laser based hadron therapy: a report on the map-cluster of ...micronuclei in 3d skin ... 1.42 ±...

Klinik und Poliklinik für Strahlentherapie und Radiologische Onkologie

© Molls

Prof. Dr. Michael Molls Klinik und Poliklinik für Strahlentherapie und Radiologische Onkologie

Technische Universität München

Bologna 05.11 2011

Laser based Hadron therapy: a report on the MAP-Cluster of

Excellence (http://www.munich-photonics.de/) and radiobiological results


© Molls

Munich Centre for Advanced Photonics (MAP)

Directors: F. Krausz, M. Molls

112 graduated scientists

LMU, TUM, MPI

Development of high-power lasers for the production of laser-generated X-rays and particle beams

Laser-generated particle beams for tumor therapy

Investigating quantum phenomena for information technology

Real-time analysis and control of molecular processes

Imaging of biomolecules

Probing fundamental laws of nature with unprecedented accuracy

Controlling electron motion in microscopic systems

Developing electronics to their ultimate limits (frequency of light)

Medical Applications

MAP has established close

cooperation between health

professionals and physicists.

Co-funded by Siemens Healthcare.

Medical imaging with brilliant X-rays


© Molls

Only about 50% of cancer patients can be cured

The number of cancer patients increases with increasing

life expectancy of modern societies

Improving cancer cure is a big medical and socio-

economic challenge in research

The scientific cooperation between physicists, physicians

and biologists in MAP offers innovative perspectives to

significantly improve cancer cure

Medicine: MAP application in 2006


© Molls


Strategy to combat cancer

Early tumor detection (diameter of 1mm)

and local curative radiation treatment!

Gordon Steel, Basic Clinical Radiobiology, 2002

Clinical evidence

Solid tumors at a size of about 106 – 107 cells

(about 1mm3) have not yet metastasized.

Thus efficient local treatment in this early

stage of the cancer disease is curative!

Future

Imaging

Imaging

Today

Vision of MAP/ CALA: Early Tumor Detection

Optical Imaging

Visualization of a

4 mm cancer in the

peritoneum of a

mouse (injected colon

cancer cells, i.p.;

fluorescence labeled

antibody , i.v. )

(Multhoff,

Ntziachristos, 2011)


© Molls

Diagnosis Diagnosis

1981 - 84 1990 – 94

Patients 469 520

Average age 56 y 53 y

Tumor < 1cm 11% 22%

Tumor > 2cm 44% 34%

Lymph node metast. 50% 38%

Stage 1 32% 46%

Stage 2 61% 47%

Stage 3 7% 7%

5 y survival 74% 84%

Breast Cancer Improvement of survival by earlier tumor detection

(Patients with breast carcinoma in Brisbane, Australia: Webb et al, The Breast 2004)


© Molls

MAP after the Mid Term Review (2010-2012)

A. Photon and Particle Beams

D.3 Radiation Therapy

Molls (Wilkens, Dollinger)

D.2 Clincal Imaging

Reiser (Coan, Hoeschen)

D.3.3 Radiation Therapy Studies on Tumor

Models in Mice

Schmid/ Dollinger/ Zlobinskaya

D.3.4 The Medical Beamline

Habs/ Wilkens

D.1.1 Coherent Diffractive Imaging of Proteins

and Biomolecules - Hajdu/ van der Spoel

D.1.3 Phase-Contrast Nanoscopy of Cells and

Tissue Samples - Pfeiffer/ Kleineberg

D.2.1 Phase-Contrast Imaging of Cartilage

Glaser/ Coan + ESRF

D2.2 Phase-Contrast Imaging of Breast

Coan/ Glaser + ESRF

D.1.5 Phase-Contrast Imaging of Tumor Models

Pfeiffer/ Bech

D.3.2 Radiobiology and Cellular Response

Friedl/ Dollinger

D.3.1 Physical Dosimetry and Spatial

Distribution

Assman/ Kneschaurek

D.1.4 Nanoscopy with Broadband Infrared

Radiation

Keilmann/ Apolonsky

D.1.2 Coherent X-Ray Diffraction on Biological

Microcrystals - Parak/ Achterhold

D.3.5 Design Study: Integrated System for Laser

Driven Ion Beam Radiation Therapy (L-IBRT)

Wilkens/ Tajima/ Habs/ Molls/ Nüsslin/ …

PMRC/ HIBMC/ Industrial Partners

D.1 Biological and Preclinical Imaging

Pfeiffer (Hajdu, Kleineberg )

