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CLINICAL STUDIES WITH THE AID OF

RADIO-PHOSPHORUS. IV. THE RETENTION IN

BLOOD, THE EXCRETION AND THE

THERAPEUTIC EFFECT OF

RADIO-PHOSPHORUS ON

PATIENTS WITH

LEUKEMIA *

By L. A. ERF, M.D.,f L. W. TUTTLE, and J. H. LAWRENCE, M.D.,

Berkeley, California

Previous studies 19'20' 8 1»2 2'3 4'3 5 have shown that radiophosphorus (mP32)

(which owes its radioactivity to the spontaneous emission of beta rays) when administered in the form of sodium phosphate, at first concentrates in the bone marrow and those tissues infiltrated with leukemic cells and later con-centrates in the osseous tissues. Radio-phosphorus has been used as a thera-peutic agent during the past three years in all types of leukemia, with en-couraging results. The principal advantages offered by radio-phosphorus appear to lie in its ease of administration (it may be given orally, intra-venously, etc.), in its therapeutic effectiveness and in the fact that nausea, " radiation sickness " and other symptoms do not occur following its

admin-istration. This report deals with the rate at which P32 is absorbed into the

blood and is excreted in the urine and feces of various patients and normal individuals, in addition to its therapeutic effectiveness in patients with leukemia. One hundred case studies are presented.

MATERIALS AND METHODS

A. Radio-phosphorus.

1. Production and quantitation.

The radioactive phosphorus was produced by the Berkeley cyclotron.18

This instrument directs streams of very rapidly moving (16 Mev) deuterons (nuclei of heavy hydrogen) into ordinary red phosphorus (atomic weight, 31), and thereby converts some of it into radioactive phosphorus (atomic weight 32), which emits beta-particles only, with energies averaging 600,000 electron-volts and has a half-life of 14.3 days (i.e., at the end of a period of 14.3 days, one-half as many beta-rays are emitted as were being emitted at the start of the period). During bombardment the number of phosphorus atoms that become radioactive depends on the number and the energies of the striking deuterons. At present about one in every million atoms is made radioactive. This mixture of radio-phosphorus and inactive phosphorus is then converted into an aqueous solution of dibasic sodium phosphate

* Received for publication May 7, 1941.

Aided by a grant from the Blanche and Frank Wolf Fund of the University of California. fWm. R. Kenan, Jr., Fellow.

(2)

4 8 8 L. A. ERF, L. W. TUTTLE AND J . H. LAWRENCE

(Na2HP04) of various concentrations (15 to SO mg. per cc.) for oral and

intravenous use. The amount of radiation emitted by the sodium phosphate solution depends upon the number of atoms of radioactive phosphorus

present. When a sample emits 3.7 X 107 beta-particles per second it is said

to contain one millicurie of beta-radiation. One microcurie is 1/1000 of a millicurie. Because of the innumerable factors which must be taken into consideration it is difficult to discuss this type of radiation in terms of " r " units with which the roentgenologist is familiar, but the radiations emitted by radio-phosphorus may be converted into " r " units by using the following equivalents: 1 microcurie = 37,000 beta-particles per second; 1 " r " = l e.s.u. of ions per cubic centimeter of air at S.T.P. The number of beta-particles multiplied by their average energy gives the total energy. This total energy, divided by the energy required to form one ion pair (about 32 eV) gives the number of ion pairs. Therefore the number of ion pairs formed by one microcurie of radio-phosphorus per second is equal to 37,000 (number of beta-particles) X 600,000 (average energy of one beta-particle)

divided by 32 (energy to form one ion pair) = 7 X 108. To compare this

with 1 " r " unit in water (or tissue) we must consider that 1 " r " unit in

air = 1 e.s.u./c.c. = 2.1 X 109 ion pairs/c.c; the same dose of x-radiation

in water produces an ionization greater than this by the ratio (density of

water) divided by (density of air), or 2.1 X 109 X 800 = 1.7 X 1012 ion

pairs/c.c. Therefore 1 microcurie of radio-phosphorus contained in 1 cc.

of water produces an ionization in this volume equal to 7 X 108 divided by

1.7 X 1012 = 4.1 X 10"4 " r " units per second. The dose in one day is now

obtained by multiplying this result by the number of seconds in a day (86,000), which gives the result:

1 microcurie/cc of water physically equals approximately 35 " r " units, dosage per day.

