The Use of Large Amounts of Radioactive Sulfur in
Patients with Advanced Chondrosarcomas
I. Clinical and Hematologic Observations*
RAYMOND G. GOTTSCHALK,~LOUISK. ALPERT, AND ROY E. ALBERT
(Departments of Pathology and of Medicine, The George Washington University School of Medicine,
Washington, D.C., and Cancer Research Laboratory, Veterans Administration Center,
Martinsburg, W.Va.)
S 35 that would have a radiobiological action in
man could only be inferred from the data on animal toxicity (6, 11), the relative rates of excretion
in man (5), rat (~), and mouse (10), and the uptake
in various human tissues obtained by biopsy after
injection of tracer amounts (7). ~ The proposed
plan was approved in April, 1957, by the U.S.
Atomic Energy Commission for use at The George
Washington University Hospital in cases of chondrosarcoma with fatal prognosis. The plan included a maximum of eight intravenous injections of
~50 mc. of sulfate-S ~5 each, to be given at least 1
week apart, with a rest period of 3 weeks after the
fourth injection, to permit observation of maximal
hematologic effects.
The total amounts that were actually administered to the patients were lower, and the injections
were directed by the hematologic response, by the
condition of the patients, by the rate of excretion
of S a5 after each injection, and by the concentrations of S 35 in the tissues obtained by biopsy. Three
patients were treated with total amounts of S 35
ranging from 559 to 9~6 inc. of sulfate-S 35. The
patients who received treatment were not chosen
because of unusually high uptake after tracer
doses, but as they became available. Chondrosarcomas, although one of the more common primary
malignant tumors of bone, is only about half as
common as osteogenic sarcoma (13).
The observations provided data on the hematologic and clinical effects in man of large doses of
* This investigation was supported in part by a research S 35. The dosimetry calculations based on the tissue
grant (C ~770) from the National Cancer Institute, U.S. Public analyses will be presented in a subsequent
Health Service, and by a grant of the Alexander and Margaret paper (9).
Stewart Trust Fund. Part of these observations were presented
MATERIALS AND METHODS
on April 1~, 1959, at the Annual Meeting of the American
Association for Cancer Research (8).
Radioactive sulfur was obtained from Oak Ridge National
~fMailing address: Veterans Administration Center, Mar- Laboratories as carrier free H2S3504.Sterile isotonic solutions
tinsburg, West Virginia.
of sodium sulfate at pH 7 were prepared by adding NaOH,
1Also R. G. Gottschalk, unpublished data.
Received for publication May ~5, 1959.
The use of large amounts of radioactive sulfur
in the therapy of chondrosarcoma was first considered when it was demonstrated that this tumor
selectively retained tracer doses of sulfate-S 35 administered intravenously (7). This affinity seemed
due to the elaboration of chondroitin sulfate in the
tumor ground substance, and the uptake generally
exceeded that in normal cartilage, presumably because of faster growth. The fixation of S 35 at the
growing edges of the chondrosarcomas (5, 7), the
long-term retention of the isotope in cartilaginous
tissues (3, 7), and its significant physical half-life
(87.1 days) appeared favorable to therapeutic application. On the other hand, its fixation in the
hematopoietic bone marrow (~, 7, 15), the uneven
distribution in the chondrosarcomas (5, 7), their
known radioresistance (1~, 13), and the weakness
of the beta radiation of S 35 made it appear doubtful that the isotope could be of therapeutic value.
Actual therapeutic trials in man could be considered only after it was initially demonstrated that
massive amounts of sulfate-S a5 (0.2-1 mc/gin body
weight) selectively destroyed the growing epiphysial cartilages of mice, while producing only a
temporary leukopenia (10, 11). Slightly smaller
amounts (0.1 mc/gm) of S 35 destroyed the growing
epiphysial cartilages of young rats in our experiments (6, 11) and in those of Rubin et al., who also
considered the use of S 35 in the treatment of chondrosarcomas (16).
