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PubMed2004

Recent advances in light ion radiation therapy.

BACKGROUND: The fast development of energy- and intensity-modulated radiation therapy during the last two decades using photon and electron beams has when implemented resulted in a considerable improvement of radiation therapy, particularly if combined with radiobiologically based treatment optimization techniques. This has made intensity-modulated electron and photon beams as powerful as today's uniform dose proton therapy. To be able to cure also the most advanced hypoxic and radiation-resistant tumors of complex local spread, intensity-modulated light ion beams are really the ultimate tool and in clinical practice 2 to 3 times less expensive per patient treated than proton therapy. This development and the recent development of advanced tumor diagnostics based on PET-CT imaging of the tumor cell density open the field for new powerful radiobiologically based treatment optimization methods. The ultimate step is to use the unique radiobiologic and dose distributional advantages of light ion beams for truly optimized bioeffect planning where the integral three-dimensional dose delivery and tumor cell survival can be monitored by PET-CT imaging and corrected by biologically based adaptive therapy optimization methods. PURPOSE: The main purpose of the present paper is to discuss the principal areas of development of therapy optimization, by considering the therapy chain from tumor diagnostics and the use of three-dimensional predictive assay to biologically based treatment optimization with special focus on the rapid clinical development of advanced light ion therapy. METHODS: Besides the "classical" approaches using low ionization density hydrogen ions (protons, but also possibly deuterons and tritium nuclei) and high ionization density carbon ions, two new approaches will be discussed. In the first one, lithium or beryllium or boron ions, which induce the least detrimental biologic effect to normal tissues for a given biologic effect in a small volume of the tumor, will be key particles. In the second approach, referred patients will be given a high-dose, high-precision "boost" treatment with carbon or oxygen ions during 1 week preceding the final treatment with conventional radiation in the referring hospital. The rationale behind these approaches is to minimize the high ionization density dose to the normal-tissue stroma outside but sometimes also inside the tumor bed and to ensure a more uniform and optimal biologic effectiveness in the tumor, also on the microscopic scale. The present discussion indicates that BIologically Optimized predictive Assay based light ion Radiation Therapy (Bio-Art) is really the ultimate way to perform high-precision radiation therapy using checkpoints of the integral dose delivery and the tumor response and, based on this information, perform compensating corrections of the dose delivery. By using biologically optimized scanned high-energy photon or ion beams, it is possible to measure in vivo the three-dimensional dose delivery using the same PET-CT camera that was used for diagnosing the tumor spread. This method thus opens up the door for truly three-dimensional biologically optimized adaptive radiation therapy, where the measured dose delivery to the true target tissues can be used to fine-adjust the incoming beams, so that possible errors in the integral therapy process are eliminated toward the end of the treatment. Interestingly enough, practically all major error sources--such as organ motion, treatment planning errors, patient setup errors, and dose delivery problems due to gantry, multileaf, or scanning beam errors--can be corrected for in this way. RESULTS AND CONCLUSIONS: Radiobiologically optimized dose delivery using intensity and radiation quality modulation based on high-resolution PET-CT or Magnetic Resonance Spectroscopic Imaging (MRSI)-based tumor and normal-tissue imaging is probably the ultimate development of radiation therapy, taking the unique physical and biologic advantages of light ions fully into account in truly patient-individualized curative treatment schedules. Using recently available biologically based treatment ilable biologically based treatment optimization algorithms, it is possible to improve the treatment outcome for advanced tumors by as much as 10-40%. The adaptive radiotherapy process based both on three-dimensional tumor cell survival and dose delivery monitoring has the potential of percent accuracy in tumor response and dose delivery monitoring, using two-dimensional, narrow high-energy photon beam scanning and three-dimensional (11)C Bragg peak scanning for radiation quality and intensity-modulated dose delivery. There is no doubt that the future of radiation therapy is very promising, and gradually more and more patients may not even need advanced surgery. Instead, they could be cured by biologically optimized electron, photon, or light ion therapy, where the densely ionizing Bragg peak is placed solely in the gross tumor, and a lower ionization density is used in microscopically invasive tumor volumes.

