2. Slatkin DN, Jansen CR, Cronkite EP, Robertson JS. Extracorporeal irradiation of blood: calculations of the radiation dose. Radiat Res 1963 Jul;19:409-418.
3. Slatkin DN, Spare PD. Umbilical-cord IgM and amniotic infection. Lancet 1969 Jan 11;1(7585):107.
4. Slatkin DN, Robertson JS. Extracorporeal irradiation of blood by beta-emitting isotopes: principles of dose calculations. Radiat Res 1970 Dec;44(3): 846-854.
5. 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): 361-363.
6. Slatkin DN, Pearson J. Intramyofiber metastases in skeletal muscle. Hum Pathol 1976 May;7(3): 347-349.
7. 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): 752-754.
8. 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): 641-647.
9. 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): 259-267.
10.Gaffney JS, Irsa AP, Friedman L, Slatkin DN. Natural 13C/12C ratio variations in human populations. Biomed Mass Spectrom. 1978 Aug;5(8):495-497.
11.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.
12.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): 467-472.
13.Slatkin DN, Commerford SL. Statistical dosimetry of radiation to oocytes from DNA-bound tritium. Health Phys 1982 Jan;42(1):77-80.
14.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.
15.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): 281-287.
16.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): 3480-3484.
17.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): 248-251.
18.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): 1383-1385.
19.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.
20.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): 1447-1451.
21.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.
22.Adams WH, Stoner RD, Adams DG, Slatkin DN, Siegelman HW. Pathophysiologic effects of a toxic peptide from Microcystis aeruginosa. Toxicon 1985;23(3): 441-447.
23.Slatkin DN, Friedman L, Irsa AP, Micca PL. The stability of DNA in human cerebellar neurons. Science 1985 May 24;228(4702): 1002-1004.
25.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): 1771-1776.
26.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 USA 1988 Jun;85(11): 4020-4024.
27.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.
28.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 USA 1989 Jan;86(2):685-689. Erratum in: Proc Natl Acad Sci USA 1989 Oct;86(19): 7595.
29.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): 825-828.
30.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: 325-332.
31.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: 179-191.
32.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.
33.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: 243-249.
34.Marshall PG, Miller ME, Grand S, Micca PL, Slatkin DN. Toxicities of Na2B12H11SH and Na4B24H22S2 in mice. Basic Life Sci 1989;50: 333-351.
35.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.
36.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..
37.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.
38.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): 167-170.
39.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): 244-246.
41.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): 521-528.
42.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): 309-318.
43.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: 317-320.
44.Stoner RD, Adams WH, Slatkin DN, Siegelman HW. Cyclosporine A inhibition of microcystin toxins. Toxicon. 1990;28(5):569-73.
45.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): 217-218.
46.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 USA 1990 Sep;87(18): 7265-7269.
47.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 USA 1990 Dec;87(24): 9808-9812.
48.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): 969-973.
49.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. Environ Health Perspect 1991 May;92: 181).
50.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: 271-277.
51.Slatkin DN. A history of boron neutron capture therapy of brain tumours. Postulation of a brain radiation dose tolerance limit. Brain 1991 Aug;114 ( Part 4): 1609-1629. Erratum. "Gabel G" should read 'Gabel D': 1624.
52.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): 177-185.
53.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. Biochem Pharmacol 1995 Sep 7;50(6): 893-894).
54.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): 290-296.
55.Slatkin DN, Spanne P, Dilmanian FA, Sandborg M. Microbeam radiation therapy. Med Phys 1992 Nov-Dec;19(6): 1395-1400.
56.Rosen JF, Slatkin DN. A commentary on in vivo lead X-ray fluorescence with reference to the 1992 workshop. Neurotoxicology 1993 Winter;14(4): 537-540.
57.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): 1121-1129.
58.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): 1167-1173.
60.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 Sep 12;92(19): 8783-8787.
61.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): 114-119.
63.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): 141-152.
64.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): 163-170.
65.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.
66.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): 773-781.
67.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): 654-660.
68.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):1182-1192; discussion 1192-1193.
69.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.
70.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): 231-240.
71.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):1664-1675. (Erratum. Med Phys 2001 Feb;28(2): 290)
72.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. Review. Cell Mol Biol (Noisy-le-grand). 2000 Sep;46(6): 1053-1063.
