A randomized, double-blind, placebo-controlled, sixteen-week study of subcutaneous golimumab in patients with active nonradiographic axial spondyloarthritis.

OBJECTIVE: Axial spondyloarthritis (SpA) is a chronic inflammatory disease characterized by back pain and stiffness. The objective of this study was to determine whether golimumab is superior to placebo in patients with nonradiographic axial SpA. METHODS: This phase III, double-blind, randomized, placebo-controlled trial was performed to evaluate subcutaneous golimumab (50 mg) versus placebo in patients ages ≥18 years to ≤45 years who had active nonradiographic axial SpA according to the Assessment of SpondyloArthritis international Society (ASAS) criteria for ≤5 years since diagnosis, high disease activity, and an inadequate response to or intolerance of nonsteroidal antiinflammatory drugs. Patients were randomized 1:1 to receive golimumab or placebo subcutaneously every 4 weeks. The primary end point was 20% improvement according to the ASAS criteria (ASAS20) at week 16. Key secondary end points were an ASAS40 response, ASAS partial remission, 50% improvement in the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), and change in the Spondyloarthritis Research Consortium of Canada (SPARCC) magnetic resonance imaging (MRI) index for sacroiliac (SI) joint inflammation (SPARCC score). RESULTS: Of the 198 patients randomized, 197 were treated (97 received golimumab, and 100 received placebo). The mean age of the patients was 31 years, and 57.1% were male. At baseline, the mean ± SD BASDAI was 6.5 ± 1.5, the mean ± SD ASDAS was 3.5 ± 0.9, and the mean ± SD SPARCC score was 11.3 ± 14.0. The primary end point, an ASAS20 response, was achieved by significantly more patients in the golimumab group compared with the placebo group (71.1% versus 40.0%; P < 0.0001). An ASAS40 response was also achieved by significantly more patients in the golimumab group compared with the placebo group (56.7% versus 23.0%; P < 0.0001). The incidence of adverse events did not differ meaningfully between groups. CONCLUSION: Patients with active nonradiographic axial SpA treated with golimumab had significantly greater improvement in symptoms compared with patients treated with placebo. Golimumab was well tolerated and had a favorable risk/benefit profile.

Presurgical pharmacokinetic analysis of a von Willebrand factor/factor VIII (VWF/FVIII) concentrate in patients with von Willebrand's disease (VWD) has limited value in dosing for surgery.

Optimal doses of von Willebrand Factor/Factor VIII (VWF/FVIII) concentrates for surgical procedures in patients with VWD need to be determined. A prospective, multicenter study was performed that included an initial pharmacokinetic (PK) assessment following a standard dose of VWF/FVIII concentrate (Humate-P®) to determine individual PK parameters and guide therapeutic dosing during surgery. Forty one subjects received 60 IU kg⁻¹ VWF: RCo. Median plasma levels, half-life, mean change from baseline and in vivo recovery (IVR) values were determined for VWF:RCo, VWF:Ag, and FVIII: C, and area under the plasma time-concentration curve (AUC), mean residence time (MRT), clearance, volume of distribution and dose linearity were also assessed for VWF:RCo at various time points. Median baseline VWF:RCo level was 13 IU dL⁻¹ (range, 6-124); with a mean change from baseline >100 IU dL⁻¹ immediately after the infusion, decreasing to 10 IU dL⁻¹ at 48 h postinfusion. The group median incremental in vivo recovery (IVR) for VWF:RCo was 2.4 IU dL⁻¹ per IU kg⁻¹, for VWF:Ag 2.3 IU dL⁻¹ kg⁻¹ and for FVIII:C was 2.7 IU dL⁻¹ per IU kg⁻¹. When analysing individual recovery values on repeated infusions, a very weak correlation was observed between presurgery IVR and IVR for both VWF:RCo and FVIII, measured at various times just prior to and after the surgical procedure. Although group median values were fairly consistent among repeated IVR measurements, the intra-individual IVR values for FVIII and VWF:RCo with repeated infusions showed a large degree of variability. IVR values obtained from pharmacokinetic analyses performed in advance of anticipated surgery do not reliably predict postinfusion circulating levels of VWF:RCo or FVIII attained preoperatively or with subsequent peri-operative infusions.

Detection of differentially expressed genes in mouse lung adenocarcinomas.

