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Credentials

Education ?

Medical School Score
Saint Louis University (1988)
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Awards & Distinctions ?

Awards  
One of America's Leading Experts on:
Urologic Cancer (Urologic Neoplasm)
Compassionate Doctor Recognition (2015)
Appointments
University of Southern California School of Medicine
Assistant Professor of Clinical
Associations
American College of Surgeons
American Board of Surgery

Affiliations ?

Dr. Roth is affiliated with 6 hospitals.

Hospital Affiliations

Score

Rankings

  • USC University Hospital
    1500 San Pablo St, Los Angeles, CA 90033
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    Top 25%
  • Providence Holy Cross Medical Center
    15031 Rinaldi St, Mission Hills, CA 91345
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    Top 25%
  • Huntington Hospital
    100 W California Blvd, Pasadena, CA 91105
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    Top 25%
  • USC Norris Cancer Hospital
    1441 Eastlake Ave, Los Angeles, CA 90089
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  • USCNorris Cancer Hospital
  • Northridge Hosp Med Ctr, Northridge, Ca
  • Publications & Research

    Dr. Roth has contributed to 228 publications.
    Title Acute Coronary Syndrome and Cardiac Arrest: Using Simulation to Assess Resident Performance and Program Outcomes.
    Date November 2011
    Journal Journal of Graduate Medical Education
    Excerpt

    Simulation training has emerged as an effective method of educating residents in cardiac emergencies. Few studies have used emergency simulation scenarios as an outcome measure to identify training deficiencies within residency programs.

    Title How Hyperpolarization and the Recovery of Excitability Affect Propagation Through a Virtual Anode in the Heart.
    Date September 2011
    Journal Computational and Mathematical Methods in Medicine
    Excerpt

    Researchers have suggested that the fate of a shock-induced wave front at the edge of a "virtual anode" (a region hyperpolarized by the shock) is a key factor determining success or failure during defibrillation of the heart. In this paper, we use a simple one-dimensional computer model to examine propagation speed through a hyperpolarized region. Our goal is to test the hypothesis that rapid propagation through a virtual anode can cause failure of propagation at the edge of the virtual anode. The calculations support this hypothesis and suggest that the time constant of the sodium inactivation gate is an important parameter. These results may be significant in understanding the mechanism of the upper limit of vulnerability.

    Title Mechanical Bidomain Model of Cardiac Tissue.
    Date April 2011
    Journal Physical Review. E, Statistical, Nonlinear, and Soft Matter Physics
    Excerpt

    Intracellular and extracellular spaces are separately considered in an electrical bidomain model of tissue. We propose a mechanical bidomain model separately considering the intracellular and extracellular spaces, coupled through a linear restoring force proportional to the displacement difference of the two spaces. We consider a mechanically passive model of heart fibers (no tension) with an action potential, and an electrically passive model (no action potential) in tissue with an ischemic boundary. We find the pressure and displacement fields arising from our consideration of a bidomain instead of a monodomain and note interesting characteristics evident only with a bidomain approach.

    Title The Role of Magnetic Forces in Biology and Medicine.
    Date April 2011
    Journal Experimental Biology and Medicine (maywood, N.j.)
    Excerpt

    The Lorentz force (the force acting on currents in a magnetic field) plays an increasingly larger role in techniques to image current and conductivity. This review will summarize several applications involving the Lorentz force, including (1) magneto-acoustic imaging of current; (2) 'Hall effect' imaging; (3) ultrasonically-induced Lorentz force imaging of conductivity; (4) magneto-acoustic tomography with magnetic induction; and (5) Lorentz force imaging of action currents using magnetic resonance imaging.

    Title Deep Soft-tissue Necrosis of the Foot and Ankle Caused by Catfish Envenomation: a Case Report.
    Date March 2011
    Journal Journal of the American Podiatric Medical Association
    Excerpt

    Catfish envenomations represent a relatively rare cause of complications in podiatric medicine. We report a case of an unusual event eliciting a severe soft-tissue necrosis in a 21-year-old man and his complicated wound-healing process. This case reviews the potential complications of catfish envenomations.

    Title Measurements of Transmembrane Potential and Magnetic Field at the Apex of the Heart.
    Date March 2011
    Journal Biophysical Journal
    Excerpt

    We studied the transmembrane potential and magnetic fields from electrical activity at the apex of the isolated rabbit heart experimentally using optical mapping and superconducting quantum interference device microscopy, and theoretically using monodomain and bidomain models. The cardiac apex has a complex spiral fiber architecture that plays an important role in the development and propagation of action currents during stimulation at the apex. This spiral fiber orientation contains both radial electric currents that contribute to the electrocardiogram and electrically silent circular currents that cannot be detected by the electrocardiogram but are detectable by their magnetic field, B(z). In our experiments, the transmembrane potential, V(m), was first measured optically and then B(z) was measured with a superconducting quantum interference device microscope. Based on a simple model of the spiral structure of the apex, V(m) was expected to exhibit circular wave front patterns and B(z) to reflect the circular component of the action currents. Although the circular V(m) wave fronts were detected, the B(z) maps were not as simple as expected. However, we observed a pattern consistent with a tilted axis for the apex spiral fiber geometry. We were able to simulate similar patterns in both a monodomain model of a tilted stack of rings of dipole current and a bidomain model of a tilted stack of spiraled cardiac tissue that was stimulated at the apex. The fact that the spatial pattern of the magnetic data was more complex than the simple circles observed for V(m) suggests that the magnetic data contain information that cannot be found electrically.

    Title Transfusion Medicine Knowledge in Postgraduate Year 1 Residents.
    Date October 2010
    Journal Transfusion
    Excerpt

    Transfusion medicine is a complex important subspecialty of pathology. A transfusion carries measurable risks and benefits. Although fellowship training exists in transfusion medicine, the majority of transfusion decisions are made by clinicians without formal training.

    Title Lorentz Effect Imaging of Ionic Currents in Solution Using Correct Values for Ion Mobility.
    Date September 2010
    Journal Journal of Magnetic Resonance (san Diego, Calif. : 1997)
    Excerpt

    Truong and his colleagues have recently published a paper introducing a new method called Lorentz effect imaging (LEI) to detect ionic currents in a solution. Their main goal was to prove that the Lorentz force acting on ions in the presence of a static magnetic field could be used as a contrast mechanism to measure neural currents with magnetic resonance imaging. However, they failed to use the correct values for the ion mobilities. In this investigation, we have used correct ion mobility values and show that LEI cannot be used as a contrast mechanism to directly image neural currents.

    Title Digital Fracture After a Flexor Tendon Transfer for Hammertoe Repair: a Case Report.
    Date June 2010
    Journal The Journal of Foot and Ankle Surgery : Official Publication of the American College of Foot and Ankle Surgeons
    Excerpt

    The authors present a case report of a complication of a complete phalangeal fracture after flexor digitorum longus tendon transfer used for the surgical correction of a hammertoe deformity.

    Title A Model for Multi-site Pacing of Fibrillation Using Nonlinear Dynamics Feedback.
    Date May 2010
    Journal Journal of Biological Physics
    Excerpt

    Traditionally, cardiac defibrillation requires a strong electric shock. Many unwanted side effects of this shock could be eliminated if defibrillation were performed using weak stimuli applied to several locations throughout the heart. Such multi-site pacing algorithms have been shown to defibrillate both experimentally (Pak et al., Am J Physiol 285:H2704-H2711, 2003) and theoretically (Puwal and Roth, J Biol Systems 14:101-112, 2006). Gauthier et al. (Chaos, 12:952-961, 2002) proposed a method to pace the heart using an algorithm based on nonlinear dynamics feedback applied through a single electrode. Our study applies a related but simpler algorithm, which essentially configures each electrode as a demand pacemaker, to simulate the multi-site pacing of fibrillating cardiac tissue. We use the numerical model developed by Fenton et al. (Chaos, 12:852-892, 2002) as the reaction term in a reaction-diffusion equation that we solve over a two-dimensional sheet of tissue. The defibrillation rate after pacing for 3 s is about 30%, which is significantly higher than the spontaneous defibrillation rate and is higher than observed in previous experimental and theoretical studies. Tuning the algorithm period can increase this rate to 45%.

    Title Nccn Clinical Practice Guidelines in Oncology: Prostate Cancer.
    Date April 2010
    Journal Journal of the National Comprehensive Cancer Network : Jnccn
    Title Effect of Peripheral Nerve Action Currents on Magnetic Resonance Imaging.
    Date March 2010
    Journal Conference Proceedings : ... Annual International Conference of the Ieee Engineering in Medicine and Biology Society. Ieee Engineering in Medicine and Biology Society. Conference
    Excerpt

    Many researchers have attempted to detect neural currents directly using magnetic resonance imaging (MRI). The action currents of a peripheral nerve create their own magnetic field that can cause the phase of the spins to change. Our goal in this paper is to use the measured magnetic field of a nerve to estimate the resulting phase shift in the magnetic resonance signal. We examine three cases: the squid giant axon, the frog sciatic nerve, and the human median nerve. In each case, the phase shift is much less than one degree, and will be very difficult to measure with current technology.

    Title Detection of Peripheral Nerve and Skeletal Muscle Action Currents Using Magnetic Resonance Imaging.
    Date December 2009
    Journal Annals of Biomedical Engineering
    Excerpt

    Many researchers have attempted to detect neural currents directly using magnetic resonance imaging (MRI). The action currents of a peripheral nerve or skeletal muscle create their own magnetic field that can cause the phase of the spins to change. Our goal in this paper is to use the measured magnetic field of a nerve or muscle to estimate the resulting phase shift in the magnetic resonance signal. We examine four cases: the squid giant axon, the frog sciatic nerve, the human median nerve, and the rat EDL muscle. In each case, the phase shift is much less than one tenth of one degree, and will be very difficult to measure with current technology.

    Title Ultrasonically-induced Lorentz Force Tomography.
    Date October 2009
    Journal Medical & Biological Engineering & Computing
    Excerpt

    Electrical conductivity can be measured using the ultrasonically-induced Lorentz force. An ultrasonic wave is passed through tissue in the presence of a magnetic field. Moving charges in a magnetic field are subject to the Lorentz force, which acts as the source of current and potential. This paper shows that ultrasonically-induced Lorentz force imaging can be formulated in a way that makes it similar to tomography: an image can be reconstructed using waves propagating in various directions. More specifically, measuring the dipole strength for a particular direction and wavelength is equivalent to measuring the Fourier transform of the conductivity distribution at one point in frequency space. Measurements at a variety of wavelengths and directions are equivalent to mapping the Fourier transform of the conductivity distribution. The conductivity can then be found by an inverse Fourier transform.

    Title Phase 2 Trial of Sorafenib in Patients with Advanced Urothelial Cancer: a Trial of the Eastern Cooperative Oncology Group.
    Date October 2009
    Journal Cancer
    Excerpt

    There is no effective second-line systemic chemotherapy for patients with disease progression after cisplatin-based chemotherapy. A phase 2 trial of sorafenib was performed to determine the activity and toxicity of this agent in a multi-institutional setting in patients previously treated with 1 prior chemotherapy regimen.

    Title Optimization of Feedback Pacing for Defibrillation.
    Date September 2009
    Journal Ieee Transactions on Bio-medical Engineering
    Excerpt

    A mathematical model of multisite feedback pacing for defibrillation is optimized for electrode spacing and stimulus period. For four electrodes, the defibrillation success rate is highest at 88% when the electrodes are spaced as far apart as possible. For a single electrode, the optimum success rate was 26%.

    Title Development of an Imaging Modality Utilizing 2d Optical Signals During an Epi-fluorescent Optical Mapping Experiment.
    Date July 2009
    Journal Physics in Medicine and Biology
    Excerpt

    Optical mapping is a commonly used technique to visualize the electrical activity in the heart. Recently, several groups have attempted to use the signals acquired in optical mapping to image the transmembrane potential in the heart, which would be particularly advantageous when studying the effects of defibrillation-type shocks throughout the wall of the heart. Our work presents an alternative imaging method that makes use of data obtained using multiple wavelengths and therefore multiple optical decay constants. A modified form of the diffusion equation Green's function for a semi-infinite slab of tissue is derived and used to relate the detected optical signals to the source of emission photons. Images using the optical signals are reconstructed using Gaussian quadrature and matrix inversion. Our results show that images can be obtained for source terms located below the tissue surface. Furthermore, we demonstrate that our reconstruction method's susceptibility to noise can be alleviated using sophisticated matrix inverse techniques, such as singular value decomposition. Sources that rapidly decay with depth or are highly localized in the image plane require more sophisticated techniques (e.g., regularization methods) to image the electrical activity in the heart. The work presented here demonstrates the feasibility of a new imaging technique of cardiac electrical activity using optical mapping.

    Title What Does the Ratio of Injected Current to Electrode Area Not Tell Us About Tdcs?
    Date June 2009
    Journal Clinical Neurophysiology : Official Journal of the International Federation of Clinical Neurophysiology
    Title A Mechanism for the Upper Limit of Vulnerability.
    Date June 2009
    Journal Heart Rhythm : the Official Journal of the Heart Rhythm Society
    Excerpt

    The strongest shock that induces reentry in the heart is the upper limit of vulnerability (ULV). In order to understand defibrillation, one must know what causes the ULV.

    Title Long Versus Short Duration Fibrillation: What's the Difference?
    Date March 2009
    Journal Heart Rhythm : the Official Journal of the Heart Rhythm Society
    Title Mechanical Model of Neural Tissue Displacement During Lorentz Effect Imaging.
    Date February 2009
    Journal Magnetic Resonance in Medicine : Official Journal of the Society of Magnetic Resonance in Medicine / Society of Magnetic Resonance in Medicine
    Excerpt

    Allen Song and coworkers recently proposed a method for MRI detection of biocurrents in nerves called "Lorentz effect imaging." When exposed to a magnetic field, neural currents are subjected to a Lorentz force that moves the nerve. If the displacement is large enough, an artifact is predicted in the MR signal. In this work, the displacement of a nerve of radius a in a surrounding tissue of radius b and shear modulus mu is analyzed. The nerve carries a current density J and lies in a magnetic field B. The solution to the resulting elasticity problem indicates that the nerve moves a distance BJ/4mu a2ln(b/a). Using realistic parameters for a human median nerve in a 4T field, this calculated displacement is 0.013 microm or less. The distribution of displacement is widespread throughout the tissue, and is not localized near the nerve. This displacement is orders of magnitude too small to be detected by conventional MRI methods.

    Title Education Research: Evaluating Acute Altered Mental Status: Are Incoming Interns Prepared?
    Date December 2008
    Journal Neurology
    Excerpt

    Clinical evaluation of hospitalized patients with acute altered mental status (AMS) is a common task of interns, regardless of medical specialty. The effectiveness of medical education to ensure competence in this area is unknown.

    Title Photon Density Measured over a Cut Surface: Implications for Optical Mapping of the Heart.
    Date August 2008
    Journal Ieee Transactions on Bio-medical Engineering
    Excerpt

    During optical mapping of the heart, the signal represents a weighted average of the transmembrane potential. Researchers sometimes illuminate the epicardium and record over a cut surface. My goal is to compare their signal to the photon density within an intact tissue. Does cutting the tissue affect the signal?

    Title Calculation of Optical Signal Using Three-dimensional Bidomain/diffusion Model Reveals Distortion of the Transmembrane Potential.
    Date August 2008
    Journal Biophysical Journal
    Excerpt

    Optical mapping experiments allow investigators to view the effects of electrical currents on the transmembrane potential, V(m), as a shock is applied to the heart. One important consideration is whether the optical signal accurately represents V(m). We have combined the bidomain equations along with the photon diffusion equation to study the excitation and emission of photons during optical mapping of cardiac tissue. Our results show that this bidomain/diffusion model predicts an optical signal that is much smaller than V(m) near a stimulating electrode, a result consistent with experimental observations. Yet, this model, which incorporates the effect of lateral averaging, also reveals an optical signal that overestimates V(m) at distances >1 mm away from the electrode. Although V(m) falls off with distance r from the electrode as exp(-r/lambda)/r, the optical signal decays as a simple exponential, exp(-r/lambda). Moreover, regions of hyperpolarization adjacent to a cathode are emphasized in the optical signal compared to the region of depolarization under the cathode. Imaging methods utilizing optical mapping techniques will need to account for these distortions to accurately reconstruct V(m).

    Title Phase 2 Trial of Pemetrexed Disodium and Gemcitabine in Advanced Urothelial Cancer (e4802): a Trial of the Eastern Cooperative Oncology Group.
    Date July 2008
    Journal Cancer
    Excerpt

    BACKGROUND: There is a need to identify active new regimens in patients with advanced urothelial cancer. Pemetrexed and gemcitabine are active agents in advanced urothelial cancer. A phase 2 trial of the combination of these 2 agents was performed in patients with advanced urothelial cancer who were previously untreated for metastatic disease. METHODS: Forty-six patients with advanced urothelial carcinoma received pemetrexed disodium 500 mg/m2 and gemcitabine 1000 mg/m2 intravenously on Day 1, with gemcitabine repeated on Day 8. Cycles were repeated every 3 weeks for a maximum of 6 cycles. RESULTS: Two patients attained a complete response, and 12 patients attained a partial response for an overall response rate of 31.8% (90% confidence interval, 20.4%-45.2%). The median time to disease progression was 5.8 months, and the median overall survival was 13.4 months. Thirty-three patients (75%) experienced grade>or=3 neutropenia, and 5 patients (11%) had febrile neutropenia. There were 2 therapy-related deaths. CONCLUSIONS: The combination of pemetrexed and gemcitabine had moderate antitumor activity in previously untreated patients with advanced urothelial cancer at the expense of significant myelosuppression.

    Title The Effect of Electrical Anisotropy During Magnetoacoustic Tomography with Magnetic Induction.
    Date June 2008
    Journal Ieee Transactions on Bio-medical Engineering
    Excerpt

    Magnetoacoustic tomography with magnetic induction (MAT-MI) is a technique for imaging electrical conductivity in tissue. A time-varying magnetic field induces currents that interact with a static magnetic field to produce a Lorentz force, initiating ultrasonic waves. The goal of this communication is to examine the effect of anisotropy during MAT-MI.

    Title The Potential Induced in Anisotropic Tissue by the Ultrasonically-induced Lorentz Force.
    Date June 2008
    Journal Medical & Biological Engineering & Computing
    Excerpt

    In the presence of a magnetic field, an ultrasonic wave propagating through tissue will induce Lorentz forces on the ions, resulting in an electrical current. If the electrical conductivity is anisotropic, this current is tilted toward the fiber direction, causing charge to accumulate between half-wavelengths: positive charge where the current vectors converge and negative where the current vectors diverge. This charge produces an electric field in the direction of propagation that is associated with an electrical potential, and this electric field causes an additional current that is also tilted by the anisotropy. The final result is the total current pointing perpendicular to the direction of propagation and a charging of the tissue every half wavelength. The potential has a greater magnitude than that obtained from colloidal suspensions or ionic solutions (ultrasonic vibration potentials) and may be used as the basis of a technique to image conductivity.

    Title Back to the Future: Using Inhalers Correctly.
    Date May 2008
    Journal Respiratory Care
    Title How to Explain Why "unequal Anisotropy Ratios" is Important Using Pictures but No Mathematics.
    Date March 2008
    Journal Conference Proceedings : ... Annual International Conference of the Ieee Engineering in Medicine and Biology Society. Ieee Engineering in Medicine and Biology Society. Conference
    Excerpt

    "Unequal anisotropy ratios" is an important property of cardiac tissue. Many of the fundamental mechanisms governing how the heart responds to an electrical shock require unequal anisotropy ratios. In this paper, I explain the role of unequal anisotropy ratios using pictures rather than mathematics. My goal is to develop physical insight, so has to understand qualitatively why the condition of unequal anisotropy ratios is so important.

    Title Training Physicians for Combat Casualty Care on the Modern Battlefield.
    Date September 2007
    Journal Journal of Surgical Education
    Excerpt

    INTRODUCTION: Trauma training among nonsurgical physicians in the military is highly variable in amount and quality. However, all deployed military physicians, regardless of specialty, are expected to provide combat casualty care. The goal was to assess the effectiveness of an intense modular trauma refresher course for nonsurgical physicians deploying to a combat zone. METHODS: All graduating nonsurgical residents participated in this 2.5-day course, consisting of 4 modules: (1) didactic session; (2) simulation with interactive human surgical simulators; (3) case presentations and triage scenarios from Iraq/Afghanistan with associated skill stations; and (4) live tissue surgical procedure laboratory. Competency tests, surveys, and after action comments were reviewed and compared before and after course completion. RESULTS: Between May 2005 and April 2007, 60 physicians participated in the course. By specialties, there were 32 internists, 16 pediatricians, 7 general practitioners, 4 obstetricians/gynecologists, and 1 "other" nonsurgical physician represented. Precourse and postcourse tests were administered to 31 of 60 participants. The mean test scores improved from 76% to 96% upon completion of the course (p < 0.01). Additionally, self-perceived confidence levels in handling battlefield casualties from questionnaires based on Likert scale responses (1 = not confident, 5 = confident) improved from an average of 2.3 before the course to 3.9 upon completion of the course (p < 0.01). CONCLUSION: All military physicians must be prepared to manage combat casualties. This hybrid training model may be an effective method to prepare nonsurgeons to deal with battle injuries. This course significantly improved the knowledge and confidence among primary care physicians.

    Title Phase 2 Trial of Epothilone B Analog Bms-247550 (ixabepilone) in Advanced Carcinoma of the Urothelium (e3800): a Trial of the Eastern Cooperative Oncology Group.
    Date September 2007
    Journal Cancer
    Excerpt

    BACKGROUND: Paclitaxel and docetaxel are active agents in advanced urothelial cancer. BMS-247550 (ixabepilone) has activity in preclinical models in paclitaxel resistant models. A phase 2 trial of this epothilone was performed to determine the activity and toxicity of this agent in a multi-institutional setting in patients previously treated with 1 prior chemotherapy regimen. METHODS: Forty-five patients with advanced urothelial carcinoma were treated with BMS-247550 40 mg/m(2) over 3 hours intravenously on Day 1 of a 21-day cycle and continued therapy until progression or unacceptable toxicity. RESULTS: Five patients obtained an objective partial response (PR) among the 42 eligible patients for an overall response rate of 11.9% (90% confidence interval [5.3%, 26.5%]). Median overall survival of the group was 8 months. Toxicity was moderate with granulocytopenia, fatigue, and sensory neuropathy being the most common side effects noted. CONCLUSIONS: BMS-247550 (ixabepilone) has very modest activity as a second-line therapy for advanced urothelial cancer. Responses in visceral, nodal, and soft tissues sites were observed. Granulocytopenia without fever, fatigue, and sensory neuropathy was common.

    Title Churg-strauss Syndrome and Pregnancy: Successful Treatment with Intravenous Immunoglobulin.
    Date July 2007
    Journal Journal of Clinical Rheumatology : Practical Reports on Rheumatic & Musculoskeletal Diseases
    Excerpt

    Churg-Strauss syndrome is an extremely rare disease, and even less common in women of childbearing age. The initial management of Churg-Strauss syndrome consists of high doses of corticosteroids. Patients with severe disease, or those who are unresponsive to corticosteroids, usually are treated with cytotoxic drugs. Intravenous immunoglobulin (IVIg) has become a promising, but not completely accepted, form of treatment for systemic vasculitis that is unresponsive to standard therapy. We present a case of a woman diagnosed with Churg-Strauss syndrome that was refractory to corticosteroid and cyclophosphamide treatment. When she was found to be 3 months pregnant, treatment with IVIg was instituted with successful results. This case not only supports the beneficial effect of IVIg in Churg-Strauss syndrome, it illustrates its successful use in a patient who was pregnant.

    Title Forward Euler Stability of the Bidomain Model of Cardiac Tissue.
    Date June 2007
    Journal Ieee Transactions on Bio-medical Engineering
    Excerpt

    The bidomain model describes the anisotropic electrical properties of cardiac tissue. One common numerical technique for solving the bidomain equations is the explicit forward Euler method. In this communication we derive a relationship between the time and space steps that ensures the stability of this numerical method.

    Title Simulations of Optical Mapping During Electroporation.
    Date June 2007
    Journal Conference Proceedings : ... Annual International Conference of the Ieee Engineering in Medicine and Biology Society. Ieee Engineering in Medicine and Biology Society. Conference
    Excerpt

    Experiments using optical mapping suggest that electroporation occurs in cardiac tissue when the transmembrane potential, Vm, is observed to be significantly less than +/- 400 mV. Our hypothesis, which we test by numerical simulation, is that Vm is greater than +/- 400 mV at the tissue surface, but optical mapping underestimates Vm because it averages over depth. Results indicate a significant underestimation of Vm. Experimental studies indicate a depolarization of the resting transmembrane potential, Vrest, after a strong shock. In a homogeneous model, electroporation only occurs near the tissue surface. Just as Vm during the stimulus is underestimated due to averaging, we hypothesize that the depolarization of Vrest is also underestimated.

    Title Adjuvant Weekly Docetaxel for Patients with High Risk Prostate Cancer After Radical Prostatectomy: a Multi-institutional Pilot Study.
    Date May 2007
    Journal The Journal of Urology
    Excerpt

    PURPOSE: Patients with adverse pathological features are at high risk for recurrence following radical prostatectomy. To improve outcomes in this population we performed a phase II study of adjuvant docetaxel in these high risk patients. MATERIALS AND METHODS: Patients with nonmetastatic radical prostatectomy at greater than 50% risk for recurrence by 3 years were eligible. Pathological findings were centrally reviewed and risk assessment was based on a validated multivariate Cox proportional hazards model. Treatment consisted of 6 cycles of 35 mg/m(2) docetaxel weekly given 4 to 12 weeks following surgery. Progression was defined as a prostate specific antigen of 0.4 ng/ml or greater, radiological/pathological evidence of recurrent disease or death from any cause. To screen for the potential benefit of adjuvant weekly docetaxel we used nomogram predicted progression-free survival as a historical control. RESULTS: A total of 77 patients were registered between April 2002 and January 2004. Two patients had grade IV hyperglycemia and 20 had grade III toxicity. At a median followup of 29.2 months (range 1.6 to 39.2) 46 of 76 evaluable cases (60.5%) progressed. Observed median progression-free survival was 15.7 months (95% CI 12.8-25.1). Predicted median progression-free survival in a matched population was 10 months. Seven patients died, including 4 of prostate cancer, 1 with intra-abdominal bleeding during treatment and 2 of pneumonia and sudden cardiac death, respectively, following treatment. CONCLUSIONS: Adjuvant docetaxel for prostate cancer is feasible with significant reversible but acceptable toxicity. The actual median progression-free survival of 15.7 months was longer than the nomogram predicted rate for this patient population. Adjuvant docetaxel treatment should be further evaluated in phase III trials in patients with high risk prostate cancer.

    Title Omeprazole-associated Digoxin Toxicity.
    Date May 2007
    Journal Southern Medical Journal
    Excerpt

    Omeprazole is a commonly prescribed inhibitor of the gastric proton pump and has numerous indications in the treatment of gastrointestinal diseases. It is primarily metabolized through the CYP2C19 enzyme, a member of the P450 mixed-function oxidase group, although a minor pathway of metabolism is through CYP3A4, another P450 enzyme. Digoxin is primarily metabolized outside the P450 system, but a minor pathway of metabolism is by CYP3A4. To our knowledge, this is the first known case of digoxin toxicity associated with omeprazole. The possible pathways for such an interaction are reviewed, including increased stomach absorption, p-glycoprotein activity and interactions in the P450 system.

    Title Electrostriction of Anisotropic Tissue.
    Date April 2007
    Journal Physical Review. E, Statistical, Nonlinear, and Soft Matter Physics
    Excerpt

    The electrostrictive effects in anisotropic tissue, such as muscle, are interesting and qualitatively different than in an isotropic material. A striking feature in anisotropic tissue is the presence of a charge distribution, which is absent in isotropic tissue. This charge interacts with the electric field to give rise to body forces that deform the tissue. We develop an electromechanical model to investigate how anisotropic tissue deforms due to an electric field, and find analytical solutions for the pressure and displacement. The distribution of the pressure and displacement are complex and dependent on the boundary conditions. The effects of electrostriction are small, but comparable in size to pressures and displacements in other imaging modalities that utilize similar mechanical effects.

