Loxapine delivered as a thermally generated aerosol does not prolong QTc in a thorough QT/QTc study in healthy subjects.

The objective of this study was to establish effects of inhaled loxapine on the QTc interval in this randomized, placebo-controlled, double-blind crossover study. Forty-eight healthy volunteers received a single inhaled placebo or 10 mg loxapine. Plasma concentrations of loxapine increased with a median Tmax of 1 minute and a mean Cmax of 312 ng/mL. After an initial rapid distribution phase, plasma concentrations of loxapine declined with a terminal half-life of 8 hours. Exposure to the active metabolite 7-OH-loxapine was 15% of the parent compound based on mean AUCinf and its terminal half-life was 12 hours. Inhaled loxapine did not increase QT intervals, as demonstrated by the upper bound of the 1-sided 95% CIs placed on the point estimate of the placebo-subtracted change of QTcI (ΔΔQTcI) being less than 10 milliseconds at all 11 post-dose times. The maximum ΔΔQTcI occurred at 1 hour post-dose (LSmean 5.42 milliseconds, upper confidence bound 7.75 milliseconds). The study outcome was validated by the demonstrated assay sensitivity using the positive control moxifloxacin maximum ΔΔQTcI occurred at 3 hour post-dose (LSmean 8.36 milliseconds, lower confidence bound 5.82 milliseconds). The analyses of QTc outliers, and the lack of emergent diagnostic findings for QTcI, QTcB, and QTcF; and simple mean placebo-subtracted changes of QTcI and QTcF supported the primary QT analysis conclusion that this is a negative finding and there is no apparent QT prolongation associated with the therapeutic dose of inhaled loxapine.

Generation and external validation of a tumor-derived 5-gene prognostic signature for recurrence of lymph node-negative, invasive colorectal carcinoma.

BACKGROUND: One in 4 patients with lymph node-negative, invasive colorectal carcinoma (CRC) develops recurrent disease after undergoing curative surgery, and most die of advanced disease. Predicting which patients will develop a recurrence is a significantly growing, unmet medical need. METHODS: Archival formalin-fixed, paraffin-embedded (FFPE) primary adenocarcinoma tissues obtained at surgery were retrieved from 74 patients with CRC (15 with stage I disease and 59 with stage II disease) for Training/Test Sets. In addition, FFPE tissues were retrieved from 49 patients with stage I CRC and 215 patients with stage II colon cancer for an External Validation (EV) Set (n = 264) from 18 hospitals in 4 countries. No patients had received neoadjuvant/adjuvant therapy. Proprietary genetic programming analysis of expression profiles for 225 prespecified tumor genes was used to create a 36-month recurrence risk signature. RESULTS: Using reverse transcriptase-polymerase chain reaction, a 5-gene rule correctly classified 62 of 92 recurrent patients and 87 of 172 nonrecurrent patients in the EV Set (sensitivity, 0.67; specificity, 0.51). "High-risk" patients had a greater probability of 36-month recurrence (42%) than "low-risk" patients (26%; hazard ratio, 1.80; 95% confidence interval, 1.19-2.71; P = .007; Cox regression) independent of T-classification, the number of lymph nodes examined, histologic grade/subtype, anatomic location, age, sex, or race. The rule outperformed (P = .021) current National Comprehensive Cancer Network Guidelines (hazard ratio, 0.897). The same rule also differentiated the risk of recurrence (hazard ratio, 1.63; P = .031) in a subset of patients from the EV Set who had stage I/II colon cancer only (n = 251). CONCLUSIONS: To the authors' knowledge, the 5-gene rule (OncoDefender-CRC) is the first molecular prognostic that has been validated in both stage I CRC and stage II colon cancer. It outperforms standard clinicopathologic prognostic criteria and obviates the need to retrieve ≥12 lymph nodes for accurate prognostication. It identifies those patients most likely to develop recurrent disease within 3 years after curative surgery and, thus, those most likely to benefit from adjuvant treatment.

