Daniel N. Slatkin
University Scholar, 1951-1955 and B.Sc. (Honours in Mathematics and Physics), 1955; Faculty of Science, McGill University, Montreal, Canada
M.D., 1959; Faculty of Medicine, McGill University, Montreal, Canada
Certification in Anatomic Pathology, 1965; American Board of Pathology
Research Consultant, 1997-2009; Nanoprobes, Inc., Yaphank, New York
Pathologist and Scientist, 1972-1996 and Visiting Scientist, 1996-present; Brookhaven National Laboratory, Upton, New York.
==============
dnslatkin@gmail.com
Post Office Box 334, Essex, Connecticut 06426-0334, USA.
===============
Citations in PubMed: [slatkin dn and slatkin d]
==============
Other citations:
Co-inventor of US patents:
H505 Boron uptake in tumors, cerebrum and blood from [10B]NA4B24H22S2; August 2, 1988
4,845,729 Method and apparatus for diagnosis of lead toxicity; July 4, 1989
5,339,347 Method for microbeam radiation therapy; August 16, 1994
5,455,022 Halogenated sulfidohydroboranes for nuclear medicine and boron neutron capture therapy; October 3, 1995
5,583,343 Flexible nuclear medicine camera and method of using; December 10, 1996
5,612,017 Halogenated sulfidohydroboranes for nuclear medicine and boron neutron capture therapy; March 18, 1997
5,653,957 Halogenated sulfidohydroboranes for nuclear medicine and boron neutron capture therapy; August 5, 1997
5,877,165 Boronated porhyrins and methods for their use; March 2, 1999
6,299,873 Method for improvement of radiation therapy of malignant tumors; October 9, 2001
6,566,517 Metalloporphyrins and their uses as imageable tumor-targeting agents for radiation therapy; May 20, 2003
6,759,403 Metalloporphyrins and their uses as radiosensitizers for radiation therapy; July 6, 2004
6,818,199 Media and methods for enhanced medical imaging; November 16, 2004
6,951,640 Use of novel metalloporphyrins as imageable tumor-targeting agents for radiation therapy; October 4, 2005
6,955,639 Methods of enhancing radiation effects with metal nanoparticles; October 18, 2005
7,367,934 Methods of enhancing radiation effects with metal nanoparticles; May 6, 2008
7,530,940 Methods of enhancing radiation effects with metal nanoparticles; May 12, 2009
=============
Project Proposal *PROJECT NUMBER : 91-10 Brookhaven National Laboratory: *pages 36-37 of: Laboratory Directed Research and Development Program Annual Report; G. J. Ogeka, Editor.
PROJECT TITLE: FEASIBILTY STUDY FOR MICROBEAM RADIATION THERAPY WITH 30-90 keV X-RAYS FROM THE NSLS X17 BEAMLINE
PRINCIPAL INVESTIGATOR: Slatkin, Daniel N.
LDRD FUNDING: FISCAL YEAR 1991 AMOUNT $60,742
PROJECT DESCRIPTION:
Summary:
MICROBEAM RADIATION THERAPY: Microscopically fractionated 40-55 keV synchrotron x-rays produce no cerebrovascular damage in the rat at doses up to 5000 gray. For MRT, this means that crossfired bundles of planar microbeams will ablate targeted CNS tissues and spare non-targeted tissues when a peak microbeam dose in the ~10 -100 gray range is delivered in several milliseconds.
.........
This LDRD proposes to carry out feasibility studies in the mouse for the use of monochromatic X-rays from the X17 superconducting wiggler at the NSLS for Microbeam Radiation Therapy (MRT). The studies to be conducted under this LDRD will be: a) Design and assemble a set of computer-driven beam slits to provide square microbeams of 20-1000 micrometer dimensions; b) design and assemble a set of positioning stands for the animal apparatus to position the animal in the beam and move it across the beam in steps of 50-100 micrometers; c) Carry out experiments in which the mouse cerebrum, cerebellum, and eye are irradiated unilaterally with a single monochromatic microbeam at energies of about 30, 60, and 90 keV, at beam dimensions of 25, 50, 100, and 1000 micrometers, and with doses of 20,000, 100,000, and 400,000 rad; d) Evaluate mouse neuropathology and ophthalmic pathology as a function of these irradiation parameters; and e) Repeat the studies indicated in sections (c) and (d) for selected energies, beam dimensions, and radiation doses, with a square pattern of 25 equally spaced parallel pencil beams with a center-to-center beam spacing in the 50- to 150-micrometer range. The goal of the latter study will be to discover the critical interbeam separation at which the probablilty for delayed CNS radiation necrosis is expected to increase sharply with decreasing separation.
TECHNICAL PROGRESS AND RESULTS - FISCAL YEAR 1991:
Synchrotron radiation from the wiggler insertion device of the X17B beamline at the National Synchrotron Light source (NSLS) is practically non-divergent and has enormous flux at photon energies under 100 keV. This means that it is suitable for development of a new type of radiosurgery called 'microbeam radiation therapy' (MRT). As was recently predicted from studies by Curtis et al. using 22 MeV deuteron microbeams at Brookhaven National Laboratory (BNL) three decades ago, and from recent Monte Carlo photon transport and secondary-electron transport computations, a spatially fractionated bundle of parallel, 25 µm-wide, 4 mm-high, 40-55 keV microbeams (delivered at ≈250 gray per second) yields no cerebrovascular damage in the rat one month after irradiation, even at peak microbeam doses of 2500 or 5000 gray. A 1 mm x 1 mm pencil beam of the same quality of radiation delivered at the same dose rate without such spatial fractionation produces colliquative necrosis of the rat cerebrum in its path within two weeks after a dose of only 156 gray.
It is predicted that multiple crossfired bundles of appropriately- dimensioned parallel, planar, synchrotron x-ray microbeams in the 50-150 keV range will ablate tissues in the target zone of a human brain where the bundles overlap, but will spare tissues where they do not overlap when peak/valley doses are as much as 100 gray/5 gray. Such MRT will help to renew radiotherapy in pediatric neuro-oncology and will treat tumors in patients of any age with greatly diminished probability of collateral damage to non-targeted CNS vital structures such as medulla and spinal cord.
=========================
Abstracts: Syrad Symposium, Grenoble, 2008
Microbeam radiation therapy (MRT): Milestones - Clinical prospects. JA Laissue 1, H Blattmann 1 , MA Grotzer 2 , B Kaser-Hotz 3, DN Slatkin 4, HP Wagner 5
1 Institut für Pathologie, Universität Bern, CH-3010 Bern, Switzerland 2 Universitäts-Kinderkliniken, CH-8032 Zürich, Switzerland 3 Vetsuisse Fakultät, Universität Zürich, CH-8057 Zürich, Switzerland 4 Brookhaven National Laboratory, Upton, New York 11973-5000, USA 5 Universitäts-Kinderkliniken des Inselspitals, CH-3010 Bern, Switzerland
Keywords: synchrotron X-ray microbeam radiotherapy - MRT - radiosurgery - pediatric neuro-oncology - CNS tumors
Abstract of the presentation by Jean Laissue at the 'Syrad' workshop: New prospects for brain tumour radiotherapy: Synchrotron light and Microbeam Radiation Therapy, Grenoble, France, June 2-4, 2008. http://www.esrf.eu/events/conferences/Syrad/DetailedProgramme
Rationale and objectives
Collateral damage to vital normal tissues during radiotherapy can be reduced by using three-dimensional treatment planning and external sources of ionizing radiation. Nevertheless, pediatric oncologists try to postpone or forgo 4 any radiosurgery or radiotherapy, especially for children under three years old because irradiating a child’s CNS entails a substantial risk of dysfunctional central nervous system (CNS) development 1, 2, 3. In radiosurgery, spatially accurate and highly conformal beams of radiation are targeted toward a well-delineated tumor in a single session 5. High-dose radiosurgery using multiple millimeters-wide beams of X rays was first described in 1909 6. In modern radiosurgery 7, multiple millimetres-wide beams of linac-generated X rays, or of gamma rays, converge in the target. Might MRT, a radiosurgery mediated by multiple microscopically thin planar beams of synchrotron-generated X rays, yield larger therapeutic indices for CNS tumors than other forms of radiosurgery or radiotherapy?
Methods
MRT, a spatially fractionated radiotherapy, uses an array of microscopically thin, nearly parallel synchrotron-generated X-ray beams 8, 9. Peak radiation doses are up to fifty times higher than in other radiosurgeries. Unlike conventional radiotherapy, for which the effect of changing an irradiation parameter, e.g., the dose fractionation schedule, is predictable, methods to predict the effect of varying an MRT parameter are only beginning to be developed. Among MRT parameters are array width and height, slit width, spacing of microbeams, energy spectrum, changes in tissue dose microdistribution with tissue depth and, possibly in the future, the schedule selected for temporal fractionation of multidirectional MRT.
Results
In animal experiments, MRT has shown unprecedented sparing of normal radiosensitive tissues as well as preferential damage to malignant tumor tissues growing into and around such normal tissues in laboratory animals 10, 11, 12-15, 16-18, 19, 21, 22, 23-25, 26-28. MRT research at the National Synchrotron Light Source (NSLS), Upton, New York, and at the European Synchrotron Radiation Facility (ESRF), Grenoble, France, has shown that single-fraction, unidirectional MRT yields a larger therapeutic index than does single-fraction unidirectional broad beam irradiation for the intracerebral rat 9L gliosarcoma (9L GS) 13, 15-17, 23-26 and for the transplanted subcutaneous murine mammary carcinoma EMT-6 13-15, as does bidirectional (orthogonally cross-fired) MRT for the subcutaneously transplanted, aggressively invasive, extraordinarily radioresistant murine squamous cell carcinoma VII20.
Since postponing radiotherapy may jeopardize survival of some children with brain tumors 29, MRT has been undergoing and undergoes experimental assessment in living animals because it is believed to be potentially useful for inhibiting children’s brain tumors while sparing nearby normal CNS tissues, which should reduce the burden of malignant cells and, therefore, enhance the effectiveness of ancillary therapies 30. The relative sparing by X-ray microbeams of normal tissues of vertebrates - particularly of their normal central nervous system tissues - has been documented in suckling and adult rats 18, 24, 26, 28, duck embryos 12, and weanling piglets 19. These preclinical results, although encouraging, are not yet sufficient to justify a Phase I (safety) trial of MRT for human patients because they are all based on small animal models, except for a set of studies at the ESRF that used the normal piglet cerebellum 16. All other normal-tissue microbeam tolerance studies at the NSLS and ESRF have used fruit-fly pupae 21, rabbits, rats 17, 18, 24-26, gerbils, mice 14, 20, 22, 27, duck embryos 12, and chick embryos 10, 11.
Conclusions
The 6 GeV ESRF ring is the only source of synchrotron radiation in Europe generating intense X ray microbeams for experimental MRT, having a broad energy spectrum of photons peaking in the 80 – 120 keV range and beam intensities high enough, potentially, to deliver an absorbed physical radiation dose to deep targets in large animals, small children, and adult humans; MRT requires the delivery of several hectogray doses within a fraction of a second, deep to the skin. Regulatory and logistic requirements for implementation of clinical MRT will be stringent. The impetus for investigating the potentially unique advantages of MRT for certain human diseases has been recognized and is sustained by the recent consensus of an ESRF scientific advisory panel of sufficient diversity and broad expertise in its membership to merit serious consideration by the ESRF directorate. Accordingly, we propose that ID17 be used to implement a large-animal veterinary MRT study for veterinary radio-oncology. In that way, a wider community of clinical veterinarians and physicians will be able to assess outcomes from MRT in relation to those from existing radiotherapies for similar lesions in large animals.
References
1. Wagner HP. Cancer in childhood and supportive care. Support Care Cancer 1999; 7: 293-294. 2. Mulhern RK, Merchant TE, Gajjar A, Reddick WE, Kun LE. Late neurocognitive sequelae in survivors of brain tumours in childhood. Lancet Oncol 2004; 5: 399-408. 3. Ribi K, Relly C, Landolt MA, Alber FD, Boltshauser E, Grotzer MA. Outcome of medulloblastoma in children: long term complications and quality of life. Neuropediatrics 2005; 36: 357-365. 4. Rutkowski S, Bode U, Deinlein F, Ottensmeier H, Warmuth-Metz M, Soerensen N, Graf N, Emser A, Pietsch T, Wolff JE, Kortmann RD, Kuehl J. Treatment of early childhood medulloblastoma by postoperative chemotherapy alone. N Engl J Med 2005; 352: 978-986. 5. Adler JR Jr, Colombo F, Heilbrun MP, Winston K. Toward an expanded view of radiosurgery. Neurosurgery 2004; 55: 1374-1376. 6. Köhler A. Une nouvelle méthode permettant de faire agir, dans la profondeur des tissus, de hautes doses de rayons Roentgen et un moyen nouveau de protection contre les radiodermites. Annales d'Électrobiologie et de Radiologie 1909; 10: 661-664. 7. Kondziolka D, Lunsford LD, Loeffler JS, Friedman WA Radiosurgery and radiotherapy: observations and clarifications. J Neurosurg 2004; 101: 585-589. 8. Slatkin DN, Spanne P, Dilmanian FA. Sandborg M: Microbeam radiation therapy. Med Phys 1992; 19: 1395-1400. 9. Laissue J, Spanne PO, Dilmanian FA, Gebbers J-O, Slatkin DN: Zell- und Gewebeläsionen nach räumlich fraktionierter Mikro-Bestrahlung des ZNS mit Synchrotron-Photonen. Schweiz Med Wochenschr 1992; 122: 1627. 10. Blattmann H, Burkard W, Djonov V, Di Michiel M, Brauer E, Stepanek J, Bravin A, Gebbers JO, Laissue JA. Microbeam irradiation of the chorio-allantoic membrane (CAM) of chicken embryo. Strahlentherapie und Onkologie 2002; 178 (Suppl. June 1): 118 11. Blattmann H, Gebbers J-O, Bräuer-Krisch E, Bravin A, Le Duc G, Burkard W, Di Michiel M, Djonov V, Slatkin DN, Stepanek J, Laissue JA. Applications of synchrotron X-rays to radiotherapy. Nucl Instr Meth Physics Res A 2005; 548: 17-22. 12. Dilmanian FA, Morris GM, Le Duc G, Huang X, Ren B, Bacarian T, Allen JC, Kalef-Ezra J, Orion I, Rosen EM, Sandhu, T, Sathe P, Wu XY, Zhong Z, Shivaparasad HL. Response of avian embryonic brain to spatially segmented xray microbeams. Cell Mol Biol 2001; 47: 485-493. 13. Dilmanian FA, Button TM, Le Duc G, Zhong N, Peña LA, Smith JA, Martinez SR, Bacarian T, Tammam J, Ren B, Farmer PM, Kalef-Ezra J, Micca PL, Nawrocky MM, Niederer JA, Recksiek FP, Fuchs A, Rosen EM. Response of rat intracranial 9L gliosarcoma to microbeam radiation therapy. Neuro-Oncol 2002; 4: 26-38. 14. Dilmanian FA, Morris GM, Zhong N, Bacarian T, Hainfeld JF, Kalef-Ezra J, Brewington LJ, Tammam J, Rosen EM. (2003) Murine EMT-6 carcinoma: high therapeutic efficacy of microbeam radiation therapy. Radiat Res 159: 632-641. 15. Dilmanian FA, Qu Y, Liu S, Cool CD, Gilbert J, Hainfeld JF, Kruse CA, Laterra J, Lenihan D, Nawrocky MM, Pappas G, Sze C-I, Yuasa T, Zhong N, Zhong Z, McDonald JW. X-ray microbeams: Tumor therapy and central nervous system research. Nucl Instr Meth Physics Res A 2005; 548: 30-37. 16. Laissue JA, Spanne P, Dilmanian FA, Nawrocky MM, Gebbers J-O, Slatkin DN, Joel DD: Mikrobestrahlung von Gliosarkomen der Ratte: Zell- und Gewebeläsionen (Microbeam irradiation of rat gliosarcomas: Cell and tissue lesions). Schweiz med Wochenschr 1995; 125:1887. 17. Laissue JA, Geiser G, Spanne PO, Dilmanian FA, Gebbers JO, Geiser M, Wu XY, Makar MS, Micca PL, Nawrocky MM, Joel DD, Slatkin DN. Neuropathology of ablation of rat gliosarcomas and contiguous brain tissues using a microplanar beam of synchrotron-wiggler-generated X rays. Int J Cancer 1998; 78: 654-660. 18. Laissue JA, Lyubimova N, Wagner HP, Archer DW, Slatkin DN, Di Michiel M, Nemoz C, Renier M, Brauer E, Spanne PO, Gebbers JO, Dixon K, Blattmann H. Microbeam radiation therapy. Proc SPIE 1999; 3770: 38-45. . 19. Laissue JA, Blattmann H, Di Michiel M, Slatkin DN, Lyubimova N, Guzman R, Zimmermann W, Birrer S, Bley T, Kircher P, Stettler R, Fatzer R, Jaggy A, Smilowitz HM, Brauer E, Bravin A, Le Duc G, Nemoz C, Renier M, Thomlinson W, Stepanek J, Wagner HP. The weanling piglet cerebellum: a surrogate for tolerance to MRT (microbeam radiation therapy) in pediatric neuro-oncology. Proc SPIE 2001; 4508: 65-73. 20. Miura M, Blattmann H, Bräuer-Krisch E, Bravin A, Hanson AL, Nawrocky MM, Micca PL, Slatkin DN, Laissue JA. Radiosurgical palliation of aggressive murine SCCVII squamous cell carcinomas using synchrotron-generated X-ray microbeams. Br J Radiol 2006; 79: 71-75. 21. Schweizer PM, Spanne P, Di Michiel M, Jauch U, Blattmann H, Laissue JA: Tissue lesions caused by microplanar beams of synchrotron-generated x-rays in Drosophila melanogaster. Int J Radiat Biol 2000; 76 (4): 567-574. 22. Serduc R, Vérant P, Vial J-C, Farion R, Rocas L, Rémy C, Fadlallah T, Bräuer E, Bravin A, Laissue J, Blattmann H, van der Sanden B. In vivo two-photon microscopy study of short term effects of microbeam irradiation on normal mouse brain microvasculature . Int J Radiat Oncol Biol Phys; 2006; 64 (5):1519-1527. 23. Slatkin DN, Dilmanian FA, Nawrocky MM, Spanne P, Gebbers J-O, Archer DW, Laissue JA. Design of a multislit, variable width collimator for microplanar beam radiotherapy. Rev Sci Instrum 1995; 66:1459-1460. 24. Slatkin DN, Spanne P, Dilmanian FA, Gebbers JO, Laissue JA. Subacute neuropathological effects of microplanar beams of x-rays from a synchrotron wiggler. Proc Natl Acad Sci USA 1995; 92: 8783-8787. . 25. Smilowitz HM, Blattmann H, Bräuer-Krisch E, Bravin A, Di Michiel M, Gebbers J-O, Hanson AL, Lyubimova N, Slatkin DN, Stepanek J, Laissue JA. Synergy of gene-mediated immunoprophylaxis and microbeam radiation therapy (MRT) for advanced intracerebral rat 9L gliosarcomas. J Neurooncol 2006;78: 135-143. 26. Regnard P, Le Duc G, Bräuer-Krisch E, Troprès I, Siegbahn EA, Kusak A, Clair C, Bernard H, Dallery D, Laissue JA , Bravin A: Irradiation of intracerebral 9L gliosarcoma by a single array of microplanar X-ray beams from a synchrotron: balance between curing and sparing. Phys Med Biol 2008; 53: 861-878. 27. Serduc R, van de Looij Y, Francony G, Verdonck O, van der Sanden B, Laissue J, Farion R, Bräuer-Krisch E, Siegbahn EA, Bravin A, Prezado Y, Segebarth C, Rémy C, Lahrech H. Characterization and quantification of cerebral edema induced by synchrotron x-ray microbeam therapy. Phys Med Biol 2008; 53: 1153-1166.
..................
MRT-planning (similarities and differences with and between planning for therapy with photons, hadrons and MR) Authors: Blattmann Hans1, Kaser-Hotz Barbara2, Laissue Jean A.1, Rohrer Bley Carla2, Stepanek Jiri1, Bräuer-Krisch Elke3, Bravin Alberto3, Le Duc Géraldine3, Siegbahn Erik3, Hanson Albert L.4, Miura Michiko4, Slatkin Daniel N. 4
Affiliations: 1Institute of Pathology, University of Bern, Switzerland, 2Freie Universität Berlin, and Animal Oncology and Imaging Center, Switzerland, 3Medical Beamline, European Synchrotron Radiation Facility, Grenoble, France 4Brookhaven National Laboratory, Upton, New York; USA Keywords: MRT, treatment planning, dosimetry.
Abstract of the presentation by Hans Blattmann at the 'Syrad' workshop: New prospects for brain tumour radiotherapy: Synchrotron light and Microbeam Radiation Therapy, Grenoble, France, June 2-4, 2008. http://www.esrf.eu/events/conferences/Syrad/DetailedProgramme
Rationale and objectives:
Using established radiosurgical techniques, acute and delayed radiobiological responses of tissues are predictably dependent on the quality, the rate, and the density of ionisation energy imparted to them (i.e., radiation 'doses' and 'dose' rates). Although different kinds of tissue display various early and late responses to a given irradiation, whether the imparted dose be uniform or not, normal tissue reactions are predicted reliably for clinical radio-oncology by analysing overlays of dose distributions on serial tomographic images of the irradiated volume.
Treatment planning for MRT will be more complex. Microscopically contiguous cells in the same tissue may be exposed to drastically different doses. Unfamiliar tissue responses may be elicited by various microscopic dose distributions, depending on the organization of the tissue, its milieu intérieur, and its microvasculature. It is natural that we concentrate on the most obvious factors first. Radiation dose-response curves for cells grown in vitro have yielded relative biological effectivenesses (RBEs) applicable to broad-beam radiation therapies, including hadron and pion therapy. Since microscopically contiguous cells in the same tissue may be exposed to drastically different doses from microbeams, RBE data for MRT are needed more for vascularized normal vital animal tissues in vivo than for colonies of non-vascularized cells in vitro. Established treatment planning systems have to be checked on a regular basis by physical dosimetry. This is done in homogeneous phantoms, preferably with calibrated ionization chambers. While this technique is well established for photon, electron and proton irradiations, for hadron therapy absolute calibration, demanding and imprecise, remains elusive. For MRT, dose calibration is even more difficult, as precise physical microdosimetry is still under development. Even Monte-Carlo (MC) dose computations (1), so far the method of choice for MRT, should be provided with large error bars. Accordingly, an MRT treatment planning program for large animals will be developed in an iterative process.
Methods:
The most important single parameter responsible for tissue response to microbeams is believed to be the ‘valley’ dose. The valley dose will be calculated by MC calculation for microbeam exposures in a geometrical phantom, built up by solid tissue substitutes. The resulting dose distribution will be measured with radio-chromic films and at some locations with ionization chambers, to establish the relationship between calculated and measured dose.
For treatment of animal patients the valley dose is calculated in a simplified geometry, but taking into account volumes of significantly higher or lower x-ray absorption as bone or air. The calculated doses will be checked in a parallel plate phantom setup imitating the volume to be irradiated. If the starting dose for the dose escalation program is selected conservatively normal tissue damage will be avoided.
Results / Conclusion: The proposed course of action aims at making full use of the existing results from rodent and pig irradiations (2,3) and at the same time moving from the predominantly used exposures of around 28 µm beam width and 200 µm beam separation of small irradiation volumes to 50 µm beam width and 400 µm separation in significantly larger volumes.
References:
Treatment of spontaneous tumors in pet animals as part of the development of a new radiation treatment modality. Kaser-Hotz B, Blattmann H, Laissue JA, Stepanek J, Bräuer-Krisch E, Bravin A, Le Duc G, Siegbahn E, Dilmanian A, Hanson AL, Miura M, Slatkin DN.
Abstract of the presentation by Barbara Kaser-Hotz at the 'Syrad' workshop: New prospects for brain tumour radiotherapy: Synchrotron light and Microbeam Radiation Therapy, Grenoble, France, June 2-4, 2008. http://www.esrf.eu/events/conferences/Syrad/DetailedProgramme
Rationale and objectives
Treatment of spontaneous (autochthonous) benign and malignant tumors in animal patients is considered a major step between experiments on laboratory animals and humans. The dimensional and physiological characteristics of spontaneous tumors of dogs and cats have more similarity to many human malignancies than implanted tumors of mice and rats. The biological response of tumors and normal tissues is dependent on the volume irradiated.
For MRT the radiation quality, i.e. peak to valley dose ratio (PVDR) is also volume dependent. Obviously, treatment of pet animals involves a more heterogeneous treatment population and smaller numbers of animals can be included into a study. However, the model is more realistic and a closer follow up done by the owners can be done. An important aspect for the implementation of a new radio-oncology modality is the testing of all practical procedures, from treatment planning to follow up care.
Methods
Animal patients eligible are: Animals with a) small, superficial skin or subcutaneous tumors b) superficial benign or malignant tumors of the central nervous system d) other neoplasms to be considered individually. Six animals per group should suffice for a preliminary evaluation of normal tissue tolerance and sensitivity to MRT. A dose escalation will be performed, starting at a conservative dose, expected to produce no significant side effects. After an observation period of at least 6 months the dose will be escalated in small steps to determine the optimal dose.
Results
In the past, the treatment of dog patients with protons at Paul Scherer Institute, Villigen has contributed to the establishment of routine human patient treatment procedures. It has further shown that the spot scanning technique for protons, developed at PSI, was safe and did not lead to any unexpected biological response. Conclusion
The treatment of spontaneous animal tumors can be to the benefit of the animal treated and at the same time give valuable information for a safe start of a human patient program.
MRT-planning (similarities and differences with and between planning for therapy with photons, hadrons and MR). Blattmann H, Kaser-Hotz B, Laissue JA, Rohrer Bley C, Stepanek J, Bräuer-Krisch E, Bravin A, Le Duc G, Siegbahn E, Hanson AL, Miura M, Slatkin DN.
Abstract of the presentation by Hans Blattmann at the 'Syrad' workshop: New prospects for brain tumour radiotherapy: Synchrotron light and Microbeam Radiation Therapy, Grenoble, France, June 2-4, 2008. http://www.esrf.eu/events/conferences/Syrad/DetailedProgramme
Rationale and objectives:
Using established radiosurgical techniques, acute and delayed radiobiological responses of tissues are predictably dependent on the quality, the rate, and the density of ionisation energy imparted to them (i.e., radiation 'doses' and 'dose' rates). Although different kinds of tissue display various early and late responses to a given irradiation, whether the imparted dose be uniform or not, normal tissue reactions are predicted reliably for clinical radio-oncology by analysing overlays of dose distributions on serial tomographic images of the irradiated volume.
Treatment planning for MRT will be more complex. Microscopically contiguous cells in the same tissue may be exposed to drastically different doses. Unfamiliar tissue responses may be elicited by various microscopic dose distributions, depending on the organization of the tissue, its milieu intérieur, and its microvasculature. It is natural that we concentrate on the most obvious factors first. Radiation dose-response curves for cells grown in vitro have yielded relative biological effectivenesses (RBEs) applicable to broad-beam radiation therapies, including hadron and pion therapy. Since microscopically contiguous cells in the same tissue may be exposed to drastically different doses from microbeams, RBE data for MRT are needed more for vascularized normal vital animal tissues in vivo than for colonies of non-vascularized cells in vitro.
Established treatment planning systems have to be checked on a regular basis by physical dosimetry. This is done in homogeneous phantoms, preferably with calibrated ionization chambers. While this technique is well established for photon, electron and proton irradiations, for hadron therapy absolute calibration, demanding and imprecise, remains elusive. For MRT, dose calibration is even more difficult, as precise physical microdosimetry is still under development. Even Monte-Carlo (MC) dose computations (1), so far the method of choice for MRT, should be provided with large error bars. Accordingly, an MRT treatment planning program for large animals will be developed in an iterative process.
Methods:
The most important single parameter responsible for tissue response to microbeams is believed to be the ‘valley’ dose. The valley dose will be calculated by MC calculation for microbeam exposures in a geometrical phantom, built up by solid tissue substitutes. The resulting dose distribution will be measured with radio-chromic films and at some locations with ionization chambers, to establish the relationship between calculated and measured dose.
For treatment of animal patients the valley dose is calculated in a simplified geometry, but taking into account volumes of significantly higher or lower x-ray absorption as bone or air. The calculated doses will be checked in a parallel plate phantom setup imitating the volume to be irradiated. If the starting dose for the dose escalation program is selected conservatively normal tissue damage will be avoided.
Results / Conclusion:
The proposed course of action aims at making full use of the existing results from rodent and pig irradiations (2,3) and at the same time moving from the predominantly used exposures of around 28 µm beam width and 200 µm beam separation of small irradiation volumes to 50 µm beam width and 400 µm separation in significantly larger volumes.
References:
=============
English translations of four reports on grid therapy (1909-1912) by Alban Köhler (born 1874 - died 1947):
Köhler A. Zur Röntgentiefentherapie mit Massendosen. Münchener medizinische Wochenschrift 56: 2314-2316, 1909. (Slatkin DN and Laissue JA. English translation. May 2005)
The author presented a lecture with a similar title at the Belgian Röntgen Society in Antwerp on May 30, 1909. It concerned the theory of a method designed to deliver doses to deep tumors that are about ten to twenty times greater than have been hitherto possible without damaging the overlying skin. The significance of the method for the treatment of deep malignancies should be obvious. The principle, which has been described in detail in "Fortschritten auf dem Gebiet der Röntgenstrahlen, Bd. 14, Heft 1" (Advances in the Applications of Roentgen Rays, Vol. 14, Part 1), could not be simpler; it is summarized here in a couple of sentences:
An X-ray tube with a very large cathode-ray hot-anode target area -- 4 to 8 times larger than usual -- produces very sharp shadows of a metal grid if the latter is positioned close to a photographic plate or fluoroscopic screen. However, if one distances the grid 4 to 5 centimeters from the plate and brings the tube to within a few centimeters of the grid, the shadows disappear and the plate is uniformly exposed, leaving no trace of the grid.
The implications of this for therapy are as follows. If one places a grid right on the skin overlying a several cm-deep malignancy and if an X- ray tube with a large target area is positioned only a few centimeters from the grid, the skin will be shielded underneath the metal and only irradiated through the grid's spaces, but the tumor will be irradiated evenly. If one applies this method to deliver a massive dose, for example tenfold greater than one full erythema dose, the resulting multiple foci of burned or necrotic skin - whatever the case may be - will be healed within a few weeks by surrounding surviving skin cells. Without the grid, the same dose would cause an extensive, continuous skin burn that would never heal, or would only heal with scarring many years later. X-ray tubes with such large targets must be made to order, as they make fuzzy radiographs and therefore can be used only for therapy. However, they are simpler to manufacture than are X-ray tubes with small, sharply focused target spots. This report also reflects ideas that I developed from the discussions that followed my Antwerp lecture. Whatever may come of the proposed method, the physical basis for it is not in doubt.