    Title Management of Recurrent Testicular Germ Cell Tumors.
    Date March 2007
    Journal The Oncologist
    Excerpt

    Although front-line chemotherapy cures most men with testicular germ cell tumors, salvage therapy is still important in a small but significant minority. Second-line conventional-dose or high-dose chemotherapy with stem cell rescue may cure 25%-50% of patients. New chemotherapeutic agents, including the taxanes gemcitabine and oxaliplatin, have added to the therapeutic armamentarium. Salvage surgical resection has an important role in selected patients. Cisplatin-refractory patients have a poor prognosis with current therapy, and novel chemotherapeutic and biologic agents need to be discovered for such patients.

    Title Quatrefoil Reentry Caused by Burst Pacing.
    Date February 2007
    Journal Journal of Cardiovascular Electrophysiology
    Excerpt

    BACKGROUND: Experiments and clinical studies have shown that high-frequency (burst) pacing can induce reentry and fibrillation without a strong shock. We hypothesize that a train of weak stimuli induces quatrefoil reentry, and investigate the mechanism and threshold for this mode of reentry induction. METHODS: We apply a train of weak stimuli at different pacing rates to determine the threshold necessary to induce quatrefoil reentry. Numerical calculations are used to simulate cardiac tissue, based on the bidomain model with unequal anisotropy ratios. We consider both anodal and cathodal stimuli. RESULTS: Quatrefoil reentry is initiated using much smaller currents during burst pacing (0.9 mA) compared to a single premature pulse (8.6 mA). As we varied the pacing rate, we observed reentry at the border between different modes of phase locking, such as between 1:1 and 2:1 responses. CONCLUSION: Burst pacing can significantly reduce the threshold for reentry. However, the extreme sensitivity of reentry induction to the exact number of stimuli in the pulse train makes the method difficult to use as a consistent, reproducible way to induce reentry.

    Title Sperm Banking: Use and Outcomes in Patients Treated for Testicular Cancer.
    Date February 2007
    Journal Bju International
    Excerpt

    OBJECTIVE: To identify the frequency that sperm banking was used by men being treated for testicular cancer at our institution, and to characterize the differences between men choosing to bank sperm or not, and outcomes in terms of after-treatment pregnancies. PATIENTS AND METHODS: A questionnaire addressing sperm banking and fertility was administered to men treated for testicular cancer at our institution between 1994 and 2004; the results were evaluated statistically. RESULTS: Overall, 31 of 129 (24%) respondents had banked sperm. Of these, two had used their banked sperm to father a child, and 12 had had children naturally. Men who banked sperm were a mean of 10.3 years younger (P < 0.001) and less likely to have children at the time of diagnosis (P < 0.025) than men choosing not to bank sperm. The cost of banking sperm was reported to include a mean fee of US dollars 358 (median 300, range 0-1000), and a mean annual maintenance fee of US dollars 243.86 (median 300, range 0-1200). CONCLUSIONS: Only a minority of men in this study chose to bank sperm (24%). Among those who did, the use of banked sperm was low (<10%), and many men could have children without using banked sperm. Given the relatively high costs of sperm banking and the low rate of sample use, patients should be counselled on the costs and benefits of sperm banking before treatment for testicular cancer.

    Title Virtual Electrode Effects Around an Artificial Heterogeneity During Field Stimulation of Cardiac Tissue.
    Date October 2006
    Journal Heart Rhythm : the Official Journal of the Heart Rhythm Society
    Title The Effect of the Fiber Curvature Gradient on Break Excitation in Cardiac Tissue.
    Date October 2006
    Journal Pacing and Clinical Electrophysiology : Pace
    Excerpt

    BACKGROUND: Break excitation has been hypothesized as a mechanism for the initiation of reentry in cardiac tissue. One way break excitation can occur is by virtual electrodes formed due to a curving fiber geometry. In this article, we are concerned with the relationship between the peak gradient of fiber curvature and the threshold for break stimulation and the initiation of reentry. METHODS: We calculate the maximum gradient of fiber curvature for different scales of fiber geometry in a constant tissue size (20x20 mm), and also examine the mechanisms by which reentry initiation fails. RESULTS: For small peak gradients, reentry fails because break excitation does not occur. For larger peak gradients, reentry fails because break excitation fails to develop into full-scale reentry. For strong stimuli above the upper limit of vulnerability, reentry fails because the break excitation propagates through the hyperpolarized region and then encounters refractory tissue, causing the wave front to die.

    Title Phase Ii Study of Pemetrexed for Second-line Treatment of Transitional Cell Cancer of the Urothelium.
    Date August 2006
    Journal Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
    Excerpt

    PURPOSE: To assess the antitumor activity and toxicity of pemetrexed as second-line chemotherapy in patients with locally advanced or metastatic transitional cell carcinoma (TCC) of the urothelium. PATIENTS AND METHODS: Eligible patients had a performance status of 0 or 1, adequate organ function, previous treatment with one prior chemotherapy regimen for locally advanced or metastatic TCC of the urothelium or relapsed within 1 year of adjuvant or neoadjuvant treatment. Patients received pemetrexed 500 mg/m2 intravenously on day 1 every 21 days, with vitamin B12, folic acid, and dexamethasone prophylaxis. RESULTS: Forty-seven patients were enrolled and included in the intent-to-treat efficacy analysis. Responses: 3 (6.4%) complete responses and 10 (21.3%) partial responses produced an overall response rate of 27.7%. Ten patients (21.3%) had stable disease and 22 patients (46.8%) progressed. The median time to progressive disease was 2.9 months (95% CI, 1.7 months to 4.6 months) and median overall survival was 9.6 months (95% CI, 5.1 months to 14.6 months). Median duration of response was 5.0 months (95% CI, 3.9 months to 13.8 months). Of the 47 patients assessable for safety, grade 3 or 4 hematologic events were thrombocytopenia (8.5%; 0.0%), neutropenia (4.3%; 4.3%) and anemia (2.1%; 2.1%), respectively. Nonlaboratory toxicities included grade 4 stomatitis/pharyngitis, sepsis syndrome (one patient each), and grade 3 fatigue (three patients) and diarrhea (two patients). CONCLUSION: Single-agent pemetrexed is safe and active as second-line treatment of patients with advanced TCC of the urothelium. Additional evaluation in the first- or second-line setting in TCC of the urothelium is warranted.

    Title Changing Perspectives of the Role of Chemotherapy in Advanced Prostate Cancer.
    Date July 2006
    Journal The Urologic Clinics of North America
    Excerpt

    The use of cytotoxic chemotherapy in advanced prostate adenocarcinoma has been validated by the recent demonstration of survival benefit in two large randomized phase III trials. Before publication of these landmark trials, SWOG 9916 and TAX 327, no chemotherapeutic regimen had shown survival benefit in the treatment of androgen independent prostate cancer (AIPC). These trials provide new encouragement for the use of chemotherapy in all stages of disease. Improved communication between medical and urologic oncologists and early patient referral for clinical trial participation remains essential for identifying new chemotherapeutic regimens with improved activity in AIPC and for defining the role of chemotherapy in earlier-stage disease. This article discusses the role of chemotherapy as the current standard of care for the treatment of AIPC and provides a historical perspective of the trials that preceded the development of current docetaxel-based regimens.

    Title The Effect of the Cut Surface During Electrical Stimulation of a Cardiac Wedge Preparation.
    Date July 2006
    Journal Ieee Transactions on Bio-medical Engineering
    Excerpt

    Optical mapping from the cut surface of a "wedge preparation" allows observation inside the heart wall, below the epicardium or endocardium. We use numerical simulations based on the bidomain model to illustrate how the transmembrane potential is influenced by the cut surface. The distribution of transmembrane potential around a unipolar cathode depends on the fiber angle. For intermediate angles, hyperpolarization appears on only one side of the electrode, and is large and widespread.

    Title Approximate Solution to the Bidomain Equations for Electrocardiogram Problems.
    Date March 2006
    Journal Physical Review. E, Statistical, Nonlinear, and Soft Matter Physics
    Excerpt

    Simulating the electrocardiogram requires specifying the transmembrane potential distribution within the heart and calculating the potential on the surface of the body. Often, such calculations are based on the bidomain model of cardiac tissue. A subtle but fundamental problem arises when considering the boundary between the cardiac tissue and the surrounding volume conductor. In general, one finds that two potentials--the extracellular potential in the tissue and the potential in the surrounding bath--obey three boundary conditions, implying that the potentials are overdetermined. In this paper, we derive a general method for handling bidomain boundary conditions that eliminates this problem. The gist of the method is that we add an additional term to the transmembrane potential that falls exponentially with depth into the tissue. The purpose of this term is to satisfy the third boundary condition. Then, we take the limit as the length constant associated with this extra term goes to zero. Our result is two boundary conditions that approximately account for the full set of three boundary conditions at the tissue surface.

    Title Automating Phase Singularity Localization in Mathematical Models of Cardiac Tissue Dynamics.
    Date February 2006
    Journal Mathematical Medicine and Biology : a Journal of the Ima
    Excerpt

    Electrical wave-fronts are responsible for contraction in heart tissue. Rotary wave-fronts break up into daughter waves and it is this break up that is believed to underlie ventricular fibrillation. Mathematical methods abound for simulation of fibrillation, and localizing the core of rotary wave-fronts (the phase singularities) is key to characterizing the state of fibrillation and effectiveness of defibrillation in these models. We present a formal method for automating this process in these various models. Automation will allow for side-by-side comparisons of suggested mechanisms of fibrillation, comparison of various models of these mechanisms and faster evaluation of defibrillation strategies making use of these models.

    Title Michael Faraday and Painless Defibrillation.
    Date February 2006
    Journal Heart Rhythm : the Official Journal of the Heart Rhythm Society
    Title The Puzzle of Defibrillation: Putting the Pieces Together.
    Date January 2006
    Journal Journal of Cardiovascular Electrophysiology
    Title Performance-enhancing Supplement Use in Patients with Testicular Cancer.
    Date November 2005
    Journal Urology
    Excerpt

    OBJECTIVES: To identify supplement use among patients diagnosed with testicular cancer. The incidence of testicular cancer has increased, as has supplement use, including those designed specifically for exercise performance enhancement. METHODS: A questionnaire was administered to patients with testicular germ cell cancer treated at our institution between 1990 and 2004. This survey addressed the use of supplements before, during, and after the diagnosis of cancer. RESULTS: Of the 129 patients who completed the questionnaire, 26 (20.1%) used some form of supplements, most of which were ingested for exercise performance enhancement. The most common supplement taken was protein/amino acids (12.4%) followed by creatine (9.3%) and androstenedione (1.6%). The mean duration of supplement use was 17.0 months. The mean age of the patients who had used supplements was 27.6 years (median 26, range 17 to 47) compared with 35.7 years (median 34, range 14 to 76) for patients who had not used supplements. Of the 57 patients diagnosed before 2000, 9 (16%) reported supplement use and 3 (5%) reported creatine use. Of the 72 patients diagnosed during or after 2000, 17 (24%) reported supplement use and 9 (13%) reported creatine use. CONCLUSIONS: Supplement use is common and increasing among patients with testicular cancer. The use of exercise performance-enhancing supplements was as great as 20%. Given the increasing incidence of testicular cancer, coupled with the widespread use of these performance-enhancing supplements in this at-risk group, additional study is required to determine what association, if any, exists between the use of these substances and the development of testicular cancer.

    Title Instruction of Hospitalized Patients by Respiratory Therapists on Metered-dose Inhaler Use Leads to Decrease in Patient Errors.
    Date November 2005
    Journal Respiratory Care
    Excerpt

    BACKGROUND: Hospitalized patients have been shown to make several errors in using metered-dose inhalers (MDIs), which can lead to poor medication delivery. METHODS: This study was designed to look at the potential benefit of a respiratory therapist (RT) giving instruction on the use of MDIs to hospitalized patients with obstructive lung disease. A baseline group of 58 patients was observed by a physician while performing 2 actuations of their MDI and the number of errors they committed, based on the National Institutes of Health's recommended 8 steps for proper MDI use, was recorded. After a program of MDI instruction (which included encouragement to use a spacer) by an RT was performed, a second group of hospitalized patients was again observed by a physician to determine if their error rate was reduced. RESULTS: The baseline error rate was 6.72 (out of 15 possible) errors per patient, and improved to 2.43 errors per patient after RT-provided instruction (p < 0.001). This improvement was still significant after controlling for an increased use of spacers in the post-instruction group of patients (27.6% and 91.7% spacer use before and after education). CONCLUSIONS: Instruction of hospitalized patients with obstructive lung disease by an RT improves their correct use of MDIs and increases their use of spacers while in the hospital.

    Title How the Spatial Frequency of Polarization Influences the Induction of Reentry in Cardiac Tissue.
    Date October 2005
    Journal Journal of Cardiovascular Electrophysiology
    Excerpt

    Influences of spatial frequency of polarization. INTRODUCTION: The mechanism by which an electric field induces a rotor during cross-field stimulation of cardiac tissue is not entirely known. Different heterogeneous aspects of cardiac tissue have been offered as possible theories, a prominent one being fiber curvature. The polarization produced when an electric field is applied to a sheet of tissue is varied over many spatial frequencies, depending upon the fiber angle. This article compares the effect of high and low spatial frequencies of polarization on reentry induction. METHODS AND RESULTS: We incorporate a randomized fiber angle geometry into a two-dimensional active cardiac tissue model with unequal anisotropy ratios already exhibiting smooth, curving fibers. We simulate cross-field stimulation to initiate reentry in the tissue model, and compare the electric field thresholds at different S1-S2 intervals for tissue with randomized fiber angles, tissue with a smooth fiber geometry, and tissue with randomized fiber angles plus smooth, curving fibers. The tissue with both small, random fiber angles and curving fibers has a significantly lower threshold for reentry at certain intervals on the strength-interval curve than for the two cases individually. CONCLUSION: Cardiac tissue exhibiting a random fiber geometry in conjunction with a smooth fiber geometry includes high and low spatial frequencies of polarization that may have an effect on the mechanism for reentry at certain S1-S2 intervals. Low spatial frequency regions of hyperpolarization carve out excitable pathways, and high spatial frequency regions provide the large gradient of transmembrane potential required to initiate break excitation.

    Title Optical Measurements Reveal Nature of Intercellular Coupling Across Ventricular Wall.
    Date October 2005
    Journal American Journal of Physiology. Heart and Circulatory Physiology
    Excerpt

    Previously, we showed that intercellular uncoupling through gap junctions is an important mechanism for maintaining transmural heterogeneities of repolarization that are responsible for ventricular arrhythmias in disease states such as heart failure. However, rotational anisotropy between transmural muscle layers also may influence coupling. To determine the effect of rotational anisotropy on transmural coupling, we developed a numerical three-dimensional model of passive cardiac tissue in which rotational anisotropy was varied in a controlled fashion. Simulations of optical mapping demonstrated that spatial averaging produced a voltage decay in space best fit by a single decaying exponential compared with the theoretically predicted decay. As fiber orientation varied by 90 degrees with respect to the transmural surface, the effective transmural space constant (lambda(TM)) changed by only 0.31% in simulations. In contrast, reducing intercellular conductivity by 24% decreased lambda(TM) by 7.7%. In the canine wedge preparation (n = 5), lambda measured by optical mapping of the epicardial and subepicardial surface was similar transverse (lambda(TV) = 0.73 +/- 0.10 mm) and transmural (lambda(TM) = 0.70 +/- 0.08 mm) to subepicardial fibers. We confirmed previous findings that lambda(TM) in subepicardial layers was significantly reduced by 14 +/- 2% compared with deeper layers of myocardium, providing evidence for transmural uncoupling in the epicardial-midmyocardial interface. These data establish the theoretical and experimental basis for measuring intercellular coupling between muscle layers spanning the ventricular wall with optical mapping techniques. Furthermore, this study demonstrates that transmural uncoupling at the epicardial-midmyocardial interface may be attributable to heterogeneous expression of cardiac gap junctions and not rotational anisotropy.

    Title Effect of Plunge Electrodes in Active Cardiac Tissue with Curving Fibers.
    Date July 2005
    Journal Heart Rhythm : the Official Journal of the Heart Rhythm Society
    Excerpt

    OBJECTIVES: Our goal is to determine if plunge electrodes change how the heart responds to electrical stimulation. BACKGROUND: Several experiments designed to study the induction of a rotor in cardiac tissue have used plunge electrodes to measure the transmural potential. It is our hypothesis that these electrodes may have affected the electrical response of the tissue to a shock. METHODS: We previously have shown that a single plunge electrode in two-dimensional, passive cardiac tissue induces a significant transmembrane potential when stimulated by a large shock. In this study, we expand our simulation to include an array of nine electrodes in active tissue with curving fibers. We compare the thresholds for rotor induction in tissue with and without electrodes by initiating a planar S1 wavefront and then stimulating the tissue at different intervals with a uniform S2 electric field perpendicular to S1. In tissue without plunge electrodes, virtual electrode polarization due to the curving fibers is generally widespread over the entire tissue, whereas polarization tends to be localized around the electrodes in tissue including them. RESULTS: Our results show that at some S1-S2 intervals, the presence of plunge electrodes can result in reentry when it otherwise would not be possible. For other S1-S2 intervals, such as during the vulnerable period when the reentry threshold is at a minimum, the induction of reentry is unaffected by the presence of plunge electrodes. CONCLUSIONS: Plunge electrodes can play an important role during the stimulation of cardiac tissue, but this is highly dependent on the chosen S1-S2 interval.

    Title Prostate Cancer Chemotherapy: Emerging from the Shadows.
    Date June 2005
    Journal Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
    Title Approximate Solution to the Bidomain Equations for Defibrillation Problems.
    Date May 2005
    Journal Physical Review. E, Statistical, Nonlinear, and Soft Matter Physics
    Excerpt

    The bidomain model can be used for calculating the electrical potential in the heart during defibrillation. However, this model consists of a coupled system of two partial differential equations that are, in general, difficult and time consuming to solve. In this paper, we present an approximate, iterative method of solving the bidomain equations. After working out the general method, we apply it to four problems: (i) a cylindrical strand in a uniform electric field, (ii) a nonuniform electric field applied to tissue with straight fibers, (iii) a spherical heart in a uniform electric field, and (iv) a two-dimensional sheet of cardiac tissue with curving fibers. Finally, we analyze the general case of three dimensions.

    Title Cardiac Optical Mapping Under a Translucent Stimulation Electrode.
    Date February 2005
    Journal Annals of Biomedical Engineering
    Excerpt

    Major effects of stimulation on cardiac transmembrane potentials (Vm) are thought to occur under the electrode, however these have not been optically mapped due to blockage of light by electrodes. Here we optically mapped under translucent indium tin oxide (ITO) electrodes in hearts stained with transmembrane voltage sensitive fluorescent dye, di-4-ANEPPS excited at 488 nm. Emissions in wavelength bands 510-570 nm and >590 nm were similarly affected by changes in ITO transmittance due to electrochemical effects of current at the electrode interface. Dual-wavelength ratiometric mapping with the two emission bands revealed Vm under the electrode during plateau-phase stimulation (220 mA). Changes in Vm were heterogeneous under the electrode, and were anisotropic with larger values along the fiber axis. These results explain early excitation sites for sufficiently strong diastolic stimulation, and agree with theoretical predictions based on summation of anisotropic effects of point stimulation and a linear 3-d cardiac bidomain computer model. The bidomain model and experiments disagree under the edge of the electrode, where modeled Vm is much larger. Thus, changes in Vm under an electrode are anisotropic with greater Vm in the direction parallel to fibers. Nonlinear effects of stimulation in hearts may limit changes in Vm under the electrode edge.

    Title A Mathematical Model for Electrical Stimulation of a Monolayer of Cardiac Cells.
    Date December 2004
    Journal Biomedical Engineering Online
    Excerpt

    BACKGROUND: The goal of our study is to examine the effect of stimulating a two-dimensional sheet of myocardial cells. We assume that the stimulating electrode is located in a bath perfusing the tissue. METHODS: An equation governing the transmembrane potential, based on the continuity equation and Ohm's law, is solved numerically using a finite difference technique. RESULTS: The sheet is depolarized under the stimulating electrode and is hyperpolarized on each side of the electrode along the fiber axis. CONCLUSIONS: The results are similar to those obtained previously by Sepulveda et al. (Biophys J, 55: 987-999, 1989) for stimulation of a two-dimensional sheet of tissue with no perfusing bath present.

    Title Art Winfree and the Bidomain Model of Cardiac Tissue.
    Date November 2004
    Journal Journal of Theoretical Biology
    Excerpt

    This paper reviews Art Winfree's contributions to the bidomain model of cardiac tissue. Specifically, he first predicted quatrefoil reentry, he showed that an S1 refractory gradient is not required for an S2 stimulus to induce reentry, and his work on spiral wave meandering led to studies on how the path of the tip of a spiral wave is influenced by tissue anisotropy.

    Title A Phase I Dose-escalation and Pharmacokinetic Study of Brostallicin (pnu-166196a), a Novel Dna Minor Groove Binder, in Adult Patients with Advanced Solid Tumors.
    Date October 2004
    Journal Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
    Excerpt

    PURPOSE: This study was performed to determine the maximum tolerated dose, dose-limiting toxicities, and pharmacokinetics of brostallicin, a nonalkylating DNA minor groove binder and a synthetic derivative of distamycin A, given as a weekly i.v. infusion. EXPERIMENTAL DESIGN: Using an accelerated dose escalation design, patients with advanced solid tumor malignancies were treated with brostallicin administered as a 10-min i.v. infusion on days 1, 8, and 15 of a 28-day cycle. The starting dose of brostallicin was 0.3 mg/m(2)/week. To study the pharmacokinetic behavior of brostallicin, serial blood samples were obtained before and after the first and last infusions during cycle 1, and in cycles 2 and 4 in a limited number of patients. RESULTS: Fourteen patients received 32 complete cycles of brostallicin. Dose-limiting toxicity was febrile neutropenia and was observed in 3 of 5 patients treated at 4.8 mg/m(2)/week. The maximum tolerated dose and recommended Phase II dose was 2.4 mg/m(2)/week. The mean +/- SD terminal half-life at the maximum tolerated dose was 4.6 +/- 4.1 h. There was moderate distribution of brostallicin into tissues, and the clearance was approximately 20% of the hepatic blood flow. The area under the concentration time curve(0- infinity ) of brostallicin increased in a dose-linear fashion. No significant relationship was observed between any plasma pharmacokinetic parameter and clinical toxicities. There were no objective responses during the trial, but 5 patients had stable disease after two cycles of treatment. CONCLUSIONS: The dose-limiting toxicity of weekly brostallicin was neutropenia. Systemic exposure increases linearly with dose. The recommended dose for Phase II studies is 2.4 mg/m(2) on days 1, 8, and 15 of a 28-day cycle.

    Title Topotecan-induced Bronchiolitis.
    Date August 2004
    Journal Southern Medical Journal
    Excerpt

    Topotecan HCl is an antitumor drug exhibiting topoisomerase 1-inhibitory activity. Topotecan is used in the treatment of metastatic carcinoma of the ovary and as second-line treatment of small-cell lung cancer. Reported dose-limiting adverse reactions to topotecan are primarily hematologic in nature. To date, only one other case of lung toxicity in a patient taking topotecan has been reported. The authors describe the development of obliterative bronchiolitis, as evidenced by radiographic and pulmonary function testing abnormalities, in a 61-year-old woman who presented with dyspnea, and who was receiving topotecan for peritoneal carcinomatosis.

    Title Phase Iii Trial of Methotrexate, Vinblastine, Doxorubicin, and Cisplatin Versus Carboplatin and Paclitaxel in Patients with Advanced Carcinoma of the Urothelium.
    Date May 2004
    Journal Cancer
    Excerpt

    BACKGROUND: The regimens of carboplatin plus paclitaxel (CP) and methotrexate, vinblastine, doxorubicin, and cisplatin (M-VAC) were compared in patients with advanced urothelial carcinoma. METHODS: Patients with metastatic urothelial carcinoma were randomized to receive either CP (paclitaxel at a dose of 225 mg/m(2) and carboplatin [targeted area under the concentration-time curve (AUC) of 6] given every 21 days) or the standard M-VAC dosage. RESULTS: Eighty-five patients were randomized to the respective treatment regimens (41 to CP and 44 to M-VAC). Response rates and overall survival were similar for both treatment arms. Patients treated with CP had an overall response rate of 28.2% (95% binomial confidence interval, 15.0-44.9%) compared with an overall response rate of 35.9% for the M-VAC arm (95% binomial confidence interval, 21.2-52.8%) (P = 0.63, Fisher exact test). The median progression-free survival among patients who were treated with M-VAC was 8.7 months and was 5.2 months for patients receiving CP (P = 0.24, log-rank test). At a median follow-up of 32.5 months, the median survival for patients treated with M-VAC was 15.4 months versus 13.8 months for patients treated with CP (P = 0.65, log-rank test). Patients treated with M-VAC were found to have more severe worst-degree toxicities compared with patients treated with CP (P = 0.0001). There were no significant differences with regard to quality of life as assessed by the Functional Assessment of Cancer Therapy-Bladder (FACT-BL) instrument (P = 0.33). CONCLUSIONS: Interpretation of the results of this study must be made with caution because the study failed to reach its accrual goal. Patients treated with CP had a median survival of 13.8 months compared with 15.4 months for patients treated with M-VAC. Patients treated with CP appeared in general to better tolerate their treatment; however, there were no significant differences noted with regard to measured quality of life parameters.

    Title Effects of Elevated Extracellular Potassium Ion Concentration on Anodal Excitation of Cardiac Tissue.
    Date March 2004
    Journal Journal of Cardiovascular Electrophysiology
    Excerpt

    INTRODUCTION: Anodal excitation of cardiac tissue occurs by two mechanisms: "make" and "break." Anodal strength-interval curves are divided into two sections, with break excitation occurring at short intervals and make at long intervals. Our goal is to determine how an elevated extracellular potassium ion concentration, [K]o, affects the mechanism of anodal excitation and influences the anodal strength-interval curve. METHODS AND RESULTS: Computer simulations of unipolar stimulation were performed using the bidomain model, with membrane kinetics governed by the Luo-Rudy model. The diastolic threshold for anodal stimulation first decreased and then increased with increasing [K]o, reaching a minimum value at [K]o = 12 mM. The mechanism for diastolic anodal excitation was make for all [K]o values except 13.3 mM, in which case it was break. For low [K]o (4 and 8 mM) the break section of the anodal strength-interval contained a "dip," but for high [K]o (12 and 13 mM), the dip disappeared. CONCLUSION: High [K]o predisposes cardiac tissue to break excitation, which is thought to play an important role in reentry induction and defibrillation. Because fibrillation raises extracellular [K]o levels, break excitation may play a more important role in defibrillation than is suggested by simulations and experiments using normal [K]o values.

    Title Approximate Analytical Solutions of the Bidomain Equations for Electrical Stimulation of Cardiac Tissue with Curving Fibers.
    Date January 2004
    Journal Physical Review. E, Statistical, Nonlinear, and Soft Matter Physics
    Excerpt

    The mechanism by which an applied electric field stimulates cardiac tissue far from the stimulating electrodes is not wholly understood. One possible mechanism relates the curving cardiac fibers to the induced membrane currents and transmembrane potentials. However, we lack a qualitative understanding of where these areas of polarization will occur when an electric field is applied to a sheet of cardiac tissue with curving fibers. In our study, we derive an analytical model for the transmembrane potential, dependent on the gradient of the fiber angle theta, for a two-dimensional passive sheet of cardiac tissue exhibiting various fiber geometries. Unequal anisotropy ratios are crucial for our results. We compare the results from our analytical solution to a numerical calculation using the full bidomain model. The results of our comparison are qualitatively consistent, albeit numerically different. We believe that our analytical approximation provides a reliable prediction of the polarization associated with an electric field applied to cardiac tissue with any fiber geometry and a qualitative understanding of the mechanisms behind the virtual electrode polarization.

