Anaemia and its functional consequences in cancer patients: current challenges in management and prospects for improving therapy

Anaemia is a common occurrence in patients with cancer and contributes to the clinical symptomatology and reduced quality of life (QOL) seen in cancer patients. Many aspects of reduced QOL, including fatigue, are known to be associated with suboptimally low levels of haemoglobin. Even mild-to-moderate anaemia adversely affects patient-reported QOL parameters. Red blood cell transfusions are associated with many real and perceived risks, inconveniences, costs, and only temporary benefits. Recombinant human erythropoietin (rHuEPO) is an effective therapy to increase haemoglobin values in over half of anaemic cancer patients receiving concurrent chemotherapy. These increased haemoglobin values are closely correlated with improvements in QOL. Despite these objectively defined benefits, less than 50% of anaemic patients undergoing cytotoxic chemotherapy receive rHuEPO, in contrast to patients with chronic renal failure on dialysis, where anaemia is universally and aggressively treated to more optimal haemoglobin values. However, there are several barriers that may limit more widespread use of rHuEPO. These include inconvenience associated with frequent dosing; failure of a large proportion (40 to 50%) of patients to respond; relatively slow time to response; absence of reliable early indicators of response; and current lack of rigorous pharmacoeconomic data demonstrating cost-effectiveness. Darbepoetin alfa is a novel erythropoiesis stimulating protein (NESP) that is biochemically distinct from rHuEPO, and which has been proven to stimulate red blood cell production. The molecule has a 3-fold longer half-life and increased biological activity that will allow less frequent dosing, facilitating improved management of the anaemia of cancer. With this new option for therapy, further avenues of investigation should lead to renewed interest in the clinical benefits of optimal haemoglobin levels for patients with cancer. © 2001 Cance Cancer Research Campaig

In Search of the Criterion Standard Test in Diagnostic Testing

Given a certain technology or procedure for diagnostic testing, different cutoff points produce different sensitivity and specificity rates. The cutoff point that generates highest sensitivity and specificity establishes the Criterion Standard Test (otherwise known as the Gold Standard Test). If, subject to good reason, a new testing technology or procedure emerges, the optimum cutoff point associated with it may generate higher sensitivity and specificity and thus a new improved Criterion Standard Test. Various cutoff selection methodologies have been proposed, all based on Euclidean geometry, involving the so-called Receiver Operating Characteristic (ROC) curve. Our purpose in this paper is to recommend a new selection methodology based on the P-Value associated with the well-known Pearson’s chi-squared test (χ2) – the conventional test utilized when testing for dependence between state of nature (disease present or not present) and evidence (test positive or negative measures). Using a hypothetical numerical example, we demonstrate that the cutoff point associated with the lowest P-Value of the Pearson’s chi-squared test is the one that maximizes sensitivity and specificity, or overall accuracy, thus establishing the Criterion Standard Test. Although the best geometric method (sums of squares) and the proposed method are equally effective in selecting the optimum cutoff point, only the proposed new procedure selects based on statistical significance. Additionally, we propose a simple theoretical benefits / costs linear setting to discuss the importance of net benefits associated with testing accuracy and reference harmful as well as beneficial testing cases found in various literature sources

Targeted disruption of the even-skipped gene, evx1, causes early postimplantation lethality of the mouse conceptus.

Journal ArticleImplantation within the mammalian uterus elicits dramatic changes in the growth, differentiation, and morphogenesis of the conceptus. This process is interrupted in mice carrying a targeted disruption of the murine evx1 gene, a homolog of the Drosophila even-skipped (eve) gene. Upon implantation, presumptive evx1- homozygotes elicit a decidual response, invade the uterine epithelium, and attach to the basement membrane between uterine stroma and epithelium, but fail to differentiate extraembryonic tissues or to form egg cylinders prior to resorption. Retrograde analysis of embryo genotypes demonstrates that homozygotes could be isolated as free-floating blastocysts but not as gastrulating egg cylinders. Homozygous mutant blastocysts appeared normal and, when grown in vitro, attach, proliferate, and form trophoblastic giant cells surrounding a growing inner cell mass before rapidly degenerating. In situ hybridization analysis demonstrates evx1 gene expression within the visceral endoderm after implantation and prior to gastrulation, at a time in which the mutant phenotype is first detected

