July 1979
Letters to the Editor Cleidocranial Dysplasia Editor: Cleidocranial dysplasia (CCD) is an autosomal dominant disorder with a wide phenotypical heterogeneity since more than 100 associated osseous malformations have been described in about 700 cases (1). We recently studied five children from 6 to 13 years of age in whom typical features of CCD were present. Also, two rare osseous malformations were observed: bilateral macrodactyly of the second toe in all cases and twelfth rib agenesis in 4; hypoplasia was observed in one. No functional impairment was seen. These findings constitute further evidence of the variable expressivity of the CCD gene and of the generalized skeletal involvement in this disorder, formerly considered a dysostosis (2)~
REFERENCES 1. Gorlin RJ, Pindborg JM, Cohen MM: Syndromes of the Head and Neck. New York, McGraw-Hili, 2nd ed, 1976, p 180
2. McKusick VA: Mendelian Inheritance in Man. Baltimore, Johns Hopkins, 5th ed, 1978, p 72 INDEX TERMS:
ties. Ribs, 4[O].1524)
Bones, osteochondrodysplasias • Fingers and toes, abnormaliabnormalities. (Skeletal system, cleidocranial dysplasia,
Radiology 132:238, July 1979
ZAMIRA NAZARA, M.D. RUBEN FRAGOSO, M.D. ALEJANDRO HERNANDEZ, M.D. JOSE-MARiA CANTU, M.D. Departamento de Radiodiagnostico (HE) Division de Genetica y Hernatoloqia Instituto Mexicano del Seguro Social Apartado Postal 1-3838 Guadalajara, Jalisco, Mexico
Dose-Latency Period for Radiation-Induced Myelitis in Rodents 100
Editor: In the September 1978 issue of RADIOLOGY, in "The Dose-Latent Period Relationship in the Irradiated Cervical Spinal Cord of the Rat" (1), Hubbard and Hopewell conclude that the latent period for myelopathy after irradiation of rat spinal cords is not a reliable experimental endpoint. Consequently, the validity of recent results using this endpoint to assess the effects of oxygen (2), dose fractionation schemes (3,4), and neutron irradiations (5) should be reconsidered. Similar to Hubbardand Hopewell, we have also found that the latency periods for adjacent dose groups sometimes overlap (Fig. 1) (5). However, when an analysis using many different dose groups is made over a large enough dose range, a linear exponential relationship between dose and latency period is clearly evident. The dose range of 35-50 Gy (3,500-5,000 rad) studied by Hubbard and Hopewell, which is indicated by the dotted line in Figure 1, is insufficient in itself to establish this relationship of dose versus latency period. These investigators studied an even smaller dose range in their split-dose experiment. Nevertheless, they do report a statistically significant difference in the latency period between single doses of 40 and 45 Gy (4,000 and 4,500 rad) of photons. This represents a difference of approximately 12 % in dose, which is smaller than that expected to occur with different fractionation schemes, neutron versus photon irradiation, and oxygen versus hypoxic spinal cords. The potential usefulness of the latency period as a biological endpoint is indicated by the close agreement on the mean latency period obtained by these authors and values obtained from the best fit line of Figure 1 as shown in TABLE I. This agreement is remarkable, considering that the experiments were performed by different investigators using different species of animals, and irradiating different sections of the cord. In summary, due to the inadequate dose range examined, the conclusion presented by Hubbard and Hopewell is as inconclusive as the results are admitted to be, and should perhaps be reconsidered.
\ \
_1_ - 6T
I
ja
(?) .. (9) I
- - - - - - - - -(4) .
(a)
. (7)
(710 . (a)
(/) ~
w w
10
~ g(l2)
(II) . (9)
6D-1
. (3)
I I
I
5~0
15.0
Fig. 1. Mean latent period preceding paralysis as a function of x-ray dose. Mean latent periods are calculated for animals which developed paralysis within one year. The number of animals developing paralysis in each dose group is indicated in parentheses. Dotted lines indicate the region studied by Hubbard and Hopewell (1).
