radiobiology and clinical new issues in hadron current therapy nicolae verga 1, dariush sardari 2, s...

RADIOBIOLOGY AND CLINICAL NEW ISSUES IN HADRON CURRENT THERAPY

Nicolae Verga1, Dariush Sardari2, S R Mehdi Mahdavi3

1.“Carol Davila”, University of Medicine and Pharmacy, Bucharest, Romania, 2. Faculty of Engineering, Science and Research Branch, Azad University,

Tehran, Iran, 3. Iran University of Medical Sciences

THE AIM OF THE CURRENT PRESENTATION

We all recognize the current in the world who claims about the survival in cancerous disease and especially about survival in better living conditions.

New and easy means of communication, and especially the Internet, leading to the formation of a social anti-cancer views, opinion that obliged us, all those who collaborate in the act of radiotherapy, medical doctors, medical physicists, dosimetrists, engineers, clinicians and researchers, to review, redesign, invent new equipments for treatment.

This is the reason for what I posing in front you the point of view that militate for a systemic approach of a living matter and from this the invitation of physicians stimulated by patients to review and redesign the radiotherapy equipment in order to respond at this systemic point of view, biological integrallist.

THE ORGANISM, A UNITARY AND COHERENT WHOLE

1) Radiation treatment plan (TPS) must respect the human body unity

2) The foundation of the radiotherapeutical planning on the characteristics the ICRU set, on the Hounsfield units offered by X ray CT scan is insufficient

3) In recent years, biological monitoring radiotherapeutical indication, only partially meet the requirements of paragraph 1, the oncology it being inundated with data on tumor-host signaling

4) Many information, less knowledge!

5) The lack of an system who integrate data from clinical, imaging, laboratory, physics, chemistry, computer science, mathematics, etc. investigations, leads to a weakness in diagnosis and from there to unsatisfactory results in radiological treatment of cancer.

RADIOBIOLOGICAL STUDIES OFFERS a. A strong platform of proves for rationale of hadrontherapyb. A common “language” for:

data communications easily comparison between the different clinical trials used in hadrontherapy

because the heterogeneity of data (different dose prescriptions, fractionation , physical beam properties)

similar dose prescription for protons (low LET) and carbon –or other ions – (high LET)

c. A possibility to predict the treatment efficiency based on common parameters (alpha/beta ratio, hypoxia, proliferation, tumor volume, etc)

d. Possiblity to calculation the therapeutic gain (Ando et al 2005) :

e. A good tool for intercomparison of the justification of the different methods of radiotherapy (classically or hadron therapy)

f. The concomitant evaluation of an adverse effect data on normal tissue and the curing data on the tumor

g. Establishing a common QA rules and conditions

LoLETOAR

LoLETTumor

HiLETOAR

HiLETTumor

RBERBERBERBEf

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The Definitions of the Biology Systems• Previous attempts

– “There are many different definitions of Systems Biology; like an elephant it is easy to recognize and hard to define.” (Kell, 2004)

– “Integrative approaches in which scientists study and model pathways and networks, with an interplay between experiment and theory.” (Henry, 2003)

– “Systems biology has two distinct branches: Knowledge discovery and data mining, which extract the hidden pattern from huge quantities of experimental data, forming hypothesis as result and simulation-based analysis, providing predictions to be tested by in vitro and in vivo studies.” (Kitano, 2003)

Our more limited definition: “An interdisciplinary approach for integrating experimental data with mathematical modeling tools to analyze & predict the behavior of biological systems.” (Henson, 2005)

THE BIOLOGICAL CHANNELThe Necessity of this theory

It is imposed by enormous amount of data who must be integrated into a theoretical system, research and daily practice.

It is impose by the practice in biology, bio informatic and computational biomedicine, applied in bio-electromagnetic compatibility, radiotherapy, HIFU, hyperthermia,etc. for prevention:

empirical knowledge, pragmatically narrow of researches , positivism (simplistically arranging or systematize of the dates ) .

The definition of the biological channelUnified methodology for conceptualization and research in computational bio-medicine based on a biogeometrical concept and model of alive system named biological channel.

It is part of general theory of systems like an application of the theory of information in biology. Dangers

Thanks to the novelty of the theory and the lack of the methods and instruments, we could be dogmatic or speculative.

The mains components of the matter are Substance, Energy and Information, ordinate in Space, Movement and Time.

