Study of active controlled monotherapy used for rheumatoid arthritis, an IL-6 inhibitor (SAMURAI): evidence of clinical and radiographic benefit from an x ray reader-blinded randomised controlled trial of tocilizumab

OBJECTIVE: To evaluate the ability of tocilizumab (a humanised anti-IL-6 receptor antibody) monotherapy to inhibit progression of structural joint damage in patients with RA. METHODS: In a multi-centre, x ray reader-blinded, randomised, controlled trial, 306 patients with active RA of <5 years' duration were allocated to receive either tocilizumab monotherapy at 8 mg/kg intravenously every 4 weeks or conventional disease-modifying antirheumatic drugs (DMARDs) for 52 weeks. Radiographs of hands and forefeet were scored by the van der Heijde modified Sharp method. RESULTS: Patients had a mean disease duration of 2.3 years and a disease activity score in 28 joints of 6.5 at baseline. Mean total modified Sharp score (TSS) was 29.4, which was very high despite the relatively short disease duration. At week 52, the tocilizumab group showed statistically significantly less radiographic change in TSS (mean 2.3; 95% CI 1.5 to 3.2) than the DMARD group (mean 6.1; 95% CI 4.2 to 8.0; p<0.01). Tocilizumab monotherapy also improved signs and symptoms. The overall incidences of AEs were 89% and 82% (serious AEs: 18% and 13%; serious infections: 7.6% and 4.1%) in the tocilizumab and DMARD groups, respectively. CONCLUSION: Tocilizumab monotherapy was generally well tolerated and provided radiographic benefit in patients with RA.     

Organ motion in image-guided radiotherapy: lessons from real-time tumor-tracking radiotherapy

External radiotherapy using imaging technology for patient setup is often called image-guided radiotherapy (IGRT). The most important problem to solve in IGRT is organ motion. Four-dimensional radiotherapy (4DRT), in which the accuracy of localization is improved – not only in space but also in time – in comparison to 3DRT, is required in IGRT. Real-time tumor-tracking radiotherapy (RTRT) has been shown to be feasible for performing 4DRT with the aid of a fiducial marker near the tumor. Lung, liver, prostate, spinal/paraspinal, gynecological, head and neck, esophagus, and pancreas tumors are now ready for dose escalation studies using RTRT.     

Activation of downstream epidermal growth factor receptor (EGFR) signaling provides gefitinib-resistance in cells carrying EGFR mutation

Patients with pulmonary adenocarcinoma carrying the epidermal growth factor receptor (EGFR) mutation tend to display dramatic clinical response to treatment with the EGFR tyrosine kinase inhibitor gefitinib. Unfortunately, in many cases the cancer cells eventually acquire resistance, and this limits the duration of efficacy. To gain insight into these acquired resistance mechanisms, we first prepared HEK293T cell line stably transfected with either wild-type (WT) or mutant (L858R) EGFR, and then expressed oncogenic K-Ras12V mutant in the latter transfectant. Although 293T cells expressing wild-type EGFR did not show any growth inhibition by gefitinib treatment similarly to the non-transfected cells, the cells expressing the EGFR-L858R were exquisitely sensitive. Consistently, phospho-Akt levels were decreased in response to gefitinib in cells expressing EGFR-L858R but not in cells with EGFR-WT. In contrast, 293T cells expressing both EGFR-L858R and oncogenic K-Ras were able to proliferate even in the presence of high concentration of gefitinib probably by inducing Erk1/2 activation. We also expressed K-Ras12V in the gefitinib-sensitive pulmonary adenocarcinoma cell line PC-9, which harbors an in-frame deletion in the EGFR gene. The activated K-Ras inhibited the effects of gefitinib treatment on cell growth, cell death induction and levels of phospho-Akt, as well as phospho-Erk. These data indicate that activated Ras could substitute most of the upstream EGFR signal, and are consistent with the hypothesis that mutational activation of targets immediately downstream from the EGFR could induce the secondary resistance to gefitinib in patients with lung cancer carrying EGFR mutation.     