238
JOSEPH P. GERACI, PH.D. Radiological Sciences University of Washington Seattle, Wash. 98195
239
LETTERS TO THE EDITOR
Vol. 132
TABLE I:
REFERENCES 1. HubbardBM, Hopewell JW: The dose-latent period relationship in the irradiated cervical spinal cord of the rat. Radiology 128:779-781, Sep 1978 2. Asbell SO, Kramer S: Oxygen effect on the production of radiation-induced myelitis in rats. Radiology 98:678-681, Mar 1971 3. Goffinet DR, Marsa GW, Brown JM: The effects of single and multifraction radiation courses on the mouse spinal cord. Radiology 119:709-713, Jun 1976 4. Leith JT, Lewinsky BS, Woodruff KH, et al: Tolerance of the spinal cord of rats to irradiation with cyclotron-accelerated helium ions. Cancer 35:1692-1700, Jun 1975 5. Geraci JP, Thrower PO, Jackson KL, et al: The relative biological effectiveness of fast neutrons for spinal cord injury. Radiat Res 59:496-503, Aug 1974
INDEX TERMS: Radiobiology, time-dose studies • (Spine and contents, effects of radiation, 3 [0].470)
Letters
LATENCY PERIOD AS A FUNCTION OF DOSE Mean Latency Period (weeks)
Dose (Gy [radj) 50 45
5,000 4,500
40
4,000
35
3,500
Hubbard & Hopewell (1) * 21.5 ± 1.3 19.0 ± 1.4
ro.a
25.4± ± 22.2 ± 21.8 ± 26.5 ± 20.3 ± 18.4 ± 25.2 ±
Geraci et al. (5)t 18.8 21.0
O.7( 1.7 1.0 1.6 0.6 0.9 0.5 0.9
22.2 ± 1.1 t
24.0
27.8
* Errors are the standard errors of the mean latency period of 6 rats. tValues are derived from least-square best-fit curve in Figure 1. tErrors are the standard errors of the mean of 7 independent experiments.
Dr. Hubbard and Dr. Hopewell Reply
Editor: We have read the ietter by Dr. Geraci with interest. The question of a dose-latent period relationship for the irradiated spinal cord is an important issue, and we welcome the opportunity for further discussion. The demonstration of a dose-latent period relationship by Geraci et al. (1) and other authors for both the spinal cord (2) and brain (3) was only achieved by the use of a very wide range of radiation doses. Exposure of the mammalian central nervous systems (CNS)to doses in the order of 100 Gy (10,000 rad) or more results in early death from so-called CNS-syndrome effects (4). The mechanism responsible for the development of this short-term effect is not comparable with that for the development of delayed radiation myelopathy as seen after clinical exposure. Therefore, using latent period to evaluate extremes of doses is to confuse two, possibly more, biological endpoints. We must therefore re-examine the case for a significant dose-latent period response for radiation doses in the range 25-50 Gy (2,500-5,000 rad) (a 100 % dose increment) where the pathogenesis of radiation necrosis would seem to be most clinically relevant. In his letter, Geraci draws attention to the similarities in mean latency period for animals in our study and those derived in his own, from a least squares fit of the dose-effect curve. The range of latency periods quoted by him for a 43 % increment in total dose, between 35 and 50 Gy (3,500 and 5,000 rad), would seem to agree exactly with the range of mean latency periods we obtained for different groups of animals treated with a fixed dose of 40 Gy (4,000 rad) (5). The suggested significant difference in latency period between single doses of 40 and 45 Gy (4,000 and 4,500 rad) reported in our own initial study was clearly a chance occurrence. Additional evidence to support the lack of a truly significant doselatent period effect over a clinically relevant dose range can be obtained by examining the crude data of Geraci (his present letter) and that of others (2); the latent period over the dose range 25-40 Gy (2,500-4,000 rad) was apparently unchanged. Furthermore, Kogel and Barendsen (6) noted no change in the latency period for myelopathy following irradiation of the rat lumbar cord with doses of 20-40 Gy (2,000-4,000 rad). We maintain that following clinically applicable doses of radiation, latent period is not a reliable experimental endpoint for the spinal cord
and should not therefore be used in the evaluation of experimental treatment regimes related to therapy.
