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THE EFFECT OF MILD HYPERTHERMIA ON TUMOR OXYGENATION AND RESULTANT RESPONSE TO RADIATION THERAPY (TEMPERATURE, MICROWAVE)

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University
Microfilms
International
SOON.Zeeb Hoad
Ann Artyor, Ml 46106
6504902
O ’H a ra , M ichael D e n n is
THE EFFECT O F MILD HYPERTHERMIA ON TUMOR OXYGENATION AND
RESULTANT RESPONSE TO RADIATION THERAPY
Wayne S ta te U niversity'
University
Microfilms
International
PH.O,
300 N. Zeeb R oad, Ann Arbor, Ml 48108
1984
THE EFFECT OF MILD HYPERTHERMIA ON TUMOR OXYGENATION
AND RESULTANT RESPONSE TO RADIATION THERAPY
BY
MICHAEL DENNIS O'HARA
SUBMITTED TO THE GRADUATE SCHOOL
OF WAYNE STATE UNIVERSITY
DETROIT, MICHIGAN
IN PARTIAL FULFILLMENT OF THE REQUIREMENTS
FOR THE DEGREE OF
DOCTOR OF PHILOSOPHY
1984
ADVISOR
/ f Wl
DATE
D e d ic a tio n
T h is t h e s i s I s d e d ic a te d t o my p a r e n t s , E duard a n d ( t h e l a t e )
M axine O’ H a ra . T h e i r p a t i e n c e , wisdom , c o u ra g e an d lo v e h av e g u id e d me
th r o u g h o u t ray g r a d u a te work a s w e l l a s ray e n t i r e l i f e .
ii
Acknowledgements
I w ould l i k e t o e x p r e s s my s i n c e r e a p p r e c i a t i o n to D r, F re d H e tz e l
f o r h i s e n c o u ra g e m e n t d u r in g th e d a r k e s t h o u r s , h e lp w i t h p ro b le m s ,
t u t e l a g e th ro u g h o u t my g r a d u a te w ork, an d good f r i e n d s h i p ,
I w ould a l s o l i k e t o th a n k D r, T a l j i t Sandhu f o r h i s h e l p , a d v ic e ,
e n c o u ra g e m e n t, a n d f r i e n d s h i p th ro u g h o u t iny g r a d u a te w o rk ,
I g r a t e f u l l y ac k n o w led g e th e work a n d e f f o r t s i n toy b e h s l f o f
D rs . W a lte r C h a v ln , K a z u to s h l Kayeda a n d L id a M attm an.
I a l s o th a n k
them f o r s e r v i n g on my g r a d u a te c o m m itte e .
My th a n k s t o D r, T .T . Tchen f o r s e r v i n g a s my o u t s i d e r e a d e r a n d to
D r. K .L . K ra b h e n h o ft f o r s e r v i n g a s m o d e ra to r o f my g r a d u a t e c o m m itte e .
The h e l p , and a d v ic e i n p e rfo rm in g th e s e e x p e rim e n ts o f Mr. M ic h a e l
G. M en sin g er i s g r a t e f u l l y a c k n o w led g e d .
I a l s o th a n k Mr. S ta n F r ln a k , Mr. K u rt A v e ry , Mr. H arvey F a rm e r,
Mr. C a r r o l l R ange, M r. C a r l T id w e ll a n d Mr, A la n M orton f o r t h e i r
e x c e lle n t d is c u s s io n and te c h n ic a l a s s is ta n c e .
I w ould a l s o l i k e t o th a n k Mr. R o b e rt S e d le c e k , M a s s a c h u s e tts
G e n e ra l H o s p i t a l , f o r p r o v id in g me w ith th e tum or s y s te m u se d f o r th e s e
e x p e rim e n ts an d a n s w e rin g my many q u e s ti o n s on t h i s s y s te m 's c h a r a c t e r ­
is tic s .
1 a l s o g r a t e f u l l y ack n o w led g e Ms. P a t r i c i a C la rk s o n a n d Ms. J o y c e
A u b re c h t f o r ty p in g t h i s m a n u s c r ip t.
ill
Table of Contents
Page
D e d ic a tio n
11
A cknow ledgem ents
ill
L i s t o f F ig u r e s
vl
L i s t o f T a b le s
ix
I . In tro d u c tio n
H is to r y
1
b.
C e l l u l a r S tu d ie s
3
c.
A nim al S t u d ie s H y p e rth e rm ia A lone
5
d.
A nim al S t u d ie s R a d ia tio n P lu s H y p e rth e rm ia
7
e.
Im p o rta n c e o f S equence (H y p e rth e rm ia a n d R a d ia tio n )
S
f.
Normal T is s u e E f f e c t s
11
g.
H y p e rth e rm ia a n d t h e V a s c u la tu r e
13
h.
E f f e c t s o f H y p e rth e rm ia on pH
16
1.
Oxygen a n d H y p e rth e rm ia
17
J.
The E f f e c t o f Oxygen on I o n i z i n g R a d ia tio n
17
k*
Oxygen a n d H y p e rth e rm ia
19
1.
H y p e rth e rm ia R e o x y g e n a tio n
2 0
m.
T herm al D i s t r i b u t i o n
2 0
n.
S ta te m e n t o f th e P roblem
2 2
0
II.
*
M a t e r i a l s a n d M ethods
a.
A nim als
25
b>
Tumor S ystem
26
c.
Tumor S to ra g e
26
iv
d.
Tumor T r a n s p l a n t a t i o n
28
e.
R a d ia tio n S o u rc e
28
f.
H y p e rth e rm ia E quipm ent
29
g.
T herm om etry
31
h.
P r o d u c tio n o f T r i p l e M ic ro th e rm o c o u p le s
32
!•
E x a m in a tio n o f t h e P o s s i b i l i t y o f " C r o s s ta lk "
33
b e tw e en th e T herm ocouple J u n c t i o n s I n a S in g le
T r i p l e M ic ro th e rm o c o u p le
j.
E quipm ent u s e d f o r T e m p e ra tu re D i s t r i b u t i o n
34
k.
P ro c e d u re f o r M easurem ents o f T e m p e ra tu re D l s t r i -
35
b u tto n
III.
1.
P r o d u c tio n o f Oxygen E l e c t r o d e s
39
m.
Oxygen M easurem ents
40
n.
C o n c o m ita n t H eat (4Q°C) a n d I r r a d i a t i o n Equipm ent
43
o.
C o n c o m ita n t H eat (40°C ) and I r r a d i a t i o n P ro c e d u re
45
R e s u lts
a.
T e m p e ra tu re D i s t r i b u t i o n
47
b.
U n p e rtu rb e d Normal T is s u e T e m p e ra tu re D i s t r i b u t i o n
47
c.
U n p e rtu rb e d M a lig n a n t T is s u e T e m p e ra tu re D l s t r i
51
b u t to n
d.
H e a ted Norm al T is s u e T e m p e ra tu re D i s t r i b u t i o n
56
e.
H e a ted M a lig n a n t T is s u e T e m p e ra tu re D i s t r i b u t i o n
67
f.
M easurem ents o f Oxygen T e n s io n
78
g.
