Citations

Introduction We retrospectively compared the outcomes of open reduction and internal fixation (ORIF) with volar locking plate versus standard external fixation and percutaneous pinning in treating similar unstable distal radius fractures with a minimum 2-year follow-up. Methods The ORIF group included 41 patients with an average follow-up of 29 months. The external fixation group comprised 14 patients with an average follow-up of 33 months. Average age at presentation was 45 years in the external fixation group and 48 years in the ORIF group. The male/female ratios were 16:25 among the ORIF group and 6:8 in the external fixation group. The two groups were compared for clinical and functional outcomes measured by the disabilities of the arm, shoulder, and hand (DASH) score. Pain scores were similar. Radiographic measurements were also evaluated between groups. Results Final ranges of motion and grip strengths were similar between the two groups. The mean DASH score of the locked volar plate group was 9 compared to 23 for the external fixation group. Radiographically, volar tilt and radial length were significantly better in the patients treated with ORIF. The ORIF group required less therapy visits. No complications occurred in the locked volar plate group whereas two patients had pin tract infections and one had prolonged finger stiffness in the external fixation group. Conclusion Locked volar plating compares favorably to external fixation and pinning for amenable fracture patterns. Whereas grip and range-of-motion data were similar, DASH scores, frequency of rehabilitation, and some radiographic parameters were superior in patients treated with ORIF.

Inhibition of proliferative neointima formed by vascular smooth muscle cells is a potential target in preventing angioplasty-induced restenosis. We have created a potent antiproliferative by fusing the active regions of the p27 and p16 cell cycle inhibitors. Intravascular delivery of a replication-deficient adenoviral vector (AV) encoding this p27-p16 fusion protein, named W9, inhibited balloon injury–induced neointimal hyperplasia in rabbit carotid arteries. In a therapeutically more relevant model, AV-W9 was delivered to balloon-injured porcine coronary arteries in vivo using an infusion catheter. Of the three coronary arteries, two were injured with a 15-mm balloon catheter and either were left untreated or were treated with 10 12 viral particles of either AV-W9 or a control null virus. AV-W9 treatment significantly inhibited neointimal hyperplasia in this porcine arterial balloon injury model compared with untreated or control virus–treated vessels. The average intimal area of the AV-W9–treated group 10 days after balloon injury and treatment was 0.42±0.36 mm 2 , whereas the AV-null group demonstrated an intimal area of 0.70±0.52 mm 2 . At day 10 the average intimal thickness of the AV-W9–treated vessels was 9.1 μm (n=5, ×20 magnification) compared with 21.2 μm (n=5, ×20 magnification) in control virus–treated vessels. This trend was also observed at 28 days after balloon injury and gene transfer during which AV-W9–treated vessels demonstrated an average intimal thickness of 4.7 μm (n=8, ×20 magnification) compared with 13.3 μm (n=3, ×20 magnification) in control virus–treated vessels and 7.3 μm (n=5, ×20 magnification) in the sham-treated vessels. The AV-W9 treatment was safe and well tolerated. These data suggest that AV-W9 gene therapy may be useful in preventing angioplasty–induced intimal hyperplasia in the coronary artery.

The goal of “Practice Abstracts” is to present interesting, topical, and novel applications of operations research methodology to a wide range of industrial applications. “Practice Abstracts” are intended to provide Interfaces readers with short (2–4 page) descriptions of the most relevant aspects of operations research-based projects, in a form that is accessible to academics and practitioners in other organizations. Contributions should be sent for evaluation to the editor of “Practice Abstracts,” Brian T. Denton, Division of Health Care Policy and Research, Pavilion 3, Mayo Clinic, 200 First Street SW, Rochester, Minnesota 55905, denton.brian@mayo.edu.

Aging and hypertension lead to arterial remodeling and tandem increases in arterial (Ea) and ventricular (LV) systolic stiffness (ventricular-arterial [VA] coupling). Age and hypertension also predispose to heart failure with normal ejection fraction (HFnlEF), where symptoms during hypertensive urgencies or exercise are common. We hypothesized that: (1) chronic VA coupling also occurs in diastole, (2) acute changes in Ea are coupled with shifts in the diastolic and systolic pressure-volume relationships (PVR), and (3) diastolic VA coupling reflects changes in LV diastolic stiffness rather than external forces or relaxation. Old chronically hypertensive (OHT, n=8) and young normal (YNL, n=7) dogs underwent assessment of PVR (caval occlusion) and of aortic pressure, dimension, and flow, at baseline and during changes in afterload and preload. Concomitant changes in the slope/position of PVR were accounted for by calculating systolic (ESV 200 ) and diastolic (EDV 20 ) volumes at common pressures (capacitance). OHT displayed marked vascular remodeling. Indices reflecting the pulsatile component of Ea (aortic stiffness and systemic arterial compliance) were more impaired in OHT at any distending pressure. In both groups, acute increases in Ea were associated with decreases in ESV 200 and EDV 20 . However, at any load, OHT had lower ESV 200 and EDV 20 , associated with LV remodeling and myocardial endothelin activation. Acute changes in EDV 20 were not mediated by changes in relaxation or external forces. These observations provide insight into the mechanisms whereby arterial remodeling and acute and chronic VA coupling in both systole and diastole may predispose to and interact with increases in load to cause HFnlEF.