Thus, according to the above calculations, if a man weighing 50 kg. com-pletely absorbed 1 millicurie of radio-phosphorus, and if these atoms are temporarily and evenly distributed throughout the body, he would be receiv-ing in terms of roentgens the followreceiv-ing calculated dose of irradiation for twenty-four hours:

1 fi c/50 gm. (body weight) = 1/50 /* c/gm. or c c of tissue. 1/50 X 35 = 35/50 or 0.7 " r " whole body irradiation in 24 hours. Since absorption is not complete, and since there is excretion and decay of

P82, the actual dose of irradiation decreases from day to day. Furthermore,

the phosphorus atoms are not uniformly distributed and some tissues, such as bone marrow and tissues infiltrated with leukemia cells, receive by far the greatest amounts of irradiation.

The words " microcurie " or " millicurie " which appear throughout this paper refer to the number of beta-particles per second emitted by the solution

(3)

CLINICAL STUDIES WITH AID OF RADIO-PHOSPHORUS 4 8 9

or tissue in question, as compared with a uranium standard (which emits 500 beta-particles per second), and not to standards emitting mixed radiations

(alpha, gamma and beta) such as radium. 2. Dosage.

After the solution of dibasic sodium phosphate has been assayed for radioactivity, it may be administered by several routes. The most con-venient is, of course, the oral route. The solution is mixed with equal parts

of orange juice and is administered to the patient before breakfast.8 It may

be given intravenously, intraperitoneally, subcutaneously, intramuscularly, directly into tumors, or as an unction.

Single oral doses have varied from 1 to 20 millicuries, depending on the age of the patient and the type of the disease; single intravenous doses have varied from 0.5 to 6 millicuries. Less than 3 grams of sodium phosphate have been administered orally in each dose; less than 1 gram when given intravenously. Two factors especially have governed the dosages admin-istered to the patients reported in this paper. First, tolerance of patients to irradiation of any kind varies markedly so that the first doses given were always small. Second, the concentration of radiation had to be kept at a level which would do only minimal damage to the normal cells of the body. The first doses administered were determined by the following considera-tions :

a. The lethal dose of radio-phosphorus for a 20-gram mouse is approxi-mately that amount given intraperitoneally which emits 70 microcuries of beta-radiation; for a 6-pound monkey, 7 millicuries by the same route. These results suggest that the lethal dose of radio-phosphorus for an average adult human would be well over one hundred millicuries.

b. By the Heublein technic 4 as much as 20 " r " of x-radiation have been administered to the whole body daily for a period of three weeks' time to patients with various diseases.

Therefore the first doses of radio-phosphorus administered to adult pa-tients were those which emitted between 1 and 5 millicuries of beta-radiation. The succeeding doses varied according to the clinical status and the levels of the red and white blood cells of the patient—the same guides used by roentgenologists.

Since the half-life of radio-phosphorus is but 14.3 days, there is no danger of cumulative radiation effects similar to those produced by such agents as radium or thorium which have half-lives of hundreds of years. Furthermore, from 25 to 50 per cent of a dose of radio-phosphorus is ex-creted by normal individuals during the six days after administration and

1 to 2 per cent daily thereafter. At that rate of excretion and considering the constant rate of decay, about 15 per cent of a dose would be retained at the end of two weeks. Six to eight weeks after a single administration of radio-phosphorus only insignificant amounts of radiation are found in any

(4)

TABLES

Clinical Data Previous to Administration of Radio-Phosphorus

Phy. and Lab. Findings on Adm. Biopsy

Nam e an d Number s Se x an d Ag e Dat e o f Admissio n Chie f Complaint s an d Duratio n o f Chie f Com -plaint s o n Admissio n Diagnosi s an d Treatmen t Previou s t o Admissio n Characteristic s o f Periphera l Lymp h Node s Extensio n o f Splee n Belo w Costa l Margi n i n Cm . Extensio n o f Live r Belo w Costa l Margi n i n Cm . Othe r Finding s On Admis-sion M = Sterna l Marro w L = Lymp h Nod e R = Ri b Marro w S = Ski n Hype r = Hyperplasti c Chemistr y an d Serology , etc . Roentgenologica l Finding s R = Rarefactio n Nam e an d Number s Se x an d Ag e Dat e o f Admissio n Chie f Complaint s an d Duratio n o f Chie f Com -plaint s o n Admissio n Diagnosi s an d Treatmen t Previou s t o Admissio n Characteristic s o f Periphera l Lymp h Node s Extensio n o f Splee n Belo w Costa l Margi n i n Cm . Extensio n o f Live r Belo w Costa l Margi n i n Cm . Othe r Finding s H b (% ) Sahl i WBC/Cu . mm . in lOOO' s M = Sterna l Marro w L = Lymp h Nod e R = Ri b Marro w S = Ski n Hype r = Hyperplasti c Chemistr y an d Serology , etc . Roentgenologica l Finding s R = Rarefactio n 1 2 3 4 5 6 7 8 9 10 11 12 13 14 T A B L E I.