STRUCTURE, FUNCTION AND LEARNING

The Substance is defined like a body, composed by the same atoms and molecules and has characteristic properties; it is measured by mass. The distribution of components of the substance in Space forms and defines

a Structure The Structure of a substance determines its properties, every times the same , in the same environmental conditions. The biological structure may be defined like a way of arrangement of the substances into the space of an alive system.

The components of the biological channel

Every biological structure, especially when we refer at the alive matter, has their own FUNCTION, and this connection structure -function is the first biology dogma.

“THE FUNCTION MAKES THE STRUCTURE”We define the Biological Function, like an ensemble of specifically activities of

organs, apparatuses, tissues, cells or sub cellular systems, from the alive systems. A sufficient characterization of an alive system function can be made by self qualities:

Energy and Movement.

MOLECULAR LEVEL - MOLECULAR TOPOLOGY

Molecular topology is part of mathematical chemistry dealing with algebraic description chemical compounds, thus allowing a unique and easy characterization.The chemical structure of compound has to be represented by a set of structure descriptors. Establishing structure–property or structure–activity relationships (SPR or SAR) or even finding such relationships in a quantitative manner (QSPR or QSAR)Applied Topology explains how large molecules and how molecules reach the final forms performed their biological activity.Circuit topology is a topological property of linear polymers folded. This notion it was applied to the structural analysis of biomolecules such as proteins and RNA. “*

SPACE, STRUCTURE, SUBSTANCE

HIGHER BIOLOGICAL EFFECTIVENESS at nanometer scaleComplex damage due to localised energy deposition

Local Effect Model – Status and future perspectivesThilo Elsässer, GSI Darmstadt, ENLIGHT MEETING

LEM concept respond to a radiobiological realism: there is a reaction of a biological targets at radiological aggression

It is necessary an evaluation of the TIME in that happen the radiobiological effects not only of their space:

time Dose rate

Radio-physics effects 1*10-12 – 1*102 sec pico Gy s−1

Radiochemical effects 1*10-1 - 1*105 sec mili Gy s−1 Radiobiological effects 1*102 -1*1010 sec mili Gy s−1

Units of measurement are needed:- If we want to measure the effects on the submicroscopic level- If we want to measure the effects which takes very little time in the atto- radiochemistry- If we want to digitize radiochemical and radiobiological effects in computational oncology

The time(s)

The process The reactions The species formed

10-18 1 MeV electron passes through a molecule

H2O+

10-17 A particle of 1 MeV energy crosses a molecule

H2OH2O++eH2OH2O*

e-

H2O

10-16 A thermal electron 0,025 eV passes through a molecule

Located in the path of radiation10-15

10-14 The time between successive ionization of an 1 MeV electron

The physical stageThe time(s)


10-13 Ion-molecule reactions. Period of a molecular vibrations. Dissociation of the excited molecules. Secondary electrons reach the thermal energy. Electron capture.

H2O+

+H2OH3O+

+OHH2O*H+OHH3O++e-

H+H2O

OH•H•

10-12 Diffusion of radicals

10-11 The relaxation time for guiding of the water dipoles

e-eaq-

(Platzman)e-+H2OH+OHaq (Lea, Gray)

HOHeaq

-

H2O

10-10 The minimum time for controlled reactions by the diffusion

H+OHH2O2OHH2O22HH22eaq

-H2+2OH-

In pore or on trajectory

Physico-chemical stage

Radical-radical reactions in the active zone, the diffusion of the radicals, formation of the molecular products. The reactions with dissolved substances.

CHEMICAL STAGE

The time(s)


10-9 The lifetime for singlet excited state. The formation of molecular products in the trajectory (pores) of radiation

OH+H2O2HO2+H2O HOHeaq

-

H2OH2H2O2

10-8 - 10-7 Molecular product formation in a trajectory of a a particle

10-6

10-5The reaction time between radical and dissolved substance in the molar concentration (energy of activation 5kcal / mole)

10-4 The time required for a radical disseminate on the distance between two trajectories of electrons 1MeV

10-3 The lifetime of the triplet excited state

0 Complete chemical reactions H2, H2O2 and the reaction

products with dissolved substances

BEGINING A

BIOLOGICALSTAGE

STRUCTURE, FUNCTION AND LEARNING

The Information is another form of existence of matter. The arrangement of the information in Time characterizes the Memory of the alive structure . At the level of biologic system we can not think only at the memory of this. The mnemonic character of living structures are characterized by learning, reason for we use the term mathemabiotic (mathema learn, vio life), living structures being matemabiotics. The reverse learning is forgetfulness, loss of functional information assigned to a living structure which would mean bioamnesia (vio life amnisia forgetting). The autonomy of this system in comparison with the environment supposes an active adaptation too, based on the history of phylogeneticaly adaptation events. Will be describe the LEARNING like a characteristic of the alive system.