In planning the therapeutic trials, the doses of
1070
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GOTTSCHALK et al.--Radioactive Sulfur Treatment of Chondrosarcoma. I
NaCI, and pyrogen-ftee H20 and autoclaving. These solutions
were assayed for activity and for radiochemical purity by comparison with standardized solutions of S a5 supplied by the
National Bureau of Standards. The solutions of S 35 were used
only when they contained less than 0.02 per cent of P~, to
avoid cumulative toxicity of the two isotopes. The proportion
of P a decreased with time because of more rapid decay. Previous animal experiments had shown that S 35 solutions containing more P~ than the stated limit of 0.1 per cent produced
higher mortality in mice.
The injections of S 35 were administered through the tubing
of intravenous drips of 5 per cent glucose in water. The solutions used had concentrations in the range of 20 mc/ml.
Biopsies were obtained 64 hours after administration of a
tracer dose (2.2-3.8 me.) to determine the uptake in the tumors
and in various normal tissues. After longer delays following the
series of injections of large amounts, additional tissue specimens were obtained in two patients by operations, and in one
patient at autopsy. Twenty-four-hour urine specimens were
TABLE
1071
the attached tumor, and the invaded right lung were resected
in one mass at the Mayo Clinic. In December, 1957, a cystic
tumor mass in the anterior chest wall was incised and abundant
mucoid fluid drained. This was followed by a course in radiotherapy over the anterior chest given at Michael Reese Hospital from December 19 to January 9, 1958 (two portals, 2000 r
each, s kv). Some signs of radiation sickness occurred.
At the time of the first admission to The George Washington University Hospital (February, 1958) the patient was
weak and chronically ill. A funnel-shaped deformity of the
right anterior chest corresponded to the thoracotomy, and a
small granulating wound indicated the site of the previous
drainage. Staphylococcus aureus was cultured from the purulent discharge. There was neoplastic induration at the edges
of the operative defect. The only superficial tumor that could
be measured accurately was an ovoid mass, 7 X 4.5 cm. in
diameter, extending from the clavicle to the axilla. On roentgenograms the right pleural cavity did not appear involved by
tumor, and the mediastinum was deviated to the right with a
1
INJECTIONS OF SULFATE-S ~ TO C H O N D R O S A R C O M A
PATIENTS
PATIENT
#~
Age, sex
Average weight (kg.)
Total S ~ injected (me.)
No. injections*
Interval, first to Iast inj. (days)*
Period observed after last inj. (days)
Minimum leukocytes/cu mm
Minimum neutrophils in 100 WBC
Minimum platelets/cu mm
Average urinary excretion of S 35 in
first ~4 hours (per cent of inj.
amounts)*
59, F
45.7
559
6
57
144
2150
41
60,700
69
63, F
830
926
5
42
265
1600
24
99,800
64
43, M
69.7
686
3
15
39t
35O
14
5,340
48
* Excluding initial tracer injection.
t Expired.
collected throughout the periods of hospitalization and were
analyzed for radioactivity.
Blood counts were made on either venous or fingertip
samples as feasible. The volume of packed red blood cells was
deter mined only on venous blood. Platelets were counted after
supravital staining with new methylene blue. The progress of
the tumors was recorded by repeated measurements, photographs, and roentgenograms.
RESULTS
CLINICAL OBSERVATIONS
Data on the patients treated and on the radiosulfur injections are summarized in Table 1.