Frequent silencing of RUNX3 in esophageal squamous cell carcinomas is associated with radioresistance and poor prognosis

Radiotherapy is an effective treatment for some esophageal cancers, but the molecular mechanisms of radiosensitivity remain unknown. RUNX3, a novel tumor suppressor of gastric cancer, functions in transforming growth factor (TGF)-beta-dependent apoptosis. We obtained paired samples from 62 patients with advanced esophageal cancers diagnosed initially as T3 or T4 with image diagnosis; one sample was obtained from a biopsy before presurgical radiotherapy, and the other was resected in surgical specimens after radiotherapy. RUNX3 was repressed in 67.7% cases of the pretreatment biopsy samples and 96.7% cases of the irradiated, resected samples. The nuclear expression of RUNX3 was associated with radiosensitivity and a better prognosis than cytoplasmic or no RUNX3 expression (P<0.003); cytoplasmic RUNX3 expression was strictly associated with radioresistance. RUNX3 was downregulated and its promoter was hypermethylated in all radioresistant esophageal cancer cell lines examined. Stable transfection of esophageal cancer cells with RUNX3 slightly inhibited cell proliferation in vitro, enhanced the antiproliferative and apoptotic effects of TGF-beta and increased radiosensitivity in conjunction with Bim induction. In contrast, transfection of RUNX3-expressing cells with a RUNX3 antisense construct or a Bim-specific small interfering RNA induced radioresistance. Treatment with 5-aza-2'-deoxycytidine restored RUNX3 expression, increased radiosensitivity and induced Bim in both control and radioresistant cells. These results suggest that RUNX3 silencing promotes radioresistance in esophageal cancers. Examination of RUNX3 expression in pretreatment specimens may predict radiosensitivity, and induction of RUNX3 expression may increase tumor radiosensitivity.     

Alcohol consumption is associated with an increased risk of distal colon and rectal cancer in Japanese men: the Miyagi Cohort Study

The association between alcohol consumption and the risk of cancer of the proximal or distal colon or rectum remains controversial. We examined this association in a large population-based cohort of Japanese men. In 1990, a self-administered questionnaire on alcohol drinking and other health habits was delivered to 25,279 Japanese men aged 40 to 64 years of age. After exclusion of subjects who gave incomplete responses on alcohol drinking or prevalent cancer cases at the baseline, a total of 21,199 men remained. Of these, 307 men were diagnosed as having colorectal cancer after 11 years of follow-up. Cox proportional hazards regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs), with adjustments made for potential confounders. Compared with never drinkers, past and current drinkers had multivariate HRs of 1.1 (95% CI, 0.6-1.9) and 1.6 (95% CI, 1.1-2.2) for colorectal cancer, respectively. A dose-response relationship with current volume of alcohol drinkers was observed for cancer of the distal colon and rectum, but not for proximal colon. The multivariate HRs for distal colon and rectal cancer among current heavy drinkers (45.6 g or more ethanol per day) as compared with never drinkers were 4.2 (1.6-10.7; p for trend=0.0002) and 1.8 (1.1-3.2; p for trend=0.04), respectively. In contrast, no significant linear association was found for proximal colon cancer (p for trend=0.2). These data indicate that alcohol consumption in Japanese men is associated with a statistically significant increased risk of cancer of the distal colon and rectum, but not cancer of the proximal colon.     

Etodolac, a selective cyclooxygenase-2 inhibitor, induces apoptosis by activating caspases in human malignant rhabdoid tumor cells (FRTK-1)

Malignant rhabdoid tumor (MRT) is a rare and highly aggressive tumor presenting in the kidney and soft tissue in childhood. However, effective treatment for MRT has not been established. We investigated the antitumor effect of etodolac, a selective cyclooxygenase-2 inhibitor, on MRT cells in vitro using the MRT cell line FRTK-1. Etodolac induced apoptosis of FRTK-1 cells through activation of caspase-8, -9 and -3. Moreover, several caspase inhibitors completely or partially inhibited etodolac-induced apoptosis. Our data indicated that etodolac had an antitumor effect on MRT cells and holds promise as a novel therapeutic strategy for MRT.     