    Title Cadaveric Organ Donor Recruitment at Los Angeles County Hospital: Improvement After Formation of a Structured Clinical, Educational and Administrative Service.
    Date January 2004
    Journal Clinical Transplantation
    Excerpt

    BACKGROUND/AIMS: There remains a critical shortage of cadaveric organs. At a large inner city level one trauma centre, several strategies were devised and combined to (a). optimize the physiologic status of potential donors, (b). promote awareness of the donation process among health care professionals and (c). perform quality control on the organ donation system - all in an effort to improve organ donation rates. Resuscitative and maintenance protocols were devised and implemented through a multidisciplinary team approach for patients diagnosed with brain death. We report the effect this approach has had on organ donation in a single centre. METHOD: A death record review (DRR) by the local organ procurement agency (OPO) was used to identify the number of patients diagnosed with brain death at Los Angeles County Hospital each year from 1995 through 2001. Data were collected to determine the number of these potential donors that eventually underwent organ donation. Data were collected for two time intervals: Phase I (1995-98) and Phase II (1999-2001). During Phase I, there was no focused institutional programme for the approach to potential donors. During Phase II, an institutional programme including the following characteristics was implemented: 1). donor resuscitation protocol, 2). assignment of a dedicated OPO coordinator liaison to interact with families, hospital personnel and the coroner's office, 3). assignment of the primary role of stabilization and care of potential donors and the integration of all medical services to the trauma service, and 4). biweekly conferences to review policies, protocols, and outcomes of donor management strategies. RESULTS: From 1995 to 2001 there was a large increase in patient referrals for donor evaluation from 86 (Phase I) to 124 (Phase II). There was a smaller increase in the number of suitable donors: Phase I (mean: 51/year) and Phase II (mean: 63/year). There was, however, an increase in the mean number of actual organ donors from 14.2/year to 25.7/year from Phase I to Phase II and an increase in organs donated from 29 to 49. Organ donor declines decreased from 53% (Phase I) to 39% (Phase II). CONCLUSIONS: Strategies to increase the number of cadaveric organs available for organ transplantation are crucial. A strategy combining prompt identification of potential organ donors, institution of resuscitative protocols, a multidisciplinary team approach, educational activities and utilization of personnel expert in organ procurement led to a marked increase in the number of organ donors and the number of organs donated at a single institution. Wider application of this approach should prove successful in increasing organ donation in a similar fashion in other institutions.

    Title Magneto-encephalogram Artifacts Caused by Electro-encephalogram Electrodes.
    Date July 2003
    Journal Medical & Biological Engineering & Computing
    Excerpt

    The electro-encephalogram (EEG) and magneto-encephalogram (MEG) are often measured simultaneously. By Faraday's law of induction, the changing magnetic field of the MEG can induce eddy currents in the EEG electrodes. These eddy currents produce their own magnetic field that adds to that produced by current sources in the brain, resulting in an artifact in the MEG recording. It is shown that, under typical conditions, this artifact is less than 1%, but, during measurements of high temporal frequency and high spatial resolution, the artifact can be as large as 3%.

    Title Analytical Model for Predicting Mechanotransduction Effects in Engineered Cardiac Tissue.
    Date June 2003
    Journal Tissue Engineering
    Excerpt

    Mechanochemical and mechanoelectrical signaling is imperative for cardiac organogenesis and underlies pathophysiological events. New techniques for engineering cardiac tissue allow unprecedented means of modeling these phenomena in vitro. However, experimental design is often hampered by a lack of models that can be adapted to the ideal conditions these methods allow. To address these deficiencies, we developed a mathematical model to calculate the distribution of stress and strain in fibrous cardiac tissue. The fluid-fiber-collagen model characterizes the mechanical behavior of cardiac tissue and is solved analytically for the distributions of stress and strain along the myocardial fibers. An example application of the model is presented: modeling the distribution of strains in the vicinity of an ischemic region. The ischemic region is stretched during systole, as has been shown in previous one-dimensional models. Our model predicts a complex distribution of stretch in the border zone surrounding the ischemic region and in nonischemic regions surrounding the border zone. These strain patterns may predict patterns of mechanochemical coupling that results in localized fibrosis, altered gene expression, or the mechanoelectrical signaling events that potentiate cardiac arrhythmias.

    Title Phase Ii Trial of Gemcitabine and Docetaxel in Patients with Advanced Carcinoma of the Urothelium: a Trial of the Eastern Cooperative Oncology Group.
    Date June 2003
    Journal Cancer
    Excerpt

    BACKGROUND: Gemcitabine and docetaxel are active agents in advanced urothelial carcinoma. A Phase II trial of this combination was performed to determine the activity and toxicity of these agents in a multiinstitutional setting in patients previously treated with one prior chemotherapy regimen. METHODS: Twenty-nine eligible patients with advanced urothelial carcinoma were treated with docetaxel at a dose of 40 mg/m(2) over 1 hour followed by gemcitabine, 800 mg/m(2), over 30 minutes, both intravenously (i.v.) on Days 1 and 8. Cycles were repeated every 21 days until disease progression or a maximum of 6 cycles. RESULTS: Five patients obtained an objective response for an overall response rate of 17% (90% confidence interval, 7-33%). One patient achieved a complete clinical response. The median overall survival of the group was 7.7 months. Toxicity was moderate with granulocytopenia, anorexia, and fatigue being the most commonly noted side effects. CONCLUSIONS: Gemcitabine and docetaxel is an active second-line combination in patients with advanced urothelial carcinoma. Responses in visceral, lymph node, and soft tissues sites were observed. Granulocytopenia without fever, fatigue, and anorexia was common. Thromboembolic symptoms were reported and are of concern. The combination of gemcitabine and docetaxel has the potential to palliate a subset of previously treated patients with an adequate performance status.

    Title Piritrexim in Advanced, Refractory Carcinoma of the Urothelium (e3896): a Phase Ii Trial of the Eastern Cooperative Oncology Group.
    Date April 2003
    Journal Investigational New Drugs
    Excerpt

    This was a single-agent phase II clinical trial of the antifol piritrexim in patients with advanced transitional cell carcinoma of the bladder. METHODS: Patients with previously-treated, advanced urothelial carcinoma were treated with oral piritrexim at a dose of 25 mg three times daily for 5 consecutive days each week for 3 consecutive weeks followed by a 1-week rest period. Courses were repeated every 28 days. RESULTS: Thirty-five patients were enrolled in the study, with 28 patients evaluable for survival and toxicity and 27 evaluable for response. TOXICITY: Myelosuppression was the major dose-limiting toxicity, with WHO grade 3/4 thrombocytopenia in 4 patients, granulocytopenia in 1 patient, and anemia in 3 patients. Grade 3 nonhematologic toxicity consisted of neuropathy in 5 patients, hepatotoxicity in 2, nausea in 2, and 1 each with pulmonary toxicity and rash. EFFICACY: Of the 27 patients evaluable for response, 2 (7%) achieved an objective response, lasting 112 and 142 days, respectively. CONCLUSION: Piritrexim has minimal activity in patients with previously treated transitional cell carcinoma of the bladder, regardless of prior exposure to methotrexate, and further evaluation of this compound in this clinical setting is not warranted.

    Title Averaging over Depth During Optical Mapping of Unipolar Stimulation.
    Date October 2002
    Journal Ieee Transactions on Bio-medical Engineering
    Excerpt

    Numerical simulations have predicted the distribution of transmembrane potential during electrical stimulation of cardiac tissue. When comparing these predictions to measurements obtained using optical mapping techniques, the optical signal should not be compared to the transmembrane potential calculated at the surface of the tissue, but instead to the transmembrane potential averaged over depth. In this paper, the bidomain model is used to calculate the transmembrane potential in a three-dimensional slab of cardiac tissue, stimulated by a unipolar electrode on the tissue surface. For an optical decay constant of 0.3 mm and an electrode radius of 1 mm, the surface transmembrane potential is more than a factor of three larger than the transmembrane potential averaged over depth. Our results suggest that optical mapping underestimates the surface transmembrane potential during electrical stimulation.

    Title Beneficial Impact of a Clinical Care Pathway in Patients with Testicular Cancer Undergoing Retroperitoneal Lymph Node Dissection.
    Date July 2002
    Journal The Journal of Urology
    Excerpt

    PURPOSE: Since 1997, we have used a clinical collaborative care pathway for patients undergoing retroperitoneal lymph node dissection. We examined its impact on perioperative care and outcome. MATERIALS AND METHODS: We examined the records of all patients with germ cell carcinoma who underwent retroperitoneal lymph node dissection from July 1990 to July 2001. Variables examined included clinical/pathological stage, hospital stay, postoperative care and the complication rate. RESULTS: A total of 118 patients underwent retroperitoneal lymph node dissection for germ cell carcinoma during this period, including 46 (39%) before pathway implementation in 1997 and 72 patients (61%) after pathway implementation. Of the 118 patients 40 (34%) underwent the procedure after chemotherapy. This rate remained fairly constant in the period before and after pathway initiation (31% and 36%, respectively). After pathway implementation fewer patients received a nasogastric tube (94% versus 5%, p <0.001) and had complications (26% versus 16%, p = 0.036). Mean hospital stay decreased after pathway implementation in all primary and post-chemotherapy retroperitoneal lymph node dissection cases (4.2 versus 6.4 days, p <0.005). Although patients who underwent the procedure after chemotherapy were more likely to have complications than those who underwent a primary procedure, the difference was not statistically significant (p = 0.09). CONCLUSIONS: Our collaborative clinical care pathway safely and efficiently outlines routine postoperative care and significantly decreased hospital stay.

    Title How Epicardial Electrodes Influence the Transmembrane Potential During a Strong Shock.
    Date June 2002
    Journal Annals of Biomedical Engineering
    Excerpt

    This paper analyzes a possible artifact that may corrupt experiments studying defibrillation of the heart. Our hypothesis is that surface recording electrodes can influence the transmembrane potential during a shock. In the vicinity of an electrode, current leaves the intracellular space to take advantage of the low resistance of the extracellular path, thereby depolarizing the tissue. We calculate the transmembrane potential induced around a circular electrode when exposed to a uniform electric field. The bidomain model represents the electrical behavior of the cardiac tissue, and we account for electrode polarization impedance. Our results show that adjacent regions of depolarization and hyperpolarization exist around the electrode, and that the induced depolarization is greater than 100 mV for a 0.5 mm radius silver-silver chloride electrode in a 500 V/m electric field. We conclude that surface electrodes may produce artifacts during experiments designed to study defibrillation-strength electrical shocks.

    Title Sawtooth Effect: Fact or Fancy?
    Date March 2002
    Journal Journal of Cardiovascular Electrophysiology
    Title Simulation of Protective Zones During Quatrefoil Reentry in Cardiac Tissue.
    Date February 2002
    Journal Journal of Cardiovascular Electrophysiology
    Excerpt

    INTRODUCTION: An S3 stimulus can exert a protective effect by terminating reentry induced by an S2 stimulus. Our goal was to examine the mechanism by which an S3 pulse terminates reentry and the role that virtual electrodes and break excitation play in this process. METHODS AND RESULTS: In our simulation, the bidomain model represents the electrical properties of the tissue and the Beeler-Reuter model represents the membrane kinetics. Quatrefoil reentry is initiated by S1-S2 stimulation, and then a third stimulus S3 is applied at different intervals after S2. All stimuli are applied through the same unipolar electrode. For some S2-S3 intervals, the S2 and S3 wavefronts interact destructively, terminating reentry (protective zones). For other S2-S3 intervals, S2 and S3 wavefronts interact constructively, and reentry continues. Protective zones appear recurrently, with approximately the period of the S2 reentrant circuit. The protective zones are wider for anodal stimulation than for cathodal stimulation. CONCLUSION: Virtual electrodes, break excitation, and S2-S3 timing all play important roles in determining the electrical response of the tissue.

    Title Chemotherapy for Genitourinary Malignancies: a Few Victories, More Promises, and a Lot of Unfinished Business.
    Date January 2002
    Journal Seminars in Urologic Oncology
    Title Systemic Chemotherapy for Urothelial Transitional Cell Carcinoma: an Overview of Toxicity.
    Date January 2002
    Journal Seminars in Urologic Oncology
    Excerpt

    Chemotherapy for urothelial transitional cell carcinoma improves disease-related symptoms and overall survival. Unfortunately, many commonly used cytotoxic regimens affect normal as well as malignant tissue, resulting in toxicities that may require prompt medical diagnosis and management. This article reviews the reported toxicities of both single agent and combination chemotherapy regimens used to treat metastatic transitional cell carcinoma.

    Title New Currents in Electrical Stimulation of Excitable Tissues.
    Date January 2002
    Journal Annual Review of Biomedical Engineering
    Excerpt

    Electric fields can stimulate excitable tissue by a number of mechanisms. A uniform long, straight peripheral axon is activated by the gradient of the electric field that is oriented parallel to the fiber axis. Cortical neurons in the brain are excited when the electric field, which is applied along the axon-dendrite axis, reaches a particular threshold value. Cardiac tissue is thought to be depolarized in a uniform electric field by the curved trajectories of its fiber tracts. The bidomain model provides a coherent conceptual framework for analyzing and understanding these apparently disparate phenomena. Concepts such as the activating function and virtual anode and cathode, as well as anode and cathode break and make stimulation, are presented to help explain these excitation events in a unified manner. This modeling approach can also be used to describe the response of excitable tissues to electric fields that arise from charge redistribution (electrical stimulation) and from time-varying magnetic fields (magnetic stimulation) in a self-consistent manner. It has also proved useful to predict the behavior of excitable tissues, to test hypotheses about possible excitation mechanisms, to design novel electrophysiological experiments, and to interpret their findings.

    Title The Effect of Plunge Electrodes During Electrical Stimulation of Cardiac Tissue.
    Date December 2001
    Journal Ieee Transactions on Bio-medical Engineering
    Excerpt

    The mechanism for far-field stimulation of cardiac tissue is not known, although many hypotheses have been suggested. This paper explores a new hypothesis: the insulated plunge electrodes used in experiments to map the extracellular potential may affect the transmembrane potential when an electric field is applied to cardiac tissue. Our calculation simulates a 10-mm-diameter sheet of passive tissue with a circular insulated plunge electrode in the middle of it, ranging in diameter from 0.05 to 2 mm. We calculate the transmembrane potential induced by a 500-V/m electric field. Our results show that a transmembrane potential is induced around the electrode in alternating areas of depolarization and hyperpolarization. If the electric field is oriented parallel to the myocardial fibers, the maximum transmembrane potential is 89 mV. A layer of fluid around the electrode increases the transmembrane potential. We conclude that plunge electrodes may introduce artifacts during experiments designed to study the response of the heart to strong electric shocks.

    Title Experimental and Theoretical Analysis of Phase Singularity Dynamics in Cardiac Tissue.
    Date October 2001
    Journal Journal of Cardiovascular Electrophysiology
    Excerpt

    INTRODUCTION: Quantitative analysis of complex self-excitatory wave patterns, such as cardiac fibrillation and other high-order reentry, requires the development of new tools for identifying and tracking the most important features of the activation, such as phase singularities. METHODS AND RESULTS: Image processing operations can be used to detect the phase singularity at the tip of a spiral wave. The phase space behavior of a spatiotemporal sequence of data may be reconstructed using time-series analysis. The phase singularities then are localized efficiently by computing the topologic charge density as the curl of the spatial phase gradient. We analyzed the singularity interaction dynamics of both experimentally observed and numerically simulated instances of quatrefoil reentry and found that the singularity behavior in the experimental preparations can be classified into three categories on the basis of how their separation changes with time. CONCLUSION: Topologic charge densities can be calculated easily and efficiently to reveal phase singularity behavior. However, the differences between theoretical and experimental observations of singularity separation distances indicate the need for more sophisticated numerical models.

    Title Penetrating Trauma in Patients Older Than 55 Years: a Case-control Study.
    Date October 2001
    Journal Injury
    Excerpt

    BACKGROUND: Multiple studies have compared young and elderly blunt trauma patients, and concluded that, because elderly patients have outcomes similar to young patients, aggressive resuscitation should be offered regardless of age. Similar data on penetrating trauma patients are limited. STUDY DESIGN: In a retrospective review, 79 patients with penetrating injuries and age > or =55 were blindly matched for Injury Severity Score (ISS) and Abbreviated Injury Scores (AIS) with 79 penetrating trauma patients aged 15-35 years, who were admitted to the hospital over the same 4 year period (June 1994-June 1998). Mortality rates and length of stay in the intensive care unit (ICU) and the hospital were compared between the two groups. RESULTS: The average ISS for all patients was 12 (range 1-75) and identical for both groups. Both groups had similar injuries and were evaluated by an equal number and type of diagnostic studies. The mean ISS was not different between severely injured older and younger patients who required ICU admission or died. Among 32 nonsurvivors (18 older and 14 younger), older patients were more likely than younger patients to present with normal vital signs, although the comparison did not reach statistical significance (50% vs. 13%, P=0.25). There was a clinically significant trend for longer ICU (15+/-30 vs. 3+/-2 days, P=0.096) and hospital stay (10+/-18 vs. 6+/-8 days, P=0.08) among older patients, but mortality rates were similar (23% in older vs. 18% in younger, P=NS). Furthermore, these outcome parameters showed no difference when both groups were classified according to severity of injury or physiologic response. CONCLUSIONS: Following penetrating trauma, older patients arriving alive and admitted to the hospital are as likely to survive as younger patients who have injuries of similar severity, but at the expense of longer ICU and hospital stays.

    Title Optical Measurement of Cell-to-cell Coupling in Intact Heart Using Subthreshold Electrical Stimulation.
    Date August 2001
    Journal American Journal of Physiology. Heart and Circulatory Physiology
    Excerpt

    Electrical coupling between myocytes plays a critical role in propagation, repolarization, and arrhythmias. On the basis of predictions from cable theory, we hypothesized that the cardiac space constant (lambda) measured from the decay of subthreshold transmembrane potential (ST-Vm) in space would provide an index of regional cell-to-cell coupling in the intact heart. With the use of voltage-sensitive dyes, the distribution of ST-Vm was measured from hundreds of sites in close proximity to the site of subthreshold stimulation. lambda was calculated from the exponential decay of ST-Vm in space. Consistent with known directional differences in axial resistance, the spatial distribution of ST-Vm was strongly dependent on fiber orientation, because lambda was significantly (P < 0.001) longer along (1.5 +/- 0.1 mm) compared with across (0.8 +/- 0.1 mm) fibers. There was a close linear relationship (P < 0.001) between conduction velocity (CV) and lambda along all fiber angles tested. Reducing gap junctional conductance by heptanol reversibly decreased CV and lambda in parallel by approximately 50%. In contrast, sodium channel blockade by flecainide slowed CV by 40% but had no effect on lambda, reaffirming that lambda was an index of passive but not active membrane properties. These data establish the feasibility of measuring lambda as an index of cell-to-cell coupling in the intact heart, and indicate strong dependency of lambda on fiber orientation and pharmacological alterations of gap junction conductance.

    Title Methacholine Challenge Testing in Reserve Officer Training Corps Cadets.
    Date April 2001
    Journal Chest
    Excerpt

    STUDY OBJECTIVE: To determine the prevalence of positive results for methacholine challenge tests in asymptomatic Reserve Officer Training Corps (ROTC) cadets with no history of asthma. DESIGN: Prospective, blinded cohort comparison study. SETTING: Pulmonary diseases clinic in a US Army tertiary-care medical center. PATIENTS: One hundred three college students who were undergoing a physical examination before entering active duty. Group 1 subjects, 58 men and 5 women with an average age of 22.7 years, had no symptoms or personal history of asthma. Group 2 patients, 34 men and 6 women with an average age of 22.2 years, had a history or recent suggestive symptoms of asthma. INTERVENTIONS: Methacholine challenge testing using concentrations of 0.025, 0.25, 2.5, 10, and 25 mg/mL for a total dose of 188 inhalation units or until FEV(1) had declined by 20%. RESULTS: Group 2 had significantly more patients with positive results for methacholine challenge tests or reversible airflow obstruction at baseline (23 of 40 patients [57.5%]) than group 1 (8 of 63 patients [12.7%]; p < 0.05). The cadets in group 1 with positive results for methacholine challenge tests reacted with a 20% decline in FEV(1) at the following concentrations: 25 mg/mL (188 IU), 2 patients; 10 mg/mL (64 IU), 4 patients; and 2.5 mg/mL (13.8 IU), 2 patients. Using values calculated for the provocative concentration of a substance causing a 20% fall in FEV(1) and the new American Thoracic Society criteria, four patients would have borderline bronchial hyperresponsiveness (4 to 16 mg/mL) and three patients (4.8%) would have mild bronchial hyperresponsiveness (1 to 4 mg/mL). CONCLUSIONS: Asymptomatic US Army ROTC cadets with no history of asthma have possible false-positive responses to methacholine at concentrations > 0.25 mg/mL.

    Title Phase I Trial of Paclitaxel and Etoposide for Recurrent Ovarian Carcinoma: a Gynecologic Oncology Group Study.
    Date February 2001
    Journal American Journal of Clinical Oncology
    Excerpt

    A phase I study was performed to determine the maximum tolerated doses of intravenous etoposide and paclitaxel for women with previously treated persistent or recurrent ovarian cancer. Starting doses were paclitaxel 135 mg/m2 during 24 hours and etoposide 50 mg/m2/day for 3 consecutive days. The study was designed to escalate first the dose of etoposide, and then the dose of paclitaxel, in successive cohorts of patients. In an attempt to determine whether toxicity was affected by sequence of the drugs, the order of administration of the two drugs was reversed on alternate cycles. The starting doses of paclitaxel (135 mg/m2/24 hours) and etoposide (50 mg/m2/day x 3) caused severe neutropenia even with the addition of granulocyte colony-stimulating factor, and the trial was amended to administer the paclitaxel during 3 hours. However, this also proved too myelosuppressive without growth factor support. Twenty-one women were treated. A complete response was observed in one of nine patients with measurable disease, and a major decrease in CA-125 was noted in two patients who did not have measurable disease. Because of the severe myelosuppression observed in most patients, dose reduction was often required after the first cycle. The power to detect sequence-dependent variation in toxicity was minimal; however, no large differences were observed. A combination of the usual doses of these drugs will be difficult to administer in patients who have received previous chemotherapy for ovarian cancer.

    Title How Electrode Size Affects the Electric Potential Distribution in Cardiac Tissue.
    Date November 2000
    Journal Ieee Transactions on Bio-medical Engineering
    Excerpt

    We investigate the effect of electrode size on the transmembrane potential distribution in the heart during electrical stimulation. The bidomain model is used to calculate the transmembrane potential in a three-dimensional slab of cardiac tissue. Depolarization is strongest under the electrode edge. Regions of depolarization are adjacent to regions of hyperpolarization. The average ratio of peak depolarization to peak hyperpolarization is a function of electrode radius, but over a broad range is close to three.

    Title Androgen-independent Prostate Cancer: Not So Chemorefractory After All.
    Date July 2000
    Journal Seminars in Oncology
    Excerpt

    Historically, hormone-refractory prostate cancer has not been routinely treated with chemotherapy, based on perceptions that single agents were not all that active, this patient population was too fragile to receive such therapy, responses were virtually impossible to verify given the rarity of bidimensionally measurable disease, and, if seen, responses were not clinically meaningful. The "truths" of the 1970s and 1980s are the "myths" of the 1990s, but unfortunately many physicians continue to propagate these myths despite accumulating data to the contrary. Newer combination regimens produce objective response rates in measurable disease that rival those seen in other solid tumors that are uniformly labeled as "chemosensitive." The widespread use of the serum prostate-specific antigen level has allowed the detection of progressive disease at an earlier stage in patients with an excellent performance status. Although chemotherapy to date has not had an impact on patient survival, quality of life analyses have clearly demonstrated improved palliation in treated patients. Hopefully, as this knowledge is disseminated more widely, more patients will be offered cytotoxic therapy for this currently undertreated disease.

    Title An S1 Gradient of Refractoriness is Not Essential for Reentry Induction by an S2 Stimulus.
    Date June 2000
    Journal Ieee Transactions on Bio-medical Engineering
    Excerpt

    This communication reports a numerical simulation of reentry induction by successive stimulation (S1-S2) that does not require an S1 gradient of refractoriness. The S1 action potential is uniform in space, so before the S2 stimulus there is no refractory gradient. Nevertheless, a unipolar S2 stimulus initiates quatrefoil reentry. The result supports the growing realization that virtual electrodes, hyperpolarization, de-excitation, and break excitation may be important during reentry induction.

    Title Role of Virtual Electrodes in Arrhythmogenesis: Pinwheel Experiment Revisited.
    Date May 2000
    Journal Journal of Cardiovascular Electrophysiology
    Excerpt

    INTRODUCTION: Recent experimental evidence demonstrates that a point stimulus generates a nonuniform distribution of transmembrane potential (virtual electrode pattern) consisting of large adjacent areas of depolarization and hyperpolarization. This simulation study focuses on the role of virtual electrodes in reentry induction. METHODS AND RESULTS: We simulated the electrical behavior of a sheet of myocardium using a two-dimensional bidomain model with straight fibers. Membrane kinetics were represented by the Beeler-Reuter Drouhard-Roberge model. Simulations were conducted for equal and unequal anisotropy ratios. S1 wavefront was planar and propagated parallel or perpendicular to the fibers. S2 unipolar stimulus was cathodal or anodal. With regard to unequal anisotropy, for both cathodal and anodal stimuli, the S2 stimulus negatively polarizes some portion of membrane, deexciting it and opening an excitable pathway in a region of otherwise unexcitable tissue. Reentry is generated by break excitation of this tissue and subsequent propagation through deexcited and recovered areas of myocardium. Figure-of-eight and quatrefoil reentry are observed, with figure-of-eight most common. Figure-of-eight rotation is seen in the direction predicted by the critical point hypothesis. With regard to equal anisotropy, reentry was observed for cathodal stimuli only at strengths > -95 A/m. CONCLUSION: The key to reentry induction is the close proximity of S2-induced excited and deexcited areas, with adjacent nonexcited areas available for propagation.

    Title Virtual Electrodes and Deexcitation: New Insights into Fibrillation Induction and Defibrillation.
    Date May 2000
    Journal Journal of Cardiovascular Electrophysiology
    Excerpt

    Previous models of fibrillation induction and defibrillation stressed the contribution of depolarization during the response of the heart to a shock. This article reviews recent evidence suggesting that comprehending the role of negative polarization (hyperpolarization) also is crucial for understanding the response to a shock. Negative polarization can "deexcite" cardiac cells, creating regions of excitable tissue through which wavefronts can propagate. These wavefronts can result in new reentrant circuits, inducing fibrillation or causing defibrillation to fail. In addition, deexcitation can lead to rapid propagation through newly excitable regions, resulting in the elimination of excitable gaps soon after the shock and causing defibrillation to succeed.

    Title Abnormal Mammogram As the Presenting Sign of Renal Cell Carcinoma.
    Date April 2000
    Journal The Journal of Urology
    Title Phase Ii Study of Cisplatin and Paclitaxel in Advanced Carcinoma of the Urothelium: an Eastern Cooperative Oncology Group Study.
    Date March 2000
    Journal Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
    Excerpt

    PURPOSE: Cisplatin and paclitaxel are active agents in advanced urothelial cancer. A phase II trial of this combination was performed to determine the activity and toxicity of these agents in a multi-institutional setting. PATIENTS AND METHODS: Fifty-two patients with advanced urothelial carcinoma were treated on one day with paclitaxel 175 mg/m(2) over 3 hours followed by cisplatin 75 mg/m(2), both intravenously, every 21 days. Cycles were repeated every 21 days until progression or a maximum of six cycles. RESULTS: Twenty-six patients obtained an objective response, for an overall response rate of 50% (95% confidence interval, 36% to 64%). Four patients achieved complete clinical responses. The median overall survival time for the group was 10.6 months. Toxicity was moderate, with granulocytopenia and neurotoxicity being the most common side effects noted. CONCLUSION: The combination of cisplatin and paclitaxel is active in advanced urothelial cancer. Responses in visceral, nodal, and soft tissues sites were observed. Granulocytopenia without fever and grade 2/3 neurotoxicity were common. The confidence interval of the overall response rate in this study overlaps most of the other reported regimens. The optimal therapy for advanced urothelial cancer remains undefined.