Case 1.wWhen admitted to The George Washington University Hospital, patient 1 had recurrences in the chest wall
of a chondrosarcoma that arose in the fourth right rib. The
diagnosis was established and the neoplasm treated in February, 1955, at Michael Reese Hospital, Chicago, by resection of
the involved anterior portion of the rib ("central" chondrosarcoma). In November, 1955, a recurrence in the soft tissues
of the upper chest was excised. In January, 1957, a portion of
the chest wall, including three ribs and part of the sternum,
mediastinal hernia. Following injection of a tracer dose of S aS,
tissues were obtained on February 21 from one of the neoplastic
areas close to the upper limit of the irradiation field. The biopsy
showed chondrosarcoma with marked inflammatory and
fibrous reaction, and neoplastic involvement of the resected
bone. The tumor was mainly myxomatous and precartilaginous
with infiltrating, degenerating, and inflamed portions. Cells
with double or bizarre nuclei were numerous.
In view of the debilitated condition of the patient, the
chronic infection, and the previous radiotherapy, the increments of S 36 were kept under the maximum dosage planned for
therapy, and the largest single dose administered was 126.8 me.
The leukocyte counts (Chart 1) which initially reflected the
inflammatory condition returned to about a normal level prior
to the isotope treatment, probably as a result of the use of
antibiotics. Moderate leukopenia and thrombocytopenia appeared during the rest period following the fourth injection,
and this became somewhat more pronounced after the two ensuing injections. The isotope injections were discontinued after
administration of a total of 559 inc. because of the leukopenia.
Numerous measurements of the axillary mass for about 80
days during and after the period of treatment showed no appreciable increase in size. Tissue specimens were obtained from
this area on May 21, 2~2 days after the last injection. The biop-
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Cancer Research
1072
sy showed a fluctuant cystic mass containing a mucinous fluid
with semisolid degenerated tumor particles. The outer layer of
neoplastic tissue was extremely thin, less than 89mm. thick,
and supported by a fibrous capsule. At the time of discharge
on May ~9 the general condition appeared to have improved,
and the size and distribution of the loci of neoplastic induration
were about the same as prior to the S 35 injections. The condition remained stationary until the end of June when the small
wound, that had drained intermittently, started to enlarge. An
ulcerated tumor 6 cm. in diameter developed in this area and
required transfusions and emergency excision on July ~4 because of bleeding.
The patient was readmitted to The George Washington
University Hospital on August 30. She had a fungating neoplastic mass 10 cm. wide on the anterior chest. For the first
time there was evidence of metastases to a lower dorsal vertebra and to the right femur. A fluctuant, not ulcerated mass had
developed above the clavicle, and mucinous fluid with tumor
particles was aspirated from it on September ~0. Further
studies2 were made on this patient as she followed a downhill
course.
R. G. Gottschalk, to be published.
V o l . 19, N o v e m b e r ,
1959
Case 2.--This patient had a large chondrosarcoma encircling the right femur. A swelling of the thigh was first noted
in the winter of 1956-57. In March, 1957, the patient was admitted for cholecystectomy to the Grace-New Haven Community Hospital. At that time the leg tumor, which had
reached a significant size, was biopsied, and the diagnosis of
chondrosarcoma was made. The tumor proved to be transplantable in the anterior eye chamber (Dr. Greene's laboratory). The patient repeatedly refused radical resection and was
followed at the Yale University Tumor Clinic. During the following winter the tumor began to bulge anteriorly and to interfere with the patient's activity. In March, 1958, the right
thigh had increased considerably in size as compared with
March, 1957.
The patient was admitted on April 13, 1958, to The George
Washington University Hospital, and she again refused radical
surgical treatment or even attempt at local resection of the
tumor. On examination the thigh was distended by a huge
tumor mass and measured 80 cm. in maximum circumference.
On roentgenograms (Fig. 1) the tumor showed a typical pattern of chondrosarcoma with calcified areas in the center and
multilobulated, less calcified portions. There were no demonstrable osteophytes or signs of destruction of the femur. The
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CHXRT 1.--Blood counts of Case 1. Red blood cells in
millions per cu. mm. Hemoglobin in gm. per cent. Volume of
packed cells in per cent. White blood cells, neutrophils, and
lymphocytes in thousands per cu. mm. Platelets in hundred
thousands per cu. mm. Columns indicate the amounts of
29 6
16 26 I0 15 9 2 20
MAY
dUN JUL AUG SEPT
radiosulfur in millicuries. The blood counts plotted on the
days of S ~ injection were made on blood samples taken before
the injection. T indicates the day a transfusion was given and
X the day when tissues were obtained for analysis. Time scale
reduced -~ after May 31.
