1977, British Journal of Radiology, 50, 652-657

RBE of neutrons generated by 50 MeV deuterons on beryllium for control of artificial pulmonary metastases of a mouse fibrosarcoma* By Kathryn A . Mason, B.S., M.S., and H. R. Withers, M.D., Ph.D. Section of Experimental Radiotherapy, The University of Texas System Cancer Center, M. D. Anderson Hospital and Tumor Institute, 6723 Bertner Avenue, Houston, Texas 77030, U.S.A. {Received November, 1976 and in revised form April, 1977)

ABSTRACT

Artificial pulmonary metastases of a mouse fibrosarcoma mouse colony, were used for all experiments. The were produced by the intravenous injection of 104 cells mice were maintained on a sterilized pellet diet 6 admixed with 2 X 10 plastic microspheres into mice preconditioned with 600 rad whole-body irradiation 24 hours (Wayne Sterilizable Lab Bloc), sterile acidified water earlier. Four days after injection of tumour cells, mice were (pH 2.5), and a 12-hour light-dark cycle. irradiated with neutrons generated by 50 MeV deuterons on The tumour, a fibrosarcoma, was originally inBe at the Texas A & M Variable Energy Cyclotron or with 137 Cs y rays. One, three or six fractions of radiation were duced in a young female mouse by a single subdelivered on a three-hour fractionation schedule. Surviving cutaneous injection of 1 mg methylcholanthrene suslung metastases were scored macroscopically 16 days after irradiation. The data indicate that: (1) the RBE (njy) was in pended in peanut oil (Suit and Suchato, 1967). the range 1.6-2.6 depending on the size of dose per fraction; Tumours of the fifth generation were used for all (2) the slopes of the y-ray curves decreased with increasing experiments. fraction number (i.e. decreasing fraction size); (3) the slopes The enzymatic (trypsin digestion) procedure for of the neutron curves decreased only slightly with increasing fraction number (and decreasing fraction size); (4) no addi- obtaining single cell suspensions was that described tional sparing was achieved by further fractionating doses of previously (Milas et al., 1974). Briefly, non-necrotic neutrons of 300 rad or less.

The aim of this investigation was two-fold: first to develop an in vivo system with which the radiobiological characteristics of artificial pulmonary metastases of an experimental rodent fibrosarcoma could be studied using clinically-relevant doses of radiation (100-400 rad per fraction); and second, to establish the relative biological effectiveness (RBE) of neutrons generated by 50 MeV deuterons on Be with respect to y rays for control of this tumour using single and fractionated doses. RBE is defined as the inverse of the ratio of the dose of a test radiation to the dose of a reference standard radiation giving the same biological effects (Storer et al., 1957). MATERIALS AND METHODS

Mice and tumours Female CaHf/Bu mice, 10-12 weeks old from the M. D. Anderson Hospital specific pathogen-free * This study was supported in part by the Department of Health, Education, and Welfare, National Institutes of

Health, National Cancer Institute grants CA-12542 and CA-11138. Animals used in this study were maintained in facilities approved by the American Association for Accreditation of Laboratory Animal Care, and in accordance with current United States Department of Agriculture and Department of Health, Education, and Welfare, National Institutes of Health regulations and standards.

tissue was minced and trypsinized for 20 minutes. The resulting digest was mixed with medium 199 (Difco Laboratories) containing 10% fetal calf serum (FCS). This suspension was passed through a stainless steel mesh (80 wires per cm) into 15 ml conical centrifuge tubes and centrifuged once at 1000 rpm and once at 700 rpm in a clinical benchtop centrifuge. The resulting cell pellet was resuspended in fresh medium 199 with 10% FCS. Cell viability as determined by phase contrast microscopy and exclusion of 0.25% trypan blue was routinely greater than 90%. The desired number of tumour cells (104) was suspended in medium 199 with 10% FCS and mixed with 2 X 106 plastic microspheres with diameters of 15 ± 5 /*ni (Minnesota Mining and Manufacturing) to increase the cloning efficiency (Hill and Bush, 1969). The resulting suspension was injected into a lateral tail vein of whole-body irradiated recipient mice (see below). Untreated controls were sacrificed 14 days after injection of cells while treated animals were sacrificed 16 days after thoracic irradiation (see Results). The mice were sacrificed by cervical fracture. Lungs were removed, the five lobes separated and placed in Bouin's fixative for 24 hours. The colonies of tumour cells were seen as round white nodules on the surface of the yellowish lung. Colony counts were made with the naked eye.