O v e r ly in g S k in R e a c tio n t o 4 0 “C H y p e rth e rm ia an d
80
C o n c o m ita n t I r r a d i a t i o n
h.
Tumor R esponse t o C o n c o m ita n t H eat ( 4 0 aC) a n d
Irra d ia tio n
v
8 6
XV. D iecub 8 io n
V. B ib lio g r a p h y
V I. A b s t r a c t
V I I . A u to b io g r a p h ic a l S ta te m e n t
vi
List of Figures
F ig u re
1
.
2
.
Pafie
U n p e rtu rb e d G row th C urve f o r th e C3 H Mouse Mammary
C arcinom a
27
A rran g em en t o f t h e T r i p l e M ic ro th e rm o c o u p le a i n
t h e P e r p e n d i c u la r D i r e c t i o n
37
3.
A rran g em en t o f th e T r i p l e M ic ro th e rm o c o u p le s i n t h e
P a r a l l e l D ire c tio n
38
4.
A v erag e T e m p e ra tu re + A verage D e v ia tio n f o r H eated
Norm al T is s u e i n th e ” P a r a l l e l D i r e c t i o n w ith o u t
A i r C o o lin g
57
5.
A verage T e m p e ra tu re + A verage d e v i a t i o n f o r H eated
Norm al T is s u e i n th e ” P a r a l l e l d i r e c t i o n w ith A ir
C o o lin g
60
A v erag e T e m p e ra tu re
A verage D e v ia tio n f o r H eated
Norm al T is s u e i n t h e ~ P e r p e n d ic u la r D i r e c t i o n w ith
A i r C o o lin g
63
A v erag e T e m p e ra tu re + A verage d e v i a t i o n f o r H eated
Norm al T is s u e i n th e P e r p e n d i c u la r D i r e c t io n w ith o u t
A i r C o o lin g
65
A verage T e m p e ra tu re + A verage D e v ia tio n f o r H eated
M a lig n a n t T is s u e i n t h e P a r a l l e l D i r e c t i o n w ith o u t
A i r C o o lin g
70
A verage T e m p e ra tu re Hh A verage D e v ia tio n f o r H eated
M a lig n a n t T is s u e i n The P a r a l l e l D i r e c t i o n w ith A ir
C o o lin g
72
A verage T e m p e ra tu re +_ A v erag e D e v ia tio n f o r H e a ted
M a lig n a n t T is s u e i n t h e P e r p e n d i c u la r D i r e c t i o n w ith
A i r C o o lin g
74
A verage T e m p e ra tu re + A v erag e D e v ia tio n f o r H eated
M a lig n a n t T is s u e i n The P e r p e n d i c u la r D i r e c t i o n
w ith o u t A ir C o o lin g
76
Oxygen H is to g ra m , A ir B r e a th in g w ith No M icrow ave
H y p e rth e rm ia
79
Oxygen H is to g ra m , Oxygen B r e a th in g w ith No M icrowave
H y p e rth e rm ia
81
6.
7.
8
.
9.
10
.
U.
12
.
13.
vii
Figure
14.
Oxygen H is to g ra m , A i r B r e a th in g d u r in g 4 0 8C
M icrow ave H y p e rth e rm ia
82
15.
Oxygen H is to g ra m , Oxygen B r e a th in g d u r in g 40“ C
M icrow ave H y p e rth e rm ia
83
16.
Tumor R esponse to 40°C H eat A lone Volume v s . Time
91
17*
Tumor R esp o n se t o R a d ia tio n A lone o r t o One o f th e
Combined T h e r a p ie s a t 3000 r a d s , Volume v s . Time
92
18.
Tumor R esponse t o R a d ia tio n A lone o r to One o f th e
Combined T h e r a p ie s a t 4000 r a d s , Volume v s . Time
93
19*
Tumor R esp o n se t o R a d ia tio n A lone o r t o One o f th e
Combined T h e r a p ie s a t 4500 r a d s , Volume v s . Time
94
20.
TXimor R esponse t o R a d ia tio n A lone o r t o One o f th e
Combined T h e r a p ie s a t 5250 r a d s , Volume v s . Time
95
21.
Tumor R esp o n se t o R a d ia tio n A lone o r t o One o f th e
Combined T h e r a p ie s a t 5500 r a d s , Volume v s . Time
96
22.
Dose R esponse C urve f o r th e Two T h e r a p ie s Oxygen
B r e a th in g d u r in g I r r a d i a t i o n , an d Oxygen B r e a th in g
d u r in g I r r a d i a t i o n w ith C o n c o m ita n t 40°C
98
23.
Dose R esponse C urve f o r th e Two t h e r a p i e s A ir
B r e a th in g d u r in g I r r a d i a t i o n , a n d A ir B r e a th in g
d u r in g I r r a d i a t i o n w ith C o n c o m ita n t 40°C
99
v lll
L i s t o f T a b le s
Page
Table
1*
A verage T e m p e ra tu re + A verage D e v ia tio n an d t h e H igh
a n d Low P o i n ts f o r Norm al T is s u e w ith o u t H e a tin g I n
th e P a r a l l e l D ire c tio n
49
2.
A v erag e T e m p e ra tu re + A v erag e D e v ia tio n an d t h e High
a n d Low P o in ts f o r N orm al T is s u e w ith o u t H e a tin g I n
t h e P e r p e n d i c u la r D i r e c t i o n
50
3.
A verage T e m p e ra tu re + A verage D e v ia tio n an d t h e H igh
a n d Low P o i n t s f o r M a lig n a n t T is s u e w ith o u t H e a tin g
I n th e P a r a l l e l D i r e c t i o n
54
4.
A verage T e m p e ra tu re + A v erag e D e v ia tio n a n d t h e High
a n d Low P o i n ts f o r M a lig n a n t T is s u e w ith o u t H e a tin g I n
t h e P e r p e n d i c u la r D i r e c t io n
55
5.
L o c a tio n o f t h e H igh a n d Low T e m p e ra tu re P o i n ts f o r
Norm al T is s u e i n t h e P a r a l l e l D i r e c t i o n w ith No A ir
C o o lin g , d u r in g H e a tin g
58
.
L o c a tio n o f t h e H igh an d Low T e m p e ra tu re P o i n ts f o r
Norm al T is s u e I n t h e P a r a l l e l D i r e c t i o n w ith A ir
C o o lin g d u r in g H e a tin g
61
7.
L o c a tio n o f th e H igh an d Low T e m p e ra tu re P o i n ts f o r
Norm al T is s u e I n th e P e r p e n d i c u la r D i r e c t i o n w ith A ir
C o o lin g d u r in g H e a tin g
64
.
L o c a tio n o f t h e H igh an d Low T e m p e ra tu re P o i n ts f o r
Norm al T is s u e s i n t h e P e r p e n d i c u la r D i r e c t i o n w ith o u t
A i r C o o lin g d u r in g H e a tin g
66
9.
L o c a tio n o f t h e H igh an d Low T e m p e ra tu re P o in t f o r
M a lig n a n t T is s u e i n th e P a r a l l e l D i r e c t i o n w ith o u t
A i r C o o lin g d u r in g H e a tin g
71
10.