lMie M43 5/27/40 Fracture external malleolus of right foot

Normal None None Body weight 201 lbs.

77 6 Wass.-neg.

2 Per M35 7/19/40 Fracture external malleolus of right foot Body weight 154 lbs. 85 8 Wass.-neg.

3 Rob M31 3/25/40 Fracture radius of

right arm Body weight

144 lbs. 93 7

4 Vic M32 6/17/40 Wire (4.5 cm.) for-eign body removed surgically from right foot Body weight 152 lbs. 85 6 Wass.-ne;$. TABLE IV. 92Agn M40 2/ 9/38 Fatigue 1 Anorexia [5 mo. Cough j Abdominal pain— 3 wks. None

NoR, Small and shotty 1 Fundal hemor-rhage and pallor 75 41 S. lesion-no leu^ kemia in-filtration M—hyper (many mono-blasts) Wass.-neg. * 93 Mac T A B L E V. a. Lymphemic 94 Bio M59 5/19/39 Generalized) aches [2 wks. Weakness J None No I* Small and shotty 2 4 70 10 M—hyper infiltrated with plas-ma cell R—plas-ma cell infiltration

Total blood protein 6.6% Benoe-Jones Proteinuria + + + +

b. Non-Lymphemic

95 Ril M42 6/ 7/40 Backache—1 yr. Multiple myeloma March 1940 X-radiation— amount unknown Shotty 77 4 M—hyper 15% plasma cells Bence-Jenes Proteinuria + + + Dif-fuse R bony de- struc-tion of many bones * Previously published.

(5)

I, IV, V p « AND Treat Radia-tion VI ment Transfusion Clinical

Phy. and Lab. Findings

Data

Remis-sions

after Adm inisl tration of Radio-Phosphorus

pa2 Postmortem Findings Studies

Date s an d Tota l Dosage s of Radio-Phosphoru s (i n Millicuries ) Adm . 0 . = Orall y I.V . = Intravenousl y c 2 § § CJ C 11 1 et Q S 3 18 "5 ° o 5 o °

3

19

1 :*s

!

i l l ,

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525 1 I I J m J i H Q P Min. and Max. Levels i . §<* B13S3

115

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it

11

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8 .5 -o c £ 'E. o

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3

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3 15 16 17 S 3 18 "5 ° o 5 o °

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Si W 21 22 23 24 25 26 27 28 29 30 Normal Persons 7/22/40 1.5 (0.) 1 j -76 to 77 6 to 7 P B E 1 7/22/40 1.5 (I.V.) -76 to 85 5 to 8 P B E 2 7/22/40 1.5 (0.) -88 to 93 7 t o 8 P B E 3 7/22/40 1.5 (I.V.) -84 to 85 6 to 7 P B E 4

Monocytoid Leukemia (Acute)

3/1/39 to 3/3/39 6.9 (0.) -3/ 6/39 4 Gums swollen and ecohymotic Liver 2840; spleen 900 Bone marrow —red Reticuloendothelial hyperplasia of most organs including the kidneys and submucosa of G.I. tract T 92 1 1/13/38 to 2/18/38 23.24 (0.) -2/21/38 18 Gums edema-tous and ecohymotic Liver 2325; spleen 750 Marrow—red Monocytoid infiltration lungs and heart, kid-neys, adrenal, ovaries, breast, submucosa of G.I. tract, gall bladder, liver and hemopoietic organs

T 93

Plasmacytoid Leukemia (Acute)

a. Lymphemic G/10/39 to 6/29/39 14.9 (0.) 6/10/39 to 6/25/39 6 3000 L N - U s-u L - U 30 to 70 10 to 20 8/19/39 17 Liver 2720; spleen 760 Marrow—red