Trainable immunohistochemical HER2/neu image analysis: a multisite performance study using 260 breast tissue specimens.

CONTEXT: Aperio Technologies, Inc (Vista, California) provides a new immunohistochemistry (IHC) HER2 Image Analysis (IA) system that allows tuning of the intensity thresholds of the HER2/ neu scoring scheme to adapt to the staining characteristics of different reagents. OBJECTIVE: To compare the trainable IHC HER2 IA system for different reagents to conventional manual microscopy (MM) in a multisite study. DESIGN: Two hundred sixty formalin-fixed, paraffin-embedded breast cancer specimens from 3 clinical sites were assayed: 180 specimens stained with Dako's HercepTest (Carpinteria, California), and 80 specimens stained with Ventana's PATHWAY HER-2/neu (Tucson, California). At each site, 3 pathologists performed a blinded reading of the glass slides with the use of a light microscope. The glass slides were then scanned and after a wash-out period and randomization, the same pathologists outlined a representative set of tumor regions to be analyzed by IHC HER2 IA. Each of the methods, MM and IA, was evaluated separately and comparatively by using κ statistics of negative HER2/neu scores (0, 1+) versus equivocal HER2/neu scores (2+) versus positive HER2/neu scores (3+) among the different pathologists. RESULTS: κ Values for IA and MM were obtained across all sites. MM: 0.565-0.864; IA: 0.895-0.947; MM versus IA: 0.683-0.892 for site 1; MM: 0.771-0.837; IA: 0.726-0.917; MM versus IA: 0.687-0.877 for site 2; MM: 0.463-0.674; IA: 0.864-0.918; MM versus IA: 0.497-0.626 for site 3. CONCLUSION: Aperio's trainable IHC HER2 IA system shows substantial equivalence to MM for Dako's HercepTest and Ventana's PATHWAY HER-2/neu at 3 clinical sites. Image analysis improved interpathologist agreement in the different clinical sites.

Reading immunohistochemical slides on a computer monitor--a multisite performance study using 180 HER2-stained breast carcinomas.

BACKGROUND: With the adoption of digital pathology, image analysis (IA) of immunohistochemistry (IHC) slides can be integrated seamlessly into the digital pathology workflow. A pathologist can now use IA efficiently while reading the digital IHC slides on a computer monitor. Thus, the clinical acceptance of a digital pathology system for IHC quantitation depends both on the performance of the IHC IA, and the ability to manually read digital IHC slides on the monitor. A multisite study was conducted to compare the manual reading of IHC Human Epidermal Growth Factor Receptor 2 (HER2) slides on a monitor, using Aperio Technologies, Inc. ScanScope XT instrument and the Spectrum digital pathology information management system to conventional manual microscopy (MM). DESIGN: A total of 180 breast cancers were immunohistochemically stained using Dako HercepTest and assayed: (site 1) 80 retrospective specimens with equal HER2 score distribution from an academic center, and (site 2) 100 prospective specimens from a reference laboratory. At each site, 3 pathologists carried out a blinded read of the glass slides using a conventional light microscope, and reporting the HER2 score for each. The glass slides were scanned using a 20× objective, and after a wash-out period and randomization of the slides, the same 3 pathologists carried out another blinded read of the same slides, but this time of the digital image of the slides on the monitor, again reporting the HER2 score. Each of the methods: MM and reading digital slides on a computer monitor, from now on called manual digital read (MDR) were evaluated separately and comparatively using Percent Agreement (PA) of negative HER2 scores (0, 1+) versus equivocal (2+) versus positive HER2 scores (3+). RESULTS: Comparable PA values were obtained for MM and MDR IHC HER2 images on the monitor (MM: 76.3% to 91.3%; MDR: 70.0% to 86.0%; MM vs. MDR: 61.3% to 92.5%). CONCLUSIONS: Results of manually reading IHC HER2 slides on a monitor using Aperio Technologies, Inc. digital pathology system show substantial equivalence to those obtained by conventional manual microscopy. The digital slides are easily read on a monitor.