    Title Mechanism for Polarisation of Cardiac Tissue at a Sealed Boundary.
    Date March 2000
    Journal Medical & Biological Engineering & Computing
    Excerpt

    If current is flowing in cardiac tissue, and if the myocardial fibres approach a sealed boundary at an angle, then the tissue within a few length constants of the boundary is polarised. This polarisation occurs when the cardiac tissue has different anisotropy ratios in the intracellular and extracellular spaces. This new mechanism of tissue polarisation is demonstrated using a simple, analytical model, and it is shown quantitatively that this polarisation can be nearly as large as that occurring near an electrode.

    Title Influence of a Perfusing Bath on the Foot of the Cardiac Action Potential.
    Date February 2000
    Journal Circulation Research
    Excerpt

    Recently, Spach et al (Circ Res. 1998;83:1144-1164) measured the transmembrane action potential 150 to 200 microm below the tissue surface during longitudinal and transverse propagation. They found that "during longitudinal propagation there was initial slowing of V(m) [action potential] foot that resulted in deviations from a simple exponential. " (p 1144). They attributed this behavior to the effects of capillaries on propagation. The purpose of this commentary is to show that the perfusing bath plays an important role in determining the time course of the action potential foot, even when the transmembrane potential is measured 150 microm below the tissue surface. Using numerical simulations based on the bidomain model, we find that the action potential foot for transverse propagation is nearly exponential (tau(foot)=314 micros). For longitudinal propagation, the action potential foot is not exponential because of an initial slowing (best-fit tau(foot)=483 micros). We conclude that the perfusing bath must be taken into account when interpreting data showing differences in the shape of the action potential foot with propagation direction, even if the transmembrane potential is measured 150 microm below the tissue surface.

    Title The Magnetic Field Associated with a Plane Wave Front Propagating Through Cardiac Tissue.
    Date December 1999
    Journal Ieee Transactions on Bio-medical Engineering
    Excerpt

    An action potential propagating through a two-dimensional sheet of cardiac tissue produces a magnetic field. In the direction of propagation, the intracellular and extracellular current densities are equal and opposite, so the net current is zero. However, because of the unequal anisotropy ratios in the intracellular and extracellular spaces, the component of the current density perpendicular to the direction of propagation does not, in general, vanish. This line of current produces the magnetic field. The amplitude of the magnetic field is zero only if the action potential propagates parallel to or perpendicular to the fiber direction, or if the tissue has equal anisotropy ratios.

    Title Time Dependence of Anodal and Cathodal Refractory Periods in Cardiac Tissue.
    Date October 1999
    Journal Pacing and Clinical Electrophysiology : Pace
    Excerpt

    Mehra et al. (PACE 1980; 3:526) observed that immediately after implantation of a pacing electrode in a dog heart, the anodal refractory period (RP) is shorter than the cathodal RP, but after several weeks the anodal RP becomes longer than the cathodal RP. We examine this experiment using numerical simulations based on the bidomain model of cardiac tissue and a Beeler-Reuter membrane. Our hypothesis is that accumulation of inexcitable tissue around the electrode following implantation causes the effective size of the electrode to increase and that this increase is the mechanism underlying the change in RP. We calculate that the anodal RP is shorter than the cathodal RP for both large and small electrodes. However, for large electrodes the threshold for anode "break" stimulation is greater than 8 mA. Mehra et al. defined RP experimentally as the interval at which the threshold stimulus strength becomes greater than 8 mA. If we restrict the stimulus current in our calculations to less than 8 mA, we exclude anode break stimulation from our calculation of the RP. In that case, our results are consistent with Mehra et al. and suggest that their observation resulted from their definition of RP.

    Title Searching for Tuberculosis in the Pleural Space.
    Date August 1999
    Journal Chest
    Title A Phase Ii Study of Paclitaxel and Ifosfamide for Patients with Advanced Refractory Carcinoma of the Urothelium.
    Date August 1999
    Journal Cancer
    Excerpt

    BACKGROUND: Cisplatin-based combination chemotherapy for patients with advanced transitional cell carcinoma (TCC) of the urothelium has limitations, and new therapies need to be evaluated. METHODS: Ifosfamide 1.0 gm/m2 on Days 1-4 and paclitaxel 135 mg/m2 by 24-hour infusion on Day 4 were administered to 26 patients with locally unresectable or metastatic TCC. Cycles were repeated every 21 days for a maximum of 6 cycles; dose escalation was dependent on whether Grade 3 or 4 toxicities occurred. RESULTS: There were 24 males and 2 females, with a median age of 66 years and a median Eastern Cooperative Oncology Group performance status of 0. The median number of cycles administered was 3. Twelve patients had Grade 3 or 4 hematologic toxicities, including 1 patient who died of a gastrointestinal hemorrhage while pancytopenic. There were no episodes of neutropenic fever. Two patients each had a complete response (CR) that lasted 5 and 28 months, respectively (response rate: 15%; 95% CI: 2-45%), among the 13 patients who had received prior chemotherapy. Of the 13 patients without prior chemotherapy, there were 3 with complete responses and 1 with a partial response ranging from 8 to 25+ months (RR: 30.7%; 95% CI: 9-61%). CONCLUSIONS: The combination of ifosfamide and paclitaxel is well tolerated and can produce objective responses in patients who are chemonaïve or have had prior therapy. For previously untreated patients, the addition of ifosfamide does not appear to result in a better response rate than single agent paclitaxel; and for previously treated patients, the addition of paclitaxel does not appear to result in a better response rate than single agent ifosfamide.

    Title Dependence of Cardiac Strength-interval Curves on Pacing Rate.
    Date July 1999
    Journal Medical & Biological Engineering & Computing
    Excerpt

    The purpose of the research is to determine how the pacing rate affects the strength-interval curve in cardiac tissue. Computer simulations are used to calculate the cathodal and anodal strength-interval curves. The tissue is represented by the bidomain model with Beeler-Reuter membrane properties. The strength-interval curves shift to shorter intervals as the pacing rate increases. However, the shape of the strength-interval curve, including the separation into 'make' and 'break' sections and the presence of a 'dip', is insensitive to pacing rate.

    Title Quatrefoil Reentry in Myocardium: an Optical Imaging Study of the Induction Mechanism.
    Date July 1999
    Journal Journal of Cardiovascular Electrophysiology
    Excerpt

    INTRODUCTION: The "critical point hypothesis" for induction of ventricular fibrillation has previously been extended to infer the coexistence of four critical points, and hence four simultaneous spiral reentries or a quatrefoil reentry, resulting from only one premature stimulus delivered to the same location as the pacing stimulus. An optical imaging technique was used to explore its existence and to study the induction mechanism of this peculiar reentry pattern. METHODS AND RESULTS: In 16 isolated, Langendorff-perfused rabbit hearts, high-speed optical imaging at 133 or 267 frames/sec was performed to observe the induced response with a unipolar point electrode. A novel quatrefoil-shaped reentry pattern consisting of two pairs of opposing rotors was created by delivering long stimuli during the vulnerable phase. Successful induction occurred in a narrow range of coupling intervals. A dogbone pattern of virtual electrodes was established during the premature stimulus. Propagating wavefronts launched from the virtual anodes immediately after the termination of S2. The alternating blocking and conducting effects of the virtual electrodes, as well as the boundary between virtual cathode and virtual anode, provided the necessary pathways for quatrefoil reentry. Propagation directions of the reentrant spiral wavefronts reversed with a reversal in S2 polarity. Quatrefoil reentries were not sustained and lasted 1 to 4 complete cycles. CONCLUSION: The initiation of quatrefoil reentry followed anodal- or cathodal-break stimulation as a result of local symmetrical enhancement of the dispersion of tissue excitability. The "critical point hypothesis" provides the minimum topology required for this type of reentry; the "graded response hypothesis" can be viewed as providing a more detailed explanation of how this topology is actually realized. Triggering mechanisms due to the "break" mode of stimulation also posits a new mechanism for defibrillation.

    Title Effect of a Bath on the Epicardial Transmembrane Potential During Internal Defibrillation Shocks.
    Date June 1999
    Journal Ieee Transactions on Bio-medical Engineering
    Excerpt

    Using a three-dimensional model of cardiac tissue, we consider a rectangular slab of tissue. We examine the effect of a defibrillating shock from an intracavitary electrode upon the epicardial transmembrane potential (Vm) for two cases: one in which the epicardium is bounded by air and another in which it is bounded by a conductive bath. We find that the inclusion of the bath changes the polarity of the steady-state Vm in the epicardial region that is closest to the shock electrode. In addition, the magnitude of Vm is increased dramatically if the bath is present; the degree of hyperpolarization increases twenty-fivefold, while the degree of depolarization increases elevenfold. The remaining bulk of the cardiac tissue is relatively unaffected by the inclusion of the bath.

    Title Unipolar Stimulation of Cardiac Tissue.
    Date April 1999
    Journal Journal of Electrocardiology
    Title Images of Ca2+ Flux in Astrocytes: Evidence for Spatially Distinct Sites of Ca2+ Release and Uptake.
    Date April 1999
    Journal Cell Calcium
    Excerpt

    In this study, we have developed a mathematical method to derive the Ca2+ fluxes underlying agonist-evoked Ca2+ waves in cultured rat cortical astrocytes. Astrocytes were stimulated with norepinephrine (100 nM) to evoke Ca2+ waves, which were recorded by measuring Fluo-3 fluorescence changes with high spatial and temporal resolution. Normalized fluorescence (delta F/F) was analyzed in discrete cellular spaces in a series of successive slices along the length of the cell. From these data, Ca2+ flux was then calculated using a one dimensional reaction-diffusion equation which utilizes the temporal and spatial derivatives of the fluorescence data and the diffusion coefficient of Ca2+ in the cytosol. This method identified distinct sites of positive flux (Ca2+ release into the cytosol) and of negative flux (Ca2+ removal from cytosol) and showed that in astrocytes, sites of Ca2+ release from stores regularly alternate with sites of Ca2+ removal from the cytosol. Cross correlation analysis of the two distribution patterns gave positive correlation at 2 microns out of phase and a negative correlation in phase. Thapsigargin-induced Ca2+ waves were analyzed to determine if the negative flux was due to Ca2+ uptake via thapsigargin-sensitive Ca2+ pumps. Negative flux sites were still found under these conditions, suggesting that multiple mechanisms of Ca2+ removal from the cytosol may contribute to negative flux sites. This method of calculation of flux may serve as a means to describe the distribution of functional ion channels and pumps participating in cellular Ca2+ signalling.

    Title Electrical Stimulation of Cardiac Tissue by a Bipolar Electrode in a Conductive Bath.
    Date January 1999
    Journal Ieee Transactions on Bio-medical Engineering
    Excerpt

    A three-dimensional (3-D) computer simulation of the electrical stimulation of passive cardiac tissue from a bipolar electrode placed within a conductive bath is presented. Through the bidomain model, the syncytial and anisotropic properties of cardiac tissue are taken into account; tissues with equal anisotropy and no transverse coupling are also considered. The membrane is represented by a capacitor and passive resistor in parallel. Located within an isotropic bath, the bipolar electrode is oriented either perpendicular or parallel to the tissue surface. For anisotropic tissue with a small cathode-tissue separation, the tissue surface is highly depolarized under the cathode with the depolarization persisting a considerable distance from the electrode in the transverse fiber direction. Adjacent to this region in the longitudinal direction, areas of hyperpolarization exist. At large distances from the cathode, the tissue surface is hyperpolarized in all directions when the electrode axis is perpendicular to the tissue. In the parallel case, surface depolarization creates buried regions of hyperpolarization. For the perpendicular configuration, the ratio of the steady-state maximum depolarization to steady-state maximum hyperpolarization, an estimate of the ratio of anodal to cathodal threshold, decreases rapidly with increasing cathode-tissue separation. In the parallel case, the depth of the conductive bath significantly affected the transmembrane potential distribution in the tissue. The use of a 3-D model more realistically simulates real-life electrical stimulation (such as stimulation with an implantable pacemaker) and provides insight into the effect of the volume conductor adjacent to the tissue.

    Title Modeling of Spreading Cortical Depression Using a Realistic Head Model.
    Date December 1998
    Journal Brain Topography
    Excerpt

    Barkley and colleagues in 1990 reported large amplitude waves (LAWs) in time series magnetoencephalography (MEG) recordings from migraine patients and inferred that these LAWs arose from spreading cortical depression (SCD). SCD propagates slowly across the cortex in all species in which it has been observed. Previously, we reported that LAWs could be simulated and compared with the recorded signals using the four-sphere model (Wijesinghe and Tepley 1997). We showed that LAWs could arise from the propagation of SCD across a sulcus. In this paper, we model LAWs using a realistically shaped head model based on magnetic resonance images (MRI) (Roth et al. 1993). Simulated signals using this model are similar to the recorded signals. In this model, current dipoles represent the excitable neurons in the cortex and magnetic fields created by these individual dipoles are calculated. The magnetic field arising from the excited area of cortex is obtained by summing the fields due to these individual dipoles.

    Title Comments on "hall Effect Imaging".
    Date December 1998
    Journal Ieee Transactions on Bio-medical Engineering
    Title Bilateral Testicular Tumors: Management and Outcome in 21 Patients.
    Date August 1998
    Journal Cancer
    Excerpt

    BACKGROUND: The authors examined the clinical course of patients with bilateral testicular tumors to determine whether the outcome after treatment was different from patients with unilateral tumors. METHODS: Using a computerized data base of 2088 patients with testicular carcinoma at Indiana University, 21 patients (1%) were identified with bilateral testicular carcinoma. A retrospective review of hospital and clinic charts was performed. Sixteen patients with metachronous and 5 patients with synchronous testicular tumors were identified. RESULTS: Treatment was based on clinical stage and was similar to therapy given for unilateral disease. The mean age at presentation of the first testicular tumor was 28.4 years (range, 16-47 years). Approximately 50% of the second primary tumors presented > 5 years after the contralateral tumor. At a mean follow-up of 49.9 months (range, 1-276 months), 18 patients were without evidence of disease, 2 were alive with disease, and 1 patient had died of disease. CONCLUSIONS: The treatment of patients with bilateral germ cell tumors is based on the pathology and clinical stage and should not be different from the traditional management of unilateral testicular carcinoma. Patients with unilateral testicular carcinoma should be informed of the necessity of long term follow-up because contralateral testicular carcinoma may occur as long as 25 years later.

    Title Effects of Doxycycline on Human Prostate Cancer Cells in Vitro.
    Date June 1998
    Journal Cancer Letters
    Excerpt

    Prostate cancer is the most common form of cancer in older men and the major cause of death from prostate cancer is metastatic disease. The matrix metalloproteinases (MMPs) play a significant role in the growth, invasion and metastasis of many tumors, including those of the prostate. We previously demonstrated that doxycycline, a synthetic tetracycline, inhibits MMPs and cell proliferation and induces apoptosis in several cancer cell lines. We also demonstrated that in an in vivo model of metastatic breast cancer in athymic mice doxycycline inhibits tumor size and regrowth after resection. In the present study, gelatinolytic activity in the human prostate cancer cell line, LNCaP, was suppressed and significant inhibition of cell growth occurred after exposure to 5 or 10 microg/ml of doxycycline, while cell growth was normal in untreated cells. Radioisotope incorporation into proteins was reduced by doxycycline. DNA fragmentation, consistent with apoptosis, was demonstrated in cells treated with doxycycline. These data suggest that doxycycline may have potential utility in the management of prostate cancer.

    Title The Pinwheel Experiment Revisited.
    Date May 1998
    Journal Journal of Theoretical Biology
    Excerpt

    The critical point hypothesis explains the origin of some cardiac arrhythmias, and the bidomain model describes electrical stimulation of the heart. In this paper, the critical point hypothesis is combined with the bidomain model. The result is four new predictions about the pinwheel experiment, a fundamental experiment in cardiac electrophysiology. These are: (1) The duration of the vulnerable period during cathodal S2 stimulation is longer for an S1 wavefront propagating perpendicular to the fibers than for an S1 wavefront propagating parallel to the fibers. (2) For anodal S2 stimulation with the S1 wavefront propagating parallel to the fibers, the vulnerable period splits into two periods with an "invulnerable period" between them. (3) For anodal S2 stimulation with the S1 wavefront propagating perpendicular to the fibers, the vulnerable period consists of only one period. (4) A previously suggested mechanism for the upper limit of vulnerability (S2 is so strong that the entire tissue is depolarized by an amount greater than S*) is no longer applicable.

    Title Clinical Stage I Nonseminoma: Surgery Versus Surveillance.
    Date May 1998
    Journal Seminars in Oncology
    Excerpt

    The presentation of nonseminomatous germ cell tumor confined clinically to the testicle (clinical stage I) is associated with a 30% incidence of occult retroperitoneal metastases. For decades, the standard of care in these patients has been a retroperitoneal lymph node dissection (RPLND), both for staging purposes, and, in the pre-modern chemotherapy era, it was performed with curative intent. The improvements in combination chemotherapy during the past 20 years have resulted in the cure of most individuals with small volume recurrent disease, calling into question the continued need for RPLND. The strategy of surveillance and chemotherapy for the 30% who relapse has gained acceptance, and, with meticulous follow-up, can result in the same excellent cure rates seen in patients treated with the surgical option. Although primary chemotherapy has also been suggested as a treatment option, the majority of patients will receive that chemotherapy unnecessarily, and cure rates with this strategy will not surpass those for surveillance or RPLND. Prognostic factors have been developed that can successfully identify a group of patients who are at an extremely low risk of relapse, thus potentially sparing these individuals any additional therapy. However, attempts to define a very high risk population have been unsuccessful to date, and we await the development of newer biologic markers able to predict which patients are most likely to have occult retroperitoneal disease and therefore most likely to benefit from additional "adjuvant" therapy post-orchiectomy.

    Title A Phase Ii Trial of Paclitaxel in Refractory Germ Cell Tumors.
    Date April 1998
    Journal Cancer
    Excerpt

    BACKGROUND: A significant percentage of patients with refractory germ cell tumors will not respond to standard salvage regimens. Thus there is a need for new active agents. Paclitaxel has demonstrated activity against a variety of solid tumors in both laboratory and clinical studies. METHODS: Eighteen patients with refractory germ cell tumors who failed initial cisplatin-based chemotherapy and a maximum of 2 salvage regimens were enrolled into a Phase II trial of paclitaxel at a dose of 170 mg/m2 by intravenous infusion over 24 hours every 21 days without growth factor support. The median age of the patients was 32.5 years (range, 18-49 years). The testis was the primary site of tumor for 13 patients (72%) and the tumor was extragonadal in 5 patients (28%). Six patients (33%) were late recurrences. Twelve patients (67%) had > or = 2 metastatic sites. The median number of previous chemotherapy cycles was six (range, four to nine). Three patients (17%) previously had undergone autologous bone marrow transplantation. RESULTS: Two patients (11%) responded to paclitaxel. Major toxicities were Grade 3-4 neutropenia (55% of patients) and Grade 3-4 neurotoxicity (2 patients). Neutropenic fever occurred in 3 patients (17%). CONCLUSIONS: Paclitaxel demonstrated minimal activity in heavily pretreated patients with multiple, poor risk clinical features. These results in part may be due to the unfavorable characteristics of the patients in the current study, specifically the high percentage of patients with late recurrences and extragonadal primary tumors, both of which are known to respond poorly to salvage therapy. Other trials with different patient populations and doses of paclitaxel reported response rates ranging from 13.3%-26%. The role of paclitaxel in the treatment of patients with refractory germ cell tumors remains to be defined in future studies.

    Title Postchemotherapy Retroperitoneal Lymph Node Dissection is Effective Therapy in Selected Patients with Elevated Tumor Markers After Primary Chemotherapy Alone.
    Date February 1998
    Journal Urology
    Excerpt

    OBJECTIVES: Elevated tumor markers after primary chemotherapy for metastatic testis cancer are usually an indication of persistent cancer. Subsequent treatment has usually been salvage chemotherapy. This article examines the possibility that selected patients can achieve long-term disease-free survival with surgery alone. METHODS: Using a computerized data base of 627 postinduction chemotherapy retroperitoneal lymph node dissections (PC-RPLND), 23 patients with elevated tumor markers who have undergone PC-RPLND after induction chemotherapy alone were identified. Of the 23 patients, 15 were considered candidates for salvage chemotherapy, but instead underwent salvage surgery. Case histories were reviewed to establish selection criteria for PC-RPLND. RESULTS: Eight patients originally presented as clinical Stage C, 6 as clinical Stage B-3, and 1 as clinical Stage B-2. All patients initially received cisplatin combination chemotherapy. Twelve patients had an elevated alpha-fetoprotein level and 3 patients had an elevated beta human chorionic gonadotropin level prior to PC-RPLND. Seven patients had rising markers at the time of PC-RPLND. Seven patients had teratoma only in their resected specimen and all have no evidence of disease (NED) at a median of 35 months. Two patients had necrosis only in their RPLND specimen and both are NED at 10 and 42 months. Six patients had cancer in their resected specimen and 2 are NED, 1 is alive with disease, and 3 are dead of disease. Five of the 6 patients with cancer in their resected specimen were the only patients who received postoperative chemotherapy. CONCLUSIONS: Some patients with modest elevations of tumor markers after induction chemotherapy may only have teratoma or necrosis in the postchemotherapy resected specimen. These patients (n = 9) remain continuously NED. Patients who undergo salvage surgery and have cancer in the resected specimen do less well, but selected patients can be cured with this modality and thus avoid the morbidity of salvage chemotherapy.

    Title Differences Between the Time Constant of Sensory and Motor Peripheral Nerve Fibers: Further Studies and Considerations.
    Date January 1998
    Journal Muscle & Nerve
    Excerpt

    Using a method of latent addition, we previously demonstrated that sensory fibers had time constants that were about three times longer than those of motor fibers. The aim of the present work was to confirm this difference by determining the time constants for single sensory axons by using microneurography and for single motor axons by recording single motor units with bipolar concentric needle electrodes. To determine the influence of the conditioning pulse on the neural time constant, we used both depolarizing and hyperpolarizing conditioning pulses. When hyperpolarizing conditioning pulses at comparable intensity were applied, the tendency was to find shorter time constants than when depolarizing pulses were applied, although still with the motor time constant being slightly shorter. Although the absolute values varied with the different methods, the sensory time constant was generally three times the motor time constant for depolarizing conditioning stimuli, whereas for hyperpolarizing conditioning stimuli the difference dropped to about one and a half. These characteristics improve understanding of the behavior of sensory and motor axons, and, in particular, explain the differential excitability. Determination of neural time constants might prove valuable for clinical use.

    Title Is Ph Paper an Acceptable, Low-cost Alternative to the Blood Gas Analyzer for Determining Pleural Fluid Ph?
    Date November 1997
    Journal Chest
    Excerpt

    BACKGROUND: Our laboratory uses pH paper rather than a blood gas analyzer to measure pleural fluid pH to decrease cost and avoid analyzer malfunction due to viscous fluids. METHODS: To compare these two methods of determining pleural fluid pH, 42 patients undergoing diagnostic or therapeutic thoracentesis had two 1-mL aliquots of pleural fluid anaerobically collected in a heparinized syringe and placed on ice. pH measurements were made using litmus paper (pHydron Vivid 6-8 brand litmus paper; MicroEssential Labs; Brooklyn, NY) and the model 995-Hb blood gas analyzer (AVL Instruments; Roswell, GA) within 1 h of collection. Agreement analysis was performed in three ways: on the entire group; in subcategories of complicated or uncomplicated parapneumonic effusions (<7.1, 7.1 to 7.3, >7.3); and in subcategories of poor prognosis or better prognosis malignant effusions(<7.3, >7.3). RESULTS: pH measured with pH paper was significantly more variable (SD=0.55, coefficient of variation [CV]=7.5%) than was pH measured with the blood gas analyzer (SD=0.11, CV=1.5%). There was no significant correlation between values obtained with the two techniques (r=-0.26, SD of the differences=0.59). Using the pH subcategories, there was 72% discordance in classification between litmus paper and arterial blood gas (ABG) determinations for patients with parapneumonic effusions. In patients with malignant effusions, there was 30% discordance. The pH values obtained by the ABG analyzer predicted tube thoracostomy 72% of the time, whereas the pH values obtained using pH paper were consistent only 36% of the time. CONCLUSION: Determination of pleural fluid pH using pH paper is unreliable and should not be considered an acceptable alternative to the blood gas analyzer. There is no need to determine pH on purulent samples. Hospital laboratories will be more likely to allow the use of the ABG analyzer on fluids other than blood if clinicians keep this in mind.

    Title Nonsustained Reentry Following Successive Stimulation of Cardiac Tissue Through a Unipolar Electrode.
    Date October 1997
    Journal Journal of Cardiovascular Electrophysiology
    Excerpt

    INTRODUCTION: Using numerical simulations, we predict that nonsustained reentry occurs following a strong, premature stimulus through a unipolar electrode. METHODS AND RESULTS: Our simulations were based on the bidomain model of cardiac tissue, and the active membrane properties were represented by the Beeler-Reuter model. An outwardly propagating wavefront was excited by an initial stimulus (S1). A second stimulus (S2) was then applied through the same electrode. Nonsustained reentry or reentrant-like behavior followed the S2 stimulus for both cathodal and anodal stimulation, and were associated with "break" stimulation but not with "make" stimulation. The direction of spiral-wave rotation was reversed when the polarity of the stimulus was reversed. These complex dynamics occur only for a narrow window of S1-S2 intervals. During anodal S2 stimulation, two different modes of reentry exist. Our simulations also explain the "no response" phenomenon. CONCLUSION: Our mathematical model predicts that both anodal and cathodal unipolar S2 stimulation results in reentry. This behavior arises from an interaction of virtual anodes and cathodes surrounding the stimulating electrode.

    Title Coronary Artery Calcification at Ct As a Predictor for Cardiac Complications of Thoracic Surgery.
    Date July 1997
    Journal Journal of Computer Assisted Tomography
    Excerpt

    PURPOSE: Our goal was to determine the predictive value of coronary artery calcification (CAC) on preoperative CT of the thorax for cardiac complications of noncardiac thoracic surgery. METHOD: Of 117 patients undergoing noncardiac thoracic surgical procedures between January 1, 1993, and June 1, 1995, at our institution, 75 had inpatient records and chest CTs available for retrospective review. Inpatient records were reviewed for postoperative cardiac complications (arrhythmia, hypotension with ECG changes, myocardial infarction, congestive heart failure, stroke, and death). The CT scans were scored for the presence and extent of CAC by an independent observer. RESULTS: Six of the 75 patients had cardiac complications including 1 death. Thirty-nine of the 75 patients had a CAC score of > or = 7. The sensitivity, specificity, positive predictive value, and negative predictive value of a CAC score of > or = 7 for cardiac complications were 100, 71, 23, and 100%, respectively. CONCLUSION: The presence of CAC on preoperative CT scanning is associated with cardiac complications of noncardiac thoracic surgery; however, the positive predictive value is low. The absence of CAC was a reliable predictor of a favorable postoperative cardiac course.

    Title Dipole Localization in Patients with Epilepsy Using the Realistically Shaped Head Model.
    Date June 1997
    Journal Electroencephalography and Clinical Neurophysiology
    Excerpt

    Dipole sources were localized in 3 patients with epilepsy using both the realistically shaped head model and the 3-sphere model. Interictal spikes were recorded from 63 closely spaced scalp electrodes. The scalp, skull, and brain surfaces were digitized from a MRI of each patient's head, and each surface was tessellated by 1600 triangles. Single dipole fits to the EEG were performed using both the realistically shaped head model and the 3-sphere model. The 2 models localized dipoles to positions that differed from one another by 1-3 cm. For dipoles localized to the temporal lobe, the most important difference between models was that the realistically shaped head model localized the dipole lower in the brain than the 3-sphere model. The realistically shaped head model was more in accordance with the ECoG findings than the 3-sphere model.