D2.3 Dual-Energy Imaging with Brilliant X-Ray

Beams

Hoeschen/ Gruener

D2.4 Bioinformatics –

3D Registration of Histology and X-Ray Imaging

Navab/ Groher/ Glaser/ Coan

D. Biomedical Applications (coordinator: M. Molls)

C. Structure and Dynamics of Matter

B. Fundamental Interactions and Quantum Engineering


© Molls

Vision of MAP/ CALA: Image Guided Radiation Therapy

Today

Modern linac with CT

www.varian.com

integrated system

for imaging and

radiation treatment

(tumors of smaller and

larger sizes)

brilliant

x-rays ions

protons Future


© Molls

PULSED PROTONS CONTINUOUS PROTONS

Room size Football stadion

Laser based particle beams for Medicine

Conventional Laser


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Pulsed character of laser-accelerated protons

Factor 108 corresponds to an application of a 3 year event in only 1 second

“conventional“ proton therapy

2 Gy in 100ms (=10-1 s)

per cell / tissue voxel

laser-based proton therapy

2 Gy in 1ns (=10-9 s)

per cell / tissue voxel

factor 108

Is this difference in dose-rate

of biological relevance?


© Molls

Munich 14 MV Tandem Accelerator and SNAKE

SNAKE: superconducting nanoscope for applied nuclear (Kern) physics experiments


© Molls

9

mFISH

Mouse-Tumor-

Model

mRNA

Response

Hsp70 Analysis

Apoptosis

Micronuclei

In 3D Skin

-H2AX

Assay

Micronuclei

Assay

Comet Assay

Endpoints


© Molls

20 MeV protons (tandem accelerator)

1 Gy (single dose)

continuous pulsed

(1 Gy in 100 ms) (1 Gy in 1 ns)

Foci per cell 26.54 ± 2.54 23.29 ± 2.04

RBE 1.13 ± 0.21 0.96 ± 0.18

-H2AX-foci in HeLa cells / repair of DNA DSBs

pulsed cont.

Dose, Gy

0.0 0.25 0.50 0.75 1.00 1.25

Ga

mm

a-H

2A

X F

oci p

er

ce

ll

0

5

10

15

20

25

30

35

X-Ray

regression line

95% Confidence interval

Protons, pulsed

Protons, continuous

continuous


© Molls

Histology of EpiDermFT

(from MatTek Corporation, USA)

Epidermis containing basal, spinous,

granular keratinocytes and stratum

corneum.

Dermis contains numerous viable

fibroblasts.

Investigations in 3D skin tissue

More natural environment compared to cell culture

Accounting for interaction between cells and with matrix


© Molls

Epiderm FT human skin tissue

3 Gy (single dose)

continuous pulsed (3 Gy in 100 ms) (3 Gy in 1 ns)

MN per cell 0.08 ± 0.01 0.07 ± 0.01

RBE 1.13 ± 0.14 1.00 ± 0.14

Micronucleus assay in human skin tissue

Dose, Gy

0 1 2 3 4 5

mic

ronucle

i per

cell

-0.1

0.0

0.1

0.2

X-Ray 70kV

Protons, pulsed

Protons, continuous

regression line

95% Confidence interval


© Molls

Endpoint Test Biological

system

RBE for

contin. RT

RBE for

pulsed RT

p-value

DNA-DSB -H2AX foci count HeLa cells 1.13 ± 0.21

1.16 ± 0.09

0.96 ± 0.18

1.13 ± 0.09

n.s.

Comet assay HeLa cells 1.18 ± 0.021 1.11 ± 0.023 n.s.

Chromosome

Aberrations

Micronucleus assay HeLa cells 1.06 ± 0.07

1.05 ± 0.07

1.07 ± 0.07

1.09 ± 0.08

n.s.

EpidermFT

tissue

1.22 ± 0.15

1.13 ± 0.14

1.08 ± 0.20

1.00 ± 0.14

n.s.

Chromosome

aberration test

AL cells 0.84 ± 0.06

0.87 ± 0.05

0.88 ± 0.17

0.93 ± 0.04

0.008

Apoptosis Caspase-3 staining Human

fibroblasts

1.20 ± 0.38 1.20 ± 0.17 n.s.

EpidermFT

tissue

1.42 ± 0.12 1.24 ± 0.12 n.s.

Annexin test Human blood

lymphocytes

1.22 ± 0.45 1.05 ± 0.35 n.s.