L o c a tio n o f t h e H igh a n d Low T e m p e ra tu re P o i n ts f o r
M a lig n a n t T is s u e I n th e P a r a l l e l D i r e c t i o n w ith A ir
C o o lin g d u r in g H e a tin g
73
11.
L o c a tio n o f t h e High a n d Low T e m p e ra tu re P o i n t s f o r
M a lig n a n t T is s u e i n th e P e r p e n d i c u la r D i r e c t i o n w ith
A i r C o o lin g d u r in g H e a tin g
75
12.
L o c a tio n o f t h e H igh a n d Low T e m p e ra tu re P o i n ts f o r
M a lig n a n t T is s u e i n t h e P e r p e n d i c u la r D i r e c t i o n w ith o u t
A i r C o o lin g d u r in g H e a tin g
77
13.
C h a rt D e s c r ib in g t h e N u m e ric al S k in S c o re System
85
6
8
ix
Page
Table
14.
Mean T in e t o Maximum S k in S c o re w ith R e s p e c t t o
T re a tm e n t Type a n d R a d i a ti o n Dose
15.
Mean Maximum S k in S c o re w ith R e s p e c t t o T re a tm e n t
Type an d R a d ia tio n Dose
x
87
8 8
I n tro d u c tio n
H i s to r y
F o r more th a n 20 y e a r s now, c a n c e r r e s e a r c h e r s h a v e b e e n a c t i v e l y
I n v e s t i g a t i n g t h e e f f e c t s o f h e a t on m a lig n a n t a n d n o rm a l t i s s u e s *
C u r r e n t l y , t h e r e I s a w e a lth o f l i t e r a t u r e a v a i l a b l e d e a l i n g w ith a l l
a s p e c t s o f i n c r e a s e d te m p e r a tu r e e f f e c t s on c e l l s an d t i s s u e s .
H eat I n
o n e form o r a n o t h e r h a s b een u s e d I n t h e tr e a tm e n t o f m a lig n a n t
n e o p la sm s f o r th o u s a n d s o f y e a r s .
Red h o t I r o n s (fe rru m
c a n d e n s ) w ere
m e n tio n e d I n t h e Ramajama (2000 B .C .) a l s o by H ip p o c r a te s (400 B .C .)
an d by G alen (200 A .D .) ( 1 ) .
I n th e m id d le o f th e th e l a s t c e n tu r y ,
m ore w e l l d e f in e d e f f o r t s to o k p la c e t o u s e h e a t a s a t h e r a p e u t i c
to o l.
I n 1866 Bush ( 2 ) d e m o n s tra te d th e d is a p p e a r a n c e o f a sarcom a d u r -
i n g a n e p is o d e o f h y p e r e x ia in d u c e d by e r y s i p e l a s .
F e h e is e a , ( 3 ) I n
1883 t r e a t e d f i v e p a t i e n t s w ith ad v a n ce d sa rc o m as o r c a rc in o m a s , w ith
a n i n j e c t i o n n e a r th e tu m o r, o f a s i n g l e s t r a i n o f c u l t u r e d stre p to * *
c o c c u s , p ro d u c in g f e b r i l e e r y s i p e l a s *
F e h l e i s e n n o te d th e In v o lv e d
lym ph n o d e s r e g r e s s e d , one f u l l r e m is s io n and t h r e e p a r t i a l tum or r e ­
g re s s io n s .
(5 ).
S i m i la r o b s e r v a t io n s w ere n o te d by B runs ( 4 ) a n d by C oley
B runs d i s c u s s e d t h e r e g r e s s i o n o f a p a t i e n t w ith t e r m in a l
m a lig n a n t m elanom a.
C o le y ,( 6 ) u s in g m ixed t o x i n s , d i s c u s s e d h i s r e s u l t s
i n 38 p a t i e n t s w ith in d u c e d f e b r i l e e r y s i p e l a s .
H a te r-c irc u la tin g
c i s t e r n s (4 2 ° -4 4 ° C ) w ere p la c e d I n t o i n o p e r a b le u t e r i n e c a r d n o n a s f o r
4B h o u r s by F . V e s te rm a rk i n 1889 ( 7 ) .
M u l l e r , ( 8 ) i n 1910, uBed d ia th e rm y a n d “r o e n tg e n r a y s " f o r th e t r e a t ­
m ent o f m a lig n a n c ie s .
M u l l e r , (9 ) i n 1912, r e p o r t e d 32Z c o m p le te d
r e g r e s s i o n an d 36Z te m p o ra ry r e g r e s s i o n a s com pared to r o e n tg e n th e r a p y
a lo n e .
R ohdenburg and P r im e ,(1 0 ) i n 1921, u s e d mouse sarcom a 180 t o
exam ine th e e f f e c t s o f h e a t i n v i t r o a n d i n v iv o , a lo n e o r i n com bina­
t i o n w ith r a d i a t i o n .
They fo u n d t h a t tum or fra g m e n ts ( h e a t e d i n v i t r o )
w ere m ax im a lly i n h i b i t e d f o r " ta k e s " a t 42°C f o r 180 m in u te s an d 60Z
i n h i b i t i o n a t 46°C f o r 30 m in u tes*
T h e y 'a ls o s a i d t h e r e was a "m arked
l e t h a l e f f e c t " when s u b l e t h a l d o s e s o f h e a t a n d r a d i a t i o n w ere com bined
b u t s e q u e n c e was n o t I m p o r ta n t .
Mikawa (1 1 ) i n 1937 exam ined h e a t w ith
r e s p e c t t o r a d i o s e n a l t i v i t y a n d p r e s e n t e d some p r e l i m i n a r y te m p e ra tu re
d is tr ib u tio n d a ta .
The te m p e r a tu r e m e a s u rin g e q u ip m e n t, h o w ev er, was
r u d im e n ta r y .
N. W esterm ark ( 6 ) d e m o n s tra te d two b a s i c p o i n t s i n 1927.
U sing th e
F l e x n e r - J o b l l n g c a rc in o m a a n d th e H ansen sarcom a o f r a t s , W esterm ark
showed t h a t th e tim e r e q u i r e d to o b t a i n r e g u l a t i o n i n tu m o rs was p a r a l ­
l e l t o t h a t n eed ed t o i n h i b i t r e s p i r a t i o n .
S e c o n d ly , h e d e m o n s tra te d
t h a t n o rm a l t i s s u e s w ere l e s s s e n s i t i v e to h e a t th a n m a lig n a n t t i s s u e s .
U sin g t h e N o v ik o ff hepatom a an d E h r l l c h a s c i t e s c a rc in o m a , R o s s l - F a n e l l l
( 1 3 ) d e m o n s tra te d a s i m i l a r f i n d i n g r e l a t i n g i n h i b i t i o n o f r e s p i r a t i o n
a n d h y p e r th e r m ia .
C r l l e , i n th e e a r l y 6 0 's a l s o s u p p o r te d th e e a r l i e r
w ork o f N. W e ste rm a rk .
An I n t e r e s t i n g r e l a t i o n s h i p em erged from th e
w ork o f C r l l e (1 4 ) - f o r e a c h 1°C above 42°C o f tum or t e m p e r a tu r e , th e
t o t a l tr e a tm e n t tim e c o u ld be re d u c e d by o n e - h a l f .
