Citations

Purpose The combination of fludarabine and cyclophosphamide is an effective regimen for patients with chronic lymphocytic leukemia (CLL). However, it may be accompanied by increased toxicity compared with fludarabine alone. E2997 is a phase III randomized Intergroup trial comparing fludarabine and cyclophosphamide (FC arm) versus fludarabine (F arm) alone in patients receiving their first chemotherapy regimen for CLL. Patients and Methods Symptomatic, previously untreated patients with CLL were randomly assigned to receive either fludarabine 25 mg/m 2 intravenously (IV) days 1 through 5 or cyclophosphamide 600 mg/m 2 IV day 1 and fludarabine 20 mg/m 2 IV days 1 through 5. These cycles were repeated every 28 days for a maximum of six cycles. Results A total of 278 patients were randomly assigned in this Intergroup study. Treatment with fludarabine and cyclophosphamide was associated with a significantly higher complete response (CR) rate (23.4% v 4.6%; P < .001) and a higher overall response (OR) rate (74.3% v 59.5%, P = .013) than treatment with fludarabine as a single agent. Progression-free survival (PFS) was also superior in patients treated with fludarabine and cyclophosphamide than those treated with fludarabine (31.6 v 19.2 months, P < .0001). Fludarabine and cyclophosphamide caused additional hematologic toxicity, including more severe thrombocytopenia (P = .046), but it did not increase the number of severe infections (P = .812). Conclusion Fludarabine and cyclophosphamide produced an increase in OR and CR, and it improved PFS in patients with previously untreated CLL compared with fludarabine alone and was not associated with an increase in infectious toxicity.

Abstract To determine if replacement of GH improves BMD in adult-onset GHD, we administered GH in physiologic amounts to men and women with GHD. GH replacement significantly increased spine BMD in the men by 3.8%. Introduction: Growth hormone (GH) deficiency (GHD) acquired in adulthood results in diminished BMD; the evidence that replacement of GH improves BMD is not conclusive. We therefore performed a randomized, placebo-controlled trial to determine whether GH replacement would increase lumbar spine BMD in a combined group of men and women with adult-onset GHD. Materials and Methods: We randomized 67 men and women to receive GH (n = 33) or placebo (n = 34) for 2 yr. The GH dose was initially 2 μg/kg body weight/d, increased gradually to a maximum of 12 μg/kg/d and adjusted to maintain a normal IGF-I concentration for age and sex. BMD was assessed before treatment and at 6, 12, 18, and 24 mo of treatment. Fifty-four subjects completed the protocol. Results: BMD of the lumbar spine in the entire group increased by 2.9 ± 3.9% above baseline in the GH-treated subjects, which was significantly (p = 0.037) greater than the 1.4 ± 4.5% increase in the placebo-treated subjects. In a secondary analysis, spine BMD in GH-treated men increased 3.8 ± 4.3% above baseline, which was significantly (p = 0.001) greater than that in placebo-treated men (0.4 ± 4.7%), but the change in GH-treated women was not significantly different from that in placebo-treated women. Treatment with GH did not increase total hip BMD more than placebo treatment after 2 yr. Conclusions: We conclude that GH replacement in men who have adult-onset GHD improves their spine BMD, but we cannot draw any conclusions about the effect of GH replacement on spine BMD in women with adult-onset GHD.

Purpose Identify features on preoperative computed tomography (CT) scans to predict suboptimal primary cytoreduction in patients treated for advanced ovarian cancer in institution A. Reciprocally cross validate the predictors identified with those from two previously published cohorts from institutions B and C. Patients and Methods Preoperative CT scans from patients with stage III/IV epithelial ovarian cancer who underwent primary cytoreduction in institution A between 1999 and 2005 were retrospectively reviewed by radiologists blinded to surgical outcome. Fourteen criteria were assessed. Crossvalidation was performed by applying predictive model A to the patients from cohorts B and C, and reciprocally applying predictive models B and C to cohort A. Results Sixty-five patients from institution A were included. The rate of optimal cytoreduction (≤ 1 cm residual disease) was 78%. Diaphragm disease and large bowel mesentery implants were the only CT predictors of suboptimal cytoreduction on univariate (P < .02) and multivariate analysis (P < .02). In combination (model A), these predictors had a sensitivity of 79%, a specificity of 75%, and an accuracy of 77% for suboptimal cytoreduction. When model A was applied to cohorts B and C, accuracy rates dropped to 34% and 64%, respectively. Reciprocally, models B and C had accuracy rates of 93% and 79% in their original cohorts, which fell to 74% and 48% in cohort A. Conclusion The high accuracy rates of CT predictors of suboptimal cytoreduction in the original cohorts could not be confirmed in the cross validation. Preoperative CT predictors should be used with caution when deciding between surgical cytoreduction and neoadjuvant chemotherapy.

Animal studies indicate that oversupply of fatty acids derived from the action of cardiac lipoprotein lipase (LPL) on plasma lipoproteins may contribute to myocardial dysfunction. However, the contribution of circulating triglycerides to myocardial fatty acid supply in humans is not known. Six postabsorptive nondiabetic subjects who were scheduled for diagnostic coronary angiography were studied. 14C oleate and a lipid emulsion labeled with 3H triolein were infused to assess myocardial uptake of free fatty acids (FFAs) and triglycerides, as well as myocardial spillover of LPL-generated fatty acids. Six paired blood samples were taken from the femoral artery and the coronary sinus. Coronary sinus concentrations of unlabeled triglycerides were slightly, but not significantly, lower than arterial (P = 0.12), whereas labeled triglyceride concentrations were significantly lower in the coronary sinus than in the artery (P &lt; 0.05; extraction fraction ≅11%). Triglycerides and FFAs accounted for ∼17% and ∼83%, respectively, of myocardial fatty acid uptake. Systemic and myocardial fractional spillover of LPL-generated fatty acids was 49.0 ± 7% and 34.7 ± 13%, respectively. The myocardium was a minor contributor to systemic triglyceride uptake (∼3%) and a trivial contributor to systemic FFA production (∼0.5%). These results indicate that circulating triglycerides may be a significant source of fatty acids for myocardial respiration.