Increasing evidence suggests that altered gene expression is associated with the induction and maintenance of malignancy in various organs including mouse lung adenocarcinomas. A competitive cDNA library screening (CCLS) was used to examine gene expression in 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced lung adenocarcinomas from (C3H/HeJ x A/J])F1 mice. Comparisons of RNA expression in lung adenocarcinomas to those of normal surrounding lung tissue revealed altered expression in 220 clones from more than 50,000 clones screened. Fifty clones were selected for quantitative reverse transcriptase-polymerase chain reaction (PCR) analysis to verify altered expression. PCR primers were designed based on partial sequence analysis of the clones. Twenty-two clones were found to be differentially expressed in lung adenocarcinomas compared with normal lungs. GenBank database analysis showed that 14 of the 22 clones were homologous with known genes, whereas 8 clones contained novel sequences. Thirteen clones were down regulated in tumors compared to normal lung tissues, and 9 were overexpressed. The clones underexpressed or absent include adipocyte p27, carbonic anhydrase III, carbonyl reductase, cytochrome CYP2E1, skelemin, myosin, major urinary protein, and contrapsin. Overexpressed clones include Bruton's tyrosine kinase, cyclin D3, poly(A)-binding protein, alpha-fetoprotein, transferrin, and mouse B2 family repetitive sequence. Further examination of biologic implications of the differentially expressed genes in lung adenocarcinomas is necessary to understand their role(s) in mouse lung carcinogenesis.

Pheochromocytoma of the heart.

This is a presentation of a unique case of cardiac pheochromocytoma during pregnancy. The case is significant because pheochromocytoma is a difficult diagnosis and its rarity during pregnancy may lead to this important diagnosis being overlooked, even though treatment is specific and highly successful.

A novel tableted purgative for colonoscopic preparation: efficacy and safety comparisons with Colyte and Fleet Phospho-Soda.

BACKGROUND: Currently available aqueous purgatives used before colonoscopy are poorly tolerated. We designed a tableted sodium phosphate purge that we believe will yield much greater patient acceptance. METHODS: A total of 305 outpatients undergoing routine diagnostic colonoscopy were randomized to one of three preparation groups: Colyte (100 patients), Fleet Phospho-Soda (106 patients), or sodium phosphate tablets (99 patients). Endoscopists were blinded to the type of preparation administered and answered a questionnaire regarding preparation quality. Patients answered a questionnaire designed to analyze tolerability. Adverse events were closely followed and recorded. RESULTS: There were no significant differences in quality of preparation across the groups (80% excellent or good, 4% repreparation). Although hypocalcemia (4 of 71), hypokalemia (18 of 68), and hyperphosphatemia (39 of 69) were observed in patients receiving the tablets, no adverse events occurred. Patients preferred taking the tablets over Colyte and Fleet Phospho-Soda. CONCLUSION: The evaluation of a novel delivery system of a sodium phosphate purge is described. Intended for use before colonoscopy, it circumvents the poor taste and excessive volume of ingestion that are aversive to patients. The tableted purgative is equally effective, safe, and greatly preferred over the existing aqueous preparations. This may improve patient compliance with recommendations for screening colonoscopy.

Plasma antioxidant status after high-dose chemotherapy: a randomized trial of parenteral nutrition in bone marrow transplantation patients.

BACKGROUND: Chemotherapy and radiation therapy result in increased free radical formation and depletion of tissue antioxidants. It is not known whether parenteral nutrition (PN) administered during bone marrow transplantation (BMT) supports systemic antioxidant status. OBJECTIVE: The aims of the study were to determine 1) whether high-dose chemotherapy decreases concentrations of major circulating antioxidants in patients undergoing BMT and 2) whether administration of standard PN maintains systemic antioxidant concentrations compared with PN containing micronutrients and minimal lipids alone. DESIGN: Twenty-four BMT patients were randomly assigned to receive either standard PN containing conventional amounts of dextrose, amino acids, micronutrients, and lipid (120 kJ/d) or a solution containing only micronutrients (identical to those in standard PN) and a small amount of lipid (12 kJ/d). Plasma antioxidant status was measured before conditioning therapy and serially at days 1, 3, 7, 10, and 14 after BMT. RESULTS: Plasma glutathione (GSH) and alpha- and gamma-tocopherol concentrations decreased and the GSH redox state became more oxidized after conditioning chemotherapy. Plasma cysteine concentrations were unchanged, whereas cystine concentrations increased. Plasma vitamin C and zinc concentrations and GSH peroxidase activity increased over time. Plasma alpha-tocopherol concentrations were lower in patients given standard PN. There were no differences in other plasma antioxidants between groups. CONCLUSIONS: A significant decline in GSH-glutathione disulfide, cysteine-cystine, and vitamin E status occurs after chemotherapy and BMT. Standard PN does not improve antioxidant status compared with administration of micronutrients alone. Further evaluation of PN formulations to support patients undergoing high-dose chemotherapy and BMT are needed.

