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Development of a noninvasive intensive care system calls for the use of evoked potentials (EPs), as a means of diagnosing traumatic head-injured patients. The experiment entails surgically placing two subarachnoid bolts and a subdural balloon through the skull to simulate a subdural hematoma. Using various levels of ICP and/or different sizes of balloons, auditory evoked potentials (AEPs) were recorded from a rabbit. Six positive peak latencies (P1-P6) and five negative peak latencies (Nl-N5) were extracted from an averaged AEP waveform. Multiple regression analyses were performed for determining a relationship between the ICP and AEP peak latencies. The results indicate that a major correlation of changes on AEP peak latencies is due to mechanical forces of a mass (inflated balloon simulating a hematoma) in the distortion of the brain matter rather than increased ICP.

Pressure waveform fidelity was examined in two sizes of the Bard catheter introducer. The purpose of this endeavor was to determine whether accurate blood pressure measurements could be achieved directly via the catheter introducers. The introducers were incorporated into a mock circulatory system for the study. The effects of supporting dilators and catheters within the introducer sheath during pressure measurements were also considered. Parameters used to explain pressure waveform response within the catheter introducers included the damping coefficient and the natural frequency of the catheter introducer, and the effects of impedance mismatching between the transducer and the mock circulatory system. Overall, the pressure measurements obtained from the catheter introducer were distorted. Mean pressure levels measured in the introducers were up to 15 mmHg higher than the true mean pressure. The distortion in the pressure measurements can be attributed for the most part to impedance mismatching. In sum, the pressure measurements obtained from catheter introducer-manometer systems should be used only referentially, and not as an absolute standard.

e13515 Background: P and PLD are clinically active as single agents and synergistic in preclinical models. This phase I, open-label trial determined the maximum tolerated dose (MTD) and safety profile of P followed by PLD in patients (pts) with breast or gynecologic cancers. Methods: Using standard phase I (3+3 dose escalation) study design, cohorts of 3–9 pts received escalating doses of P followed by PLD in 28-day cycles: P 400–500 mg/m2 on Days 1 and 15 and PLD 30–45 mg/m2 on Day 1. All pts received folic acid (350–1000 μg daily) and vitamin B12 (1000 μg) until 21 days after last dose of P. Pts continued until dose-limiting toxicity (DLT) or disease progression (PD) occurred. Results: From 11/05 to 1/08, 29 pts were registered/treated. Median age: 60.6 years (range, 47.5–80.1); ECOG performance status 0/1: 28%/72%; primary disease sites: ovarian (55%), breast (35%), peritoneal (10%); prior therapies: chemotherapy (100%), surgery (72%), hormones/biologics (35%), radiation (21%). Dosing results are shown below. At dose level (L) 2 and L3, 1 pt/cohort had DLTs; L5 was added and 3/3 pts had DLTs; 4 more pts were treated at L4 (1 pt replaced). Most frequent drug-related Grade 3–4 hematologic toxicities: neutropenia (86%), leukopenia (59%), thrombocytopenia (48%), anemia (41%). Most frequent drug-related Grade 3–4 nonhematologic toxicities: hand-foot syndrome (14%), hypokalaemia (10%). Major reasons for discontinuation: PD (48%), toxicity (28%), pt request (14%). Overall best responses (n=24): 5 pts (21%) had partial response (PR), 14 pts (58%) had stable disease (SD), 2 pts (8%) had PD, 3 pts (13%) were not evaluable. All 5 PR and 8 SD pts were ovarian; 5 SD and both PD pts were breast. Conclusions: P followed by PLD was reasonably tolerated in this heavily-pretreated population. The MTD was P 500 mg/m2 and PLD 40 mg/m2. These dose levels may be carried forward to phase II studies in more specific patient populations. [Table: see text] [Table: see text]

4081 Background: Perifosine (Peri), a synthetic alkylphospholipid, inhibits or modifies a number of different signal transduction pathways (AKT, MAPK and JNK). Peri as a single agent or in combination with other cytotoxic agents, has shown clinical benefit with a manageable safety profile. In a phase I solid tumor trial, Peri was safely combined with capecitabine (Cap) and demonstrated interesting activity in patients (pts) with metastatic colorectal cancer (mCRC), with one patient progression-free for 49 weeks (wks). To assess the true effect of Peri, a phase II was initiated as an exploratory randomized double-blind, placebo controlled study where mCRC pts received Cap in combination with Peri or placebo. Methods: Pts with 2nd or 3rd line mCRC, not previously treated with single agent Cap. ECOG PS 0–1, normal organ/marrow function required. Dose for Cap was 825 mg/m2 BID d 1–14 q 3 weeks. Dose for Peri or placebo was 50 mg qd. Primary outcome analyses included median time to progression (TTP) and response rate (CR+PR). Results: 37 pts have been randomized. Median age 68 (range 32–83) and 57% were male. Median prior Rx was 2 (range 1 - 5). For the analyses, 25 pts were unblinded (12 too early) with 22/25 pts evaluable for response (2 pts off for toxicity at d 14, 46 and 1 patient off at d 4 for other disease; all 3 pts were on Cap + placebo). Results in table below. The log-rank p-value comparing active to placebo for TTP is 0.01. As of 12/08, all unblinded pts are off treatment and 11/12 that were too early remain on treatment with enrollment ongoing. Most frequent (>5%) grade 3 /4 adverse events for Cap + Peri was hand/foot syndrome (16%) and anemia (8%); for Cap + placebo was fatigue (8%). Conclusions: Perifosine in combination with capecitabine was well tolerated, clinically active and more than doubled median TTP over capecitabine alone in pts with advanced, metastatic CRC. [Table: see text] [Table: see text]