I n th e p a s t tw e n ty y e a r s c o n s id e r a b l e e x p e r im e n ta l tim e and
th o u g h t h av e gone i n t o t h e u s e o f h e a t a lo n e o r i n c o m b in a tio n w ith
ra d ia tio n o r a n ti-c a n c e r d ru g s.
Many o f th e e x p e rim e n ts o f t h e o ld
l i t e r a t u r e h av e b e e n r e p e a te d w ith new er a n d more p r e c i s e e q u ip m e n t.
Many o f t h e s e new w orks w i l l be d i s c u s s e d i n s u b s e q u e n t p a r a g r a p h s .
C e l l u l a r S tu d ie s
Much o f w hat I s now known a b o u t h y p e rth e rm ia h a s b e e n shown th ro u g h
th e u s e o f I n v i t r o t i s s u e c u l t u r e te c h n iq u e s *
exam ined many f a c e t s o f h y p e rth e rm ia *
T h e se te c h n iq u e s have
Many s m a ll d e t a i l s o f how h e a t ,
o r h e a t a n d I r r a d i a t i o n , a f f e c t s c e l l s , h av e b een w orked o u t I n v i tr o *
Some o f t h e f i r s t I n v i t r o e x p e rim e n ts t o q u a n t i t a t e h y p e rth e rm ic
c e l l k i l l i n g w ere p e rfo rm e d by H a r r i s , (1 5 ) u s in g p ig k id n e y c e l l s *
I f e s tr a a n d Dewey (1 6 ) u s in g C h in e s e h a m s te r o v a ry c e l l s (CHO)
g e n e r a te d a s e r i e s o f s u r v i v a l c u rv e s f o r te m p e r a tu r e s betw een 43*5 a n d
46*5°C .
T h ese s u r v i v a l c u rv e s w ere s i m i l a r t o th o s e o f E lk ln d and
W hitm ore (1 7 ) o b ta in e d w ith I o n i z i n g r a d i a t i o n , show ing a s h o u ld e r
i n th e low d o se r e g i o n ( o r s m a ll h e a t i n g tim e r e g i o n ) and a n exponen­
t i a l p o r tio n *
W estra a n d Dewey (1 6 ) d e m o n s tra te d , by c o m p arin g th e D37
(Do) f o r v a r i o u s tr e a tm e n t t e m p e r a t u r e s , a 1°C I n c r e a s e I n te m p e ra tu re
r e s u l t e d i n a p p r o x im a te ly a tw o - f o ld i n c r e a s e i n th e i n a c t i v a t i o n r a te *
T h is i s d e m o n s tra te d n i c e l y w ith th e u s e o f a n A rr h e n iu s p l o t , when lo g
1/Do i s p l o t t e d on t h e o r d i n a t e a n d 1/T (°K ) i s p l o t t e d on th e a b s c i s s a .
The A rr h e n iu s p l o t a l s o shows a n i n f l e c t i o n p o i n t a t a p p ro x im a te ly
42.5°C *
The d i f f e r e n c e i n t h e I n a c t i v a t i o n r a t e s s e e n on th e c u rv e
m ig h t be a r e f l e c t i o n o f t h e d i f f e r e n t modes o f i n a c t i v a t i o n above and
below t h i s p o i n t ( 1 8 ) .
B e l l i a n d B onte (1 9 ) p e rfo rm e d t h e f i r s t q u a n t i t a t i v e i n v i t r o s t u ­
d i e s I n v o lv in g h y p e rth e rm ia I n c o m b in a tio n w ith r a d i a t i o n ( 1 9 ) .
Ben-H ur
a n d E lk ln d (2 0 ) o b s e rv e d t h a t u s in g a te m p e r a tu r e ab o v e 37°C slo w s down
a n d d i s o r g a n i z e s t h e r e p a i r o f t h e DNA-complex w h ile I t a p p e a r s to
a s s i s t t h e r e p a i r o f s i n g l e - s t r a n d DNA b r e a k s ( 2 0 ) .
T h e re a r e many r e p o r t s I n th e o l d e r l i t e r a t u r e (2 1 ) t h a t n orm al c e l l s
a r e more r e s i s t a n t t o h y p e rth e rm ia th a n m a lig n a n t c e l l s *
O v e rg a ard and
O v e rg a a rd ( 2 2 ) , o b s e rv e d t h a t c e l l d e s t r u c t i o n o c c u rs p r e f e r e n t i a l l y
I n m a lig n a n t c e l l s w ith o u t damage t o n o rm al c e l l s *
O s s o v s k l an d Sach
(2 3 ) d e m o n s tra te d a p r o l i f e r a t i v e I n h i b i t i o n w ith c e l l s t h a t w ere
i r r a d i a t e d o r m e th y lc h o la n th r e n e tra n s fo r m e d d u r in g a 48 hr* In c u b a ­
t i o n a t 4 1 DC and th e c o rr e s p o n d in g n orm al c e l l s w ere o n ly s l i g h t l y l e s s
s e n s itiv e .
K echanl a n d S a b in (2 4 ) u s in g v i r a l l y tra n s fo r m e d CHO c e l l s ,
fo u n d t h a t t h e s e c e l l s w ere r e l a t i v e l y r e s i s t a n t t o t h e e f f e c t s o f h e a t ,
b u t c e l l s from tu m o rs i n v iv o w ere more s e n s i t i v e th a n th e n orm al c e l l s *
Hahn (2 5 ) u s in g
lOTl/ 2 c e l l s , n o rm al an d tr a n s f o r m e d , found t h a t th e
tr a n s f o r m e d c e l l s
v a r i e d g r e a t l y i n t h e i r a b i l i t y t o In d u c e tum ors
f o llo w in g h y p e rth e rm ia t r e a t m e n t s .
I t seem s t h a t h y p e rth e rm ia a f f e c t s some a s p e c t s o f c e l l b io lo g y
w h ich a r e m in im a lly a f f e c t e d by r a d i a t i o n .
s y n t h e t i c p h a s e (S
One o f th e s e I s th e DNA
phase) s e n s i t i v i t y .
T e ra slm a and Tolm ach (2 6 ) f i r s t
m
d e m o n s tra te d th e e f f e c t s o f r a d i a t i o n on th e c e l l c y c l e . U sin g H ela
c e l l s th e y fo u n d t h a t m i t o t i c c e l l s a r e th e m ost s e n s i t i v e t o r a d i a t i o n
w h ile mid t o l a t e S p h a s e c e l l s a r e t h e m ost r e s i s t a n t .
s u p p o r te d by S i n c l a i r a n d H o rto n (2 7 ) w ith mouse L c e l l s .
T h is work was
The c e l l
s y n c h ro n y w ork o f V e s tr a a n d Dewey (1 6 ) w ith CHO c e l l s c l e a r l y i n d i c a t e s
th e s e n s i t i v i t y o f l a t e G1 an d S p h a se c e l l s ex p o sed t o h y p e rth e rm ia .
P a l z e r a n d H e ld e lb e r g e r (2 8 ) and H en d erso n (2 9 ) h av e a l s o exam ined
th is e ffe c t.