Detection of genetic alterations in mouse lung adenocarcinomas by two-dimensional gel electrophoresis.

DNA from 14 mouse lung adenocarcinomas and 7 normal lungs were examined by 2-dimensional gel electrophoresis (2-DGE) for genetic alterations. 2-DGE profiles from tumor samples were compared with those profiles from normal lung tissues through a computer-assisted color overlay system. Compared to the profiles in normal lung DNA, 6 spots were amplified and 16 spots were partially reduced in their intensity in tumors. Two spots were detectable only in tumor tissues. These altered spots indicate genetic changes in mouse lung tumor development. The identification of these genetic alterations is probably important in understanding mouse lung carcinogenesis.

Angiogenesis gene therapy: phase I assessment of direct intramyocardial administration of an adenovirus vector expressing VEGF121 cDNA to individuals with clinically significant severe coronary artery disease.

BACKGROUND: Therapeutic angiogenesis, a new experimental strategy for the treatment of vascular insufficiency, uses the administration of mediators known to induce vascular development in embryogenesis to induce neovascularization of ischemic adult tissues. This report summarizes a phase I clinical experience with a gene-therapy strategy that used an E1(-)E3(-) adenovirus (Ad) gene-transfer vector expressing human vascular endothelial growth factor (VEGF) 121 cDNA (Ad(GV)VEGF121.10) to induce therapeutic angiogenesis in the myocardium of individuals with clinically significant coronary artery disease. METHODS AND RESULTS: Ad(GV)VEGF121.10 was administered to 21 individuals by direct myocardial injection into an area of reversible ischemia either as an adjunct to conventional coronary artery bypass grafting (group A, n=15) or as sole therapy via a minithoracotomy (group B, n=6). There was no evidence of systemic or cardiac-related adverse events related to vector administration. In both groups, coronary angiography and stress sestamibi scan assessment of wall motion 30 days after therapy suggested improvement in the area of vector administration. All patients reported improvement in angina class after therapy. In group B, in which gene transfer was the only therapy, treadmill exercise assessment suggested improvement in most individuals. CONCLUSIONS: The data are consistent with the concept that direct myocardial administration of Ad(GV)VEGF121.10 to individuals with clinically significant coronary artery disease appears to be well tolerated, and initiation of phase II evaluation of this therapy is warranted.

Anterior cruciate ligament injury: fast spin-echo MR imaging with arthroscopic correlation in 217 examinations.

OBJECTIVE: Our objective was to evaluate the accuracy of MR imaging strategy that uses primarily fast spin-echo sequences for the diagnosis of anterior cruciate ligament tears. MATERIALS AND METHODS: The original clinical interpretations of MR images of 217 examinations of the knee joint were correlated with subsequent arthroscopic results. Each MR examination included a double-echo fast spin-echo sequence as the only imaging sequence in the sagittal plane. Subsequent discordant MR and arthroscopic examinations were then subjected to reanalysis by two observers who were unaware of arthroscopic results to determine if misinterpretations were observer or image dependent. Two hundred sixteen patients who underwent MR imaging for suspected internal derangement of the knee subsequently underwent arthroscopic surgery. Two patients had both knees evaluated. One patient was excluded because he was referred for evaluation for osteomyelitis, not internal derangement. This yielded a total number of 217 MR examinations for suspected internal derangement of the knee. RESULTS: For 56 arthroscopically proven tears, the sensitivity of MR imaging was 96%. The specificity was 98%, yielding an overall accuracy rate of 98%. The positive and negative predictive values were 95% and 99%, respectively. These values are within the ranges of previously reported MR imaging strategies using conventional spin-echo sequences. CONCLUSION: Fast spin-echo MR imaging of the knee can be an alternative to conventional spin-echo imaging for the detection of anterior cruciate ligament tears.

Preclinical and clinical models of lung cancer chemoprevention.