Editor: The recent paper in RADIOLOGY by Hubbard and Hopewell (1), which deals with the relationship between radiation dose to the spinal cord and latent period for development of myelopathy, appears at least su-
perficially to contradict earlier published results, such as those of Geraci et al. (2). However, careful analysis of the data in the two papers reveals that the differences may be more apparent than real. Geraci et al. demonstrated that the latent period is inversely pro-
BETHAN M. HUBBARD, D. PHIL. Department of Pathology Ninewells Hospital Dundee Scotland J. W. HOPEWELL, PH.D. Churchill Hospital Research Institute University of Oxford Headington Oxford England OX3 7LJ
REFERENCES 1. Geraci JP, Thrower PO, Jackson KL, et al: The relative biological effectiveness of fast neutrons for spinal cord injury. Radiat Res 59:496-503, Aug 1974 2. Goffinet DR, Marsa GW, Brown JM: The effects of single and multifraction radiation courses on the mouse spinal cord. Radiology 119:709-713, Jun 1976 3. Pourquier H, Baker JR, Giaux G, et al: Localized roentgen-ray beam irradiation of the hypophysohypothalamic region of guinea pigs with a 2 million volt Van de Graaff generator. Am J Roentgenol 80: 840-850, Nov 1958 4. Zeman W: Radiosensitivity of nervous tissue. (In) Fundamental Aspects of Radiosensitivity. Brookhaven Symp in Bioi 14:176-199, 1961 5. Hubbard BM, Hopewell JW: The dose-latent period relationship in the irradiated cervical spinal cord of the rat. Radiology 128:779-781, Sep 1978 6. Kogel AJ van der, Barendsen GW: Late effects of spinal cord irradiation with 300 kV x rays and 15 MeV neutrons. Br J Radiol 47: 393-398,JuI1974
240
LETTERS TO THE EDITOR
portional to x-ray doses ranging from 20 to 150 Gy (2,000 to 15,000 rad), and that the relationship is a simple exponential function (Figure 3 of Reference 2). Unfortunately, they did not publish their results in tabular form or provide statistical analysis of their data. However, inspection of their plot indicates the absence of significant differences in latent periods from radiation doses differing by less than about 10 Gy (1,000 rad). Hubbard and Hopewell found no significant differences in latent period with single radiation doses ranging from 35 to 50 Gy (3,500 to 5,000 rad), unless doses differed by at least 10 Gy (1,000 rad). When the dose was delivered in two fractions (5 + 40 or 10 + 40 Gy [500 + 4,000 or 1,000 + 4,000 radj) separated by either 24 hours or one week, they found no significant differences between latent periods between the fractionated exposure and a single dose of 40 Gy (4,000 rad). However, if the fractions were separated by one month, the latent period from fractionated exposure was significantly shorter than that from a single dose of 40 Gy. (Their choice of 40 Gy as the single-dose control is another matter, and will not be discussed here.) The authors attributed this result to an effect of age at exposure, but they found no consistent relationship between age at exposure and duration of the latent period. The most logical explanation of their aberrant results of fractionation and age at exposure is biologic variation. An inverse relationship between dose and latent period for the development of an effect is a fundamental principle of radiobiology. This
July 1979
principle appears to hold for injury to the spinal cord, provided the dose range is sufficiently large. However, if doses are confined to the range of interest in clinical radiation oncology, biologic variation may obscure this fundamental result, as in the results of Hubbard and Hopewell. Judging from the results of both papers considered here, it appears that the use of the latent period may be unreliable as an end point for clinically relevant studies in radiation oncology, such as relative tolerance of various fractionation schemes.