Downloaded from cancerres.aacrjournals.org on June 17, 2017. © 1959 American Association for Cancer
Research.
GOTTSCHALKet al.--Radioactive Sulfur Treatment of Chondrosarcoma. I
chondrosareoma may have developed in soft tissues (13, 17),
or from tendinous insertions (4), or possibly from an osteophyte and have been of the "peripheral" type (13).
Following intravenous injection of a tracer dose of S 3~,
biopsies were obtained on April o_1 from the ninth costal cartilage, the iliac crest, the adjacent skin and muscle, and the
thigh tumor. The latter was encapsulated under the stretched
muscles and showed well differentiated cartilaginous chondrosarcoma nodules. The neoplastic cells varied in size and often
had double, bizarre, or giant nuclei9 They were scattered in
lacunae in the abundant ground substance. There were foci of
calcification and incomplete ossification. The stroma contained neoplastic mesenchymatous portions as well as fibrous
and adipose tissue.
During and after a series of five injections of S ~ totaling
923 mc. moderate leukopenia and slight thrombocytopenia developed (Chart ~). Biopsy specimens at varied depths in the
tumor mass were obtained on June ~7, 16 days after the last
injection.
The circumference of the thigh was regularly measured at
5
15
1073
five different levels. During and immediately after the period
of injections there was no detectable increase of the average
or of the maximum circumference. The very tense induration
of the anterior aspect of the thigh decreased moderately as indicated by palpation, by measurements of its vertical extent
(reduced from ~3 to 1~ era.) and by the statements of the patient. She volunteered the information that the cutaneous sensitivity had improved in the area and that flexion of the thigh
was easier. After discharge on July 13, she was followed in New
Haven and returned to Washington for check-up in November,
1958, and in March, 1959. The circumference of the thigh had
increased slightly. The extent of the induration was still less
than before the injections.
Over-all comparison of the roentgenograms taken in March,
1957, and March, 1958, in New Haven and of the numerous
films taken in Washington since April, 1958 (Fig. 1), indicated
that the tumor had grown rapidly from March, 1957, to April,
1958, and that it had not grown from beginning of treatment
to the first discharge. The radiologist considered that in November, 1958, the tumor was still about the same size as before
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CHART ~.--Blood counts of Case ~. Abbreviations same as Chart 1
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Research.
Cancer Research
1074
the injections, but later it grew more rapidly. Measurements
on antero-posterior and lateral roentgenograms of the different
diameters of the tumor and of its calcified portions all indicated
an arrest or a marked reduction of the rate of growth after the
injections (Chart 3). Roentgenograms of the lungs showed no
metastases in March, 1959.
Case 3.--This patient had a bulky chondrosarcoma involving the left chest. The tumor arose in the posterior part of left
seventh rib. It was biopsied in October, 1957, about 10 months
after the initial symptoms, and was considered inoperable because of pulmonary involvement and of massive bloody hydrothorax on the left. Local radiotherapy was administered from
December 3 to January 4 (two portals, 38~5 r each, 200 kv).
On admission to the Roswell Park Memorial Institute, Buffalo,
in April, 1958, the patient was pale and dyspneic. The left chest
V o ] . 19, N o v e m b e r ,
the heart was in the right anterior axillary line. Because of
dyspnea the patient remained propped up with the feet hanging
down. Pedal edema became more pronounced after June 1.