Plasma cell infiltration of most organs including marrow, kidneys and submucosa of G.I. tract

T 94 b. Non-Lymphemic 6/7/40 to 9/3/40 20 (0.) 12/8/40 to 2/12/41 4.6 radio-strontium 11/7/40 to 3/1/41 2 1200 LN—U S - U L - U 50 to 77 1 to 4 Good (Pt. being treated with

radiostrontium)

P B E

(6)

TABLES Clinical Data Previous to Administration of Radio-Phosphorus

Phys. and Lab. Findings i on A dm. Biopsy

| 8 ow * Admis-On c Nam e an d Number s Se x an d Ag e Dat e o f Admissio n Chie f Complaint s an d Duratio n o f Chie f Co m plaint s o n Admissio n Diagnosi s an d Treatm e Previou s t o Admissio n Characteristic s o f Periphera l Lymp h No d Extensio n o f Splee n B e Costa l Margi n i n Cm . Extensio n o f Live r Bel c Costa l Margi n i n Cm . Othe r Finding s 1 sion M = Sterna l Marro w L = Lymp h Nod e R = Ri b Marro w S = Ski n Hype r = Hyperplasti c Chemistr y an d Serology , etc . Roentgenologica l Find i R = Rarefactio n Nam e an d Number s Se x an d Ag e Dat e o f Admissio n Chie f Complaint s an d Duratio n o f Chie f Co m plaint s o n Admissio n Diagnosi s an d Treatm e Previou s t o Admissio n Characteristic s o f Periphera l Lymp h No d Extensio n o f Splee n B e Costa l Margi n i n Cm . Extensio n o f Live r Bel c Costa l Margi n i n Cm . Othe r Finding s H b (% ) Sahl i WBC/Cu . mm . in lOOO' s M = Sterna l Marro w L = Lymp h Nod e R = Ri b Marro w S = Ski n Hype r = Hyperplasti c Chemistr y an d Serology , etc . Roentgenologica l Find i R = Rarefactio n 1 2 3 4 5 1 1 6 7 8 ! 9 10 11 12 13 14 TABLE VI.

a. Myeloid (Associated with Neuroblastoma)

96 Rich M10 4 / 7 / 3 9 Mass in upper right None Left 7 85 13 L—neuro- N P N - 4 9 . 5 m R. R—

mo. quadrant and in left supraclavicular region—3 mos. NoR supra- cla-vicular 3 cm. in diam. blastoma C a . 9 . 7 \ ^ -Phos.-5.8 1 0 0 c-c -most bones

b. Myeloid (Associated with Polycythemia)

97 Hey M59 2/14/40 Weakness 1 2 4

M a s s i n a b 4 : L ,

Leukemia Shotty 24 6 110 55 M—hyper Sedimentation

Weakness 1 2 4

M a s s i n a b 4 : L , March 1938 normal 1 mm./hr.

domen J yra' X-radiation differential Wa8S.—neg.

Loss of weight (50 with 30%

lbs.) during pre-

normo-vious 6 mos. blasts

c. Lymphoid (Associated with Leukosarcoina)

98 Mil M52 1/ 9/41 Generalized lym-phadenopathy Leukosarcoma with leukemia Gen. | enlarg. • | i Scrotal edema 81 45 L—Lym-

phosar-Ascites Dec. 1940 i 3 X ! coma

Edema of lower NoR, ! j i

extremities

1

| i

d. Monocytoid (Associated with (99) Chloroma and (100) Diffuse Miliary Tuberculosis)

99 Ave M i l 1/ 2/41 Weakness and en-largement of the cervical nodes Nov. 1940 Lympho-sarcoma Nov. 1940 Much X-radia-tion Gen. enlarg. 3 X 2 i Protrusion of eyes and generalized subcu-taneous masses 86 3 L—leu-kemic in-filtration

100 Bla F 32 4/ 6/39 Weakness! None 1 59 12 Wass. and

hetero-Headache}4 wks. NoR, phile antibody—neg.