Abstract Rationale Treatment and prognoses of diffuse parenchymal lung diseases (DPLDs) varies by diagnosis. Obtaining a uniform diagnosis among observers is difficult. Objectives Evaluate diagnostic agreement between academic and community-based physicians for patients with DPLDs, and determine if an interactive approach between clinicians, radiologists, and pathologists improved diagnostic agreement in community and academic centers. Methods Retrospective review of 39 patients with DPLD. A total of 19 participants reviewed cases at 2 community locations and 1 academic location. Information from the history, physical examination, pulmonary function testing, high-resolution computed tomography, and surgical lung biopsy was collected. Data were presented in the same sequential fashion to three groups of physicians on separate days. Measurements and Main Results Each observer's diagnosis was coded into one of eight categories. A κ statistic allowing for multiple raters was used to assess agreement in diagnosis. Interactions between clinicians, radiologists, and pathologists improved interobserver agreement at both community and academic sites; however, final agreement was better within academic centers (κ = 0.55–0.71) than within community centers (κ = 0.32–0.44). Clinically significant disagreement was present between academic and community-based physicians (κ = 0.11–0.56). Community physicians were more likely to assign a final diagnosis of idiopathic pulmonary fibrosis compared with academic physicians. Conclusions Significant disagreement exists in the diagnosis of DPLD between physicians based in communities compared with those in academic centers. Wherever possible, patients should be referred to centers with expertise in diffuse parenchymal lung disorders to help clarify the diagnosis and provide suggestions regarding treatment options.

This work presents an approach to inversely determine material properties for solids immersed in fluids through the use of steady-state dynamic response. The methodology uses measured acoustic pressure amplitudes in the fluid surrounding a structure being vibrated with a harmonic force to determine the parameters for elastic and viscoelastic material models. Steady-state dynamic finite element analysis is used to compute the frequency response function of homogeneous and heterogeneous solids. The frequency response is then used to inversely estimate material parameters. In order to solve the inverse problem, an optimization method is presented which combines the global search capabilities of the random search method with the reduced computational time of a surrogate model approach. Through numerical and laboratory experiments, this work shows that acoustic emissions hold sufficient information for quantifying both elastic and viscoelastic material behaviors. Furthermore, the examples show that the surrogate model accelerated random search algorithm is an efficient and accurate method for solving these types of inverse problems. This research has direct and important implications in nondestructive evaluation of material properties in general. However, the examples shown in this paper are based on applications related to noninvasive characterization of biological materials through methodologies currently applied to medical imaging.

Intermittent claudication is the most common symptom of peripheral arterial disease (PAD), in part due to an inadequate rise in limb blood flow with exercise. Claudication causes a severe impairment in functional capacity and quality of life in over 3 million Americans. Basic fibroblast growth factor (bFGF) stimulates angiogenesis in vivo and improves limb blood flow in several animal models of hindlimb ischemia. However, the relative safety and efficacy of angiogenic molecules in the treatment of claudication has not been fully evaluated in prospective, blinded clinical trials. In this study, a randomized, double-blind, placebo-controlled, phase II trial of recombinant human bFGF for the treatment of intermittent claudication was performed. bFGF was administered weekly by intravenous infusions of 2 μg/kg for 6 sequential weeks (total dose 12 μg/kg). The primary efficacy endpoint was change in peak walking time (PWT) on a graded exercise treadmill protocol. Secondary efficacy endpoints included changes in functional status as measured by validated questionnaires. The study was stopped prematurely after treatment of the first 24 subjects due to proteinuria in five of the 16 subjects who received systemic bFGF, which exceeded 1000 mg/24 h in four of these five subjects. The small sample size limited evaluation of the predefined efficacy endpoints; however, there was no significant difference between the treatment and control groups for any of the measures of efficacy. In conclusion, intravenous administration of bFGF delivered at low doses weekly for 6 weeks was associated with a high rate of severe proteinuria. It is speculated that bFGF-related proteinuria in this study was primarily related to the systemic route of administration and the frequent dosing schedule. Future clinical trials of bFGF protein should carefully monitor renal function and consider alternative dosing schedules and drug administration routes.

The critical decisions regarding thoracotomy for trauma occur soon after the injury, when decisions have to be made that may influence survival or have an impact on morbidity if operation is delayed. Roadside thoracotomy is impractical, and should not be considered; instead, patients should be taken rapidly to the nearest hospital. Endotracheal intubation prior to transport appears to be beneficial, but the application of MAST trousers and the infusion of large volumes of fluid for hypovolaemia before control of haemorrhage offers no advantage and may be hazardous. On the whole, resuscitative thoracotomy is associated with a low salvage rate, especially for the patient sustaining blunt trauma, but may be worthwhile in the patient with penetrating trauma. Urgent, as opposed to immediate thoracotomy, should be undertaken once the patient has been stabilized. This may occur in most patients with penetrating injuries of the heart who survive to reach hospital, those with continuing, significant haemorrhage through chest drains, and those with tracheal, oesophageal and diaphragmatic injuries. Extensive open chest wounds require considerable ingenuity in closure, often with plastic surgical help. Patients with blunt traumatic rupture of the aorta often have multiple injuries, which may also be life threatening. If bleeding into the abdomen is demonstrated, then laparotomy should precede thoracotomy: musculoskeletal injuries and neurological injuries can usually be dealt with after the aortic rupture has been repaired.