73.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): 603-610.
74.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):111-117.
75.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.
76.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): 573-580.
77.Slatkin DN. Uniaxial and biaxial irradiation protocols for microbeam radiation therapy. Phys Med Biol 2004 Jul 7;49(13): N203-N204.
78.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-N315.
79.Hainfeld JF, Slatkin DN, Focella TM, Smilowitz HM. In vivo vascular casting. Microscopy and Microanalysis 11: 1216-1217, 2005.
80.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. BrJ Radiol 2006 79: 71-75.
81.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.
82.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.
83.Slatkin DN. Tetrahedral irradiation protocol for microbeam radiation therapy. Phys Med Biol 2006 September 7; 51(17): N295-N297.
84.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.
85.Hainfeld JF, Dilmanian FA, Slatkin DN, Smilowitz HM. Radiotherapy enhancement with gold nanoparticles. Journal of Pharmacy and Pharmacology 2008 Aug;60(8):977-985
86.Slatkin DN, Blattmann H, Wagner HP, Glotzer MA, Laissue JA. Prospects for microbeam radiation therapy of brain tumours in children. (Letter). Dev Med Child Neurol 2009 February:51(2): 163.
87. Hainfeld JF, Dilmanian FA, Zhong Z, Slatkin DN, Kalef-Ezra JA, Smilowitz HM. Gold nanoparticles enhance the radiation therapy of a murine squamous cell carcinoma. Phys Med Biol 2010 55(11) :3045-59.
88.Hainfeld JF, O'Connor MJ, Dilmanian FA, Slatkin DN, Adams DJ, Smilowitz HM. MicroCT enables microlocalization and quantification of Her2-targeted gold nanoparticles within tumor regions. Brit J Radiol 2011 (June); 84: 526 - 533.
89.Laissue JA, Blattmann H, Slatkin DN. Alban Köhler (1874-1947): Erfinder der Gittertherapie. Z Med Phys 2012; 22(2): 90-99. Erratum. 2013; 23(4): 332.
90.Laissue JA, Blattmann H, Siegbahn EA, Slatkin DN. A misprint in a description of microbeam irradiations of rats' heads: Letter to the editor. Vet Ophth 2012 15(3): 210-211.
91.Hainfeld JF, Smilowitz HM, O'Connor MJ, Dilmanian FA, Slatkin DN. Gold nanoparticle imaging and radiotherapy of brain tumors in mice. Nanomedicine (Lond) 2013; 8: 1601-1609.
92.Laissue JA, Bartzsch S, Blattmann H, Bräuer-Krisch E, Bravin A, Dalléry D, Djonov V, Hanson AL, Hopewell JW, Kaser-Hotz B, Keyriläinen J, Laissue PP, Miura M, Serduc R, Siegbahn AE, Slatkin DN. Response of the rat spinal cord to X-ray microbeams. Radiother Oncol 2013; 106: 106-111.
93.Smilowitz HM, Slatkin DN, Micca PL, Miura M. Microlocalization of lipophilic porphyrins: non-toxic enhancers of boron neutron-capture therapy. Int J Radiat Biol 2013; 89: 611-617.
94.Hainfeld JF, O'Connor MJ, Lin P, Qian L, Slatkin DN, Smilowitz HM. Infrared-transparent gold nanoparticles converted by tumors to infrared absorbers cure tumors in mice by photothermal therapy. PLOS ONE 2014; 9(2): e88414.
95.Hainfeld JF, Lin L, Slatkin DN, Dilmanian FA, Vadas TM, Smilowitz HM. Gold nanoparticle hyperthermia reduces radiotherapy dose. Nanomedicine. 2014 Nov;10(8):1609-17. doi: 10.1016/j.nano.2014.05.006. Epub 2014 Jun 3.
1. Farr LE, Calvo WG, Stickley EE, Robertson JS, Easterday OD, Slatkin DN. Neutron capture therapy: Clinical and animal investigation. Bulletin of the Medical Department, Brookhaven National Laboratory, July 1, 1961. BNL-83280. pp 25-28.
2. 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.
3. Slatkin DN, Commerford SL. 2H incorporation into oocytes: Stable isotope tracer for 3H. Appendix 1 in Proceedings of the International Workshop on Tritium Toxicity; August 3, 1979. ed. E. P. Cronkite. Brookhaven National Laboratory, Upton, New York. BNL-27148, pp 20-24.