RBE: No difference in single experiments, RBE for continuous protons mostly higher

Publications of our group:

Schmid et al. Radiat. Res. 2009; Schmid et al. Int. J. Radiat Biol. 2010; Schmid et al. Radiother. Oncol. 2010;

Schmid et al. Radiat Res. 2011; Schmid et al. Radiat. Res. 2011; Greubel et al. Radiat. Environ. Biophys. 2011


© Molls

Tumor growth delay experiment (nude mice, FaDu tumor)

air

2 mm

Tumor

Kapton

7,5 µm

Protons

23 MeV

Gafchromic

Film

Whell with

Al-Folie

0,2 – 3,0 mm

Protons

22 MeV

air

2 mm


© Molls

36 ± 4 Days 34 ± 4 Days

Tumor growth delay

No significant difference in tumor growth delay between pulsed and

continuous proton irradiation


© Molls

Cell Irradiations at Biomedical Beamline (Proof of Principle)

cells

ATLAS

laser

target

protons

focussing

film 5.2 MeV

dose distribution

nuclei, γ-H2AX, 53BP1

• laser-driven protons (5.2 MeV)

• nanosecond proton bunches

• high dose (up to 9 Gy) in a single shot


© Molls

Summary: Radiobiology and Radiation Treatment

RBE for continuous protons in accordance with literature results

RBE for pulsed protons not significantly different in most single

experiments

For other endpoints we anticipate that differences in RBE will be

small, if present

Successful proof of principle experiment: application of

laser generated protons in a radiobiological experiment


© Molls

Comparison of Phase-

Contrast Techniques at

Large-Scale Synchrotron

Radiation Facilities

1

Grating-Based Phase

Contrast & Atherosclerotic

Plaque Imaging Using

Compact X-Ray Sources

2

Grating-Based Phase

Contrast & Diffuse Lung

Disease in Experimental

Animal Models

3

Dynamic Phase-Contrast

Perfusion Imaging in

Small-Animal Models with

Compact X-Ray Sources

4

Dark-Field

Radiography

and Computer

Vector

Tomography

for

Osteoporosis

Diagnostics

5

Monitoring and Dosimetry 1

Radiation Therapy with

Laser-Driven Ion Beams 2

Cellular and Molecular

Radiation Biology of

Laser-Driven Particle

Therapy

3

Bio-Medical Aspects of

Laser Driven Particle

Therapy

4

Radiation Therapy with

Brilliant X-Ray Beams 5

Grating-Based

Phase-

Contrast

Breast CT and

Tomosyn-

thesis using

Compact

X-Ray Sources

4

Early Tumor

Detection in

Small-Animals

for Image-

Guided

Radiation

Therapy

3

Nano-

Tomography

with Brilliant

X-Ray Beams

for Tissue and

Bone samples

2

Sub-cellular

Imaging by

Scanning

Transmission

X-Ray

Microscopy

1

Multispectral Monochromatic

Phase Contrast – Tissue

Characterization, Image

Quality and Dose

5

C2 C3

C1

Advanced

Image

Reconstruction

and

Visualization

for Brilliant

X-Ray

Diagnostics

6

application

MAP II


© Molls

ENDE


© Molls

MAP: 4 research areas

A – Photon and particle beams A.1 – Next generation light sources

A.2 – Laser-driven particle and photon sources

B – Fundamental interactions and

quantum engineering

B.1 – Fundamentaal physics and nuclear transitions

B.2 – Quantum state engineering

C – Structure and dynamics of

matter

C.1 – Electron dynamics in atoms, molecules, solids

and plasmas

C.2 – Molecular dynamics and elementary chemical

reactions

D – Biomedical Applications

D.1 – Biomedical Imaging

D.2 – Clinical Imaging

D.3 – Radiation Therapy


© Molls

MAP II

A Next-generation sources and device technology

A.1 Broadband and intense coherent light sources (Major, Krausz)

A.2 New technologies for broadband laser, ultrashort x-ray & high-energy particle

beams

(Kleineberg, Apolonskiy)

A.3 Laser-based high-energy particle (x-ray, proton, ion) sources (Karsch, Schreiber)

B Probing & controlling electrons

B.1 Electronic structure and dynamics (Barth, Kienberger)

B.2 Molecular processes (Riedle, Domcke)

B.3 Light-wave electronics (Goulielmakis, Kling)

C Biomedical Diagnosis & Therapy: Translation to Clinical Applications

C.1 Biomedical physics and technology (Pfeiffer, Nüsslin)