Purine analog-based regimens have emerged as highly active regimens in the treatment of chronic lymphocytic lymphoma (CLL). Promising results have been reported with the combination of fludarabine (F), cyclophosphamide (C), and rituximab (R) (FCR) by Keating and colleagues at the University of Texas M.D. Anderson. A previous USOR trial, as well as a Mayo clinic trial, evaluated the combination of pentostatin (P), cyclophosphamide (C), and rituximab (R) (PCR); results suggested similar efficacy with less infectious complications than that seen with FCR. The current multicenter, randomized, community-based trial was conducted to compare FCR and PCR in previously untreated or minimally treated B cell CLL. The primary endpoint was infectious complications with efficacy and safety as secondary endpoints. Correlative studies of immune function were conducted by Kay and colleagues at the Mayo Clinic and will be reported separately. Patients (pts) were assigned to either PCR (P 4 mg/m2 Day 1, C 600 mg/m2 Day 1, R 375 mg/m2 Day 1) (2 1-day cycles) or FCR (F 20 mg/m2 Day 1–5, C 600 mg/m2 Day 1, R 375 mg/m2 Day 1) (28-day cycles). In both regimens the first dose of R 100 mg/m2 was given on Day 8 Cycle 1 and the remainder of the 375 mg/m2 dose was given on Day 9; in subsequent cycles the entire 375 mg/m2 dose was given on Day 1. 92 pts were randomized to each group (N=184). Groups were well balanced for sex, race, and age. Stage II/III/IV were 41%/22%30% for FCR vs 55%/17%/22% for PCR and ECOG PS 0/1/2 were 74%/22%/1% for FCR vs 62%/34%/2% for PCR; ~20% of pts in both groups had received prior chemotherapy; 80% were previously untreated. The infection rate (temperature □101 requiring antibiotics) in FCR was 30.7% vs 33.7% in PCR (p=0.67) while infective events (temperature □101°F w/o symptoms or

13502 Background: We have previously shown that capecitabine/irinotecan (XELIRI) is effective and well-tolerated in metastatic colorectal cancer (mCRC). Cetuximab targets EGFR and is active in mCRC either alone or combined with chemotherapy. This study evaluated potential improved outcomes with cetuximab+XELIRI in first-line treatment of mCRC. Subjects and Methods: Subjects had histologically confirmed colorectal adenocarcinoma with T4 lesions that were deemed unresectable after preoperative chemoradiation and/or metastatic disease. Treatment: capecitabine 1700 mg/m2 (850 mg/m2 PO BID Days 1–14), irinotecan 200 mg/m2 IV Day 1 every 3 weeks, and weekly cetuximab (initial dose 400 mg/m2 IV over 120 minutes, subsequent doses 250 mg/m2 over 30 minutes). Toxicity was assessed at each visit. Results: Between February and October 2005, 70 subjects enrolled. Baseline characteristics: 43 males (61%), 79% White, median age 61.5 years (range, 32.2 - 85.4), and ECOG PS 0/1= 66%/34%. 63% of subjects had Stage IV disease at diagnosis; 87% of subjects had adenocarcinoma. Prior therapy: surgery (n=60, 86%), chemotherapy (n=14, 20%), and radiotherapy (n=5, 7%). Grade 3–4 treatment-related toxicities in >1 subject included diarrhea (17%); neutropenia and rash (8.5% each); dehydration (7%); nausea/vomiting (5%); and anorexia, dyspepsia, and hypokalemia (3% each). 30 subjects discontinued due to progressive disease (PD) (n=9), toxicity (n=12), MD decision (n=2), patient request/withdrew consent (n=3), death (n=1) and other (n=3; doses delayed >3 weeks). To date 5 subjects have died; no death was treatment-related. Evaluation of tumor responses is ongoing. Conclusions: The combination of cetuximab+XELIRI is feasible and well-tolerated in first-line mCRC. Updated safety and efficacy data will be presented. Funded in part by Bristol-Myers Squibb, Plainsboro, NJ. [Table: see text]

6676 Background: OSI-461 is a selective apoptotic antineoplastic drug (SAAND), a novel class of drugs that induce apoptosis by inhibiting cGMP phosphodiesterases. OSI-461 has about 100x more affinity for cGMP PDE than does exisulind, the first generation of this drug class. OSI-461 has been shown to inhibit the growth of a variety of human tumor cell lines as well as lymphocytes from CLL patients (pts). Phase-I clinical studies have also demonstrated that OSI-461 administration is well-tolerated. In this multicenter pilot study, we sought to assess the safety and activity of OSI-461 in previously untreated CLL pts. Methods: Between June 2001 and February 2002, 23 pts with progressing CLL were registered; 1 was ineligible (prior chemotherapy). Fifteen pts received OSI-461 400 mg (Group 1) and 7 received 800 mg (Group 2) PO as a split dose (200 mg [Group1] or 400 mg [Group 2]) twice daily every 28-day cycle. Patients continued to receive treatment in the absence of intolerable toxicity or disease progressio...

