A randomized trial of cisplatin, etoposide and bleomycin (PEB) versus carboplatin, etoposide and bleomycin (CEB) for patients with 'good-risk' metastatic non-seminomatous germ cell tumors

BACKGROUND: Cisplatin-based combination chemotherapy will cure 70% to 80% of patients with metastatic non-seminomatous germ cell tumors but is associated with the possibility of severe neuro-, oto- and nephro-toxicities. Carboplatin, a cisplatin analogue, is an active drug in testicular cancer with a more favourable spectrum of side effects. In a randomized trial, the German Testicular Cancer Study Group compared a combination regimen of carboplatin, etoposide and bleomycin (CEB) to standard cisplatin, etoposide and bleomycin (PEB) chemotherapy for patients with 'minimal-' and moderate-disease' non-seminomatous germ cell tumors, according to the Indiana University classification. PATIENTS AND METHODS: PEB was given for three cycles at standard doses (given days 1-5), and the CEB regimen consisted of carboplatin (target AUC of 5 mg/ml x min) on day 1, etoposide 120 mg/m2 on days 1 to 3 and bleomycin 30 mg on days 1, 8 and 15. Four cycles of CEB were given, with the omission of bleomycin in the fourth cycle. Thus, the cumulative doses of etoposide and bleomycin applied in the two treatment arms were comparable. Fifty-four patients were entered on the trial, 29 were treated with PEB and 25 with CEB chemotherapy. Patients were stratified according to disease extent (minimal versus moderate) and the degree of tumor marker elevation. Thirty-two patients (59%) belonged to the group with minimal disease and low markers. RESULTS: No significant difference in response to chemotherapy was seen between the two arms, with CR rates of 81% for the PEB arm and 76% for CEB treatment. However, more patients treated with CEB (32% versus 13%) have relapsed after therapy, and 4 patients (16%) have died of disease progression after CEP in contrast to 1 (3%) after PEB therapy. The first interim analysis of negative events (relapse, vital tumor at secondary resection, death from disease and therapy-associated death) showed a significantly higher rate after CEB than after PEB therapy, and the trial was terminated early. After a median follow-up of 33 months for all patients, the calculation of negative events is still significantly in favour of PEB-treated patient, particularly since three late relapses > 2 years have been observed in the CEB arm (P = 0.03). CONCLUSION: This randomized trial demonstrates that even with the use of adequate doses of etoposide and full-dose bleomycin, carboplatin cannot altogether replace cisplatin in patients with testicular cancer. Treatment with the PEB regimen remains the standard approach in patients with 'good-risk' non-seminomatous germ cell tumors.     

The genotype of the human cancer cell: implications for risk analysis

An extremely large database describes genotypes associated with the human cancer phenotype and genotypes of human populations with genetic predisposition to cancer. Aspects of this database are examined from the perspective of risk analysis, and the following conclusions and hypotheses are proposed: (1) The genotypes of human cancer cells are characterized by multiple mutated genes. Each type of cancer is characterized by a set of mutated genes, a subset from a total of more than 80 genes, that varies between tissue types and between different tumors from the same tissue. No single cancer-associated gene nor carcinogenic pathway appears suitable as an overall indicator whose induction serves as a quantitative marker for risk analysis. (2) Genetic defects that predispose human populations to cancer are numerous and diverse, and provide a model for associating cancer rates with induced genetic changes. As these syndromes contribute significantly to the overall cancer rate, risk analysis should include an estimation of the effect of putative carcinogens on individuals with genetic predisposition. (3) Gene activation and inactivation events are observed in the cancer genotype at different frequencies, and the potency of carcinogens to induce these events varies significantly. There is a paradox between the observed frequency for induction of single mutational events in test systems and the frequency of multiple events in a single cancer cell, suggesting events are not independent. Quantitative prediction of cancer risk will depend on identifying rate-limiting events in carcinogenesis. Hyperproliferation and hypermutation may be such events. (4) Four sets of data suggest that hypermutation may be an important carcinogenic process. Current mechanisms of risk analysis do not properly evaluate the potency of putative carcinogens to induce the hypermutable state or to increase mutation in hypermutable cells. (5) High-dose exposure to carcinogens in model systems changes patterns of gene expression and may induce protective effects through delay in cell progression and other processes that affect mutagenesis and toxicity. Paradigms in risk analysis that require extrapolation over wide ranges of exposure levels may be flawed mechanistically and may underestimate carcinogenic effects of test agents at environmental levels. Characteristics of the human cancer genotype suggest that approaches to risk analysis must be broadened to consider the multiplicity of carcinogenic pathways and the relative roles of hyperproliferation and hypermutation. Further, estimation of risk to general human populations must consider effects on hypersusceptible individuals. The extrapolation of effects over wide exposure levels is an imprecise process.     