There was no albuminuria. In view of the almost terminal condition, large amounts of radiosulfur, totaling 684 mc., were
given in a relatively short period of time from May 29 to June
13. The rate of urinary excretion of S 35 following the injection
of large doses was slower than that in the other patients
(Table 1), and the blood levels of isotope were correspondingly
higher. Leukopenia and thrombocytopenia developed and became severe ~ weeks after the last injection (Chart 4). On July
3 scattered petechiae appeared on the trunk and limbs with a
few small ecchymotic areas. The purpura did not increase
thereafter. Capillary blood coagulation time and bleeding
time were within normal limits on July 4. Partial recovery of
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CaART 3.--Case ~. Maximum horizontal transverse diameter of chon~osarcoma and of calcified areas measured on
roentgenograms. The surface of the projection of the tumor on
A-P films is plotted as the diameter of a circle of the same
surface ("average diameter").
was bulging, and a tumor mass protruded from the posterior
wall. Thick bloody fluid of high viscosity was obtained by
thoracentesis.
The life expectancy appeared very short when the patient
was admitted to the Veterans Administration Center, Martinsburg, on May 6, 1958. The left chest was expanded in all
diameters and the left shoulder was held higher than the right.
Roentgenograms showed that the left lung field was obliterated
by tumor which contained a fluid level. The mediastinum and
heart were considerably shifted to the right. A Horner's syndrome appeared during the hospitalization. The liver edge was
irregular and extended 5 cm. below the costal margin. The
volume of urinary output was small. Following injection of a
tracer dose of radiosulfur, biopsy specimens were obtained on
May 1~ from the tumor mass under the left scapula. The chondrosarcoma was mainly precartilaginous, with cartilaginous
and myxomatous areas and minimal calcification. The ground
substance contained numerous neoplastic cells, often with
bizarre nuclei.
The patient was admitted to The George Washington University Hospital on May 28, 1958. The maximum impulse of
the leukocyte level started about July 13. The platelet counts
remained around 7000 per cu. mm. There were no signs of
gastrointestinal hemorrhage or of complications of agranulocytosis. No transfusions were given. During and after the
radiosulfur injections the chest deformity, dysphagia, dysphonia, and signs of cardiac impairment continued to increase.
Mercurial diuretics were administered. The mass on the posterior chest bulged somewhat higher. The emaciation and
dyspnea became very severe, and the patient expired on
July 2~.
Necropsy showed that death was due to the widespread
neoplastic involvement. The left pleural cavity was obliterated
by semi-liquid chondrosarcoma tissue containing residual areas
of old hemorrhage. The tumor extended directly into the chest
from the primary endosteal chondrosarcoma of the rib. The
completely collapsed left lung, the pericardial cavity and the
mediastinum were invaded by tumor that extended, anterior
to the right lung, up to 4 cm. from the right chest wall. There
were metastases in the liver, mesentery and skin, and in a vertebra. The bone marrow was hypoplastic with loci of regeneration including young cells of the myeloid, erythroid, and
megakaryocytic series.
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Research.
GOTTSCHALK
et al.--Radioactire Sulfur l'reab~te~t o.f ('ho~drosar~:o~ta. I
HEMATOLOGICOBSERVATIONS
In the three patients (Table 1 and Charts 1, 2,
and 4) the fractionated isotope injections had a
cumulative effect and the maximum leukopenia
was generally observed after the last injection. The
delay from injection to maximum response was
longest (25 days) and the leukopenia was most
severe in patient 8, who had received large doses
at relatively short intervals. There was some suggestion in this patient of a temporary increase of
neutrophils soon after the injections of radiosulfur.
The lymphocytes fell moderately and progressively. A subsequent more severe fall of neutrophils
than of lymphocytes resulted in all cases in rela-
1075
rive lymphocytosis at the time of the maximum
leukopenia. An increasing proportion of the neutrophils showed toxic granulations as the leukopenia became marked. At the onset of the severe
neutropenia of patient 8 only hypersegmented
forms were found in the blood. Recovery of myelopoiesis was heralded by the reappearance of stab
cells. The degree of platelet depression generally
paralleled that of the white blood cells.