Fever J

(7)

I, I V , V A N D V I (Continued)

T r e a t m e n t Clinical D a t a after A d m i n i s t r a t i o n of R a d i o - P h o s p h o r u s

P » R t^n a- Transfusion Phy. and Lab. Findings R 8^ " Postmortem Findings Studies

Date s an d Tota l Dosage s of Radio-Phosphoru s (i n Millicuries ) Adm . 0. = Orall y I.V . = Intravenousl y a o

u

ss

*3 S a o AS jg Q 1 18 o

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II ro o a « "H 5.2 " ^ 3 - g ® £(8*H Date s an d Tota l Dosage s of Radio-Phosphoru s (i n Millicuries ) Adm . 0. = Orall y I.V . = Intravenousl y a o

u

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"3 «! 19 20 21 22 23 24 25 26 27 28 29 30 L e u k e m o i d R e a c t i o n s

a. Myeloid (Associated with Neuroblastoma)

11/17/39 ! to 11/29/39 8.3 (0.) 12/4/39 to 12/7/39 1100 r L N - U s-u L—I (12 cm.) 65 to 85 9 to 13 12/8/39 1 ! 18 Neuroblastoma with generalized metastases in most organs Typical microscopic findings T 90

b. Myeloid (Associated with Polycythemia)

2/26/40 to 8/10/40 29.12 (0.) L N - U S—D (6 cm.) L—D (2 cm.) 110 to 115 15 to 83 Yes Excel-lent P B E 97

c. Lymphoid (Associated with Leukosarcoma)

1/9/41 to 3/4/41 6.9 (I.V.) 7.5 (0.) 1 !

I M

1 ! i 1 Ascites and edema of legs entirely disap-peared 81 to 85 8 to 30 Excel-lent 98

d. Monocytoid (Associated with (99) Chloroma and (100) Diffuse Miliary Tuberculosis)

1/2/41 to 3/8/41 14.08 (I.V.) 1.7 (O.) LN—D S—not palpable L—not palpable Sub. masses dis-appeared. Pro-trusion of eyes unchanged 85 to 111 3 to 6

3/27/41 Liver and spleen normal size. Kidneys and ad-renal sur- #

rounded with tumor. All nodes 3 X nor-mal size. Retro-bulbar masses present

Liver—not infill.; spleen —fibrotic marked infil. of heart, kidneys, adrenals, G.I.# tract, pancreas, pituitary gland and brain. Marrow—re-placed by round cells

T 99 4/5/39 to 4/26/39 7.3 (0.) L N - U S - U L - U 50 to 59 12 to 24

6/ 6/39 6 Splenomegaly Diffuse miliary tubercu-losis of peritoneum, spleen, marrow, liver, adrenals, lymph nodes, but not lungs

(8)

Clinica l Dat a Previou s t o Administratio n o f Radio-Phosphoru s Treatmen t G #o *co «H CO G u H

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c '3'0 Ul j pooja jo tmnotuy IB;OX a 50

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c jaquinx X - o <*> - <* Clinica l Dat a Previou s t o Administratio n o f Radio-Phosphoru s Treatmen t G #o *co «H CO G u H

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c S9}BfJ t>. 5/9/3 9 4/30/4 0 to 7 / 3/4 0 1/22/4 0 to 2/ 1/4 0 3/31/4 0 11/17/3 8 to 12 / 4/3 8 Clinica l Dat a Previou s t o Administratio n o f Radio-Phosphoru s Treatmen t G #o *co «H CO G u H

•i

c S 9 ; B Q puB uopBipB^

uoj^n9X"io u°ni3ipi3'k-x o 5/25/4 0 to 6/8/4 0 35 0 r Clinica l Dat a Previou s t o Administratio n o f Radio-Phosphoru s Treatmen t G #o *co «H CO G u H

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c AlSnOU9ABJ;UI =s ' ^ J AUBJO = O p9J9^siuiuipv (s9unDjnij^ j ui) s h j o q d s o q j - o i p B ^ | jo S93B'SOQ I B ; O X puB S 9 ; B Q IO 5/23/3 9 4.8 8 (O. ) 4/28/4 0 t o 7/3/4 0 24.1 1 (O. ) 1/22/4 0 t o 2 / 1/4 0 2. 0 (O. ) 3/10/4 0 t o 7/11/4 0 11.84(0. ) 11/30/3 8 t o 12/11/3 8 15.3 6 (O. ) Clinica l Dat a Previou s t o Administratio n o f Radio-Phosphoru s Treatmen t Physica l an d Lab . Finding s o n Admis . Biops y | UOpDBJ9iB*a = "H Tt Ro f mos t bone s Clinica l Dat a Previou s t o Administratio n o f Radio-Phosphoru s Treatmen t Physica l an d Lab . Finding s o n Admis . Biops y SSuipulJ IBDlS0I0U98)U9O-^ Tt Ro f mos t bone s Clinica l Dat a Previou s t o Administratio n o f Radio-Phosphoru s Treatmen t Physica l an d Lab . Finding s o n Admis . Biops y •D19 j *X8oiOi9s puB Aj^siui9q3