S. JULIAN GIBBS, D.D.S., PH.D. Department of Radiology Vanderbilt University Hospital Nashville, Tenn. 37232
REFERENCES 1. Hubbard BM, Hopewell JW: The dose-latent period relationship in the irradiated cervical spinal cord of the rat. Radiology 128:779-781, Sep 1978 2. Geraci JP, Thrower PO, Jackson KL, et al: The relative biological effectiveness of fast neutrons for spinal cord injury. Radiat Res 59:496-503, Aug 1974
Letters to the Editor Cleidocranial Dysplasia Editor: Cleidocranial dysplasia (CCD) is an autosomal dominant disorder with a wide phenotypical heterogeneity since more than 100 associated osseous malformations have been described in about 700 cases (1). We recently studied five children from 6 to 13 years of age in whom typical features of CCD were present. Also, two rare osseous malformations were observed: bilateral macrodactyly of the second toe in all cases and twelfth rib agenesis in 4; hypoplasia was observed in one. No functional impairment was seen. These findings constitute further evidence of the variable expressivity of the CCD gene and of the generalized skeletal involvement in this disorder, formerly considered a dysostosis (2)~
REFERENCES 1. Gorlin RJ, Pindborg JM, Cohen MM: Syndromes of the Head and Neck. New York, McGraw-Hili, 2nd ed, 1976, p 180
2. McKusick VA: Mendelian Inheritance in Man. Baltimore, Johns Hopkins, 5th ed, 1978, p 72 INDEX TERMS:
ties. Ribs, 4[O].1524)
Bones, osteochondrodysplasias • Fingers and toes, abnormaliabnormalities. (Skeletal system, cleidocranial dysplasia,
Radiology 132:238, July 1979
ZAMIRA NAZARA, M.D. RUBEN FRAGOSO, M.D. ALEJANDRO HERNANDEZ, M.D. JOSE-MARiA CANTU, M.D. Departamento de Radiodiagnostico (HE) Division de Genetica y Hernatoloqia Instituto Mexicano del Seguro Social Apartado Postal 1-3838 Guadalajara, Jalisco, Mexico
Dose-Latency Period for Radiation-Induced Myelitis in Rodents 100
Editor: In the September 1978 issue of RADIOLOGY, in "The Dose-Latent Period Relationship in the Irradiated Cervical Spinal Cord of the Rat" (1), Hubbard and Hopewell conclude that the latent period for myelopathy after irradiation of rat spinal cords is not a reliable experimental endpoint. Consequently, the validity of recent results using this endpoint to assess the effects of oxygen (2), dose fractionation schemes (3,4), and neutron irradiations (5) should be reconsidered. Similar to Hubbardand Hopewell, we have also found that the latency periods for adjacent dose groups sometimes overlap (Fig. 1) (5). However, when an analysis using many different dose groups is made over a large enough dose range, a linear exponential relationship between dose and latency period is clearly evident. The dose range of 35-50 Gy (3,500-5,000 rad) studied by Hubbard and Hopewell, which is indicated by the dotted line in Figure 1, is insufficient in itself to establish this relationship of dose versus latency period. These investigators studied an even smaller dose range in their split-dose experiment. Nevertheless, they do report a statistically significant difference in the latency period between single doses of 40 and 45 Gy (4,000 and 4,500 rad) of photons. This represents a difference of approximately 12 % in dose, which is smaller than that expected to occur with different fractionation schemes, neutron versus photon irradiation, and oxygen versus hypoxic spinal cords. The potential usefulness of the latency period as a biological endpoint is indicated by the close agreement on the mean latency period obtained by these authors and values obtained from the best fit line of Figure 1 as shown in TABLE I. This agreement is remarkable, considering that the experiments were performed by different investigators using different species of animals, and irradiating different sections of the cord. In summary, due to the inadequate dose range examined, the conclusion presented by Hubbard and Hopewell is as inconclusive as the results are admitted to be, and should perhaps be reconsidered.
\ \
_1_ - 6T
I
ja
(?) .. (9) I
- - - - - - - - -(4) .
(a)
. (7)
(710 . (a)
(/) ~
w w
10
~ g(l2)
(II) . (9)
6D-1
. (3)
I I
I
5~0
15.0
Fig. 1. Mean latent period preceding paralysis as a function of x-ray dose. Mean latent periods are calculated for animals which developed paralysis within one year. The number of animals developing paralysis in each dose group is indicated in parentheses. Dotted lines indicate the region studied by Hubbard and Hopewell (1).