The injection of large amounts of S35 was followed by a distinct fall in the erythrocyte values
only in patient 3. Interpretation of moderate
changes in red blood cell values was made difficult
by the anemia due to the operations and to the
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CHART 4.--Blood counts of Case 3. Abbreviations same as Chart 1
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Cancer Research
1076
neoplasms and by the long life span of the erythrocytes.
The hematologic changes observed were generally similar to those elicited in man by a large dose
of total-body irradiation (1); they developed more
slowly than in mice given radiosulfur injections (ll).
SYSTEMIC EFFECTS
There was no radiation-type sickness, diarrhea,
or gastric upset following the administration of
SaS. Petechiae were observed only in patient 3.
There were no articular pains, despite the fixation
of S35 in cartilage. Some complaints of patient 1
were referrable to the development of metastases
and pressure on nerve roots. No signs of radiation
damage to the skin were noted.
Vol. 19, N o v e m b e r , 1959
sues, and especially the bone marrow, and not the
injury to the skin. The "Handbook on Maximum
Permissible Amounts of R a d i o i s o t o p e s . . . " (18)
considers that the site of main toxicity of S 35 is the
skin, but this is based on metabolic data for labeled amino acid sulfur and not for oxidized sulfur.
The most severe blood changes were observed in
patient 3 who, without receiving the maximum
total dosage, received relatively large amounts at
short intervals. A slower rate of renal excretion of
S35 in this patient also contributed to higher blood
levels and to larger doses of radiation delivered in
a short period to the blood (9). The size and frequency of the injections as well as the rate of excretion of radiosulfur appeared to influence the
severity of the leukopenic and thrombocytopenic
effects. The delay occurring between the admin-
TABLE 2
BLOOD AND SERUM ANALYSES OF PATIENTS BEFORE AND AFTER INJECTIONS OF LARGE AMOUNTS OF SULFATE-S~
PATIENT #1
Before
Total protein, gm.%
Albumin-globulin ratio
Thymol turbidity units
Bilirubin, direct, mg.%
"
total, mg.%
Urea nitrogen, mg.%
Calcium, mg.%
Phosphorus, mg.%
Alk. phosphataset
6.0
4.2
3.2
PATIENT #2
PATIENT #3
During
After
Before
During
After
Late*
Before
After
8.2
1.6
6.0
0.3
0.6
18.0
9.4
4.~
2.1
8.3
1.4
4.0
0.2
0.4
11.0
9.5
3.8
3.8
7.4
1.7
5.5
0.1
0.5
21.0
9.8
3.3
2.8
7.8
1.7
5.2
0.1
0.4
17.0
9.8
31
3.0
6.8
1.3
4.5
0.1
0.2
15.2
10.0
3.4
2.5
7.6
1.9
6.3
0.2
0.4
12.8
10.1
3.4
2.7
6.8
s
2.0
03
07
14 0
10 4
40
52
5.9
2.3
1.0
0.~
0.g
81.4
8.6
3.5
4.7
* Follow-up analyses in November, 1958, and March, 1959.
Table ~ lists the average blood chemistry values
before, during, and after the injections. The
changes in blood constituents, if any, seemed related to the clinical condition of patients with
advanced neoplasms and not to the injections of
radiosulfur per se. There were no demonstrable
changes of the clinical laboratory tests of patient
up to 9 months after the injections.
DISCUSSION AND CONCLUSION
When this study was undertaken the largest
amounts of radioactive sulfur which had been used
in man were approximately 7 inc. (7). The observations following the administration of amounts
up to 926 me. of sulfate-S 35 demonstrated that in
man as in animals (10, 16) the limiting factor was
the injury to the radiosensitive hematopoietic tis-
t Bodansky units.
istration of sulfate-S 35 and the maximum hematologic response requires further caution if the use
of large doses of radiosulfate is contemplated in
patients, although the observed bone marrow depression seemed to be reversible.