4. Allen P. Freedman, Daniel Slatkin, F. H. Y. Green. The ferrimagnetic content of autopsied coal workers lungs —Assessment of the correlation of magnetopneumographic measurement with analysis of extracted dust. in Proceedings of the Fourth International Workshop on Biomagnetism, (eds Gian Luca Romani and Samuel J. Williamson, September 14-16, Rome, Italy, 1982. Il Nuovo Cimento D, Volume 2, Number 2; Editrice Compositori, Bologna, Italy. March, 1983.
5. 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.
6. Laissue J, Altermatt HJ, Bally E, Berchtold W, Gebbers JO, Suter T, Slatkin DN. Radioprotektion durch schweres Wasser (D20). Verhandlungen der Deutschen Gesellschaft für Pathologie 67: 596, 1983.
7. 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.
8. 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.
9. 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.
10. Fairchild RG, Slatkin DN, Gabel D, Coderre J, Glass J, Laster BH, Borg DC, Elmore JJ, Foster S, Micca P, Kalef-Ezra J. Neutron capture therapy at Brookhaven National Laboratory. In: Workshop on neutron capture therapy, January 22-23, 1986. Medical Department, Brookhaven National Laboratory, Upton, New York. BNL-51994. UC-48. TIC-4500. pp 106-122.
11. Slatkin DN, Micca PL, Laster BH, Fairchild RG. Distribution of sulfhydryl boranes in mice and rats. In: Workshop on neutron capture therapy, January 22-23, 1986. Medical Department, Brookhaven National Laboratory, Upton, New York. BNL-51994. UC-48. TIC-4500. pp 173-177.
12. Wallwork JC, Cholewa M, Jones KW, Hanson AL, Slatkin DN. Microlocalization of brain zinc in zinc-deficient rats. Fed Proc., Fed Am Soc Exp Biol 1986; 45(4), 1086.
13. 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.
14. 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.
15. 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.
16. 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
18. 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.
19. 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 37:111-116, 1991.
20. Slatkin DN. Feasibility study for microbeam radiation therapy with 30-90 keV x rays from the NSLS X17 beamline. in Laboratory Directed Research & 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.
21. 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.
22. Slatkin DN, Kalef-Ezra JA, Balbi KE, Wielopolski L, Rosen JF. L-Line X Ray fluorescence of tibial lead: Correction and adjustment of radiation risk to ICRP 60. Radiation Protection Dosimetry 42:319-322 (1992)
23. Kabalka GW, Cheng QC, Bendel P, Slatkin DN, Micca PL. A new boron MRI method for imaging 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.
24. 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.
25. 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.
26. 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.
27.Hatanaka H, Fairchild R, Joel D, Slatkin D, Coderre J, Sweet WH. Current status of boron neutron capture therapy (BNCT) for intracranial tumors. Abstract. In: Proceedings of the Society of British Neurological Surgeons with the New England Neurosurgical Society, London, September 1991. J Neurol Neurosurg Psychiat 55: 513-521, 1992. p. 513.
28. 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.
29. Kabalka GW, Cheng GQ, Anderson C, Bendel P, Micca P, Slatkin DN. In vivo pharmacokinetics of a boron neutron capture agent in 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.
30. 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.
31. Kabalka GW, Cheng GQ, Anderson C, Bendel P, Micca P, Slatkin DN. In vivo phamacokinetics of a boron neutron capture agent in 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.
32. Joel DD, Slatkin DN, Coderre JA. Uptake of 10B in gliosarcomas following the injection of glutathione monoethyl ester and sulfhydryl borane. in Neutron Capture Therapy, eds. Soloway AH, Barth RF, and Carpenter DE. Plenum Press, New York, 1993. pp 501-504.
33. Slatkin DN, Spanne P, Dilmanian FA, Nawrocky MM, Gebbers JO, 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.
34. 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.
35. 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.
36. 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. (Abstract).
37. 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.
38. Coderre JA, Bergland R, Chadha M, Chanana AD, Elowitz E, Joel DD, Liu HB, Slatkin DN, Wielopolski L. Boron neutron capture therapy of glioblastoma multiforme using the p-boronophenylalanine-fructose complex and epithermal neutrons. in Cancer Neutron Capture Therapy. (ed. Y Mishima) Plenum Press, New York, 1996. pp 553-561.