A multisite performance study comparing the reading of immunohistochemical slides on a computer monitor with conventional manual microscopy for estrogen and progesterone receptor analysis.

A multisite study was conducted to assess the performance of the Aperio digital pathology system (Aperio Technologies, Vista, CA) for reading estrogen receptor (ER) and progesterone receptor (PR) slides on a computer monitor. A total of 520 formalin-fixed breast tissue specimens were assayed at 3 clinical sites for ER and PR (260 each). Percentage and average staining intensity of positive nuclei were assessed. At each site, 3 pathologists performed a blinded reading of the glass slides using their microscopes initially and later using digital images on a computer monitor. Comparable percentages of agreements were obtained for manual microscopy (MM) and manual digital slide reading (MDR) (ER, percentage of positive nuclei with cutoffs: MM, 91.3%-99.0%/MDR, 91.3%-100.0%; PR, percentage of positive nuclei with cutoffs: MM, 83.8%-99.0%/MDR, 76.3%-100.0%). Reading ER and PR slides on a computer monitor using the Aperio digital pathology system is equivalent to reading the slides with a conventional light microscope.

A new immunohistochemical ER/PR image analysis system: a multisite performance study.

BACKGROUND: Aperio provides a new image analysis (IA) solution for immunohistochemistry (IHC) as part of its digital pathology system. To be used in a clinical setting, substantial equivalence to scoring by manual microscopy (MM) needs to be shown. A multisite study was conducted to assess the performance of Aperio's IHC IA solution for estrogen receptor (ER) and progesterone receptor (PR). DESIGN: A total of 260 formalin-fixed, paraffin-embedded breast tissue specimens were assayed at 2 clinical sites for ER and PR. The ability to score ER/PR slides in terms of (1) percentage of positive nuclei with cutoffs of 1%, 5%, and 10% and (2) average staining intensity as 0, 1+, 2+, and 3+ score was assessed. At each site, 3 pathologists performed a blinded read of the glass slides using their microscopes. The glass slides were then scanned, and after a wash-out period and randomization of the slides, the pathologists viewed the images on a computer monitor and outlined a representative set of tumor regions to be analyzed by IA. Each of the methods: MM and IA were evaluated separately and comparatively. RESULTS: Comparable or higher percent agreements were obtained for IA compared with MM (ER--percent of positive nuclei with cutoffs: MM: 91.3% to 98.8%/IA: 93.8% to 98.8%/IA vs. MM: 92.5% to 97.5%, and intensity score: MM: 55.0% to 86.3%/IA: 88.8% to 90.0%/IA vs. MM: 63.8% to 86.3%; PR-percent of positive nuclei with cutoffs: MM: 83.8% to 99.0%/IA: 85.0% to 99.0%/IA vs. MM: 81.3% to 99.0%, and intensity score: MM: 58.8% to 88.0%/IA: 68.8% to 88.0%/IA vs. MM: 58.8% to 84.0%). CONCLUSIONS: The study results show that Aperio's digital IHC IA solution for ER/PR is substantially equivalent to scoring by MM.

Correlates of adverse events during saphenous vein graft intervention with distal embolic protection: a PRIDE substudy.