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SEPTEMBER 1977

RBE of 50 MeV neutrons for pulmonary metastases in mice TABLE I

Whole-body irradiation All animals were preconditioned with 600 rad yradiation to the total body 24 hours prior to the intravenous (i.v.) injection of viable tumour cells, for two reasons: to increase the cloning efficiency of the tumour cells in the lungs (Withers and Milas, 1973), and to minimize bias caused by immune suppression associated with the technical requirement of irradiating the whole-body when treating artificial lung metastases with neutrons compared with irradiating the thorax only with y rays. Groups of five animals were irradiated to the whole-body in a 137Cs unit with a single source situated 28 cm from mid-mouse as described previously (Stone and Withers, 1975). Irradiation of artificial pulmonary metastases 1. y rays: Mice were irradiated locally to the thorax using a dual source 137Cs unit. A similar unit has been described (Hranitzky et al., 1973). The dose rate was 195 rad per minute, determined by lithium fluoride thermoluminescent dosimeters. The mice were held in position in a tubular Lucite jig with the thorax positioned in the 3 cm diameter field. The fractionation interval for all split dose experiments was three hours. Thoracic irradiations were performed four days after the i.v. injection of tumour cells into preconditioned mice. 2. Neutrons: The Texas A & M Variable Energy Cyclotron (TAMVEC) was used for all neutron irradiations. Neutrons were produced by bombarding a beryllium target with a beam of 50 MeV deuterons. Mice received whole-body irradiation at a dose rate of 90 rad per minute. Whole-body irradiation was given because of difficulties in collimating the neutron beam for local irradiation of the thorax. The mice were protected from haematopoietic death by bone marrow reconstitution (see below). Mid-line doses in rads were determined using a 0.1 cm3 tissue-equivalent ion chamber inserted in a mouse phantom which was a 1.9 X 1.9 X 7.0 cm block of Shonka A-150 tissue equivalent plastic (Shonka et al., 1958). Groups of eight mice were positioned in individual well ventilated Lucite boxes on the front face of a 40 cm Lucite tank containing tissue-equivalent liquid (Frigerio et al., 1972). The distance from target to mid-mouse was 141 cm. The average distance from the front face of the Lucite mouse holder to the surface of the lung was 5 mm. At 3 mm depth, the dose is 92% of maximum; at 4 mm, 98% of maximum; at 5 mm 99% of maximum (Almond et al, 1973). 3. Comparison of irradiation techniques: Experiments were performed to determine if the techniques used for neutron irradiation to the whole body and

EFFECT OF IRRADIATION TECHNIQUE

Lung colonies Mean±SEM y-ray dose (rad) 750 900 1050 1200

Whole-body irradiation

Local thoracic irradiation

10.5±1.6 5.6±1.5 0.5±0.3 0.6±0.3

6.9±0.9 4.5±0.8 0.8±0.2 0.1 ±0.1

No significant difference in the number of surviving FSA lung colonies was found at the doses assayed when compared using the student's t test. In addition, the slopes of the survival curves were not significantly different (Do = 127 rad).

y irradiation to the thorax alone yield comparable results. Animals were given 600 rad of y rays to the whole body 24 hours prior to the i.v. injection of 104 tumour cells and 2 x 1 0 6 plastic microspheres. Four days after injection, groups of eight animals were irradiated either whole-body or locally to the thorax with y rays. The results in Table I show no difference between the two groups in the slopes of the survival curves, both values of Dy being 127 rad. Although the difference in numbers of lung colonies was not significant at p =0.05 it should be noted that the number of surviving colonies in whole-body irradiated mice tended to be higher. The effect of more colonies surviving in WBI mice would be to make the RBE for the neutrons slightly larger than that reported. All mice exposed to neutrons were rescued from haematopoietic death by the i.v. injection of 5 x 106 viable bone marrow cells 24 hours after irradiation. For this purpose bone marrow from tibiae and femora of donor mice was expelled into a beaker by forcing medium 199 through a needle inserted into the marrow cavity. Viability, determined by phase contrast microscopy, was greater than 90%. Analysis of results The number of surviving clonogenic tumour cells was plotted as a function of radiation dose in rad on semilogarithmic coordinates. The curves were fitted to the data using a least squares regression analysis. Date were plotted as the mean ^standard error of the mean (SEM). The results were statistically evaluated using student's t test. RESULTS