C.2 Preclinical and Clinical imaging (Reiser, Pfeiffer)

C.3 Radiation therapy (Molls, Wilkens)


© Molls

Entwicklung von MAP

MAP-I

2006 2012 2017

MAP-II

CALA Vorantrag zu Gebäude & Infrastruktur (von WR bewilligt)

2 CALA Großgeräte-Anträge bei DFG eingereicht (ATLAS-300 & BRIX)

BRIX ATLAS-

300

CALA

Vision: Zelle – Gewebe - Kleintier – Patient

Center of Advanced

Laser Applications

Brilliante X-Strahlung für med. Bildgebung

Lasererzeugte Ionen für die Krebstherapie

07/2009

10/2009

MAP Mid Term Evaluation und Review führen zu Umstrukturierungen

und neuen Projekten für 2010 – 2012 (inkl. weiterer Stärkung der

Biomedizin)

01/2010

02/2010

283 Publikationen

25 in Science, Nature, Nature Physics,

Nature Photonics

45 in high-impact-factor Journalen

MAP Publikationen bis 2009


© Molls

Hochauflösende

Phasenkontrastbildgebung

Zielgenaue

Strahlentherapie

Vision von CALA

Brillante

Röntgenstrahlung

Ionen-/

Protonenstrahlen

Patient

Kompakte, kosteneffiziente Anlage zur Diagnose

und Behandlung von Krebs


© Molls

between fields: irradiated by table movement

within fields: irradiated by magnetic scanning

tumor outline

Verification measurement

with Gafchromic film

Treatment planning

Position Mausrad

DSOLL

[Gy] DIST [Gy]

1 4,52 4,58

2 2,05 2,14

3

4

5

1,21

1,22

1,25

1,20

6

7

8

9

0,79

0,84

0,89

0,92

0,88

10

11 0,55

0,65

0,62


© Molls

The National Lung Screening Trial in persons at high risk for

lung cancer at 33 U.S. medical centers

(The New England Journal of Medicine, June 2011)

• Randomization

Low-Dose CT n = 26722

Chest radiography n = 26732

• Enrollment for randomization: August 2002 to April 2004

• Three annual screenings: T0, T1, T2

Adherence to screening more than 90%

• Collection on 1) cases of lung cancer and 2) deaths from lung

cancer that occurred through Dec. 31, 2009.


© Molls

The National Lung Cancer Screening Trial

• Positive screening

24.2 % with CT

6.9 % with radiography

• False positive results of the positive screening

96.4 % with CT

94.5 % with radiography

• Incidence of lung cancers

645 cases per 100 000 person-years (1060 cancers) with CT

572 cases per 100 000 person-years (941 cancers) with radiography

• Cancer deaths

247 deaths per 100 000 person-years with CT

309 deaths per 100 000 person-years with radiography

• A relative reduction in mortality from lung cancer with low-dose CT

screening of 20.0% (95% CI, 6.8 to 26.7; p = 0.004)


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MAP Mid Term Review 10/2009 by the International Scientific Advisory Board

„Generally, the Board was unanimously and without reservation impressed by the

world-class quality of the research being performed at MAP.“

Integration in national & international scientific environment

Both MAP´s source development and scientific applications are well integrated

into all relevant national and international activities, including the world´s first

international laser projects ELI and HIPER.

Added Value The interdisciplinary collaboration between physics and medicine appears unique. The goals – novel applications of innovative laser-based particle- and photon sources for medical and biomedical problems – are of considerable risk but, if successful, of highest societal relevance. The added value provided by the MAP project is overwhelming even after such short project duration


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Munich Centre for Advanced Photonics (MAP) (Speakers: F. Krausz, M. Molls)


• Participating Institutions of the Munich area: LMU, TUM, MPI, etc.

• Interdisciplinary collaborations: 50 projects in 4 research areas

• 112 graduated scientists from Physics, Medicine, Biology, Chemistry, Informatics

• More than 1000 publications in about 5 years, 23 of these in Nature and 18 in Science

• Worldwide networking with leading institutions


© Molls

In the context of future imaging and visualization of early

stages of cancers and chronic diseases MAP scientists

discuss:

Is it necessary to combine future imaging strategies with

(blood) biomarkers for early stage detection of cancer and

chronic diseases?

Is it possible that innovative imaging methods substitute

histopathology?

laser based hadron therapy: a report on the map-cluster of ...micronuclei in 3d skin ... 1.42 ±...

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