OBJECTIVES: We sought to identify correlates of 30-day adverse events among patients undergoing percutaneous coronary intervention (PCI) of saphenous vein grafts (SVG). BACKGROUND: Although the use of distal embolic protection devices during SVG intervention reduces major adverse cardiac events (MACE), many patients still experience MACE despite distal embolic protection, and the major predictors of MACE among these patients are not well-characterized. METHODS: Correlates of 30-day MACE and peri-procedural creatine kinase-myocardial band (CK-MB) elevation were assessed among 631 patients undergoing SVG intervention with distal embolic protection enrolled in the PRIDE (PRotection during saphenous vein graft Intervention to prevent Distal Embolization) study, a randomized comparison of the TriActiv System (Kensey-Nash Corp., Exton, Pennsylvania) with an active control group (Guardwire [Medtronic, Santa Clara, California] or Filterwire [Boston Scientific, Minneapolis, Minnesota]). RESULTS: Baseline covariates associated with MACE were longer lesion length, greater angiographically assessed estimated plaque volume, and higher SVG degeneration score. Graft age and angina class were not associated with adverse events. Angiographic lesion length was significantly correlated with more complex angiographic metrics such as estimated plaque volume and the SVG degeneration score. In multivariable analyses, angiographic lesion length was the strongest independent correlate of MACE (odds ratio [OR] 2.81 [95% confidence interval (CI) 1.82 to 4.34]/log-increase in lesion length, p < 0.001) with a graded increase in MACE observed with increasing lesion lengths. Similarly, the strongest independent correlate of CK-MB elevation was lesion length (OR 2.54 [95% CI 1.59 to 4.04]/log-increase in lesion length, p < 0.001). The associations between lesion length and both MACE and CK-MB elevation were consistent among the studied embolic protection devices (TriActiv, Guardwire, or Filterwire). CONCLUSIONS: Angiographic lesion length was the strongest correlate of short-term adverse events among patients undergoing SVG intervention with distal embolic protection, with incremental effects noted at even relatively short lesion lengths.

Prospective randomized study evaluating an absorbable cyanoacrylate for use in vascular reconstructions.

BACKGROUND: An easy-to-use vascular sealant with good safety and efficacy is needed to prevent anastomotic bleeding in vascular surgery. This study evaluated the safety and efficacy of cyanoacrylate surgical sealant in establishing hemostasis of expanded polytetrafluoroethylene to arterial vascular anastomoses in arteriovenous (AV) grafts and femoral bypass grafts. METHODS: This multicenter, randomized, controlled, open-label study was conducted in a hospital setting at 12 sites: 10 in the United States and 2 in Europe. A total of 151 patients undergoing femoral bypass procedures or AV shunt procedures for hemodialysis access using expanded polytetrafluoroethylene grafts were randomized 2:1 to receive cyanoacrylate surgical sealant or the control (oxidized cellulose) between April 26, 2004, and January 18, 2005. Randomization was stratified by clinical site and type of procedure. After the anastomosis, cyanoacrylate surgical sealant or the control was applied to all anastomosis sites for patients undergoing femoral bypass procedures and to only the arterial anastomosis sites for patients undergoing AV shunt procedures. The primary end point was the elapsed time from clamp release to hemostasis. Secondary end points were the proportion of patients achieving hemostasis at t = 0 (immediate), 1, 5, or 10 minutes after clamp release, use of additional adjunctive measures to achieve hemostasis, and occurrence of adverse events. RESULTS: Baseline demographics and clinical characteristics showed that the two treatment groups were similar at baseline. The mean time from clamp release to hemostasis was 119.3 seconds with cyanoacrylate surgical sealant vs 403.8 seconds with the control (P < .001). Immediate hemostasis was achieved in 54.5% of patients receiving cyanoacrylate surgical sealant and in 10% of those receiving the control. The proportion of patients requiring additional adjunctive measures was lower with cyanoacrylate surgical sealant, and the occurrence of adverse events was similar in both groups. CONCLUSIONS: This study demonstrates that cyanoacrylate surgical sealant is effective at reducing the time to hemostasis and achieving immediate hemostasis in AV shunt and femoral bypass procedures and that it is safe for internal use. Cyanoacrylate surgical sealant is an easy-to-use vascular sealant with good safety and efficacy that significantly decreases anastomotic bleeding in vascular surgery.

Extracorporeal shockwave therapy versus placebo for the treatment of chronic proximal plantar fasciitis: results of a randomized, placebo-controlled, double-blinded, multicenter intervention trial.

