Increasing chemotherapy in small-cell lung cancer: from dose intensity and density to megadoses

The hypothesis that increasing cytotoxic dose intensity will improve cancer cure rates is compelling. Although supporting evidence for this hypothesis has accrued for several tumor types, including lymphomas, breast cancer, and testicular cancers, it remains unproven. Small-cell lung cancer is extremely chemo- and radiosensitive, with a response rate of 80% achieved routinely, but few patients are cured by chemoradiotherapy. In this setting, increased cytotoxic dose intensity might improve cure rates. The finding that response rates in small-cell lung cancer correlate with received cytotoxic dose intensity merely confirms that "less is worse" and "more is better." Within conventional ranges, dose intensity can be increased with the support of hematopoietic growth factors and/or by shortening treatments intervals; however, dose intensity could be increased by only 20%-30%, and a survival advantage has not been clearly demonstrated. Given its high chemosensitivity, small-cell lung cancer was one of the first malignancies deemed suitable for increasing dose intensity and even for the use of a megadose with the support of autologous bone marrow transplantation. Some interest is emerging again due to improvements in supportive care, such as the availability of hematopoietic growth factors and peripheral blood progenitor cells.     

Discovery of diaryl imidazolidin-2-one derivatives, a novel class of muscarinic M3 selective antagonists (Part 1)

Pharmacophore-based structural identification, synthesis, and structure-activity relationships of a new class of muscarinic M3 receptor antagonists, the diaryl imidazolidin-2-one derivatives, are described. The versatility of the discovered scaffold allowed for several structural modifications that resulted in the discovery of two distinct classes of compounds, specifically a class of tertiary amine derivatives (potentially useful for the treatment of overactive bladder by oral administration) and a class of quaternary ammonium salt derivatives (potentially useful for the treatment of respiratory diseases by the inhalation route of administration). In this paper, we describe the synthesis and biological activity of tertiary amine derivatives. For these compounds, selectivity for the M3 receptor toward the M2 receptor was crucial, because the M2 receptor subtype is mainly responsible for adverse systemic side effects of currently marketed muscarinic antagonists. Compound 50 showed the highest selectivity versus M2 receptor, with binding affinity for M3 receptor Ki = 4.8 nM and for M2 receptor Ki = 1141 nM. Functional in vitro studies on selected compounds confirmed the antagonist activity toward the M3 receptor and functional selectivity toward the M2 receptor.     

Obesity and inflammation: evidence for an elementary lesion

In obesity, an inflammatory process of the adipose tissue has been hypothesized; however, direct evidence for a tissue lesion is still lacking. Macrophage infiltration in the adipose tissue of obese individuals seems to be proven, but other alterations of the tissue have not been demonstrated. Moreover, in humans it has not been clarified whether inflammation is an early characteristic of obesity, because no data from obese children are available. In the present study, we assessed the inflammatory involvement of the adipose tissue and identified the elementary "inflammatory" lesion in a group of obese children. The study of children gives us the chance to investigate adipose tissue during early phases of obesity. In all the obese subjects, ultramicroscopic analysis of the adipose tissue demonstrated inflammatory involvement, and the extent of the lesions seemed to depend on the SD score of body mass index. The elementary lesion is a microgranuloma, with fragments of adipocytes, that evolves to fibrosis. Macrophages (and less frequently, lymphocytes or granulocytes) were found in perivascular positions. The lesions were not found in nonobese children. Our study proved that an "inflammatory" process exists in the adipose tissue of obese children, confirming previous findings in animals and obese adults and demonstrating that it is an early alteration in humans. However, the accumulation of macrophages was just one of the components of the inflammatory lesion, which also involved adipocyte degeneration, fibrosis, and, to a lesser extent, granulocyte/lymphocyte accumulation. The finding of fragments of adipocytes in the elementary lesion suggests that, at the beginning of the process, adipocytes may degenerate and that the materials generated by this process can recruit macrophages and other leukocytes. These preliminary results suggest that additional studies should be designed to clarify the cause of adipocyte fragility in obese children.     