39. Elowitz EH, Chadha M, Iwai J, Coderre JA, Joel DD, Slatkin DN, Chanana AD. A phase I/II trial of BNCT for glioblastoma multiforme using intravenous boronophenylalanine-fructose complex and epithermal neutrons: early clinical results. In: Advances in Neutron Capture Therapy. Vol. I, Chemistry and Biology. Eds. B. Larsson, J. Crawford, and R. Weinreich. Elsevier, Amsterdam, 1997: 56-59.
40. Miura M, Joel DD, Nawrocky MM, Micca PL, Fisher CD, Heinrichs JC, Rising CE, Walker W, Slatkin DN. Carborane-containing metalloporphyrins for BNCT. In: Advances in Neutron Capture Therapy. Vol. II, Chemistry and Biology. Eds. B. Larsson, J. Crawford, and R. Weinreich. Elsevier, Amsterdam, 1997: 56-61.
41. Joel DD, Chadha M, Chanana AD, Coderre JA, Elowitz EH, Gebbers J-O, Liu HB, Micca PL, Nawrocky MM, Shady M, Slatkin DN. Uptake of BPA intop glioblastoma multiforme correlates with tumor cellularity. In: Advances in Neutron Capture Therapy. Vol. II, Chemistry and Biology. Eds. B. Larsson, J. Crawford, and R. Weinreich. Elsevier, Amsterdam, 1997: 225-228.
42. 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.
43. Miura M, Micca PL, Nawrocky MM, Slatkin DN. Might iodomethyl-alpha-tyrosine be a surrogate for BPA in BNCT? In: Advances in Neutron Capture Therapy. Vol. II, Chemistry and Biology. Eds. B. Larsson, J. Crawford, and R. Weinreich. Elsevier, Amsterdam, 1997: 302-307
44. Chanana AD, Coderre JA, Joel DD, Slatkin DN. Protocols for BNCT of glioblastoma multiforme at Brookhaven National Laboratory: Practical considerations. In: Advances in Neutron Capture Therapy. Vol. II, Chemistry and Biology. Eds. B. Larsson, J. Crawford, and R. Weinreich. Elsevier, Amsterdam, 1997: 571-574.
45. 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.
46. Laissue JA, Lyubimova N, Wagner HP, Archer DW, Slatkin DN, Di Michiel M, Nemoz C, Renier M, Bräuer E, Spanne PO, Gebbers JO, Dixon K, Blattmann H. Microbeam radiation therapy. Proceedings of SPIE 3770: 38-45, 1999.
47. 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.
48. 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]
49. 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.
50. Diaz AZ, Chanana AD, Capala J, Chadha M, Coderre JA, Elowitz EH, Iwai J, Joel DD, Liu HB, Ma R, Pendzik N, Peress NS, Shady MS, Slatkin DN, Tyson GW, Wielopolski L. Boron neutron capture therapy for glioblastoma multiforme. In: Frontiers in Neutron Capture Therapy, Vol. 1. Eds. M. F. Hawthorne, K. Shelly, and R. J. Wiersema. Kluwer Academic/Plenum Publishers, New York, 2001: 61-72.
51. Ma R, Capala J, Coderre J, Diaz AZ, Greenberg D, Liu HB, Slatkin DN, Chanana AD. Radiation risks from p-boronophenylalanine-mediated BNCT for glioblastoma multiforme. In: Frontiers in Neutron Capture Therapy, Vol. 1. Eds. M. F. Hawthorne, K. Shelly, and R. J. Wiersema. Kluwer Academic/Plenum Publishers, New York, 2001: 571-574.
52. 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).
53. 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.
54. 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).
55. Daniel N. Slatkin, cited in: Judy Pasternak. 'Blighted Homeland: A Peril That Dwelt Among the Navajos.' The Los Angeles Times: November 19, 2006.
57. Smilowitz HM, Graham T, Tellides G, Oaks M, Hainfeld J, Slatkin DN. Immunoprophylaxis against recurrence of aggressive F98 rat gliomas after radiosurgery: Treg depletion and injections of GMCSF-transfected irradiated F98 cells with uric acid. Neuro-Oncology, 9(4):IM-22, 2007 (Abstract).