Extracorporeal shockwave therapy (ESWT) has demonstrated efficacy in the treatment of recalcitrant proximal plantar fasciitis. The objective of this investigation was to compare the outcomes of participants treated with a new ESWT device with those treated with placebo. A total of 172 volunteer participants were randomized in a 2:1 active-to-placebo ratio in this prospective, double-blind, multicenter trial conducted between October 2003 and December 2004. ESWT (n=115) or placebo control (n=57) was administered on a single occasion without local or systemic anesthesia or sedation, after which follow-up was undertaken. The primary outcomes were the blind assessor's objective, and the participant's subjective assessments of heel pain during the first 3 months of follow-up. Participants were also followed up to 1 year to identify any adverse outcomes that may have been related to the shockwave device. On the visual analog scale, the blind assessor's objective assessment of heel pain displayed a mean reduction of 2.51 in the shockwave group and 1.57 in the placebo group; this difference was statistically significant (P=.045). On the visual analog scale, the participant's self-assessment of heel pain displayed a mean reduction of 3.39 in the shockwave group and 1.78 in the placebo group; this difference was statistically significant (P<.001). No serious adverse events were observed at any time. It was concluded that ESWT was both efficacious and safe for participants with chronic proximal plantar fasciitis that had been unresponsive to exhaustive conservative treatment.

Recombinant variant of ciliary neurotrophic factor for weight loss in obese adults: a randomized, dose-ranging study.

CONTEXT: Obese individuals tend to resist the weight-regulating effects of exogenously administered leptin. A genetically engineered recombinant human variant ciliary neurotrophic factor (rhvCNTF) that signals through leptinlike pathways in the hypothalamus has been shown to bypass leptin resistance in animal models of obesity. OBJECTIVE: To identify a safe and well-tolerated dose of rhvCNTF that causes weight loss in obese adults. DESIGN, SETTING, AND PATIENTS: Twelve-week, double-blind, randomized, parallel-group, dose-ranging, multicenter clinical trial conducted at 2 university obesity clinics and at 5 independent clinical research clinics from March 2000 to August 2001, and including 173 nondiabetic obese adults, 82.6% of whom were women, with a mean (SD) body mass index of 41.1 (4.1). INTERVENTIONS: Patients were randomly assigned to receive daily for 12 weeks subcutaneous injections of placebo (n = 32) or 0.3 microg/kg (n = 32), 1.0 microg/kg (n = 38), or 2.0 microg/kg (n = 33) of rhvCNTF. Another group received 1.0 microg/kg for 8 weeks and placebo for 4 weeks (n = 38), but they were not included in the primary analysis. All participants received instructions for a reduced-calorie diet (World Health Organization formula minus 500 kcal/d). MAIN OUTCOME MEASURES: Change in weight during the 12-week double-blind treatment period and proportion of patients who achieved a weight loss of at least 5%. RESULTS: Of the 173 randomized patients, 123 (71%) completed the double-blind dosing period. Mean (SEM) changes in kilograms from baseline body weights were 0.1 (0.6) for placebo and -1.5 (0.6) for the 0.3, -4.1 (0.6) for the 1.0, and -3.4 (0.7) for the 2.0 microg/kg of rhvCNTF dosage groups (P<.001, test for trend). Two patients (8.7%) in the placebo and 2 (8.3%) in the 0.3- microg/kg, 8 (29.6%) in the 1.0- microg/kg, and 5 (26%) in the 2.0- microg/kg treatment groups achieved a weight loss of at least 5%. Recombinant human variant CNTF was generally well tolerated although adverse events occurred in 75% of patients receiving placebo and 78% to 93% of patients receiving rhvCNTF, in a dose-related fashion, with mild injection site reactions as the most frequently reported adverse event. CONCLUSIONS: In this initial, dose-ranging, 12-week study, treatment with rhvCNTF resulted in more weight loss than placebo. These preliminary findings require confirmation in large prospective clinical trials.