Reverse mapping of normal tissue complication probabilities onto dose volume histogram space: the problem of randomness of the dose volume histogram sampling

A very important issue in contemporary inverse treatment radiotherapy planning is the specification of proper dose-volume constraints limiting the treatment planning algorithm from delivering high doses to the normal tissue surrounding the tumor. Recently we have proposed a method called reverse mapping of normal tissue complication probabilities (NTCP) onto dose-volume histogram (DVH) space, which allows the calculation of appropriate biologically based dose-volume constraints to be used in the inverse treatment planning. The method of reverse mapping requires random sampling from the functional space of all monotonically decreasing functions in the unit square. We develop, in this paper, a random function generator for the purpose of the reverse mapping. Since the proposed generator is based on the theory of random walk, it is therefore designated in this work, as a random walk DVH generator. It is theoretically determined that the distribution of the number of monotonically decreasing functions passing through a point in the dose volume histogram space follows the hypergeometric distribution. The proposed random walk DVH generator thus simulates, in a random fashion, trajectories of monotonically decreasing functions (finite series) that are situated in the unit square [0, 1] X [1,0] using the hypergeometric distribution. The DVH generator is an important tool in the study of reverse NTCP mapping for the calculation of biologically based dose-volume constraints for inverse treatment planning.     

Cost of tracheoesophageal prostheses in developing countries. Facing the problem from an internal perspective

CONCLUSIONS: All the discussants of our questionnaire agreed that the price of tracheoesophageal (TE) prostheses was too expensive for developing countries. The problem could be addressed in terms of international laws regarding companies' patent rights. TE prosthesis manufacturers from rich countries could move their manufacturing in part to developing countries. High production standards could allow TE prostheses to be exported to developed countries. Another approach to the problem may be based on a partnership between non-profit-making Western laryngological societies with specific medical and technical prosthetic know-how and local manufacturers. The aim of this cooperation could be the low-cost production of advanced TE prostheses in the developing countries. OBJECTIVES: In communities in the developing world, most laryngeal and hypopharyngeal carcinomas are diagnosed at advanced stages and require total laryngectomy. Prosthetic TE voice restoration is the method of choice for voice rehabilitation after total laryngectomy in developed countries. Unacceptably high costs are a significant limitation to Third World use of TE voice prostheses. The aims of this paper are to discuss the consequences of the high costs of TE prostheses in developing countries with head and neck surgeons working in Third World hospitals and to propose how European and American laryngological societies can promote TE speech in the developing countries. MATERIAL AND METHODS: A questionnaire was given to a group of expert head and neck surgeons working in developing countries and their answers and suggestions discussed.     

A KSR/CNK complex mediated by HYP, a novel SAM domain-containing protein, regulates RAS-dependent RAF activation in Drosophila

RAF is a critical effector of the small GTPase RAS in normal and malignant cells. Despite intense scrutiny, the mechanism regulating RAF activation remains partially understood. Here, we show that the scaffold KSR (kinase suppressor of RAS), a RAF homolog known to assemble RAF/MEK/ERK complexes, induces RAF activation in Drosophila by a mechanism mediated by its kinase-like domain, but which is independent of its scaffolding property or putative kinase activity. Interestingly, we found that KSR is recruited to RAF prior to signal activation by the RAF-binding protein CNK (connector enhancer of KSR) in association with a novel SAM (sterile alpha motif) domain-containing protein, named Hyphen (HYP). Moreover, our data suggest that the interaction of KSR to CNK/HYP stimulates the RAS-dependent RAF-activating property of KSR. Together, these findings identify a novel protein complex that controls RAF activation and suggest that KSR does not only act as a scaffold for the MAPK (mitogen-activated protein kinase) module, but may also function as a RAF activator. By analogy to catalytically impaired, but conformationally active B-RAF oncogenic mutants, we discuss the possibility that KSR represents a natural allosteric inducer of RAF catalytic function.