In smokers, beta-carotene, retinol, and vitamins E and C appear to have little or a negative effect against human lung cancer development. Similarly, these chemicals have generally failed to inhibit lung tumorigenesis in rodents. The agents that have been shown to inhibit lung tumorigenesis in rodents, such as glucocorticoids, green tea, NSAIDs, and isothiocyanates, have not been tested yet in humans. These agents may be more effective in preventing human lung cancer in smokers than are the chemicals tested so far, especially if they are delivered by inhalation route.

Genomic instability in the type II TGF-beta1 receptor gene in atherosclerotic and restenotic vascular cells.

Cells proliferating from human atherosclerotic lesions are resistant to the antiproliferative effect of TGF-beta1, a key factor in wound repair. DNA from human atherosclerotic and restenotic lesions was used to test the hypothesis that microsatellite instability leads to specific loss of the Type II receptor for TGF-beta1 (TbetaR-II), causing acquired resistance to TGF-beta1. High fidelity PCR and restriction analysis was adapted to analyze deletions in an A10 microsatellite within TbetaR-II. DNA from lesions, and cells grown from lesions, showed acquired 1 and 2 bp deletions in TbetaR-II, while microsatellites in the hMSH3 and hMSH6 genes, and hypermutable regions of p53 were unaffected. Sequencing confirmed that these deletions occurred principally in the replication error-prone A10 microsatellite region, though nonmicrosatellite mutations were observed. The mutations could be identified within specific patches of the lesion, while the surrounding tissue, or unaffected arteries, exhibited the wild-type genotype. This microsatellite deletion causes frameshift loss of receptor function, and thus, resistance to the antiproliferative and apoptotic effects of TGF-beta1. We propose that microsatellite instability in TbetaR-II disables growth inhibitory pathways, allowing monoclonal selection of a disease-prone cell type within some vascular lesions.

Efficacy and safety of monoclonal antibody purified factor IX concentrate in haemophilia B patients undergoing surgical procedures.

The present study summarizes results of the efficacy and safety of monoclonal antibody (MAb) purified factor IX concentrate [Mononine® Coagulation Factor IX (Human), Centeon L.L.C., King of Prussia, PA, USA] for surgical prophylaxis in 74 patients with mild, moderate or severe haemophilia B who underwent a total of 81 different operative interventions. Surgical procedures included joint replacement/arthroplasty (n= 12), gastrointestinal (GI) or rectal surgery (n= 6), synovectomy/osteotomy (n= 8), hernia repair (n= 4), central catheter insertion (n= 3), ENT surgery (n= 4), dental procedures (n= 14), biopsies (n= 2), gynaecological procedures (n= 4), ophthalmological surgery (n= 4), spinal surgery (n= 4), urogenital surgery (n= 2), other orthopaedic surgery (n= 4) or other miscellaneous procedures (n= 10). All patients demonstrated haemostasis rated as 'excellent' by the investigators. No patients experienced clinically evident thromboembolic complications during treatment with MAb factor IX. These results, from a large and varied random group of patients, demonstrate that this highly purified factor IX concentrate is safe and effective for surgical prophylaxis in patients with haemophilia B, including those patients who have experienced thromboembolic complications during prior treatment with prothrombin complex concentrates.

Reduction in angioplasty complications after the introduction of coronary stents: results from a consecutive series of 2242 patients.

The introduction of coronary stents for the treatment of acute vessel closure has probably improved the safety of angioplasty, but little data are available regarding angioplasty complication rates when bailout stenting is available. Therefore baseline and patient outcome data for 2242 consecutive patients treated at a single tertiary referral center were compared before and after bailout coronary stenting was introduced. Patients treated after stents became available were more likely to have diabetes (16% prestent availability vs 19% poststent, p < 0.05), unstable angina (61% prestent vs 70% poststent, p < 0.01), and to have received intravenous nitroglycerin before the procedure (22% prestent vs 28% poststent, p < 0.01). Major complications occurred in 4.1% of patients before stent availability and 2.0% afterwards (p < 0.01). These complications included in-hospital death (1.1% prestent vs 0.7% poststent, p = not significant [NS]), Q wave myocardial infarction (0.5% prestent vs 0.3% poststent, p = NS), and emergency bypass surgery (2.9% prestent vs 1.1% poststent, p < 0.01). The introduction of coronary stents was associated with a > 50% reduction in major complications despite greater patient acuity. The traditionally reported complication rates for angioplasty appear not to apply when ballout stenting is available.

Gadolinium-DTPA-enhanced magnetic resonance imaging of musculoskeletal infectious processes.