238
JOSEPH P. GERACI, PH.D. Radiological Sciences University of Washington Seattle, Wash. 98195
239
LETTERS TO THE EDITOR
Vol. 132
TABLE I:
REFERENCES 1. HubbardBM, Hopewell JW: The dose-latent period relationship in the irradiated cervical spinal cord of the rat. Radiology 128:779-781, Sep 1978 2. Asbell SO, Kramer S: Oxygen effect on the production of radiation-induced myelitis in rats. Radiology 98:678-681, Mar 1971 3. Goffinet DR, Marsa GW, Brown JM: The effects of single and multifraction radiation courses on the mouse spinal cord. Radiology 119:709-713, Jun 1976 4. Leith JT, Lewinsky BS, Woodruff KH, et al: Tolerance of the spinal cord of rats to irradiation with cyclotron-accelerated helium ions. Cancer 35:1692-1700, Jun 1975 5. Geraci JP, Thrower PO, Jackson KL, et al: The relative biological effectiveness of fast neutrons for spinal cord injury. Radiat Res 59:496-503, Aug 1974
INDEX TERMS: Radiobiology, time-dose studies • (Spine and contents, effects of radiation, 3 [0].470)
Letters
LATENCY PERIOD AS A FUNCTION OF DOSE Mean Latency Period (weeks)
Dose (Gy [radj) 50 45
5,000 4,500
40
4,000
35
3,500
Hubbard & Hopewell (1) * 21.5 ± 1.3 19.0 ± 1.4
ro.a
25.4± ± 22.2 ± 21.8 ± 26.5 ± 20.3 ± 18.4 ± 25.2 ±
Geraci et al. (5)t 18.8 21.0
O.7( 1.7 1.0 1.6 0.6 0.9 0.5 0.9
22.2 ± 1.1 t
24.0
27.8
* Errors are the standard errors of the mean latency period of 6 rats. tValues are derived from least-square best-fit curve in Figure 1. tErrors are the standard errors of the mean of 7 independent experiments.
Dr. Hubbard and Dr. Hopewell Reply
Editor: We have read the ietter by Dr. Geraci with interest. The question of a dose-latent period relationship for the irradiated spinal cord is an important issue, and we welcome the opportunity for further discussion. The demonstration of a dose-latent period relationship by Geraci et al. (1) and other authors for both the spinal cord (2) and brain (3) was only achieved by the use of a very wide range of radiation doses. Exposure of the mammalian central nervous systems (CNS)to doses in the order of 100 Gy (10,000 rad) or more results in early death from so-called CNS-syndrome effects (4). The mechanism responsible for the development of this short-term effect is not comparable with that for the development of delayed radiation myelopathy as seen after clinical exposure. Therefore, using latent period to evaluate extremes of doses is to confuse two, possibly more, biological endpoints. We must therefore re-examine the case for a significant dose-latent period response for radiation doses in the range 25-50 Gy (2,500-5,000 rad) (a 100 % dose increment) where the pathogenesis of radiation necrosis would seem to be most clinically relevant. In his letter, Geraci draws attention to the similarities in mean latency period for animals in our study and those derived in his own, from a least squares fit of the dose-effect curve. The range of latency periods quoted by him for a 43 % increment in total dose, between 35 and 50 Gy (3,500 and 5,000 rad), would seem to agree exactly with the range of mean latency periods we obtained for different groups of animals treated with a fixed dose of 40 Gy (4,000 rad) (5). The suggested significant difference in latency period between single doses of 40 and 45 Gy (4,000 and 4,500 rad) reported in our own initial study was clearly a chance occurrence. Additional evidence to support the lack of a truly significant doselatent period effect over a clinically relevant dose range can be obtained by examining the crude data of Geraci (his present letter) and that of others (2); the latent period over the dose range 25-40 Gy (2,500-4,000 rad) was apparently unchanged. Furthermore, Kogel and Barendsen (6) noted no change in the latency period for myelopathy following irradiation of the rat lumbar cord with doses of 20-40 Gy (2,000-4,000 rad). We maintain that following clinically applicable doses of radiation, latent period is not a reliable experimental endpoint for the spinal cord
and should not therefore be used in the evaluation of experimental treatment regimes related to therapy.
