Comparative effectiveness of cisplatin-based and carboplatin-based chemotherapy for treatment of advanced urothelial carcinoma.

BACKGROUND: 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. METHODS: PubMed was searched for articles published from 1966 to 2010. Eligible studies included prospective randomized trials evaluating cisplatin- versus carboplatin-based regimens in patients with metastatic UC. Individual patient data were not available and survival data were inconsistently reported. Therefore, the analysis focused on overall response (OR) and complete response (CR) rates. The Mantel-Haenszel method was used for combining trials and calculating pooled risk ratios (RRs). RESULTS: A total of 286 patients with metastatic UC from four randomized trials were included. Cisplatin-based chemotherapy was associated with a significantly higher likelihood of achieving a CR [RR = 3.54; 95% confidence interval (CI) 1.48-8.49; P = 0.005] and OR (RR = 1.34; 95% CI 1.04-1.71; P = 0.02). Survival end points could not be adequately assessed due to inconsistent reporting among trials. CONCLUSIONS: Cisplatin-based, as compared with carboplatin-based, chemotherapy significantly increases the likelihood of both OR and CR in patients with metastatic UC. The impact of improved response proportions on survival end points could not be assessed.

Magneto-encephalogram artifacts caused by electro-encephalogram electrodes.

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%.

The effect of plunge electrodes during electrical stimulation of cardiac tissue.

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.

Simulation of protective zones during quatrefoil reentry in cardiac tissue.

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.

Systemic chemotherapy for urothelial transitional cell carcinoma: an overview of toxicity.

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.

Penetrating trauma in patients older than 55 years: a case-control study.

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.

Optical measurement of cell-to-cell coupling in intact heart using subthreshold electrical stimulation.

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.

Experimental and theoretical analysis of phase singularity dynamics in cardiac tissue.

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.

Methacholine challenge testing in Reserve Officer Training Corps cadets.

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.

How epicardial electrodes influence the transmembrane potential during a strong shock.

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.

How electrode size affects the electric potential distribution in cardiac tissue.

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.

An S1 gradient of refractoriness is not essential for reentry induction by an S2 stimulus.

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.

Role of virtual electrodes in arrhythmogenesis: pinwheel experiment revisited.

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.

Virtual electrodes and deexcitation: new insights into fibrillation induction and defibrillation.

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.

Phase II study of cisplatin and paclitaxel in advanced carcinoma of the urothelium: an Eastern Cooperative Oncology Group Study.

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.

Influence of a perfusing bath on the foot of the cardiac action potential.

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.

Phase I trial of paclitaxel and etoposide for recurrent ovarian carcinoma: a Gynecologic Oncology Group Study.

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.