It should be stressed that misunderstanding of the method may result, for example, in poor placement of the grid. The grid must be on the skin, preferably pressed close to it. Moreover, for fundamental reasons indicated below, the most critical aspect of the system is a thin filter separating the grid from the skin. Only with that filter can cells beneath the metal strands remain entirely viable, enabling rapid healing of necrosis in their vicinity. An important question arises: In general, is it necessary to insert a thin filter (for example, of leather or aluminium) under the grid? Probably, one should reply confidently in the affirmative, in particular because skin cells under the metal are directly irradiated by the grid's secondary radiations. Although the smaller the atomic weights of absorbing substances, the softer and less penetrating are their secondary radiations, even secondaries from elements of high atomic weight such as lead or iron are so feeble that they can scarcely penetrate a thin sheet of paper. Nonetheless, secondary radiations from such metal strands, if generated by the equivalent of 10 to 20 primary-radiation erythema doses, could deliver enough dose immediately under the strands to damage skin cells not shielded by our thin-filter technique. Therefore it is recommended that one insert a thin filter between grid and skin to absorb all but a small, higher-energy portion of those secondaries. Furthermore, we gain another advantage by using a thin, light filter: it absorbs the preferentially skin-damaging soft portion of primary X rays that bypass the strands without absorbing a significant portion of those primaries of intermediate hardness that also act therapeutically at depth.
The shape and thickness of the metal strands of the grid and the size of the grid spaces were also considered during those discussions. It was recommended that the metal strands be triangular or rectangular - not circular - in cross section. The reasons for that are so clear that they need not be specified -- indeed so obvious that the author has already had such grids manufactured.
In metallurgy it is feasible to make grids of platinum or lead (those metals would appear to be the best) --- although even ordinary window screens might suffice. A filter made like the platinum upper screen of a Bunsen burner would have metal filaments too fine to shield the skin effectively, so I would prefer a different material. To be pressed against the skin, a grid should be as stiff as possible - another reason for choosing a different material. G. Schwarz** has recently shown that susceptibility of the skin to X-ray damage is reduced if one inhibits its metabolism, for example by direct pressure; the stiffer the grid, the more effectively could pressure be applied. Since thick platinum wires are very expensive, one should prefer a grid of iron wires. The somewhat smaller X- ray absorption coefficient of iron than platinum would be inconsequential.
Theoretically, it might be preferred that the metal strands of the grid not overlap; the grid could then be stamped from a metal sheet. In practice, however, not only should overlapping strands of metal cause no harm, they could even save areas of unshielded skin after the latter receive erythema doses intense enough to damage epidermal cells beneath non- overlapping strands. This provides all the more reason for not discounting the potential of islands of epidermis beneath overlapping strands of metal to remain intact after such irradiation to heal adjacent zones of skin necrosis. It is left for further investigation to judge what gauges of iron wire would be best for a grid. In the meantime, I have ordered a grid of 1 millimeter-wide wire with 2.5 x 2.5 square millimeter spaces between them from the firm of Reiniger, Gebbert, and Schall. So that grid and filter remain as close as possible to the skin --- on the trunk, minimally perturbed by breathing --- it is best if they are pressed so hard against the skin as to blanch it. This can be done, for example, using the cylindrical glass housing of an X-ray collimator.
Makers of Röntgen tubes all know that it is much less difficult to make tubes with a broad, rather than a precise, narrow cathode-ray target spot. This author was pleased to hear from a tube-maker during our conversation in Antwerp that fabrication of tubes with broad target spots was really a straightforward matter, involving no challenging steps. Moreover, I learned from an electricity technologist there that such tubes enable higher power to be used for therapy, so that if one doubled the size of the cathode, there could result a proportionate increase in the radiation dose rate --- which could also damage the tube. Alternatively, it has long been known that a tube can have several cathodes, which would be particularly advantageous for our method. If such a tube had a wide anode with three or four separate, broad target spots, its X-ray output would be intensified, which would likewise speed up our work - an appreciable advantage.
Several points should be mentioned about the stress on the tube. Even if the distance from tube to skin were minimized, it would still take 1 to 2 hours to deliver 10 to 15 full erythema doses. One would wish that to be quicker, which would overload the tube somewhat; an overloaded tube would of course soon be weakened to the point of uselessness. With its vacuum compromised, such a tube could not deliver an exact dose -- and one would not want a 10- to 15-fold increase of dose to be inexact by more than one- half of a full erythema dose. A solution would be to wire several tubes in series and position them securely in their housings; with collimators close to grid and filter, it would be unimportant if individual tubes were not perfectly aligned toward the same target. Alternatively, one could implement the author's deep-irradiation technique by using several readily available Röntgen tubes. Each tube, having a small target spot, would be aligned and centered individually in a common housing. Other improvements might be to operate four of the ordinary tubes at the same distance from the skin . and so on. It goes without saying that this method, which can be simple, should not be made more complex needlessly. For example, the deeper the irradiation target, the less is it required that the target spot be extra-large, so even an ordinary Röntgen tube could be used confidently to use the grid technique for a 10 centimenter-deep lung tumor.
An objection to the method was voiced during the aforementioned discussions which, at first, appeared reasonable: the grid itself cuts down considerably on a dose intended to be delivered at depth. For example, about half of the incident radiation on a grid with 1 millimeter-wide wires and 2.5 millimeter-square holes would be blocked. To compensate for that, the unshielded zones of skin would have to receive double the dose they would receive without the grid. Strictly speaking, the facts underlying that objection are true, but it should not be accepted unreservedly. With a grid, unshielded zones of skin can receive 10 to 20 times the dose deliverable to unshielded skin because strands of shielded cells surround each hole; without a grid, such doses could not be delivered. Even with thinner wires and much larger holes, rapid healing of many small zones of skin would follow. Should a problem of non-healing skin arise, it could be addressed by constructing tubes with several special, large cathodes or with several small cathodes per tube.
We now turn to matters of biology. It is known that necrotic or ulcerated zones of skin are prone to infection, which would lead to destruction of zones of remaining viable skin cells and subsequent confluence of those zones to form an extensive, non-healing skin ulcer. Since that could indeed occur, the radiologist must thoroughly disinfect the irradiated zone and, immediately after the irradiation, bandage it to keep it so until it heals. Should that prove insufficient to prevent an infection the grid could be made of thicker wires, but the grid method should not fail on that account in any case.
The restriction that a grid irradiation cannot be repeated is quite beside the point. If one can increase a dose 20-fold using this method, one will have achieved very much more than what has been achieved to date by delivering a maximum tolerable dose in fractions. Moreover, there are a number of regions in the body (breast, bones of the extremities, and such) that can be irradiated from 3 or 4 different directions. Granted, a zone of the skin once stressed by this grid technique cannot be so stressed ever again, but since this technique permits delivery of an enormous total dose, perhaps 40 times greater than has been possible to date, one should be encouraged by its development. That said, however, the radiotherapist should remain vigilant --- aware of the importance of sufficient shielding of the surrounding tissues, even of the whole body, from such large doses of X rays.
Animal experiments have been initiated, but for a number of reasons I don't have much to say in their favour. I have decided that my primary obligation is to apply this method as soon as possible to treat malignancies that are likely to kill a patient within several months.
In summary, I concede that this grid method carries some disadvantages with its advantages, as do all kinds of therapy. Among its advantages are: delivery of massive doses, relatively short exposure times, and (even with filters and compression) straightforward implementation. Those compensate for its few disadvantages, the most important being the risk of losing potentially healing strands of cells to infection --- the likelihood of which is lessened by using aseptic techniques.
**Gottwald Schwarz (1880-1959)
...............
Alban Köhler. "Une nouvelle méthode permettant de faire agir, dans la profondeur des tissues, de hautes doses de rayons Roentgen et un moyen nouveau de protection contre les radiodermites" (A new method to deliver high doses of Roentgen rays to deep tissues and to mitigate radiation dermatitis.) Annales d'Électrobiologie et de Radiologie 10, 661-664, 1909. (Slatkin DN and Laissue JA. English translation. December 2006)
Previously, radiologists who wanted to deliver a high dose of Roentgen rays to tissues several centimeters deep faced a Hobson's choice. Delivering a high dose of unfiltered Roentgen rays to deep tissues caused intractable skin ulcers. Although filtration of the rays enabled deeper penetration, it deprived them of almost all their therapeutic efficacy - to such an extent that, in a good many cases, cell division seemed to be stimulated instead of inhibited or stopped by them.
Recently, various studies have been directed toward alleviating these problems by irradiating from a great distance, but they are not yet ready for evaluation; certainly, it should be understood that any such technique could, at best, only partially improve the efficacy of these radiations. However, were it possible to deliver doses to deep tissues 10-15 times greater than are achievable at present without exposing patients to the concomitant risk of intractable skin ulcers, that would obviously supersede existing methods, especially if greater simplicity and convenience counted among its advantages.
I now submit the following method for consideration; I have been led to it by experiments that, so far, have not been designed to test its therapeutic efficacy but rather to investigate analogous setups in roentgenography.
If one puts a 1- to 2-millimeter-mesh grid of metal wires on a photographic plate and exposes the assembly to X rays from a cathode-ray tube [CRT], of course one gets a distinct photographic image of the grid. However, if one distances that grid about 20 centimeters from the plate, parallel to it, then positions the CRT close behind the former, one gets only a very hazy grid image; if one then proceeds to distance the grid 40 or 50 centimeters from the plate, one no longer obtains any grid image - not even the least indication of it; the radiosensitive layer of the plate is uniformly darkened as if there were nothing to block X rays between the CRT and the plate.
The reason for this effect is well known by now: Investigations of the physical properties of Roentgen rays show, in brief, that the effect does not involve refraction or diffraction, but simply depends on the design of the CRT's focus. In ordinary CRTs, the focal zone on which the convergent cathode rays impact is, of course, not a geometric point but rather a circle of greater or lesser diameter, usually 1 to 5 mm. (One should note, however that so-called precision CRTs have much smaller focal zones.) Thus, to obtain equal, constant darkening of the plate, i.e., disappearance of any trace of the grid, for a given distance from CRT to metal grid, the closer the grid to the plate, the larger should be the CRT's focal zone.
For therapeutic applications, the corollaries of those simple, well- known observations are as follows: First, a small focal zone, so important in roentgenography, is of course unnecessary for Roentgen-ray therapy. Suppose one had an appropriate CRT with a large focal zone, say 1.0 - 1.5 cm in diameter. Suppose also that one selected a metal grid - either a grid of ordinary iron wire or, better, a mesh of lead or, best, of platinum wire - and applied it directly to the skin or to a thin leather filter on the skin; the CRT is positioned several centimeters from the grid. If we so irradiate the surface of the grid, we will achieve constant, uniform irradiation of tissue at a certain tissue depth - as homogeneous as if there were no metal grid between CRT and deep tissue.
Moreover, having that grid on the skin surface enables the delivery of enormous doses of X rays to deep tissues in comparison with those possible to date, without risk of non-healing ulcers or of nearly incurable radiodermatitis. Whereas each cell is homogeneously irradiated in deep tissue, for example in a deep tumor, X rays penetrate the skin only between the grid elements, so cells directly under the metal grid elements remain, in effect, intact.
With large doses, the skin between the grid elements is certainly subject to erythema and necrosis, but those lesions are spontaneously repaired within a few weeks because individual zones of necrosis are surrounded on each side by a narrow slice of healthy, well vascularized tissue. An analogous method is already established in surgery where, for example, one treats an angioma by thermocautery; as is well known, the many eschars that result are healed rapidly. The conditions for healing such deep eschars are not as favorable after grid-mediated radiotherapy as after thermocautery. Nevertheless, the principles of those techniques are analogous. In any case, it is much better to reduce radiodermatitis by using a metallic grid than to cause large, deep ulcers by exceptionally high X-ray doses delivered without a grid.
The question of knowing how many times more intense the irradiation may be with than without a metallic grid is difficult to answer; it depends, to a certain extent, on what kind of metal is used to make the strands of the grid and on their thickness. Thus, as many as one hundred erythema doses* might be needed to elicit necrosis of skin cells shielded by such strands of metal, and perhaps as many as fifty erythema doses might be needed to cause any visible lesions at all in zones of skin so shielded. Using approximately fifteen-fold greater erythema doses to unshielded than to shielded skin cells, the skin recovers so well that radiation damage may be discounted entirely. Although this leaves metal-shielded tissues apparently unaffected by the irradiation, it is not absolutely certain that such doses will allow necroses in exposed zones to heal readily. Based on my preliminary studies, it seems wise in practice to use not more than ten erythema doses. More detailed experiments will establish exactly how extendable that dose limit may be.
I have not yet had a chance to practice this technique. However, since the procedure I have outlined here is based on simple and precise physical and biological phenomena, there is no doubt that its practical value will be recognized some day. By then, animal studies will have shown whether doses that are twenty-fold or even fifty-fold greater than those allowed currently can cause skin damage too severe to be justifiable by the benefits of their efficacy for deep lesions. For the first clinical trials, one should be able to enlist patients in whom a laparotomy will have already revealed an inoperable malignant tumor.
This method appears to have no disadvantage other than causing minuscule zones of necrosis, already described. On the other hand, it has the following advantages in addition to those already mentioned: Fundamentally, the method depends on irradiating at a very short distance, which will allow much shorter exposure times than those used at present. For example, for a distance of 5 cm between the glass wall of a 15 centimeter-diameter CRT and the skin surface (i.e., 7.5 + 5 cm from focal zone to skin), one gets a 16-fold stronger X-ray effect than would be obtained during the same exposure time with the CRT distanced 50 cm from the skin.
Another advantage of my method is that it allows X-ray-energy filters to be used just as well as in older methods. Any kind of filter may be placed underneath the metal grid1; leather filters are recommended in particular. It would be advantageous to apply some pressure to the grid against the filter, either with a diaphragm or with the leaded-glass cylindrical tubes used for the radiotherapy. Finally, one can augment the method's effectiveness by irradiating from various directions. In this way, one can treat a deep lesion, for example a sarcoma of the thigh, with exceptionally high doses by directing X rays toward four different sides of it in succession.
Another aspect is that the metal grid is of value in protection against skin burns from irradiation of superficial lesions, particularly for inexperienced technologists not yet certain of the doses they are delivering. Using the grid, an overdose that causes an ulcer or a zone of necrosis should be healed very rapidly. Using this method, irradiations of lesions in patients with blood dyscrasias should also become less dangerous. In therapy of cutaneous lesions, however, it should be kept in mind that zones of skin underneath metal strands will not be treated. It is not certain that cells exposed to X rays traversing the spaces of the grid, having received intense radiation, might have a palliative effect on unexposed cells; judging from certain well-known phenomena, that would not be impossible, but experiments will decide the question. Neither should it be forgotten, in using the method for benign lesions of the face, that one should carefully avoid causing a gridlike pattern of pigmentation in exposed areas.
1 It is especially advisable to use filters to block secondary radiations originating in the metal strands of the grid.
*Translators' note: In 1909, one 'erythema dose' was considered to be the minimum exposure to X rays that resulted in skin erythema. One 'erythema dose' is now considered to have represented a dose of from 2 to 5 gray, depending on the types of X-ray tubes and radiation filters used at a hospital, on the different susceptibilities to erythema of patients typically treated there, and on the different kinds and concentrations of pigment in areas of their skin exposed to X rays.
......................
Theorie einer Methode, bisher unmöglich unwendbar hohe Dosen Röntgenstrahlen in der Tiefe des Gewebes zur therapeutischen Wirksamkeit zu bringen ohne schwere Schädigung des Patienten, zugleich eine Methode des Schutzes gegen Röntgenverbrennung überhaupt. Von Dr. Alban Köhler - Wiesbaden
(Slatkin DN. and Laissue JA, English translation, October 2, 2008): Dr. Alban Köhler - Wiesbaden (Germany). Theory of a method that permits penetration of therapeutically effective roentgen rays in hitherto dangerously high doses deep in tissue without severe sequelae, including a special method of protection against radiation burns. Fortschritte auf dem Gebiete der Röntgenstrahlen 14: 27-29, 1909.
There are two main factors that have made it impossible so far to use high doses of roentgen rays therapeutically several centimeters deep in tissue: achieving desired doses in deep tissues by irradiating without a filter causes severe, intractable skin ulcers; filtration indeed does allow roentgen rays to penetrate tissues deeply, but only in doses so weak that, in many cases, they stimulate rather than inhibit cell growth. It is still unknown whether recently announced efforts to rectify those problems by irradiating from a greater distance will succeed, but they could only improve the therapy slightly, at best. If a method were developed that increased deep doses tenfold or, possibly, fifty-fold without causing a non-healing skin ulcer, it would certainly be preferred to existing techniques, especially if it were simpler and more convenient. The following is intended to describe a method developed by the author's experiments, which were admittedly not originally intended to improve roentgen-ray therapy, but rather aimed toward improving photographic apertures for roentgen-ray imaging.
If one puts a 1- to 2-millimeter-mesh grid of metal wires on a photographic plate and exposes the assembly to roentgen rays, of course one gets a very sharp image of the grid. However, if one takes the same grid about 20 centimeters away from, yet parallel to the plate, then exposes the photographic plate to roentgen rays from an ordinary roentgen tube positioned immediately behind the grid, one obtains only a very fuzzy image of the grid on the plate; if one then takes the grid about 40-50 cm from the plate and again positions the tube immediately behind it as described, not only does the plate fail to capture a shadow of the grid, but not even does the slightest trace of it remain. Instead, the plate is entirely and uniformly blackened, as if there were no sieve-like obstacle between tube and plate whatsoever. We know of no reason for such an effect on the basis of roentgen-ray physics; neither refraction nor diffraction could have been involved. Instead, that effect depends only on the spot impacted by cathode rays in the roentgen tube. One knows that in an ordinary roentgen tube, the zone of the anticathode impacted by convergent cathode rays is not the smallest spot achievable, but usually a circular spot more or less 1 to 5 mm in diameter. In contrast, so-called 'precision tubes' are characterized by the smallest possible cathode-ray impact spots. To achieve uniform darkening of a plate situated at a certain distance from the tube, i.e., to darken it so any trace of the grid is eliminated, the closer the grid to the plate, the larger must be an anticathode's impact spot.
For therapeutic applications, the corollaries of those simple principles are as follows: First, a small anticathode impact zone, so important in roentgenography, is of course unnecessary for roentgen-ray therapy. Suppose one had a tube manufactured specifically for therapy with a large impact zone, say 1.0 - 1.5 cm in diameter. Suppose also that one selects a metal grid - either a grid of ordinary iron wire or, better, a mesh of lead or, best, of platinum wire - and applies it directly to the skin or to a thin leather filter on the skin. We now position our tube several centimeters from the grid. If we then irradiate the surface of the grid, we will achieve constant, uniform irradiation of tissue at a certain tissue depth - as homogeneous an irradiation as could be achieved with no metal grid between the tube and deep tissues. Moreover, having that grid on the skin surface enables the delivery of roentgen rays to deep tissues in doses that are much higher than those possible at present without the risk of inducing a poorly healing ulcer. Whereas each cell, whether in normal tissue or in tumor, is irradiated similarly at depth, only the skin beneath the grid's spaces is significantly irradiated, leaving skin cells directly beneath the grid's metal wires essentially intact. Admittedly, the skin between the grid elements is burned or necrotized by severe roentgen-ray overdosing, but it is repaired within several weeks because each small, necrotic zone of it is enclosed by a continuous wall of tissue containing viable cells and viable segments of blood vessels.
A comparable method is already established in surgery when, for example, we treat an angioma by punctiform thermocautery using the Paquelin apparatus. We know how fast the resultant scabs heal. Although conditions for healing deep necrotic tissues after grid-mediated roentgen therapy are not as favorable as those for healing tissues after punctiform thermocautery, they are analogous. In any case, the relatively little harm from grid-mediated roentgen therapy causing punctiform necrosis would not be comparable to the severe harm from roentgen-ray overdosing without protection from a metallic grid causing very extensive, deep skin ulceration.
The question of knowing how many times more intense irradiation could be applied with than without a metallic grid is difficult to answer; it depends to a certain extent on what kind of metal is used to make the strands of the grid and on the strands' thicknesses. Thus, it might take no less than one hundred erythema doses to kill skin cells shielded by such strands of metal, and perhaps no less than fifty erythema doses to visibly injure any zone of the skin so shielded at all. Approximately fifteen erythema doses would leave skin cells so robust in such numbers that side effects of the irradiation would be practically undetected. It is however not inconceivable that even fifty erythema doses applied to the grid would damage tissue directly under its metallic threads so slightly that necroses in the exposed skin would soon be healed. Nevertheless, for the initial trials, it is recommended that one should not exceed ten erythema doses. How much higher doses could be would become clear from more extensive studies.
The author has not yet had an opportunity to test this method clinically. However, the theory of the method is based on simple physical and biological principles, so its applicability to practice is beyond doubt. Besides that, animal studies could indicate if skin damage caused by using 20 to 50 erythema doses might outweigh the benefit achieved by using those doses for deep lesions. Initial applications to humans could be implemented, for example, for malignant, inoperable tumors confidently identified as such at laparotomy beforehand.
This method appears to carry no disadvantage to the patient other than causing minuscule zones of necrosis, already described. On the other hand, it has the following advantages in addition to those already mentioned: Fundamentally, the method depends on irradiating at a very short distance, which will allow much shorter exposure times than those used at present. For example, for a distance of 5 cm between the glass wall of a 15 cm-diameter roentgen-ray tube and the skin surface (i.e., 7.5 + 5 cm from the anticathode's impact zone to the skin), one achieves a 16-fold stronger roentgen-ray dose than that achieved during the same exposure time with the tube positioned 50 cm away from the skin.
Another advantage of my method is that it allows roentgen-ray-energy filters to be used just as effectively as they were before. Any kind of filter may be placed underneath the metal grid*; leather filters are recommended in particular. It would be advantageous to apply some pressure to the grid against the filter, either with a diaphragm or with the leaded-glass cylindrical tubes used for the radiotherapy. Finally, one can increase the method's effectiveness by irradiating from several directions. That would enable treatment of a deep lesion, a sarcoma of the thigh for example, with exceptionally high doses by directing roentgen rays toward four different sides of it in succession.
Another consideration is that the metal grid is of value in protection against skin burns from irradiation of superficial lesions, particularly for inexperienced technologists not yet certain of the doses they are delivering. Using the grid, an overdose that causes an ulcer or a zone of necrosis should be healed very rapidly. Using this method, irradiations of lesions in patients with blood dyscrasias should also become less dangerous. In therapy of cutaneous lesions, however, it should be kept in mind that zones of skin underneath metal strands will not be treated. It is not certain that cells exposed to roentgen rays traversing the spaces of the grid, having received intense radiation, might have a palliative effect on unexposed cells; judging from certain well-known phenomena, that would not be impossible, but practice will decide the question. Using the method for benign lesions of the face is not advisable, as it could cause a gridlike pattern of indelible pigmentation in exposed areas.
(To implement the method described above, the firm Reiniger, Gebbert & Schall, Erlangen, upon order, will deliver a tube with the largest possible anticathode impact zone.)
*It is especially advisable to use filters to block secondary radiations originating in the metal strands of the grid.
...................
Dr. A. Köhler (Wiesbaden). Deep X-ray Therapy Through a Protective Metal Screen. (Report III: Clinical Applications). Strahlentherapie 1, 121-131, 1912.
Before describing the most important clinical applications of the author's method for high-dose radiotherapy of deep lesions, one should first explain not only the requirements for it to be considered a rational technique but also the most important factors and developments about it that have come to light since the method was first disclosed.
Anyone with basic knowledge of radiotherapy, even a beginner, should understand that most X rays are absorbed in superficial tissues: theoretically, only a small percentage of them are therapeutically effective more than several centimeters deep. Further, it has been shown and is generally understood that a small dose of X rays is physiologically inconsequential, that an intermediate dose may either inhibit or stimulate actively growing tissues, including tumors, and that only a high dose retards tumor or other pathologic growths enough to initiate some healing and palliate the patient. Therefore, to be therapeutically effective, one would have to deliver a much greater dose to the skin or mucous membrane in the radiation-entrance zone overlying a centimeters-deep tumor than to the tumor itself. Although an exposure of 4 skin-erythema doses [EDs] would be therapeutically effective for a tumor only a few centimeters deep, that radiation dose would also cause radiogenic inflammation of the skin, resistant to therapy. However, the much greater incident dose required to arrest the growth of a considerably deeper tumor would certainly elicit frank cutaneous and subcutaneous necrosis - ultimately, a non-healing radiogenic ulcer.
For a rational, new deep-tumor irradiation technique to be accepted, it must at least damage a tumor without causing irreversible necrosis of the skin over it. Thin leather and metal filters have been tested to achieve this on the presumption that at least one of them might be helpful. Knowing that an X-ray tube emits a mixture of radiations that penetrate to different depths, one reasoned as follows: the radiations that injure the bare human skin would be absorbed by a thin, protective leather filter - i.e., the bare skin of another animal - while the radiations that penetrate deep beneath the skin obviously could not be absorbed by either the overlying leather filter or the skin. However, the reasoning whereby so-called 'filter-protected' skin might not be burned by such radiation is untenable. Indeed, the author employed such a technique of X-ray therapy in the early days of his practice and nearly caused a terrible skin burn. Although 'filter-protected' skin is not assuredly protected from radiation dermatitis, nevertheless it appears that leather filters may provide several theoretical and practical advantages for treatment of some very radiosensitive tissues, even deep ones (e.g., lymph nodes, spleen, bone marrow, ovaries). However, leather is of little use for X-ray therapy of most deep malignant tumors.
Another technique for radiotherapy of deep lesions is to increase the focal distance from the X-ray tube, i.e., the distance from the impact of its cathode rays on its anticathode to the surface of the irradiated skin. At a certain theoretical level, that might seem somewhat convincing; i.e., the greater that distance, the less the importance would be the distinction between the first centimeter and the first decimeter of penetration in tissue. On deeper analysis, however, irradiating from a large distance appears less reasonable than irradiating from a short distance because a much more important factor has to be considered: the duration of irradiation. For example, a sixfold increase in focal distance would necessitate a clinically unacceptable exposure time, extended 36-fold. Not only would the doctor's valuable time be wasted, but the patient's discomfort would also be prolonged excessively. Moreover, the cost to a clinic of replacing so many more worn-out X-ray tubes would be unaffordable. Even so, those disadvantages would be taken in stride if the technique really worked: 'Salus aegroti summa lex' - 'the welfare of the patient is the highest priority.' The long-range irradiation technique, unfortunately, is not merely inconvenient, it is not even effective. Actually, employing a one-meter focal distance to treat a deep malignant tumor is malignant to the patient but not to the tumor: the requisite 3-4 hour exposure would only stimulate the tumor to grow without the slightest promise of its ablation. If the foregoing reasoning is faulty, then the world's accumulated knowledge about physiological and biological effects of X rays must be faulty, too.
An alternative technique to bring therapeutically effective radiation to a deep tumor is to spread out the exposure on the skin, irradiating the tumor from different angles, whether in one or several successive treatment sessions. Examples: A femoral sarcoma can be irradiated from four different sides of the thigh. A pituitary tumor can be irradiated from over a dozen different angles. Another good step forward was enabled by G. Schwarz's finding that compressed, blanched skin is less sensitive to damage from X rays than is normally perfused skin. Accordingly, one should blanch the skin during its exposure to X rays, either by direct compression using a piece of radiolucent wood or an inflated rubber balloon, by preinjection of adrenaline, etc.
The situation remains that one would wish tenfold more dose several centimeters deep in tissue than can be achieved at present, even by combining two or three existing techniques that aim to achieve deep X-ray therapy. Again and again, unacceptable skin damage prevents progress. That's why, for example, Czerny and Werner's proposal to expose inoperable tumors, then sew them into the skin incision for ablation by X rays has fallen into disfavor. One must pursue a new, significantly different strategy for X-ray therapy of deep, surgically inoperable tumors - perhaps using the metal-screen method implemented by the procedure described below. The author did not invent that method while searching for better treatment of deep tumors. Rather, its principle emerged during the author's months-long, unsuccessful, unpublished attempts to improve irradiation apertures for roentgenography. The principle is as follows:
It is well known that one will obtain a very sharp image of a metal screen with 1- to 2-mm holes if it is placed directly on a photographic plate and exposed to X rays. However, if one displaces the screen about 20 cm away from and parallel to a photographic plate, then irradiates the screen from an ordinary X-ray tube placed just behind it, at best only a very blurry image of the screen will appear on the plate; using most tubes, no screen image will be seen at all: instead, the plate will be completely and uniformly darkened. The reason for these observations is known. The physics of roentgenography teaches one that neither reflection nor refraction of X rays comes into play; instead, the effect depends entirely on the focal zone on the anticathode of the X-ray tube. In common X-ray tubes, cathode rays do not converge to a tiny point on the anticathode, but to a roughly circular zone on it, usually 1 to 5 mm in diameter. For a given distance from the X-ray tube to the metal screen, the less the displacement of the photographic plate from the screen, the bigger must be the impact zone of cathode rays on the anticathode to uniformly darken the plate, i.e., to completely eliminate the screen's image in a roentgenograph.
If one wishes to apply the foregoing observations to roentgenotherapy, the following ideas emerge: the smallest possible anticathode impact point is the best for roentgenography, but the worst for roentgenotherapy. For the latter, one should use a tube with an anticathode focal point of substantial area, roughly 1 to 2 cm in diameter. Moreover, one should place a protective screen with approximately 2 mm-wide holes directly on the skin or on an intervening thin leather filter - the screen woven with sufficiently thick metal strands, e.g., about 1 mm in diameter. An X-ray tube with a large anticathode focus zone should be placed only a few cm away from the protective metal screen. If one uses such a setup, tissues are uniformly irradiated to a considerable depth beneath the skin, almost as uniformly as if there were no metal screen between the tube and the targeted tissue. Advantageously, the metal screen allows an enormous, unprecedented radiation dose to be delivered to a deep tumor without causing an intractable radiogenic skin ulcer. Whereas tumor cells several cm deep to the skin are irradiated evenly, only skin cells exposed through the screen's holes are irradiated; skin cells immediately under the screen's metal strands remain undamaged. Although multiple zones of skin exposed through the screen's holes are burned and become necrotic, those zones are healed several weeks later because each necrotic zone is enclosed by a divider of healthy cells and blood vessels. Severe damage to the skin - e.g., a large, intractable ulcer caused by Roentgen-ray overdosing without a protective metal screen, is not comparable with the slight, transient, punctiform skin lesions associated with metal-screen therapy.
To apply the technique in practice, the procedures described below are recommended: it is not required, neither is it even feasible to expose the patient to a Roentgen tube with a wide anticathode focal zone for 5-8 minutes using a current of 2-4 mA, because six such tubes would be required for each treatment. Not even the busiest roentgenotherapy institute could afford them. However, a surprising simplification of the method has been developed to implement the technique somewhat differently, yet economically and effectively.
One selects an ordinary Roentgen tube - one used for roentgenography - and turns it on during the first exposure of the treatment until its glass wall begins to soften. A second ordinary tube is then used similarly for the second exposure, and a third, fourth, fifth, sixth, etc., … so that each tube is turned on for successive exposures of the treatment, using as many ordinary Roentgen tubes as one has available for the treatment. Each time a different Roentgen tube replaces the previous one in the Pb-shielded aperture box, its focal point is placed a few millimeters (with respect to the aperture) from the previous one. For example, if one uses six tubes, each positioned with its small anticathode focal point several millimeters from that of the others, the overall distribution of their combined radiations at depth will be the same as if one had used only one tube with a very large focal point repeatedly. Thus, although having only one aperture box allows only one ordinary Roentgen tube at a time to be oriented toward the aperture using three adjustment blocks (designed by Gocht), that strategy enables irradiation from many tubes oriented slightly differently, as desired, because the focus zone of any particular tube can hardly ever be reoriented identically toward an aperture in the same shielded box with mathematical precision, as one can learn from any manufacturer of Roentgen-ray equipment. This enables an enormous simplification of the technique.