The purpose of this study was to assess whether gadolinium-enhanced magnetic resonance imaging (MRI) provides diagnostic information beyond that given by nonenhanced imaging in the evaluation of musculoskeletal infectious processes and whether it can be used for differentiating infectious from noninfectious inflammatory lesions. Magnetic resonance images performed with and without intravenous gadolinium-DTPA in 34 cases in which musculoskeletal infection had been clinically suspected were reviewed. Infectious lesions--including osteomyelitis, pyarthrosis, abscess, and cellulitis--were confirmed in a total of 22 cases: in 15 by biopsy or drainage and in 7 by clinical course. Our results show that gadolinium-DTPA-enhanced MRI is a highly sensitive technique in diagnosing musculoskeletal infectious lesions. It is especially useful in distinguishing abscesses from surrounding cellulitis/myositis. Lack of contrast enhancement rules out infection with a high degree of certainty. However, contrast enhancement cannot be used to reliably distinguish infectious from noninfectious inflammatory conditions.

Variability of in vivo recovery of factor IX after infusion of monoclonal antibody purified factor IX concentrates in patients with hemophilia B. The Mononine Study Group.

Monoclonal antibody purified factor IX concentrate, Mononine (Armour Pharmaceutical Company, Kankakee, Illinois, USA), is a recently developed replacement factor concentrate for the treatment of patients with hemophilia B. The pharmacokinetic properties of monoclonal antibody purified factor IX concentrate (MAb Factor IX concentrate) have been evaluated in only small samples of patients, and little is known about those factors that might influenced in vivo recovery of factor IX after infusion is a larger patient population. In vivo recovery of factor IX was therefore evaluated for 80 different indications in 72 patients who received MAb Factor IX concentrate for the management of spontaneous or trauma-induced bleeding, or as prophylaxis with surgery. The average recovery after infusions for presurgical pharmacokinetic analysis (mean +/- standard deviation) was 1.28 +/- 0.56 U/dl rise per U/kg infused (range 0.41-2.80), and the average recovery after all infusions for treatment was 1.23 +/- 0.49 U/dl rise per U/kg infused (range - 0.35-2.92). Recovery values for multiple MAb Factor IX doses in a given patient were also variable; the average recovery was 1.22 +/- 0.53 U/dl rise per U/kg given, and standard deviations ranged from 0.03 to 1.26. Patient age, weight, and MAb Factor IX concentrate dose minimally but significantly influenced factor IX recovery. There was no significant effect of either race, history of previous thrombotic complications during treatment with other replacement factor concentrates, or bleeding state on recovery. All of the patients treated with this preparation experienced excellent hemostasis, and no thrombotic complications were observed.

Magnetization transfer contrast MRI of musculoskeletal neoplasms.

Magnetic resonance imaging (MRI) examinations were performed in 15 patients with musculoskeletal neoplasms to assess the value of magnetization transfer contrast in tumor characterization. Multiplanar gradient-recalled echo sequences (TR 500-600/TE 15-20/flip angle 20-30 degrees) were performed first without and then with magnetization transfer contrast generated by a zero degree binomial pulse (MPGR and MTMPGR). Standard T1-weighted spin echo images (SE; TR 300-400/TE 12-20) and either T2-weighted SE (TR 2000-2900/TE 70-80) or T2-weighted fast spin echo (FSE; TR 4000-5000/TE 100-119 effective) images were also obtained. Signal intensities on MTMPGR scans were compared to those on MPGR scans for both tumors and normal tissues. Signal intensity ratios (SIR) and contrast-to-noise ratios (CNR) were also compared for all sequences. MTMPGR images provided better contrast between pathologic tissues and muscle than did standard MPGR images, increasing both conspicuity of lesions and definition of tumor/muscle interfaces. Benign and malignant tumors, with the exception of lipoma, underwent similar degrees of magnetization transfer and could not be distinguished by this technique.

Blister cells in children with sickle hemoglobinopathies.

The presence of blister cells in the peripheral blood of patients with sickle hemoglobinopathies was investigated to assess whether their presence was predictive of the patients' clinical state and would be diagnostically useful. Peripheral blood smears (PBS) were examined from 23 children with sickle hemoglobinopathies, 20 children with iron deficiency, and 29 healthy control children. The number of blister cells per 1,000 red blood cells was then correlated with the child's health state: well, minor illness, and illness requiring hospitalization. The presence or number of blister cells was found to be unreliable to predict the state of health or the cause of a pulmonary insult in children with sickle hemoglobinopathies.