58. Laissue JA, Blattmann H, 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. 'Syrad' workshop: New prospects for brain tumour radiotherapy: Synchrotron light and microbeam radiation therapy. Grenoble, France, June 2-4, 2008. Abstract.
59. Hanson AL, Slatkin DN, Laissue JA. Unidirectional X-ray microbeam radiosurgery of infantile neuraxial malignancies: Estimations of tolerable valley doses. Proceedings of SPIE 8565/5G: 1-16, 2013.
1996. Boron neutron capture therapy of glioblastoma multiforme. Pathologisches Institut der Universität Bern, Switzerland. February 27.
2000. 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. Per Spanne Memorial Lecture, Annual Meeting of the Swedish Society for Radiation Physics, Gothenberg, Sweden. November 30.
**2009. Microbeam Radiation Therapy (MRT) - historical perspective. Canadian Light Source, Inc., Saskatoon, Canada; August 27.
2011 Lessons from the past: What aspects of medical research should be avoided at the NSLS-II? Workshop on Medical Imaging and Radiation Therapy (MIRT) for the NSLS-II. Room 4, Building 817, Brookhaven National Laboratory; May 9.
Co-author of nineteen US inventions and patents, 1988-2016:
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
8,033,977 Methods of enhancing radiation effects with metal nanoparticles; October 11, 2011
8,798,233 Low dose-rate radiation for medical and veterinary therapies. August 5, 2014
9,233,260 Magnetic confinement for microbeam radiation damage area. January 12, 2016 ……….
Project proposal 91-10, Brookhaven National Laboratory: pages 36-37 in: Laboratory Directed Research and Development Program Annual Report; G. J. Ogeka, Editor. Project Title: Feasibility 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: $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.
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(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:
1. 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.
2. Laissue JA et al, Microbeam radiation therapy. Proceedings of SPIE: 1999; 3770: 38-45.
3. 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.
1. 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.
2. Laissue JA et al, Microbeam radiation therapy. Proceedings of SPIE: 1999; 3770: 38-45.
3. 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.
*Per Oscar Spanne: [August 17, 1945 - September 2, 1998]
Grace and Fervent Creativity
Presented by Daniel Slatkin 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 ProfessorAke Falka, 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.
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.
aErratum, 2014: Professor Åke Kvick, the distinguished scientist presently associated with Max-lab, the synchrotron radiation research facility in Bollnas, Sweden, should have been cited by his correct name, not as "Professor Ake Falk."
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, 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/ (footnote 1). 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 (Footnote 2). 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.
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.
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.
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 ].
Footnote 1: Presently (October, 2014) posted at http://dnslatkin.weebly.com.
Footnote 2: English translations of Alban Köhler's early reports are no longer posted at Slatkin's website. More detailed information about Köhler's early reports was published subsequently: Laissue JA, Blattmann H, Slatkin DN. Alban Köhler (1874-1947): Erfinder der Gittertherapie. Z Med Phys 2012; 22(2): 90-99. Erratum. 2013; 23(4): 332.
***Slatkin DNa, Javid MJb, Soloway AHc, Joel DDd, Laissue JAe. Advances and setbacks during the trailblazing of clinical neutron-capture therapy. 16th International Congress on Neutron Capture Therapy, June 14-19, 2014. Helsinki, Finland. Poster: June 16, 2014.