The Expressive Power of Complex Values in Object-Based Data Models

In object-based data models, complex values such as tuples or sets have no special status and must therefore be represented by objects. As a consequence, different objects may represent the same value, i.e., duplicates may occur. This paper contains a study of the precise expressive power required for the representation of complex values in typical object-based data models supporting first-order queries, object creation, and while-leaps. Such models are sufficiently powerful to express any reasonable collection of complex values, provided duplicates are allowed. It is shown that in general, the presence of such duplicates is unavoidable in the case of set values. In contrast, duplicates of tuple values can easily be eliminated. A fundamental operation for elimination of duplicate set values, called abstraction, is considered and shown to be a tractable alternative to explicit powerset construction. Other means of avoiding duplicates, such as total order, equality axioms, or copy elimination, are also discussed.     

Finite element stress analysis of a new design of synthetic leaflet heart valve

This paper presents a parametric finite element analysis of the stresses in the leaflets of a new design of polyurethane heart valve in the closed position. The alpharabola geometry of the valve has previously been reported by Leat and Fisher (1) and has been shown to demonstrate good opening characteristics. The effects of variations in leaflet offset parameter, g, length, h, and local thickening have been determined for a valve where the frame is assumed rigid. A spherical leaflet geometry has also been analysed for comparative purposes. Results have shown that the alpharabola leaflet geometry can reduce the maximum principal tensile stress to 60 per cent of that for a spherical valve of the same mesh density.     

A unified formulation for Chebyshev and Legendre superdirective endfire array design

Contents A unified formulation for superdirective end-fire arrays by using Chebyshev and Legendre Polynomials and their maximum directivities as well as the corresponding efficiency index and theQ factor are found. Several examples show the simplicity of the formulation.

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Eine einheitliche Formulierung zum Design von Supergain-Längsstrahlern mit Tschebyscheff- und Legendre-Polynomen

Übersicht Es wird eine einheitliche Formulierung für Supergain-Längsstrahler mit Tschebyscheff- und Legendre-Polynomen vorgestellt. Die Strahlergruppen werden für unterschiedliche Kombinationen dieser Polynome angegeben, ebenso ihre optimalen Richtgewinne wie auch der dazugehörige Strahlungs- Wirkungsgrad in der Hauptrichtung und der GütefaktorQ. Einige Beispiele belegen die Einfachheit der Formulierung.

     

Hierarchical production control for a flow shop with dynamic setup changes and random machine breakdowns

In this paper, we study a manufacturing system consisting of two machines separated by two intermediate buffers, and capable of producing two different products. Each product requires a constant processing time on each of the machines. Each machine requires a constant non-negligible setup change time from one product to the other. The demand rate for each product is considered to be piecewise constant. Each machine undergoes failure and repair. The time-to-failure and time-to-repair are exponentially distributed random variables. The setup change and processing operations are resumable. We model our system as a continuous time, continuous flow process. An optimal control problem is formulated for the system to minimize the total expected discounted cost over an infinite horizon. To determine the optimal control policy structure, a discrete version of the problem is solved numerically using a dynamic programming formulation with a piecewise linear penalty function. A real-time control algorithm is then developed with the objective of maintaining low work-in-process inventory and keeping the production close to the demand. The algorithm uses a hierarchical control structure to generate the loading times for each product on each machine in real time and to respond to random disruptions in the system. The system is simulated using this algorithm to study its performance. The performance of the algorithm is also compared to alternative policies.     

Chemical characterization of in vivo aged zinc phosphate dental cements

The chemical composition of zinc phosphate dental cements aged in vivo was studied. Twenty-seven samples aged 2 to 43 years were investigated using X-ray diffraction, infrared spectroscopy, ³¹P nuclear magnetic resonance spectroscopy, thermogravimetric analysis and differential scanning calorimetry. Evidence for the presence of zinc oxide, amorphous zinc phosphate, water of hydration and crystalline zinc phosphate tetrahydrate was found. The latter was identified as hopeite; it was present in 92% of the cements studied. No correlation with time concerning either the chemical structure of the components or their relative amounts was found. Zinc phosphate dental cements show very good chemical stability on long-term use.