The optimum time at which to sacrifice the animals after irradiation was determined on the basis of

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the size and number of lung nodules. It can be seen in Fig. 1 that in control animals which received 104 cells the maximum number of lung nodules was observed by 10-12 days after injection and thereafter they increased only in size. Day 14 was chosen as the optimum time to sacrifice control animals because lung nodules were most easily counted then. If the animals were irradiated to the thorax with 600 or 1000 rad of y rays four days after injection of tumour cells, the nodule counts did not significantly change from 16 to 22 days after injection (Fig. 1). The nodule size in these mice was most like that in control animals when scored 20 days after injection, that is 16 days after irradiation. Lung colonies in neutron irradiated and y-ray treated animals were of comparable size 16 days after irradiation.

from eight animals plotted with the SEM. The important features to be noted are: 1. The y-ray curves show a progressive shift to the right to higher doses as the fraction number is increased. This reflects repair of sublethal damage between dose fractions (Elkind, 1967). 2. The RBE of neutrons is greater than 1 at all doses tested. 3. The slopes of the y-ray curves decrease (and values for DQ increase) with increasing fraction number, the result of decreasing size of dose per fraction (Table II). Since the slope of the survival curve obtained with multiple equal fractions reflects the slope of the single dose survival curve over the range of doses used in multifraction exposures (Withers et ah, 1975), the decreasing

Single and multifraction dose response of tumour cells to y rays and neutrons generated by 50 MeV deuterons on Be The single and multifraction dose response curves of the artificial pulmonary metastases are shown in Fig. 2. Each point represents the mean colony count

TABLE II Z>0 VALUES FOR 1 , 3 AND 6 FRACTION SURVIVAL CURVES FOR ARTIFICIAL PULMONARY METASTASES EXPOSED TO y RAYS OR NEUTRONS

Control

I00

100 600 Rods Day 4

Fraction number

Range of doses per fraction

Slope A>(95% confidence limits)

y rays 1 3 6

700-1350 375-650 175^25

150(124-189) 189(171-210) 259 (232-292)

Neutrons 1 3 6

300-700 180-310 80-160

101 (91-112) 119(111-128) 115 (113-118)

1000 Rods Day 4 10

12

16

20

24

0.1

II00

1500

I900

2300

Total Dose (Rods)

Days After FSA Injection FIG. 1.

Number of macroscopic fibrosarcoma (FSA) lung colonies plotted as a function of time after injection in untreated controls and after irradiation with 600 or 1000 rad thoracic irradiation with y rays. Thoracic irradiations 4 were performed four days after i.v. challenge with 10 FSA cells admixed with 2 X 106 plastic microspheres. Data are plotted as the mean±SEM.

FIG. 2. One, three and six fraction survival curves for pulmonary metastases exposed to neutrons or y rays. Preconditioned (600 rad to whole-body) animals were irradiated four days after the i.v. injection of 104 cells admixed with 2 X 106 plastic microspheres. Animals were sacrificed 16 days after irradiation. Data are plotted as the mean ± SEM. Colony forming units are plotted as a function of radiation dose on semi-logarithmic coordinates.

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RBE of 50 MeV neutrons for pulmonary metastases in mice Broerse, 1969; Stone and Withers, 1975; Suit and Maeda, 1966). Neutrons have been found to be more effective, relative to y rays, in damaging hypoxic cells (Barendsen and Broerse, 1966; Hall et al., 1975). However, the importance is not that a tumour contains hypoxic cells, but that these cells may limit the curability of the tumour. It has been found in many tumours that a natural continuing process of reoxygenation occurs between dose fractions (Van Putten and Kallman, 1968). In this situation, neutrons lose some of their therapeutic advantage over y rays. In the tumour model used in this study, it is unlikely that hypoxic cells, if present, significantly affect the radioresponse of this tumour as evidenced by the radiosensitivity of the cells to single doses of y rays (DQ 150 rad) which is similar to that of most well oxygenated tissues, and by the low RBE values. At present, it cannot be predicted which tumours will remain sufficiently hypoxic during fractionated dose radiotherapy that they would respond better to neutrons than to conventional radiotherapy. A comparison of the responses of a variety of animal tumours to neutrons and y rays may help to predict those types of tumours which could benefit from neutron therapy (Howlett et al., 1975). The second potential therapeutic advantage of neutrons is that their biological effect is influenced to a lesser extent than that of y rays by progression of cells through the division cycle (Withers et ah, 1974b). Exploitation of this difference is difficult without detailed knowledge of the kinetics of both the tumour and the adjacent normal tissues. Therefore, this difference has not been systematically exploited and any advantages gained from this differential response has been strictly fortuitous. A third potential advantage of neutron therapy is in reducing the variability in tumour response that may result if different tumours vary in their capacities for accumulating sublethal injury from y ray exposure, that is, if tumour cells vary in the width of the shoulder of their survival curves. Once again, any