    Title Bedside Videoscopic Placement of Feeding Tubes: Development of Fiberoptics Through the Tube.
    Date June 1997
    Journal Critical Care Medicine
    Excerpt

    OBJECTIVE: Transpyloric small intestine feeding tube placement can be difficult and tedious. Currently accepted techniques are associated with disadvantages and risk. The purpose of this study is to describe the development of a new technique: bedside videoscopic placement using fiberoptics through the tube. DESIGN: Prospective, descriptive case study. SETTING: Intensive care unit in a teaching hospital. PATIENTS: Subjects were divided into two groups: a) group 1: eight healthy volunteers (seven male, one female); b) group 2: nine critically ill patients (six male, three female; eight of these patients were intubated). INTERVENTIONS: Standard 12-Fr (4.0-mm) feeding tubes (n = 19) were placed. Two patients from group 2 had feeding tubes placed on two separate occasions. The feeding tubes were inserted by the oral (n = 8) or nasal (n = 11) route under direct vision, using a 6.7-Fr (2.2-mm) fiberoptic scope through the feeding tube. MEASUREMENTS AND MAIN RESULTS: We visualized enteric structures clearly through the feeding tube in all subjects and patients. Based on visual landmarks, we advanced the feeding tube through the pylorus and into the duodenum in all individuals. Transpyloric tube placement was confirmed videoscopically (n = 19) and radiographically (n = 18). In three subjects from group 1, the feeding tube entered the first part of the duodenum, while, in the remainder of the subjects, the tube passed into or beyond the second portion of the duodenum. In eight (73%) of 11 attempts on the nine critically ill patients from group 2, the feeding tubes were advanced to the distal duodenum or jejunum. The time required for placement in group 2 ranged from 2 to 43 mins (mean 18 +/- 12 [SD]). The feeding tubes remained in place 10 +/- 4 days and patients met their estimated caloric needs within 24 hrs. Residual volumes of nutrition in the small bowel were < 5 mL. There were no documented episodes of aspiration. CONCLUSION: This new technique has the potential for rapid, accurate, and safe feeding tube placement in patients requiring nutritional support.

    Title Electrical Conductivity Values Used with the Bidomain Model of Cardiac Tissue.
    Date May 1997
    Journal Ieee Transactions on Bio-medical Engineering
    Excerpt

    Electrical conductivities in the bidomain model of cardiac tissue are expressed as functions of four parameters. These expressions allow simulations to be performed using nominal, equal, and reciprocal anisotropy without introducing undesired effects, such as length constant variations. Relative values of the bidomain conductivities are estimated to be: sigma iL = 1, sigma iT = 0.1, sigma eL = 1, and sigma eT = 0.4.

    Title Effect of a Perfusing Bath on the Rate of Rise of an Action Potential Propagating Through a Slab of Cardiac Tissue.
    Date February 1997
    Journal Annals of Biomedical Engineering
    Excerpt

    Experiments show that the rate of rise of the action potential depends on the direction of propagation in cardiac tissue. Two interpretations of these experiments have been presented: (i) the data are evidence of discrete propagation in cardiac tissue, and (ii) the data are an effect of the perfusing bath. In this paper we present a mathematical model that supports the second interpretation. We use the bidomain model to simulate action potential propagation through a slab of cardiac tissue perfused by a bath. We assume an intracellular potential distribution and solve the bidomain equations analytically for the transmembrane and extracellular potentials. The key assumption in our model is that the intracellular potential is independent of depth within the tissue. This assumption ensures that all three boundary conditions at the surface of a bidomain are satisfied simultaneously. One advantage of this model over previous numerical calculations is that we obtain an analytical solution for the transmembrane potential. The model predicts that the bath reduces the rate of rise of the transmembrane action potential at the tissue surface, and that this reduction depends on the direction of propagation. The model is consistent with the hypothesis that the perfusing bath causes the observed dependence of the action-potential rate of rise on the direction of propagation, and that this dependence has nothing to do with discrete properties of cardiac tissue.

    Title Highlights of Abstracts on Hormone-refractory Prostate Cancer Presented at the 1996 Annual Meeting of the American Society of Clinical Oncology.
    Date February 1997
    Journal Seminars in Oncology
    Excerpt

    Among the more interesting studies at the 1996 annual meeting of the American Society of Clinical Oncology that related to hormone-refractory prostate cancer were several that reported on the use of cis-retinoic acid both alone and in combination with interferon-alpha. Interferon-alpha and interferon-alpha plus cis-retinoic acid have antiproliferative effects in vitro against both PC3 and D-145 prostate cancer cells in culture. BCL2 expression is increased in androgen-independent cells, which may block apoptosis, and retinoids induce transforming growth factor-beta and apoptosis in prostate cancer cell lines. This regimen raises many questions. For example, it is difficult to determine what prostate-specific antigen (PSA) level one should expect from cis-retinoic acid, 4HPR, or any of the other differentiating agents. Should there be an increase in PSA1 Should one expect a slower decline in PSA when giving additional agents that are in fact cytotoxic? What is the significance of a changing level of PSA after this and other types of treatment? These and other questions remain to be determined in future studies.

    Title New Therapeutic Agents for Hormone-refractory Prostate Cancer.
    Date February 1997
    Journal Seminars in Oncology
    Excerpt

    The identification of active chemotherapeutic agents for use in the treatment of advanced hormone-refractory prostate cancer remains a priority of clinical research. An estimated 317,100 new cases will be diagnosed in 1996. This increased diagnosis of disease can be directly attributed to the widespread use of screening serum prostate-specific antigen. However, this has not been associated with a reduction in mortality; more than 41,000 men in the United States are expected to die of the disease this year. The natural history of hormone-resistant disease has remained unaltered, with patients having a median survival of only approximately 12 months. Use of surrogate endpoints, such as a reduction in prostate-specific antigen or improvement in pain, may be appropriate for the evaluation of novel agents or combinations. A number of promising new approaches have been recently tested and brought to trial, including combined antimicrotubular therapy, camptothecins, and matrix metalloproteinase inhibitors. It is only through the development of these and other novel compounds that we can hope to affect the natural course of prostate cancer.

    Title Vinblastine, Ifosfamide, and Gallium Nitrate--an Active New Regimen in Patients with Advanced Carcinoma of the Urothelium. A Phase Ii Trial of the Eastern Cooperative Oncology Group (e5892).
    Date January 1997
    Journal Cancer
    Excerpt

    BACKGROUND: This study was conducted to assess the efficacy and toxicity of vinblastine, ifosfamide, and gallium nitrate (VIG) as first-line chemotherapy in patients with locally advanced or metastatic carcinoma of the urothelium. METHODS: Forty-five eligible patients were enrolled and stratified into good and poor risk groups. Poor risk was defined as age > or = 70 years, 1 functioning kidney, and prior adjuvant or neoadjuvant chemotherapy. Good risk patients were treated with vinblastine, 0.11 mg/kg, on Days 1 and 2; ifosfamide, 1.2 g/m2, on Days 1-5 with mesna uroprotection; and gallium nitrate, 300 mg/m2, as a continuous infusion on Days 1-5. Poor risk patients received similar therapy with doses decreased by 20% and administered over 4 days. All patients received recombinant human granulocyte-colony stimulating factor. Cycles were repeated at 21-day intervals until disease progression or to a maximum of 6 cycles. RESULTS: Twenty of 45 patients (44%; 95% confidence interval, 30-60%) demonstrated an objective response, with 6 patients (13%) achieving a complete clinical response. The median duration of response was 47 weeks and the median survival duration for all patients was 10 months. Hematologic toxicity was significant, with 28 patients and 31 patients experiencing Grade 3 or 4 leukopenia and anemia, respectively. Six patients had clinically significant cardiac events (primarily atrial arrhythmias). There were two early deaths that were possibly treatment related. CONCLUSIONS: VIG is an active regimen in patients with advanced urothelial carcinoma. Toxicity is significant but acceptable. Patients with significant cardiac disease (especially arrhythmias) should be treated with extra care. The 4-day regimen appears to have similar therapeutic efficacy with less toxicity.

    Title Strength-interval Curves for Cardiac Tissue Predicted Using the Bidomain Model.
    Date December 1996
    Journal Journal of Cardiovascular Electrophysiology
    Excerpt

    INTRODUCTION: Strength-interval curves are predicted for unipolar anodal and cathodal stimulation of cardiac muscle. METHODS AND RESULTS: Cardiac tissue is represented by the bidomain model, and the active properties of the membrane are described by the Beeler-Reuter model. Two successive stimuli (S1 and S2) are delivered through a single extracellular electrode. The S2 threshold is determined as a function of the S1-S2 interval, for anodal and cathodal S2 stimuli with 2-, 5-, 10-, and 20-msec durations. Each of the resulting cathodal and anodal strength-interval curves is divided into two parts: one section corresponding to make stimulation (long intervals) and the other section corresponding to break stimulation (short intervals). Generally, the cathodal strength-interval curves are decreasing functions of interval, except for an anomalous section of the 20-msec duration cathodal curve in the interval range from 310 to 318 msec. At short intervals, the anodal strength-interval curve contains a deep dip, which is more prominent for longer S2 durations. The cathodal threshold is less than the anodal threshold for all intervals except those corresponding to the end of the refractory period. CONCLUSION: The bidomain model predicts complex anodal and cathodal strength-interval curves, with the anodal curve containing a dip (supernormal stimulation). These results resemble the experimental observations of Dekker.

    Title Chemotherapy for Advanced Bladder Cancer.
    Date November 1996
    Journal Seminars in Oncology
    Excerpt

    For the past 10 years, chemotherapy for advanced urothelial carcinoma has centered on cisplatin-based combination regimens such as methotrexate, vinblastine, doxorubicin and cisplatin (MVAC). Although such regimens have provided modest improvements in response rates, time to progression and survival, this has been achieved with moderate to severe toxicity. The median survival of patients with advanced disease remains at 12 to 13 months, and attempts to increase the dose intensity of existing regimens have been unsuccessful. Increasingly, attention has turned to the identification of new active agents, and a number have been recently identified, including paclitaxel, gemcitabine, ifosfamide, trimetrexate, piritrexim, and gallium nitrate. These agents will form the basis of new combination regimens that will attempt to improve on the advances in response and survival achieved with combination chemotherapy during the past decade.

    Title Cost- and Risk-benefit Considerations in the Management of Clinical Stage I Nonseminomatous Testicular Tumors.
    Date October 1996
    Journal Annals of Surgical Oncology
    Excerpt

    BACKGROUND: The high curability of clinical stage I nonseminomatous germ cell tumors (NSGCTs) and the availability of equally effective management options (retroperitoneal lymph node dissection [RPLND] and surveillance) allows for treatment decisions based on secondary end points, including sort- and long-term toxicity and cost relative to benefit. The purpose of this study was to perform cost-benefit and risk-benefit analyses of management options in clinical stage I NSGCT using data from the literature and Indiana University. METHODS: The overall costs for 100 patients undergoing a primary RPLND were compared with the total costs of 100 patients managed by surveillance for clinical stage I disease. These two options were then analyzed in terms of survival, late relapse, acute and chronic toxicity (including fertility), and perioperative morbidity. RESULTS: The overall costs of these two approaches were essentially identical. The two options were similar in terms of survival, although RPLND demonstrated superiority in terms of fertility, toxicity, and late relapse. CONCLUSIONS: The choice of nerve-sparing RPLND or surveillance in clinical stage I NSGCT patient cannot be made on the basis of cost as a discriminator. Instead, the decision should be made based on patient desires, physician expertise, biological predictors, and short- and long-term toxicity.

    Title The Role of Ifosfamide in the Treatment of Testicular and Urothelial Malignancies.
    Date September 1996
    Journal Seminars in Oncology
    Excerpt

    The activity of ifosfamide in genitourinary malignancies has been documented in testicular cancer and bladder cancer. The use of ifosfamide in germ cell tumors spans 20 years and has involved three distinct clinical settings: as a component of salvage therapy in cisplatin-resistant or recurrent disease, as part of initial therapy for patients with poor-risk disease, and as part of an ablative regimen for patients undergoing high-dose therapy with stem cell support. The use of ifosfamide in salvage therapy is well established, with approximately 40% to 50% of patients treated with a second-line ifosfamide-based regimen expected to achieve a complete response; however, only 25% of these patients will be long-term disease-free survivors. The drug's incorporation into standard-dose first-line regimens in patients with poor-risk disease has failed to improve the efficacy of therapy over standard, less toxic regimens. The value of ifosfamide as a component of high-dose salvage therapy with stem cell support in patients with refractory disease or of its increasing use as first-line therapy in patients with poor-risk features remains to be demonstrated. In urothelial carcinoma, data on the activity of ifosfamide are more sparse. Older trials in previously untreated patients in Japan and Egypt suggest an overall response rate of 30% to 40%, while a recent Eastern Cooperative Oncology Group trial in patients with prior chemotherapy reported a response rate of 20%. Ifosfamide has therefore been identified as one of six new active agents in urothelial cancer, and trials of combination regimens including ifosfamide are under way. The vinblastine/ifosfamide/gallium nitrate (VIG) combination was tested in a pilot study at Indiana University with a 67% overall response rate and in a confirmatory Eastern Cooperative Oncology Group phase II trial with a 56% response rate. Trials of ifosfamide plus paclitaxel with or without cisplatin are ongoing, but the role of ifosfamide in the routine therapy of urothelial malignancies remains to be determined.

    Title Sulfasalazine Pulmonary Toxicity in Ulcerative Colitis Mimicking Clinical Features of Wegener's Granulomatosis.
    Date September 1996
    Journal Chest
    Excerpt

    The centrally accentuated antineutrophil cytoplasmic antibody test (c-ANCA) is widely regarded as a sensitive and specific marker for Wegener's granulomatosis (WG). There are increasing reports, however, of false-positive c-ANCAs, usually in the setting of other vasculidities. We report a case of a 27-year-old man with ulcerative colitis who developed pulmonary symptoms, peripheral nodular lung infiltrates, and an elevated c-ANCA suggesting WG. Chest CT and open lung biopsy specimens were consistent with WG. The symptoms and pulmonary infiltrates resolved after discontinuation of sulfasalazine therapy. The c-ANCA remained elevated due to the occurrence of false-positive values in ulcerative colitis. We conclude sulfasalazine toxicity can mimic clinical aspects of WG and that c-ANCA testing should be interpreted with caution in patients with ulcerative colitis.

    Title Evaluating Pleural Fluid.
    Date August 1996
    Journal Chest
    Title Ifosfamide in the Treatment of Bladder Cancer.
    Date August 1996
    Journal Seminars in Oncology
    Excerpt

    Although chemotherapy for advanced bladder cancer has historically been based on cisplatin-based combination regimens, the limitations of these regimens both in terms of efficacy and toxicity are now widely appreciated. In response to these limitations, other single agents have been studied, and a number have demonstrated significant activity, including ifosfamide. Older single-agent phase II trials of ifosfamide in previously untreated patients suggested a response rate as high as 40%, including objective responses in nontransitional histologies. More recently, the Eastern Cooperative Oncology Group has defined the response rate for ifosfamide in patients with one prior chemotherapy regimen to be 20%, with central nervous system toxicity, nephrotoxicity, and myelosuppression as the dose-limiting toxicities. Phase II trials of ifosfamide in combination with vinblastine and gallium nitrate have been completed, while others, including trials with paclitaxel alone or paclitaxel plus cisplatin, are ongoing. The precise role of ifosfamide in the therapy of advanced bladder cancer is in the process of being defined. However, the frequency of occult or clinically evident renal insufficiency in this patient population may limit ifosfamide's role in this disease.

    Title Response of Bidimensionally Measurable Metastases to Flutamide Withdrawal in a Patient with Advanced Prostate Cancer.
    Date August 1996
    Journal Indiana Medicine : the Journal of the Indiana State Medical Association
    Title Prospective, Randomized Trial of Survivor Values of Cardiac Index, Oxygen Delivery, and Oxygen Consumption As Resuscitation Endpoints in Severe Trauma.
    Date June 1996
    Journal The Journal of Trauma
    Title Mechanisms for Electrical Stimulation of Excitable Tissue.
    Date April 1996
    Journal Critical Reviews in Biomedical Engineering
    Excerpt

    Electric fields excite electrically active tissue by several mechanisms. A long, straight, uniform fiber is polarized by an activating function, proportional to the axial gradient of the axial electric field. During unipolar anodal stimulation, the activating function results in two areas of depolarization (virtual cathodes) that are responsible for anode-make stimulation. During unipolar cathodal stimulation, the virtual anodes can be exploited to produce unidirectional propagation and physiological recruitment of axons. Anode-break stimulation of nerves arises from the intrinsic properties of the sodium channel kinetics; cathode-break stimulation in nerves is anode-break stimulation at a virtual anode. The activating function applies to magnetic stimulation as well as to electric stimulation. Other important mechanisms of stimulation arise if the fiber is terminated, nonuniform, or curved. In the brain, cortical neurons are excited when the electric field is directed from the dendrites toward the axon. Possible mechanisms for cortical excitation are the impedance mismatch between the axon and dendritic tree, and the axon bending as it enters the white matter. Transcranial magnetic stimulation differs from transcranial electric stimulation because during magnetic stimulation the electric field is parallel to the brain surface, whereas during electric stimulation the electric field has components both parallel and perpendicular to the brain surface. Cardiac tissue can be represented by use of the bidomain model. This model predicts that a point-source stimulus results in adjacent areas of depolarized and hyperpolarized tissue. The presence of virtual anodes during cathodal stimulation is analogous to the creation of virtual anodes along a one-dimensional fiber by the activating function. Anode- and cathode-break stimulation both occur in cardiac tissue, but the mechanism may be different than for nerve and may depend on diffusion of depolarization into a previously hyperpolarized region. Electrical stimulation of cardiac tissue can cause reentry through a critical point mechanism. Two mechanisms for defibrillation have been hypothesized: (1) the relatively high junctional resistance between cardiac cells causes each cell to be depolarized on one side and hyperpolarized on the other; and (2) the fiber tracts within the heart behave like individual fibers, with fiber curvature providing a mechanism for polarization. Similarities among nerve, brain, and cardiac stimulation are emphasized.

    Title A Mathematical Model of Make and Break Electrical Stimulation of Cardiac Tissue by a Unipolar Anode or Cathode.
    Date February 1996
    Journal Ieee Transactions on Bio-medical Engineering
    Excerpt

    Numerical simulations of electrical stimulation of cardiac tissue using a unipolar extracellular electrode were performed. The bidomain model with unequal anisotropy ratios represented the tissue, and the Beeler-Reuter model represented the active membrane properties. Four types of excitation were considered: cathode make (CM), anode make (AM), cathode break (CB), and anode break (AB). The mechanisms of excitation were: for CM, tissue under the cathode was depolarized to threshold; for AM, tissue at a virtual cathode was depolarized to threshold; for CB, a long cathodal pulse produced a steady-state depolarization under the cathode and hyperpolarization at a virtual anode. At the end (break) of the pulse, the depolarization diffused into the hyperpolarized tissue, resulting in excitation. For AB, a long anodal pulse produced a steady-state hyperpolarization under the anode and depolarization at a virtual cathode. At the end (break) of the pulse, the depolarization diffused into the hyperpolarized tissue, resulting in excitation. For AB stimulation, decay of the hyperpolarization faster than that of the depolarization was necessary. The thresholds for rheobase and diastolic CM, AM, CB, and AB stimulation were 0.038, 0.41, 0.49, and 5.3 mA, respectively, for an electrode length of 1 mm and a surface area of 1.5 mm2. Threshold increased as the size of the electrode increased. The strength-duration curves for CM and AM were similar except when the duration was shorter than 0.2 ms, in which case the AM threshold rose more quickly with decreasing duration than did the CM threshold. CM and AM resulted in similar strength-frequency curves. The model agrees qualitatively, but (in some cases) not quantitatively, with experiments.

    Title Eosinophilic Pneumonia and Respiratory Failure Associated with a Trazodone Overdose.
    Date January 1996
    Journal American Journal of Respiratory and Critical Care Medicine
    Excerpt

    Drug-induced eosinophilic lung disease commonly presents as a simple pulmonary eosinophilia-like syndrome consisting of transient pulmonary infiltrates, peripheral eosinophilia, and mild pulmonary symptoms that disappear promptly upon withdrawal of the offending medication. However, a more fulminant presentation most resembling acute eosinophilic pneumonia has been recently described. We present a patient with BAL-confirmed eosinophilic pneumonia (EP) and respiratory failure after a trazodone overdose. This is the first case of EP associated with trazodone and only the third drug-mediated EP reported to precipitate respiratory failure.

    Title Digital Clubbing Associated with Polymyositis and Interstitial Lung Disease.
    Date January 1996
    Journal Chest
    Excerpt

    Clubbing of the fingers is commonly associated with interstitial lung diseases (ILDs). Although ILD occurs in as many as 40% of patients with polymyositis/dermatomyositis (PM/DM), clubbing of the digits has never been reported to occur in patients with PM/DM and ILD. We report the first case of clubbing associated with PM/DM and ILD.

    Title The Role of Paclitaxel in the Therapy of Bladder Cancer.
    Date December 1995
    Journal Seminars in Oncology
    Excerpt

    Although significant strides have been made in the development of effective chemotherapy for metastatic bladder cancer, those benefits have plateaued and prompted a search for new, active agents. The most active of a new generation of investigational agents is paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ). The only single-agent phase II trial to date, which used paclitaxel at a dose of 250 mg/m2 by 24-hour infusion every 3 weeks, resulted in a 42% response rate and a 27% complete response rate in previously untreated patients. With granulocyte colony-stimulating factor support, this therapy was well tolerated, with fewer than 10% of patients developing neurtropenic fever during therapy. Paclitaxel's potential as a radiation sensitizer and its relatively low renal excretion make it an attractive agent for use in patients with urothelial carcinoma. The goal of ongoing and planned clinical trials will be to (1) identify potential paclitaxel-containing combination regimens, (2) define the optimal dose and schedule of administration in patients with bladder cancer, and (3) define the activity of paclitaxel in previously treated patients.

    Title A Mathematical Model of Agonist-induced Propagation of Calcium Waves in Astrocytes.
    Date November 1995
    Journal Cell Calcium
    Excerpt

    In astrocytes, calcium signals evoked by neurotransmitters appear as waves within single cells, which spread to other cells in the network. Recent analysis has shown that waves are initiated at a single invariant site in the cell and propagated within the cell in a nonlinear and saltatory manner by regenerative amplification at specific predestined cellular sites. In order to gain insight into local cellular waves and wave collisions we have developed a mathematical model of cellular wave amplification loci. This model is in good agreement with experimental data which includes: ambient calcium gradients in resting cells, wave origination and local amplification and generation of local waves. As observed in experiments, the model also predicts that different locations in the cell can have different frequencies of oscillation. The amplification loci are thought to be specialized areas of the endoplasmic reticulum membrane containing a higher density or higher sensitivity of IP3 receptors. Our analysis suggests that the cellular loci act as weakly coupled oscillators each with its intrinsic latency and frequency of oscillation. Thus the appearance of the propagated calcium wave may be a reflection of these differences rather than an actual diffusional wave propagation.

    Title Magnetic Stimulation of Axons in a Nerve Bundle: Effects of Current Redistribution in the Bundle.
    Date August 1995
    Journal Annals of Biomedical Engineering
    Excerpt

    Recently, we developed a model of magnetic stimulation of a concentric axon in an anisotropic nerve bundle. In that earlier paper, we considered a single axon surrounded by a nerve bundle represented as a homogeneous anisotropic monodomain medium. In this paper we extend our previous calculations to examine excitation of axons within a nerve bundle without neglecting the presence of other axons in the nerve bundle. A three-dimensional axial symmetry volume conductor model is used to determine the transmembrane potential response along an axon due to induced electric fields produced by a toroidal coil. Our principal objective is to examine the effect of current redistribution to other axons in the bundle on excitation characteristics. We derive the transmembrane potential along an axon for two currently available models of current redistribution: the biodomain model and the spatial--frequency monodomain model. Results indicate that a reduction in the transmembrane potential along an axon due to the presence of other nerve fibers in the bundle is observed. Axons located at the periphery of a nerve bundle have lower thresholds and different excitation sites compared with axons located near the center of a nerve bundle.

    Title Preliminary Experience with Paclitaxel in Advanced Bladder Cancer.
    Date July 1995
    Journal Seminars in Oncology
    Excerpt

    In a phase II Eastern Cooperative Oncology Group trial, single-agent paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) was administered to 26 patients with advanced urothelial cancer who had not received prior systemic chemotherapy. Paclitaxel was given at a dose of 250 mg/m2 by 24-hour continuous infusion along with prophylactic granulocyte colony-stimulating factor. Despite a 23% incidence of grade 3 or 4 neutropenia, only two patients developed febrile neutropenia; other hematologic toxicity was mild and not dose limiting. Nonhematologic toxicity included grade 3 neurologic toxicity in three patients, grade 3 mucositis in three patients, and grade 4 diarrhea in one patient. Eleven of 26 (42%) patients had an objective response (seven clinical complete responses, four partial responses), two had stable disease as their best response, and 13 patients progressed while on therapy. Preliminary response data suggest significant single-agent activity for paclitaxel in transitional cell carcinoma of the bladder. Future studies will evaluate paclitaxel-containing combination regimens as first-line therapy for advanced disease and define the role of paclitaxel in salvage therapy following conventional chemotherapy.

    Title Cost and Risk Benefit in the Management of Clinical Stage Ii Nonseminomatous Testicular Tumors.
    Date July 1995
    Journal Cancer
    Excerpt

    BACKGROUND. Two similarly effective treatment options exist for managing clinical low volume Stage II nonseminomatous germ cell testis tumors (NSGCT). Primary retroperitoneal lymph node dissection (RPLND) (with immediate adjuvant chemotherapy or chemotherapy at relapse) and primary chemotherapy have resulted in similar survival rates in large series. Because the chance for cure is similar with either approach, the cost and morbidity of therapy should be considered important discriminating factors in deciding which option to pursue for an individual patient. The purpose of this study was to undertake a cost/benefit and risk/benefit analysis of these two options using data and costs from the Indiana University experience. METHODS. The overall direct costs for 100 patients undergoing primary RPLND were compared with the total direct costs of 100 patients receiving primary chemotherapy for low volume Stage II disease, including the costs of adjuvant chemotherapy, salvage chemotherapy in relapsing patients, and routine follow-up for a 5-year period. In addition, the two treatment options were analyzed relative to survival, late relapse, acute and chronic toxicity, (including fertility), and perioperative morbidity. RESULTS. In this analysis, the overall 5-year costs of RPLND were significantly less than the costs of primary chemotherapy. The two options did not differ significantly in terms of survival or quality of life. Patients receiving RPLND were found to have an advantage also in terms of fertility, toxicity, and late relapse. CONCLUSIONS. Treatment decisions for patients with clinical low volume Stage II NSGCT may be based on cost/benefit and risk/benefit considerations, including relative toxicity, long term cure rate, and individual patient preference. Patient compliance with follow-up, the specific expertise of the physicians, and the availability of specialized therapeutic care ultimately may influence such decisions.

    Title Palliative Chemotherapy in Advanced Bladder Cancer.
    Date June 1995
    Journal Seminars in Oncology
    Excerpt

    Transitional cell carcinoma of the urothelium is a chemosensitive tumor, and combination chemotherapy can provide not only palliation but a modest survival advantage in patients with advanced disease. While the four-drug regimen methotrexate/vinblastine/doxorubicin/cisplatin remains the standard combination therapy, its toxicity can be formidable. The overall response rate in phase III trials with this combination is in the 35% to 45% range, with a median survival duration in treated patients of only 12 months. Although attempts to decrease the toxicity of the regimen with the addition of hematopoietic growth factors have been successful, attempts to increase its efficacy by dose escalation have not. This has prompted a search for new active agents that can be incorporated into alternative combination regimens. Recently, activity has been noted for several drugs (including gallium nitrate, ifosfamide, and gemcitabine). In untreated patients, paclitaxel has demonstrated significant activity and is certainly among the most active single agents in the treatment of advanced bladder cancer. Studies incorporating these new agents into novel combination regimens are ongoing, with the goal of providing a regimen that has superior efficacy in advanced disease and, ultimately, in earlier stages of disease with curative intent.

