph nodes were found to have poor prognosis in univariate analysis (P = 0.004 and P < 0.0001). Multivariate analysis indicated pathological stage and bladder recurrence (bladder recurrence being a better prognostic factor) to be independent predictors of metastasis-free survival, but not of OAS or cause-specific survival (CSS). Conclusion  Pathological stage and bladder recurrence were found to be the predictors of metastasis-free survival in this study. Further searching for reliable biomarkers is needed to accurately predict the prognosis of this malignancy.     

Behavioral characteristics and c‐Fos expression in the medullary dorsal horn in a rat model for orofacial cancer pain

It is well known that patients with orofacial cancer suffer from cancer‐induced pain which produces feeding difficulties. To understand the mechanisms of pain associated with orofacial cancer, we have recently created a model for rat orofacial cancer by inoculation with Walker carcinosarcoma 256B‐cells into the vibrissal pads. The present study used both behavioral and immunohistochemical techniques to investigate changes in pain‐related and ingestive behavior, along with c‐Fos expression in the medullary dorsal horn which is a site for processing orofacial pain. The tumor mass grew gradually and contacted the nerve trunks within days after the inoculation of tumor cells. Physical difficulties in ingestion were observed after day 10 post‐inoculation and facial grooming periods were prolonged. Sensitivities of the inoculated vibrissal pads to mechanical and thermal stimuli were increased on days 4 and 7, suggesting the development of mechanical allodynia and thermal hyperalgesia. Although hyposensitivity to mechanical and thermal stimulation was observed in the inoculated region after day 10, hyperalgesia developed on the margin of the tumor, suggesting that the hypersensitive region spread with growth of tumor mass. In the medullary dorsal horn, the levels of c‐Fos immunoreactivity of the ipsilateral side increased significantly on days 4, 7 and 10, supporting the behavioral observations. These results indicate that the rat model shows symptoms similar to those in patients with orofacial cancer, for example, induction of feeding disorder and neuropathic pain.     

Novel tubulin-polymerization inhibitor derived from thalidomide directly induces apoptosis in human multiple myeloma cells: possible anti-myeloma mechanism of thalidomide

To ascertain the exact anti-myeloma mechanism of thalidomide in vivo, we performed structural development studies of thalidomide, and obtained various analogues with specific molecular properties. Among these derivatives, we found that a new thalidomide analogue, 2-(2,6-diisopropylphenyl)-5-hydroxy-1H-isoindole-1,3-dione (5HPP-33) had the most potent anti-myeloma effect and tubulin-polymerization-inhibiting activity. 5HPP-33 directly inhibited the growth and survival of various myeloma cell lines (RPMI8226, U266, and IM9) in a dose-dependent manner with IC50 of 1-10 microM. In contrast, thalidomide itself did not inhibit cellular growth of RPMI8226 cells. Cultivation with 10 microM 5HPP-33 induced G2/M phase cell cycle arrest, followed by apoptosis of myeloma cells. Treatment with 5HPP-33 induced caspase-3 activity and PARP cleavage. A tubulin polymerization assay using microtubule protein from porcine brain revealed that 5HPP-33 showed potent tubulin-polymerization-inhibiting activity with IC50 of 8.1 microM, comparable to that of the known tubulin-polymerization inhibitor, rhizoxin. Moreover, its activity was more potent than that of a known thalidomide metabolite, 5-hydroxythalidomide. Notably, the structural requirement for its activity was critical, as other analogues and derivatives of 5HPP-33 showed only slight tubulin-polymerization-inhibiting activity. Our data suggest that 5HPP-33 is a promising candidates for a therapeutic agent of multiple myeloma. In addition, these results suggest that the tubulin-polymerization inhibiting activity of thalidomide might be a possible mechanism for inducing the apoptosis of myeloma cells by thalidomide.