The ab o v e m en tio n e d w orks c l e a r l y show t h a t h y p e rth e rm ia
a f f e c t s a d i f f e r e n t g ro u p o f c e l l s i n th e c e l l c y c l e .
By c o m b in in g h y p e rth e rm ia a n d i o n i z i n g r a d i a t i o n , t h e c e l l s t h a t w ere
t h e m ost r e s i s t a n t t o i o n i z i n g r a d i a t i o n a r e now b e in g a f f e c t e d .
T h is
a d d e d e f f e c t (o n t h e S p h a s e c e l l s ) c o u ld p o s s i b l y h e lp r a d i a t i o n e r a d i ­
c a t e m a lig n a n t c e l l s more e f f e c t i v e l y .
A nim al S tu d ie s w ith H y p e rth e rm ia A lone
T r a n s p l a n ta b l e a n im a l tu m o rs h a v e b e e n u se d f o r many y e a r s a s a
m odel o f s p o n ta n e o u s human tu m o rs .
T h e re a r e many r e a s o n s to u s e
t r a n s p l a n t a b l e r o d e n t tu m o rs .
A few o f th e s e r e a s o n s a r e a v a i l a b i l i t y ,
r e p r o d u c t l b l l l t y an d s t a g i n g .
F u r th e r m o r e , t h e s e a r e p h y s i o l o g i c a l l y
c l o s e r t o s p o n ta n e o u s tu m o rs th e n i n v i t r o c u l t u r e p r o c e d u r e s .
As men­
t i o n e d , t r a n s p l a n t a b l e tu m o rs h a v e b e e n u s e d t o exam ine t h e e f f e c t s o f
h y p e rth e rm ia w ith a n d w ith o u t x o r gamma r a d i a t i o n f o r many y e a r s
( 7 ,1 0 ,1 1 ,1 4 ,3 0 ).
O v e rg a ard an d O v e rg a a rd (2 1 ) d e s c r i b e d a s e r i e s o f e x p e rim e n ts
e x a m in in g th e e f f e c t o f h e a t on a n a n a p l a s t i c mammary c a rc in o m a .
They exam ined tum or " c u r e " a s a f u n c t i o n o f i n t r a t u m o r a l te m p e r a tu r e .
A t 4 l . 5 “C f o r 240 m in u te s ,
m in u te s ,
8
8
o u t o f 20 m ice w ere c u r e d , a t 4 2 .5 * 0 f o r 90
o u t o f 34 m ice w ere c u re d an d a t 4 3 .5 °C f o r 60 m in u te s , 41
o u t o f 162 m ice w ere c u re d .
T h r a l l e t a l . d e s c r ib e d a s e r i e s o f
e x p e rim e n ts i n w hich t h e tim e o f h e a t i n g was v a r i e d , b u t t h e maximum tem ­
p e r a t u r e was h e ld c o n s ta n t a t 44,5® C.
In t h i s t r i a l T h r a l l , e t a l . (3 1 )
u s e d a n e s t h e t i z e d m ice an d c o n c lu d e d t h a t tum or g ro w th d e la y p ro d u ce d by
h e a t i n g was d e p e n d e n t upon t h e m ag n itu d e o f th e h e a t t r e a t m e n t .
T h ra ll
e t a l . s t a t e d t h a t th e y p r e v i o u s ly o b s e rv e d a l a r g e num ber o f am puta­
t i o n s i n t h e h e a te d lim b s .
T h r a l l s t a t e s t h a t t h e r e w ere o n ly t h r e e
l e g a m p u ta tio n s i n t h e more r e c e n t s t u d y , a t 4 4 .5 ° C .
T h is pro b lem
I s d i s c u s s e d f u r t h e r i n th e h e a t i n g s e c t i o n o f t h e m a t e r i a l s and
m e th o d s .
D ick so n e t a l .
(3 2 ) u s in g r a d i a f r e q u e n c y (RF) h e a t i n g a n d
t h r e e tu m o rs o f r a t (Y o sh id a Sarcom a, D23 C a rc in o m a , MC7 Sarcom a) exam­
in e d t h e e f f e c t s o f h e a t i n g f o r v a r io u s te m p e r a tu r e s a n d t im e s .
The
a u t h o r s fo u n d t h a t two o f t h e t h r e e tu m o rs re s p o n d e d w i t h one h u n d red
p e rc e n t re g re s sio n .
T hese same a u t h o r s a l s o found t h a t f o r l a r g e
tu m o rs (6 -1 2 m l . ) , t r e a t e d w ith e i t h e r 45*C f o r 30 m in u te s o r 50QC f o r
15 m in u te s a l l o f th e r a t s d ie d so o n a f t e r t r e a t m e n t .
M alangone e t a l ,
(3 3 ) u s in g 4 l.5 " C r a d io f r e q u e n c y h y p e rth e rm ia a n d / o r I . P . c y c lo p h o s p h a ­
m id e , t r e a t e d m ice w ith lym phosarcom a an d fo u n d t h a t th e a n im a ls g iv e n
h e a t an d d ru g s u r v iv e d th e l o n g e s t .
M agin e t a l .
(3 4 ) u s e d a v a r i e t y o f
mouse tu m o rs i n c l u d i n g two f a s t g ro w in g tu m o rs ( L e s l s lu n g c a rc in o m a
a n d B12 m elan o m a).
They found t h a t Che f a s t e r g ro w in g tu m o rs d id n o t
re s p o n d a s w e ll a s th e s lo w e r g ro w in g o n e s .
C alderw ood a n d D ick so n
(3 5 ) i n a f o llo w - u p t o t h e i r p r e v io u s p a p e r , (3 2 ) exam ined t h e
I n f l u e n c e o f tum or volum e a n d c e l l k i n e t i c s o f th e Y o sh id a Sarcom a t o
h y p e r th e r m ia .
The a u th o r s s t a t e t h a t t h e dam aging e f f e c t s o f th e h e a t
tr e a tm e n t (42°C f o r 1 h r . ) w e re a t l e a s t a s e f f e c t i v e i n th e l a r g e
tum or a s t h e s m a ll tum or b u t th e d a ta i s a t b e s t d i f f i c u l t to i n t e r p r e t .
Marraor e t a l . ( 3 6 ) exam ined t h e e f f e c t s o f l o c a l i z e d r a d io f r e q u e n c y
h e a t i n g o f EMT- 6
tu m o rs and found t h a t a te m p e r a tu r e o f 44°C f o r 30
m in u te s r e s u l t e d i n 100% c u r e a t 30 d a y s .
F a r ja r d o e t a l . (3 7 ) s t u d i e d t h e m echanism s o f Im m ed iate a n d
d e la y e d tu m o r c e l l k i l l i n g w ith h y p e rth e rm ia (44°C f o r 30 m in u t e s ) .
They fo u n d t h a t by 48 h o u rs t h e r e w ere o n ly 0*0003% v i a b l e c e l l s i n th e
tum or com pared t o t h e c o n t r o l a n d a t 14 d a y s a s c a r had r e p la c e d th e tum or
b e d . They c o n c lu d e d t h a t im m ed iate n e c r o s i s was due Co plasm a membrane
e f f e c t s and th e d e la y e d p o s t tr e a tm e n t d e a th was due t o tum or bed m odi­
f ic a tio n s .