Furthermore, if one uses an iron screen that is so stiff as to be virtually unbendable, it can compress the skin almost to bloodlessness*; for this, either the aperture box or the leaded-glass tube itself can be pressed hard on the screen, but the screen should be first affixed to the skin at its edges with some adhesive, as it definitely must not move during irradiation. It is recommended that a very thin leather filter or tissue paper be placed under the metal screen to absorb the rather high dose from secondary radiations emitted by the screen's metal strands during high-dose therapy; this allows the skin under the strands to survive undamaged.
The fear has been expressed that the combination of mechanical pressure, radiation damage, and bacterial contamination would combine to cause intractable confluent suppurative necrosis, resulting in a large ulcer rather than transient punctiform necrosis of the skin. I'm not sure that such an outcome is likely, although it does seem possible. So, I take care to cleanse the irradiated skin aseptically - to date so thoroughly, it seems, that this complication has not arisen. Should it ever arise, i.e., if such a complication should became the rule and should there be no reliable method available to prevent it consistently, the writer would abandon the technique and advise others to do likewise even without knowing the reason for the problem, although there is little chance of that happening.
To criticize the method because one irradiates once, not repeatedly, is quite inappropriate. First, if one can use this method to deliver 10-15 times more dose than one can deliver otherwise, one can accomplish much more than can be accomplished any other way, for example by temporally fractionated X-ray therapy. Second, there are many parts of the body (e.g., breast tissues, limb bones, deep in the lungs, etc.) that can be irradiated from 3 or 4 different angles. Granted, a zone of the skin that has already been stressed by screen therapy once cannot be so stressed again, but one could derive profound satisfaction from delivering an enormous dose to a femoral sarcoma, for example in four separate exposures from four different angles.
One should also consider what happens to normal tissues proximal to a targeted tumor, especially because they absorb higher doses than does the tumor itself. In most situations, that problem is minor because of the relative radiation-resistance of muscle and adipose tissues vis-à-vis that of normal epithelial tissues: the method would be inconceivable without taking that radiation-resistance into account. On the other hand, I take the radiation-sensitivities of intestinal blood vessels and epithelia into account too; experience has shown that the those tissues are prone to severe injury from high doses of X rays. All aspects of the method that were taken into consideration during its implementation since it was introduced cannot be discussed here. Those interested in further theoretical details should read the two original communications1)
An exposure of 10 EDs lasts, on the average, 45 to 75 minutes. The practice of screen therapy turns out to be time-consuming. It must be obvious that delivery of a massive radiation dose cannot be implemented by the radiotherapist during consultation hours; at least 60 to 90 extra minutes are needed. Just as preparations must be made in advance for a surgical operation, preparations for screen therapy must be made in advance, too. Before the patient enters the treatment room, one lines up three to six of the best X-ray tubes available in a stand - from the one of highest strength downward. The higher the strengths of tubes selected for the treatment the better, since the overall time to treat a patient by a prescribed radiation dose should be as short as possible, each tube consuming as little energy as possible. One also selects a shielded Roentgen-tube box for the treatment having an aperture as wide as the greatest diameter of the tumor.
One should use longer X-ray tubes to treat tumors of the neck and axilla. For such cases, one should cut the screen about 2 cm wider than the tube. The screen is pushed against the skin covered by a filter about 3 mm wider than the screen so that the margins of the screen will not stick into the skin (the filter: very thin leather or two layers of tissue paper), using three or four strong, narrow adhesive strips: better, one should also turn the edges of the screen outward.
The dose is determined by using a high-voltage balance, then by referring to Walter's milliampere-minute [mA-min] tables (see "Fortschritte auf dem Gebiet der Röntgenstrahlen," Volume 4, pages 343-344). The high doses required by our treatment are not delivered more exactly than +/- 0.5 ED, accurate enough for this simple, forgiving treatment method. Suppose I referred to Table II and, for the initial exposure, chose a tube of 0.4 mm-thick glass and a strength of 5 BW (7 W). From Table II, 4 minutes of exposure at an 18 cm anticathode-to-skin focal distance with a tube current of 3 mA would deliver 1 ED (as, according to Table II, the same dose could be delivered at the same focal distance with a tube current of 1 mA during 12.3 minutes of exposure). Suppose I chose a second tube that could deliver 1 ED in 6 minutes with a current of 2 mA; a third that could deliver 1.5 ED in 6 minutes with a current of 3 mA; a fourth that could deliver … etc., etc. By repeatedly recording the irradiation parameters of the exposure from each tube and calculating the dose accumulated from all previous exposures, one can quickly plan the duration of exposure required of the following tube.
After that, the patient is prepared for the treatment: A wide zone in and around that to be irradiated is washed with soap then defatted with ether. Although it would not be necessary to cleanse the skin before the treatment, for the reasons stated above, cleansing would certainly be required afterwards. The patient is very carefully placed in the most comfortable possible position for the treatment using large and small cushions supported by sandbags. The patient must be given to understand that the position must be held, unchanged, for at least 45 minutes. Although even a slight twist or backward stretch of the neck can be most uncomfortable, in fact I have had no complaints from patients about their position. The screen, together with the filter (e.g., the thinnest available chamois leather, 2-3 layers of tissue paper, table napkin), is stretched out tightly on the skin and bound to it firmly using 2-4 strips of thin adhesive tape. After that, the X-ray tube's aperture box or its Pb shield is pressed hard enough against the screen so the latter cannot be moved.
Now something is mentioned that is very important but easily overlooked by a doctor using the technique for the first time: shielding the patient. Using an X-ray tube box with Pb walls, a Pb base, and an aperture in Pb through which ten or more EDs can delivered in one treatment, only minimal protection is provided, even for bystanders, especially if one uses the shortest possible anticathode-to-skin focal distance. Accordingly, one must place additional pieces of Pb shielding around the apparatus up to about 40 cm from it. Finally, the (robust) tube is turned on to start the irradiation, optimally stressed by a current of no more than 2 to 3 mA. Lower currents are not suitable because they might require two hours of exposure or more.
If one should become aware of something wrong with either the instrumentation, the tube holder, or the patient's position during the first 2 to 3 minutes of an exposure, there is still enough time to interrupt the irradiation and put things right; later, however, interrupting it can be done only if the adhesive plaster has stuck the screen tightly to the skin. After five to ten minutes of exposure, when the hot tube becomes perceptibly softer, one removes it from the aperture box and replaces it with the second tube. Since a tube can be shifted within the box to a some extent, the second tube is aligned to the aperture in the box about 1 cm farther to the right than was the first; later, the third tube is aligned to the aperture about 1 cm farther to the left than was the second; etc., etc. One proceeds in this manner, continuing to make note of each successively accumulated tumor dose until the desired total tumor dose has been delivered. If all the available tubes have been used, yet the desired dose has not been delivered, one reuses the first tube that had cooled off in the meantime.
Each time a tube is positioned in the box, its focal point is aligned with the center of the aperture slightly differently. It is immaterial that a tube cannot move in the aperture box after it had been stabilized by the three adjustment blocks because, as explained previously, the alignment of each successive tube in the box is deliberately not reproduced.
Just after the last exposure, of course, one notices nothing other than the physical imprint of the screen's pressure on the skin; the irradiated zone is then washed carefully again - without hard rubbing or such - then bandaged with thin muslin and adhesive plaster. The skin's reaction to its irradiation is noticed only after several days. It is recommended that one should check it at four days post therapy. Before each treatment, one should have explained to the patient that the irradiated zone would become a persistent, hard scar; this should be presented as a minor side effect so the patient might not hesitate to tolerate the lesser evil.
Animal experimentation had to be canceled at the last moment because the anesthesia injected did not immobilize the animal. Even a few muscle twitches should signal a halt to the procedure and postponement of the study. Moreover, one cannot expect a colleague to administer anesthesia to an animal for many hours near a Roentgen tube: just as a patient is protected by angling his/her recumbent body as far as possible away from the radiation source, so too should an anesthesiologist be kept as far away from it as possible.
Thus, the author has had to proceed with clinical tests of metal-screen therapy very slowly - gradually increasing radiation doses. Lacking sufficient clinical and hospital support, he has experience with only a few cases - to date, three cases in all, each with a very poor prognosis. He has had to handle these cases personally: neither he nor anyone else expected cures. Although only a few cases have been treated, and within the near future only a few more are expected to be treated, the benefits of high-dose treatments have been shown clearly superior to benefits expected from standard X-ray therapy of similar tumors up to now.
The salient features of these cases are as follows:
1. (Th. Nr. 208. J. G.) Recurrent cancer in the neck glands. 65 year-old man, well until 7 months ago, when a small tumor was noticed above his left clavicle, which soon grew to the size of a hen's egg. It was excised four months ago: microscopy showed a carcinoma. A similar excision was performed 4.5 weeks later but as soon as the patient left the hospital the tumor began to regrow rapidly, so the surgeon, deeming the tumor inoperable, prescribed mild X-ray therapy (10 exposures). At that stage the tumor was half the size of a child's head, occupying the entire (left) side of the patient's neck. A scar from the operation was noticed in the center of the skin over the tumor, which was discolored patchy purple. The skin was stuck tightly to the tumor and to the (left) clavicle. Neck circumference: 46 cm. The tumor was treated by screen therapy using several approximately 4 cm-diameter fields in succession at 1- to 10-day intervals: durations of exposure were increased gradually, so that the first field received 1 ED, the second, 2 EDs; the third, 4 EDs; the fourth, 5 EDs - the exposures totaling 227 mA-min, with no greater than 2- to 3-mA current during each exposure. These four exposures were implemented with different focal distances during 20, 38, 25, and 18 minutes, successively. Only the most intensely irradiated zone of skin showed any trace of the screen's pattern upon examination 4-5 days afterwards: later, the irradiated skin exhibited severe desquamation, but never necrosis. A report from the attending physician eight days after the final irradiation stated "It is greatly diminished; enormous shrinkage of the largest lumps of tumor forward of its center with even more shrinkage beneath that point. On account of distant metastases, however, the patient is not expected to survive much longer." Neck circumference: 41 cm - a reduction of 5 cm during eight days. A few days after the (last) exposure, the patient had experienced mild chills, which should be attributed to resorption of the tumor. The patient weakened gradually, but I had a chance to see him shortly before death. The tumor remained shrunken where it had been irradiated, but elsewhere in the neck it had grown toward the face and the occiput. There were many local metastases. Although the skin over the tumor appeared distinctly dark blue, traces of the screen were no longer seen on it.
2. (Th. Nr. 262. W. B.) Branchiogenic cancer. 49 year-old man. Five and one-half years ago, one side of the neck began to thicken and became fist-size soon thereafter. This was irradiated in his home town by 10 exposures to X rays, which shrank the growth. A recurrence of the growth later was treated with a very large dose of X rays. The irradiated skin then became severely inflamed; it never regained a normal appearance. Three and one-half weeks ago, the tumor enlarged suddenly. It was irradiated twice in succession; a small dose was delivered during each exposure. As there had been no response to the latter irradiations, he was referred to my office in Wiesbaden a couple of days before I examined him there: a large, sturdy, seemingly vigorous man presented himself. His urine sugar level was 1 part per 1000. There was an apple-size growth on the left side of his neck. The overlying skin was atrophied, with scattered telangiectasias and irregular pigmentation. One could palpate a tri-lobed tumor, two lobes of which each seemed the size of a duck egg; the lobe under them seemed somewhat smaller. Clinical diagnosis: "Lymphosarcoma or carcinoma." Screen therapy was implemented - one zone with 4 EDs, another zone with 6 EDs, another with 3 EDs, and between those three zones, another three central zones were treated with 1.5 EDs each: in all, 230 mA-min of tube energy were consumed during 23, 31, 36, 44, and 16 minutes of exposure. The first two irradiations were implemented one after the other on two days in succession. When the patient returned to my office three days after the last exposure, his tumor was appreciably reduced in size. He had to travel then, but he wrote me four weeks later that the tumor had begun to regrow. Two small doses of X rays administered in Berlin did not change the situation, so an operation on it was performed at the Bier Clinic. "Diagnosis: Branchiogenic carcinoma. The pattern of tumor growth was alveolar, with scattered zones of densely cellular, new connective tissue between the carcinoma cells. Most of the tumor was not viable; in part overtly necrotic, in part with fragmented nuclei. In certain zones, small-cell infiltrates are noticed among tumor cells. Prof. Stricker." The patient died several months thereafter.
3. (Th. Nr. 323. T.K.) Recurrent cancer of the sigmoid colon. 26 year-old woman. Her illness began with severe constipation and pain 20 months ago. Two months later, she consulted a surgeon who operated on her intestinal tumor, described by Dr. Heile as a carcinoma of the sigmoid colon. Some pelvic bone was removed at the same operation. During the past few weeks she has experienced pain at the site of that operation, varying greatly in severity with changes in weather conditions. The tumor palpated at the site of the operation was about the size of a hen's egg; it was deemed inoperable. A dose of 6 EDs was delivered to the region of the posterior inferior iliac spine using metal-screen therapy (70 mA-min; 8 cm focus-to-skin distance; actual exposure time, 35 minutes). Two weeks after irradiation, the author had the opportunity of seeing the patient once more during her short life. The screen was imprinted clearly on her skin. Eight weeks later, a letter from the patient's attending physician stated that her strength had waned rapidly and that she was expected to die soon. There had been no improvement in bowel function: "The tumor seemed unchanged. Operative sites on the skin were darkly pigmented but scabs were never seen, nor did I notice any sloughing from those sites." Since it remains uncertain as to whether or not the tumor was examined post mortem, this case is now closed. Whatever the circumstances, changes in that pelvic tumor's size could have been assessed clinically only by palpation. I don't think that severely ill patients should be subjected to bimanual pelvic examinations after X-ray therapy just to track the size of a tumor. On the other hand, without such examinations little credence can be given to the opinion expressed that the pelvic cancer seemed minimally inhibited by screen therapy, especially because it was growing rapidly just before the treatment and because that opinion was only expressed ten weeks after therapy.
The salient features of these cases may be summarized as follows:
The malignancies, in one case, even a recurrent carcinoma, shrank within a few days after screen therapy. That happened in the face of experience that a recurrent carcinoma is much less responsive to X-ray therapy than is the responsiveness of a primary carcinoma of the same kind to similar X-ray therapy. Until now, no skin necrosis has been observed in patients treated by screen therapy using the skin-compression technique with incident doses up to 6 ED. Although much better inhibition of malignant tumors by screen therapy is anticipated, how far one may safely increase the dose to achieve confluent necrosis of a network of tumor-bearing tissues at a given depth beneath the skin has yet to be assessed by clinical experience.
Because it is practically impossible to provide any useful therapy of a deep malignancy using a focus-to-skin distance over 80 cm, even the most stubborn champion of such long focal distances should be impressed by an irradiation technique that delivers 6-10 EDs during one 45- to 90-minute irradiation session.
For screen therapy, the necessity of optimizing the area of the targeted lesion while minimizing the discomfort of immobility during the irradiation generally requires that the anticathode-skin distance be constrained to within 15 - 30 cm.
Finally, the author would also like to draw attention to the potential usefulness of low-dose screen therapy of targets in the spleen and bones (especially in cases of leukemia) as well as of uterine myomas, ovarian tumors, lymphomas and similar common tumors. However, it should be emphasized, especially to novices, that there is scant experience with such treatments and that safe doses of them have not been established.
In summary, it is recommended that:
1. For one-fraction therapy, when dose is critical, one should place a metal screen on the skin before the irradiation.
2. For multi-fraction therapy, a metal screen should be placed on the skin before each fraction.
Even if an inexperienced practitioner overdoses a patient, a screen will enable faster recovery, because the small, burned zones under the screen's holes will be healed by cells that had survived just beneath the metal strands between those holes, each surviving cell having received as little radiation as the other.
* Such iron screen are manufactured by Reiniger, Gebbert & Schall (Erlangen), best in 0.5 m2 squares which, however, can barely be cut by orthopaedic plaster-cutting shears. So, it is recommended that other shears be at hand that can cut through those iron screens.
1. Fortschritte auf dem Gebiete der Röntgenstrahlen, Bd. 14 (the same was published verbatim, in French, in the "Journal Belge de Radiologie" 1909, and in the "Annales d'Électrobiologie et de Radiologie" 1909).
2. Münchener Medizinische Wochenschrift 1909, Nr. 45.
==================
Invited Lectures
* Daniel N. Slatkin. Unpublished seminar: A Therapeutic Advantage Factor for Boronophenylalanine (BPA)-Mediated Boron Neutron-Capture Therapy (BNCT) of Glioblastoma Multiforme. Föreläsningsalen Onkologiska Kliniken, Jubileum Institute, Lund University, Lund, Sweden. November 28, 2000.
* Daniel N. Slatkin. Per Spanne Memorial Lecture, Annual Meeting of the Swedish Society for Radiation Physics, Gothenberg, Sweden. November 30, 2000.
* Daniel N. Slatkin. Microbeam Radiation Therapy (MRT) - historical perspective. Canadian Light Source, Inc., Saskatoon, Saskatchewan, Canada; August 27, 2009.
=================
Microbeam Radiation Therapy (MRT) - historical perspective
Daniel Slatkin (Nanoprobes, Inc., Yaphank, New York, USA)
Presented at the Canadian Light Source, Inc., Saskatoon, Saskatchewan, Canada; August 27th, 2009.
I am grateful to have been allowed by Tomasz Wysokinski and Dean Chapman to visit the Canadian Light Source [CLS] this week and to speak today about microbeam radiation therapy [MRT] from a 'historical perspective.' I don't feel historical just yet - maybe that should have read 'personal perspective.' Anyway, I thank each of you for choosing to listen to my presentation, whatever its title should be.
Radiation therapy for cancer is generally undervalued among sophisticated, modern medical professionals, often with justification. Most cancers cannot be cured by standard techniques of radiation therapy, and some cannot even be ameliorated by them. So, well should it be with considerable trepidation that physicians contemplate the development of extremely intense, maybe dangerously intense X rays to treat cancer at the Canadian Light Source's [CLS]'s BioMedical Imaging and Therapy [BMIT] facility, indeed at any synchrotron radiation facility. I have no quarrel with those who would ignore or dismiss the development of MRT on the grounds that existing methods of radiation therapy are adequately palliative, when indicated, for most patients harbouring cancer and that introducing MRT would be very costly and hazardous. However, such viewpoints need not be held by every physician. At present, at least every other patient diagnosed with cancer derives benefit from radiation therapy at some stage of the disease. Just as it's difficult for one to imagine a medical future not heavily inclined toward molecular, immunologic, and genetic therapies, so is it difficult -- difficult for me, at least, -- to imagine a medical future without ancillary radiation modalities to supplement, perhaps to synergize with leading-edge therapeutic anti-mitotics, anti-angiogenics, genes, antigens, antisenses, immunomodulators, antibodies, viruses, bacterial cells, and/or syngeneic eukaryotic cells - whether or not transfected or otherwise modified. However, pending safe and effective clinical use of such advanced therapies, is it not rather reasonable to try to improve upon existing therapies too, when an opportunity arises?
My opportunity arose 53 years ago. A mediocre McGill medical student, I happened to be reading a newspaper at my family's summer home in Ste-Agathe-des-Monts during the break between semesters and noticed its report (New York Times 1956) mentioning Dr. Lee Farr's ongoing boron neutron-capture therapy [BNCT] research at Brookhaven National Laboratory [BNL]. It was only my sheer luck that Farr responded favorably to my naïve letter asking that I be allowed to work on BNCT experiments during the following summer. By chance, for Dr. Stuart Lippincott, then the BNL Medical Department's pathologist - formerly a McGill pathologist - reportedly told Farr that my undergraduate physics and mathematics courses at McGill justified his taking that risk. I could not have been so very lucky then had I not been almost inconceivably fortunate two years previously also, when the neurosurgeon William Cone recommended me for enrollment in McGill's MD program, possibly because I had helped him as an unskilled laboratory assistant at the Montreal Neurological Institute during a couple of summers. I had sought such temporary work to glimpse a world beyond physics and mathematics - the only subjects one was permitted to study for credit after admission to that double-honours program at McGill. BNCT hooked me at BNL during the following summer, and I'm still far from being inclined to unhook myself, BNCT's present lowly status in medicine notwithstanding. A feature of those years that sticks in my mind is a chance meeting with Howard Curtis, then the Biology Department's chairman, when he gave me a ride. He asked me what was going on in BNCT. After responding as quickly and quietly as possible - since I knew very little about BNCT - I asked Dr. Curtis about what sort of experiments he was doing. I got the better of the deal. Whereas during my short ride I could only mumble briefly about my minor technical help with BNCT of malignant leg tumors in mice, Curtis spoke with assurance of the resistance of normal mouse brains to gigantic doses of radiation from a cyclotron-generated microbeam, which I did not understand, but could not forget either. Years later, I realized that Curtis was counted among the leading radiobiologists of his generation.
Because clinical BNCT is now successful, one can at last rest assured that the direct and indirect pioneering contributions to BNCT research projects at BNL from Maurice Goldhaber, William Sweet, Donald Van Slyke, Albert Soloway, Lee Farr, James Robertson, Ralph Fairchild, Victor Bond, George Cotzias, Lewis Dahl, Otto Easterday, Elmer Stickley, Tadeusz Konikowski, Stanley Sajnacki, Darrel Joel, Michiko Miura, Gerald Finkel, Henry Smilowitz, Arjun Chanana, Jeffrey Coderre, Aidnag Diaz, Marta Nawrocky, Peggy Micca, Dennis Greenberg, Michael Makar, Henry Hauptman, and very many others I regret failing to mention here or not knowing, were worth their close attention to research plans and to the innumerable steps they each took over many years to implement them. Nevertheless, the original BNL clinical trials of BNCT (1951-1961) finally failed (Slatkin 1991). Certainly, the original purpose, to palliate some patients with brain tumors using BNCT, was not realized. Decades later, much less disappointing results of the second BNL/BNCT trials of brain tumour therapy from 1994 through 1999 (Diaz 2003) were cited as reasons to stop BNL's BNCT program altogether, especially because it was decided, for various other reasons also, to make BNL a reactor-free laboratory. Despite the failures of BNCT at BNL, techniques developed in the USA, not the least at BNL, in Japan and elsewhere to implement BNCT, further refined in Finnish hands (Kankaanranta 2007; http://www.clinicaltrials.gov/ct2/results?term=BNCT), now seem to me to be among the best, if not the best currently available to palliate patients with recurrent cancers of the head and neck. That the Finns have devised a method of magnetic resonance spectroscopic imaging calibrated for the in vivo assessment of boronophenylalanine-boron concentrations in tissue at the 10 ppm level (Timonen 2009) bodes well for their work and should draw BNCT to the renewed attention of North American radiation oncologists, I hope, of the distinguished ones at my alma mater also (Sham 2008).
Why a presentation on MRT's history should be dominated by a discussion of BNCT is simply this: BNCT research begun at BNL 60 years ago by Lee Farr and Donald Van Slyke (New York Times 1949) led to MRT research there 40 years later; even that - only by chance. As a Canadian citizen with a US student visa about to expire during 1965 upon completion of my residencies in pathology, I applied for a British medical licence on the basis of reciprocity with its Canadian counterpart. That, together with my training in autopsies, qualified me as a Registrar at Hammersmith Hospital, Du Cane Road, London. Registrars in morbid anatomy there under Professor C. V. Harrison were generously freed for one full month per year, at full salary, to do medically related work that interested them. The endocrinologist in charge of Hammersmith's metabolic diseases clinic, Professor Graham F. Joplin, told of my background in BNCT, agreed to have me assigned to postmortem analyses of some pituitary glands that had been therapeutically ablated by trans-nasopharyngeal implantation of a pair of yttrium-90 rods. Those analyses (Talbot 1980) astonished me, showing threshold beta-radiation (2.27 MeV; half-life 64 hours) doses for hypophyseal tissue necrosis with a median of 1.8 kGy. Microscopic outlines of necrosis in transition from the adeno- to the neuro-hypophysis were continuous. Corresponding median thresholds for disappearance of osteocytes from lacunae in the contiguous cranial bone and for necrosis in the nearby tunica media of the internal carotid arteries were somewhat less: 1.5 and 1.2 kGy, respectively. Remarkably, mural thromboses in the adjacent cavernous sinuses of those patients were few, non-occlusive, and clinically silent. One should therefore not be surprised that enormous radiation doses are required to ablate a normal tissue if its vasculature can be regenerated from slightly irradiated, microscopically contiguous blood vessels - in this case, peripheral blood vessels. In the Hammersmith experience, surviving margins of pituitary tissue may have become revascularized from branches of the internal carotid arteries that enter the pituitary from each side, and/or revascularized from above through several small branches of the circle of Willis that enter the pituitary in the loose connective tissue enveloping its infundibular stalk.
Upon returning to Canada in 1969, I was very lucky to secure a professionally fulfilling and generously paid position at the McKellar General Hospital in Fort William under its pathologist Fred O'Brien and its clinical chemist Peter Spare. However, after less than two years in that vast, remote, beautiful, and invigorating, only occasionally chlorinous and/or sulfurous sector of Ontario, family obligations coupled with reluctance to give up my research connections led me to apply for work again at BNL. Eugene Cronkite, for whom I had devised an obscure formula for the dosimetry of extracorporeal irradiation of blood (Slatkin 1963), had become the Chaiman of BNL's Medical Department and, perhaps as reward for helping him, allowed me back to BNL. That move very nearly killed me within a year of my return, as the decade-old Galaxie clunker without seatbelts I had stupidly imported two years after they were mandatory in the USA, was struck nearly head on at high speed by a brand-new Corvette out of control, with a stone-drunk young man at the wheel. That was on May 30th, 1970, the last US Memorial Day observed on a Saturday. My flesh and bones were cut and smashed, but I was left miraculously alive - virtually immobilized during the next six months. I was finally able to return to BNL, where, for many years afterwards I gleaned whatever knowledge I could of analytical biochemistry from Lewis Commerford and William Siegelman, of mass spectrometry from Peter Irsa and Lewis Friedman, of heavy water analysis from Alfred Wolf, of atomic physics from Hobart Kraner, Keith Jones, Fred Geisler, and Albert Hanson, and of other laboratory techniques from Edwin Popenoe, Richard Stoner, Jean Laissue, Jeffrey Gaffney, Joanna Fowler, Michiko Miura, John Heinrichs, Harry Ulyat, and the many others at BNL who gave generously of their time to try, as best they could personally, to make me do my part adequately. In different words, Dr. Cronkite enabled me to begin peeking into some of the promises, the uncertainties, and the bitter disappointments that hands-on biomedical research held in store for me - and to inure myself to the worst. He also recommended me as a junior faculty member to Arthur Upton, who had just then been enlisted by the New York State Department of Education to assemble the senior faculty of a new medical school being established at Stony Brook, about 20 miles west of BNL. Not only was the BNL BNCT program well-nigh moribund by then, but Cronkite himself had been quite openly skeptical of it as long as I knew him. To his great credit, Dr. Cronkite understood clearly the critical differences between skepticism and hostility - providing many precious opportunities for development of innovative programs in radiation research in his department beyond his own wide-ranging, deep expertise in hematology and radiobiology - I believe even beyond any interest of his own.
I had almost forgotten BNCT when, toward the latter 1970s, an unstoppable scientist - Ralph Fairchild, previously James Robertson's technican - collided with me. Far from bashing me, he swept me up and away with his single-minded determination and boundless energy to revive BNCT at BNL - this time with an epithermal rather than with a thermal neutron beam. I became involved in BNCT research again, this time under Fairchild's sponsorship. After Fairchild's sudden death at age 55 on December 17th, 1990, I continued working on BNCT under the supervision of Darrel Joel and Michiko Miura until my retirement from BNL on September 30, 1996. The story of how MRT accidentally spun off from BNCT research during those years was told in my 'Per Spanne Memorial Lecture' on November 30th, 2000, a copy of which is posted at http://dnslatkin.vatavia.net/. English translations of early reports by Alban Köhler, the inventor of sieve therapy (Köhler 1912; Jolles 1953; Becker and Kuttig 1965), of more than historical relevance to MRT, are also posted at that website. I should also point out respectfully that Börje Larsson was the first, to my knowledge, to propose using synchrotron-generated X rays for radiosurgery (Larsson 1983). Per Spanne worked hard to initiate MRT experiments at the NSLS during the late 1980s, helped greatly by Avraham Dilmanian in particular. Spanne's accidental death on September 2nd, 1998 was not only a grievous shock to his research colleagues, but a significant setback to MRT research at the ESRF and the NSLS. That the dynamic radiosurgery pioneer Larsson died just 40 days later compounded the seriousness of the impact.
Despite nearly two decades of effort by Jean Laissue, Hans Blattmann, HansPeter Wagner, Jiri Stepanek, Avraham Dilmanian, and other mature experts, together with those of a handful of generally younger engineers, radiobiologists, medical physicists, mathematicians, and physicians, it has been only during the past couple of years that MRT has garnered attention from more than a handful of clinical oncologists. So, I would respectfully submit that biomedical research politics are not just side issues. It is not merely advisable for those engaged in experimental radiation therapies to work very closely with active, ambitious clinicians as Larsson did so brilliantly - it is essential. Just as BNL's epithermal-neutron-based BNCT research program, initiated virtually singlehandedly by Fairchild in the 1970s, was brought to its knees ten years ago, while it was clinically active and internationally respected, by a variety of US Federal Government-appointed medical consultants, some less expert in BNCT than others, so will the experimental MRT program at the CLS eventually peter out or be stopped unless priority is consistently given by staff at every level of authority, from directors to maintenance personnel, to both the substance and the appearance of collaboration with physicians responsible for the care of desperately ill cancer patients. There should be developed a strong clinical program of microbeam therapy at the CLS to inform, justify, supplement, and back up the sciences of microbeam radiobiology and microbeam radiotoxicology that could help untangle the molecular bases of various abscopal microbeam effects analogous to those cited by Jolles 56 years ago. Whether a clinical program at the CLS, for example one focused on pediatric neuro-oncology (Laissue 2001) could be implemented with the existing 4.5 T wiggler, or would require one with even stronger fields (Dilmanian 2001), is quite beyond my understanding to analyze. Nevertheless, that some clinical program, however narrowly focused it may be, is important to the long-term health of the BMIT program is beyond doubt in my mind. Everyone is entitled to my opinion, and fortunately none is obliged to agree with it.
I wish you all the best of good fortune in pursuing your valuable work. Whether or not what I said pleased you, I thank you again for listening to it.
References:
Curtis HJ (1967). The use of a deuteron microbeam for simulating the biological effects of heavy cosmic-ray particles. Radiat Res Suppl 7: 250-257.
Diaz AZ (2003) Assessment of the results from the phase I/II boron neutron capture therapy trials at the Brookhaven National Laboratory from a clinician's point of view. J Neurooncol 62: 101 - 109.