    Title Advanced Bladder Cancer: the Need to Identify New Agents in the Post-m-vac (methotrexate, Vinblastine, Doxorubicin and Cisplatin) World.
    Date March 1995
    Journal The Journal of Urology
    Title Examining the Pleura.
    Date March 1995
    Journal Chest
    Title Salvage Chemotherapy for Recurrent Germ Cell Cancer.
    Date January 1995
    Journal Seminars in Oncology
    Excerpt

    Clinical trials of chemotherapy in germ cell cancer have explored the full range of the relationship of chemotherapy dose and intensity. In good-risk patients, successful efforts have diminished the duration of treatment or number of drugs required to reliably cure the illness. In patients with a poor prognosis, efforts to intensify therapy have been undertaken. In the setting of disease recurrence after primary chemotherapy, the outlook is considerably less hopeful, as only 20% to 30% of patients survive recurrent illness. Current standard treatment in this setting is combination therapy with ifosfamide and cisplatin, given with either etoposide or vinblastine. High-dose chemotherapy with bone marrow or peripheral blood stem cell support can cure a small portion of selected patients with multiple recurrences of germ cell cancer. The impact of earlier treatment with high-dose chemotherapy (either as initial salvage therapy or primary treatment) is less certain. Clinical trials in these settings have not yet demonstrated a definite advantage over less toxic conventional-dose therapies.

    Title Significant Activity of Paclitaxel in Advanced Transitional-cell Carcinoma of the Urothelium: a Phase Ii Trial of the Eastern Cooperative Oncology Group.
    Date December 1994
    Journal Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
    Excerpt

    PURPOSE: To assess the efficacy and toxicity of single-agent paclitaxel as first-line chemotherapy in patients with locally advanced or metastatic transitional-cell carcinoma of the urothelium. PATIENTS AND METHODS: Twenty-six eligible patients were enrolled onto this cooperative group study and treated with paclitaxel at a dosage of 250 mg/m2 by 24-hour continuous infusion every 21 days until progression or patient intolerance. All patients received recombinant human granulocyte colony-stimulating factor (rhG-CSF) at 5 micrograms/kg/d for at least 10 days during each cycle. RESULTS: Eleven of 26 patients (42%; 95% confidence interval [CI], 23% to 63%) demonstrated an objective response, with seven achieving a complete clinical response (CR) (27%; 95% CI, 12% to 48%) and four (15%) a partial response (PR). The median duration of response in the 11 responders is 7+ months (range, 4 to 17), with five responders (four CRs, one PR) remaining progression-free at 5, 6, 10, 12, and 16 months from the start of therapy. The estimated median survival duration for all patients is 8.4 months. Hematologic toxicity consisted of anemia (12% grade 3) and granulocytopenia (4% grade 3, 19% grade 4), with two patients developing granulocytopenic fevers. Nonhematologic toxicity included grade 3 mucositis in 11%, grade 3 neuropathy in 11%, and grade 4 diarrhea in 4%. CONCLUSION: Single-agent paclitaxel at this dosage and schedule is one of the most active single agents in previously untreated patients with advanced urothelial carcinoma, and is well tolerated by this patient population when given with hematopoetic growth factor support.

    Title Phase Ii Trial of Vinblastine, Ifosfamide, and Gallium Combination Chemotherapy in Metastatic Urothelial Carcinoma.
    Date December 1994
    Journal Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
    Excerpt

    PURPOSE: Phase II trial in metastatic urothelial carcinoma using a novel combination chemotherapy regimen consisting of vinblastine, ifosfamide, and gallium nitrate (VIG). PATIENTS AND METHODS: Twenty-seven patients were entered onto this phase II study. Dosages were vinblastine 0.11 mg/kg days 1 and 2, ifosfamide 1.2 gm/m2 days 1 through 5 (with mesna), and gallium 300 mg/m2 as a 24-hour infusion days 1 through 5, with calcitriol (1,25-dihydroxycholecalciferol) 0.5 microgram/d orally starting 3 days before each course (except the first) and continuing throughout gallium administration, plus recombinant human granulocyte colony-stimulating factor (rhG-CSF) (filgrastim) 5 micrograms/kg/d days 7 through 16. Courses were repeated every 21 days for a maximum of six cycles. RESULTS: The major toxicity was granulocytopenia. Fifteen patients (55.6%) had grade 3 or 4 granulocytopenia, including eight patients with granulocytopenic fevers. Eleven patients had grade 3 or 4 anemia and four had grade 3 or 4 nephrotoxicity, which was reversible. Other grade 3 to 4 toxicities included hypocalcemia (three patients), thrombocytopenia (two), encephalopathy (one), and temporary blindness (one). There was one treatment-related mortality. Toxicity was more severe in patients older than 70 years and those with prior pelvic irradiation, prior cisplatin adjuvant therapy, or prior nephrectomy. We now decrease VIG by 20% in this patient population. Eighteen patients (67%) achieved an objective response, including 11 (41%) who attained a disease-free status (five with VIG alone and six with subsequent surgery). Median duration of remission was 20 weeks, with five patients still in remission at 22+ to 56+ weeks. CONCLUSION: VIG combination chemotherapy is very active in patients with metastatic urothelial carcinoma. Toxicity was significant but manageable.

    Title Combination Chemotherapy in Advanced Prostate Cancer: a Silk Purse?
    Date November 1994
    Journal Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
    Title A Theoretical Model for Magneto-acoustic Imaging of Bioelectric Currents.
    Date October 1994
    Journal Ieee Transactions on Bio-medical Engineering
    Excerpt

    A theoretical model of magneto-acoustic current imaging is derived, based on fundamental equations of continuum mechanics and electromagnetism. In electrically active tissue, the interaction between an applied magnetic field, B, and action currents, J, creates a pressure distribution. In the near field limit, this pressure obeys Poisson's equation, with a source term (delta x J).B. The displacement and pressure fields are calculated for a dipole (q), oriented either parallel or perpendicular to the applied magnetic field (B), at the center of an elastic, conducting sphere (radius a, shear modulus G). Surface displacements are on the order of qB/(4 pi Ga), which is about 1 nm for typical biological parameters. If the applied magnetic field is changing with time, eddy currents induced in the tissue may be larger than the action currents themselves. The frequency of the pressure and displacement arising from these eddy currents, however, is twice the frequency of the applied magnetic field, so it may be possible to eliminate this artifact by filtering or lock-in techniques. Magneto-acoustic and biomagnetic measurements both image delta x J in a similar way, although magneto-acoustic current imaging has the disadvantage that acoustic properties vary among tissues to a greater degree than do magnetic properties.

    Title Electrical Stimulation of Cardiac Tissue: a Bidomain Model with Active Membrane Properties.
    Date August 1994
    Journal Ieee Transactions on Bio-medical Engineering
    Excerpt

    Numerical calculations simulated the response of cardiac muscle to stimulation by electrical current. The bidomain model with unequal anisotropy ratios represented the tissue, and parallel leak and active sodium channels represented the membrane conductance. The speed of the wavefront was faster in the direction parallel to the myocardial fibers than in the direction perpendicular to them. However, for cathodal stimulation well above threshold, the wavefront originated farther from the cathode in the direction perpendicular to the myocardial fibers than in the direction parallel to them, consistent with observations of a dog-bone-shaped virtual cathode made by Wikswo et al., Circ. Res. 68:513-530, 1991. The model showed that the virtual cathode size and shape were dependent upon both membrane and tissue conductivities. Increasing the peak sodium conductance or reducing the transverse intracellular conductivity accentuated the dog-bone shape, while the opposite change caused the virtual cathode to become more elliptical, with the major axis of the ellipse transverse to the fiber direction. A cathodal stimulus created regions of hyperpolarization that slowed conduction of the wavefront propagating parallel to the fibers. An anodal stimulus evoked a wavefront with a complex shape; activation originated from two depolarized regions 1 to 2 mm from the stimulus site along the fiber direction. The threshold current strength (0.5 ms duration pulse) for a cathodal stimulus was 0.048 mA, and for an anodal stimulus was 0.67 mA. When the model was modified to simulate the effect of electropermeabilization, which may be present when the transmembrane potential reaches very large values near the stimulating electrode, our qualitative conclusions remained unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)

    Title Algorithm for the Design of Magnetic Stimulation Coils.
    Date August 1994
    Journal Medical & Biological Engineering & Computing
    Title Roentgenographic Evaluation of the Cervical Spine. A Selective Approach.
    Date July 1994
    Journal Archives of Surgery (chicago, Ill. : 1960)
    Excerpt

    BACKGROUND: To determine if routine radiographic evaluation of the cervical spine could be eliminated in the alert, sober trauma patient who has no neck pain, tenderness, or other major injuries without a significant increase in missed occult injury. DESIGN: Prospective cohort study. SETTING: Emergency department and general surgery service at a military tertiary medical center. MAIN OUTCOME MEASURE: Those patients with cervical spine injuries. RESULTS: Sixteen patients (2%) had cervical spine injuries, all had signs and/or symptoms of their injury on presentation. Ninety-six patients (14%) who were not intoxicated and had no neck pain, tenderness, or other major injuries were evaluated. None of these patients had abnormal cervical spine studies. Two hundred ninety patients (43%) were followed up between 30 to 150 days. No missed injuries were noted. CONCLUSIONS: These results indicate that blunt trauma patients may not require cervical spine roentgenography if they meet the following criteria: absence of mental status changes, intoxication, neck pain or tenderness, neurologic signs or symptoms, or simultaneous major distracting injury. Because of the small incidence of cervical spine injuries, further studies are necessary to evaluate the positive predictive value of history and physical examination of the cervical spine in a trauma patient.

    Title Incidence of Neutropenic Fever in Patients Treated with Standard-dose Combination Chemotherapy for Small-cell Lung Cancer and the Cost Impact of Treatment with Granulocyte Colony-stimulating Factor.
    Date June 1994
    Journal Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
    Excerpt

    PURPOSE: We sought to determine the incidence of neutropenic fever associated with the use of standard-dose combination chemotherapy for small-cell lung cancer (SCLC) and to use these data as a template to analyze the costs and benefits of the routine use of granulocyte colony-stimulating factor (G-CSF). PATIENTS AND METHODS: We retrospectively reviewed records of 137 consecutive, unselected patients with SCLC treated with combination chemotherapy from January 1987 to March 1992. Admission criteria for neutropenic fever were temperature > or = 38.5 degrees C and an absolute neutrophil count < or = 500/microL. Neutropenic fevers were managed with a 25% dose reduction of the myelosuppressive drugs in subsequent cycles. Charge estimates for hospitalization ($1,244 per day) and G-CSF use ($2,027 per course) were estimated by reviewing charges to patients at Indiana University hospitalized for neutropenic fever or treated with outpatient G-CSF. We imposed assumptions from the Neupogen (filgrastim; Amgen Inc, Thousand Oaks, CA) licensing trial regarding the effectiveness of G-CSF and the Indiana University charge estimates on three models of G-CSF use: (1) preemptive--with all courses of chemotherapy, (2) reactive--with all cycles of chemotherapy following a neutropenic fever, and (3) dose reduction only (no G-CSF)--to derive charge estimates for G-CSF use. RESULTS: Records of 137 patients with SCLC were identified and reviewed. The incidence of neutropenic fever was 12% in the first cycle of chemotherapy, and 18% overall, compared with the placebo- and G-CSF-treated arms of the Neupogen licensing trial, in which the incidence of neutropenic fever was 77% and 40%, respectively. Other therapeutic outcomes, such as neutropenic septic deaths, response rates, and survival, were comparable. We derived the following charge estimates for the three models of G-CSF: (1) preemptive--total charges = $1,287,481; (2) reactive--total charges = $276,154; and (3) dose reduction only--total charges = $192,820. CONCLUSION: The incidence of neutropenic fever with standard-dose chemotherapy for SCLC was 18%. Routine use of G-CSF in SCLC patients treated with standard-dose chemotherapy appears to be expensive and is not associated with an obvious therapeutic benefit or cost savings. We suggest that careful analysis of the incidence of infectious complications, rather than granulocyte nadir and duration, be performed, and that clinical guidelines for the use of these effective, but expensive, products be developed.

    Title The Time Constants of Motor and Sensory Peripheral Nerve Fibers Measured with the Method of Latent Addition.
    Date May 1994
    Journal Electroencephalography and Clinical Neurophysiology
    Excerpt

    The time constants of motor and sensory fibers in the human ulnar, median and tibial nerves were determined using the method of latent addition. Two square-wave stimuli were applied: the first one was subthreshold and the second, at various delays relative to the first, was adjusted to achieve threshold activation. Strength-delay curves were obtained, from which the time constant was determined using a mathematical model. Sensory fibers had time constants that were about 3 times the time constant for motor fibers. The strength-delay curves gave similar time constants as those obtained from strength-duration curves.

    Title Early Salvage Therapy for Germ Cell Cancer Using High Dose Chemotherapy with Autologous Bone Marrow Support.
    Date May 1994
    Journal Cancer
    Excerpt

    BACKGROUND. Patients with relapsed germ cell cancer (GCT) have a poor prognosis when treated solely with conventional chemotherapy; high dose chemotherapy with autologous bone marrow rescue (ABMR) has shown curative potential in patients with relapsed and refractory GCT. This protocol was designed to incorporate high dose therapy with initial salvage therapy. METHODS. Twenty-three patients in the first relapse of GCT received two cycles of conventional dose cisplatin-based therapy (either vinblastine, ifosfamide and cisplatin [VeIP] or cisplatin, vinblastine, and bleomycin) followed by carboplatin (1500-2100 mg/m2) and etoposide (1200-2250 mg/m2) given in divided doses with ABMR. RESULTS. Eighteen of 23 patients completed protocol therapy including high dose therapy. Five of 23 did not undergo high dose therapy due to: insurance refusal (1); patient refusal (1); active infection (1); central nervous system metastasis (1); death on induction therapy (1). Response to two courses of conventional dose induction therapy (N = 23) was complete response (CR), 8; partial response (PR), 12; stable disease (SD), 2; and toxic death, 1. Two of five individuals who did not continue with high dose therapy are alive and progression free after conventional salvage therapy and surgery with at least 24 months of follow-up. Outcome after high dose therapy (N = 18) was CR, 9, PR, 6, SD, 1, and PD, 2. Two patients who were in PR after receiving two cycles of conventional dose therapy were converted to CR using high dose therapy. There was only one treatment-related death in this cohort, a septic death during VeIP induction therapy. There were no transplant related deaths. Of those patients completing high dose therapy, 7 of 18 (39%) survived, progression free with a median follow-up of 26 months, 2 of 18 are alive with active disease, and 9 of 18 died of recurrent disease. CONCLUSIONS. Conventional dose induction therapy followed by consolidation with high dose therapy and ABMR is well tolerated and provides prolonged disease-free survival in some patients with chemosensitive relapsed germ cell cancer.

    Title In Vitro Evaluation of a 4-leaf Coil Design for Magnetic Stimulation of Peripheral Nerve.
    Date May 1994
    Journal Electroencephalography and Clinical Neurophysiology
    Excerpt

    The performance of a 4-leaf magnetic coil was evaluated during magnetic stimulation of a peripheral nerve in vitro. The site of stimulation was below the coil center, and a 90 degrees rotation of the coil was equivalent to a change in current polarity. A hyperpolarizing magnetic stimulus failed to slow or block a propagating action potential.

    Title The Response of a Spherical Heart to a Uniform Electric Field: a Bidomain Analysis of Cardiac Stimulation.
    Date February 1994
    Journal Ieee Transactions on Bio-medical Engineering
    Excerpt

    A mathematical model describing electrical stimulation of the heart is developed, in which a uniform electric field is applied to a spherical shell of cardiac tissue. The electrical properties of the tissue are characterized using the bidomain model. Analytical expressions for the induced transmembrane potential are derived for the cases of equal anisotropy ratios in the intracellular and interstitial (extracellular) spaces, and no transverse coupling between fibers. Numerical calculations of the transmembrane potential are also performed using realistic electrical conductivities. The model illustrates several mechanisms for polarization of the cell membrane, which can be divided into two categories, depending on if they polarize fibers at the heart surface only or if they polarize fibers both at the surface and within the bulk of the tissue. The latter mechanisms can be classified further according to whether they originate from continuous or discrete properties of cardiac tissue. If cardiac tissue had equal anisotropy ratios, a large membrane polarization would be induced at the heart surface that would become negligible a few length constants into the tissue. If cardiac tissue were continuous and had no transverse coupling between fibers, a membrane polarization would be induced throughout the bulk that would arise from an "activating function" similar to the one used to describe neural stimulation. Polarization would occur if the fibers were curving, if the cross-sectional area of the tissue were changing (fiber branching), or both. The numerically calculated transmembrane potential is intermediate between those predicted using the assumptions of equal anisotropy ratios and no transverse coupling between fibers. Although discrete properties of cardiac tissue are not incorporated into this model, an estimate of their effect indicates that the amplitude of the polarization caused by the resistance of the cellular junctions is similar to that caused by fiber curvature and branching. The spatial distribution of the polarization, however, is quite different.

    Title 5-azacytidine (nsc 102816) in Refractory Germ Cell Tumors. A Phase Ii Trial of the Eastern Cooperative Oncology Group.
    Date January 1994
    Journal Investigational New Drugs
    Title How Well Does a Three-sphere Model Predict Positions of Dipoles in a Realistically Shaped Head?
    Date November 1993
    Journal Electroencephalography and Clinical Neurophysiology
    Excerpt

    The electrical potential produced by a dipole in the temporal or frontal lobe was calculated for a realistically shaped scalp, skull, and brain. This potential distribution was then used with a 3-sphere model to predict the position, orientation, and strength of the dipole source. The original and predicted dipole positions differed by an average of 1.97 cm, with a difference of more than 4 cm in some cases. Control calculations demonstrated that this difference was not caused by numerical artifacts in the computation, but instead was due to a true difference between the 3-sphere and realistically shaped head models.

    Title The Use of a Cap-shaped Coil for Transcranial Magnetic Stimulation of the Motor Cortex.
    Date November 1993
    Journal Journal of Clinical Neurophysiology : Official Publication of the American Electroencephalographic Society
    Excerpt

    A cap-shaped coil is introduced as a superior design for inducing transcranial magnetic motor evoked potentials for spinal cord monitoring. Evaluation of the magnetic characteristics of the cap coil showed higher induced electrical fields at and below the depth of the cortical surface, compared to a 9-cm, butterfly-shaped coil. Twenty normal adults were stimulated with the cap coil and a 9-cm round coil in three positions. Compound muscle action potentials were recorded from the left and right abductor digiti minimi and anterior tibialis muscles. The cap coil induced potentials with higher intensities and lower variability between consecutive stimuli. The cap coil was also more able to simultaneously induce motor evoked potentials from the four muscles studied. This coil design should provide superior means of inducing transcranial magnetic motor evoked potentials in multiple muscles.

    Title Taxol in Advanced, Hormone-refractory Carcinoma of the Prostate. A Phase Ii Trial of the Eastern Cooperative Oncology Group.
    Date November 1993
    Journal Cancer
    Excerpt

    BACKGROUND. Recent clinical trials have documented activity for combinations of chemotherapeutic agents that target the microtubular apparatus in patients with hormone-refractory prostate cancer. Taxol has a novel antimicrotubular mechanism, acting by stabilizing polymerized tubulin. METHODS. Twenty-three patients with hormone-refractory prostate cancer and bidimensionally measurable disease were treated with Taxol by 24-hour continuous infusion at 135-170 mg/M2 every 21 days for a maximum of 6 cycles. RESULTS. Eighty-five courses of Taxol were administered to 23 patients. One patient (4.3%) experienced a partial response lasting 9 months, and four other patients with radiographically stable disease had minor reductions in the serum prostate-specific antigen (PSA) of 16-24%. Eleven patients (47.8%) had stable disease, and progressive disease developed in 9 patients (39.1%) during therapy. Median survival was 9 months. Leukopenia was the dose-limiting toxicity with 13% of patients having Grade 3 and 61% having Grade 4 toxicity, and granulocytopenic fever developed in 26%. Three patients experienced sudden cardiovascular events while participating in the study, including one patient with a nonfatal, non-Q-wave myocardial infarction that occurred during a taxol infusion, and two patients who had sudden deaths 9 days and 30 days after receiving their last taxol dose, respectively. CONCLUSIONS. In the subset of patients with hormone-refractory prostate cancer and bidimensionally measurable disease, Taxol at this dosage has only minor activity.

    Title Dose Intensity in Germ Cell Cancer: Continued Lessons from a Model Neoplasm.
    Date May 1993
    Journal European Urology
    Excerpt

    Clinical trials of chemotherapy in germ cell cancer have explored the full range of dose intensity. In good risk patients, efforts have been successful in diminishing duration of treatment or number of drugs required to cure the illness reliably. In patients with poor prognosis, efforts to intensify therapy have been undertaken. It has been difficult to demonstrate improved outcome using higher doses of conventional agents in the setting of primary treatment of poor risk disease. It is more likely that improvement will come with the discovery of new active agents. High dose chemotherapy with bone marrow or peripheral blood stem cell support can cure a small portion of selected patients with multiple recurrences of germ cell cancer. The impact of earlier treatment with high dose chemotherapy as initial salvage therapy or even primary treatment is less certain. Clinical trials in these settings have not yet demonstrated a definite advantage over less toxic conventional dose therapies.

    Title Source Analysis of Scalp-recorded Movement-related Electrical Potentials.
    Date April 1993
    Journal Electroencephalography and Clinical Neurophysiology
    Excerpt

    We used brain electric source analysis to study the sources generating the movement-related cortical potentials during the interval from 200 msec before to 200 msec after the movement onset. Dipole solutions were obtained for the peak of the negative slope (pNS') and the frontal peak of the motor potential (fpMP) on scalp-recorded movement-related electrical potentials elicited by self-paced, repetitive unilateral finger movements in 10 normal volunteers. Two sources in homologous areas on each side of a spherical head model provided a satisfactory solution for the activity occurring at the instant of the pNS' in all subjects. The fpMP was modeled by a contralateral source and a midline source in 6 subjects and by a single contralateral source in the remaining 4 subjects. The percentage of the residual variance, or goodness-of-fit, over the interval from -200 to 200 msec, using the derived at pNS' and fpMP, was low. The results support the hypothesis that the NS' originates from the activity of bilateral generators in the sensorimotor cortex, and the motor potential arises from the combined activity of sources in the contralateral postcentral regions and the supplementary motor area.

    Title Surgical Salvage of Chemorefractory Germ Cell Tumors.
    Date March 1993
    Journal Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
    Excerpt

    PURPOSE: Patients with disseminated germ cell tumors who relapse after salvage chemotherapy, or who progress during cisplatin-based therapy, have chemorefractory disease and a very poor prognosis. A subset of these patients will have chemorefractory but resectable disease. We have therefore evaluated the role of salvage surgery in this patient population. PATIENTS AND METHODS: We performed a retrospective review of all patients with disseminated germ cell tumors who were felt to have chemorefractory disease and underwent salvage surgery from 1977 to 1990 at Indiana University. All patients had elevated serum markers or other signs of progressive carcinoma. A total of 48 patients underwent surgery (33 retroperitoneal lymph node dissections [RPLNDs], six thoracotomies, three thoracoabdominal resections, and multiple asynchronous procedures in six patients). RESULTS: Thirty-eight of 48 patients (79%) were rendered grossly free of disease and 29 (60%) obtained a serologic remission. Ten patients (21%) remain continuously disease-free with no postoperative treatment with a median follow-up of 46 months (range, 31 to 89). Six additional patients who relapsed after salvage surgery are currently disease-free with further treatment (four with repeat surgery and two with high-dose chemotherapy and autologous bone marrow transplantation [ABMT]). CONCLUSION: Selected patients with chemorefractory but resectable germ cell tumors have definite potential for cure with salvage surgery.

    Title The Activating Function for Magnetic Stimulation Derived from a Three-dimensional Volume Conductor Model.
    Date February 1993
    Journal Ieee Transactions on Bio-medical Engineering
    Excerpt

    A three-dimensional volume conductor model of magnetic stimulation is proposed that relates transmembrane potential of an axon to the induced electric field in a uniform volume conductor. This model validates assumptions used to derive a one-dimensional cable model of magnetic stimulation (Roth & Basser, IEEE Trans. Biomed. Eng., vol. 37, pp. 588-597, 1990) of unmyelinated axons. The three-dimensional volume conductor model reduces to this one-dimensional cable equation forced by the activating function, -delta EzA/delta z.

    Title Comparison of N-acetylcysteine and Mesna As Uroprotectors with Ifosfamide Combination Chemotherapy in Refractory Germ Cell Tumors.
    Date December 1992
    Journal Investigational New Drugs
    Excerpt

    From January 1983 through August 1988, 318 consecutive patients with refractory germ cell neoplasms were treated with ifosfamide-containing combination chemotherapy. The patients received ifosfamide at 1.2 gm/m2/day with cis-platin 20 mg/m2/day for 5 days and etoposide 75 mg/m2/day for 5 days or vinblastine 0.11 mg/kg on days 1 and 2 for each cycle. Of 277 evaluable patients, NAC was used as an uroprotector in the initial 86 patients while the latter 191 consecutive patients received mesna to reduce urothelial toxicity. Dosages of NAC was 2.0 gm po q 6 hr and for mesna 120 mg/m2 IV push prior to ifosfamide and then 1200 mg/m2/day as continuous infusion of 5 consecutive days. All patients received 3.0 liters of normal saline per day. The number of courses of chemotherapy given in the two groups were similar. Twenty-four of the 86 patients (27.9%) receiving NAC developed hematuria (13 patients - grade 1, 4 patients - grade 2, and 7 patients - grade 3 toxicity). While 8 out of 191 (4.2%) mesna patients developed hematuria (6 - grade 1 and 2 - grade 3) (p < 0.0001). The incidence of severity of renal toxicity was similar in the two groups. Ifosfamide dosage was reduced solely for urothelial toxicity in 11 patients receiving NAC compared with none of the patients receiving mesna (p < 0.0001). Chemotherapy response was similar in the two groups. In conclusion, mesna provides better urothelial protection from ifosfamide-induced toxicity than NAC and allows better maintenance of the drug dosage.

    Title Determining the Site of Stimulation During Magnetic Stimulation of a Peripheral Nerve.
    Date September 1992
    Journal Electroencephalography and Clinical Neurophysiology
    Excerpt

    Magnetic stimulation has not been routinely used for studies of peripheral nerve conduction primarily because of uncertainty about the location of the stimulation site. We performed several experiments to locate the site of nerve stimulation. Uniform latency shifts, similar to those that can be obtained during electrical stimulation, were observed when a magnetic coil was moved along the median nerve in the region of the elbow, thereby ensuring that the properties of the nerve and surrounding volume conductor were uniform. By evoking muscle responses both electrically and magnetically and matching their latencies, amplitudes and shapes, the site of stimulation was determined to be 3.0 +/- 0.5 cm from the center of an 8-shaped coil toward the coil handle. When the polarity of the current was reversed by rotating the coil, the latency of the evoked response shifted by 0.65 +/- 0.05 msec, which implies that the site of stimulation was displaced 4.1 +/- 0.5 cm. Additional evidence of cathode- and anode-like behavior during magnetic stimulation comes from observations of preferential activation of motor responses over H-reflexes with stimulation of a distal site, and of preferential activation of H-reflexes over motor responses with stimulation of a proximal site. Analogous behavior is observed with electrical stimulation. These experiments were motivated by, and are qualitatively consistent with, a mathematical model of magnetic stimulation of an axon.