T h e re a r e o t h e r d a ta t h a t s u p p o r t o t h e r p o s s i b l e m echanism
in v o lv e d i n th e r m a l I n j u r y .
f o ll o w s :
T hese o t h e r m echanism s c o u ld be g ro u p ed a s
A) damage to s t r u c t u r a l p r o t e i n s ( 1 6 ) , B) a c t i v a t i o n o f th e
ly so s o m e s ( 3 8 ) , C) damage t o RNA ( 3 9 ) .
F a ja r d o e t a l . (3 7 ) p o in te d o u t
t h a t t h e r e a r e many lo n g te rra r e s p o n s e s w hich c o u ld be r e s p o n s i b l e f o r
a d d i t i o n a l c e l l d e a th a f t e r t r e a t m e n t .
Some o f t h e s e p o s s i b l e tum or bed
ch a n g e s a r e pH, t o x i c m e t a b o l i t e s , ly so s o m a l a c t i v i t y o r hu m o ral o r c e l l
m e d ia te d im m u n ity .
R a d ia tio n P lu s H y p e rth e rm ia
O v e rg a a rd and O v e rg a a rd (4 0 ) com bined h e a t and r a d i a t i o n a t v a r io u s
d o s e s t o a s s a y tum or " c u r e " .
They found a 9Z c u re when r a d i a t i o n
(3200 r a d s ) was g iv e n a l o n e , a 10Z " c u r e " when 4 0 .5 aC /180 m in u te s was
com bined w ith 1600R a n d 77Z when 4 2 .5 ° C /6 0 m in u te s was com bined w ith
1600R.
The a u t h o r s d e m o n s tra te d t h e r e was a c l e a r d o se r e d u c tio n when
h e a t was ad d ed t o c o n v e n tio n a l r a d i a t i o n t r e a t m e n t s .
R o b in so n e t
a l . (4 1 ) d e s c r ib e d t h e t h e r a p e u t i c enhancem ent r a t i o (TER) f o r s k in and
mammary tu m o rs o f C3 H m ic e t r e a t e d a t te m p e r a tu r e s from 41.0®C t o 4 3 .0 aC.
They d e f in e d th e TER a s :
th e r a d i a t i o n s e n s i t i v i t y a t a n e le v a te d tem ­
p e r a t u r e r e l a t i v e t o t h a t m easu red a t 3 7 .5 “C .
At 4 l.0 ° C t h e tum or TER
e q u a le d 1 .4 2 a n d t h e s k i n e q u a le d 1 .1 6 w h ile a t 43"C th e tum or TER was
4 .3 3 a n d t h e s k in TER was 2 .0 6 .
T h ese d a ta c l e a r l y s u g g e s t a d e f i n i t e
a d v a n ta g e i n co m b in in g h e a t a n d r a d i a t i o n , w ith more o f a n e f f e c t p r o ­
d u c e d on m a lig n a n t th a n on n o rm a l t i s s u e s .
H i l l an d Denekamp (4 2 )
exam ined th e e f f e c t s o f w a te r b a th h e a ti n g an d r a d i a t i o n on s i x t r a n s p l a n ­
t a b l e tu m o rs o f m ic e .
They fo u n d t h a t i n f i v e o u t o f th e s i x tu m o rs th e
d e g re e o f s e n s i t i z a t i o n I n c r e a s e d w ith th e s i z e o f th e x - r a y d o s e .
The tum or c o n t r o l d o se (TCD) h a s been u s e d i n r a d i a t i o n b io lo g y f o r
many y e a r s t o exam ine th e e f f e c t s o f a p a r t i c u l a r tr e a tm e n t on a p o p u l ­
a t i o n o f tu m o rs .
to rie s *
I t i s u s u a l l y w r i t t e n a s TCD 5 0 /1 2 0 i n many l a b o r a ­
The s u b s c r i p t 50 s t a n d s f o r 50 p e r c e n t tum or c o n t r o l a n d 120
s t a n d s f o r th e tim e ( i n d a y s ) t h a t th e a s s a y was t e r m in a te d .
R obinson
e t a l . ( 4 1 ) u s in g C3 H mammary tu m o rs i n th e f l a n k , T h r a l l e t a l . ( 4 3 ) u s in g
C3H mammmary tu m o rs i n th e l e g , an d S u i t (4 4 ) u s in g C3 H mammary tum ors
i n t h e f o o t a l l fo u n d t h a t th e TCD50 d e c r e a s e d when h y p e rth e rm ia was
com bined w ith r a d i a t i o n .
Im p o rta n c e o f Sequence ( h y p e r th e r m ia a n d r a d i a t i o n )
An im p o r ta n t a s p e c t o f co m b in in g h e a t an d r a d i a t i o n i s th e se q u e n c e
o f t h e two a g e n t s .
S hould h e a t p r e c e d e , f o llo w o r be g iv e n c o n c u r r e n t ­
l y w ith r a d i a t i o n ?
A seco n d im p o r ta n t p o i n t i s how lo n g s h o u ld th e I n ­
t e r v a l be betw een t h e two a g e n t s , i f a n i n t e r v a l i s used*
In a n y t r e a t ­
m e n t, th e o v e r l y i n g a n d s u r r o u n d in g n orm al t i s s u e s m ust be ta k e n i n t o
a c c o u n t.
A tr e a tm e n t t h a t e r a d i c a t e s th e tum or a n d s e v e r e l y damages th e
n o rm a l t i s s u e i s o b v io u s ly n o t a s s e l e c t i v e a th e r a p y a s i t s h o u ld b e .
C r i l e (4 5 ) s t a t e d t h a t th e d e s t r u c t i v e e f f e c t s o f r a d i a t i o n a r e
e n h a n ce d when h e a t (4 4 aC) was g iv e n Im m e d ia te ly b e f o r e o r a f t e r i r r a d i ­
a tio n .
He g o e s on t o s a y t h a t com bined t r e a tm e n t w ith h e a t a n d r a d i a ­
t i o n c a u se d a n e a r l i e r a p p e a ra n c e o f r a d i a t i o n s k i n damage and t h e r e i s
n o d i f f e r e n c e i n t h e m ag n itu d e o f damage when h e a t i s g iv e n b e f o r e o r
a f t e r Irra d ia tio n .
F u th e rm o re , h e a t m ax im a lly i n c r e a s e d th e e f f e c t s o f
r a d i a t i o n when g iv e n w i t h in a few h o u rs o f e a c h o t h e r r e g a r d l e s s o f th e
seq u en ce.
R obinson e t a l . ( 4 1 ) r e p o r t e d on a s e r i e s o f e x p e rim e n ts w here
t h e v a r i o u s d o s e s o f r a d i a t i o n w ere g iv e n d u r in g th e h e a t i n g p e r io d
( w i th e q u a l p r e and p o s t h e a t i n g ) .
They r e p o r t e d a p ro n o u n ced TER i n
t h e tum or a s com pared t o th e s k in when th e two t r e a tm e n ts w ere g iv e n
s im u l ta n e o u s l y .