We can represent this in graphical mode :

The components of the biological channel

THE COMPONENCY OF THE BIOLOGICAL

CHANNELSThis biogeometrical model

represents the “BIOLOGICAL CHANNEL”.

It is a biomathematics model of a biologic system and can defines:The composition of the biologic system and the

relations between componentsThe mode of integration of alive system dateThe relations between alive system and lifeless its.

THE MNESICAL STRUCTUREIt is born into a biologic system by the phenomenon of transforming of the information into the structure

The biologic systems or subsystems with fixed program

When the information is inscribed in the structure of the system by arrangement, interconnection and properties of the component elements, the quantity of information is the same during functioning program.

THE COMPONENCY OF THE BIOLOGICAL CHANNELS

The biologic systems or subsystems with variable program and different degree of liberty

The functional structure has certain grade of liberty, the program is included into a special structure named the system memory, which is attached by functional structure itself.

THE MNESICAL STRUCTURE Properties

The performance of organization of an alive system depends of the degree of obedience of the system at its law of function : self reproduction, self control,

metabolism and homeostasis.

The organization degree of a structure with memory is reflected by its

performance of organization.

The performance of organization of an alive system ≡

The informational energy


The informational energy measures the organization degree of a system and determines the probability of the apparition of the event [A]:

n

jj ApE

1

2where p represents probability of the apparition of the event [A].

O.ONICESCU 1979

THE MNESICAL STRUCTURE Properties

In comparison with the degree of the organization and with an event with sense, which that participates alive mnesical structure, the organizational degree can be appreciated by degree of the action, its power and its sense.

The performance of the organization of a structure depends directly by its memory and it is writing in this.

At an alive structure, the variation of the memory is made step by step and is associated with the restructuration.

In this way is sustained the idea of quality of learning of the alive matter, which is different by the structure and function,

so, the learning represents the third caracteristic of the alive

matter.

THE CONSEQUENCES


The performance of organization

Structural Carriers Of Memory Its Organization And Clinical Application


THE MNESICAL STRUCTURE

NANOSCOPICALLY

Genom

Cancers classified by molecular phenotypes. Organ site → secondary classificationMolecular phenotypes will be determined by molecular imaging studies (PET, SPECT, MRI, optical) with biopsy

Protenom Targeted Molecular Imaging and Therapy - The Key-Lock Principle

Receptron Ga-68 SMS Receptor PET – Imaging Technique

MICROSCOPICALLY

Cells with immunological role. Molecular imaging Ga68-SSTR PET-CT and corelation to immunohistochemistry of somatostatin in neuroendocrine tumors

Neuronal synaptic associations WHITE ZONESpecifically structure of transport ways Sentinel node probe

MESOSCOPICALLYSpecialized mesoscopically receptors

Quantification of Correlation between PET-CT and Tumor Tissue Morphology using Knowledge Driven Image Analysis - Digitalized Histopathological Classification

The points and the meridians in acupuncture WHITE ZONE

MACROSCOPICALLY

Specialized macroscopically receptorsDigitalised Histopathology Combined with Somatostatin Receptor PET-CT. From Tissue to Molecular Imaging to Therapy

Sensitive and motors metamers Cognition Network Tech. For Automatic Analysis Of Molecular PET-CT ImagesSensitive and motor homunculus

Psychic Memory GRAY ZONE

THE MNESICAL STRUCTUREThe properties of the structural memory

The functions of the MEMORYIt has the same characteristics, like the other functions of the alive matter :The metabolism of informationThe homeostasis of informationThe self control of informationThe self reproduction of information

THE FORMES OF EXISTENCE AND MANIFESTATION OF THE MEMORY

The memory of the human organism exists and manifests like punctual properties, patterns and images, characteristic for structural-functional units at that level which are manifest and where are investigated.