slope of the y-ray curves with decreasing fraction size reflects the shallower slope in the shoulder region of the single dose curve. 4. The slopes of the neutron curves decrease only slightly with decreasing fraction size (Table II). This is consistent with a single dose survival curve which is exponential over a wide dose range (at least from 80 to 300 rad). Changes in radiosensitivity of surviving cells related to the division cycle during the fractionated dose regimens could account for small differences in slope; this makes definite statements about survival curve shape impossible. 5. The three and six fraction neutron curves are superimposed on each other (Fig. 2). Thus, when doses per fraction are 300 rad or less, no additional sparing is achieved by further fractionation into lower doses per fraction. This implies that all cell killing from doses up to at least 300 rad results from "single-event", non-repairable injury. RBE values derived from the survival curves in Fig. 2 are plotted as a function of y-ray dose on linear coordinates in Fig. 3. On linear coordinates the curve bends, the RBE increasing as the dose per fraction is decreased. Plotted on logarithmic coordinates, RBE values may be fitted by a straight line (Fig. 4) over the dose range tested. Both graphs demonstrate that the RBE increases with decreasing size of dose per fraction. For example, at 200 rad of y rays the RBE was 2.55, while at 1500 rad it was 1.70. DISCUSSION

The rationale for neutron therapy has been threefold. First, most solid animal tumours have been found to contain hypoxic cells (Barendsen and 2.8

1

T"

1

1

1

i

i

FSa ^

2.4

z UJ

-

g 2.01.6 -

~o" 400

800

1200

1600

Dose / Fraction 7 Ray FIG. 3. RBE values for neutrons and y rays for control of artificial pulmonary metastases. RBE is plotted as a function of dose per fraction of y rays on linear coordinates. The data are derived 137 from the survival curves in Fig. 2. The RBE is the dose of Cs y rays divided by the total dose (n+y) given when neutrons were used (50 MeV d on Be).

200

600

I000

I500 2000

Dose /Fraction /Ray FIG. 4. RBE plotted as a function of y-ray dose on logarithmic coordinates.

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advantage of using neutrons will require that the tumour be affected more than the normal tissue by eliminating the shoulder of the survival curve. The results presented in this paper suggest that the microscopic fibrosarcoma metastases would be relatively less affected by neutrons than would several normal tissues for which RBE values are greater than 2.5 at 200 rad of y rays (Field, 1975). The limiting factor determining the total dose delivered in radiotherapy is not the response of malignant tissue, but rather the acute and late normal tissue responses. In order for the RBE for tumour control to have any relevance, it must be compared with the RBE for effects on the normal tissues which are adjacent to the malignancy. Clearly, if the RBE for injury to the normal tissue is higher than for the malignant tissue, no therapeutic gain is achieved by using neutron therapy. In this situation, conventional radiotherapy would be the treatment of choice. Conversely, when the RBE is higher for the tumour than for the normal tissue around it, neutron therapy would be preferred. Table III presents RBE values at doses of about 180 rad of neutrons for some normal and malignant tissues exposed to neutrons generated at TAMVEC by 50 MeV deuterons on Be. While it has been shown that the RBE of neutrons generated by 16 MeV deuterons on Be for producing lung damage is relatively low (Field, 1975), this RBE has not been determined for the higher energy neutrons at TAMVEC. If it were less than 2.25 at 180 rad of neutrons (i.e. less than the RBE for control of fibrosarcoma tumour cells at this dose), TABLE III R B E VALUES OF SOME NORMAL AND MALIGNANT TISSUES IRRADIATED AT T A M V E C WITH NEUTRONS GENERATED BY 50 M E V DEUTERONS ON BE