    Title How the Anisotropy of the Intracellular and Extracellular Conductivities Influences Stimulation of Cardiac Muscle.
    Date September 1992
    Journal Journal of Mathematical Biology
    Excerpt

    The bidomain model, which describes the behavior of many electrically active tissues, is equivalent to a multi-dimensional cable model and can be represented by a network of resistors and capacitors. For a two-dimensional sheet of tissue, the intracellular and extracellular conductivity tensors can be visualized as two ellipses. For any pair of conductivity tensors, a coordinate transformation can be found that reduces the extracellular ellipse to a circle and aligns the intracellular ellipse with the coordinate axes. The eccentricity of the intracellular ellipse in this new coordinate system is an important parameter. It can have two special values: zero (in which case the tissue has equal anisotropy ratios) or one (in which case the tissue is comprised of one-dimensional fibers coupled through the two-dimensional extracellular space). Thus the bidomain model provides a unifying framework within which the electrical behavior of a wide variety of nerve and muscle tissues can be studied. When the anisotropy ratios in the intracellular and extracellular domains are not equal, stimulation with an anode always causes depolarization of some region of tissue. An analogous effect occurs in models that describe one-dimensional fibers, in which an "activating function" determines the site of stimulation. Experiments indicate that cardiac muscle does not have equal anisotropy ratios. Therefore, models developed to describe stimulation of axons may also help in understanding stimulation of two- or three-dimensional cardiac tissue, and may explain the concept of anodal stimulation of cardiac tissue through a "virtual cathode".

    Title Steady-state Point-source Stimulation of a Nerve Containing Axons with an Arbitrary Distribution of Diameters.
    Date August 1992
    Journal Medical & Biological Engineering & Computing
    Excerpt

    The paper extends a mathematical model for point-source electrical stimulation of a nerve. In the original model, it was assumed that all the axons in the nerve have the same diameter. In this paper the model is extended to represent a nerve with an arbitrary distribution of axon diameters. It is shown that the assumption of identical axons is justified for a typical human nerve if the 'representative' axon diameter is taken as the area-weighted average of the diameter distribution.

    Title Acute Respiratory Compromise Resulting from Tracheal Mucous Impaction Secondary to a Transtracheal Oxygen Catheter.
    Date June 1992
    Journal Chest
    Excerpt

    Transtracheal oxygen catheters are being increasingly used because of savings in oxygen usage and patient preference. The complications of the catheter are believed to be minor and easily managed. Inspissated mucous collections that form at the tip of the SCOOP 1 (Transtracheal Systems, Denver, Colorado) catheter have been reported but are usually easily expectorated by the patient. This report describes a patient who had development of acute respiratory compromise from crusted mucoid impaction of the trachea secondary to transtracheal catheter use. General anesthesia and rigid bronchoscopy were required for removal of the obstructing impaction. Unexplained worsening of respiratory symptoms in patients with transtracheal oxygen catheters should be addressed by prompt stripping of the catheter.

    Title No Evidence of Acute Cardiovascular Complications of Chemotherapy for Testicular Cancer: an Analysis of the Testicular Cancer Intergroup Study.
    Date May 1992
    Journal Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
    Excerpt

    PURPOSE: The purpose of this study is to evaluate the risk of acute vascular events in patients receiving cisplatin-based chemotherapy for testicular cancer. PATIENTS AND METHODS: A questionnaire assessing cardiovascular toxicity was distributed to all participants in the Testicular Cancer Intergroup study and details of toxicity from the chemotherapy flow sheets were reviewed. Patients with pathologic stage I testicular cancer were registered on to the study and observed after retroperitoneal lymphadenectomy. Patients with pathologic stage II disease were randomized to receive two postoperative courses of adjuvant cisplatin-based chemotherapy or observation. Any patient who had disease recurrence after observation or adjuvant therapy was given four cycles of cisplatin-based chemotherapy. RESULTS: Review treatment-related toxicity for those patients receiving adjuvant chemotherapy (n = 97) or chemotherapy for recurrent disease (n = 83) showed no cases of acute cardiovascular toxicity. The median follow-up period after study enrollment was 5.1 years; 459 questionnaires were mailed and 270 were returned. The percent return was equal among the observed adjuvant and recurrent groups (59%, 54%, and 64%). There was a significant increase in the incidence of extremity paresthesias in the two groups receiving chemotherapy. Fatal myocardial infarction was reported in two patients in the observation group and one nonfatal infarction was reported in the adjuvant treatment group. No patient in any group reported an incidence of stroke. Three patients in the observation group and one patient in the recurrent group experienced a thromboembolic event. CONCLUSION: Despite sporadic case reports suggesting a causal association between chemotherapy for testicular cancer and acute vascular events, this retrospective analysis provides no evidence of an increased risk for subsequent cardiovascular disease in this patient population.

    Title The Heating of Metal Electrodes During Rapid-rate Magnetic Stimulation: a Possible Safety Hazard.
    Date May 1992
    Journal Electroencephalography and Clinical Neurophysiology
    Excerpt

    The temperature of electrodes and metal disks positioned close to a coil was measured during rapid-rate magnetic stimulation. The temperature rise ranged from a fraction of a degree to almost half a degree per stimulus pulse and increased with the electrical conductivity of the metal, the square of the electrode radius and the square of the stimulus strength, and was independent of the electrode thickness. During a brief high-frequency train, the temperature increase from each pulse added; during a long, high-frequency train the temperature increase approached a steady state. After the stimulus ended, an electrode on the arm cooled with a time constant of about 45 sec. A standard silver EEG electrode on the surface of the skin did not increase in temperature enough to induce a skin burn if the stimulating rate was below 0.4 Hz or the total number of stimuli was less than 20. Heating was reduced by cutting gaps in the electrode.

    Title Optimal Focal Transcranial Magnetic Activation of the Human Motor Cortex: Effects of Coil Orientation, Shape of the Induced Current Pulse, and Stimulus Intensity.
    Date April 1992
    Journal Journal of Clinical Neurophysiology : Official Publication of the American Electroencephalographic Society
    Excerpt

    We studied the effects of coil orientation, stimulus intensity, and shape of the induced current pulse on the amplitudes of motor evoked potentials in the left abductor pollicis brevis of 10 normal adults who had transcranial magnetic stimulation. The optimal direction of currents induced in the brain is approximately perpendicular to the central sulcus, flowing diagonally from back to front. The most effective coil orientation depends on the shape of the induced current pulse and, when the first and second phases of the pulse are of similar size, also on the intensity of stimulation. Optimal mapping of the human motor cortex with magnetic stimulation requires knowledge of the influences of all these factors.

    Title Testicular Cancer in the 90s: Victory ... and a New Call to Arms.
    Date April 1992
    Journal Seminars in Oncology
    Title Relevance of Stimulus Duration for Activation of Motor and Sensory Fibers: Implications for the Study of H-reflexes and Magnetic Stimulation.
    Date April 1992
    Journal Electroencephalography and Clinical Neurophysiology
    Excerpt

    Electric stimuli with durations of 0.5-1.0 msec are optimal for studies of H-reflexes. It is more difficult to obtain H-reflexes with shorter duration stimuli or with magnetic stimulation. In order to understand this behavior, we studied the excitation thresholds for motor and sensory fibers in the ulnar, median and tibial nerves using both electric and magnetic stimulation. For short duration electrical stimuli (0.1 msec) the threshold for motor fibers is lower than for sensory fibers. For longer duration electric stimuli (1.0 msec) the threshold for sensory fibers is lower. For magnetic stimulation the threshold for motor fibers is much lower than for sensory fibers. Thus, stimulus duration is a critical parameter for sensory fiber excitation, and current magnetic stimulators are not optimal.

    Title A Comparison of Two Boundary Conditions Used with the Bidomain Model of Cardiac Tissue.
    Date March 1992
    Journal Annals of Biomedical Engineering
    Excerpt

    In the bidomain model, two alternative sets of boundary conditions at the interface between cardiac tissue and a saline bath have been used. It is shown that these boundary conditions are equivalent if the length constant of the tissue in the direction transverse to the fibers is much larger than the radius of the individual cardiac cells. If this is not the case, the relative merits of the two boundary conditions are closely related to the question of the applicability of a continuum model, such as the bidomain model, to describe a discrete multicellular tissue.

    Title The Electric Field Induced During Magnetic Stimulation.
    Date March 1992
    Journal Electroencephalography and Clinical Neurophysiology. Supplement
    Excerpt

    The electric field induced in tissue during magnetic stimulation is calculated. There are two sources of the electric field: charge and a time-dependent magnetic field: both sources are important in magnetic stimulation. Charge accumulation on the tissue surface tends to shield the nerve from the stimulus. The induced electric field is generally parallel to the tissue surface. Simulations of both peripheral and central nervous system stimulation are presented.

    Title Topographic Maps of Human Motor Cortex in Normal and Pathological Conditions: Mirror Movements, Amputations and Spinal Cord Injuries.
    Date March 1992
    Journal Electroencephalography and Clinical Neurophysiology. Supplement
    Excerpt

    We studied motor evoked potentials to transcranial magnetic stimulation in patients with unilateral upper limb amputations, complete T10-T12 spinal cord transection, and congenital mirror movements and in controls. Different muscles in the trunk and upper and lower extremities were evaluated at rest. In controls, muscles could be activated with stimulation of regions several centimeters wide. These areas overlapped extensively when muscles studied were from the same limb and shifted positions abruptly when muscles were from different limbs. Distal muscles were easier to activate than proximal muscles and normally evidenced exclusively a contralateral representation. Congenital defects in motor control in patients with mirror movements resulted in marked derangement of the map of outputs of distal hand muscles with enlarged and ipsilateral representations. Peripheral lesions, either acquired (amputations) or congenital (congenital absence of a limb), resulted in plastic reorganization of motor outputs targeting muscles immediately proximal to the stump. Central nervous system lesions (i.e., spinal cord injury producing paraplegia) also resulted in enlargement of the map of outputs targeting muscles proximal to the lesion. These results indicate that magnetic stimulation is a useful non-invasive tool for exploring plastic changes in human motor pathways following different types of injury.

    Title Randomized Study of Cyclophosphamide, Doxorubicin, and Vincristine Versus Etoposide and Cisplatin Versus Alternation of These Two Regimens in Extensive Small-cell Lung Cancer: a Phase Iii Trial of the Southeastern Cancer Study Group.
    Date February 1992
    Journal Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
    Excerpt

    PURPOSE: The trial was undertaken to determine (1) the relative efficacy/toxicity of two commonly used combination chemotherapy regimens in patients with extensive small-cell lung cancer (SCLC) and (2) whether the rapid alternation of these two regimens could provide superior therapeutic results compared with either regimen alone. PATIENTS AND METHODS: In this phase III trial, 437 eligible patients were stratified by performance status (PS) and sex and were randomly assigned to receive either 12 weeks of cisplatin and etoposide (EP); 18 weeks of cyclophosphamide, doxorubicin, and vincristine (CAV); or 18 weeks of alternation of these two regimens (CAV/EP). RESULTS: There were no significant differences in treatment outcome for EP, CAV, or CAV/EP in terms of response rate (61%, 51%, 59%, respectively), complete response rate (10%, 7%, 7%, respectively), or median survival (8.6 months, 8.3 months, 8.1 months, respectively), with a non-statistically significant trend toward a longer median time to progression with alternating therapy (4.3 months, 4.0 months, 5.2 months, respectively). Crossover second-line chemotherapy given at progression produced low response rates and short survival, regardless of the regimen used. Myelosuppression was the dose-limiting toxicity for all patients, although the pattern and severity differed among the treatment arms. CONCLUSIONS: The combination regimens EP and CAV can be considered equivalently effective induction therapies in extensive SCLC, and these two regimens are, to some degree, crossresistant. Alternating therapy provides no therapeutic advantage compared with the use of either of these regimens alone and should not be considered as standard treatment in this clinical setting.

    Title Chemotherapy of Testis Cancer: a Review.
    Date January 1992
    Journal International Journal of Radiation Oncology, Biology, Physics
    Title Stimulation of a Myelinated Nerve Axon by Electromagnetic Induction.
    Date December 1991
    Journal Medical & Biological Engineering & Computing
    Excerpt

    A model of electromagnetic stimulation predicts the transmembrane potential distribution along a myelinated nerve axon and the volume of stimulated tissue within a limb. Threshold stimulus strength is shown to be inversely proportional to the square of the axon diameter. It is inversely proportional to pulse duration for short pulses and independent of pulse duration for long ones. These results are also predicted by dimensional analysis. Two dimensionless numbers, Sem, the ratio of the induced transmembrane potential to the axon's threshold potential, and Tc/T, the ratio of the pulse duration to the membrane time constant, summarise the dependence of threshold stimulus strength on pulse duration and axon diameter.

    Title A Theoretical Comparison of Electric and Magnetic Stimulation of the Brain.
    Date November 1991
    Journal Annals of Biomedical Engineering
    Excerpt

    We present a theoretical comparison of the electric field produced in the brain by three modalities of transcranial stimulation of the cortex: magnetic stimulation, bifocal electric stimulation, and unifocal electric stimulation. The primary focus of this comparison is the focality and direction of the electric fields produced. A three-sphere model is used to represent the scalp, skull, and brain. All electric fields are calculated numerically. For magnetic stimulation we consider only a figure-of-eight coil. We find that magnetic stimulation produces the most focal field, while unifocal electric produces the least. Fields produced during magnetic stimulation are parallel to the head surface, while fields produced during electric stimulation have components both parallel and perpendicular to the head surface. The electric field produced by magnetic stimulation is shown to be insensitive to the skull conductivity, while that produced by electric stimulation is very sensitive to it.

    Title Complications Associated with Thoracentesis.
    Date November 1991
    Journal Archives of Internal Medicine
    Title Binding of Insulin-like Growth Factors to Tera-2 Human Embryonal Carcinoma Cells During Differentiation.
    Date September 1991
    Journal Cancer Research
    Excerpt

    Differentiation of Tera-2 human embryonal carcinoma cells by exposure to 2.1 mM alpha-difluoromethylornithine resulted in changes in morphology, a decrease in growth rate, and changes in the expression of SSEA-1 differentiation antigen. While the binding of 125I-insulin-like growth factor I (IGF-I) remained relatively constant during differentiation, binding of 125I-IGF-II increased 2-3-fold. Further, the binding of IGF-II was 87 times greater than IGF-I in both undifferentiated and differentiated cells. Undifferentiated Tera-2 cells exhibited a single class of binding sites for both IGF-I (KD = 1.2 nM, 7.0 x 10(3) sites/cell) and IGF-II (KD = 8.3 nM, 3.4 x 10(5) sites/cell). Following differentiation, IGF-I continued to bind to a single class of binding sites (KD 1.0 nM, 6.7 x 10(3) sites/cell) whereas IGF-II bound to both high-affinity sites (KDH 0.3 nM, 2.2 x 10(5) sites/cell) and low-affinity sites (KDL 15.1 nM, 1.6 x 10(7) sites/cell). The binding of iodinated IGF-II was blocked by unlabeled IGF-II but not IGF-I. In contrast, 125I-IGF-I binding was prevented by either IGF-I or IGF-II. Affinity cross-linking experiments demonstrated the presence of both type I and type II IGF receptors along with a number of IGF binding proteins. IGF-I failed to stimulate the incorporation of [3H]thymidine in both undifferentiated and differentiated cells. Although IGF-II caused a significant increase in [3H]thymidine incorporation in both undifferentiated and differentiated Tera-2 cells, the magnitude of the response and the sensitivity of the cells to IGF-II stimulation was diminished following differentiation. The observed changes in IGF-II binding, which occur in conjunction with cellular differentiation, may be an important feature of the expression of the differentiated phenotype by human germ cell tumors.

    Title Methotrexate, Vinblastine, Doxorubicin, and Cisplatin in Metastatic Breast Cancer. A Phase Ii Trial of the Hoosier Oncology Group.
    Date August 1991
    Journal Cancer
    Excerpt

    Forty-six eligible patients with metastatic breast cancer (MBC) were treated with a combination of methotrexate, vinblastine, doxorubicin, and cisplatin (M-VAC) as first-line chemotherapy. Of 44 patients evaluable for response, 28 (64%) had an objective response, including seven (16%) who had a complete response. The median duration of response was 4 months (range, 0 to 38 months), and the median survival from the time of entry was 14 months (range, less than 1 to greater than 45 months). Myelosuppression was the most common dose-limiting toxicity, with 54% of patients experiencing Grade 3 or 4 leukopenia (including 28% with granulocytopenic fever and one septic death), and cumulative Grade 3 anemia occurred in 28% of patients. Grades 3 to 4 stomatitis was observed in 18% of patients. An active, although highly toxic regimen when used as first-line therapy in MBC, M-VAC has a response rate and survival duration similar to existing, less toxic combination regimens. As such, M-VAC cannot be recommended in preference to other combination chemotherapy regimens in this clinical setting.

    Title Latency of Motor Evoked Potentials to Focal Transcranial Stimulation Varies As a Function of Scalp Positions Stimulated.
    Date June 1991
    Journal Electroencephalography and Clinical Neurophysiology
    Excerpt

    We recorded motor evoked potentials (MEP) to transcranial magnetic stimulation from abductor pollicis brevis (APB), flexor carpi radialis (FCR), biceps brachii and deltoid muscles at rest and during slight voluntary activation. An 8-shaped coil connected to a Cadwell MES-10 magnetic stimulator was positioned over different scalp positions 1 cm apart. At least 24 stimuli were delivered at each location. Latencies of MEPs were compared with those obtained by electrical and magnetic stimulation during muscle activation. Progressively longer MEP latencies were obtained in 5 groups depending on the type and position of stimulation. The shortest latencies were obtained with (1) electrical stimulation during muscle contraction and (2) non-focal magnetic stimulation during muscle contraction; magnetic stimulation at rest produced longer latencies with stimulation of (3) an optimal position, (4) a suboptimal position, and (5) a non-optimal position. Mean latency differences between successive groups were 1.9, 2.0, 1.6, and 2.6 msec for APB. Similar latency differences were found for the other arm muscles. The results are compatible with the hypothesis that the different latencies evoked by stimulation at different scalp locations are determined by the summation at spinal motoneurons of excitatory postsynaptic potentials generated by successive numbers of I waves.

    Title Magnetic Stimulation of the Human Cerebral Cortex, an Indicator of Reorganization in Motor Pathways in Certain Pathological Conditions.
    Date May 1991
    Journal Journal of Clinical Neurophysiology : Official Publication of the American Electroencephalographic Society
    Excerpt

    Basic principles of magnetic stimulation of biological tissues are reviewed. Noninvasive magnetic stimulation of the brain delivered over sensorimotor areas evokes movements and less commonly paresthesias in contralateral limbs. We have evaluated the maps of motor outputs in patients with (1) congenital mirror movements, which resulted in marked derangement of the map of outputs of distal hand muscles with enlarged and ipsilateral representations; (2) amputations, which resulted in plastic reorganization of motor outputs targeting muscles immediately proximal to the stump; (3) spinal cord injury, which also resulted in enlargement of the map of outputs targeting muscles proximal to the lesion level; and (4) hemispherectomy performed at an early age for intractable seizures, which resulted in the remaining hemisphere controlling ipsilateral arm muscles. These results demonstrate the potential for reorganization in motor systems following lesions in the peripheral as well as in the central nervous system.

    Title A Theoretical Calculation of the Electric Field Induced in the Cortex During Magnetic Stimulation.
    Date April 1991
    Journal Electroencephalography and Clinical Neurophysiology
    Excerpt

    We present a mathematical model for calculating the electric field induced in the head during magnetic stimulation of the cortex. The electric field arises from 2 sources: (1) the changing magnetic field creates an electric field in the tissue by electromagnetic induction, and (2) a charge distribution arises on the surface of the head and produces its own electrostatic field. A 3-sphere model is used to represent the brain, skull and scalp. The electric field as a function of the coil position, shape and orientation is computed numerically. The charge distribution partially shields the brain from the stimulus. The electric field is insensitive to the skull conductivity, in contrast with electrical stimulation using surface electrodes. Different coil shapes and orientations are considered, and a figure-of-eight coil is shown to deliver the largest and most focal stimulus.

    Title Biomagnetic Studies of Peripheral Nerves and Skeletal Muscle.
    Date February 1991
    Journal Advances in Neurology
    Title Action Potential Propagation in a Thick Strand of Cardiac Muscle.
    Date February 1991
    Journal Circulation Research
    Excerpt

    A theoretical model of action potential propagation in a thick strand of cardiac muscle is presented. The calculation takes into account the anisotropic and syncytial properties of the tissue, the presence of the interstitial space, the effect of the surrounding tissue bath, and the variation of the potential both along the strand length and across the strand cross section. The bidomain model is used to represent the electrical properties of the tissue, and the Ebihara-Johnson model is used to represent the properties of the active sodium channels. The calculated wave front is curved, with the action potential at the surface of the strand leading that at the center. The rate of rise of the action potential and the time constant of the action potential foot vary with depth into the tissue. The velocity of the wave front is nearly independent of strand radius for radii greater than 0.5 mm. The conduction velocity decreases as the volume fraction of the interstitial space decreases. In the limit of tightly packed cells, an action potential propagates quickly over the surface of the strand; the bulk of the tissue is then excited by a slow inward wave front initiated on the surface. This model does not predict an increase in conduction velocity when cells are tightly packed, a hypothesis that has been proposed previously to explain the fast conduction velocity in Purkinje fibers of some species.

    Title Risk of Burns During Rapid-rate Magnetic Stimulation in Presence of Electrodes.
    Date December 1990
    Journal Lancet
    Title Management of Patients with Non-seminomatous Germ Cell Tumours Stage I.
    Date November 1990
    Journal Progress in Clinical and Biological Research
    Title The Serum-effusion Albumin Gradient in the Evaluation of Pleural Effusions.
    Date October 1990
    Journal Chest
    Excerpt

    The objective of the study was to compare the serum-effusion albumin gradient (serum albumin level minus pleural effusion albumin level) to Light's traditional criteria (pleural fluid/serum total protein ratio greater than 0.5, pleural fluid/serum LDH ratio greater than 0.6, and pleural fluid LDH greater than 200 U/L) for identifying exudative pleural effusions. The design included prospective measurement of the serum-effusion albumin gradient and Light's criteria in patients with pleural effusions in an inpatient ward in a military teaching hospital. Fifty-nine consecutive patients with pleural effusions who were undergoing diagnostic or therapeutic thoracentesis in whom the etiology of the effusion could be determined were studied. Serum and pleural effusion fluid chemistries were measured in order to determine both the serum-effusion albumin gradient and Light's criteria. Using an albumin gradient of 1.2 g/dl or less to indicate exudates and greater than 1.2 g/dl to indicate transudates, 57 of the 59 patients (41 exudates; 18 transudates) were correctly classified. Two patients with malignant effusions were misclassified as having transudates. Although Light's criteria correctly identified all of the exudates, five patients with congestive heart failure were misclassified as exudates. Four of these patients had had previous diuretic therapy, and all had a clinical response to further diuretic therapy. We conclude that although Light's criteria for exudates are very sensitive, an albumin gradient of 1.2 g/dl or less tends to be more specific, especially in cases of chronic congestive heart failure.

    Title A Theoretical Calculation of the Electric Field Induced by Magnetic Stimulation of a Peripheral Nerve.
    Date September 1990
    Journal Muscle & Nerve
    Excerpt

    A mathematical model is presented that predicts the electric field induced in the arm during magnetic stimulation of a peripheral nerve. The arm is represented as a homogeneous, cylindrical volume conductor. The electric field arises from two sources: the time-varying magnetic field and the accumulation of charge on the arm surface. In magnetic stimulation both of these contributions are significant. The magnitude of the electric field is greatest near the surface of the arm, and is well localized. Various coil orientations are examined; the smallest electric fields are induced when the coil is perpendicular to the arm surface, the largest when the coil is parallel. These results are consistent with many experimental observations in the literature, and aid in the basic understanding of magnetic stimulation of the peripheral nervous system.

    Title The Magnetic Field of Cortical Current Sources: the Application of a Spatial Filtering Model to the Forward and Inverse Problems.
    Date August 1990
    Journal Electroencephalography and Clinical Neurophysiology
    Excerpt

    We extend our theoretical model based on spatial filtering to determine the ability of a SQUID magnetometer to resolve 2 localized current sources in the brain. We find that in order to resolve 2 separated but coaxial cortical sources, the source-to-pickup coil distance must be comparable to the distance between the 2 sources. The size of the current sources affects the resolving power of a magnetometer, but an anisotropy of 3 in the cortical tissue does not produce a significant effect. The model also provides a solution of the inverse calculation, either to reconstruct the original current source distribution from the measured magnetic field, or to continue the field at the magnetometer inward towards the sources. Both the inverse and inward calculations are limited by the fact that the inverse filter function serves as a high-pass filter, which leads to instabilities at high spatial frequencies, particularly in the presence of noise. The instabilities can be minimized by choosing an appropriate window to attenuate the noise, but this in turn reduces the spatial resolution.

    Title A Model of the Stimulation of a Nerve Fiber by Electromagnetic Induction.
    Date July 1990
    Journal Ieee Transactions on Bio-medical Engineering
    Excerpt

    A model is presented to explain the physics of nerve stimulation by electromagnetic induction. Maxwell's equations predict the induced electric field distribution that is produced when a capacitor is discharged through a stimulating coil. A nonlinear Hodgkin-Huxley cable model describes the response of the nerve fiber to this induced electric field. Once the coil's position, orientation, and shape are given and the resistance, capacitance, and initial voltage of the stimulating circuit are specified, this model predicts the resulting transmembrane potential of the fiber as a function of distance and time. It is shown that the nerve fiber is stimulated by the gradient of the component of the induced electric field that is parallel to the fiber, which hyperpolarizes or depolarizes the membrane and may stimulate an action potential. Finally, it predicts complicated dynamics such as action potential annihilation and dispersion.

    Title Hematologic Neoplasia Associated with Primary Mediastinal Germ-cell Tumors.
    Date May 1990
    Journal The New England Journal of Medicine
    Excerpt

    Between September 1983 and December 1988, we observed 16 cases of hematologic neoplasia associated with mediastinal germ-cell tumors. Twenty-eight similar cases have been reported in the literature. A review of the clinical and cytogenetic details in these patients suggests that the hematologic neoplasia is not the result of cisplatin-based chemotherapy of the mediastinal germ-cell cancer. This syndrome was found only in patients with nonseminomatous mediastinal germ-cell tumors, particularly those with serologic or histologic evidence of yolk-sac elements. The two most common hematologic neoplasms seen in this syndrome were acute megakaryoblastic leukemia and malignant histiocytosis. Consistent cytogenetic abnormalities have not yet been identified, but the finding of the marker chromosome isochromosome (12p) in the mediastinal germ-cell tumor and associated leukemic blasts in one patient suggests that these tumors may arise from a common progenitor cell.

    Title Effects of Coil Design on Delivery of Focal Magnetic Stimulation. Technical Considerations.
    Date May 1990
    Journal Electroencephalography and Clinical Neurophysiology
    Excerpt

    The localization of effects from magnetic coil stimulation is not immediately obvious. We measured the magnetic fields produced by several different coils and compared the results with theoretical calculations. Magnetic stimuli were delivered from a Cadwell MES-10 magnetic stimulator using 3 circular coils (one 9 cm in diameter; two with an angulated extension, 5 and 9 cm in diameter) and twin oval coils arranged in a butterfly shape (each coil approximately 4 cm in diameter) and from a Novametrix Magstim 200 using two circular flat-spiral coils (6.7 and 14 cm in diameter). Peak-induced strength of the magnetic field was recorded with a measuring loop (1 cm in diameter) at different distances from the center of the coil. When the measuring loop was moved in the same plane laterally from the center of the coil, for all coils except the butterfly-shaped coil, the field was highest in the center and fell off near the circumference of the coil. The field dropped progressively when measurements were made more distant from the plane of the coils. The electric field induced from the magnetic coil could be calculated from the coil geometry. For all coils except the butterfly-shaped coil, the largest electric field was at the circumference of the coils. The 6.7 cm flat-spiral coil induced currents similar to those induced by the larger coils but more focally. The butterfly-shaped coil induced the largest currents under its center, where the circumferences of the two component coils come together. The component of the electric field parallel to the wire in the center of this coil was the largest and most localized.