Dilmanian FA, Krinsky S, Bacarian T, Slatkin DN, Torikoshi M. Design of a dedicated medical synchrotron X-ray facility primarily for microbeam radiation therapy (MRT). National Synchrotron Light Source 2001 Annual Report, eds. Corwin MA et al., Brookhaven National Laboratory, Upton, New York. dilm437 [http://www.pubs.bnl.gov/nsls01/pdf/section%206%20abstracts/toc.htm#X17B1]
Köhler A. (1912) Deep X-ray therapy through a protective metal screen. (Report III: Clinical Applications). Strahlentherapie 1, 121-131. (2009 translation by D. N. Slatkin and J. A. Laissue; posted at http://dnslatkin.vatavia.net/)
Jolles B (1953). X-ray sieve therapy in cancer. Little, Brown and Company, Boston; 192 pages.
Becker J, Kuttig H. (1965) The use of the grid in supervoltage therapy. in Progress in Radiation Therapy, Vol. III. ed. Buschke F., Grune & Stratton, New York and London. pp 50-67.
Kankaanranta L, Seppälä T, Koivunoro H, Saarilahti K, Atula T, Collan J, Salli E, Kortesniemi M, Uusi-Simola J, Mäkitie A, Seppänen M, Minn H, Kotiluoto P, Auterinen I, Savolainen S, Kouri M, Joensuu H (2007). Boron neutron capture therapy in the treatment of locally recurred head and neck cancer. Int J Radiat Oncol Biol Phys 69: 475-482.
Laissue JA, Blattman H, Wagner HP, GrotzerMA, Slatkin DN (2007). Prospects for microbeam radiation therapy of brain tumours in children to reduce neurological sequelae. Dev Med Child Neurol 49: 577–81.
Larsson B (1983). Potentialities of synchrotron radiation in experimental and clinical radiation surgery.
Acta Radiol Ther Phys Biol Suppl 365: 58-64.
New York Times (1949). Brookhaven names 2 to medical staff. April 21.
New York Times (1956). Atomic reactor for medical use. August 26.
Sham E, Seuntjens J, Devic S, Podgorsak EB (2008). Influence of focal spot on characteristics of very small diameter radiosurgical beams. Med Phys 35: 3317-3330.
Slatkin DN, Jansen CR, Cronkite EP, Robertson JS (1963). Extracorporeal irradiation of blood: calculations of the radiation dose. Radiat Res 19: 409-418.
Slatkin DN (1991). A history of boron neutron capture therapy of brain tumours. Postulation of a brain radiation dose tolerance limit. Brain 114: 1609-1629.
Slatkin DN, Blattmann H, Wagner HP, Glotzer MA, Laissue JA (2008).
Prospects for microbeam radiation therapy of brain tumours in children.' Letter to the Editor. Dev Med Child Neurol
DOI: 10.1111/j.1469-8749.2008.03187.x
Talbot IC, Slatkin DN, Arnot RN, Doyle FH, Joplin GF (1980). Pituitary ablation by yttrium-90 implantation: Some post mortem and clinical observations. Int J Appl Radiat Isot 31: 695-701.
Timonen M, Kankaanranta L, Lundbom N, Kortesniemi M, Seppälä T, Kouri M, Savolainen S, Heikkinen S. (2009). Acquisition-weighted MRSI for detection and quantification of BNCT (10)B-carrier
L-p-boronophenylalanine-fructose complex: a phantom study. J Radiat Res (Tokyo). July 8. [ Epub ahead of print ]
==========
Per Oscar Spanne: [August 17, 1945 - September 2, 1998]
Grace and Fervent Creativity
Presented at the Annual Meeting of the Swedish Society for Radiation Physics, Gothenburg, Sweden, November 30, 2000.
I am much moved by the honor of having been asked by the Swedish Society for Radiation Physics to deliver this Per Spanne Memorial Lecture.
Shortly after noon on Wednesday, September 12th, 1984, I found myself at age 50, by then primarily a boron neutron-capture therapy researcher in Ralph Fairchild’s group at Brookhaven National Laboratory, at Linköping University with the late Prof. Börje Larsson, Prof. Carl Carlsson, Mr. George Matscheko, and Dr. Per Spanne. The topic of discussion, I was told, would be microtomography. Although I knew and know little about microtomography, that afternoon’s encounter, especially with Spanne, was later to kindle microbeam radiation therapy (MRT) research. My talk will describe how that came about and what I know of MRT research carried out since then.
Per Spanne entered Lund University in 1966 after his military duty specializing in photographic surveillance. As an undergraduate, he studied mathematics and physics in general, then majored in radiation physics under Professor Carl A. Carlsson. In 1971, Carlsson was named the director of the Department of Radiation Physics at the newly formed Linköping University Medical School and Spanne moved with him to begin postgraduate studies. Spanne was awarded a Ph.D. from Linköping University in 1979 for his work on ultra-sensitive thermoluminescence dosimetry in the microgray range (1). Professor Larsson introduced me to Professor Carlsson and his two younger colleagues Dr. Per Spanne and Mr. George Matscheko at Linköping University on September 12th, 1984. Spanne, then a 39-year-old medical physicist and postdoctoral fellow, wanted to continue his investigations of computerized microtomography using synchrotron radiation. I was asked by Carlsson and Larsson to recommend Spanne to work at Brookhaven National Laboratory's National Synchrotron Light Source (NSLS). Keith Jones, one of my physicist collaborators at Brookhaven during the 1980s, agreed to accept Spanne in his group at the NSLS´s X26 bending magnet beamline.
In August, 1985, Spanne arrived on Long Island with his wife Vibeke Arnmark and their twin daughters Linda and Mette in tow, promised support from Linköping until he was better established at Brookhaven. A hurricane chanced to decimate the yard of their rented home shortly after they moved into it, but that was merely a minor inconvenience, I was told. Although there were no outward hints of it, their first years on Long Island must have been rather difficult. The stresses of confronting language barriers, unfamiliar professional challenges and new bureaucratic hurdles, each serious enough to discourage an unestablished visitor, not to mention the inevitable financial burden of transatlantic displacement with family, all had to be confronted and managed in parallel. Analogous stresses were to be experienced later in France. I was then a 51 year-old staff pathologist and untenured scientist trying to conduct BNCT research under Ralph Fairchild's sponsorship. I was of little use to Spanne, although I did try to support his attempt to initiate a program of microtomography of human skin biopsies at X26 in collaboration with the eminent Swedish Professor Ake Falk, whose encouragement Spanne mentioned appreciatively a number of times before and after the three of us met.
By the late 1980s, Spanne felt secure enough to attempt microtomography of the head of an anesthetized mouse using an ~30 micrometer-diameter pencil beam of x rays at X26. Although individual whiskers were imaged using absorbed doses to brain under 10 Gy, contrast was poor. We therefore decided to increase the absorbed dose by an order of magnitude, based on knowledge that a single planar 22 MeV deuteron beam of similar width (25 micrometers) failed to elicit cerebral damage in mice unless absorbed doses were over ~3000 Gy (2) and that yttrium-90 brachytherapy failed to ablate the human pituitary gland unless absorbed doses exceeded ~2000 Gy (3). We delivered ~200 Gy to a mouse’s head through its brain using the same ~30 micrometer-diameter pencil beam. The mouse recovered normally from anesthesia. I killed the mouse one month later and enlisted my colleague Professor Jean Laissue (Director, Institute of Pathology, University of Bern) to look for any histopathological evidence of damage along the beam's path. Even Laissue saw only apparently normal brain tissue by light microscopy.
At that point, Spanne and I, in collaboration with Avraham Dilmanian (who had been exploring the feasibility of dual-energy tomography and millimeter-beam radiosurgery at X17), decided to investigate the theoretical possibility of radiotherapy with 50 -150 KeV X rays using arrays of parallel 25 micrometer-wide beam slices spaced 50 to 200 micrometers apart. Spanne arranged to have Michael Sandborg, then a graduate student at Linköping, simulate microdosimetry for our various scenarios of this new concept, MRT, for a human brain tumor (4). Concurrently, in continued collaboration with Laissue, we initiated normal rat brain tissue tolerance experiments at the higher energy X17 wiggler beam. We were astonished and elated upon realizing that animals could really withstand absorbed doses of hundreds, even thousands of gray from X rays delivered to microscopic slices of their CNS tissues (5, 6). Although we did not have a multislit collimator, we decided to implement MRT at X17 for the 14-day post-initiation intracerebral rat 9L gliosarcoma, a brain tumor model that had been in use at Brookhaven in BNCT research for over a decade.
Under Laissue's sponsorship, we dove into the task of finding a machinist willing to fabricate a multislit microbeam collimator for our experiments, because we were severely limited by the necessity of translating our animals across our single microbeam in hundreds of microscopic steps to irradiate a rat (7). Four years after designing and constructing his first prototype, by 1996 the late David Archer of Mallorytown, Ontario, Canada, was able to fabricate a dimensionally adjustable multislit microcollimator (MSC), to this day the only one of its kind in use (US Patent 5,771,270: Archer, 1998).
Unfortunately, our attempts and those of the BNL Medical Department chairman Darrel Joel to secure adequate funds for further MRT research at Brookhaven had failed. Influential American critics declared our studies to be of radiobiological interest with little or no future in medicine. Professor
Le Bas of the University of Grenoble, while working to establish a medical imaging beamline at the European Synchrotron radiation facility (ESRF), had visited the NSLS medical beamline´s imaging group at X17, where his student Hélène Moulin apprised him of our MRT experiments. Moreover, a Swiss-sponsored MRT research group led by Laissue and Spanne presented the MRT concept to the ESRF Directorate (Professors Haensel, Altarelli and Branden) in person on June 12th, 1992. So Spanne, by the 1990s an internationally recognized radiation physicist, secured a promise of five years' employment as a medical beamline scientist at the ESRF. The Spannes moved to Grenoble and in September, 1994, Spanne began working as a radiation physicist in the ESRF Imaging Group with the understanding that he was expected to develop MRT there too. Per related to Laissue that Professor Branden, who was also a leading Swedish biocrystallographer, was particularly supportive of him. By March 3,1995, Spanne wrote me that he was preparing "beamline 5" for the first exposures of rats to a single microplanar beam.
My daughter Heidi and I spent several days in Mallorytown at the end of January, 1996, helping Archer in his final assembly of the MSC, which was delivered to Laissue's office in Bern on February 20, 1996 by a FedEx courier, coincidentally and dramatically, during a meeting of our MRT research group. After passing Laissue's inspection by light microscopy, Spanne brought that
Swiss-owned device to the ESRF a few days later, where he first characterized it physically. The MSC was later moved to ID17, where it has been used since then by the Swiss-led MRT research group for irradiations of the hindbrains of normal suckling rats and weanling piglets. Studies of MRT for the 9L rat gliosarcoma are also in progress at the ESRF. Among Spanne´s many supportive colleagues at the ESRF during those years, Hans Blattmann, Jean Laissue, Marco Di Michiel, Michel Renier, Pascal Schweizer, and Pekka Suortti should be mentioned in particular. Di Michiel´s input has been particularly important in the continued activity of MRT experimentation at the ESRF, for which Spanne laid such a solid foundation.
Daniel Slatkin
References
1. P. Spanne, "Thermoluminescence Dosimetry in the µGy Range", Acta Radiologica, Supplement 360, 1-118, 1979.
2. H. J. Curtis, "The Use of a Deuteron Microbeam for Simulating the Biological Effects of Heavy Cosmic-Ray Particles", Radiation Research, Supplement 7, 250-257, 1967.
3. I. C. Talbot, D. N. Slatkin, R. N. Amot, F. H. Doyle, and G. F. Joplin, "Pituitary Ablation by Yttrium-90 Implantation: Some Post Mortem and Clinical Observations", Int. J. Appl. Radiat. Isot. 31, 695-701, 1980.
4. D. N. Slatkin, P. Spanne, F. A. Dilmanian, and M. Sandborg, "Microbeam Radiation Therapy", Med. Phys. 19, 1395-1400, 1992.
5. J. Laissue, P.O. Spanne, F. A. Dilmanian, J.-O. Gebbers, and D. N. Slatkin, "Zell- und Gewebeläsionen nach räumlich fraktionierter Mikro-Bestrahlung des ZNS mit Synchrotron Photonen“, Schweiz. Med. Wochenschr. 122, 1627, 1992.
6. D. N. Slatkin, P. Spanne, F. A. Dilmanian, J.-O. Gebbers, and J. A. Laissue. "Subacute Neuropathological Effects of Microplanar Beams of X-Rays From a Synchrotron Wiggler", Proc. Nat. Acad. Sci. USA, 92, 8783-8787, 1995.
7. J. A. Laissue, G. Geiser, P. O. Spanne, F. A. Dilmanian, J.-O. Gebbers, M. Geiser, X.-Y. Wu,
M. S. Makar, P. L. Micca, M. M. Nawrocky, D. D. Joel, and D. N. Slatkin, "Neuropathology of Ablation of Rat Gliosarcomas and Contiguous Brain Tissues Using a Microplanar Beam of
Synchrotron-Wiggler-Generated X Rays.", Int. J. Cancer, 78, 654-660, 1998.
===========
M.D., 1959; Faculty of Medicine, McGill University, Montreal, Canada
Certification in Anatomic Pathology, 1965; American Board of Pathology
Research Consultant, 1997-2009; Nanoprobes, Inc., Yaphank, New York
Pathologist and Scientist, 1972-1996 and Visiting Scientist, 1996-present; Brookhaven National Laboratory, Upton, New York.
==============
dnslatkin@gmail.com
Post Office Box 334, Essex, Connecticut 06426-0334, USA.
===============
Citations in PubMed: [slatkin dn and slatkin d]
- Slatkin DN. Experimental neutron capture therapy. McGill Med J. 1958 Feb;27(1):20-1.
- Slatkin DN, Jansen CR, Cronkite EP, Robertson, JS. Extracorporeal irradiation of blood: calculations of the radiation dose. Radiat Res. 1963 Jul;19:409-18.
- Slatkin DN, Spare PD. Umbilical-cord IgM and amniotic infection. Lancet. 1969 Jan 11;1(7585):107.
- Slatkin DN, Robertson JS. Extracorporeal irradiation of blood by beta-emitting isotopes: principles of dose calculations. Radiat Res. 1970 Dec;44(3):846-54.
- Geisler FH, Jones KW, Fowler JS, Kraner HW, Wolf AP, Cronkite EP, Slatkin DN. Deuterium micromapping of biological samples by using the D(T,n)4He reaction and plastic track detectors. Science. 1974 Oct 25;186(4161):361-3.
- Slatkin DN, Pearson J. Intramyofiber metastases in skeletal muscle. Hum Pathol. 1976 May;7(3):347-9.
- Fowler JS, Gallagher BM, MacGregor RR, Wolf AP, Ansari AN, Atkins HL, Slatkin DN. Radiopharmaceuticals. XIX. 11C-labeled octylamine, a potential diagnostic agent for lung structure and function. J Nucl Med. 1976 Aug;17(8):752-4.
- Laissue JA, Slatkin DN. Uptake of 125I-iododeoxyuridine in mouse organs during deuteration of body water: evidence for a thymus-specific effect. Life Sci. 1976 Sep 1;19(5):641-7.
- Slatkin DN, Friedman L, Irsa AP, Gaffney JS. The 13C/12C ratio in black pulmonary pigment: a mass spectrometric study. Hum Pathol. 1978 May;9(3):259-67.
- Gaffney JS, Irsa AP, Friedman L, Slatkin DN. Natural 13C/12C ratio variations in human populations. Biomed Mass Spectrom. 1978 Aug;5(8):495-7.
- Talbot IC, Slatkin DN, Arnot RN, Doyle FH, Joplin GF. Pituitary ablation by Yttrium-90 implantation: some post mortem and clinical observations. Int J Appl Radiat Isot. 1980 Nov;31(11):695-701.
- Watts KP, Fairchild RG, Slatkin DN, Greenberg D, Packer S, Atkins HL, Hannon SJ. Melanin content of hamster tissues, human tissues, and various melanomas. Cancer Res. 1981 Feb;41(2):467-72.
- Slatkin DN, Commerford SL. Statistical dosimetry of radiation to oocytes from DNA-bound tritium. Health Phys. 1982 Jan;42(1):77-80.
- Costa DL, Lehmann JR, Slatkin DN, Popenoe EA, Drew RT. Chronic airway obstruction and bronchiectasis in the rat after intratracheal bleomycin. Lung. 1983;161(5):287-300.
- Slatkin DN, Løvtrup S. DNA concentrations in the human cerebellum. Computation from kinetics of deoxyribose extraction in hot acid. Acta Chem Scand B. 1983;37(4):281-7.
- Slatkin DN, Stoner RD, Gremme AM, Fairchild RG, Laissue JA. Whole-body irradiation of deuterated mice by the 10B(n, alpha)7Li reaction. Proc Natl Acad Sci U S A. 1983 Jun;80(11):3480-4.
- Wielopolski L, Rosen JF, Slatkin DN, Vartsky D, Ellis KJ, Cohn SH. Feasibility of noninvasive analysis of lead in the human tibia by soft x-ray fluorescence. Med Phys. 1983 Mar-Apr;10(2):248-51.
- Slatkin DN, Stoner RD, Adams WH, Kycia JH, Siegelman HW. Atypical pulmonary thrombosis caused by a toxic cyanobacterial peptide. Science. 1983 Jun 24;220(4604):1383-5.
- Laissue JA, Bally E, Joel DD, Slatkin DN, Stoner RD. Protection of mice from whole-body gamma radiation by deuteration of drinking water. Radiat Res. 1983 Oct;96(1):59-64.
- Slatkin DN, Levine MM, Aronson A. The use of heavy water in boron neutron capture therapy of brain tumours. Phys Med Biol. 1983 Dec;28(12):1447-51.
- Kiszenick W, Fairchild RG, Slatkin DN, Zubal G. Increased neutron penetration in partially deuterated water: application to neutron capture therapy. Med Phys. 1984 Jan-Feb;11(1):26-30.
- Adams WH, Stoner RD, Adams DG, Slatkin DN, Siegelman HW. Pathophysiologic effects of a toxic peptide from Microcystis aeruginosa. Toxicon. 1985;23(3):441-7.
- Slatkin DN, Friedman L, Irsa AP, Micca PL. The stability of DNA in human cerebellar neurons. Science. 1985 May 24;228(4702):1002-4.
- Slatkin DN, Pate HR, Cronkite EP. Extracorporeal irradiation of blood: dosimetry corrected for shortened erythrocyte lifespans. Exp Hematol. 1986 Jan;14(1):75-9.
- Slatkin D, Micca P, Forman A, Gabel D, Wielopolski L, Fairchild R. Boron uptake in melanoma, cerebrum and blood from Na2B12H11SH and Na4B24H22S2 administered to mice. Biochem Pharmacol. 1986 May 15;35(10):1771-6.
- Slatkin DN, Stoner RD, Rosander KM, Kalef-Ezra JA, Laissue JA. Central nervous system radiation syndrome in mice from preferential 10B(n, alpha)7Li irradiation of brain vasculature. Proc Natl Acad Sci U S A. 1988 Jun;85(11):4020-4.
- Adams WH, Stone JP, Sylvester B, Stoner RD, Slatkin DN, Tempel NR, Siegelman HW. Pathophysiology of cyanoginosin-LR: in vivo and in vitro studies. Toxicol Appl Pharmacol. 1988 Nov;96(2):248-57.
- Rosen JF, Markowitz ME, Bijur PE, Jenks ST, Wielopolski L, Kalef-Ezra JA, Slatkin DN. L-line x-ray fluorescence of cortical bone lead compared with the CaNa2EDTA test in lead-toxic children: public health implications. Proc Natl Acad Sci U S A. 1989 Jan;86(2):685-9. Erratum in: Proc Natl Acad Sci U S A 1989 Oct;86(19):7595.
- Stoner RD, Adams WH, Slatkin DN, Siegelman HW. The effects of single L-amino acid substitutions on the lethal potencies of the microcystins. Toxicon. 1989;27(7):825-8.
- Joel DD, Slatkin DN, Micca PL, Nawrocky MM, Dubois T, Velez C. Uptake of boron into human gliomas of athymic mice and into syngeneic cerebral gliomas of rats after intracarotid infusion of sulfhydryl boranes. Basic Life Sci. 1989;50:325-32.
- Slatkin DN, Joel DD, Fairchild RG, Micca PL, Nawrocky MM, Laster BH, Coderre JA, Finkel GC, Poletti CE, Sweet WH. Distributions of sulfhydryl borane monomer and dimer in rodents and monomer in humans: boron neutron capture therapy of melanoma and glioma in boronated rodents. Basic Life Sci. 1989;50:179-91.
- Kahl SB, Joel DD, Finkel GC, Micca PL, Nawrocky MM, Coderre JA, Slatkin DN. A carboranyl porphyrin for boron neutron capture therapy of brain tumors. Basic Life Sci. 1989;50:193-203.
- Kabalka GW, Bendel P, Davis M, Slatkin DN, Micca PL. Boron-11 magnetic resonance imaging and spectroscopy; tools for investigating pharmacokinetics for boron neutron capture therapy. Basic Life Sci. 1989;50:243-9.
- Marshall PG, Miller ME, Grand S, Micca PL, Slatkin DN. Toxicities of Na2B12H11SH and Na4B24H22S2 in mice. Basic Life Sci. 1989;50:333-51.
- Clendenon NR, Barth RF, Goodman JH, Staubus AE, Gordon WA, Moeschberger ML, Alam F, Soloway AH, Fairchild RG, Slatkin DN, Kalef-Ezra JA. Enhanced survival in a rat glioma model following BNCT. Strahlenther Onkol. 1989 Feb-Mar;165(2-3):222-225.
- Fairchild RG, Wheeler F, Slatkin DN, Coderre J, Micca P, Laster B, Kahl SB, Som P, Fand I. Recent developments in neutron capture therapy. Strahlenther Onkol. 1989 Feb-Mar;165(2-3):343-347..
- Finkel GC, Poletti CE, Fairchild RG, Slatkin DN, Sweet WH. Distribution of 10B after infusion of Na210B12H11SH into a patient with malignant astrocytoma: implications for boron neutron capture therapy. Neurosurgery. 1989 Jan;24(1):6-11.
- Joel D, Slatkin D, Fairchild R, Micca P, Nawrocky M. Pharmacokinetics and tissue distribution of the sulfhydryl boranes (monomer and dimer) in glioma-bearing rats. Strahlenther Onkol. 1989 Feb-Mar;165(2-3):167-70.
- Slatkin DN, Finkel GC, Micca PL, Laster BH, Poletti CE, Sweet WH. Distribution of boron in two (B12H11SH)2--infused patients with malignant glioma. Strahlenther Onkol. 1989 Feb-Mar;165(2-3):244-6.
- Adams WH, Stoner RD, Adams DG, Read H, Slatkin DN, Siegelman HW. Prophylaxis of cyanobacterial and mushroom cyclic peptide toxins. J Pharmacol Exp Ther. 1989 May;249(2):552-6.
- Wielopolski L, Rosen JF, Slatkin DN, Zhang R, Kalef-Ezra JA, Rothman JC, Maryanski M, Jenks ST. In vivo measurement of cortical bone lead using polarized x rays. Med Phys. 1989 Jul-Aug;16(4):521-8.
- Fairchild RG, Slatkin DN, Coderre JA, Micca PL, Laster BH, Kahl SB, Som P, Fand I, Wheeler F. Optimization of boron and neutron delivery for neutron capture therapy. Pigment Cell Res. 1989 Jul-Aug;2(4):309-18.
- Slatkin DN. Boron neutron-capture therapy. Neutron News 1, 25-28, 1990.
- Slatkin DN, Kalef-Ezra JA, Saraf SK, Joel DD. A beam-modification assembly for experimental neutron capture therapy of brain tumors. Basic Life Sci. 1990;54:317-20.
- Stoner RD, Adams WH, Slatkin DN, Siegelman HW. Cyclosporine A inhibition of microcystin toxins. Toxicon. 1990;28(5):569-73.
- Kalef-Ezra JA, Slatkin DN, Rosen JF, Wielopolski L. Radiation risk to the human conceptus from measurement of maternal tibial bone lead by L-line x-ray fluorescence. Health Phys. 1990 Feb;58(2):217-8.
- Kahl SB, Joel DD, Nawrocky MM, Micca PL, Tran KP, Finkel GC, Slatkin DN. Uptake of a nido-carboranylporphyrin by human glioma xenografts in athymic nude mice and by syngeneic ovarian carcinomas in immunocompetent mice. Proc Natl Acad Sci U S A. 1990 Sep;87(18):7265-9.
- Joel DD, Fairchild RG, Laissue JA, Saraf SK, Kalef-Ezra JA, Slatkin DN. Boron neutron capture therapy of intracerebral rat gliosarcomas. Proc Natl Acad Sci U S A. 1990 Dec;87(24):9808-12.
- Kabalka GW, Cheng GQ, Bendel P, Micca PL, Slatkin DN. In vivo boron-11 MRI and MRS using (B24H22S2)4- in the rat. Magn Reson Imaging. 1991;9(6):969-73.
- Rosen JF, Markowitz ME, Bijur PE, Jenks ST, Wielopolski L, Kalef-Ezra JA, Slatkin DN. Sequential measurements of bone lead content by L X-ray fluorescence in CaNa2EDTA-treated lead-toxic children. Environ Health Perspect. 1991 Feb;91:57-62. Erratum in: Environ Health Perspect 1991 May;92:181.
- Rosen JF, Markowitz ME, Bijur PE, Jenks ST, Wielopolski L, Kalef-Ezra JA, Slatkin DN. Sequential measurements of bone lead content by L X-ray fluorescence in CaNa2EDTA-treated lead-toxic children. Environ Health Perspect. 1991 Jun;93:271-7.
- Slatkin DN. A history of boron neutron capture therapy of brain tumours. Postulation of a brain radiation dose tolerance limit. Brain. 1991 Aug;114 ( Pt 4):1609-29.
- Coderre JA, Slatkin DN, Micca PL, Ciallella JR. Boron neutron capture therapy of a murine melanoma with p-boronophenylalanine: dose-response analysis using a morbidity index. Radiat Res. 1991 Nov;128(2):177-85.
- Miura M, Micca PL, Heinrichs JC, Gabel D, Fairchild RG, Slatkin DN. Biodistribution and toxicity of 2,4-divinyl-nido-o- carboranyldeuteroporphyrin IX in mice. Biochem Pharmacol. 1992 Feb 4;43(3):467-76. Erratum in: Biochem Pharmacol 1995 Sep 7;50(6):893-4.
- Coderre JA, Joel DD, Micca PL, Nawrocky MM, Slatkin DN. Control of intracerebral gliosarcomas in rats by boron neutron capture therapy with p-boronophenylalanine. Radiat Res. 1992 Mar;129(3):290-6.
- Slatkin DN, Spanne P, Dilmanian FA, Sandborg M. Microbeam radiation therapy. Med Phys. 1992 Nov-Dec;19(6):1395-400.
- Rosen JF, Slatkin DN. A commentary on in vivo lead X-ray fluorescence with reference to the 1992 workshop. Neurotoxicology. 1993 Winter;14(4):537-40.
- Coderre JA, Makar MS, Micca PL, Nawrocky MM, Liu HB, Joel DD, Slatkin DN, Amols HI. Derivations of relative biological effectiveness for the high-LET radiations produced during boron neutron capture irradiations of the 9L rat gliosarcoma in vitro and in vivo. Int J Radiat Oncol Biol Phys. 1993 Dec 1;27(5):1121-9.
- Liu HB, Joel DD, Slatkin DN, Coderre JA. Improved apparatus for neutron capture therapy of rat brain tumors. Int J Radiat Oncol Biol Phys. 1994 Mar 30;28(5):1167-73.
- Slatkin DN. Glioblastoma treatment. Science. 1994 Sep 16;265(5179):1644.
- Slatkin DN, Spanne P, Dilmanian FA, Gebbers JO, Laissue JA. Subacute neuropathological effects of microplanar beams of x-rays from a synchrotron wiggler. Proc Natl Acad Sci U S A. 1995 Sep 12;92(19):8783-7.
- Miura M, Micca PL, Fisher CD, Heinrichs JC, Donaldson JA, Finkel GC, Slatkin DN. Synthesis of a nickel tetracarboranylphenylporphyrin for boron neutron- capture therapy: biodistribution and toxicity in tumor-bearing mice. Int J Cancer. 1996 Sep 27;68(1):114-9.
- Dilmanian FA, Wu XY, Parsons EC, Ren B, Kress J, Button TM, Chapman LD, Coderre JA, Giron F, Greenberg D, Krus DJ, Liang Z, Marcovici S, Petersen MJ, Roque CT, Shleifer M, Slatkin DN, Thomlinson WC, Yamamoto K, Zhong Z. Single-and dual-energy CT with monochromatic synchrotron x-rays. Phys Med Biol. 1997 Feb;42(2):371-87.
- Coderre JA, Elowitz EH, Chadha M, Bergland R, Capala J, Joel DD, Liu HB, Slatkin DN, Chanana AD. Boron neutron capture therapy for glioblastoma multiforme using p- boronophenylalanine and epithermal neutrons: trial design and early clinical results. J Neurooncol. 1997 May;33(1-2):141-52.
- Coderre JA, Chanana AD, Joel DD, Elowitz EH, Micca PL, Nawrocky MM, Chadha M, Gebbers JO, Shady M, Peress NS, Slatkin DN. Biodistribution of boronophenylalanine in patients with glioblastoma multiforme: boron concentration correlates with tumor cellularity. Radiat Res. 1998 Feb;149(2):163-70.
- Wetzel DL, Slatkin DN, LeVine SM. FT-IR microspectroscopic detection of metabolically deuterated compounds in the rat cerebellum: a novel approach for the study of brain metabolism. Cell Mol Biol (Noisy-le-grand). 1998 Feb;44(1):15-27.
- Miura M, Micca PL, Fisher CD, Gordon CR, Heinrichs JC, Slatkin DN. Evaluation of carborane-containing porphyrins as tumour targeting agents for boron neutron capture therapy. Br J Radiol. 1998 Jul;71(847):773-81.
- Laissue JA, Geiser G, Spanne PO, Dilmanian FA, Gebbers JO, Geiser M, Wu XY, Makar MS, Micca PL, Nawrocky MM, Joel DD, Slatkin DN. Neuropathology of ablation of rat gliosarcomas and contiguous brain tissues using a microplanar beam of synchrotron-wiggler-generated X rays. Int J Cancer. 1998 Nov 23;78(5):654-60.
- Chanana AD, Capala J, Chadha M, Coderre JA, Diaz AZ, Elowitz EH, Iwai J, Joel DD, Liu HB, Ma R, Pendzick N, Peress NS, Shady MS, Slatkin DN, Tyson GW, Wielopolski L. Boron neutron capture therapy for glioblastoma multiforme: interim results from the phase I/II dose-escalation studies Neurosurgery. 1999 Jun;44(6):1182-92; discussion 1192-3.
- Smilowitz HM, Joel DD, Slatkin DN, Micca PL, Nawrocky MM, Youngs K, Tu W, Coderre JA. Long-term immunological memory in the resistance of rats to transplanted intracerebral 9L gliosarcoma (9LGS) following subcutaneous immunization with 9LGS cells. J Neurooncol. 2000;46(3):193-203.
- Smilowitz HM, Micca PL, Nawrocky MM, Slatkin DN, Tu W, Coderre JA. The combination of boron neutron-capture therapy and immunoprophylaxis for advanced intracerebral gliosarcomas in rats. J Neurooncol. 2000;46(3):231-40.
- Stepanek J, Blattmann H, Laissue JA, Lyubimova N, Di Michiel M, Slatkin DN. Physics study of microbeam radiation therapy with PSI-version of Monte Carlo code GEANT as a new computational tool. Med Phys. 2000 Jul;27(7):1664-75. Erratum in: Med Phys 2001 Feb;28(2):290.