Editor: The recent paper in RADIOLOGY by Hubbard and Hopewell (1), which deals with the relationship between radiation dose to the spinal cord and latent period for development of myelopathy, appears at least su-
perficially to contradict earlier published results, such as those of Geraci et al. (2). However, careful analysis of the data in the two papers reveals that the differences may be more apparent than real. Geraci et al. demonstrated that the latent period is inversely pro-
BETHAN M. HUBBARD, D. PHIL. Department of Pathology Ninewells Hospital Dundee Scotland J. W. HOPEWELL, PH.D. Churchill Hospital Research Institute University of Oxford Headington Oxford England OX3 7LJ
REFERENCES 1. Geraci JP, Thrower PO, Jackson KL, et al: The relative biological effectiveness of fast neutrons for spinal cord injury. Radiat Res 59:496-503, Aug 1974 2. Goffinet DR, Marsa GW, Brown JM: The effects of single and multifraction radiation courses on the mouse spinal cord. Radiology 119:709-713, Jun 1976 3. Pourquier H, Baker JR, Giaux G, et al: Localized roentgen-ray beam irradiation of the hypophysohypothalamic region of guinea pigs with a 2 million volt Van de Graaff generator. Am J Roentgenol 80: 840-850, Nov 1958 4. Zeman W: Radiosensitivity of nervous tissue. (In) Fundamental Aspects of Radiosensitivity. Brookhaven Symp in Bioi 14:176-199, 1961 5. Hubbard BM, Hopewell JW: The dose-latent period relationship in the irradiated cervical spinal cord of the rat. Radiology 128:779-781, Sep 1978 6. Kogel AJ van der, Barendsen GW: Late effects of spinal cord irradiation with 300 kV x rays and 15 MeV neutrons. Br J Radiol 47: 393-398,JuI1974
240
LETTERS TO THE EDITOR
portional to x-ray doses ranging from 20 to 150 Gy (2,000 to 15,000 rad), and that the relationship is a simple exponential function (Figure 3 of Reference 2). Unfortunately, they did not publish their results in tabular form or provide statistical analysis of their data. However, inspection of their plot indicates the absence of significant differences in latent periods from radiation doses differing by less than about 10 Gy (1,000 rad). Hubbard and Hopewell found no significant differences in latent period with single radiation doses ranging from 35 to 50 Gy (3,500 to 5,000 rad), unless doses differed by at least 10 Gy (1,000 rad). When the dose was delivered in two fractions (5 + 40 or 10 + 40 Gy [500 + 4,000 or 1,000 + 4,000 radj) separated by either 24 hours or one week, they found no significant differences between latent periods between the fractionated exposure and a single dose of 40 Gy (4,000 rad). However, if the fractions were separated by one month, the latent period from fractionated exposure was significantly shorter than that from a single dose of 40 Gy. (Their choice of 40 Gy as the single-dose control is another matter, and will not be discussed here.) The authors attributed this result to an effect of age at exposure, but they found no consistent relationship between age at exposure and duration of the latent period. The most logical explanation of their aberrant results of fractionation and age at exposure is biologic variation. An inverse relationship between dose and latent period for the development of an effect is a fundamental principle of radiobiology. This
July 1979
principle appears to hold for injury to the spinal cord, provided the dose range is sufficiently large. However, if doses are confined to the range of interest in clinical radiation oncology, biologic variation may obscure this fundamental result, as in the results of Hubbard and Hopewell. Judging from the results of both papers considered here, it appears that the use of the latent period may be unreliable as an end point for clinically relevant studies in radiation oncology, such as relative tolerance of various fractionation schemes.
S. JULIAN GIBBS, D.D.S., PH.D. Department of Radiology Vanderbilt University Hospital Nashville, Tenn. 37232
REFERENCES 1. Hubbard BM, Hopewell JW: The dose-latent period relationship in the irradiated cervical spinal cord of the rat. Radiology 128:779-781, Sep 1978 2. Geraci JP, Thrower PO, Jackson KL, et al: The relative biological effectiveness of fast neutrons for spinal cord injury. Radiat Res 59:496-503, Aug 1974