aNanoprobes, Inc., 95 Horseblock Road, Yaphank, NY 11980, USA
bDepartment of Neurological Surgery, 600 Highland Ave., Madison, WI 53792, USA
cThe College of Pharmacy, 500 West 12th Ave., Columbus, OH 43210, USA
d419 Eagle Lane SW, Rochester, MN 55902, USA
eUniversity of Bern, Hochschulstrasse 4, CH-3012 Bern, Switzerland
Fortschritte und Rückschläge bei der Entwicklung der klinischen Neutroneneinfangtherapie
Die 10B-Neutroneneinfangtherapie [BNCT] wurde vom Neurochirurgen William Sweet zur Behandlung chirurgisch reduzierter Glioblastome 1949–1950 am Massachusetts General Hospital [MGH] in Boston geplant und entwickelt. Diese Therapie wurde zunächst am Brookhaven National Laboratory [BNL] erprobt, unter Einsatz von Neutronen thermischer Energie, nichtinvasiv (1951–1961), dann auch invasiv (1960–1961) am Massachusetts Institute of Technology [MIT]. Diese Studien wurden 1961 vorzeitiger Todesfälle wegen abgebrochen. Sieben Jahre später nahm die klinische BNCT in Japan einen neuen Anlauf. Keiji Sano und Hiroshi Hatanaka, ehemaliger Assistent von Sweet, heilten 1972 einen Glioblastom-Patienten: Nach Infusion von teilweise zu dimeren Sulfid Na4B24H22S2 [BSSB] oxidiertem Na2B12H11SH [BSH] in die ipsilaterale Arteria carotis interna bestrahlten sie den Tumor bei offenem Schädel mit langsamen Neutronen und applizierten hernach intrakavitär Methotrexat. Am BNL und Massachusetts Institute of Technology [MIT] wurden 1994 erneut nichtinvasive klinische BNCT Studien begonnen, unter Anwendung von L–Boronophenylalanin [L–BPA] und Neutronen epithermischer Energie, 1999 aber abrupt beendet. Seither werden besonders in Japan und Finnland, aber auch andernorts mit Hilfe von Uranreaktoren oder Protonenbeschleunigern weitere klinische BNCT Versuche zur Palliation maligner Neoplasmen unternommen, auch von fortgeschrittenen, mit konventionellen Therapien „ausbehandelten“ Karzinomen im Kopf–Halsbereich.
Moritz Goldhaber was a 22–year–old physics student at Berlin University in January 1933 when the Nazis seized power. Goldhaber, recommended by his professor Erwin Schrödinger, was admitted by Ernest Rutherford (1871-1937) to Cambridge University to study theoretical nuclear physics under Professor Ralph Howard Fowler (1889-1944). On December 10, 1934, he assisted James Chadwick (who had first identified the neutron in 1932) in discovering capture of slow neutrons by lithium and boron nuclei [1, 2]. Thereby, the astrophysicist Gordon Lee Locher derived theories of slow–neutron-capture therapy, which he prepared to test . He only tested neutron-induced fruit-fly mutations. In Urbana, Illinois, during September 1938, Goldhaber, unaware of Locher, suggested to his senior colleague Peter Gerald Kruger (1902-1978) that they initiate BNCT experiments using the first cyclotron intended to provide an external ion beam. Kruger pursued the experiment with Ernest Orlando Lawrence's (1901-1958) powerful cyclotron in Berkeley and described his results in the Proceedings of the National Academy of Sciences USA (PNAS), citing his Urbana collaboration with Goldhaber .
Trailblazing of clinical BNCT
William Herbert Sweet (1910–2001) was mentored (1935–1940) by the Massachusetts General Hospital [MGH] neurosurgeon James Clarke White. After voluntary wartime service in the English Midlands under the pioneering neurosurgeon Geoffrey Jefferson's tutelage (1941–1945), Sweet was befriended by his suburban Boston neighbour, Harvard University's chief of biological chemistry Albert Baird Hastings (1895–1987), a US National Academy of Sciences [NAS] member as was Hastings' mentor, the eminent clinical chemist Donald Dexter Van Slyke (1883–1971). Hastings, an éminence grise within the Roosevelt, Truman, and Eisenhower administrations [5, 6], in 1947 invited the Harvard radiopathologist Shields Warren to lead the Atomic Energy Commission [AEC] Division of Biology and Medicine and in 1948 persuaded Van Slyke to establish Brookhaven National Laboratory's [BNL's] biology and medical departments . Van Slyke's former associate Lee Edward Farr (1907-1997), a paediatrician–nephrologist, was invited to head BNL's medical department. Arthur Kaskel Solomon (1912–2002), Harvard's leading radiophysical chemist, mentored Sweet in radioisotope technologies . Late in 1949, unaware of Locher or Goldhaber, Sweet surmised from his preview of an unpublished AEC manuscript that one–third of chromosomal damage from slow–neutron irradiation of Tradescantia stamens could be attributed to minuscule traces of boron. He reasoned that a borax–mediated clinical BNCT [cBNCT] program for malignant