The absence of radiation sickness after leukopenic doses of another beta emitter, radiophosphorus, has also been noted (14).
The three cases of chondrosarcomas which received injections of radiosulfate included one
slowly growing tumor with marked cartilaginous
differentiation and calcification (patient ~), one
more anaplastic chondrosarcoma with myxomatous
degeneration (patient 1), and one terminal case of
chondrosarcoma (patient 3). In the latter patient
the disease continued to progress. The survival
was somewhat longer than anticipated, but judg-
1~o. 1.--Roentgenograms of thigh tumor of Case 2, A-P
views. Large amounts of S = were administered from April 30
to June 11, 1958.
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Research.
1068
Cancer Research
lymphoma but rare in FL. The viral leukemia of
Gross is indistinguishable from spontaneous thymic lymphoma. Whether the thymic lymphomas
in Swiss mice are related to a virus, as in Ak mice,
remains to be established. The transplantable tumor variants of FL described here are characterized by mono- and multinucleated giant cells, not
encountered in transplantable lymphomas or
myeloid leukemias of mice.
The leukemia produced by cellular graft of the
transplantable tumor variant of FL here described (best done by intravenous injection of tumor cells) is somewhat different from that induced
by FV. Leukemia produced by cell graft has a
rapid onset and course and is often advanced after
30 days, whereas the characteristic leukemia following virus infection usually occurs after about
3 months and is seldom seen in less than 30 days.
The most characteristic gross anatomic feature of
FD is splenomegaly in which the spleen is soft and
red with rounded edges, often with frank hemorrhagic areas. In contrast, the splenomegaly induced by cell grafts is indistinguishable from other
autonomous leukemias, the organ being gray or
gray-red and firm with more sharp (less rounded)
edges.
Earlier work called attention to extensive erythrogenic hyperplasia appearing early in FD before
any manifestation of anemia (4). This may be due
to a stimulation of erythrogenic cells by virus, suggesting that this was unrelated to the proliferation
of reticulum cells. The bone marrow, the usual site
of erythrogenesis, is involved infrequently and
only at the late stage of the disease, whereas the
reticulum cells of the spleen proliferate within a
few days after virus infection. In contrast, leukemia produced by cellular grafts is characterized by
monomorphous proliferation of large reticulum
cells without erythroblastosis or anemia. In many
animals the tumors remained localized at the site
of graft (Fig. 1), in others they spread by continuity (Fig. ~). It is possible that virus was contained
Vol. 19, November, 1959
in the cells and, if slowly released, produced immunity which prevented later development of
lesions characteristic of the viral disease. In the
morphogenesis of viral leukemia, antibody production may play a prominent, hitherto poorly
explored, role.
The occurrence of "leukemic" thrombi in the
lung is characteristic, but the interpretation of its
pathogenesis is conjectural. It may be the consequence of some antibody formation against the
grafted cells. This may explain why these lesions
are common in transplanted leukemias and relatively rare in spontaneous leukemias. The development of such lesions in spontaneous (including
virus-induced) leukemias may be due to autoantibody production or perhaps to mere blocking
of the circulation by clumps of tumor cells which
have entered the pulmonary arteries.
A word of caution on the designation of the
transplantable tumor cells described here as
"autonomous": the failure of two tumors, from
animals with no gross or microscopic evidence of
FD, to yield tumors (or the generalized viral disease) on subpassage suggests the possibility that the
presence of virus is a prerequisite for tumor
growth. On the other hand, the change in character of the tumor cells, notably in their nuclei, is
also suggestive of transformation of virus-driven
normal cells to autonomous, virus-independent
cells. However, resident virus can conceivably
alter the nuclear pattern, and reliance on the latter
in determining whether a cell is autonomous
should not be dogmatic. Thus, even cells with abnormal nuclear (chromosomal) morphology can be
dependent on a "masked" resident virus.