Cell Cycle↗
PubMed1992

Cellular and molecular basis of intestinal and pancreatic adaptation.

This article reviews the structural and functional changes which develop in the intestine and pancreas in response to a variety of stimuli and which characterise adaptive hyper- or hypo-plasia. It then discusses the principal physiological mechanisms controlling this adaptive growth. In the gut, these include luminal nutrition, endocrine, autocrine and paracrine hormonal influences, growth factors, enterotrophic components of pancreatico-biliary secretions, neural factors, changes in blood flow and mesenchyme-epithelial interactions. The cell biology of adaptive growth involves cell membrane receptors (first messengers) and a cascade of intracellular second messengers, the best studied of which is changes in polyamine metabolism and in related enzymes. The effects of ornithine decarboxylase (ODC) blockade with difluoromethyl ornithine (DFMO) and of diamine oxidase (DAO) blockade with aminoguanidine, are described. In general, DFMO inhibits or prevents adaptive hyperplasia while in the small bowel, aminoguanidine treatment induces 'supranormal' adaptation. However, both the gut and the pancreas transport 'exogenous' (ingested in food and circulating in the blood stream) polyamines across their apical and basolateral membranes. The influence of this exogenous polyamine transport on 'endogenous' (enzyme-regulated) intracellular polyamine concentrations, is largely unknown. Finally, the molecular biology of adaptive growth is described briefly--as illustrated by the use of a growth hormone transgenic model in which mice develop marked intestinal mucosal hyperplasia and increases in the relative abundance of insulin-like growth factor-I (IGF-I) mRNA in the intestine.

Adaptation, Physiological↗
PubMed1964

FOSSIL FOOT BONES.

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Adaptation, Biological↗
PubMed2006

The biologic relevance of daily dose variations in adaptive treatment planning.

PURPOSE: To explore the biologic relevance of deviations from the intended uniform fractionation scheme. METHODS AND MATERIALS: We study the effect of the variance of the dose per fraction on the normalized total dose (NTD), which incorporates the linear-quadratic model of radiation effects. In regions of steep dose gradients, we determine the shift between NTD isodose lines and physical isodose lines. We also look at ways to compensate for dose-variation effects through dose adjustments, without changing the number of fractions. RESULTS: Simple equations quantify effects of dose variation on the NTD. If the standard deviation of the dose is 10% of the daily dose fraction, the effects on the NTD for a given point in the irradiated area are always less than 1%, independent of the biologic parameters. In adaptive dose-correction schemes, the dose correction should be applied uniformly over the remaining fractions, to minimize the variance. Incomplete repair leads to a coupling of doses delivered on different days, which complicates the issue. Repopulation appears to be insignificant in the context of this study (constant overall treatment time). CONCLUSIONS: A variation of the dose between fractions always leads to a larger biologic effect than does the same total dose delivered with standard uniform fractionation. The increase in NTD is negligible if the standard deviation of the dose is less than 10% of the dose per fraction.

Algorithms↗
PubMed1964

WHAT IS HEREDITY?

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Acridines↗
PubMed1976

Genetic and anthropological studies in the human adaptability section of the International Biological Programme.

In the U.K. contribution to the H.A. (Human Adaptibility) section of I.B.P., genetic and anthropological studies have focused on three concerns. First, attempts have been made in a number of investigation to gain additional descriptive information about the genetic compostition of the world's populations. Concentrating on blood groups, blood enzymes, serum proteins and other polmorphic markers important gaps have been filled in our knowledge of the geographical paterns of human variation and of the affinities of populations wig and characterizing populations which were being studied for other purposes. For example, it was of critical concern in interpreting results to know in the investigations of climatic physiology and nutrition in Ethiopia and Israel whether the various groups studied in different environments were genetically the same or not. Finally, attention was focused in a number of investigations, especially those in New Guinea, Tristan da Cunha, Tanzania, and the Orkneys, on the factors which determine the genetic structure of populations. In these the effects of such phenomena as inbreeding, genetic drift, founder effects, migration and gene flow and the relation between genetic variety and health were examined and much attention was given to the interaction between demographic forces and genetics.

Adaptation, Physiological↗