- Thomlinson W, Berkvens P, Berruyer G, Bertrand B, Blattmann H, Bräuer- Krisch E, Brochard T, Charvet AM, Corde S, Di Michiel M, Elleaume H, Esteve F, Fiedler S, Laissue JA, Le Bas JE, Le Duc G, Lyubimova N, Nemoz C, Renier M, Slatkin DN, Spanne P, Suortti P. Research at the European Synchrotron Radiation Facility medical beamline. Cell Mol Biol (Noisy-le-grand). 2000 Sep;46(6):1053-63. Review.
- Miura M, Morris GM, Micca PL, Lombardo DT, Youngs KM, Kalef-Ezra JA, Hoch DA, Slatkin DN, Ma R, Coderre JA. Boron neutron capture therapy of a murine mammary carcinoma using a lipophilic carboranyltetraphenylporphyrin. Radiat Res. 2001 Apr;155(4):603-10.
- Miura M, Joel DD, Smilowitz HM, Nawrocky MM, Micca PL, Hoch DA, Coderre JA, Slatkin DN. Biodistribution of copper carboranyltetraphenylporphyrins in rodents bearing an isogeneic or human neoplasm. J Neurooncol. 2001 Apr;52(2):111-7.
- Smilowitz HM, Coderre JA, Nawrocky MM, Tu W, Pinkerton A, Jahng GH, Gebbers N, Slatkin DN. The combination of X-ray-mediated radiosurgery and gene-mediated immunoprophylaxis for advanced intracerebral gliosarcomas in rats. J Neurooncol. 2002 Mar;57(1):9-18.
- Miura M, Morris GM, Micca PL, Nawrocky MM, Makar MS, Cook SP, Slatkin DN. Synthesis of copper octabromotetracarboranylphenylporphyrin for boron neutron capture therapy and its toxicity and biodistribution in tumour- bearing mice. Br J Radiol. 2004 Jul;77(919):573-80.
- Slatkin DN. Uniaxial and biaxial irradiation protocols for microbeam radiation therapy. Phys Med Biol. 2004 Jul 7;49(13):N203-4.
- Hainfeld JF, Slatkin DN, Smilowitz HM. The use of gold nanoparticles to enhance radiotherapy in mice. Phys Med Biol. 2004 Sep 21;49(18):N309-15.
- Miura M, Blattmann H, Bräuer-Krisch E, Hanson AL, Nawrocky MM, Micca PL, Slatkin DN, Laissue JA. Radiosurgical palliation of aggressive murine SCCVII squamous cell carcinomas using synchrotron-generated X-ray microbeams. British Journal of Radiology 79, 71-75, 2006.
- Hainfeld JF, Slatkin DN, Focella TM, Smilowitz HM. Gold nanoparticles: a new X-ray contrast agent. Br J Radiol 79:248-253, 2006; Authors' reply to M. Geso. Br J Radiol. 80:65, 2007.
- Smilowitz HM, Blattmann H, Bräuer-Krisch E, Bravin A, Di Michiel M, Gebbers J-O, Hanson AL, Lyubimova N, Slatkin DN, Stepanek J, Laissue JA. Synergy of gene-mediated immunoprophylaxis and microbeam radiation therapy for advanced intracerebral rat 9L gliosarcomas. J Neuro-Oncology 78: 135-143, 2006.
- Slatkin DN. Tetrahedral irradiation protocol for microbeam radiation therapy. Phys Med Biol. 2006 September 7; 51(17): N295-N297.
- Laissue JA, Blattmann H, Wagner HP, Grotzer MA, Slatkin DN. Prospects for microbeam radiation therapy of brain tumours in children to reduce neurological sequelae. Dev Med Child Neurol 2007 Aug;49(8):577-81.
- Hainfeld JF, Dilmanian FA, Slatkin DN, Smilowitz HM. Radiotherapy enhancement with gold nanoparticles. Journal of Pharmacy and Pharmacology 2008 Aug;60(8):977-985
- Slatkin DN, Blattmann H, Wagner HP, Glotzer MA, Laissue JA. Prospects for microbeam radiation therapy of brain tumours in children. (Letter to the Editor). Dev Med Child Neurol 2009 February:51(2): 163.
==============
Other citations:
- Slatkin DN, Carsten AL, Commerford SL, Jones KW, Kraner HW. Genetic hazard of 3H: Estimation by oocyte uptake of 2H. in IAEA Symposium on Biological Implications of Radionuclides Released from Nuclear Industries. Vienna, Austria, March 26 - 30, 1979. IAEA-SM-237/57.
- Rosander K, Slatkin DN, Stoner RD. Effects of deuterium oxide and cysteamine on the acute lethality of head irradiation. in Proceedings of the First International Symposium on Neutron Capture Therapy, eds. G. L. Brownell and R. G. Fairchild; Cambridge, Massachusetts, October 12-14, 1983. BNL 51730; pp 134-139.
- Siegelman HW, Adams WH, Stoner RD, Slatkin DN. Toxins of Microcystis aeruginosa and their hematological and histopathological effects. American Chemical Society Symposium Series 262: 407-413, 1984.
- Slatkin DN, Hanson AL, Jones KW, Kraner HW, Warren JB, Finkel GC. Damage to air-dried blood cells and tissue sections by synchrotron radiation. Nuclear Instruments and Methods in Physics Research Part A 227: 378-384, 1984.
- Slatkin DN, Shroy RE, Jones KW. Microscopic radiation damage to air-dried human blood cells caused by 1.7-MeV 1,2,3H and 4He beams. Nuclear Instruments and Methods in Physics Research Part B 9: 66-70, 1985.
- Slatkin DN, Micca PL, Forman A, Gabel D, Wielopolski L, Fairchild RG. Boron uptake in melanoma and mammary carcinoma from Na4B24H22S2 administered to mice. In: Hatanaka H (Ed.) Proceeding Second International Symposium Neutron Capture Therapy, Tokyo, October 18-20, 1985. Nishimura Co., Niigata, Japan. 306-310, 1986.
- Slatkin DN, McChesney DD, Wallace DW: A retrospective study of 457 neurosurgical patients with cerebral malignant glioma at the Massachusetts General Hospital, 1952-1981: Implications for sequential trials of postoperative therapy. In: Hatanaka H (Ed.) Proceeding Second International Symposium Neutron Capture Therapy, Tokyo, October 18-20, 1985. Nishimura Co., Niigata, Japan. 434-446, 1986.
- Laissue JA, Slatkin DN, Gebbers J-O, Altermatt HJ, Bürki H. (1987) Head and Neck - Synopsis. in Diseases of the Head and Neck; eds. WJ Arnold, JA Laissue, I Friedmann, and HH Naumann. Georg Thieme, Stuttgart.. pp 1.1 - 1.42.
- Dilmanian FA, Garrett RF, Thomlinson WC, Berman LE, Chapman LD, Gmur NF, Lazarz NM, Luke PN, Moulin HR, Oversluizen T, Slatkin DN, Stojanoff V, Thompson AC, Volkow ND, Zeman HD. Multiple Energy Computed Tomography for Neuroradiology with Monochromatic X-Rays from the National Synchrotron Light Source. Physica Medica 6: 301, 1990
- Slatkin, Daniel N., Boron neutron-capture therapy. Neutron News 1(4), 25-28, 1990.
- Dilmanian FA, Garrett RF, Thomlinson WC, Berman LE, Chapman LD, Hastings JB, Luke PN, Oversluizen T, Siddons DP, Slatkin DN, Stojanoff V, Thompson AC, Volkow ND, Zeman HD. Computed tomography with monochromatic X rays from the National Synchrotron Light Source. Nuclear Instruments and Methods in Physics Research Part B 56/57: 1208-1213, 1991.
- Slatkin DN, Kalef-Ezra JA, Balbi KE, Wielopolski L, Rosen JF. Radiation Risk from L-Line X Ray Fluorescence of Tibial Lead: Effective Dose Equivalent. Radiation Protection Dosimetry 37:111-116 (1991)
- Slatkin DN. Feasibility study for microbeam radiation therapy with 30-90 keV x rays from the NSLS X17 beamline. in Laboratory Directed Reseach & Development Program: Annual Report to the Department of Energy. (ed. G. J. Ogeka). Brookhaven National Laboratory, Upton, New York, December 1991. DOE/OSTI-4500-R75, UC-900, BNL 52320. pp 36-37.
- Dilmanian FA, Rarback H, Nachaliel E, Rivers M, Thomlinson WC, Apple R, Chapman LD, Garrett RF, Luke PN, Miller MH, Pehl R, Oversluizen T, Slatkin DN, Spanne P, Spector S, Thompson AC. CT imaging of small animals using monochromatized synchrotron X-rays. Nuclear Science Symposium and Medical Imaging Conference. Conference Record of the 1992 IEEE, Volume 2, pages 1298-1300; October 25-31, 1992.
- D.N. Slatkin, J.A. Kalef-Ezra, K.E. Balbi, L. Wielopolski and J.F. Rosen. L-Line X Ray Fluorescence of Tibial Lead: Correction and Adjustment of Radiation Risk to ICRP 60. Radiation Protection Dosimetry 42:319-322 (1992)
- Kabalka GW, Cheng QC, Bendel P, Slatkin DN, Micca PL. A new boron MRI method for iimaging BNCT agents in vivo. in Progress in Neutron Capture Therapy (eds. BJ Allen, DE Moore, and BV Harrington). Plenum Press, New York, 1992. pp 321-323.
- Coderre JA, Micca PL, Slatkin DN, Makar MS. Dose-response analysis for boron neutron capture therapy of the B16 murine melanoma using p-boronophenylalanine, in Progress in Neutron Capture Therapy (eds. BJ Allen, DE Moore, and BV Harrington). Plenum Press, New York, 1992. pp 417-419.
- Miura M, Micca P, Gabel D, Fairchild R, Slatkin D. Biodistribution, toxicity, and efficacy of a boronated porphyrin for boron neutron capture therapy. in Progress in Neutron Capture Therapy (eds. BJ Allen, DE Moore, and BV Harrington). Plenum Press, New York, 1992. pp 455-457.
- Laissue J, Spanne PO, Dilmanian FA, Gebbers J-O, Slatkin DN: Zell- und Gewebeläsionen nach räumlich fraktionierter Mikro-Bestrahlung des ZNS mit Synchrotron-Photonen. Schweiz Med Wochenschr 122: 1627, 1992.
- Joel DD, Slatkin DN, Coderre JA. Uptake of 10B in gliosarcomas following the injection of glutathione monoethyl ester and sulfhydryl borane. in Advances in Neutron Capture Therapy, eds. Soloway AH, Barth RF, and Carpenter DE. Plenum Press, New York, 1993. pp 501-504.
- Kabalka GW, Cheng GQ, Anderson C, Bendel P, Micca P, Slatkin DN. In Vivo pharmacokinetics of a boron neutron capture agent inn a tumor-bearing rat via boron-11 MRS and MRI. in Neutron Capture Therapy, eds. Soloway AH, Barth RF, and Carpenter DE. Plenum Press, New York, 1993. pp 491-494.
- Miura M, Micca PL, Heinrichs JC, Slatkin DN. Synthesis and preliminary in vivo toxicity evaluation of an iodinated sulfidoborate, in Neutron Capture Therapy, eds. Soloway AH, Barth RF, and Carpenter DE. Plenum Press, New York, 1993. pp 339-343.
- Slatkin DN, Spanne P, Dilmanian FA, Nawrocky MM, Gebbers J-O, Laissue JA. Microplanar beam radiotherapy [MRT] of malignant brain tumors in rats. in National Synchrotron Light Source Activity Report 1993 (ed. E.Z. Rothman), Brookhaven National Laboratory, Upton, New York, April, 1994. B-132; BNL 52415.
- Coderre JA, Makar MS, Micca PL, Nawrocky MM, Joel DD, Slatkin DN. Major compound-dependent variations in 10B(n,alpha)7Li RBE for the rat 9L gliosarcoma in vitro and in vivo. in Topics in Dosimetry and Treatment Planning for Neutron Capture Therapy (eds. RG Zamenhof, GR Solares, OK Harling). Advanced Medical Publishing, Madison, Wisconsin, 1994. pp 37-47.
- Slatkin DN, Dilmanian FA, Nawrocky MM, Spanne P, Gebbers J-O, Archer DW, Laissue JA. Design of a multislit, variable width collimator for microplanar beam radiotherapy. Review of Scientific Instruments 66 (Part 2): 1459-1460, 1995..
- Laissue JA, Spanne P, Dilmanian FA, Nawrocky MM, Gebbers J-O, Slatkin DN, Joel DD: Mikrobestrahlung von Gliosarkomen der Ratte: Zell- und Gewebeläsionen. Schweiz. med. Wochenschr 125:1887, 1995.
- Joel DD, Bergland R, Capala J, Chadha M, Chanana AD, Coderre JA, Elowitz E, Liu HB, Slatkin DN: Early clinical experience of boron neutron capture therapy for glioblastoma multiforme. Radiation Research 1895-1995; Volume 2: Congress Lectures. Proceedings of the 10th International Congress of Radiation Research; Eds. U. Hagen et al., Würzburg, Germany, August 27 - September 1, 1995. pp 944 - 947.
- Slatkin DN, Nawrocky MM, Coderre JA, Fisher CD, Joel DD, Lombardo DT, Micca PL. Boron concentrations in rat tissues after partial hepatectomy and a single injection of L-BPA/fructose complex. In: Advances in Neutron Capture Therapy. Vol. II, Chemistry and Biology. Eds. B. Larsson, J. Crawford, and R. Weinreich. Elsevier, Amsterdam, 1997: 229-233.
- Wetzel DL, LeVine SM, Slatkin DN, Nawrocky MM. (1998) Metabolically deuterated species determined in rat cerebella by FT-IR microspectroscopy as a novel probe of brain metabolism. in Proceedings of the 11th International Conference on Fourier Transform Spectroscopy, Athens, Georgia, August, 1997, ed. James A. de Haseth; Conference Proceedings 430, American Institute of Physics, Woodbury, New York. pp 294-297.
- Laissue JA, Lyubimova N, Wagner HP, Archer DW, Slatkin DN, Di Michiel M, Nemoz C, Renier M, Brauer E, Spanne PO, Gebbers JO, Dixon K, Blattmann H. Microbeam radiation therapy. Proceedings of SPIE 3770: 38-45, 1999.
- Laissue JA, Blattmann H, Di Michiel M, Slatkin DN, Lyubimova N, Guzman R, Zimmermann W, Birrer S, Bley T, Kircher P, Stettler R, Fatzer R, Jaggy A, Smilowitz HM, Brauer E, Bravin A, Le Duc G, Nemoz C, Renier M, Thomlinson W, Stepanek J, Wagner HP. The weanling piglet cerebellum: a surrogate for tolerance to MRT (microbeam radiation therapy) in pediatric neuro-oncology. Proceedings of SPIE 4508: 65-73, 2001.
- Dilmanian FA, Krinsky S, Bacarian T, Slatkin DN, Torikoshi M. Design of a dedicated medical synchrotron X-ray facility primarily for microbeam radiation therapy (MRT). National Synchrotron Light Source 2001 Annual Report, eds. Corwin, M. A. et al., Brookhaven National Laboratory, Upton, New York: Abstract No. dilm437 at: [http://www.pubs.bnl.gov/nsls01/pdf/section%206%20abstracts/toc.htm#X17B1]
- Smith DR, Chandra S, Coderre JA, Joel DD, Slatkin DN, Chanana AD, Elowitz EH, Nawrocky MM, Micca PL, Morrison GH. Ion microscopy imaging of boron from p-boronophenylalanine in surgically acquired samples of human brain tumor tissue. In: Frontiers in Neutron Capture Therapy, Vol. 2. Eds. M. F. Hawthorne, K. Shelly, and R. J. Wiersema. Kluwer Academic/Plenum Publishers, New York, 2001: 899-903.
- Dilmanian FA, Zhong Z, Bacarian T, Tammam J, Kalef-Ezra JA, Micca PL, Miura M, Rigon L, Scharf BA, Slatkin DN, Yakupov R, Rosen EM, Morris GM. Response of Subcutaneous Murine Mammary Carcinoma EMT-6 to Synchrotron-generated Segmented X-ray Microbeams. Proc. of Joint Symposium on Bio-sensing and Bio-imaging, Aug 2-4, 2001 (1B-6).
- Blattmann H, Gebbers J-O, Bräuer-Krisch E, Bravin A, Le Duc G, Burkard W, Di Michiel M, Djonov V, Slatkin DN, Stepanek J, Laissue JA. Applications of synchrotron X-rays to radiotherapy. Nuclear Instruments and Methods in Physics Research A 548: 17-22, 2005.
- Hainfeld JF, Slatkin DN, Focella TM, Smilowitz HM. In vivo vascular casting. Microscopy and Microanalysis 11: 1216-1217, 2005.
- Bräuer-Krisch E, Bravin A, Zhang L, Siegbahn E, Stepanek J, Blattmann H, Slatkin DN, Gebbers J-O, Jasmin M, Laissue JA. Characterization of a tungsten/gas multislit collimator for microbeam radiation therapy at the European Synchrotron Radiation Facility. Review of Scientific Instruments 76: 064303, 2005 (Erratum. ibid. 77: 039901, 2006).
- Daniel N. Slatkin, cited in: Judy Pasternak. 'Blighted Homeland: A Peril That Dwelt Among the Navajos.' The Los Angeles Times: November 19, 2006.
- Authors' reply. Hainfeld JF, Slatkin DN, Focella TM, Smilowitz HM. Br J Radiol 80: 65 (2007).
- Smilowitz, H.M., T. Graham, G. Tellides, M. Oaks, J. Hainfeld and D.N. Slatkin. Immunoprophylaxis against recurrence of aggressive F98 rat gliomas after radiosurgery: Treg depletion and injections of GMCSF-transfected irradiated F98 cells with uric acid. Abstracts for the Society for Neuro-Oncology, 15-18 Novemeber, 2007, Dallas, Texas. Neuro-Oncology, 9(4):IM-22, 2007.
- Laissue JA, BlattmannH, Bräuer-Krisch E, Bravin A, Dalléry D, Hanson AL, Hopewell JW, Kaser-Hotz B,Keyriläinen J, Laissue P, Le Duc G, Slatkin DN, Siegbahn E, Miura M. High tolerance of the rat spinal cord to microplanar irradiation. Presented by J. A. Laissue at the 'Syrad' workshop: New prospects for brain tumour radiotherapy: Synchrotron light and microbeam radiation therapy. Grenoble, France, June 2-4, 2008.
Co-inventor of US patents:
H505 Boron uptake in tumors, cerebrum and blood from [10B]NA4B24H22S2; August 2, 1988
4,845,729 Method and apparatus for diagnosis of lead toxicity; July 4, 1989
5,339,347 Method for microbeam radiation therapy; August 16, 1994
5,455,022 Halogenated sulfidohydroboranes for nuclear medicine and boron neutron capture therapy; October 3, 1995
5,583,343 Flexible nuclear medicine camera and method of using; December 10, 1996
5,612,017 Halogenated sulfidohydroboranes for nuclear medicine and boron neutron capture therapy; March 18, 1997
5,653,957 Halogenated sulfidohydroboranes for nuclear medicine and boron neutron capture therapy; August 5, 1997
5,877,165 Boronated porhyrins and methods for their use; March 2, 1999
6,299,873 Method for improvement of radiation therapy of malignant tumors; October 9, 2001
6,566,517 Metalloporphyrins and their uses as imageable tumor-targeting agents for radiation therapy; May 20, 2003
6,759,403 Metalloporphyrins and their uses as radiosensitizers for radiation therapy; July 6, 2004
6,818,199 Media and methods for enhanced medical imaging; November 16, 2004
6,951,640 Use of novel metalloporphyrins as imageable tumor-targeting agents for radiation therapy; October 4, 2005
6,955,639 Methods of enhancing radiation effects with metal nanoparticles; October 18, 2005
7,367,934 Methods of enhancing radiation effects with metal nanoparticles; May 6, 2008
7,530,940 Methods of enhancing radiation effects with metal nanoparticles; May 12, 2009
=============
Project Proposal *PROJECT NUMBER : 91-10 Brookhaven National Laboratory: *pages 36-37 of: Laboratory Directed Research and Development Program Annual Report; G. J. Ogeka, Editor.
PROJECT TITLE: FEASIBILTY STUDY FOR MICROBEAM RADIATION THERAPY WITH 30-90 keV X-RAYS FROM THE NSLS X17 BEAMLINE
PRINCIPAL INVESTIGATOR: Slatkin, Daniel N.
LDRD FUNDING: FISCAL YEAR 1991 AMOUNT $60,742
PROJECT DESCRIPTION:
Summary:
MICROBEAM RADIATION THERAPY: Microscopically fractionated 40-55 keV synchrotron x-rays produce no cerebrovascular damage in the rat at doses up to 5000 gray. For MRT, this means that crossfired bundles of planar microbeams will ablate targeted CNS tissues and spare non-targeted tissues when a peak microbeam dose in the ~10 -100 gray range is delivered in several milliseconds.
.........
This LDRD proposes to carry out feasibility studies in the mouse for the use of monochromatic X-rays from the X17 superconducting wiggler at the NSLS for Microbeam Radiation Therapy (MRT). The studies to be conducted under this LDRD will be: a) Design and assemble a set of computer-driven beam slits to provide square microbeams of 20-1000 micrometer dimensions; b) design and assemble a set of positioning stands for the animal apparatus to position the animal in the beam and move it across the beam in steps of 50-100 micrometers; c) Carry out experiments in which the mouse cerebrum, cerebellum, and eye are irradiated unilaterally with a single monochromatic microbeam at energies of about 30, 60, and 90 keV, at beam dimensions of 25, 50, 100, and 1000 micrometers, and with doses of 20,000, 100,000, and 400,000 rad; d) Evaluate mouse neuropathology and ophthalmic pathology as a function of these irradiation parameters; and e) Repeat the studies indicated in sections (c) and (d) for selected energies, beam dimensions, and radiation doses, with a square pattern of 25 equally spaced parallel pencil beams with a center-to-center beam spacing in the 50- to 150-micrometer range. The goal of the latter study will be to discover the critical interbeam separation at which the probablilty for delayed CNS radiation necrosis is expected to increase sharply with decreasing separation.
TECHNICAL PROGRESS AND RESULTS - FISCAL YEAR 1991:
Synchrotron radiation from the wiggler insertion device of the X17B beamline at the National Synchrotron Light source (NSLS) is practically non-divergent and has enormous flux at photon energies under 100 keV. This means that it is suitable for development of a new type of radiosurgery called 'microbeam radiation therapy' (MRT). As was recently predicted from studies by Curtis et al. using 22 MeV deuteron microbeams at Brookhaven National Laboratory (BNL) three decades ago, and from recent Monte Carlo photon transport and secondary-electron transport computations, a spatially fractionated bundle of parallel, 25 µm-wide, 4 mm-high, 40-55 keV microbeams (delivered at ≈250 gray per second) yields no cerebrovascular damage in the rat one month after irradiation, even at peak microbeam doses of 2500 or 5000 gray. A 1 mm x 1 mm pencil beam of the same quality of radiation delivered at the same dose rate without such spatial fractionation produces colliquative necrosis of the rat cerebrum in its path within two weeks after a dose of only 156 gray.
It is predicted that multiple crossfired bundles of appropriately- dimensioned parallel, planar, synchrotron x-ray microbeams in the 50-150 keV range will ablate tissues in the target zone of a human brain where the bundles overlap, but will spare tissues where they do not overlap when peak/valley doses are as much as 100 gray/5 gray. Such MRT will help to renew radiotherapy in pediatric neuro-oncology and will treat tumors in patients of any age with greatly diminished probability of collateral damage to non-targeted CNS vital structures such as medulla and spinal cord.
=========================
Abstracts: Syrad Symposium, Grenoble, 2008
Microbeam radiation therapy (MRT): Milestones - Clinical prospects. JA Laissue 1, H Blattmann 1 , MA Grotzer 2 , B Kaser-Hotz 3, DN Slatkin 4, HP Wagner 5
1 Institut für Pathologie, Universität Bern, CH-3010 Bern, Switzerland 2 Universitäts-Kinderkliniken, CH-8032 Zürich, Switzerland 3 Vetsuisse Fakultät, Universität Zürich, CH-8057 Zürich, Switzerland 4 Brookhaven National Laboratory, Upton, New York 11973-5000, USA 5 Universitäts-Kinderkliniken des Inselspitals, CH-3010 Bern, Switzerland
Keywords: synchrotron X-ray microbeam radiotherapy - MRT - radiosurgery - pediatric neuro-oncology - CNS tumors
Abstract of the presentation by Jean Laissue at the 'Syrad' workshop: New prospects for brain tumour radiotherapy: Synchrotron light and Microbeam Radiation Therapy, Grenoble, France, June 2-4, 2008. http://www.esrf.eu/events/conferences/Syrad/DetailedProgramme
Rationale and objectives
Collateral damage to vital normal tissues during radiotherapy can be reduced by using three-dimensional treatment planning and external sources of ionizing radiation. Nevertheless, pediatric oncologists try to postpone or forgo 4 any radiosurgery or radiotherapy, especially for children under three years old because irradiating a child’s CNS entails a substantial risk of dysfunctional central nervous system (CNS) development 1, 2, 3. In radiosurgery, spatially accurate and highly conformal beams of radiation are targeted toward a well-delineated tumor in a single session 5. High-dose radiosurgery using multiple millimeters-wide beams of X rays was first described in 1909 6. In modern radiosurgery 7, multiple millimetres-wide beams of linac-generated X rays, or of gamma rays, converge in the target. Might MRT, a radiosurgery mediated by multiple microscopically thin planar beams of synchrotron-generated X rays, yield larger therapeutic indices for CNS tumors than other forms of radiosurgery or radiotherapy?
Methods
MRT, a spatially fractionated radiotherapy, uses an array of microscopically thin, nearly parallel synchrotron-generated X-ray beams 8, 9. Peak radiation doses are up to fifty times higher than in other radiosurgeries. Unlike conventional radiotherapy, for which the effect of changing an irradiation parameter, e.g., the dose fractionation schedule, is predictable, methods to predict the effect of varying an MRT parameter are only beginning to be developed. Among MRT parameters are array width and height, slit width, spacing of microbeams, energy spectrum, changes in tissue dose microdistribution with tissue depth and, possibly in the future, the schedule selected for temporal fractionation of multidirectional MRT.
Results
In animal experiments, MRT has shown unprecedented sparing of normal radiosensitive tissues as well as preferential damage to malignant tumor tissues growing into and around such normal tissues in laboratory animals 10, 11, 12-15, 16-18, 19, 21, 22, 23-25, 26-28. MRT research at the National Synchrotron Light Source (NSLS), Upton, New York, and at the European Synchrotron Radiation Facility (ESRF), Grenoble, France, has shown that single-fraction, unidirectional MRT yields a larger therapeutic index than does single-fraction unidirectional broad beam irradiation for the intracerebral rat 9L gliosarcoma (9L GS) 13, 15-17, 23-26 and for the transplanted subcutaneous murine mammary carcinoma EMT-6 13-15, as does bidirectional (orthogonally cross-fired) MRT for the subcutaneously transplanted, aggressively invasive, extraordinarily radioresistant murine squamous cell carcinoma VII20.
Since postponing radiotherapy may jeopardize survival of some children with brain tumors 29, MRT has been undergoing and undergoes experimental assessment in living animals because it is believed to be potentially useful for inhibiting children’s brain tumors while sparing nearby normal CNS tissues, which should reduce the burden of malignant cells and, therefore, enhance the effectiveness of ancillary therapies 30. The relative sparing by X-ray microbeams of normal tissues of vertebrates - particularly of their normal central nervous system tissues - has been documented in suckling and adult rats 18, 24, 26, 28, duck embryos 12, and weanling piglets 19. These preclinical results, although encouraging, are not yet sufficient to justify a Phase I (safety) trial of MRT for human patients because they are all based on small animal models, except for a set of studies at the ESRF that used the normal piglet cerebellum 16. All other normal-tissue microbeam tolerance studies at the NSLS and ESRF have used fruit-fly pupae 21, rabbits, rats 17, 18, 24-26, gerbils, mice 14, 20, 22, 27, duck embryos 12, and chick embryos 10, 11.
Conclusions
The 6 GeV ESRF ring is the only source of synchrotron radiation in Europe generating intense X ray microbeams for experimental MRT, having a broad energy spectrum of photons peaking in the 80 – 120 keV range and beam intensities high enough, potentially, to deliver an absorbed physical radiation dose to deep targets in large animals, small children, and adult humans; MRT requires the delivery of several hectogray doses within a fraction of a second, deep to the skin. Regulatory and logistic requirements for implementation of clinical MRT will be stringent. The impetus for investigating the potentially unique advantages of MRT for certain human diseases has been recognized and is sustained by the recent consensus of an ESRF scientific advisory panel of sufficient diversity and broad expertise in its membership to merit serious consideration by the ESRF directorate. Accordingly, we propose that ID17 be used to implement a large-animal veterinary MRT study for veterinary radio-oncology. In that way, a wider community of clinical veterinarians and physicians will be able to assess outcomes from MRT in relation to those from existing radiotherapies for similar lesions in large animals.