Tissue Mouse artificial pulmonary metastases Mouse jejunum (Withers et al, 1974a) Mouse testis (Withers et al, 1976) Melanoma, in vitro (Thomson et al, 1975) CHO, in vitro (Thomson et al, 1975) Rhesus monkey oropharyngeal damage (Jardine et al, 1975) Human mucosal reaction (Hussey et al, 1974) Pig skin contraction (Withers et al, 1976)

there would be a therapeutic advantage in treating these lung metastases with neutrons compared with photons. However, the limited total dose tolerance of xthe lungs to any form of irradiation would diminish the apparent attractiveness of neutron therapy in this experimental setting. In fact, the dose required to control these pulmonary metastases in 50% of the animals (•—'1600 rad) exceeds the LDioo for late respiratory death. It should be emphasized that the relatively low RBE values reported apply only to these small, presumably well oxygenated, tumours in the lungs. The RBE for control of tumours is likely to vary with tumour type, size, site of growth and oxygenation. Therefore, it is impossible to predict from these experiments whether neutron therapy would be advantageous in the clinical management of micrometastases in the lungs. ACKNOWLEDGMENTS

We wish to thank Ms. Nancy Hunter for invaluable technical assistance, Nehama Dubravsky for helpful discussions and Dr. Lester J. Peters for assistance in the preparation of this manuscript. Appreciation is extended to Dr. Jim Smathers for performing the neutron dosimetry at TAMVEC. REFERENCES ALMOND, P. R., SMATHERS, J. B., OLIVER, G. D., JR., HRANITZKY, E. B., and ROUTT, K., 1973. Dosimetric

properties of neutron beams produced by 16-60 MeV deuterons on beryllium. Radiation Research, 54, 24-34. BARENDSEN, G. W., and BROERSE, J. J., 1966. Dependence of

the oxygen effect on the energy of fast neutrons. Nature, 212, 722-724. 1969. Experimental radiotherapy of a rat rhabdomyosarcoma with 15 MeV neutrons and 30 kV X-rays. I. Effects of single exposures. European Journal of Cancer, 5, 373-391. ELKIND, M. M., 1967. Sublethal X-ray damage and its repair in mammalian cells. In Radiation Research, ed. G. Selini, pp. 558-586 (North Holland Publishing Company, Amsterdam). FIELD, S. B., 1975. Some late effects of fast neutrons—lung and nervous system. In Particle Radiation Therapy {Proceedings of an International Workshop), pp. 211-232 (American College of Radiology, Key Biscayne, Florida). FRIGERIO, N. A., COLEY, R. F., and SAMPSON, M. J., 1972.

Depth dose determination. I. Tissue equivalent liquids for standard man and muscle. Physics in Medicine and Biology, 77,792-802.

Dose/ fraction of neutrons

RBE

180

2.25

190 160

2.5

180

2.0

180

2.0

180

2.4

180

2.4

180

2.55

HALL, E. J., ROIZIN-TOWLE, L., THEUS, R. B., and AUGUST,

L. S., 1975. Radiobiological properties of high-energy cyclotron-produced neutrons used for radiotherapy. Radiology, 117, 173-178. HILL, R. P., and BUSH, R. S., 1969. A lung-colony assay to

determine the radiosensitivity of the cells of a solid tumour. International Journal of Radiation Biology, 15, 435-444.

3.25

HOWLETT, J. F., THOMLINSON, R. H., and ALPER, T., 1975.

A marked dependence of the comparative effectiveness of neutrons on tumour line, and its implications for clinical trials. British Journal of Radiology, 48, 40-47. HRANITZKY, E. B., ALMOND, P. R., SUIT, H. D., and MOORE,

B. S., 1973. A cesium-137 irradiator for small laboratory animals. Radiology, 107, 641-644. HUSSEY, D. H., FLETCHER, G. H., and CADERO, J. B., 1974.

Experience with fast neutron therapy using the Texas A & M Variable Energy Cyclotron. Cancer, 34, 65-77. JARDINE, J. H., HUSSEY, D. H., BOYD, D. D., RAULSTON,

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RBE of 50 MeV neutrons for pulmonary metastases in mice G. L., and DAVIDSON, T. J., 1975. Acute and late effects of 16- and 50-MeVd—>BE neutrons on the oral mucosa of Rhesus monkeys. Radiology, 117, 185-192. MILAS, L., HUNTER, N., MASON, K., and WITHERS, H. R.,

1974. Immunological resistance to pulmonary metastases in CaHf/Bu mice bearing syngeneic fibrosarcoma of different sizes. Cancer Research, 34, 61-71. SHONKA, F. R., ROSE, J. E., and FAILLA, G., 1958. Con-