    Title Interpretation of Skeletal Muscle Four-electrode Impedance Measurements Using Spatial and Temporal Frequency-dependent Conductivities.
    Date March 1990
    Journal Medical & Biological Engineering & Computing
    Excerpt

    Spatial and temporal frequency-dependent conductivities are used to interpret four-electrode conductivity measurements on skeletal muscle. The model qualitatively explains the observed dependence of the experimental data on the temporal frequency of the injected current, the angle between the electrode array and the fibre direction, and the distance between the electrodes.

    Title Disseminated Testicular Cancer: Current Chemotherapy Strategies.
    Date September 1989
    Journal Seminars in Oncology
    Excerpt

    Disseminated testis cancer is a landmark adult solid tumor because of its high curability. In the last decade and a half, a number of clinical trials have been completed or are ongoing. In addition, long-term follow-up of some earlier trials is now available. This report summarizes the current treatment approaches, paying particular attention to the role of cisplatin.

    Title Cisplatin in the Management of Breast Cancer.
    Date September 1989
    Journal Seminars in Oncology
    Excerpt

    Cisplatin's role in metastatic breast cancer was initially confined to heavily pretreated patients. It had relatively little activity in these patients, except when administered with high-dose intensity (greater than 33.3 mg/m2/week). More recent trials in previously untreated patients have suggested that cisplatin is an active single agent, with response rates approaching 50% when administered at a dose of 30 mg/m2/d for four days every 3 weeks. Cisplatin has been safely incorporated into combination chemotherapy regimens, and has been used in high-dose regimens in conjunction with autologous bone marrow transplantation. Future trials should examine the use of cisplatin or platinum analogues as first-line therapy in alternating non-cross-resistant regimens, and should attempt to circumvent the dose-limiting toxicities of cisplatin when used in a dose-intensive fashion.

    Title Dose-intensive Chemotherapy in Refractory Germ Cell Cancer--a Phase I/ii Trial of High-dose Carboplatin and Etoposide with Autologous Bone Marrow Transplantation.
    Date July 1989
    Journal Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
    Excerpt

    Between September 1986 and March 1988, 33 patients with refractory germ cell cancer were entered on a phase I/II trial of two courses of high-dose carboplatin plus etoposide with autologous bone marrow support. All patients had extensive prior treatment and had either cisplatin-refractory disease (67%) defined as progression within 4 weeks of the last cisplatin dose or failed at least two cisplatin-based regimens (35%) including a cisplatin-ifosfamide salvage regimen. Patients received a fixed total dose of etoposide of 1,200 mg/m2 with each cycle. The carboplatin dose ranged from 900 mg/m2 to 2,000 mg/m2. Twenty of the 33 patients received the second cycle of therapy. Despite extensive prior therapy with cisplatin, neurotoxicity, nephrotoxicity, or hearing impairment with high-dose carboplatin and etoposide was unusual. The most common nonhematologic toxicity was moderate enterocolitis. The hematologic toxicity of this regimen was substantial at each dose level. All 53 courses were accompanied by granulocytopenic fevers. Seven of the 33 patients (21%) died from treatment. All of these deaths occurred during the granulocyte nadir, and five were related to documented sepsis. Overall, 14 of 32 patients (44%) evaluable for response obtained an objective response, including eight complete remissions. Four patients remain in complete remission, with three patients being continuously free of disease in excess of 1 year. Eight responders (including four complete remissions) had progressed while receiving cisplatin. We conclude that carboplatin and etoposide can be administered in combination at high dosages and this regimen may have curative potential for patients with germ cell tumors resistant to conventional-dose cisplatin-based therapies.

    Title Current Injection into a Two-dimensional Anisotropic Bidomain.
    Date July 1989
    Journal Biophysical Journal
    Excerpt

    A two-dimensional sheet of anisotropic cardiac tissue is represented with the bidomain model, and the finite element method is used to solve the bidomain equations. When the anisotropy ratios of the intracellular and extracellular spaces are not equal, the injection of current into the tissue induces a transmembrane potential that has a complicated spatial dependence, including adjacent regions of depolarized and hyperpolarized tissue. This behavior may have important implications for the electrical stimulation of cardiac tissue and for defibrillation.

    Title The Electrical Potential Produced by a Strand of Cardiac Muscle: a Bidomain Analysis.
    Date March 1989
    Journal Annals of Biomedical Engineering
    Excerpt

    Analytic expressions are derived relating the transmembrane potential to the intracellular, interstitial and external potentials in a cylindrical strand of cardiac muscle lying in a saline bath. The bidomain model is used to account for the anisotropy and interstitial space in the tissue. The implications of this model for interpreting potential data from strands of cardiac muscle are discussed.

    Title Cisplatin As First-line Therapy for Metastatic Breast Cancer.
    Date January 1989
    Journal Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
    Excerpt

    Cisplatin has had only minimal activity when used as second- and third-line chemotherapy for metastatic breast cancer (MBC). There have been no phase II studies in the United States evaluating cisplatin in patients with MBC with no prior chemotherapy. We therefore treated 20 consecutive patients with cisplatin 30 mg/m2/d for four days every 3 weeks for a maximum of six courses. We obtained partial responses in nine of 19 evaluable patients (47%), with responses in liver, lung, and soft tissue indicator lesions. Our data suggest that cisplatin has substantial single-agent activity as front-line therapy in MBC, and should be considered for inclusion in first-line combination chemotherapy regimens.

    Title Salvage Therapy in Recurrent Germ Cell Cancer: Ifosfamide and Cisplatin Plus Either Vinblastine or Etoposide.
    Date October 1988
    Journal Annals of Internal Medicine
    Excerpt

    STUDY OBJECTIVE: To determine the efficacy of the addition of ifosfamide to cisplatin plus etoposide (VIP), or vinblastine (VeIP), in patients with recurrent germ cell tumors. DESIGN: Nonrandomized, prospective phase II trial. SETTING: Tertiary referral university hospital. PATIENTS: Fifty-six of fifty-eight entered patients with measurable and progressive recurrent germ cell tumors of testicular (46 patients), ovarian (1 patient), and extragonadal (9 patients) origin were evaluable for response after not being cured with cisplatin, vinblastine, and etoposide regimens. INTERVENTIONS: Patients were administered cisplatin (20 mg/m2 body surface area daily for 5 days), ifosfamide (1.2 g daily for 5 days), plus either etoposide (75 mg daily for 5 days) or vinblastine (0.11 mg/kg body weight on days 1 and 2). In addition, vigorous intravenous hydration therapy with normal saline (100 to 125 mL/h) was administered during the treatment course. Uroepithelial protective agents, N-acetylcysteine (orally) or mesna (intravenously), were administered. Four courses were administered to responding patients every 3 weeks. When complete excision was feasible, surgical resection of residual tumor was done approximately 6 to 8 weeks after chemotherapy. MEASUREMENTS AND MAIN RESULTS: Twelve of fifty-six evaluable patients had a complete remission with chemotherapy alone, whereas 8 additional patients were free of disease after resection of teratoma (3 patients) or carcinoma (5 patients) for a total disease-free rate of 36% (95% CI, 23.4 to 49.6). The 95% CI median duration of remission for these patients is 34 months (range, 3 to more than 42; 95% CI, 9 months to infinity), and the median survival for all eligible patients is 12.7 months (95% CI, 10 months to 26 months), with 15 of the 20 patients who achieved disease-free status alive 18 to 53 months or more. Nine of fifty-eight patients remain free of disease, including 7 patients for 2 years or longer. Hematologic and nephrotoxicity were the predominant drug-related toxicities, with one drug-related death secondary to pneumonia. CONCLUSIONS: Ifosfamide combination chemotherapy as third-line or greater therapy can produce durable complete remissions in heavily pretreated patients with recurrent germ cell tumors.

    Title Cisplatin-based Combination Chemotherapy for Disseminated Germ Cell Tumors: Long-term Follow-up.
    Date September 1988
    Journal Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
    Excerpt

    A retrospective analysis of the initial 229 cases of disseminated germ cell tumors treated at Indiana University with cisplatin, vinblastine, and bleomycin (PVB), with or without doxorubicin revealed 146 patients who are alive and disease-free with a minimum follow-up of 6 years and a median follow-up of 8.5 years. At 12 years, the estimated probability of survival is 65.0%, and the estimated probability of relapse-free survival for complete responders is 83.5%. Long-term complications, such as clinically significant organ toxicity or therapy-related second malignancies, have not been observed. The functional status of survivors is maintained, with 95% returning to their pretherapy status, of which 88% are fully employed. Of patients receiving chemotherapy without abdominal surgery, 35% have fathered healthy children posttherapy. Achievement of complete remission (CR) in disseminated germ cell tumors with cisplatin-based combination chemotherapy translates to long-term disease-free survival and cure for the majority of patients, with preservation of functional status.

    Title Long-term Complications of Cisplatin-based Chemotherapy for Testis Cancer.
    Date September 1988
    Journal Seminars in Oncology
    Title Analysis of Phorbol Ester Stimulated Human Megakaryocyte Development.
    Date August 1988
    Journal Blood
    Excerpt

    Megakaryocytes are relatively rare components of human bone marrow, making the study of their maturation difficult. Phorbol esters can act as differentiating agents in a number of cell systems including murine megakaryocytes. We report the effects of phorbol esters on the previously described long-term human megakaryocytic leukemia cell culture, EST-IU. While two nontransforming phorbols fail to affect these cells, the transforming phorbol 12-O-tetradecanoylphorbol-13-acetate (TPA) induces a phenotype with characteristics of more mature megakaryocytes in a dose-related manner. This phenotype includes an increased adherence to untreated plastic or glass, polyploidization, an increase in cell size, and increased expression of both platelet glycoproteins and factor VIII-related antigen. Two-color flow cytometric analysis allowed simultaneous determinations of DNA content and the expression of surface membrane antigens or alpha-granule constituents, providing evidence that nuclear, membrane, and cytoplasmic maturation occur in parallel in this cellular system. TPA-induced maturation of EST-IU cells provides an important new cellular model for the further study of human megakaryocyte development.

    Title Relation of Proliferative Activity to Survival in Patients with Advanced Germ Cell Cancer.
    Date July 1988
    Journal Cancer Research
    Excerpt

    Patients with advanced disseminated germ cell tumors of the testis, retroperitoneum, and mediastinum have impaired survival compared to other patients with disseminated germ cell tumors having less bulky metastatic disease. Among patients with advanced disseminated germ cell tumors, we currently lack adequate predictors of long-term survival. Flow cytometric analysis of the paraffin-embedded, formalin-fixed tumor blocks of 50 of these patients suggests that proliferative activity is significantly correlated with survival (p less than 0.001) in multivariate analysis. Log (beta-human chorionic gonadotropin) is the only other useful predictor of long-term survival in multivariate analysis of prognostic factors in this group of patients. Flow cytometric DNA analysis may be useful in predicting survival in patients with advanced disseminated germ cell tumors.

    Title Magnetic Determination of the Spatial Extent of a Single Cortical Current Source: a Theoretical Analysis.
    Date April 1988
    Journal Electroencephalography and Clinical Neurophysiology
    Excerpt

    In this paper a model, originally developed for calculating the magnetic field produced by a single nerve fiber, is used to compare the ability of two magnetometers with different spatial resolutions to map the magnetic field distribution from a highly localized current source in the cerebral cortex. It is concluded that whenever the source-to-coil distance is much larger than the dimensions of the source it will be difficult, if not impossible, to use an inverse calculation to determine the spatial extent of the source from the magnetic field. When the source-to-coil distance is comparable to the extent of the source, an inverse calculation can provide information regarding the axial length of a localized dipolar current source.

    Title A Comparison of Two Models for Calculating the Electrical Potential in Skeletal Muscle.
    Date January 1988
    Journal Annals of Biomedical Engineering
    Excerpt

    We compare two models for calculating the extracellular electrical potential in skeletal muscle bundles: one a bidomain model, and the other a model using spatial and temporal frequency-dependent conductivities. Under some conditions the two models are nearly identical. However, under other conditions the model using frequency-dependent conductivities provides a more accurate description of the tissue. The bidomain model, having been developed to describe syncytial tissues like cardiac muscle, fails to provide a general description of skeletal muscle bundles due to the non-syncytial nature of skeletal muscle.

    Title Flow Cytometry Derived Dna Content of the Primary Lesions of Advanced Germ Cell Tumours.
    Date June 1987
    Journal International Journal of Andrology
    Excerpt

    We currently lack good prognostic indicators for patients with advanced disseminated germ cell tumours (GCT). An analysis of archival tumour samples of forty-nine patients with advanced GCT for flow cytometry derived DNA content suggests an inverse relationship between tumour proliferative activity and patient survival. The great majority of patients with advanced GCT have aneuploid tumour subpopulations. This analysis suggests that the survival of patients with advanced GCT may depend in part on kinetic variables present in the primary tumour.

    Title Purification and Characterization of a High Molecular Weight Type 1 Phosphoprotein Phosphatase from the Human Erythrocyte.
    Date March 1987
    Journal The Journal of Biological Chemistry
    Excerpt

    The major Mn2+-activated phosphoprotein phosphatase of the human erythrocyte has been purified to homogeneity from the cell hemolysate. It is sensitive to both inhibitors 1 and 2 of rabbit skeletal muscle, preferentially dephosphorylates the beta subunit of the phosphorylase kinase, and dephosphorylates a broad range of substrates including phosphorylase a, p-nitro-phenyl phosphate, phosphocasein, the regulatory subunit of cyclic AMP-dependent protein kinase, and both spectrin (Km = 10 microM) and pyruvate kinase (Km = 18 microM) purified from the human erythrocyte. The purified enzyme is stimulated by Mn2+ and to a lesser extent by higher concentrations of Mg2+. The purification procedure was selected to avoid any change in molecular weight, hence subunit composition, between the crude and purified enzyme. Maintenance of the original structure is demonstrated by non-denaturing gel electrophoresis and gel filtration chromatography. Gel filtration of the purified holoenzyme shows a single active component with a Stokes radius of 58 A at a molecular weight position of 180,000. Sedimentation velocity in a glycerol gradient gives a value of 6.1 for S20, w. Together these data indicate a molecular weight of about 135,000. Two bands of equal intensity appear on sodium dodecyl sulfate-gel electrophoresis at molecular weights of 61,700 and 36,300, suggesting a subunit composition of two 36,000 and one 62,000 subunits. The 36-kDa catalytic subunit can be isolated by freezing and thawing the holoenzyme or by hydrophobic chromatography of the holoenzyme. The catalytic subunit shows unchanged substrate and inhibitor specificity but altered metal ion activation.

    Title Electrically Silent Magnetic Fields.
    Date January 1987
    Journal Biophysical Journal
    Excerpt

    There has been a significant controversy over the past decade regarding the relative information content of bioelectric and biomagnetic signals. In this paper we present a new, theoretical example of an electrically-silent magnetic field, based on a bidomain model of a cylindrical strand of tissue generalized to include off-diagonal components in the conductivity tensors. The physical interpretation of the off-diagonal components is explained, and analytic expressions for the electrical potential and the magnetic field are found. These expressions show that information not obtainable from electrical potential measurements can be obtained from measurements of the magnetic field in systems with conductivity tensors more complicated than those previously examined.

    Title Capabilities of a Toroid-amplifier System for Magnetic Measurement of Current in Biological Tissue.
    Date December 1986
    Journal Ieee Transactions on Bio-medical Engineering
    Title Initial Characterization of a Human Megakaryocytic Leukemia Cell Line, Est-iu.
    Date August 1986
    Journal Progress in Clinical and Biological Research
    Title A Bidomain Model for the Extracellular Potential and Magnetic Field of Cardiac Tissue.
    Date May 1986
    Journal Ieee Transactions on Bio-medical Engineering
    Title Establishment in Long Term Culture of Megakaryocytic Leukemia Cells (est-iu) from the Marrow of a Patient with Leukemia and a Mediastinal Germ Cell Neoplasm.
    Date April 1986
    Journal Cancer Research
    Excerpt

    Megakaryocytes are the bone marrow cells that generate platelets. They are relatively rare cells, comprising between 0.03 and 0.06% of all nucleated marrow cells (R. L. Berkow et al., J. Lab. Clin. Med., 103: 811-818, 1984). The study of human megakaryocyte differentiation and function has been hampered by the small number of these cells available for study. Recently we have established a human cell line (EST-IU) from the marrow of a patient with an acute nonlymphocytic leukemia and a mediastinal germ cell tumor. While this cell line seems to express many of the phenotypic characteristics of human megakaryocytes, it does not appear to express any phenotypic properties associated with cells of the erythroid, lymphoid, granulocytic, or monocytic lineages. Transmission electron microscopy demonstrates frequent multinucleated cells. Staining for platelet peroxidase reactivity revealed darkening of the perinuclear envelope and the endoplasmic reticulum, a characteristic of cells of the megakaryocytic lineage. Indirect immunofluorescence assays reveal that EST-IU expresses reactivity with anti-platelet glycoprotein antisera, anti-Factor VIII-related antigen antisera, anti-Factor V antisera, anti-thrombocyte antisera, Tab (monoclonal anti-platelet glycoprotein IIb-IIIa), and anti-fibronectin antisera. Flow cytometry-derived DNA histograms demonstrate populations with multiple ploidies, ranging from approximately 4N to 32N. Based upon morphological and histochemical characteristics, antigenic expression, and nuclear characteristics, EST-IU cells appear to have a phenotype that closely resembles human megakaryocytes. This cell line should be useful in the further cell study of the molecular and cell biology of human megakaryocytopoiesis.

    Title Physicians' Estimates of the Probability of Myocardial Infarction in Emergency Room Patients with Chest Pain.
    Date March 1986
    Journal Medical Decision Making : an International Journal of the Society for Medical Decision Making
    Excerpt

    To evaluate the ability of emergency room physicians to estimate the probability of myocardial infarction in patients with acute chest pain, the authors gathered historical, physical, and electrocardiographic information from 492 patients at the time of their presentation. The physicians admitted 30% of them to intensive care: 53 of the 61 patients with infarctions (sensitivity = 87%) and 96 of the 431 without infarctions (specificity = 78%). Overall, 36% of those admitted had infarctions. The physicians' numeric estimate of the probability of infarction was a good univariate discriminator of infarction, as demonstrated by Receiver Operator Characteristics analysis, and, as indicated by their actual operating point, they seemed to maximize the accuracy of patient classification rather than sensitivity or specificity. Logistic regression analysis identified the physicians' probability estimate as the strongest multivariate predictor of infarction, considering all other clinical information available.

    Title The Magnetic Field of a Single Axon. A Comparison of Theory and Experiment.
    Date September 1985
    Journal Biophysical Journal
    Excerpt

    The magnetic field and the transmembrane action potential of a single nerve axon were measured simultaneously. The volume conductor model was used to calculate the magnetic field from the measured action potential, allowing comparison of the model predictions with the experimental data. After analyzing the experiment for all systematic errors, we conclude that the shape of the magnetic field can be accurately predicted from the transmembrane potential and, more importantly, the shape of the transmembrane potential can be calculated from the magnetic field. The data are used to determine ri, the internal resistance per unit length of the axon, to be 19.3 +/- 1.9 k omega mm-1, implying a value for the internal conductivity of 1.44 +/- 0.33 omega -1 m-1. Magnetic measurements are compared with standard bioelectric techniques for studying nerve axons.

    Title Predictors of Myocardial Infarction in Emergency Room Patients.
    Date August 1985
    Journal Critical Care Medicine
    Excerpt

    To develop a decision rule to aid in the diagnosis of myocardial infarction, we evaluated clinical and ECG data on 540 adults treated in an urban hospital emergency room for acute chest pain. Of 62 (11.5%) patients who had acute infarctions, 54 were admitted to intensive care (sensitivity 87%); 103 of 478 patients without infarctions were also admitted to intensive care (specificity 78%). Thirty-four percent of all patients admitted had infarctions. Multivariate analysis identified only four clinical variables which carried independent information predicting infarction: two from the ECG and two from the clinical history. A predictive model based on these four variables had significantly greater specificity (86% vs. 78%, p = .003) and accuracy of overall patient classification (88% vs. 79%, p = .013) but somewhat lower sensitivity (81% vs. 87%, p = .46) than physician judgments. However, a decision rule which would have admitted to intensive care those patients with a high probability of infarction who were not admitted by the emergency room physicians, would have increased the sensitivity for detecting infarction to 95% with no appreciable decrease in specificity or yield of infarctions among patients admitted to intensive care.

    Title Artifacts, Assumptions, and Ambiguity: Pitfalls in Comparing Experimental Results to Numerical Simulations when Studying Electrical Stimulation of the Heart.
    Date
    Journal Chaos (woodbury, N.y.)
    Excerpt

    Insidious experimental artifacts and invalid theoretical assumptions complicate the comparison of numerical predictions and observed data. Such difficulties are particularly troublesome when studying electrical stimulation of the heart. During unipolar stimulation of cardiac tissue, the artifacts include nonlinearity of membrane dyes, optical signals blocked by the stimulating electrode, averaging of optical signals with depth, lateral averaging of optical signals, limitations of the current source, and the use of excitation-contraction uncouplers. The assumptions involve electroporation, membrane models, electrode size, the perfusing bath, incorrect model parameters, the applicability of a continuum model, and tissue damage. Comparisons of theory and experiment during far-field stimulation are limited by many of these same factors, plus artifacts from plunge and epicardial recording electrodes and assumptions about the fiber angle at an insulating boundary. These pitfalls must be overcome in order to understand quantitatively how the heart responds to an electrical stimulus. (c) 2002 American Institute of Physics.

    Title The Induction of Reentry in Cardiac Tissue. The Missing Link: How Electric Fields Alter Transmembrane Potential.
    Date
    Journal Chaos (woodbury, N.y.)
    Excerpt

    This review examines the initiation of reentry in cardiac muscle by strong electric shocks. Specifically, it concentrates on the mechanisms by which electric shocks change the transmembrane potential of the cardiac membrane and create the physiological substrate required by the critical point theory for the initiation of rotors. The mechanisms examined include (1) direct polarization of the tissue by the stimulating current, as described by the one-dimensional cable model and its two- and three-dimensional extensions, (2) the presence of virtual anodes and cathodes, as described by the bidomain model with unequal anisotropy ratios of the intra- and extracellular spaces, (3) polarization of the tissue due to changing orientation of cardiac fibers, and (4) polarization of individual cells or groups of cells by the electric field ("sawtooth potential"). The importance of these mechanisms in the initiation of reentry is examined in two case studies: the induction of rotors using successive stimulation with a unipolar electrode, and the induction of rotors using cross-field stimulation. These cases reveal that the mechanism by which a unipolar stimulation induces arrhythmias can be explained in the framework of the bidomain model with unequal anisotropy ratios. In contrast, none of the examined mechanisms provide an adequate explanation for the induction of rotors by cross-field stimulation. Hence, this study emphasizes the need for further experimental and theoretical work directed toward explaining the mechanism of field stimulation. (c) 1998 American Institute of Physics.

    Title A Phase I Trial of Irinotecan Alternating with Epirubicin in Patients with Advanced Malignancies.
    Date
    Journal American Journal of Clinical Oncology
    Excerpt

    OBJECTIVES: This phase I study was conducted to evaluate the combination of irinotecan, a topoisomerase I inhibitor, with epirubicin, a topoisomerase II inhibitor, when administered sequentially on a once-every-three week basis. METHODS: Irinotecan was administered at doses ranging from 100 to 150 mg/m(2) intravenously over 90 minutes, 24 hours before epirubicin, in doses from 30 to 60 mg/m(2), every 3 weeks. Toxicity assessments were performed weekly. Tumor evaluation by radiographic and physical examination was performed after every 3 cycles using Response Evaluation Criteria in Solid Tumors. RESULTS: Eighteen patients with metastatic solid tumors were enrolled in this study. The maximum tolerated dose and recommended phase II dose was irinotecan 150 mg/m(2) and epirubicin 30 mg/m(2). Dose-limiting toxicities were primarily neutropenia. Other toxicities at this dose level were mild. Three patients with colon cancer, 1 patient with renal cell cancer and 1 patient with adenosquamous cell carcinoma of the ethmoid sinus had stable disease. No objective responses were observed. CONCLUSIONS: The maximum tolerated dose and recommended phase II dose for irinotecan and epirubicin administered 24 hours apart every 3 weeks was 150 mg/m(2) and 30 mg/m(2), respectively. Higher doses were limited by significant hematologic toxicity and fatigue.

    Title Spherical Topology in Cardiac Simulations.
    Date
    Journal Hfsp Journal
    Excerpt

    Computational simulations of the electrodynamics of cardiac fibrillation yield a great deal of useful data and provide a framework for theoretical explanations of heart behavior. Extending the application of these mathematical models to defibrillation studies requires that a simulation should sustain fibrillation without defibrillation intervention. In accordance with the critical mass hypothesis, the simulated tissue should be of a large enough size. The choice of biperiodic boundary conditions sustains fibrillation for a longer duration than no-flux boundary conditions for a given area, and so is commonly invoked. Here, we show how this leads to a boundary condition artifact that may complicate the analysis of defibrillation efficacy; we implement an alternative coordinate scheme that utilizes spherical shell topology and mitigates singularities in the Laplacian found with the usual spherical curvilinear coordinate system.

    Title Prostate Cancer Serum Biomarker Discovery Through Proteomic Analysis of Alpha-2 Macroglobulin Protein Complexes.
    Date
    Journal Proteomics. Clinical Applications
    Excerpt

    Alpha-2 macroglobulin (A2M) functions as a universal protease inhibitor in serum and is capable of binding various cytokines and growth factors. In this study, we investigated if immunoaffinity enrichment and proteomic analysis of A2M protein complexes from human serum could improve detection of biologically relevant and novel candidate protein biomarkers in prostate cancer. Serum samples from six patients with androgen-independent, metastatic prostate cancer and six control patients without malignancy were analyzed by immunoaffinity enrichment of A2M protein complexes and MS identification of associated proteins. Known A2M substrates were reproducibly identified from patient serum in both cohorts, as well as proteins previously undetected in human serum. One example is heat shock protein 90 alpha (HSP90α), which was identified only in the serum of cancer patients in this study. Using an ELISA, the presence of HSP90α in human serum was validated on expanded test cohorts and found to exist in higher median serum concentrations in prostate cancer (n = 18) relative to control (n = 13) patients (median concentrations 50.7 versus 27.6 ng/mL, respectively, p = 0.001). Our results demonstrate the technical feasibility of this approach and support the analysis of A2M protein complexes for proteomic-based serum biomarker discovery.

    Title Optical Imaging of the Heart: Seeing Below the Surface.
    Date
    Journal Heart Rhythm : the Official Journal of the Heart Rhythm Society
    Title Fourier-based Magnetic Induction Tomography for Mapping Resistivity.
    Date
    Journal Journal of Applied Physics
    Excerpt

    Magnetic induction tomography is used as an experimental tool for mapping the passive electromagnetic properties of conductors, with the potential for imaging biological tissues. Our numerical approach to solving the inverse problem is to obtain a Fourier expansion of the resistivity and the stream functions of the magnetic fields and eddy current density. Thus, we are able to solve the inverse problem of determining the resistivity from the applied and measured magnetic fields for a two-dimensional conducting plane. When we add noise to the measured magnetic field, we find the fidelity of the measured to the true resistivity is quite robust for increasing levels of noise and increasing distances of the applied and measured field coils from the conducting plane, when properly filtered. We conclude that Fourier methods provide a reliable alternative for solving the inverse problem.

    Title Comparative Effectiveness of Cisplatin-based and Carboplatin-based Chemotherapy for Treatment of Advanced Urothelial Carcinoma.
    Date
    Journal Annals of Oncology : Official Journal of the European Society for Medical Oncology / Esmo
    Excerpt

    Cisplatin-based chemotherapy is a standard treatment of metastatic urothelial carcinoma (UC), though carboplatin-based chemotherapy is frequently substituted due to improved tolerability. Because comparative effectiveness in clinical outcomes of cisplatin- versus carboplatin-based chemotherapy is lacking, a meta-analysis was carried out.

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