References
1. Wagner HP. Cancer in childhood and supportive care. Support Care Cancer 1999; 7: 293-294. 2. Mulhern RK, Merchant TE, Gajjar A, Reddick WE, Kun LE. Late neurocognitive sequelae in survivors of brain tumours in childhood. Lancet Oncol 2004; 5: 399-408. 3. Ribi K, Relly C, Landolt MA, Alber FD, Boltshauser E, Grotzer MA. Outcome of medulloblastoma in children: long term complications and quality of life. Neuropediatrics 2005; 36: 357-365. 4. Rutkowski S, Bode U, Deinlein F, Ottensmeier H, Warmuth-Metz M, Soerensen N, Graf N, Emser A, Pietsch T, Wolff JE, Kortmann RD, Kuehl J. Treatment of early childhood medulloblastoma by postoperative chemotherapy alone. N Engl J Med 2005; 352: 978-986. 5. Adler JR Jr, Colombo F, Heilbrun MP, Winston K. Toward an expanded view of radiosurgery. Neurosurgery 2004; 55: 1374-1376. 6. Köhler A. Une nouvelle méthode permettant de faire agir, dans la profondeur des tissus, de hautes doses de rayons Roentgen et un moyen nouveau de protection contre les radiodermites. Annales d'Électrobiologie et de Radiologie 1909; 10: 661-664. 7. Kondziolka D, Lunsford LD, Loeffler JS, Friedman WA Radiosurgery and radiotherapy: observations and clarifications. J Neurosurg 2004; 101: 585-589. 8. Slatkin DN, Spanne P, Dilmanian FA. Sandborg M: Microbeam radiation therapy. Med Phys 1992; 19: 1395-1400. 9. Laissue J, Spanne PO, Dilmanian FA, Gebbers J-O, Slatkin DN: Zell- und Gewebeläsionen nach räumlich fraktionierter Mikro-Bestrahlung des ZNS mit Synchrotron-Photonen. Schweiz Med Wochenschr 1992; 122: 1627. 10. Blattmann H, Burkard W, Djonov V, Di Michiel M, Brauer E, Stepanek J, Bravin A, Gebbers JO, Laissue JA. Microbeam irradiation of the chorio-allantoic membrane (CAM) of chicken embryo. Strahlentherapie und Onkologie 2002; 178 (Suppl. June 1): 118 11. Blattmann H, Gebbers J-O, Bräuer-Krisch E, Bravin A, Le Duc G, Burkard W, Di Michiel M, Djonov V, Slatkin DN, Stepanek J, Laissue JA. Applications of synchrotron X-rays to radiotherapy. Nucl Instr Meth Physics Res A 2005; 548: 17-22. 12. Dilmanian FA, Morris GM, Le Duc G, Huang X, Ren B, Bacarian T, Allen JC, Kalef-Ezra J, Orion I, Rosen EM, Sandhu, T, Sathe P, Wu XY, Zhong Z, Shivaparasad HL. Response of avian embryonic brain to spatially segmented xray microbeams. Cell Mol Biol 2001; 47: 485-493. 13. Dilmanian FA, Button TM, Le Duc G, Zhong N, Peña LA, Smith JA, Martinez SR, Bacarian T, Tammam J, Ren B, Farmer PM, Kalef-Ezra J, Micca PL, Nawrocky MM, Niederer JA, Recksiek FP, Fuchs A, Rosen EM. Response of rat intracranial 9L gliosarcoma to microbeam radiation therapy. Neuro-Oncol 2002; 4: 26-38. 14. Dilmanian FA, Morris GM, Zhong N, Bacarian T, Hainfeld JF, Kalef-Ezra J, Brewington LJ, Tammam J, Rosen EM. (2003) Murine EMT-6 carcinoma: high therapeutic efficacy of microbeam radiation therapy. Radiat Res 159: 632-641. 15. Dilmanian FA, Qu Y, Liu S, Cool CD, Gilbert J, Hainfeld JF, Kruse CA, Laterra J, Lenihan D, Nawrocky MM, Pappas G, Sze C-I, Yuasa T, Zhong N, Zhong Z, McDonald JW. X-ray microbeams: Tumor therapy and central nervous system research. Nucl Instr Meth Physics Res A 2005; 548: 30-37. 16. Laissue JA, Spanne P, Dilmanian FA, Nawrocky MM, Gebbers J-O, Slatkin DN, Joel DD: Mikrobestrahlung von Gliosarkomen der Ratte: Zell- und Gewebeläsionen (Microbeam irradiation of rat gliosarcomas: Cell and tissue lesions). Schweiz med Wochenschr 1995; 125:1887. 17. Laissue JA, Geiser G, Spanne PO, Dilmanian FA, Gebbers JO, Geiser M, Wu XY, Makar MS, Micca PL, Nawrocky MM, Joel DD, Slatkin DN. Neuropathology of ablation of rat gliosarcomas and contiguous brain tissues using a microplanar beam of synchrotron-wiggler-generated X rays. Int J Cancer 1998; 78: 654-660. 18. Laissue JA, Lyubimova N, Wagner HP, Archer DW, Slatkin DN, Di Michiel M, Nemoz C, Renier M, Brauer E, Spanne PO, Gebbers JO, Dixon K, Blattmann H. Microbeam radiation therapy. Proc SPIE 1999; 3770: 38-45. . 19. Laissue JA, Blattmann H, Di Michiel M, Slatkin DN, Lyubimova N, Guzman R, Zimmermann W, Birrer S, Bley T, Kircher P, Stettler R, Fatzer R, Jaggy A, Smilowitz HM, Brauer E, Bravin A, Le Duc G, Nemoz C, Renier M, Thomlinson W, Stepanek J, Wagner HP. The weanling piglet cerebellum: a surrogate for tolerance to MRT (microbeam radiation therapy) in pediatric neuro-oncology. Proc SPIE 2001; 4508: 65-73. 20. Miura M, Blattmann H, Bräuer-Krisch E, Bravin A, Hanson AL, Nawrocky MM, Micca PL, Slatkin DN, Laissue JA. Radiosurgical palliation of aggressive murine SCCVII squamous cell carcinomas using synchrotron-generated X-ray microbeams. Br J Radiol 2006; 79: 71-75. 21. Schweizer PM, Spanne P, Di Michiel M, Jauch U, Blattmann H, Laissue JA: Tissue lesions caused by microplanar beams of synchrotron-generated x-rays in Drosophila melanogaster. Int J Radiat Biol 2000; 76 (4): 567-574. 22. Serduc R, Vérant P, Vial J-C, Farion R, Rocas L, Rémy C, Fadlallah T, Bräuer E, Bravin A, Laissue J, Blattmann H, van der Sanden B. In vivo two-photon microscopy study of short term effects of microbeam irradiation on normal mouse brain microvasculature . Int J Radiat Oncol Biol Phys; 2006; 64 (5):1519-1527. 23. Slatkin DN, Dilmanian FA, Nawrocky MM, Spanne P, Gebbers J-O, Archer DW, Laissue JA. Design of a multislit, variable width collimator for microplanar beam radiotherapy. Rev Sci Instrum 1995; 66:1459-1460. 24. Slatkin DN, Spanne P, Dilmanian FA, Gebbers JO, Laissue JA. Subacute neuropathological effects of microplanar beams of x-rays from a synchrotron wiggler. Proc Natl Acad Sci USA 1995; 92: 8783-8787. . 25. Smilowitz HM, Blattmann H, Bräuer-Krisch E, Bravin A, Di Michiel M, Gebbers J-O, Hanson AL, Lyubimova N, Slatkin DN, Stepanek J, Laissue JA. Synergy of gene-mediated immunoprophylaxis and microbeam radiation therapy (MRT) for advanced intracerebral rat 9L gliosarcomas. J Neurooncol 2006;78: 135-143. 26. Regnard P, Le Duc G, Bräuer-Krisch E, Troprès I, Siegbahn EA, Kusak A, Clair C, Bernard H, Dallery D, Laissue JA , Bravin A: Irradiation of intracerebral 9L gliosarcoma by a single array of microplanar X-ray beams from a synchrotron: balance between curing and sparing. Phys Med Biol 2008; 53: 861-878. 27. Serduc R, van de Looij Y, Francony G, Verdonck O, van der Sanden B, Laissue J, Farion R, Bräuer-Krisch E, Siegbahn EA, Bravin A, Prezado Y, Segebarth C, Rémy C, Lahrech H. Characterization and quantification of cerebral edema induced by synchrotron x-ray microbeam therapy. Phys Med Biol 2008; 53: 1153-1166.
..................
MRT-planning (similarities and differences with and between planning for therapy with photons, hadrons and MR) Authors: Blattmann Hans1, Kaser-Hotz Barbara2, Laissue Jean A.1, Rohrer Bley Carla2, Stepanek Jiri1, Bräuer-Krisch Elke3, Bravin Alberto3, Le Duc Géraldine3, Siegbahn Erik3, Hanson Albert L.4, Miura Michiko4, Slatkin Daniel N. 4
Affiliations: 1Institute of Pathology, University of Bern, Switzerland, 2Freie Universität Berlin, and Animal Oncology and Imaging Center, Switzerland, 3Medical Beamline, European Synchrotron Radiation Facility, Grenoble, France 4Brookhaven National Laboratory, Upton, New York; USA Keywords: MRT, treatment planning, dosimetry.
Abstract of the presentation by Hans Blattmann at the 'Syrad' workshop: New prospects for brain tumour radiotherapy: Synchrotron light and Microbeam Radiation Therapy, Grenoble, France, June 2-4, 2008. http://www.esrf.eu/events/conferences/Syrad/DetailedProgramme
Rationale and objectives:
Using established radiosurgical techniques, acute and delayed radiobiological responses of tissues are predictably dependent on the quality, the rate, and the density of ionisation energy imparted to them (i.e., radiation 'doses' and 'dose' rates). Although different kinds of tissue display various early and late responses to a given irradiation, whether the imparted dose be uniform or not, normal tissue reactions are predicted reliably for clinical radio-oncology by analysing overlays of dose distributions on serial tomographic images of the irradiated volume.
Treatment planning for MRT will be more complex. Microscopically contiguous cells in the same tissue may be exposed to drastically different doses. Unfamiliar tissue responses may be elicited by various microscopic dose distributions, depending on the organization of the tissue, its milieu intérieur, and its microvasculature. It is natural that we concentrate on the most obvious factors first. Radiation dose-response curves for cells grown in vitro have yielded relative biological effectivenesses (RBEs) applicable to broad-beam radiation therapies, including hadron and pion therapy. Since microscopically contiguous cells in the same tissue may be exposed to drastically different doses from microbeams, RBE data for MRT are needed more for vascularized normal vital animal tissues in vivo than for colonies of non-vascularized cells in vitro. Established treatment planning systems have to be checked on a regular basis by physical dosimetry. This is done in homogeneous phantoms, preferably with calibrated ionization chambers. While this technique is well established for photon, electron and proton irradiations, for hadron therapy absolute calibration, demanding and imprecise, remains elusive. For MRT, dose calibration is even more difficult, as precise physical microdosimetry is still under development. Even Monte-Carlo (MC) dose computations (1), so far the method of choice for MRT, should be provided with large error bars. Accordingly, an MRT treatment planning program for large animals will be developed in an iterative process.
Methods:
The most important single parameter responsible for tissue response to microbeams is believed to be the ‘valley’ dose. The valley dose will be calculated by MC calculation for microbeam exposures in a geometrical phantom, built up by solid tissue substitutes. The resulting dose distribution will be measured with radio-chromic films and at some locations with ionization chambers, to establish the relationship between calculated and measured dose.
For treatment of animal patients the valley dose is calculated in a simplified geometry, but taking into account volumes of significantly higher or lower x-ray absorption as bone or air. The calculated doses will be checked in a parallel plate phantom setup imitating the volume to be irradiated. If the starting dose for the dose escalation program is selected conservatively normal tissue damage will be avoided.
Results / Conclusion: The proposed course of action aims at making full use of the existing results from rodent and pig irradiations (2,3) and at the same time moving from the predominantly used exposures of around 28 µm beam width and 200 µm beam separation of small irradiation volumes to 50 µm beam width and 400 µm separation in significantly larger volumes.
References:
- Stepanek J et al, Physics study of microbeam radiation therapy with PSI-version of Monte Carlo code GEANT as a new computational tool. Med Phys 2000; 27: 1664-1675.
- Laissue JA et al, Microbeam radiation therapy. Proceedings of SPIE: 1999; 3770: 38-45.
- Laissue JA et al, The weanling piglet cerebellum: a surrogate for tolerance to MRT (microbeam radiation therapy) in pediatric neuro-oncology. Proceedings of SPIE 2001; 4508: 65-73.
Treatment of spontaneous tumors in pet animals as part of the development of a new radiation treatment modality. Kaser-Hotz B, Blattmann H, Laissue JA, Stepanek J, Bräuer-Krisch E, Bravin A, Le Duc G, Siegbahn E, Dilmanian A, Hanson AL, Miura M, Slatkin DN.
Abstract of the presentation by Barbara Kaser-Hotz at the 'Syrad' workshop: New prospects for brain tumour radiotherapy: Synchrotron light and Microbeam Radiation Therapy, Grenoble, France, June 2-4, 2008. http://www.esrf.eu/events/conferences/Syrad/DetailedProgramme
Rationale and objectives
Treatment of spontaneous (autochthonous) benign and malignant tumors in animal patients is considered a major step between experiments on laboratory animals and humans. The dimensional and physiological characteristics of spontaneous tumors of dogs and cats have more similarity to many human malignancies than implanted tumors of mice and rats. The biological response of tumors and normal tissues is dependent on the volume irradiated.
For MRT the radiation quality, i.e. peak to valley dose ratio (PVDR) is also volume dependent. Obviously, treatment of pet animals involves a more heterogeneous treatment population and smaller numbers of animals can be included into a study. However, the model is more realistic and a closer follow up done by the owners can be done. An important aspect for the implementation of a new radio-oncology modality is the testing of all practical procedures, from treatment planning to follow up care.
Methods
Animal patients eligible are: Animals with a) small, superficial skin or subcutaneous tumors b) superficial benign or malignant tumors of the central nervous system d) other neoplasms to be considered individually. Six animals per group should suffice for a preliminary evaluation of normal tissue tolerance and sensitivity to MRT. A dose escalation will be performed, starting at a conservative dose, expected to produce no significant side effects. After an observation period of at least 6 months the dose will be escalated in small steps to determine the optimal dose.
Results
In the past, the treatment of dog patients with protons at Paul Scherer Institute, Villigen has contributed to the establishment of routine human patient treatment procedures. It has further shown that the spot scanning technique for protons, developed at PSI, was safe and did not lead to any unexpected biological response. Conclusion
The treatment of spontaneous animal tumors can be to the benefit of the animal treated and at the same time give valuable information for a safe start of a human patient program.
MRT-planning (similarities and differences with and between planning for therapy with photons, hadrons and MR). Blattmann H, Kaser-Hotz B, Laissue JA, Rohrer Bley C, Stepanek J, Bräuer-Krisch E, Bravin A, Le Duc G, Siegbahn E, Hanson AL, Miura M, Slatkin DN.
Abstract of the presentation by Hans Blattmann at the 'Syrad' workshop: New prospects for brain tumour radiotherapy: Synchrotron light and Microbeam Radiation Therapy, Grenoble, France, June 2-4, 2008. http://www.esrf.eu/events/conferences/Syrad/DetailedProgramme
Rationale and objectives:
Using established radiosurgical techniques, acute and delayed radiobiological responses of tissues are predictably dependent on the quality, the rate, and the density of ionisation energy imparted to them (i.e., radiation 'doses' and 'dose' rates). Although different kinds of tissue display various early and late responses to a given irradiation, whether the imparted dose be uniform or not, normal tissue reactions are predicted reliably for clinical radio-oncology by analysing overlays of dose distributions on serial tomographic images of the irradiated volume.
Treatment planning for MRT will be more complex. Microscopically contiguous cells in the same tissue may be exposed to drastically different doses. Unfamiliar tissue responses may be elicited by various microscopic dose distributions, depending on the organization of the tissue, its milieu intérieur, and its microvasculature. It is natural that we concentrate on the most obvious factors first. Radiation dose-response curves for cells grown in vitro have yielded relative biological effectivenesses (RBEs) applicable to broad-beam radiation therapies, including hadron and pion therapy. Since microscopically contiguous cells in the same tissue may be exposed to drastically different doses from microbeams, RBE data for MRT are needed more for vascularized normal vital animal tissues in vivo than for colonies of non-vascularized cells in vitro.
Established treatment planning systems have to be checked on a regular basis by physical dosimetry. This is done in homogeneous phantoms, preferably with calibrated ionization chambers. While this technique is well established for photon, electron and proton irradiations, for hadron therapy absolute calibration, demanding and imprecise, remains elusive. For MRT, dose calibration is even more difficult, as precise physical microdosimetry is still under development. Even Monte-Carlo (MC) dose computations (1), so far the method of choice for MRT, should be provided with large error bars. Accordingly, an MRT treatment planning program for large animals will be developed in an iterative process.
Methods:
The most important single parameter responsible for tissue response to microbeams is believed to be the ‘valley’ dose. The valley dose will be calculated by MC calculation for microbeam exposures in a geometrical phantom, built up by solid tissue substitutes. The resulting dose distribution will be measured with radio-chromic films and at some locations with ionization chambers, to establish the relationship between calculated and measured dose.
For treatment of animal patients the valley dose is calculated in a simplified geometry, but taking into account volumes of significantly higher or lower x-ray absorption as bone or air. The calculated doses will be checked in a parallel plate phantom setup imitating the volume to be irradiated. If the starting dose for the dose escalation program is selected conservatively normal tissue damage will be avoided.
Results / Conclusion:
The proposed course of action aims at making full use of the existing results from rodent and pig irradiations (2,3) and at the same time moving from the predominantly used exposures of around 28 µm beam width and 200 µm beam separation of small irradiation volumes to 50 µm beam width and 400 µm separation in significantly larger volumes.
References:
- Stepanek J et al, Physics study of microbeam radiation therapy with PSI-version of Monte Carlo code GEANT as a new computational tool. Med Phys 2000; 27: 1664-1675.
- Laissue JA et al, Microbeam radiation therapy. Proceedings of SPIE: 1999; 3770: 38-45.
- Laissue JA et al,The weanling piglet cerebellum: a surrogate for tolerance toMRT (microbeam radiation therapy) in pediatric neuro-oncology.Proceedingsof SPIE 2001; 4508: 65-73.
=============
English translations of four reports on grid therapy (1909-1912) by Alban Köhler (born 1874 - died 1947):
Köhler A. Zur Röntgentiefentherapie mit Massendosen. Münchener medizinische Wochenschrift 56: 2314-2316, 1909. (Slatkin DN and Laissue JA. English translation. May 2005)
The author presented a lecture with a similar title at the Belgian Röntgen Society in Antwerp on May 30, 1909. It concerned the theory of a method designed to deliver doses to deep tumors that are about ten to twenty times greater than have been hitherto possible without damaging the overlying skin. The significance of the method for the treatment of deep malignancies should be obvious. The principle, which has been described in detail in "Fortschritten auf dem Gebiet der Röntgenstrahlen, Bd. 14, Heft 1" (Advances in the Applications of Roentgen Rays, Vol. 14, Part 1), could not be simpler; it is summarized here in a couple of sentences:
An X-ray tube with a very large cathode-ray hot-anode target area -- 4 to 8 times larger than usual -- produces very sharp shadows of a metal grid if the latter is positioned close to a photographic plate or fluoroscopic screen. However, if one distances the grid 4 to 5 centimeters from the plate and brings the tube to within a few centimeters of the grid, the shadows disappear and the plate is uniformly exposed, leaving no trace of the grid.
The implications of this for therapy are as follows. If one places a grid right on the skin overlying a several cm-deep malignancy and if an X- ray tube with a large target area is positioned only a few centimeters from the grid, the skin will be shielded underneath the metal and only irradiated through the grid's spaces, but the tumor will be irradiated evenly. If one applies this method to deliver a massive dose, for example tenfold greater than one full erythema dose, the resulting multiple foci of burned or necrotic skin - whatever the case may be - will be healed within a few weeks by surrounding surviving skin cells. Without the grid, the same dose would cause an extensive, continuous skin burn that would never heal, or would only heal with scarring many years later. X-ray tubes with such large targets must be made to order, as they make fuzzy radiographs and therefore can be used only for therapy. However, they are simpler to manufacture than are X-ray tubes with small, sharply focused target spots. This report also reflects ideas that I developed from the discussions that followed my Antwerp lecture. Whatever may come of the proposed method, the physical basis for it is not in doubt.
It should be stressed that misunderstanding of the method may result, for example, in poor placement of the grid. The grid must be on the skin, preferably pressed close to it. Moreover, for fundamental reasons indicated below, the most critical aspect of the system is a thin filter separating the grid from the skin. Only with that filter can cells beneath the metal strands remain entirely viable, enabling rapid healing of necrosis in their vicinity. An important question arises: In general, is it necessary to insert a thin filter (for example, of leather or aluminium) under the grid? Probably, one should reply confidently in the affirmative, in particular because skin cells under the metal are directly irradiated by the grid's secondary radiations. Although the smaller the atomic weights of absorbing substances, the softer and less penetrating are their secondary radiations, even secondaries from elements of high atomic weight such as lead or iron are so feeble that they can scarcely penetrate a thin sheet of paper. Nonetheless, secondary radiations from such metal strands, if generated by the equivalent of 10 to 20 primary-radiation erythema doses, could deliver enough dose immediately under the strands to damage skin cells not shielded by our thin-filter technique. Therefore it is recommended that one insert a thin filter between grid and skin to absorb all but a small, higher-energy portion of those secondaries. Furthermore, we gain another advantage by using a thin, light filter: it absorbs the preferentially skin-damaging soft portion of primary X rays that bypass the strands without absorbing a significant portion of those primaries of intermediate hardness that also act therapeutically at depth.
The shape and thickness of the metal strands of the grid and the size of the grid spaces were also considered during those discussions. It was recommended that the metal strands be triangular or rectangular - not circular - in cross section. The reasons for that are so clear that they need not be specified -- indeed so obvious that the author has already had such grids manufactured.
In metallurgy it is feasible to make grids of platinum or lead (those metals would appear to be the best) --- although even ordinary window screens might suffice. A filter made like the platinum upper screen of a Bunsen burner would have metal filaments too fine to shield the skin effectively, so I would prefer a different material. To be pressed against the skin, a grid should be as stiff as possible - another reason for choosing a different material. G. Schwarz** has recently shown that susceptibility of the skin to X-ray damage is reduced if one inhibits its metabolism, for example by direct pressure; the stiffer the grid, the more effectively could pressure be applied. Since thick platinum wires are very expensive, one should prefer a grid of iron wires. The somewhat smaller X- ray absorption coefficient of iron than platinum would be inconsequential.
Theoretically, it might be preferred that the metal strands of the grid not overlap; the grid could then be stamped from a metal sheet. In practice, however, not only should overlapping strands of metal cause no harm, they could even save areas of unshielded skin after the latter receive erythema doses intense enough to damage epidermal cells beneath non- overlapping strands. This provides all the more reason for not discounting the potential of islands of epidermis beneath overlapping strands of metal to remain intact after such irradiation to heal adjacent zones of skin necrosis. It is left for further investigation to judge what gauges of iron wire would be best for a grid. In the meantime, I have ordered a grid of 1 millimeter-wide wire with 2.5 x 2.5 square millimeter spaces between them from the firm of Reiniger, Gebbert, and Schall. So that grid and filter remain as close as possible to the skin --- on the trunk, minimally perturbed by breathing --- it is best if they are pressed so hard against the skin as to blanch it. This can be done, for example, using the cylindrical glass housing of an X-ray collimator.
Makers of Röntgen tubes all know that it is much less difficult to make tubes with a broad, rather than a precise, narrow cathode-ray target spot. This author was pleased to hear from a tube-maker during our conversation in Antwerp that fabrication of tubes with broad target spots was really a straightforward matter, involving no challenging steps. Moreover, I learned from an electricity technologist there that such tubes enable higher power to be used for therapy, so that if one doubled the size of the cathode, there could result a proportionate increase in the radiation dose rate --- which could also damage the tube. Alternatively, it has long been known that a tube can have several cathodes, which would be particularly advantageous for our method. If such a tube had a wide anode with three or four separate, broad target spots, its X-ray output would be intensified, which would likewise speed up our work - an appreciable advantage.
Several points should be mentioned about the stress on the tube. Even if the distance from tube to skin were minimized, it would still take 1 to 2 hours to deliver 10 to 15 full erythema doses. One would wish that to be quicker, which would overload the tube somewhat; an overloaded tube would of course soon be weakened to the point of uselessness. With its vacuum compromised, such a tube could not deliver an exact dose -- and one would not want a 10- to 15-fold increase of dose to be inexact by more than one- half of a full erythema dose. A solution would be to wire several tubes in series and position them securely in their housings; with collimators close to grid and filter, it would be unimportant if individual tubes were not perfectly aligned toward the same target. Alternatively, one could implement the author's deep-irradiation technique by using several readily available Röntgen tubes. Each tube, having a small target spot, would be aligned and centered individually in a common housing. Other improvements might be to operate four of the ordinary tubes at the same distance from the skin . and so on. It goes without saying that this method, which can be simple, should not be made more complex needlessly. For example, the deeper the irradiation target, the less is it required that the target spot be extra-large, so even an ordinary Röntgen tube could be used confidently to use the grid technique for a 10 centimenter-deep lung tumor.
An objection to the method was voiced during the aforementioned discussions which, at first, appeared reasonable: the grid itself cuts down considerably on a dose intended to be delivered at depth. For example, about half of the incident radiation on a grid with 1 millimeter-wide wires and 2.5 millimeter-square holes would be blocked. To compensate for that, the unshielded zones of skin would have to receive double the dose they would receive without the grid. Strictly speaking, the facts underlying that objection are true, but it should not be accepted unreservedly. With a grid, unshielded zones of skin can receive 10 to 20 times the dose deliverable to unshielded skin because strands of shielded cells surround each hole; without a grid, such doses could not be delivered. Even with thinner wires and much larger holes, rapid healing of many small zones of skin would follow. Should a problem of non-healing skin arise, it could be addressed by constructing tubes with several special, large cathodes or with several small cathodes per tube.
We now turn to matters of biology. It is known that necrotic or ulcerated zones of skin are prone to infection, which would lead to destruction of zones of remaining viable skin cells and subsequent confluence of those zones to form an extensive, non-healing skin ulcer. Since that could indeed occur, the radiologist must thoroughly disinfect the irradiated zone and, immediately after the irradiation, bandage it to keep it so until it heals. Should that prove insufficient to prevent an infection the grid could be made of thicker wires, but the grid method should not fail on that account in any case.
The restriction that a grid irradiation cannot be repeated is quite beside the point. If one can increase a dose 20-fold using this method, one will have achieved very much more than what has been achieved to date by delivering a maximum tolerable dose in fractions. Moreover, there are a number of regions in the body (breast, bones of the extremities, and such) that can be irradiated from 3 or 4 different directions. Granted, a zone of the skin once stressed by this grid technique cannot be so stressed ever again, but since this technique permits delivery of an enormous total dose, perhaps 40 times greater than has been possible to date, one should be encouraged by its development. That said, however, the radiotherapist should remain vigilant --- aware of the importance of sufficient shielding of the surrounding tissues, even of the whole body, from such large doses of X rays.
Animal experiments have been initiated, but for a number of reasons I don't have much to say in their favour. I have decided that my primary obligation is to apply this method as soon as possible to treat malignancies that are likely to kill a patient within several months.
In summary, I concede that this grid method carries some disadvantages with its advantages, as do all kinds of therapy. Among its advantages are: delivery of massive doses, relatively short exposure times, and (even with filters and compression) straightforward implementation. Those compensate for its few disadvantages, the most important being the risk of losing potentially healing strands of cells to infection --- the likelihood of which is lessened by using aseptic techniques.
**Gottwald Schwarz (1880-1959)
...............
Alban Köhler. "Une nouvelle méthode permettant de faire agir, dans la profondeur des tissues, de hautes doses de rayons Roentgen et un moyen nouveau de protection contre les radiodermites" (A new method to deliver high doses of Roentgen rays to deep tissues and to mitigate radiation dermatitis.) Annales d'Électrobiologie et de Radiologie 10, 661-664, 1909. (Slatkin DN and Laissue JA. English translation. December 2006)
Previously, radiologists who wanted to deliver a high dose of Roentgen rays to tissues several centimeters deep faced a Hobson's choice. Delivering a high dose of unfiltered Roentgen rays to deep tissues caused intractable skin ulcers. Although filtration of the rays enabled deeper penetration, it deprived them of almost all their therapeutic efficacy - to such an extent that, in a good many cases, cell division seemed to be stimulated instead of inhibited or stopped by them.
Recently, various studies have been directed toward alleviating these problems by irradiating from a great distance, but they are not yet ready for evaluation; certainly, it should be understood that any such technique could, at best, only partially improve the efficacy of these radiations. However, were it possible to deliver doses to deep tissues 10-15 times greater than are achievable at present without exposing patients to the concomitant risk of intractable skin ulcers, that would obviously supersede existing methods, especially if greater simplicity and convenience counted among its advantages.
I now submit the following method for consideration; I have been led to it by experiments that, so far, have not been designed to test its therapeutic efficacy but rather to investigate analogous setups in roentgenography.
If one puts a 1- to 2-millimeter-mesh grid of metal wires on a photographic plate and exposes the assembly to X rays from a cathode-ray tube [CRT], of course one gets a distinct photographic image of the grid. However, if one distances that grid about 20 centimeters from the plate, parallel to it, then positions the CRT close behind the former, one gets only a very hazy grid image; if one then proceeds to distance the grid 40 or 50 centimeters from the plate, one no longer obtains any grid image - not even the least indication of it; the radiosensitive layer of the plate is uniformly darkened as if there were nothing to block X rays between the CRT and the plate.
The reason for this effect is well known by now: Investigations of the physical properties of Roentgen rays show, in brief, that the effect does not involve refraction or diffraction, but simply depends on the design of the CRT's focus. In ordinary CRTs, the focal zone on which the convergent cathode rays impact is, of course, not a geometric point but rather a circle of greater or lesser diameter, usually 1 to 5 mm. (One should note, however that so-called precision CRTs have much smaller focal zones.) Thus, to obtain equal, constant darkening of the plate, i.e., disappearance of any trace of the grid, for a given distance from CRT to metal grid, the closer the grid to the plate, the larger should be the CRT's focal zone.
For therapeutic applications, the corollaries of those simple, well- known observations are as follows: First, a small focal zone, so important in roentgenography, is of course unnecessary for Roentgen-ray therapy. Suppose one had an appropriate CRT with a large focal zone, say 1.0 - 1.5 cm in diameter. Suppose also that one selected a metal grid - either a grid of ordinary iron wire or, better, a mesh of lead or, best, of platinum wire - and applied it directly to the skin or to a thin leather filter on the skin; the CRT is positioned several centimeters from the grid. If we so irradiate the surface of the grid, we will achieve constant, uniform irradiation of tissue at a certain tissue depth - as homogeneous as if there were no metal grid between CRT and deep tissue.
Moreover, having that grid on the skin surface enables the delivery of enormous doses of X rays to deep tissues in comparison with those possible to date, without risk of non-healing ulcers or of nearly incurable radiodermatitis. Whereas each cell is homogeneously irradiated in deep tissue, for example in a deep tumor, X rays penetrate the skin only between the grid elements, so cells directly under the metal grid elements remain, in effect, intact.
With large doses, the skin between the grid elements is certainly subject to erythema and necrosis, but those lesions are spontaneously repaired within a few weeks because individual zones of necrosis are surrounded on each side by a narrow slice of healthy, well vascularized tissue. An analogous method is already established in surgery where, for example, one treats an angioma by thermocautery; as is well known, the many eschars that result are healed rapidly. The conditions for healing such deep eschars are not as favorable after grid-mediated radiotherapy as after thermocautery. Nevertheless, the principles of those techniques are analogous. In any case, it is much better to reduce radiodermatitis by using a metallic grid than to cause large, deep ulcers by exceptionally high X-ray doses delivered without a grid.
The question of knowing how many times more intense the irradiation may be with than without a metallic grid is difficult to answer; it depends, to a certain extent, on what kind of metal is used to make the strands of the grid and on their thickness. Thus, as many as one hundred erythema doses* might be needed to elicit necrosis of skin cells shielded by such strands of metal, and perhaps as many as fifty erythema doses might be needed to cause any visible lesions at all in zones of skin so shielded. Using approximately fifteen-fold greater erythema doses to unshielded than to shielded skin cells, the skin recovers so well that radiation damage may be discounted entirely. Although this leaves metal-shielded tissues apparently unaffected by the irradiation, it is not absolutely certain that such doses will allow necroses in exposed zones to heal readily. Based on my preliminary studies, it seems wise in practice to use not more than ten erythema doses. More detailed experiments will establish exactly how extendable that dose limit may be.
I have not yet had a chance to practice this technique. However, since the procedure I have outlined here is based on simple and precise physical and biological phenomena, there is no doubt that its practical value will be recognized some day. By then, animal studies will have shown whether doses that are twenty-fold or even fifty-fold greater than those allowed currently can cause skin damage too severe to be justifiable by the benefits of their efficacy for deep lesions. For the first clinical trials, one should be able to enlist patients in whom a laparotomy will have already revealed an inoperable malignant tumor.