glioma could be initiated at BNL . To our knowledge, neither Locher nor Goldhaber was cited in the BNCT literature before the mid-1950s; Hastings and/or Van Slyke might have apprised Sweet before 1952 of Kruger's pre-World-War-II BNCT research. In 1950, Sweet enlisted his neurosurgical resident Manucher Javid to help evaluate the pharmacokinetics of intravenous borax with or without glycerol in dozens of volunteer brain tumour patients, and the MIT postdoctoral physicist Gordon L. Brownell (1923-2008) to establish cBNCT's radiation dosimetry [9–11]. Late in 1950, Hastings informed Farr of Sweet's plan to implement borax–mediated cBNCT at the recently commissioned Brookhaven Graphite Research Reactor [BGRR] for newly debulked glioblastoma patients transported from Boston . To Farr's fury, confidentiality of the first cBNCT irradiation on February 15th, 1951, was broken by the intrusion of John Lear, a laymans' science reporter [13, 14]. Sweet referred nine more glioblastoma patients to the BGRR for borax-mediated BNCT during 1951–1952 . After a sojourn in South America during 1951, Brownell rejoined Sweet's research team . BNL's cBNCT program was taken over by Farr in 1953; sodium pentaborate, an analogue of borax (sodium tetraborate), was employed. In 1961, Maurice (né Moritz) Goldhaber, distinguished at BNL as a group leader since 1950, was recommended as BNL's director by Isidor Isaac Rabi (1898-1988) who, with his protégé Norman Foster Ramsey (1915-2011), had founded BNL in 1946; Goldhaber served until 1972. Several early post-BNCT fatalities in 1961, for which Farr was unfairly held responsible, had severely degraded BNCT's reputation. In 1962, Goldhaber replaced Farr by Victor Potter Bond (1919–2007), a US Navy and BNL physician and radiobiologist and steadfast champion of BNCT research.
In 1958 Sweet was appointed Harvard's scientific trustee on BNL's supervisory board, a role he filled with distinction thereafter. During 1961-1972 he also directed the MGH's neurosurgical service. The medical physicist Ralph Grandison Fairchild (1935–1990) was thus enabled in 1962 to launch BNL's program of epithermal–neutron–mediated preclinical BNCT investigations encouraged by Bond, Goldhaber, Sweet, and his research supervisor, the physician–mathematician James Sydnor Robertson (1920–2005) [17,18].
Radiovulnerability of the CNS vasculature
Shields Warren, to our knowledge, had been first to suggest in 1943 that a crucial limitation to cerebral radiotherapy was vascular damage, a limitation confirmed experimentally before 1949 by Dorothy Stuart Russell (1895-1983). However, BNCT radiation dosimetry took into account absolute and relative average boron concentrations in brain tumours and in non–tumour–bearing brain tissues, but not in blood, until 1962 [11, 15]. Of seventeen terminally ill brain–tumour patients identically infused intravenously with sodium pentaborate and irradiated with increasing fluences of thermal neutrons by Farr’s BNCT group at the new Brookhaven Medical Research Reactor during 1959–1961, four died soon after BNCT from intractable cerebral oedema. Later, those seventeen patients were ranked according to measures of total ionization energy imparted to the endothelial cell nuclei of their cerebral capillary vessels: the area of head exposed multiplied by the incident neutron fluence. Only those four with the greatest measures had died within two weeks after irradiation .
During 1960–1961, Sweet's group treated sixteen glioblastoma patients with BNCT at the MIT reactor using paracarboxyphenylboronic acid delivered intravenously. Clinical outcomes were unsatisfactory, as were those following most therapies of glioblastomas in that era. An experimentally superior agent, sodium decahydro-decaborate, was then tested in the seventeenth glioblastoma patient, but delivered via the ipsilateral internal carotid artery, also with an unexceptionally unsatisfactory effect. The outcome for the eighteenth glioblastoma patient, who was treated as was the seventeenth, was disastrous. She lapsed into coma after BNCT and died ten days later, apparently because transcarotid decahydrodecaborate infusion had allowed excessive cerebral blood and perivascular boron levels during irradiation. Both American clinical BNCT programs were suspended indefinitely. Brains were examined in fourteen of the eighteen decedents, including the two (#9 and #13) given decahydrodecaborate. The latter were more swollen, more oedematous and more friable  than were the other twelve; only in those two brains were erythrocytes extravasated diffusely .