Ingestion of thioproline suppresses rat esophageal adenocarcinogenesis caused by duodenogastroesophageal reflux

Duodenogastroesophageal reflux causes esophageal adenocarcinoma in rats without the use of a carcinogen. This etiology is unclear, but may be associated with endogenous nitrosation in the gastrointestinal tract. Thioproline (TPRO) is an effective nitrite-trapping agent and blocks endogenous nitrosation. We investigated how ingested TPRO affected esophageal adenocarcinogenesis in rats with duodenogastroesophageal reflux (DGER) or gastroesophageal reflux (GER). A series of 200 male Fischer 344 rats received surgery to induce reflux of duodenogastric contents or gastric contents alone into the esophagus. The rats were separated into two divisions according to the surgical procedure employed (DGER or GER), and each division was further subdivided into two groups: one group was fed a special diet (CRF-1 containing 0.5% of TPRO); the other group was fed a standard diet (CRF-1). The rats were given no carcinogen and sacrificed at ten-week intervals from the 25th to the 45th week after surgery. Pathological examination was carried out using hematoxylin-eosin or immunohistochemical staining. Erosion, regenerative thickening, basal cell hyperplasia and columnar-lined epithelium (CLE) were found in both groups of the DGER rats. Adenocarcinoma (AC) appeared only in the DGER rats sacrificed at 35 and 45 weeks following surgery. The incidence of AC at the 45th week was significantly lower in the group of rats fed the diet containing TPRO, as compared to those fed the standard diet, whereas the incidences of CLE were the same for both groups. iNOS protein and nitrotyrosine protein were identified in the CLE and macrophages of the DGER group using immunohistochemical staining. There were no remarkable pathological changes in the esophagi of the rats which underwent the GER procedure. In conclustion, TPRO has an inhibitory effect on esophageal reflux-induced adenocarcinogenesis in rats in that it prevents the progression from CLE to AC.     

Copper efflux transporter (ATP7B) contributes to the acquisition of cisplatin-resistance in human oral squamous cell lines

Acquired resistance to cisplatin (CDDP) is an issue in cancer chemotherapy. This resistance has been reported to be correlated with the expression of the Cu influx copper transporter 1 (CTR1) and two copper efflux transporters (ATP7A, ATP7B). We investigated the correlation between the expression of these transporters and the sensitivity to CDDP using three pairs of parent cell lines and resistant cell lines derived from various types of invasive oral squamous cell carcinoma (OSCC). Using multiple steps, each of the CDDP-resistant cell lines, HSC-4-R, OSC-19-R, HOC313-R, was selected from HSC-4 cells derived from a cancer with medium invasiveness, OSC-19 cells derived from a cancer with high invasiveness and HOC313 cells derived from a cancer with the highest invasiveness. Resistant cell lines had a stronger expression of ATP7B in conjunction with the acquisition of CDDP-resistance than parent cell lines. Furthermore, OSC-19-R cells transfected with the ATP7B siRNA had a 10.6-fold higher sensitivity to CDDP compared to OSC-19-R cells transfected with a nonsense siRNA. These results suggest that each of the resistant cell lines had acquired resistance to CDDP due to the overexpression of ATP7B. On the other hand, the expression of CTR1 was the same between sensitive cell lines and resistant cell lines and ATP7A mRNA expression was barely noted. We conclude that ATP7B is correlated with the acquisition of CDDP resistance more closely than either CTR1 or ATP7A. ATP7B may be a key determinant in the acquired resistance to CDDP in OSCC.     

Efficacy of a direct puncture approach for anterior circulation aneurysms using a newly developed guiding catheter - especially for geriatric patients

BACKGROUND: Endovascular surgery is being increasingly used as an alternative to craniotomy clipping surgery, especially for aged patients and complicated cases. However, tortuous atherosclerotic arteries sometimes interfere with advancement of catheters so that direct puncture may be necessary. Short guiding catheters for use with this approach have been newly developed, as discussed in this article. METHODS: One hundred twenty three anterior circulation aneurysms in 121 patients were consecutively treated by endovascular coil embolization, of which 42 (34%) were older than 70 years. RESULTS: With 21 aneurysms, coil embolization via the transfemoral approach failed, but all could be successfully treated with the direct puncture approach with minor complications such as 1 transient ischemic attack and 1 nonsymptomatic minor leakage. In the aged patients, the direct puncture approach with short guiding catheter resulted in complete obliteration of aneurysms in 20 (71%) of 28 with follow-up angiography. CONCLUSION: Direct puncture using newly developed short guiding catheters is an alternative to femoral approaches for patients with anterior circulation aneurysm with tortuous arteries and obvious atherosclerotic change at bifurcations of the common carotid artery.