This method appears to have no disadvantage other than causing minuscule zones of necrosis, already described. On the other hand, it has the following advantages in addition to those already mentioned: Fundamentally, the method depends on irradiating at a very short distance, which will allow much shorter exposure times than those used at present. For example, for a distance of 5 cm between the glass wall of a 15 centimeter-diameter CRT and the skin surface (i.e., 7.5 + 5 cm from focal zone to skin), one gets a 16-fold stronger X-ray effect than would be obtained during the same exposure time with the CRT distanced 50 cm from the skin.
Another advantage of my method is that it allows X-ray-energy filters to be used just as well as in older methods. Any kind of filter may be placed underneath the metal grid1; leather filters are recommended in particular. It would be advantageous to apply some pressure to the grid against the filter, either with a diaphragm or with the leaded-glass cylindrical tubes used for the radiotherapy. Finally, one can augment the method's effectiveness by irradiating from various directions. In this way, one can treat a deep lesion, for example a sarcoma of the thigh, with exceptionally high doses by directing X rays toward four different sides of it in succession.
Another aspect is that the metal grid is of value in protection against skin burns from irradiation of superficial lesions, particularly for inexperienced technologists not yet certain of the doses they are delivering. Using the grid, an overdose that causes an ulcer or a zone of necrosis should be healed very rapidly. Using this method, irradiations of lesions in patients with blood dyscrasias should also become less dangerous. In therapy of cutaneous lesions, however, it should be kept in mind that zones of skin underneath metal strands will not be treated. It is not certain that cells exposed to X rays traversing the spaces of the grid, having received intense radiation, might have a palliative effect on unexposed cells; judging from certain well-known phenomena, that would not be impossible, but experiments will decide the question. Neither should it be forgotten, in using the method for benign lesions of the face, that one should carefully avoid causing a gridlike pattern of pigmentation in exposed areas.
1 It is especially advisable to use filters to block secondary radiations originating in the metal strands of the grid.
*Translators' note: In 1909, one 'erythema dose' was considered to be the minimum exposure to X rays that resulted in skin erythema. One 'erythema dose' is now considered to have represented a dose of from 2 to 5 gray, depending on the types of X-ray tubes and radiation filters used at a hospital, on the different susceptibilities to erythema of patients typically treated there, and on the different kinds and concentrations of pigment in areas of their skin exposed to X rays.
......................
Theorie einer Methode, bisher unmöglich unwendbar hohe Dosen Röntgenstrahlen in der Tiefe des Gewebes zur therapeutischen Wirksamkeit zu bringen ohne schwere Schädigung des Patienten, zugleich eine Methode des Schutzes gegen Röntgenverbrennung überhaupt. Von Dr. Alban Köhler - Wiesbaden
(Slatkin DN. and Laissue JA, English translation, October 2, 2008): Dr. Alban Köhler - Wiesbaden (Germany). Theory of a method that permits penetration of therapeutically effective roentgen rays in hitherto dangerously high doses deep in tissue without severe sequelae, including a special method of protection against radiation burns. Fortschritte auf dem Gebiete der Röntgenstrahlen 14: 27-29, 1909.
There are two main factors that have made it impossible so far to use high doses of roentgen rays therapeutically several centimeters deep in tissue: achieving desired doses in deep tissues by irradiating without a filter causes severe, intractable skin ulcers; filtration indeed does allow roentgen rays to penetrate tissues deeply, but only in doses so weak that, in many cases, they stimulate rather than inhibit cell growth. It is still unknown whether recently announced efforts to rectify those problems by irradiating from a greater distance will succeed, but they could only improve the therapy slightly, at best. If a method were developed that increased deep doses tenfold or, possibly, fifty-fold without causing a non-healing skin ulcer, it would certainly be preferred to existing techniques, especially if it were simpler and more convenient. The following is intended to describe a method developed by the author's experiments, which were admittedly not originally intended to improve roentgen-ray therapy, but rather aimed toward improving photographic apertures for roentgen-ray imaging.
If one puts a 1- to 2-millimeter-mesh grid of metal wires on a photographic plate and exposes the assembly to roentgen rays, of course one gets a very sharp image of the grid. However, if one takes the same grid about 20 centimeters away from, yet parallel to the plate, then exposes the photographic plate to roentgen rays from an ordinary roentgen tube positioned immediately behind the grid, one obtains only a very fuzzy image of the grid on the plate; if one then takes the grid about 40-50 cm from the plate and again positions the tube immediately behind it as described, not only does the plate fail to capture a shadow of the grid, but not even does the slightest trace of it remain. Instead, the plate is entirely and uniformly blackened, as if there were no sieve-like obstacle between tube and plate whatsoever. We know of no reason for such an effect on the basis of roentgen-ray physics; neither refraction nor diffraction could have been involved. Instead, that effect depends only on the spot impacted by cathode rays in the roentgen tube. One knows that in an ordinary roentgen tube, the zone of the anticathode impacted by convergent cathode rays is not the smallest spot achievable, but usually a circular spot more or less 1 to 5 mm in diameter. In contrast, so-called 'precision tubes' are characterized by the smallest possible cathode-ray impact spots. To achieve uniform darkening of a plate situated at a certain distance from the tube, i.e., to darken it so any trace of the grid is eliminated, the closer the grid to the plate, the larger must be an anticathode's impact spot.
For therapeutic applications, the corollaries of those simple principles are as follows: First, a small anticathode impact zone, so important in roentgenography, is of course unnecessary for roentgen-ray therapy. Suppose one had a tube manufactured specifically for therapy with a large impact zone, say 1.0 - 1.5 cm in diameter. Suppose also that one selects a metal grid - either a grid of ordinary iron wire or, better, a mesh of lead or, best, of platinum wire - and applies it directly to the skin or to a thin leather filter on the skin. We now position our tube several centimeters from the grid. If we then irradiate the surface of the grid, we will achieve constant, uniform irradiation of tissue at a certain tissue depth - as homogeneous an irradiation as could be achieved with no metal grid between the tube and deep tissues. Moreover, having that grid on the skin surface enables the delivery of roentgen rays to deep tissues in doses that are much higher than those possible at present without the risk of inducing a poorly healing ulcer. Whereas each cell, whether in normal tissue or in tumor, is irradiated similarly at depth, only the skin beneath the grid's spaces is significantly irradiated, leaving skin cells directly beneath the grid's metal wires essentially intact. Admittedly, the skin between the grid elements is burned or necrotized by severe roentgen-ray overdosing, but it is repaired within several weeks because each small, necrotic zone of it is enclosed by a continuous wall of tissue containing viable cells and viable segments of blood vessels.
A comparable method is already established in surgery when, for example, we treat an angioma by punctiform thermocautery using the Paquelin apparatus. We know how fast the resultant scabs heal. Although conditions for healing deep necrotic tissues after grid-mediated roentgen therapy are not as favorable as those for healing tissues after punctiform thermocautery, they are analogous. In any case, the relatively little harm from grid-mediated roentgen therapy causing punctiform necrosis would not be comparable to the severe harm from roentgen-ray overdosing without protection from a metallic grid causing very extensive, deep skin ulceration.
The question of knowing how many times more intense irradiation could be applied with than without a metallic grid is difficult to answer; it depends to a certain extent on what kind of metal is used to make the strands of the grid and on the strands' thicknesses. Thus, it might take no less than one hundred erythema doses to kill skin cells shielded by such strands of metal, and perhaps no less than fifty erythema doses to visibly injure any zone of the skin so shielded at all. Approximately fifteen erythema doses would leave skin cells so robust in such numbers that side effects of the irradiation would be practically undetected. It is however not inconceivable that even fifty erythema doses applied to the grid would damage tissue directly under its metallic threads so slightly that necroses in the exposed skin would soon be healed. Nevertheless, for the initial trials, it is recommended that one should not exceed ten erythema doses. How much higher doses could be would become clear from more extensive studies.
The author has not yet had an opportunity to test this method clinically. However, the theory of the method is based on simple physical and biological principles, so its applicability to practice is beyond doubt. Besides that, animal studies could indicate if skin damage caused by using 20 to 50 erythema doses might outweigh the benefit achieved by using those doses for deep lesions. Initial applications to humans could be implemented, for example, for malignant, inoperable tumors confidently identified as such at laparotomy beforehand.
This method appears to carry no disadvantage to the patient other than causing minuscule zones of necrosis, already described. On the other hand, it has the following advantages in addition to those already mentioned: Fundamentally, the method depends on irradiating at a very short distance, which will allow much shorter exposure times than those used at present. For example, for a distance of 5 cm between the glass wall of a 15 cm-diameter roentgen-ray tube and the skin surface (i.e., 7.5 + 5 cm from the anticathode's impact zone to the skin), one achieves a 16-fold stronger roentgen-ray dose than that achieved during the same exposure time with the tube positioned 50 cm away from the skin.
Another advantage of my method is that it allows roentgen-ray-energy filters to be used just as effectively as they were before. Any kind of filter may be placed underneath the metal grid*; leather filters are recommended in particular. It would be advantageous to apply some pressure to the grid against the filter, either with a diaphragm or with the leaded-glass cylindrical tubes used for the radiotherapy. Finally, one can increase the method's effectiveness by irradiating from several directions. That would enable treatment of a deep lesion, a sarcoma of the thigh for example, with exceptionally high doses by directing roentgen rays toward four different sides of it in succession.
Another consideration is that the metal grid is of value in protection against skin burns from irradiation of superficial lesions, particularly for inexperienced technologists not yet certain of the doses they are delivering. Using the grid, an overdose that causes an ulcer or a zone of necrosis should be healed very rapidly. Using this method, irradiations of lesions in patients with blood dyscrasias should also become less dangerous. In therapy of cutaneous lesions, however, it should be kept in mind that zones of skin underneath metal strands will not be treated. It is not certain that cells exposed to roentgen rays traversing the spaces of the grid, having received intense radiation, might have a palliative effect on unexposed cells; judging from certain well-known phenomena, that would not be impossible, but practice will decide the question. Using the method for benign lesions of the face is not advisable, as it could cause a gridlike pattern of indelible pigmentation in exposed areas.
(To implement the method described above, the firm Reiniger, Gebbert & Schall, Erlangen, upon order, will deliver a tube with the largest possible anticathode impact zone.)
*It is especially advisable to use filters to block secondary radiations originating in the metal strands of the grid.
...................
Dr. A. Köhler (Wiesbaden). Deep X-ray Therapy Through a Protective Metal Screen. (Report III: Clinical Applications). Strahlentherapie 1, 121-131, 1912.
Before describing the most important clinical applications of the author's method for high-dose radiotherapy of deep lesions, one should first explain not only the requirements for it to be considered a rational technique but also the most important factors and developments about it that have come to light since the method was first disclosed.
Anyone with basic knowledge of radiotherapy, even a beginner, should understand that most X rays are absorbed in superficial tissues: theoretically, only a small percentage of them are therapeutically effective more than several centimeters deep. Further, it has been shown and is generally understood that a small dose of X rays is physiologically inconsequential, that an intermediate dose may either inhibit or stimulate actively growing tissues, including tumors, and that only a high dose retards tumor or other pathologic growths enough to initiate some healing and palliate the patient. Therefore, to be therapeutically effective, one would have to deliver a much greater dose to the skin or mucous membrane in the radiation-entrance zone overlying a centimeters-deep tumor than to the tumor itself. Although an exposure of 4 skin-erythema doses [EDs] would be therapeutically effective for a tumor only a few centimeters deep, that radiation dose would also cause radiogenic inflammation of the skin, resistant to therapy. However, the much greater incident dose required to arrest the growth of a considerably deeper tumor would certainly elicit frank cutaneous and subcutaneous necrosis - ultimately, a non-healing radiogenic ulcer.
For a rational, new deep-tumor irradiation technique to be accepted, it must at least damage a tumor without causing irreversible necrosis of the skin over it. Thin leather and metal filters have been tested to achieve this on the presumption that at least one of them might be helpful. Knowing that an X-ray tube emits a mixture of radiations that penetrate to different depths, one reasoned as follows: the radiations that injure the bare human skin would be absorbed by a thin, protective leather filter - i.e., the bare skin of another animal - while the radiations that penetrate deep beneath the skin obviously could not be absorbed by either the overlying leather filter or the skin. However, the reasoning whereby so-called 'filter-protected' skin might not be burned by such radiation is untenable. Indeed, the author employed such a technique of X-ray therapy in the early days of his practice and nearly caused a terrible skin burn. Although 'filter-protected' skin is not assuredly protected from radiation dermatitis, nevertheless it appears that leather filters may provide several theoretical and practical advantages for treatment of some very radiosensitive tissues, even deep ones (e.g., lymph nodes, spleen, bone marrow, ovaries). However, leather is of little use for X-ray therapy of most deep malignant tumors.
Another technique for radiotherapy of deep lesions is to increase the focal distance from the X-ray tube, i.e., the distance from the impact of its cathode rays on its anticathode to the surface of the irradiated skin. At a certain theoretical level, that might seem somewhat convincing; i.e., the greater that distance, the less the importance would be the distinction between the first centimeter and the first decimeter of penetration in tissue. On deeper analysis, however, irradiating from a large distance appears less reasonable than irradiating from a short distance because a much more important factor has to be considered: the duration of irradiation. For example, a sixfold increase in focal distance would necessitate a clinically unacceptable exposure time, extended 36-fold. Not only would the doctor's valuable time be wasted, but the patient's discomfort would also be prolonged excessively. Moreover, the cost to a clinic of replacing so many more worn-out X-ray tubes would be unaffordable. Even so, those disadvantages would be taken in stride if the technique really worked: 'Salus aegroti summa lex' - 'the welfare of the patient is the highest priority.' The long-range irradiation technique, unfortunately, is not merely inconvenient, it is not even effective. Actually, employing a one-meter focal distance to treat a deep malignant tumor is malignant to the patient but not to the tumor: the requisite 3-4 hour exposure would only stimulate the tumor to grow without the slightest promise of its ablation. If the foregoing reasoning is faulty, then the world's accumulated knowledge about physiological and biological effects of X rays must be faulty, too.
An alternative technique to bring therapeutically effective radiation to a deep tumor is to spread out the exposure on the skin, irradiating the tumor from different angles, whether in one or several successive treatment sessions. Examples: A femoral sarcoma can be irradiated from four different sides of the thigh. A pituitary tumor can be irradiated from over a dozen different angles. Another good step forward was enabled by G. Schwarz's finding that compressed, blanched skin is less sensitive to damage from X rays than is normally perfused skin. Accordingly, one should blanch the skin during its exposure to X rays, either by direct compression using a piece of radiolucent wood or an inflated rubber balloon, by preinjection of adrenaline, etc.
The situation remains that one would wish tenfold more dose several centimeters deep in tissue than can be achieved at present, even by combining two or three existing techniques that aim to achieve deep X-ray therapy. Again and again, unacceptable skin damage prevents progress. That's why, for example, Czerny and Werner's proposal to expose inoperable tumors, then sew them into the skin incision for ablation by X rays has fallen into disfavor. One must pursue a new, significantly different strategy for X-ray therapy of deep, surgically inoperable tumors - perhaps using the metal-screen method implemented by the procedure described below. The author did not invent that method while searching for better treatment of deep tumors. Rather, its principle emerged during the author's months-long, unsuccessful, unpublished attempts to improve irradiation apertures for roentgenography. The principle is as follows:
It is well known that one will obtain a very sharp image of a metal screen with 1- to 2-mm holes if it is placed directly on a photographic plate and exposed to X rays. However, if one displaces the screen about 20 cm away from and parallel to a photographic plate, then irradiates the screen from an ordinary X-ray tube placed just behind it, at best only a very blurry image of the screen will appear on the plate; using most tubes, no screen image will be seen at all: instead, the plate will be completely and uniformly darkened. The reason for these observations is known. The physics of roentgenography teaches one that neither reflection nor refraction of X rays comes into play; instead, the effect depends entirely on the focal zone on the anticathode of the X-ray tube. In common X-ray tubes, cathode rays do not converge to a tiny point on the anticathode, but to a roughly circular zone on it, usually 1 to 5 mm in diameter. For a given distance from the X-ray tube to the metal screen, the less the displacement of the photographic plate from the screen, the bigger must be the impact zone of cathode rays on the anticathode to uniformly darken the plate, i.e., to completely eliminate the screen's image in a roentgenograph.
If one wishes to apply the foregoing observations to roentgenotherapy, the following ideas emerge: the smallest possible anticathode impact point is the best for roentgenography, but the worst for roentgenotherapy. For the latter, one should use a tube with an anticathode focal point of substantial area, roughly 1 to 2 cm in diameter. Moreover, one should place a protective screen with approximately 2 mm-wide holes directly on the skin or on an intervening thin leather filter - the screen woven with sufficiently thick metal strands, e.g., about 1 mm in diameter. An X-ray tube with a large anticathode focus zone should be placed only a few cm away from the protective metal screen. If one uses such a setup, tissues are uniformly irradiated to a considerable depth beneath the skin, almost as uniformly as if there were no metal screen between the tube and the targeted tissue. Advantageously, the metal screen allows an enormous, unprecedented radiation dose to be delivered to a deep tumor without causing an intractable radiogenic skin ulcer. Whereas tumor cells several cm deep to the skin are irradiated evenly, only skin cells exposed through the screen's holes are irradiated; skin cells immediately under the screen's metal strands remain undamaged. Although multiple zones of skin exposed through the screen's holes are burned and become necrotic, those zones are healed several weeks later because each necrotic zone is enclosed by a divider of healthy cells and blood vessels. Severe damage to the skin - e.g., a large, intractable ulcer caused by Roentgen-ray overdosing without a protective metal screen, is not comparable with the slight, transient, punctiform skin lesions associated with metal-screen therapy.
To apply the technique in practice, the procedures described below are recommended: it is not required, neither is it even feasible to expose the patient to a Roentgen tube with a wide anticathode focal zone for 5-8 minutes using a current of 2-4 mA, because six such tubes would be required for each treatment. Not even the busiest roentgenotherapy institute could afford them. However, a surprising simplification of the method has been developed to implement the technique somewhat differently, yet economically and effectively.
One selects an ordinary Roentgen tube - one used for roentgenography - and turns it on during the first exposure of the treatment until its glass wall begins to soften. A second ordinary tube is then used similarly for the second exposure, and a third, fourth, fifth, sixth, etc., … so that each tube is turned on for successive exposures of the treatment, using as many ordinary Roentgen tubes as one has available for the treatment. Each time a different Roentgen tube replaces the previous one in the Pb-shielded aperture box, its focal point is placed a few millimeters (with respect to the aperture) from the previous one. For example, if one uses six tubes, each positioned with its small anticathode focal point several millimeters from that of the others, the overall distribution of their combined radiations at depth will be the same as if one had used only one tube with a very large focal point repeatedly. Thus, although having only one aperture box allows only one ordinary Roentgen tube at a time to be oriented toward the aperture using three adjustment blocks (designed by Gocht), that strategy enables irradiation from many tubes oriented slightly differently, as desired, because the focus zone of any particular tube can hardly ever be reoriented identically toward an aperture in the same shielded box with mathematical precision, as one can learn from any manufacturer of Roentgen-ray equipment. This enables an enormous simplification of the technique.
Furthermore, if one uses an iron screen that is so stiff as to be virtually unbendable, it can compress the skin almost to bloodlessness*; for this, either the aperture box or the leaded-glass tube itself can be pressed hard on the screen, but the screen should be first affixed to the skin at its edges with some adhesive, as it definitely must not move during irradiation. It is recommended that a very thin leather filter or tissue paper be placed under the metal screen to absorb the rather high dose from secondary radiations emitted by the screen's metal strands during high-dose therapy; this allows the skin under the strands to survive undamaged.
The fear has been expressed that the combination of mechanical pressure, radiation damage, and bacterial contamination would combine to cause intractable confluent suppurative necrosis, resulting in a large ulcer rather than transient punctiform necrosis of the skin. I'm not sure that such an outcome is likely, although it does seem possible. So, I take care to cleanse the irradiated skin aseptically - to date so thoroughly, it seems, that this complication has not arisen. Should it ever arise, i.e., if such a complication should became the rule and should there be no reliable method available to prevent it consistently, the writer would abandon the technique and advise others to do likewise even without knowing the reason for the problem, although there is little chance of that happening.
To criticize the method because one irradiates once, not repeatedly, is quite inappropriate. First, if one can use this method to deliver 10-15 times more dose than one can deliver otherwise, one can accomplish much more than can be accomplished any other way, for example by temporally fractionated X-ray therapy. Second, there are many parts of the body (e.g., breast tissues, limb bones, deep in the lungs, etc.) that can be irradiated from 3 or 4 different angles. Granted, a zone of the skin that has already been stressed by screen therapy once cannot be so stressed again, but one could derive profound satisfaction from delivering an enormous dose to a femoral sarcoma, for example in four separate exposures from four different angles.
One should also consider what happens to normal tissues proximal to a targeted tumor, especially because they absorb higher doses than does the tumor itself. In most situations, that problem is minor because of the relative radiation-resistance of muscle and adipose tissues vis-à-vis that of normal epithelial tissues: the method would be inconceivable without taking that radiation-resistance into account. On the other hand, I take the radiation-sensitivities of intestinal blood vessels and epithelia into account too; experience has shown that the those tissues are prone to severe injury from high doses of X rays. All aspects of the method that were taken into consideration during its implementation since it was introduced cannot be discussed here. Those interested in further theoretical details should read the two original communications1)
An exposure of 10 EDs lasts, on the average, 45 to 75 minutes. The practice of screen therapy turns out to be time-consuming. It must be obvious that delivery of a massive radiation dose cannot be implemented by the radiotherapist during consultation hours; at least 60 to 90 extra minutes are needed. Just as preparations must be made in advance for a surgical operation, preparations for screen therapy must be made in advance, too. Before the patient enters the treatment room, one lines up three to six of the best X-ray tubes available in a stand - from the one of highest strength downward. The higher the strengths of tubes selected for the treatment the better, since the overall time to treat a patient by a prescribed radiation dose should be as short as possible, each tube consuming as little energy as possible. One also selects a shielded Roentgen-tube box for the treatment having an aperture as wide as the greatest diameter of the tumor.
One should use longer X-ray tubes to treat tumors of the neck and axilla. For such cases, one should cut the screen about 2 cm wider than the tube. The screen is pushed against the skin covered by a filter about 3 mm wider than the screen so that the margins of the screen will not stick into the skin (the filter: very thin leather or two layers of tissue paper), using three or four strong, narrow adhesive strips: better, one should also turn the edges of the screen outward.
The dose is determined by using a high-voltage balance, then by referring to Walter's milliampere-minute [mA-min] tables (see "Fortschritte auf dem Gebiet der Röntgenstrahlen," Volume 4, pages 343-344). The high doses required by our treatment are not delivered more exactly than +/- 0.5 ED, accurate enough for this simple, forgiving treatment method. Suppose I referred to Table II and, for the initial exposure, chose a tube of 0.4 mm-thick glass and a strength of 5 BW (7 W). From Table II, 4 minutes of exposure at an 18 cm anticathode-to-skin focal distance with a tube current of 3 mA would deliver 1 ED (as, according to Table II, the same dose could be delivered at the same focal distance with a tube current of 1 mA during 12.3 minutes of exposure). Suppose I chose a second tube that could deliver 1 ED in 6 minutes with a current of 2 mA; a third that could deliver 1.5 ED in 6 minutes with a current of 3 mA; a fourth that could deliver … etc., etc. By repeatedly recording the irradiation parameters of the exposure from each tube and calculating the dose accumulated from all previous exposures, one can quickly plan the duration of exposure required of the following tube.
After that, the patient is prepared for the treatment: A wide zone in and around that to be irradiated is washed with soap then defatted with ether. Although it would not be necessary to cleanse the skin before the treatment, for the reasons stated above, cleansing would certainly be required afterwards. The patient is very carefully placed in the most comfortable possible position for the treatment using large and small cushions supported by sandbags. The patient must be given to understand that the position must be held, unchanged, for at least 45 minutes. Although even a slight twist or backward stretch of the neck can be most uncomfortable, in fact I have had no complaints from patients about their position. The screen, together with the filter (e.g., the thinnest available chamois leather, 2-3 layers of tissue paper, table napkin), is stretched out tightly on the skin and bound to it firmly using 2-4 strips of thin adhesive tape. After that, the X-ray tube's aperture box or its Pb shield is pressed hard enough against the screen so the latter cannot be moved.
Now something is mentioned that is very important but easily overlooked by a doctor using the technique for the first time: shielding the patient. Using an X-ray tube box with Pb walls, a Pb base, and an aperture in Pb through which ten or more EDs can delivered in one treatment, only minimal protection is provided, even for bystanders, especially if one uses the shortest possible anticathode-to-skin focal distance. Accordingly, one must place additional pieces of Pb shielding around the apparatus up to about 40 cm from it. Finally, the (robust) tube is turned on to start the irradiation, optimally stressed by a current of no more than 2 to 3 mA. Lower currents are not suitable because they might require two hours of exposure or more.
If one should become aware of something wrong with either the instrumentation, the tube holder, or the patient's position during the first 2 to 3 minutes of an exposure, there is still enough time to interrupt the irradiation and put things right; later, however, interrupting it can be done only if the adhesive plaster has stuck the screen tightly to the skin. After five to ten minutes of exposure, when the hot tube becomes perceptibly softer, one removes it from the aperture box and replaces it with the second tube. Since a tube can be shifted within the box to a some extent, the second tube is aligned to the aperture in the box about 1 cm farther to the right than was the first; later, the third tube is aligned to the aperture about 1 cm farther to the left than was the second; etc., etc. One proceeds in this manner, continuing to make note of each successively accumulated tumor dose until the desired total tumor dose has been delivered. If all the available tubes have been used, yet the desired dose has not been delivered, one reuses the first tube that had cooled off in the meantime.
Each time a tube is positioned in the box, its focal point is aligned with the center of the aperture slightly differently. It is immaterial that a tube cannot move in the aperture box after it had been stabilized by the three adjustment blocks because, as explained previously, the alignment of each successive tube in the box is deliberately not reproduced.
Just after the last exposure, of course, one notices nothing other than the physical imprint of the screen's pressure on the skin; the irradiated zone is then washed carefully again - without hard rubbing or such - then bandaged with thin muslin and adhesive plaster. The skin's reaction to its irradiation is noticed only after several days. It is recommended that one should check it at four days post therapy. Before each treatment, one should have explained to the patient that the irradiated zone would become a persistent, hard scar; this should be presented as a minor side effect so the patient might not hesitate to tolerate the lesser evil.
Animal experimentation had to be canceled at the last moment because the anesthesia injected did not immobilize the animal. Even a few muscle twitches should signal a halt to the procedure and postponement of the study. Moreover, one cannot expect a colleague to administer anesthesia to an animal for many hours near a Roentgen tube: just as a patient is protected by angling his/her recumbent body as far as possible away from the radiation source, so too should an anesthesiologist be kept as far away from it as possible.
Thus, the author has had to proceed with clinical tests of metal-screen therapy very slowly - gradually increasing radiation doses. Lacking sufficient clinical and hospital support, he has experience with only a few cases - to date, three cases in all, each with a very poor prognosis. He has had to handle these cases personally: neither he nor anyone else expected cures. Although only a few cases have been treated, and within the near future only a few more are expected to be treated, the benefits of high-dose treatments have been shown clearly superior to benefits expected from standard X-ray therapy of similar tumors up to now.
The salient features of these cases are as follows:
1. (Th. Nr. 208. J. G.) Recurrent cancer in the neck glands. 65 year-old man, well until 7 months ago, when a small tumor was noticed above his left clavicle, which soon grew to the size of a hen's egg. It was excised four months ago: microscopy showed a carcinoma. A similar excision was performed 4.5 weeks later but as soon as the patient left the hospital the tumor began to regrow rapidly, so the surgeon, deeming the tumor inoperable, prescribed mild X-ray therapy (10 exposures). At that stage the tumor was half the size of a child's head, occupying the entire (left) side of the patient's neck. A scar from the operation was noticed in the center of the skin over the tumor, which was discolored patchy purple. The skin was stuck tightly to the tumor and to the (left) clavicle. Neck circumference: 46 cm. The tumor was treated by screen therapy using several approximately 4 cm-diameter fields in succession at 1- to 10-day intervals: durations of exposure were increased gradually, so that the first field received 1 ED, the second, 2 EDs; the third, 4 EDs; the fourth, 5 EDs - the exposures totaling 227 mA-min, with no greater than 2- to 3-mA current during each exposure. These four exposures were implemented with different focal distances during 20, 38, 25, and 18 minutes, successively. Only the most intensely irradiated zone of skin showed any trace of the screen's pattern upon examination 4-5 days afterwards: later, the irradiated skin exhibited severe desquamation, but never necrosis. A report from the attending physician eight days after the final irradiation stated "It is greatly diminished; enormous shrinkage of the largest lumps of tumor forward of its center with even more shrinkage beneath that point. On account of distant metastases, however, the patient is not expected to survive much longer." Neck circumference: 41 cm - a reduction of 5 cm during eight days. A few days after the (last) exposure, the patient had experienced mild chills, which should be attributed to resorption of the tumor. The patient weakened gradually, but I had a chance to see him shortly before death. The tumor remained shrunken where it had been irradiated, but elsewhere in the neck it had grown toward the face and the occiput. There were many local metastases. Although the skin over the tumor appeared distinctly dark blue, traces of the screen were no longer seen on it.
2. (Th. Nr. 262. W. B.) Branchiogenic cancer. 49 year-old man. Five and one-half years ago, one side of the neck began to thicken and became fist-size soon thereafter. This was irradiated in his home town by 10 exposures to X rays, which shrank the growth. A recurrence of the growth later was treated with a very large dose of X rays. The irradiated skin then became severely inflamed; it never regained a normal appearance. Three and one-half weeks ago, the tumor enlarged suddenly. It was irradiated twice in succession; a small dose was delivered during each exposure. As there had been no response to the latter irradiations, he was referred to my office in Wiesbaden a couple of days before I examined him there: a large, sturdy, seemingly vigorous man presented himself. His urine sugar level was 1 part per 1000. There was an apple-size growth on the left side of his neck. The overlying skin was atrophied, with scattered telangiectasias and irregular pigmentation. One could palpate a tri-lobed tumor, two lobes of which each seemed the size of a duck egg; the lobe under them seemed somewhat smaller. Clinical diagnosis: "Lymphosarcoma or carcinoma." Screen therapy was implemented - one zone with 4 EDs, another zone with 6 EDs, another with 3 EDs, and between those three zones, another three central zones were treated with 1.5 EDs each: in all, 230 mA-min of tube energy were consumed during 23, 31, 36, 44, and 16 minutes of exposure. The first two irradiations were implemented one after the other on two days in succession. When the patient returned to my office three days after the last exposure, his tumor was appreciably reduced in size. He had to travel then, but he wrote me four weeks later that the tumor had begun to regrow. Two small doses of X rays administered in Berlin did not change the situation, so an operation on it was performed at the Bier Clinic. "Diagnosis: Branchiogenic carcinoma. The pattern of tumor growth was alveolar, with scattered zones of densely cellular, new connective tissue between the carcinoma cells. Most of the tumor was not viable; in part overtly necrotic, in part with fragmented nuclei. In certain zones, small-cell infiltrates are noticed among tumor cells. Prof. Stricker." The patient died several months thereafter.