Soloway's group at Sweet's MGH laboratory first screened BSH, derived from a polyhedral borane synthesized at the Du Pont Corporation, in tumour–bearing animals as a potential BNCT agent [22, 23]. By 1973, it was thought that higher tumour boron concentrations obtained by Hatanaka in Japan were attributable to its spontaneous slow oxidation to the yellowish dimer BSSB, which splits spontaneously into a pair of identical, exceptionally stable, highly reactive free radicals BS. bound to albumin in blood, where their concentration could be lowered by plasmapheresis. BSSB was the first agent used with BNCT to control an experimental malignant glioma . It has never been tested for cBNCT intentionally, but Hatanaka's exposure of BSH to air reportedly yellowed it and allegedly improved its efficacy for experimental BNCT [25–27]. BPA also was first screened at the MGH. Racemic BPA was then used for BNCT of human melanomas in Japan by Yutaka Mishima. Its pharmacologically effective moiety L–BPA, first synthesized enzymatically by the New York peptide chemist John David Glass, Jr., was employed thenceforth for cBNCT [18, 23].
Brookhaven trials: 1994–1999
New BNL trials of cBNCT mediated by L–BPA using epithermal neutrons were begun amidst controversy on September 13, 1994 . Over four dozen glioblastoma patients were treated before mid–1999: Intervals to tumour recurrence were generally unexceptional , but qualities of life before recurrence seemed nearly normal to some gratified patients and their families.
During 1995, the American public was bombarded by reports of unanticipated miseries endured by glioblastoma patients who had volunteered to undergo BNCT during the 1951–1961 clinical trials . Sweet was convicted of medical malpractice just as a progressive neurological disease prevented him from facing his accusers to refute their allegations. Nineteen months after Sweet's death, three Massachusetts appeals court judges reversed the conviction unanimously. They declared that the plaintiffs’ evidence rested on nothing other than information gathered and reported by Sweet and his team after the events, and that Sweet conformed to contemporary American guidelines for clinical research during the mid-20th century on therapies for rapidly progressive fatal diseases.
A slow leak of tritiated water from a holding tank at another research reactor at BNL was discovered in December 1996 but not reported to DOE until February 1997. Citizens, some remote from BNL, raised alarms among their legislators and the press about tritium-induced cancers. The DOE dismissed BNL's director Nicholas Samios because of the delayed response to its concerns, although the plume of BNL's tritiated groundwater had already been confined. Radiophobic backlashes shut down both nuclear reactors at BNL, which was then declared “neutron-free.”
Thus, BNCT research at BNL supported by the DOE was terminated by the end of the 20th century, but some was carried on nevertheless at BNL and much elsewhere . Seven major international symposia during 2000–2012, one each in Argentina, Italy, the USA, and Germany and three in Japan , attested to the vigour of modern BNCT research. The International Society for Neutron Capture Therapy will hold its 16th biennial congress in Helsinki, Finland, during June 14–19, 2014. Whether the 21-year-old BNL reports of periodinated BSSB  and of enhancing BSH's efficacy with glutathione monoethyl ester  will be cited there seems improbable. On the other hand, investigations of lipophilic carboranyl porphyrins at BNL  and elsewhere  might be cited, especially since one of them  combines the advantages of biodistribution favourable to BNCT, tumour-preferential enhancement of photon therapy, and negligible toxicity. Boron in a tumour-cell nucleus is about threefold more effective for BNCT than in the cytoplasm. An important advance, described thirteen years ago, has been the adaptation of secondary-ion mass-spectrometric microscopy to delineate 23Na, 39K, 40Ca, and 11B in thin sections of tissues from experimental animals . Although the challenges of synthesizing and testing minimally and reversibly toxic boron agents for BNCT that accumulate preferentially in tumour nuclei in vivo while clearing from the blood have not been surmounted [32, 39], at least one cyclic para-borono-carboxylamino acid, an analogue of L-4-boronophenylalanine [L-BPA], reportedly is superior in those respects to L-BPA [40, 41].
Archivists of the Louise M. Darling Biomedical Library, University of California at Los Angeles. Librarians of the University Library in Bern, Switzerland; Essex, Connecticut; Harrow, England; Madison, Wisconsin; Upton, New York; Urbana, Illinois. The authors' predecessors, colleagues, and mentors, in particular William Vernon Cone (1897–1959) of Montreal, Quebec, Canada, and Elizabeth Dutton Sweet of Brookline, Massachusetts, USA.
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