Modulational instability in a layered Kerr medium: Theory and Experiment

We present the first experimental investigation of modulational instability in a layered Kerr medium. The particularly interesting and appealing feature of our configuration, consisting of alternating glass-air layers, is the piecewise-constant nature of the material properties, which allows a theoretical linear stability analysis leading to a Kronig-Penney equation whose forbidden bands correspond to the modulationally unstable regimes. We find very good {\it quantitative} agreement between theoretical, numerical, and experimental diagnostics of the modulational instability. Because of the periodicity in the evolution variable arising from the layered medium, there are multiple instability regions rather than just one as in the uniform medium.Comment: 4 pages, 4 figures, contains experimental + computational + theoretical results, to appear in Physical Review Letter

Why tyrosine kinase inhibitor resistance is common in advanced gastrointestinal stromal tumors

Background: Most patients with advanced gastrointestinal stromal tumors (GIST) develop drug resistance to tyrosine kinase inhibitors (TKIs) within two years of starting therapy, whereas most chronic myeloid leukemia (CML) patients in chronic phase still exhibit disease control after a decade on therapy. This article aims to explain this divergence in long term outcomes. Methods and results: By combining clinical and experimental observations with mathematical formulas we estimate that, in advanced GIST, the genetic changes responsible for resistance are generally already present at disease detection. Conclusion: This result has relevant clinical implications by providing support for the exploration of combination therapies

Phase I dose-escalation and pharmacokinetic study of dasatinib in patients with advanced solid tumors

PURPOSE: To determine the maximum tolerated dose, dose-limiting toxicity (DLT), and recommended phase II dose of dasatinib in metastatic solid tumors refractory to standard therapies or for which no effective standard therapy exists. <br></br> EXPERIMENTAL DESIGN: In this phase I, open-label, dose-escalation study, patients received 35 to 160 mg of dasatinib twice daily in 28-day cycles either every 12 hours for 5 consecutive days followed by 2 nontreatment days every week (5D2) or as continuous, twice-daily (CDD) dosing. <br></br> RESULTS: Sixty-seven patients were treated (5D2, n = 33; CDD, n = 34). The maximum tolerated doses were 120 mg twice daily 5D2 and 70 mg twice daily CDD. DLTs with 160 mg 5D2 were recurrent grade 2 rash, grade 3 lethargy, and one patient with both grade 3 prolonged bleeding time and grade 3 hypocalcemia; DLTs with 120 mg twice daily CDD were grade 3 nausea, grade 3 fatigue, and one patient with both grade 3 rash and grade 2 proteinuria. The most frequent treatment-related toxicities across all doses were nausea, fatigue, lethargy, anorexia, proteinuria, and diarrhea, with infrequent hematologic toxicities. Pharmacokinetic data indicated rapid absorption, dose proportionality, and lack of drug accumulation. Although no objective tumor responses were seen, durable stable disease was observed in 16% of patients.<br></br> CONCLUSION: Dasatinib was well tolerated in this population, with a safety profile similar to that observed previously in leukemia patients, although with much less hematologic toxicity. Limited, although encouraging, preliminary evidence of clinical activity was observed. Doses of 120 mg twice daily (5D2) or 70 mg twice daily (CDD) are recommended for further studies in patients with solid tumors.<br></br&gt

Molecular simulation of hierarchical structures in bent-core nematics

The structure of nematic liquid crystals formed by bent-core mesogens (BCMs) is studied in the context of Monte Carlo simulations of a simple molecular model that captures the symmetry, shape and flexibility of achiral BCMs. The results indicate the formation of (i) clusters exhibiting local smectic order, orthogonal or tilted, with strong in-layer polar correlations and anti-ferroelectric juxtaposition of successive layers and (ii) large homochiral domains through the helical arrangement of the tilted smectic clusters, whilst the orthogonal clusters produce achiral (untwisted) nematic states.Comment: 14 pages, 2 figure

NewsTime--a graphical user interface to audio news

Thesis (M.S.)--Massachusetts Institute of Technology, Program in Media Arts & Sciences, 1993.Includes bibliographical references (leaves 103-104).by Christopher D. Horner.M.S

Liquid crystal blazed grating beam deflector

A multiple-angle liquid crystal blazed grating beam deflector has been developed. It consists of a stack of liquid crystal blazed gratings where each layer can deflect incident light with very high efficiency into one of two different directions depending on the driving condition. Four steering angles (10.8 degrees, 7.2 degrees, 3.6 degrees, 0 degrees) with about 70% diffraction efficiency are demonstrated with 15 V. The device's working principle, design considerations, fabrication process, and characterization results are described