G i l l e t t e an d E n s le y (4 6 ) exam ined th e e f f e c t o f
s e q u e n c e on mouse mammary a d e n o ca rcin o m a a n d s k i n a t 4 2 .5 °C f o r th r e e
d i f f e r e n t e x p o s u re tim e s ( 1 5 , 3 0 , 60 r a i n .) .
They found t h e g r e a t e s t
e f f e c t was s e e n f o r i r r a d i a t i o n d u r in g th e h e a t i n g i n t e r v a l , w ith th e
p o s s i b l e e x c e p t io n o f 15 m in. o f h e a t i n g .
t h a t th e s k i n was a l s o m ax im a lly a f f e c te d *
T h e se
a u th o r s a l s o found
O v e rg a a rd (4 7 ) u s in g C3 H
mouse mammary ca rc in o m a a n d w a te r b a th h e a ti n g (fro m 41“C t o 4 3 .5 °C )
fo u n d a d e c r e a s e i n th e TCD50 a n d t h e DD50 (The d o se o f r a d i a t i o n n eeded
t o a c h ie v e f u l l m o is t d e sq u a m a tio n on th e i r r a d i a t e d f o o t w i t h in 30 d a y s
i n 50Z o f t h e a n i m a l s .) v a lu e s a s th e te m p e r a tu r e s i n c r e a s e d when h e a t
a n d r a d i a t i o n w ere g iv e n s im u l ta n e o u s l y .
H ow ever, b o th tum or an d s k in
th e r m a l enhancem ent r a t i o s w ere th e sam e, show ing no g a in i n t h e r a p e u ­
t i c e ffe c t.
S a p a re to e t a l . ( 4 8 ) u s in g CHO c e l l s an d s u b l e t h a l h e a t d o s e s
( 4 2 .5 ° C ) fo u n d t h a t th e maximum r e d u c t i o n i n s u r v i v a l came when h e a t
was a p p l i e d d u r in g o r im m e d ia te ly a f t e r i r r a d i a t i o n .
M eyers e t a l . (4 9 )
u s in g th e mouse ca rc in o m a l i n e MADCAP37 a l s o fo u n d th e g r e a t e s t de­
c r e a s e i n s u r v i v a l was p r e s e n t when h e a t a n d r a d i a t i o n w ere g iv e n sim ­
u lta n e o u s ly .
I n v i t r o s t u d i e s h a v e g e n e r a l l y shown t h a t t h e c l o s e r th e
two t r e a tm e n ts a r e g iv e n t h e more p ro n o u n ced th e e f f e c t ( 4 5 ,4 9 - 5 2 ) .
The a b o v e i n v iv o a n d i n v i t r o d a ta d e m o n s tra te d t h a t th e optimum
tim e t o i r r a d i a t e tu m o rs ( w ith o u t c o n s id e r in g i n c r e a s e d e f f e c t s on n o r ­
m al t i s s u e ) o r tum or c e l l s i s d u r in g h e a t i n g .
T h is d o e s
seem l o g i c a l
10
b e c a u s e o f r e p a i r p ro b le m s , o x y g e n a tio n s t a t u s a n d pH c h a n g e s .
Com­
b in e d , theB e two m o d a l i t i e s e f f e c t c h a n g es i n a w id e r a r r a y o f t a r g e t s ,
t h u s i n c r e a s i n g th e e f f e c t i v e n e s s o f th e com bined m o d a lity .
The work
o f G i l l e t t e a n d E n s le y (4 6 ) a n d t h a t o f O v e rg a ard (4 7 ) a s w e ll a s t h a t
o f o t h e r I n v e s t i g a t o r s , d e m o n s tra te t h a t w h ile com bined h e a t ( a t tem p e r­
a t u r e s o f 4 2 .5 #C a n d a b o v e ) an d i r r a d i a t i o n B e n s i t l z e th e tum or to i r ­
r a d i a t i o n th e n o rm al t i s s u e a l s o becom es s e n s i t i z e d .
The i n t r o d u c t i o n o f a n I n t e r v a l b etw een i r r a d i a t i o n a n d h e a t t r e a t ­
m en ts re d u c e d th e th e r m a l enhancem ent e f f e c t s i n b o th n orm al a n d m a lig ­
nan t tis s u e .
T h e re a r e two r e a c t i o n s t h a t a r e I m p o r ta n t t o c o n s id e r
when a n i n t e r v a l i s in tr o d u c e d b etw een th e two m o d a l i t i e s , n orm al t i s s u e
r e a c t i o n and tum or TER.
P r e v io u s p a ra g r a p h s h a v e shown t h a t a t h y p e r­
th e r m ic t e m p e r a t u r e s , t h e maximum t i s s u e s e n s i t i z a t i o n
o c c u rs.
When
r a d i a t i o n a n d h e a t a r e g iv e n s im u l ta n e o u s l y , b o th h e a t b e f o r e an d h e a t
f o llo w in g r a d i a t i o n h a v e lo w e r TERs f o r b o th no rm al a n d tum or t i s s u e ,
how ever th e c h a n g e s i n TERs a r e n o t th e same f o r e i t h e r se q u e n c e o r f o r
th e two t i s s u e t y p e s .
S te w a rt an d Denekamp (5 3 ) u s in g a f ib r o s a r c o m a i n ( a n e s t h e t i z e d )
m ice d e m o n s tra te d t h a t h e a t i n g was m ost e f f e c t i v e when i t was g iv e n
a f t e r i r r a d i a t i o n f o r p e r io d s up t o s i x h o u r s .
H i l l and Denekamp
(4 2 ) u s i n g a v a r i e t y o f tum or s y ste m s i n m ice a t 4 2 .5 °C h e a t i n g , have
shown c l e a r l y t h a t a n I n c r e a s e d t h e r a p e u t i c a d v a n ta g e e x i s t s when h e a t
f o llo w s i r r a d i a t i o n by a t l e a s t one h o u r .
Many o t h e r a u th o r s u s in g
v a r i o u s no rm al t i s s u e s h a v e a l s o s u p p o r te d t h i s b a s i c p o i n t ( 4 6 ,4 7 ,5 4 ,
5 5 ,5 6 ) .
Norm al t i s s u e s r a p i d l y l o s e t h e i r th e r m a l s e n s i t i v i t y .
In
g e n e r a l , th e rm a l s e n s i t i z a t i o n r e c o v e r y i s c o m p le te a f t e r two t o f o u r
h o u r s ( 4 6 ,4 7 ,5 4 ,5 5 ,5 6 ) .
Tumor t i s s u e a l s o r a p i d l y l o s e s i t s
th e rm a l
11
s e n s i t i z a t i o n , b u t a f t e r i n t e r v a l s o f up t o f o u r h o u rs th e TER l e v e l s
o f f a t a n e l e v a t e d p l a t e a u ( 4 2 ,4 6 ,5 4 ,5 5 ) .
Two p o i n t s m ust b e b r o u g h t o u t a b o u t t h e d i s c u s s i o n o f i n t e r v a l b e­
tw e e n I r r a d i a t i o n an d h y p e r th e r m ia .
The f i r s t i s th e te m p e r a tu r e s o f th e
h y p e r th e r m ic tr e a tm e n t a n d th e se co n d i s t h e p o s s i b l e d i f f e r e n c e s i n th e
modes o f i n t e r a c t i o n ( w ith r a d i a t i o n ) betw een " h ig h " ( 43°C ) h y p e rth e rm ia
a n d "low " (4 0 °C ) h y p e r th e r m ia .