C5 Wass . ) bloo d [neg . culture ) Wass . ) Tuber-[neg . culi n J neg . Clinica l Dat a Previou s t o Administratio n o f Radio-Phosphoru s Treatmen t Physica l an d Lab . Finding s o n Admis . Biops y •D19 j *X8oiOi9s puB Aj^siui9q3

C5 Wass . ) bloo d [neg . culture ) Wass . ) Tuber-[neg . culi n J Wass . Tuber -culi n Hetero -phi l agg . Clinica l Dat a Previou s t o Administratio n o f Radio-Phosphoru s Treatmen t Physica l an d Lab . Finding s o n Admis . Biops y opsBjdJadAH = J9d^H 1 «PIS = S MOJJBJ^ qjH = H ! 3P°N qduiAq = q AVOiiBp^ {BUJ9)S = Yi.

CN M . hyper . (myeloblast s predominate ) M . hyper . (90 % myelo -cytes ) M . hyper . (90 % myelo -cytes ) Clinica l Dat a Previou s t o Administratio n o f Radio-Phosphoru s Treatmen t Physica l an d Lab . Finding s o n Admis . Biops y snoqx «! ™W n o / 3 a M - -* X 265 X °* TABL E I I Myeloi d Leukemi a Clinica l Dat a Previou s t o Administratio n o f Radio-Phosphoru s Treatmen t Physica l an d Lab . Finding s o n Admis . Biops y HM^S (%) qH o 5 c CN TABL E I I Myeloi d Leukemi a Clinica l Dat a Previou s t o Administratio n o f Radio-Phosphoru s Treatmen t Physica l an d Lab . Finding s o n Admis . Biops y sguipuij i9q^o Ov Petechia e ove r ski n o f chest . Pit -tin g edema — ankle s Hemorrhagi c ulceratio n lef t angl e o f mout h Pallo r Tonsil s larg e an d hy -peremi c Gum s swollen , pale , an d bleeding . Pallo r TABL E I I Myeloi d Leukemi a Clinica l Dat a Previou s t o Administratio n o f Radio-Phosphoru s Treatmen t Physica l an d Lab . Finding s o n Admis . Biops y

•ui3 ui UISJBJ^ l^so*3

Mopa J9A*n jo uoisu9}xg X - t - t

Clinica l Dat a Previou s t o Administratio n o f Radio-Phosphoru s Treatmen t Physica l an d Lab . Finding s o n Admis . Biops y

! *ui3 ui UISJBJ^ IB;SO3

A\opg u99Jdg jo uoisuaixg CN CN

-Clinica l Dat a Previou s t o Administratio n o f Radio-Phosphoru s Treatmen t Physica l an d Lab . Finding s o n Admis . Biops y S 3P°N qdiuAq [BJ9qdU9(] JO SDpSU9}DBiBq3 ^C Axillar y node s slightl y enlarge d Genera l enlarge -men t Genera l enlarge -men t (1 cm. ) Clinica l Dat a Previou s t o Administratio n o f Radio-Phosphoru s Treatmen t Physica l an d Lab . Finding s o n Admis . Biops y u o i s s i u i p y oi I snoiA9Jj }U9Ui}B9jj, *a j ' pUB S1SOU8B1Q *V c05" o o XX A . Non e B . N o R o o XX XX o o A . Non e B . N o H Clinica l Dat a Previou s t o Administratio n o f Radio-Phosphoru s Treatmen t Physica l an d Lab . Finding s o n Admis . Biops y | uoissiuipv uo s^uiBjd - u i o 3 j 9 J q 5 jo u o p B i n r j puB sVuiBidui03 j 9 i q o t 1. Tiredness— 2 mo . 1. Intermitten t 1 6 wk s abdomina l pain s j 2 . Weakness ] 3. Feve r an d L wl _ _ headach e r WRs ' recedin g J 1. Pallo r } 2 . Enlarge d abdome n [ 3 wks . 3. Feve r | 4 . Headache )

1

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References

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