3. (Th. Nr. 323. T.K.) Recurrent cancer of the sigmoid colon. 26 year-old woman. Her illness began with severe constipation and pain 20 months ago. Two months later, she consulted a surgeon who operated on her intestinal tumor, described by Dr. Heile as a carcinoma of the sigmoid colon. Some pelvic bone was removed at the same operation. During the past few weeks she has experienced pain at the site of that operation, varying greatly in severity with changes in weather conditions. The tumor palpated at the site of the operation was about the size of a hen's egg; it was deemed inoperable. A dose of 6 EDs was delivered to the region of the posterior inferior iliac spine using metal-screen therapy (70 mA-min; 8 cm focus-to-skin distance; actual exposure time, 35 minutes). Two weeks after irradiation, the author had the opportunity of seeing the patient once more during her short life. The screen was imprinted clearly on her skin. Eight weeks later, a letter from the patient's attending physician stated that her strength had waned rapidly and that she was expected to die soon. There had been no improvement in bowel function: "The tumor seemed unchanged. Operative sites on the skin were darkly pigmented but scabs were never seen, nor did I notice any sloughing from those sites." Since it remains uncertain as to whether or not the tumor was examined post mortem, this case is now closed. Whatever the circumstances, changes in that pelvic tumor's size could have been assessed clinically only by palpation. I don't think that severely ill patients should be subjected to bimanual pelvic examinations after X-ray therapy just to track the size of a tumor. On the other hand, without such examinations little credence can be given to the opinion expressed that the pelvic cancer seemed minimally inhibited by screen therapy, especially because it was growing rapidly just before the treatment and because that opinion was only expressed ten weeks after therapy.
The salient features of these cases may be summarized as follows:
The malignancies, in one case, even a recurrent carcinoma, shrank within a few days after screen therapy. That happened in the face of experience that a recurrent carcinoma is much less responsive to X-ray therapy than is the responsiveness of a primary carcinoma of the same kind to similar X-ray therapy. Until now, no skin necrosis has been observed in patients treated by screen therapy using the skin-compression technique with incident doses up to 6 ED. Although much better inhibition of malignant tumors by screen therapy is anticipated, how far one may safely increase the dose to achieve confluent necrosis of a network of tumor-bearing tissues at a given depth beneath the skin has yet to be assessed by clinical experience.
Because it is practically impossible to provide any useful therapy of a deep malignancy using a focus-to-skin distance over 80 cm, even the most stubborn champion of such long focal distances should be impressed by an irradiation technique that delivers 6-10 EDs during one 45- to 90-minute irradiation session.
For screen therapy, the necessity of optimizing the area of the targeted lesion while minimizing the discomfort of immobility during the irradiation generally requires that the anticathode-skin distance be constrained to within 15 - 30 cm.
Finally, the author would also like to draw attention to the potential usefulness of low-dose screen therapy of targets in the spleen and bones (especially in cases of leukemia) as well as of uterine myomas, ovarian tumors, lymphomas and similar common tumors. However, it should be emphasized, especially to novices, that there is scant experience with such treatments and that safe doses of them have not been established.
In summary, it is recommended that:
1. For one-fraction therapy, when dose is critical, one should place a metal screen on the skin before the irradiation.
2. For multi-fraction therapy, a metal screen should be placed on the skin before each fraction.
Even if an inexperienced practitioner overdoses a patient, a screen will enable faster recovery, because the small, burned zones under the screen's holes will be healed by cells that had survived just beneath the metal strands between those holes, each surviving cell having received as little radiation as the other.
* Such iron screen are manufactured by Reiniger, Gebbert & Schall (Erlangen), best in 0.5 m2 squares which, however, can barely be cut by orthopaedic plaster-cutting shears. So, it is recommended that other shears be at hand that can cut through those iron screens.
1. Fortschritte auf dem Gebiete der Röntgenstrahlen, Bd. 14 (the same was published verbatim, in French, in the "Journal Belge de Radiologie" 1909, and in the "Annales d'Électrobiologie et de Radiologie" 1909).
2. Münchener Medizinische Wochenschrift 1909, Nr. 45.
==================
Invited Lectures
* Daniel N. Slatkin. Unpublished seminar: A Therapeutic Advantage Factor for Boronophenylalanine (BPA)-Mediated Boron Neutron-Capture Therapy (BNCT) of Glioblastoma Multiforme. Föreläsningsalen Onkologiska Kliniken, Jubileum Institute, Lund University, Lund, Sweden. November 28, 2000.
* Daniel N. Slatkin. Per Spanne Memorial Lecture, Annual Meeting of the Swedish Society for Radiation Physics, Gothenberg, Sweden. November 30, 2000.
* Daniel N. Slatkin. Microbeam Radiation Therapy (MRT) - historical perspective. Canadian Light Source, Inc., Saskatoon, Saskatchewan, Canada; August 27, 2009.
=================
Microbeam Radiation Therapy (MRT) - historical perspective
Daniel Slatkin (Nanoprobes, Inc., Yaphank, New York, USA)
Presented at the Canadian Light Source, Inc., Saskatoon, Saskatchewan, Canada; August 27th, 2009.
I am grateful to have been allowed by Tomasz Wysokinski and Dean Chapman to visit the Canadian Light Source [CLS] this week and to speak today about microbeam radiation therapy [MRT] from a 'historical perspective.' I don't feel historical just yet - maybe that should have read 'personal perspective.' Anyway, I thank each of you for choosing to listen to my presentation, whatever its title should be.
Radiation therapy for cancer is generally undervalued among sophisticated, modern medical professionals, often with justification. Most cancers cannot be cured by standard techniques of radiation therapy, and some cannot even be ameliorated by them. So, well should it be with considerable trepidation that physicians contemplate the development of extremely intense, maybe dangerously intense X rays to treat cancer at the Canadian Light Source's [CLS]'s BioMedical Imaging and Therapy [BMIT] facility, indeed at any synchrotron radiation facility. I have no quarrel with those who would ignore or dismiss the development of MRT on the grounds that existing methods of radiation therapy are adequately palliative, when indicated, for most patients harbouring cancer and that introducing MRT would be very costly and hazardous. However, such viewpoints need not be held by every physician. At present, at least every other patient diagnosed with cancer derives benefit from radiation therapy at some stage of the disease. Just as it's difficult for one to imagine a medical future not heavily inclined toward molecular, immunologic, and genetic therapies, so is it difficult -- difficult for me, at least, -- to imagine a medical future without ancillary radiation modalities to supplement, perhaps to synergize with leading-edge therapeutic anti-mitotics, anti-angiogenics, genes, antigens, antisenses, immunomodulators, antibodies, viruses, bacterial cells, and/or syngeneic eukaryotic cells - whether or not transfected or otherwise modified. However, pending safe and effective clinical use of such advanced therapies, is it not rather reasonable to try to improve upon existing therapies too, when an opportunity arises?
My opportunity arose 53 years ago. A mediocre McGill medical student, I happened to be reading a newspaper at my family's summer home in Ste-Agathe-des-Monts during the break between semesters and noticed its report (New York Times 1956) mentioning Dr. Lee Farr's ongoing boron neutron-capture therapy [BNCT] research at Brookhaven National Laboratory [BNL]. It was only my sheer luck that Farr responded favorably to my naïve letter asking that I be allowed to work on BNCT experiments during the following summer. By chance, for Dr. Stuart Lippincott, then the BNL Medical Department's pathologist - formerly a McGill pathologist - reportedly told Farr that my undergraduate physics and mathematics courses at McGill justified his taking that risk. I could not have been so very lucky then had I not been almost inconceivably fortunate two years previously also, when the neurosurgeon William Cone recommended me for enrollment in McGill's MD program, possibly because I had helped him as an unskilled laboratory assistant at the Montreal Neurological Institute during a couple of summers. I had sought such temporary work to glimpse a world beyond physics and mathematics - the only subjects one was permitted to study for credit after admission to that double-honours program at McGill. BNCT hooked me at BNL during the following summer, and I'm still far from being inclined to unhook myself, BNCT's present lowly status in medicine notwithstanding. A feature of those years that sticks in my mind is a chance meeting with Howard Curtis, then the Biology Department's chairman, when he gave me a ride. He asked me what was going on in BNCT. After responding as quickly and quietly as possible - since I knew very little about BNCT - I asked Dr. Curtis about what sort of experiments he was doing. I got the better of the deal. Whereas during my short ride I could only mumble briefly about my minor technical help with BNCT of malignant leg tumors in mice, Curtis spoke with assurance of the resistance of normal mouse brains to gigantic doses of radiation from a cyclotron-generated microbeam, which I did not understand, but could not forget either. Years later, I realized that Curtis was counted among the leading radiobiologists of his generation.
Because clinical BNCT is now successful, one can at last rest assured that the direct and indirect pioneering contributions to BNCT research projects at BNL from Maurice Goldhaber, William Sweet, Donald Van Slyke, Albert Soloway, Lee Farr, James Robertson, Ralph Fairchild, Victor Bond, George Cotzias, Lewis Dahl, Otto Easterday, Elmer Stickley, Tadeusz Konikowski, Stanley Sajnacki, Darrel Joel, Michiko Miura, Gerald Finkel, Henry Smilowitz, Arjun Chanana, Jeffrey Coderre, Aidnag Diaz, Marta Nawrocky, Peggy Micca, Dennis Greenberg, Michael Makar, Henry Hauptman, and very many others I regret failing to mention here or not knowing, were worth their close attention to research plans and to the innumerable steps they each took over many years to implement them. Nevertheless, the original BNL clinical trials of BNCT (1951-1961) finally failed (Slatkin 1991). Certainly, the original purpose, to palliate some patients with brain tumors using BNCT, was not realized. Decades later, much less disappointing results of the second BNL/BNCT trials of brain tumour therapy from 1994 through 1999 (Diaz 2003) were cited as reasons to stop BNL's BNCT program altogether, especially because it was decided, for various other reasons also, to make BNL a reactor-free laboratory. Despite the failures of BNCT at BNL, techniques developed in the USA, not the least at BNL, in Japan and elsewhere to implement BNCT, further refined in Finnish hands (Kankaanranta 2007; http://www.clinicaltrials.gov/ct2/results?term=BNCT), now seem to me to be among the best, if not the best currently available to palliate patients with recurrent cancers of the head and neck. That the Finns have devised a method of magnetic resonance spectroscopic imaging calibrated for the in vivo assessment of boronophenylalanine-boron concentrations in tissue at the 10 ppm level (Timonen 2009) bodes well for their work and should draw BNCT to the renewed attention of North American radiation oncologists, I hope, of the distinguished ones at my alma mater also (Sham 2008).
Why a presentation on MRT's history should be dominated by a discussion of BNCT is simply this: BNCT research begun at BNL 60 years ago by Lee Farr and Donald Van Slyke (New York Times 1949) led to MRT research there 40 years later; even that - only by chance. As a Canadian citizen with a US student visa about to expire during 1965 upon completion of my residencies in pathology, I applied for a British medical licence on the basis of reciprocity with its Canadian counterpart. That, together with my training in autopsies, qualified me as a Registrar at Hammersmith Hospital, Du Cane Road, London. Registrars in morbid anatomy there under Professor C. V. Harrison were generously freed for one full month per year, at full salary, to do medically related work that interested them. The endocrinologist in charge of Hammersmith's metabolic diseases clinic, Professor Graham F. Joplin, told of my background in BNCT, agreed to have me assigned to postmortem analyses of some pituitary glands that had been therapeutically ablated by trans-nasopharyngeal implantation of a pair of yttrium-90 rods. Those analyses (Talbot 1980) astonished me, showing threshold beta-radiation (2.27 MeV; half-life 64 hours) doses for hypophyseal tissue necrosis with a median of 1.8 kGy. Microscopic outlines of necrosis in transition from the adeno- to the neuro-hypophysis were continuous. Corresponding median thresholds for disappearance of osteocytes from lacunae in the contiguous cranial bone and for necrosis in the nearby tunica media of the internal carotid arteries were somewhat less: 1.5 and 1.2 kGy, respectively. Remarkably, mural thromboses in the adjacent cavernous sinuses of those patients were few, non-occlusive, and clinically silent. One should therefore not be surprised that enormous radiation doses are required to ablate a normal tissue if its vasculature can be regenerated from slightly irradiated, microscopically contiguous blood vessels - in this case, peripheral blood vessels. In the Hammersmith experience, surviving margins of pituitary tissue may have become revascularized from branches of the internal carotid arteries that enter the pituitary from each side, and/or revascularized from above through several small branches of the circle of Willis that enter the pituitary in the loose connective tissue enveloping its infundibular stalk.
Upon returning to Canada in 1969, I was very lucky to secure a professionally fulfilling and generously paid position at the McKellar General Hospital in Fort William under its pathologist Fred O'Brien and its clinical chemist Peter Spare. However, after less than two years in that vast, remote, beautiful, and invigorating, only occasionally chlorinous and/or sulfurous sector of Ontario, family obligations coupled with reluctance to give up my research connections led me to apply for work again at BNL. Eugene Cronkite, for whom I had devised an obscure formula for the dosimetry of extracorporeal irradiation of blood (Slatkin 1963), had become the Chaiman of BNL's Medical Department and, perhaps as reward for helping him, allowed me back to BNL. That move very nearly killed me within a year of my return, as the decade-old Galaxie clunker without seatbelts I had stupidly imported two years after they were mandatory in the USA, was struck nearly head on at high speed by a brand-new Corvette out of control, with a stone-drunk young man at the wheel. That was on May 30th, 1970, the last US Memorial Day observed on a Saturday. My flesh and bones were cut and smashed, but I was left miraculously alive - virtually immobilized during the next six months. I was finally able to return to BNL, where, for many years afterwards I gleaned whatever knowledge I could of analytical biochemistry from Lewis Commerford and William Siegelman, of mass spectrometry from Peter Irsa and Lewis Friedman, of heavy water analysis from Alfred Wolf, of atomic physics from Hobart Kraner, Keith Jones, Fred Geisler, and Albert Hanson, and of other laboratory techniques from Edwin Popenoe, Richard Stoner, Jean Laissue, Jeffrey Gaffney, Joanna Fowler, Michiko Miura, John Heinrichs, Harry Ulyat, and the many others at BNL who gave generously of their time to try, as best they could personally, to make me do my part adequately. In different words, Dr. Cronkite enabled me to begin peeking into some of the promises, the uncertainties, and the bitter disappointments that hands-on biomedical research held in store for me - and to inure myself to the worst. He also recommended me as a junior faculty member to Arthur Upton, who had just then been enlisted by the New York State Department of Education to assemble the senior faculty of a new medical school being established at Stony Brook, about 20 miles west of BNL. Not only was the BNL BNCT program well-nigh moribund by then, but Cronkite himself had been quite openly skeptical of it as long as I knew him. To his great credit, Dr. Cronkite understood clearly the critical differences between skepticism and hostility - providing many precious opportunities for development of innovative programs in radiation research in his department beyond his own wide-ranging, deep expertise in hematology and radiobiology - I believe even beyond any interest of his own.
I had almost forgotten BNCT when, toward the latter 1970s, an unstoppable scientist - Ralph Fairchild, previously James Robertson's technican - collided with me. Far from bashing me, he swept me up and away with his single-minded determination and boundless energy to revive BNCT at BNL - this time with an epithermal rather than with a thermal neutron beam. I became involved in BNCT research again, this time under Fairchild's sponsorship. After Fairchild's sudden death at age 55 on December 17th, 1990, I continued working on BNCT under the supervision of Darrel Joel and Michiko Miura until my retirement from BNL on September 30, 1996. The story of how MRT accidentally spun off from BNCT research during those years was told in my 'Per Spanne Memorial Lecture' on November 30th, 2000, a copy of which is posted at http://dnslatkin.vatavia.net/. English translations of early reports by Alban Köhler, the inventor of sieve therapy (Köhler 1912; Jolles 1953; Becker and Kuttig 1965), of more than historical relevance to MRT, are also posted at that website. I should also point out respectfully that Börje Larsson was the first, to my knowledge, to propose using synchrotron-generated X rays for radiosurgery (Larsson 1983). Per Spanne worked hard to initiate MRT experiments at the NSLS during the late 1980s, helped greatly by Avraham Dilmanian in particular. Spanne's accidental death on September 2nd, 1998 was not only a grievous shock to his research colleagues, but a significant setback to MRT research at the ESRF and the NSLS. That the dynamic radiosurgery pioneer Larsson died just 40 days later compounded the seriousness of the impact.
Despite nearly two decades of effort by Jean Laissue, Hans Blattmann, HansPeter Wagner, Jiri Stepanek, Avraham Dilmanian, and other mature experts, together with those of a handful of generally younger engineers, radiobiologists, medical physicists, mathematicians, and physicians, it has been only during the past couple of years that MRT has garnered attention from more than a handful of clinical oncologists. So, I would respectfully submit that biomedical research politics are not just side issues. It is not merely advisable for those engaged in experimental radiation therapies to work very closely with active, ambitious clinicians as Larsson did so brilliantly - it is essential. Just as BNL's epithermal-neutron-based BNCT research program, initiated virtually singlehandedly by Fairchild in the 1970s, was brought to its knees ten years ago, while it was clinically active and internationally respected, by a variety of US Federal Government-appointed medical consultants, some less expert in BNCT than others, so will the experimental MRT program at the CLS eventually peter out or be stopped unless priority is consistently given by staff at every level of authority, from directors to maintenance personnel, to both the substance and the appearance of collaboration with physicians responsible for the care of desperately ill cancer patients. There should be developed a strong clinical program of microbeam therapy at the CLS to inform, justify, supplement, and back up the sciences of microbeam radiobiology and microbeam radiotoxicology that could help untangle the molecular bases of various abscopal microbeam effects analogous to those cited by Jolles 56 years ago. Whether a clinical program at the CLS, for example one focused on pediatric neuro-oncology (Laissue 2001) could be implemented with the existing 4.5 T wiggler, or would require one with even stronger fields (Dilmanian 2001), is quite beyond my understanding to analyze. Nevertheless, that some clinical program, however narrowly focused it may be, is important to the long-term health of the BMIT program is beyond doubt in my mind. Everyone is entitled to my opinion, and fortunately none is obliged to agree with it.
I wish you all the best of good fortune in pursuing your valuable work. Whether or not what I said pleased you, I thank you again for listening to it.
References:
Curtis HJ (1967). The use of a deuteron microbeam for simulating the biological effects of heavy cosmic-ray particles. Radiat Res Suppl 7: 250-257.
Diaz AZ (2003) Assessment of the results from the phase I/II boron neutron capture therapy trials at the Brookhaven National Laboratory from a clinician's point of view. J Neurooncol 62: 101 - 109.
Dilmanian FA, Krinsky S, Bacarian T, Slatkin DN, Torikoshi M. Design of a dedicated medical synchrotron X-ray facility primarily for microbeam radiation therapy (MRT). National Synchrotron Light Source 2001 Annual Report, eds. Corwin MA et al., Brookhaven National Laboratory, Upton, New York. dilm437 [http://www.pubs.bnl.gov/nsls01/pdf/section%206%20abstracts/toc.htm#X17B1]
Köhler A. (1912) Deep X-ray therapy through a protective metal screen. (Report III: Clinical Applications). Strahlentherapie 1, 121-131. (2009 translation by D. N. Slatkin and J. A. Laissue; posted at http://dnslatkin.vatavia.net/)
Jolles B (1953). X-ray sieve therapy in cancer. Little, Brown and Company, Boston; 192 pages.
Becker J, Kuttig H. (1965) The use of the grid in supervoltage therapy. in Progress in Radiation Therapy, Vol. III. ed. Buschke F., Grune & Stratton, New York and London. pp 50-67.
Kankaanranta L, Seppälä T, Koivunoro H, Saarilahti K, Atula T, Collan J, Salli E, Kortesniemi M, Uusi-Simola J, Mäkitie A, Seppänen M, Minn H, Kotiluoto P, Auterinen I, Savolainen S, Kouri M, Joensuu H (2007). Boron neutron capture therapy in the treatment of locally recurred head and neck cancer. Int J Radiat Oncol Biol Phys 69: 475-482.
Laissue JA, Blattman H, Wagner HP, GrotzerMA, Slatkin DN (2007). Prospects for microbeam radiation therapy of brain tumours in children to reduce neurological sequelae. Dev Med Child Neurol 49: 577–81.
Larsson B (1983). Potentialities of synchrotron radiation in experimental and clinical radiation surgery.
Acta Radiol Ther Phys Biol Suppl 365: 58-64.
New York Times (1949). Brookhaven names 2 to medical staff. April 21.
New York Times (1956). Atomic reactor for medical use. August 26.
Sham E, Seuntjens J, Devic S, Podgorsak EB (2008). Influence of focal spot on characteristics of very small diameter radiosurgical beams. Med Phys 35: 3317-3330.
Slatkin DN, Jansen CR, Cronkite EP, Robertson JS (1963). Extracorporeal irradiation of blood: calculations of the radiation dose. Radiat Res 19: 409-418.
Slatkin DN (1991). A history of boron neutron capture therapy of brain tumours. Postulation of a brain radiation dose tolerance limit. Brain 114: 1609-1629.
Slatkin DN, Blattmann H, Wagner HP, Glotzer MA, Laissue JA (2008).
Prospects for microbeam radiation therapy of brain tumours in children.' Letter to the Editor. Dev Med Child Neurol
DOI: 10.1111/j.1469-8749.2008.03187.x
Talbot IC, Slatkin DN, Arnot RN, Doyle FH, Joplin GF (1980). Pituitary ablation by yttrium-90 implantation: Some post mortem and clinical observations. Int J Appl Radiat Isot 31: 695-701.
Timonen M, Kankaanranta L, Lundbom N, Kortesniemi M, Seppälä T, Kouri M, Savolainen S, Heikkinen S. (2009). Acquisition-weighted MRSI for detection and quantification of BNCT (10)B-carrier
L-p-boronophenylalanine-fructose complex: a phantom study. J Radiat Res (Tokyo). July 8. [ Epub ahead of print ]
==========
Per Oscar Spanne: [August 17, 1945 - September 2, 1998]
Grace and Fervent Creativity
Presented at the Annual Meeting of the Swedish Society for Radiation Physics, Gothenburg, Sweden, November 30, 2000.
I am much moved by the honor of having been asked by the Swedish Society for Radiation Physics to deliver this Per Spanne Memorial Lecture.
Shortly after noon on Wednesday, September 12th, 1984, I found myself at age 50, by then primarily a boron neutron-capture therapy researcher in Ralph Fairchild’s group at Brookhaven National Laboratory, at Linköping University with the late Prof. Börje Larsson, Prof. Carl Carlsson, Mr. George Matscheko, and Dr. Per Spanne. The topic of discussion, I was told, would be microtomography. Although I knew and know little about microtomography, that afternoon’s encounter, especially with Spanne, was later to kindle microbeam radiation therapy (MRT) research. My talk will describe how that came about and what I know of MRT research carried out since then.
Per Spanne entered Lund University in 1966 after his military duty specializing in photographic surveillance. As an undergraduate, he studied mathematics and physics in general, then majored in radiation physics under Professor Carl A. Carlsson. In 1971, Carlsson was named the director of the Department of Radiation Physics at the newly formed Linköping University Medical School and Spanne moved with him to begin postgraduate studies. Spanne was awarded a Ph.D. from Linköping University in 1979 for his work on ultra-sensitive thermoluminescence dosimetry in the microgray range (1). Professor Larsson introduced me to Professor Carlsson and his two younger colleagues Dr. Per Spanne and Mr. George Matscheko at Linköping University on September 12th, 1984. Spanne, then a 39-year-old medical physicist and postdoctoral fellow, wanted to continue his investigations of computerized microtomography using synchrotron radiation. I was asked by Carlsson and Larsson to recommend Spanne to work at Brookhaven National Laboratory's National Synchrotron Light Source (NSLS). Keith Jones, one of my physicist collaborators at Brookhaven during the 1980s, agreed to accept Spanne in his group at the NSLS´s X26 bending magnet beamline.
In August, 1985, Spanne arrived on Long Island with his wife Vibeke Arnmark and their twin daughters Linda and Mette in tow, promised support from Linköping until he was better established at Brookhaven. A hurricane chanced to decimate the yard of their rented home shortly after they moved into it, but that was merely a minor inconvenience, I was told. Although there were no outward hints of it, their first years on Long Island must have been rather difficult. The stresses of confronting language barriers, unfamiliar professional challenges and new bureaucratic hurdles, each serious enough to discourage an unestablished visitor, not to mention the inevitable financial burden of transatlantic displacement with family, all had to be confronted and managed in parallel. Analogous stresses were to be experienced later in France. I was then a 51 year-old staff pathologist and untenured scientist trying to conduct BNCT research under Ralph Fairchild's sponsorship. I was of little use to Spanne, although I did try to support his attempt to initiate a program of microtomography of human skin biopsies at X26 in collaboration with the eminent Swedish Professor Ake Falk, whose encouragement Spanne mentioned appreciatively a number of times before and after the three of us met.
By the late 1980s, Spanne felt secure enough to attempt microtomography of the head of an anesthetized mouse using an ~30 micrometer-diameter pencil beam of x rays at X26. Although individual whiskers were imaged using absorbed doses to brain under 10 Gy, contrast was poor. We therefore decided to increase the absorbed dose by an order of magnitude, based on knowledge that a single planar 22 MeV deuteron beam of similar width (25 micrometers) failed to elicit cerebral damage in mice unless absorbed doses were over ~3000 Gy (2) and that yttrium-90 brachytherapy failed to ablate the human pituitary gland unless absorbed doses exceeded ~2000 Gy (3). We delivered ~200 Gy to a mouse’s head through its brain using the same ~30 micrometer-diameter pencil beam. The mouse recovered normally from anesthesia. I killed the mouse one month later and enlisted my colleague Professor Jean Laissue (Director, Institute of Pathology, University of Bern) to look for any histopathological evidence of damage along the beam's path. Even Laissue saw only apparently normal brain tissue by light microscopy.
At that point, Spanne and I, in collaboration with Avraham Dilmanian (who had been exploring the feasibility of dual-energy tomography and millimeter-beam radiosurgery at X17), decided to investigate the theoretical possibility of radiotherapy with 50 -150 KeV X rays using arrays of parallel 25 micrometer-wide beam slices spaced 50 to 200 micrometers apart. Spanne arranged to have Michael Sandborg, then a graduate student at Linköping, simulate microdosimetry for our various scenarios of this new concept, MRT, for a human brain tumor (4). Concurrently, in continued collaboration with Laissue, we initiated normal rat brain tissue tolerance experiments at the higher energy X17 wiggler beam. We were astonished and elated upon realizing that animals could really withstand absorbed doses of hundreds, even thousands of gray from X rays delivered to microscopic slices of their CNS tissues (5, 6). Although we did not have a multislit collimator, we decided to implement MRT at X17 for the 14-day post-initiation intracerebral rat 9L gliosarcoma, a brain tumor model that had been in use at Brookhaven in BNCT research for over a decade.
Under Laissue's sponsorship, we dove into the task of finding a machinist willing to fabricate a multislit microbeam collimator for our experiments, because we were severely limited by the necessity of translating our animals across our single microbeam in hundreds of microscopic steps to irradiate a rat (7). Four years after designing and constructing his first prototype, by 1996 the late David Archer of Mallorytown, Ontario, Canada, was able to fabricate a dimensionally adjustable multislit microcollimator (MSC), to this day the only one of its kind in use (US Patent 5,771,270: Archer, 1998).
Unfortunately, our attempts and those of the BNL Medical Department chairman Darrel Joel to secure adequate funds for further MRT research at Brookhaven had failed. Influential American critics declared our studies to be of radiobiological interest with little or no future in medicine. Professor
Le Bas of the University of Grenoble, while working to establish a medical imaging beamline at the European Synchrotron radiation facility (ESRF), had visited the NSLS medical beamline´s imaging group at X17, where his student Hélène Moulin apprised him of our MRT experiments. Moreover, a Swiss-sponsored MRT research group led by Laissue and Spanne presented the MRT concept to the ESRF Directorate (Professors Haensel, Altarelli and Branden) in person on June 12th, 1992. So Spanne, by the 1990s an internationally recognized radiation physicist, secured a promise of five years' employment as a medical beamline scientist at the ESRF. The Spannes moved to Grenoble and in September, 1994, Spanne began working as a radiation physicist in the ESRF Imaging Group with the understanding that he was expected to develop MRT there too. Per related to Laissue that Professor Branden, who was also a leading Swedish biocrystallographer, was particularly supportive of him. By March 3,1995, Spanne wrote me that he was preparing "beamline 5" for the first exposures of rats to a single microplanar beam.
My daughter Heidi and I spent several days in Mallorytown at the end of January, 1996, helping Archer in his final assembly of the MSC, which was delivered to Laissue's office in Bern on February 20, 1996 by a FedEx courier, coincidentally and dramatically, during a meeting of our MRT research group. After passing Laissue's inspection by light microscopy, Spanne brought that
Swiss-owned device to the ESRF a few days later, where he first characterized it physically. The MSC was later moved to ID17, where it has been used since then by the Swiss-led MRT research group for irradiations of the hindbrains of normal suckling rats and weanling piglets. Studies of MRT for the 9L rat gliosarcoma are also in progress at the ESRF. Among Spanne´s many supportive colleagues at the ESRF during those years, Hans Blattmann, Jean Laissue, Marco Di Michiel, Michel Renier, Pascal Schweizer, and Pekka Suortti should be mentioned in particular. Di Michiel´s input has been particularly important in the continued activity of MRT experimentation at the ESRF, for which Spanne laid such a solid foundation.
Daniel Slatkin
References
1. P. Spanne, "Thermoluminescence Dosimetry in the µGy Range", Acta Radiologica, Supplement 360, 1-118, 1979.
2. H. J. Curtis, "The Use of a Deuteron Microbeam for Simulating the Biological Effects of Heavy Cosmic-Ray Particles", Radiation Research, Supplement 7, 250-257, 1967.
3. I. C. Talbot, D. N. Slatkin, R. N. Amot, F. H. Doyle, and G. F. Joplin, "Pituitary Ablation by Yttrium-90 Implantation: Some Post Mortem and Clinical Observations", Int. J. Appl. Radiat. Isot. 31, 695-701, 1980.
4. D. N. Slatkin, P. Spanne, F. A. Dilmanian, and M. Sandborg, "Microbeam Radiation Therapy", Med. Phys. 19, 1395-1400, 1992.
5. J. Laissue, P.O. Spanne, F. A. Dilmanian, J.-O. Gebbers, and D. N. Slatkin, "Zell- und Gewebeläsionen nach räumlich fraktionierter Mikro-Bestrahlung des ZNS mit Synchrotron Photonen“, Schweiz. Med. Wochenschr. 122, 1627, 1992.
6. D. N. Slatkin, P. Spanne, F. A. Dilmanian, J.-O. Gebbers, and J. A. Laissue. "Subacute Neuropathological Effects of Microplanar Beams of X-Rays From a Synchrotron Wiggler", Proc. Nat. Acad. Sci. USA, 92, 8783-8787, 1995.
7. J. A. Laissue, G. Geiser, P. O. Spanne, F. A. Dilmanian, J.-O. Gebbers, M. Geiser, X.-Y. Wu,
M. S. Makar, P. L. Micca, M. M. Nawrocky, D. D. Joel, and D. N. Slatkin, "Neuropathology of Ablation of Rat Gliosarcomas and Contiguous Brain Tissues Using a Microplanar Beam of
Synchrotron-Wiggler-Generated X Rays.", Int. J. Cancer, 78, 654-660, 1998.
===========