VAN PUTTEN, L. M., and KALLMAN, R. F., 1968. Oxygena-

tion status of a transplantable tumor during fractionated radiotherapy. Journal of the National Cancer Institute, 40, 441-451. WITHERS, H. R., and MILAS, L., 1973. Influence of pre-

irradiation of lung on development of artificial pulmonary metastases of fibrosarcoma in mice. Cancer Research, 33, 1931-1936.

ducting plastic equivalent tissue. In Second United WITHERS, H. R., CHU, A. M., MASON, K. A., REID, B. O., Nations Conference on Peaceful Uses of Atomic Energy, BARKLEY, H. T., JR., and SMATHERS, J. B., 1974a. paper 753, Geneva, United Nations. Response of jejunal mucosa to fractionated doses of STONE, H. B., and WITHERS, H. R., 1975. Metronidazole: neutrons or y-rays. European Journal of Cancer, 10, 249effect on radiosensitivity of tumor and normal tissue in 252. mice. Journal of the National Cancer Institute. 55, 1189- WITHERS, H. R., MASON, K., REID, B. O., DUBRAVSKY, N., 1194. BARKLEY, H. T., JR., BROWN, B. W., and SMATHERS, J. B., STORER, J. B., HARRIS, P. S., FURCHNER, J. E., and LANG1974b. Response of mouse intestine to neutrons and HAM, W. H., 1957. Relative biological effectiveness of gamma rays in relation to dose fractionation and division various radiations in mammalian systems. Radiation cycle. Cancer, 34, 39-47. Research, 6, 188-288. WITHERS, H. R., CHU, A. M., REID, B. O., and HUSSEY, SUIT, H., and MAEDA, M., 1966. Oxygen effect factor and D. H., 1975. Response of mouse jejunum to multitumor volume in the C3H mouse mammary carcinoma. A fraction radiation. Journal of Radiation Oncology, Biology preliminary report. The American Journal of Roentgenand Physics, /, 41-52. ology, Radium Therapy and Nuclear Medicine, 96, 177- WITHERS, H. R., HUNTER, N., and MASON, K. A., 1976. 182. Unpublished data.

SUIT, H. D., and SUCHATO, C , 1967. Hyperbaric oxygen

and radiotherapy of fibrosarcoma and of squamous cell carcinoma in C3H mice. Radiology, 89, 713-719. THOMSON, L. F., SMITH, A. R., and HUMPHREY, R. M.,

1975. The response of a human malignant melanoma cell line to high LET radiation. Radiology, 117, 149-154.

WITHERS, H. R., FLOW, B. L., HUCHTON, J. I., HUSSEY, D. H.i JARDINE, J. H., MASON, K. A., and SMATHERS,

J. B., 1977. Effect of dose fractionation on early and late skin responses to gamma-rays and neutrons. Journal of Radiation Oncology, Biology and Physics (in press).

Book review Ultrasonography of the Abdomen. By Nasser Hassani, pp. xvi+127, illus., 1976 (W. Germany, Springer-Verlag KG), 119.80. Grey scale display has been available on commercial ultrasound equipment for over two years, but owing to the long delays in publishing medical books, there are still few books illustrating the value of this advance. There is thus a great need for an atlas of grey scale images of the abdomen, and this book attempts to fill that need. The book boasts 215 illustrations and necessarily relies heavily on these illustrations with a basic minimum of text. However, 10% of the book is taken up by the two forewords, a preface, acknowledgments and an introduction. A further 25% is filled by a section on principles, machine controls (American equipment), administration of the department, duties of the technologist, etc. The first 35% is thus essentially redundant, the principles having now been covered in almost every book ever written on ultrasound. This leaves only 90 pages of potentially useful text covering the non-obstetric uses of ultrasound and, given good

657

quality illustrations, this could be most valuable. Regrettably, the scans included in this book are very poor. The basic ultrasound technique is frequently poor with excessive compounding, incorrect swept gain settings and no mention of the use of suspended inspiration for liver scanning. The grey scale of the original images is almost completely lost in these reproductions, most having only one shade of grey, some being positive, others negative, with no explanation of this in the captions. Additionally, many pictures are laterally inverted, three with no mention of this in the text, two pictures are badly out of focus and two sets of legends transposed. The still images from a very dated "real time" scanner are very poor and serve no useful purpose. The novice ultrasonographer will find the non-uniformity of image orientation and polarity confusing, the book of little value, and will have little difficulty in obtaining better images himself. H. B. MEIRE.