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Biomedical subjects

B J Roth

Publications and source records attributed to B J Roth.

At least 37 records · Page 2Linked to original sources
PubMed2000

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.

Adult↗
PubMed1999

A Phase II study of paclitaxel and ifosfamide for patients with advanced refractory carcinoma of the urothelium.

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.

Adult↗
PubMed1999

Dependence of cardiac strength-interval curves on pacing rate.

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.

Action Potentials↗
PubMed1999

Mechanism for polarisation of cardiac tissue at a sealed boundary.

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.

Anisotropy↗
PubMed1999

Effect of a bath on the epicardial transmembrane potential during internal defibrillation shocks.

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.

Baths↗
PubMed1999

The magnetic field associated with a plane wave front propagating through cardiac tissue.

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.

Action Potentials↗
PubMed1999

Time dependence of anodal and cathodal refractory periods in cardiac tissue.

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.

Animals↗
PubMed1999

Quatrefoil reentry in myocardium: an optical imaging study of the induction mechanism.

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.

Animals↗
PubMed1999

Androgen-independent prostate cancer: not so chemorefractory after all.

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.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1998

Bilateral testicular tumors: management and outcome in 21 patients.

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.

Adolescent↗
PubMed1998

Effects of doxycycline on human prostate cancer cells in vitro.

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.

Adenocarcinoma↗
PubMed1998

A phase II trial of paclitaxel in refractory germ cell tumors.

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.

Adolescent↗
PubMed1998

The pinwheel experiment revisited.

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.

Animals↗
PubMed1998

Differences between the time constant of sensory and motor peripheral nerve fibers: further studies and considerations.

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.

Adult↗
PubMed1998

Images of Ca2+ flux in astrocytes: evidence for spatially distinct sites of Ca2+ release and uptake.

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.

Animals↗