Purpose To evaluate the efficacy and safety of ixabepilone in patients with metastatic breast cancer (MBC) resistant to anthracycline, taxane, and capecitabine, in this multicenter, phase II study. Patients and Methods Patients with measurable disease who had tumor progression while receiving prior anthracycline, taxane, and capecitabine were enrolled. Ixabepilone 40 mg/m2 monotherapy was administered as a 3-hour intravenous infusion on day 1 of a 21-day cycle. The primary end point was objective response rate (ORR), assessed by an independent radiology facility (IRF). Results A total of 126 patients were treated and 113 were assessable for response. Patients were heavily pretreated: 88% had received at least two lines of prior chemotherapy in the metastatic setting. IRF-assessed ORR was 11.5% (95% CI, 6.3% to 18.9%) for response-assessable patients. Investigator-assessed ORR for all treated patients was 18.3% (95% CI, 11.9% to 26.1%). Fifty percent of patients achieved stable disease (SD); 14.3% achieved SD ≥ 6 months. Median duration of response and progression-free survival were 5.7 and 3.1 months, respectively. Median overall survival was 8.6 months. Patients received a median of 4.0 treatment cycles (range, one to 16 cycles), and 25% of patients received ≥ eight cycles. Grade 3/4 treatment-related events included peripheral sensory neuropathy (14%), fatigue/asthenia (13%), myalgia (8%), and stomatitis/mucositis (6%). Resolution of grade 3/4 peripheral sensory neuropathy occurred after a median period of 5.4 weeks. Conclusion Ixabepilone demonstrated clear activity and a manageable safety profile in patients with MBC resistant to anthracycline, taxane, and capecitabine. Responses were durable and notable in patients who had not previously responded to multiple prior therapies.

Purpose Gemcitabine as a single agent and the combination of gemcitabine and docetaxel have activity in patients with metastatic soft tissue sarcoma. To determine if the addition of docetaxel to gemcitabine improved clinical outcome of patients with metastatic soft tissue sarcomas, we compared a fixed dose rate infusion of gemcitabine versus a lower dose of gemcitabine with docetaxel. Patients and Methods In this open-label phase II clinical trial, the primary end point was tumor response, defined as complete or partial response or stable disease lasting at least 24 weeks. A Bayesian adaptive randomization procedure was used to produce an imbalance in the randomization in favor of the superior treatment, accounting for treatment-subgroup interactions. Results One hundred nineteen of 122 randomly assigned patients had assessable outcomes. The adaptive randomization assigned 73 patients (60%) to gemcitabine-docetaxel and 49 patients (40%) to gemcitabine alone, indicating gemcitabine-docetaxel was superior. The objective Response Evaluation Criteria in Solid Tumors response rates were 16% (gemcitabine-docetaxel) and 8% (gemcitabine). Given the data, the posterior probabilities that gemcitabine-docetaxel was superior for progression-free and overall survival were 0.98 and 0.97, respectively. Median progression-free survival was 6.2 months for gemcitabine-docetaxel and 3.0 months for gemcitabine alone; median overall survival was 17.9 months for gemcitabine-docetaxel and 11.5 months for gemcitabine. The posterior probability that patients receiving gemcitabine-docetaxel had a shorter time to discontinuation for toxicity compared with gemcitabine alone was .999. Conclusion Gemcitabine-docetaxel yielded superior progression-free and overall survival to gemcitabine alone, but with increased toxicity. Adaptive randomization is an effective method to reduce the number of patients receiving inferior therapy.

The goal of “Practice Abstracts” is to present interesting, topical, and novel applications of operations research methodology to a wide range of industrial applications. “Practice Abstracts” are intended to provide Interfaces readers with short (2–4 page) descriptions of the most relevant aspects of operations research-based projects, in a form that is accessible to academics and practitioners in other organizations. Contributions should be sent for evaluation to the editor of “Practice Abstracts,” Brian T. Denton, Division of Health Care Policy and Research, Pavilion 3, Mayo Clinic, 200 First Street SW, Rochester, Minnesota 55905, denton.brian@mayo.edu.

Suppression of colon carcinogenesis by peroxisome proliferator-activated receptor (PPAR)-γ is likely due to some effect of PPAR-γ on normal colonic epithelial cells. However, our understanding of the effects of PPAR-γ in such cells is limited. We analyzed the abundance, distribution, and function of PPAR-γ in epithelial cells isolated from the murine proximal and distal colon. Marked differences in PPAR-γ abundance and distribution were observed, suggesting tissue-specific responses. Analysis of PPAR-γ effects on DNA synthesis, formation of preneoplastic lesions, and activation of MAPK signaling in proximal and distal colonic epithelial cells in vivo indicates that PPAR-γ regulates both tissue-specific and common responses within the proximal and distal colon. Three major functional cohorts of PPAR-γ target genes were identified by genomic profiling of isolated colonic epithelial cells: genes that are involved in metabolism, in signaling, and in cellular adhesion and motility. Two subsets of PPAR-γ target genes were differentially expressed in the proximal and distal epithelium. Proximal target genes were primarily involved in metabolic activities, whereas signal transduction, adhesion, and motility targets were more pronounced in the distal colon. Remarkably, those target genes that are differentially expressed in the proximal colon were all induced on activation of PPAR-γ, whereas all target genes that are preferentially expressed in the distal colon were repressed. Our data indicate that PPAR-γ exerts both common and tissue-specific effects in the colon and challenge the general conclusions that PPAR-γ is induced on differentiation of colonic epithelial cells and that this receptor stimulates differentiated function in epithelial cells throughout the colon.