A mathematical model of oxygen transport in skeletal muscle is utilized to investigate myoglobin's effect on the space-time distribution of oxygen in skeletal muscle subjected to ischemia.

A mathematical model and digital computer simulation of oxygen transport in skeletal muscle is developed to simulate conditions of periodic ischemia. The model uses the Krogh cylinder as a geometric basis for transcapillary exchange. Equations are developed which model the physical processes of convection and oxyhemoglobin dissociation in a “well stirred” capillary, and the coupled tissue processes of axial and radial diffusion, metabolic consumption, and lactic acid production. The effect of these processes on tissue oxygenation is demonstrated by solutions for steady state and transient conditions involving periodic occlusion of the capillaries. The significance of a local oxygen debt is demonstrated as a factor in recovery from ischemic conditions.

The escalating cost of energy is of concern to the hospital industry, and this cost has led to increasing interest by hospital administrators in energy conservation programs as part of their cost-containments efforts. An effective and comprehensive program should be based on an energy management approach which includes the careful analysis of the activities of the entire hospital staff. The clinical engineer has significant opportunities to contribute to this effort through his own department's activities and in other areas where his engineering training can be effectively utilized.

An analytical model based on classical piezoelectric theory was used to related electrical effects to the stress-state in a bone cross-section for simple bending of a cylindrical bone shaft. The results demonstrate that the overall polarities of the polarization volume charge and the induced electrical potential compare favorably with available experimental findings. Both the polarization charge and the induced electrical potential are shown to be highly sensitive to the angle between the material and bone axes between 0 and 10 degrees. A reduction of the bone cross-sectional area results in a higher magnitude in the polarization charges and the induced electrical potential at all points in a cross-section. No appreciable difference in the predicted electrical effects is observed for the use of two relevant piezoelectric d -matrixes.

Growth in highway spending and the loss of approximately one-third of the nation's professional engineers in state highway agencies will create significant problems and opportunities over the next decade. Careers in transportation will be attractive, rewarding and interesting, with promise for growing responsibility and advancement. This paper describes the dimensions of the problem and suggests approaches that should result in dynamic future-oriented organizations. Recruitment, education and training, compensation, professional satisfaction, skill requirements and other aspects of human resources management must be carefully matched to meet changing needs and skill requirements.

An extremum principle is presented concerning the dissipation of energy in the disturbance field caused by the presence of solid particles or liquid drops in an otherwise infinite, continuous, slow viscous flow. This is a generalization of a type of theorem originally stated by Helmholtz and extended by Keller, Rubenfeld and Molyneux and more recently by Skalak. The new aspect of the present work is the relaxation of the allowable conditions at infinity to include an arbitrary Stokes flow. A uniqueness theorem for the flow field follows from the extremum principle.

Viscous flow in a circular cylindrical tube containing an infinite line of viscous liquid drops equally spaced along the tube axis is considered under the assumption that a surface tension, sufficiently large, holds the drops in a nearly spherical shape. Three cases are considered: (1) axial translation of the drops, (2) flow of the external fluid past a line of stationary drops, and (3) flow of external fluid and liquid drops under an imposed pressure gradient. Both fluids are taken to be Newtonian and incompressible, and the linearized equations of creeping flow are used. The results show that both drag and pressure drop per sphere increase as the spacing increases at fixed radius and also increase as the radius of the drop increases. The presence of the internal motion reduces the drag and pressure gradients in all cases compared to rigid spheres, particularly for drops approaching the size of the tube.

This paper present an analysis and computed results of the flow of deformable droplets of one Newtonian flow suspended in another Newtonian fluid. Surface tension is assumed to act at the interface of the two fluids. Non-Newtonian characteristics of the suspension are demonstrated and are qualitatively similar to flow characteristics of blood in capillaries. The results show that the deformation of the drops may result in a significant reduction in the pressure gradient compared with that necessary for a suspension of rigid spheres or spherical (nondeformable) liquid drops. The decrease in the pressure gradient is velocity dependent. This constitutes a mechanism of non-Newtonain behavior of the suspension as a whole, and is attributable to the flexibility of the suspended elements. The resultant shapes of the liquid drops are similar to the shapes of red blood cells that have been observed in narrow glass capillaries as well as in blood vessels.

The forces acting on an elastic particle suspended in a shear field, and moving relative to it, are found for the case in which there are small deformations from an initially spherical shape. The deformation is the result of the viscous stresses acting on the particle. Of principal interest is that there is a component of the force perpendicular to the free-stream direction, so that the particle will migrate across the undisturbed streamlines.