Further work is needed (a) to define the cytogenetic change, suggested by chromosomal abnormalities associated with acquisition of transplantability, (b) on the association of virus with leukemic
cells or the conceivable loss of virus in the ariaplastic tumor cells, and (c) on the presumed existence of a dual type of leukemic cell population:
All sections are from tissues fixed with Zenker-formol and
stained with hematoxylin and eosin.
FIG. 1.--Large tumor, localized to graft site (right thigh),
without metastasis to regional lymph nodes and without
splenomegaly and hepatomegaly.
FIG. ~.--Small tumor at graft site (right thigh), with extensive abdominal metastases but without splenomegaly and
hepatomegaly.
FIG. 3.--Small tumor at graft site (right thigh), with
metastasis to regional lymph nodes, splenomegaly, and
hepatomegaly. Hemorrhagic "leukemic" infarcts in lungs.
I~G. 4.--Generalized leukemia and splenomegaly and hepatomegaly following intravenous injection of tumor cells.
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Research.
GOTTSCHALK
et al.--Radioactive Sulfur Treat~ne~d ~)f (hc~dro,'arcvn~a. I
ment in this matter is difficult. The patient expired
54 days after onset of the treatment. Analyses indicated that about 60 per cent of the possible irradiation dose had been delivered at that time to
the chondrosarcoma (9).
In patient 1 there was little or no progress of
the tumors for about 100 days from the start of
the injections until June when the tumor started
to grow rapidly. The beneficial effects of the external irradiation administered about 3 months
before the isotope injections cannot be excluded.
In patient 2, who had not been previously treated, the leg tumor did not increase in size during
and immediately after the period of treatment.
The induration around it decreased. The rate of
growth remained much slower than before treatment for about 6 months and later increased.
The observations on patient 2 are suggestive of
a temporary inhibition of the ehondrosarcoma by
the isotope. Since it is recognized that a regular or
logarithmic rate of growth cannot be expected in
large tumors, any such variation in the rate of
progress of neoplasms short of clear-cut regression
must be interpreted with great caution in individual patients, although dosimetric considerations demonstrated favorable ratios between the
doses of radiation delivered by radiosulfur to the
chondrosarcomas and to the normal tissues of
these patients (8, 9).
SUMMARY
Large amounts of radioactive sulfur (Na2SaS04)
were administered to three patients with advanced
chondrosarcomas because of the preferential fixation of the isotope in this tumor. Total amounts of
559-9~6 me. were given in divided intravenous injections. They produced leukopenia with relative
neutropenia and thrombocytopenia. The radiotoxic hematologic effects appeared reversible, but
they are the limiting factor in the use of large
amounts of radiosulfur and require caution in
therapeutic trials. No radiation sickness occurred
as a result of the injections. In two patients, the
rate of progress of the chondrosarcomas appeared
reduced for several months after the S ~5 injections,
b u t no m a r k e d t u m o r regression was observed.
ACKNOWLEDGMENTS
Mr. Henry Grantham, Jr., Mr. Paul Bell, Jr., and Mrs.
Kathy Smith gave valuable technical assistance. Mr. H. Busey
made the photographic reproductions. Our thanks are due to
Dr. H. S. N. Greene and Dr. D. P. Shedd of Yale University
for calling to our attention two of the patients, and to Dr. J.
Holland of the Roswell Park Memorial Institute for referring
the other patient. We acknowledge with pleasure the communication of clinical information by members of the staff of outside hospitals. Dr. W. W. Stanbro of George Washington University and Dr. H. Litwer, Martinsburg, gave valuable advice
in the interpretation of the roentgenograms.
1077
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Research.
The Use of Large Amounts of Radioactive Sulfur in Patients
with Advanced Chondrosarcomas I. Clinical and Hematologic
Observations
Raymond G. Gottschalk, Louis K. Alpert and Roy E. Albert
Cancer Res 1959;19:1070-1077.
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