INFORMATIONAL ALTERATION AT TISSUE LEVEL

Effects of heavy charged particles on electrical activity (ERG) of isolated frog retina (Trukhanov et al., 2001*)

* The outlook of investigations of photochemical, photo- and radiobiological processes of vision at JINR basic facilities - Mikhail A. Ostrovsky

IRADIATION WITH FOTONS

IRADIATION WITH DEUTERONS, IREVERSIBLE FALL OF ELECTRICAL ACTIVITY

The retinal function decrease with the time of exposure to deuteron beam.

THE MNESICAL STRUCTUREThe properties of the structural memory

The unit of measure of the human body information is the bit, referring at bit-structure and bit-function.


THE UNIT OF MEASURE OF THE HUMAN BEEN INFORMATIONS

What is means bit-structure ?Significant changes in a structure so that the same structure exert a different function can be computational measured in a bit-structure. For example the modification of a chemical structure from cis configuration in trans configuration.What is means bit-function ?The function of a competent and specific structure is characterized by purpose (finality, effect), action mode (intensity, potential, time of development). The change of these characteristics defines bit-function.

THE DEGREE OF THE ORGANIZATION OF THE FUNCTION

The degree of the organization, like a measure of life of the alive system, can be characterized by the performance and the sense of

its functionality

The degree of the organization of the biologic system has three senses:- stationary , equal with the unit (eigenvalue)- increased, bigger than the unit, obtained by training - decreased, smaller that the unit, pathologic


The organization in time and space of the function reflects the manner of the organization of the structure

Punctual functions Parallel functions (ex. liver, kidney) - in two or more planes -Serial functions (ex. blood vessels, digestive tub) – linear or cyclic -Complex functions (serial parallels – bronchus, parallel serial –nephron) –exclusive in volume -

THE ALIVE SYSTEMS, THE FUNCTION

Biogeometrical speaking, these functions can be disposed on the logarithmic spiral, where are situate at the intersection of the spire

with two perpendicular right lines.

ScM

SrH

B

P S

C

M Metabolism

H Homeostasis

Sr Self reproduction

Sc Self control

B Biologic

S Social

P Psychic

C Cosmic

EVOLUTION AND CO-EVOLUTIONTHE COMPONENCY OF THE BIOLOGICAL CHANNELS

THE ALIVE SYSTEMS, THE FUNCTION

The alive matter is organized by distinct structural functional and mnesic units, witch can be classified by their dimensions, but witch

must reflect the characteristics of components units of the alive matter.

NANOSCOPICALLY

Atomic

Multi atomic

Molecular

Multimolecular

Macromolecular

Multi macromolecular

MICROSCOPICALLYOrganellic

Multi organellic experimental

Multi organellicc alive

Cellular

MEZOSCOPICALLY Mono tissue

Mono tissue experimental

MACROSCOPICALLY

Multi tissueorgan

Multi organ (apparatus or system)

Organism on different biogenetic level

Human been

Human group


MECHANISMS AND MOLECULARITY IN RADIOLYSISA different treatment of the reaction kinetics of the experimental kinetics is the one in which radiolysis follows a certain mechanism.The molecularity expresses the number of molecules of water and other components of the living cell that participates in an elementary reaction (assumed as an individual step in a reaction mechanism). In contrast with the order of reaction, which is an amount deducted from the speed experimental law and is still applicable to a general reaction, the molecularity is applied to the individual elementary reaction, presumed steps in the reaction mechanism.

Monomolecular elementary reactionsIn an elementary monomolecular reaction one molecule undergoes a structural rearrangement or decomposition.It is of the 1st order because the number of reactant molecules that decompose in a short interval dt is proportional with the number of molecules available to react.

Elementary bimolecular reactions

In an elementary bimolecular reaction two molecules collide and exchange among them energy, atoms or groups of atoms, or suffer other exchange (electrons).A elementary bimolecular reaction is of the order 2 because its speed is proportional to the rate at which the reactants collided with one another are proportional to their concentration.

Monomolecular consecutive elementary reactions (successive)The general case of these reactions is expressed by the equation:

R1 → R2 → ... → RnRadiolysis reactions in the living cell, are consecutive reactions leading to the formation of free radicals and reactions between the free radicals, between free radicals and cellular biochemical components and subsequent extinction of these reactions.

In this situation appear two stationary states **, one to quenching the reaction between radiolysis products and cellular components, the second, as a reaction of tissues to the radiological aggression, reaction knew it lasting on average 6 hours.

*Houser JJ, Estimation of A° in reaction-rate studies (CS), J Chem Educ, 1982, 59, 776; Ball DW, Kinetics of Consecutive Reactions: First Reaction, First-Order; Second Reaction, Zero Order, J Chem Educ, 1998, 75, 917.

** Se numeşte stare staţionară, o stare a sistemului în care vitezele de variaţie ale tuturor intermediarilor sunt neglijabil de mici.

MECHANISMS AND MOLECULARITY IN RADIOLYSIS

TECHNIQUES for FOLLOW-UP PHASE OF A REACTIONTechniques follow-up phase of a reaction aimed at tracking measurable parameters: temperature, pressure (where are involved gas) concentration.Analysis of real-time kinetic techniquesKinetic techniques aimed at analyzing the composition system in real time. They have developed techniques applicable to the quick reactions (when a reaction takes less than 1s). Isotopic techniques (marking with radioactive isotopes of evidence) to observe the processes that react in time femtoseconds (1fs = 10-15s).Flash PhotolysisFlash Photolysis (flash photolysis) uses color light or laser to photograph the sample during ranging from 10-5s to 10-12s, the spectrum being recorded electronic or photographic.Dynamic methods, the enzymatic kineticsDynamic methods leads to molecules of the sample into a movement along the tubeand it is observed a composition with a spectrophotometer at different positions in space, which, for a continuous, uniform flow at a constant speed corresponding to different reaction times. The kinetics of enzymatic technique using such observation.

Noţiuni fundamentale de chimie; Legi de bază; Chimia şi rolul ei în pregătirea inginerului curs nepublicat 2010 A. Lorentz

Kinetics of consecutive reactions

Steady state

The maximum point

Our interest is to obtain during radiotherapy a maximum area of radiolysis processes and have a stationary state as late after stopping irradiation.This rejoining of DSBs appears follow a biphasic kinetic pattern, consisting of an initial rapid phase (10 -20 minutes to 2 hours) followed by a slow phase (several hours can continue for up to 24 hours).

During steady state we wish that the stability in time of atomic and molecular species appeared after radiotherapy be as high because the efficiency of cellular repair mechanisms to be as small. So it happened, DNA molecule, fix defects after repairing which leads to alterations of neoplastic of cellular metabolism and reproduction. There is an alteration of the DNA memory which transmits this information modification (learning!) to the neoplastic and / or normal cellular next generation.

The use of hadrontherapy provide extreme high radiolysis in short time, the ionization is very intense, causing known fractures atomic and molecular.

CONCLUSIONS We need a NEW VIEW ON SYSTEMS FOR RADIOTHERAPY TREATMENT PLAN !Future treatment plan will need to integrate knowledge and information at all levels of organization of the living matter:a deep integration of knowledge of the cancerous process and its

relationship with the host organism, greater effort and attention for the diagnostic;

a deep integration a knowledge in real time, from the nanoscopic at macroscopic level of radiolytic phenomena in radiothreated body, in order to increase the estimation of the evolution in time of cancer patientscheminformatics and molecular topology,times and rhythms of radiobiochemical effects,

the knowledge of the levels of integration development of a cancerous process and its relations with the host,

a strict economy in radiotherapy, radiation treatment, but only what is "necessary, sufficient and proven effective“

greater attention paid to study effects of ionizing radiation on the normal organism and to its non-oncological diseases and the possibility of applying radiological treatments in diseases other than cancer and to prevent the provoke a second cancer due to radiotherapy

a knowledge of local, regional and systemic phenomena, which occur due to combination of the radiotherapy with surgery, chemotherapy and immunotherapy

the new radiotherapy equipment must integrate feedback systems, imaging and dosimetry, with the ambition to monitor treatment from the nanoscopic to the macroscopic levels

design and production of new radiotherapy equipment, cheaper, smaller, easier to handle, theragnostics, able to combine the diagnostic to the treatment, up to the cellular level

CONCLUSIONS

FOR ALL OF THIS, IT IS ESSENTIAL AND URGENT THE STRENGTHENING OF THE

INTERDISCIPLINARY AND INTERNATIONAL EXCHANGE OF INFORMATION !

THANK YOU !

radiobiology and clinical new issues in hadron current therapy nicolae verga 1, dariush sardari 2, s...

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