A lm ost w ith o u t e x c e p t io n , th e ab o v e
a u t h o r s u s e d te m p e r a tu r e s ab o v e 4 l .0 ° C .
The h i g h e r h y p e rth e rm ic
tem -
p e r a t u r e s c a u s e a n oxygen s h i f t t o th e a n o x ic r e g i o n , I n c r e a s e i n th e
a c i d i t y , an d d e c r e a s e d b lo o d flo w w i t h i n t h e tu m o rs .
T h ese e f f e c t s
h a v e b e e n d e s c r i b e d by many a u th o r s ( 2 2 ,5 7 ,5 8 ,5 9 ,6 0 ,6 1 ) and e x c e l l e n t l y
re v ie w e d by o t h e r a u th o r s ( 1 ,6 2 ,6 3 ) .
"Low" h y p e rth e rm ic t r e a tm e n ts may
e n h a n c e t i s s u e o x y g e n a tio n by I n c r e a s i n g th e b lo o d flo w .
t h e low h y p e r th e r m ic te m p e r a tu r e s w ould seem t o be a n e a s y
Sequence a t
d e c is io n .
I n o r d e r t o a c h ie v e maximum tum or o x y g e n a tio n , h y p e rth e rm ia w ould have
t o b e g iv e n a t th e tim e o f i r r a d i a t i o n .
Norm al T is s u e E f f e c t s
I t i s g e n e r a l l y known t h a t l o c a l h e a t d o s e s below 42°C f o r one h o u r
do n o t p ro d u c e a n y a b n o rm a l s i d e e f f e c t s i n m ost n o rm al t i s s u e s
s tu d ie d (5 5 ).
I n a n y t u m o r d d a l th e r a p y t h e r e s p o n s e o f th e s u rr o u n d in g
n o rm a l t i s s u e w i l l be th e l i m i t i n g f a c t o r .
T h is makes a n e x a m in a tio n o f
th e r e s p o n s e o f n o rm al t i s s u e s a p r e r e q u i s i t e s t e p t o a n a ly z in g o v e r a l l
tu m o r r e s p o n s e .
C r l l e i n a s e r i e s o f t h r e e p a p e rs ( 1 4 ,4 5 ,6 4 ) s t a t e s
t h a t S91 melanoma o r sarcom a 180 im p la n te d i n t h e f e e t o f m ice c o u ld be
s u c c e s s f u l l y t r e a t e d w ith o u t dam aging t h e s u r r o u n d in g n orm al t i s s u e s .
R ob in so n e t a l . ( 4 1 ) u s e d a n u m e r ic a l s k in s c o r e , u s u a l l y em ployed f o r
r a d i a t i o n r e s p o n s e , a n d exam ined t h e e f f e c t s o f h y p e rth e rm ia
(41°C -43*C ) on th e f o o t o f C3H m ic e .
T h e ir m ost s t r i n g e n t h e a t th e r a p y
( 4 3 “C f o r 1 h o u r ) , p ro d u c e d no m e a s u ra b le s k i n
s c o r e w h ile s k i n i r r a ­
d i a t i o n (UOU r a d s ) a t 4 3 aU g av e a lm o s t 2 tim e s m ore
T h r a l l , e t a l . ( 4 3 ) , u s in g w a te r b a th
s e n s itiz a tio n .
h e a t i n g , f o r 15 m in u te s a t 4 4 .5 * C ,
e v a lu a te d t h e s k in r e s p o n s e i n term s
o f m o is t d e s q u a m a tio n .
They fo u n d
h e a t g iv e n b e f o r e o r a f t e r th e com bined t r e a tm e n ts o f r a d i a t i o n a n d
h y p e r b a r ic oxygen o r r a d i a t i o n u n d e r
h y p o x ic c o n d i t i o n s g av e s i m i l a r
r e s u l t s i n te rm s o f d e s q u a m a tio n d o se
f o r 5UX a t 21 d a y s , (DU5U-21).
h o w e v e r, f o r r a d i a t i o n u n d e r a m b ie n t c o n d i t i o n s , p r i o r h e a t s e n s i t i z e d
c e l l s to th e r a d ia tio n .
S te w a rt e t a l* ( 5 4 ) a l s o e v a lu a te d a k in i n
te rm s o f t h e f o o t r e a c t i o n o f a n e s t h e t i z e d
m ic e .
V ie ld e t a l . ( b 5 ) u se d
t h r e e no rm al t i s s u e s ( s k i n , i n t e s t i n e , c a r t i l a g e ) , o f a n e s t h e t i z e d m ice
a n d r a t s to exam ine t h e com bined e f f e c t s o f h y p e rth e rm ia an d i r r a ­
d ia tio n .
They fo u n d r e s u l t s
f o r t h e com bined e f f e c t s o f h e a t and
r a d i a t i o n f o r t h e s e t i s s u e s t o be
q u a l i t a t i v e l y s i m i l a r to th o s e o f
r a d ia tio n a lo n e .
U o f f ln e t e t a l . ( 6 6 ) u s e d th e s p i n a l c o rd o f a n e s t h e t i z e d , C3H m ice
t o d e m o n s tra te t h a t h y p e rth e rm ia a n d a s i n g l e d o s e o f r a d i a t i o n s i g n i f i ­
c a n t l y re d u c e d th e l a t e n t p e r io d f o r p y e l i t i s a n d l e s s r a d i a t i o n was
n e e d ed t o p ro d u c e a g iv e n m ag n itu d e o f e f f e c t when com bined w ith
h y p e r th e r m ia .
T h e re a r e two im p o r ta n t p o i n t s t o k eep i n mind when
t h i n k i n g o f e f f e c t s o f h y p e rth e rm ia on n o rm a l t i s s u e .
The f i r s t i s t h a t
h y p e rth e rm ia a lo n e ( 45“C) d o e s n o t h av e a s i g n i f i c a n t e f f e c t on norm al
tis s u e s .
Norm al t i s s u e s c a n a l t e r b lo o d flo w t o d i f f u s e h e a t more e f f i ­
c i e n t l y th a n tum or t i s s u e s .
The r e s p o n s e o f h y p e rth e rm ia when com bined
w i t h i o n i z i n g r a d i a t i o n on n orm al t i s s u e can be m in im iz ed by th e i n t r o -
d u c tl o n o f t h e p r o p e r i n t e r v a l b etw een t h e two t r e a t m e n t s .
The se co n d
p o i n t t o k e e p i n m ind I s t h e te m p e r a tu r e u s e d f o r t h e h y p e rth e rm ia
tre a tm e n t.
M ost I n v e s t i g a t o r s h a v e u s e d h i g h e r te m p e r a tu r e s to f in d
t h a t h e a t s e n s i t i z e s n o rm al t i s s u e s t o i o n i z i n g r a d i a t i o n . T h is may n o t
b e th e c a s e i n t h e low h y p e r th e r m ic te m p e r a tu r e r a n g e .
H y p e rth e rm ia a n d t h e V a s c u la tu r e
The r o l e
o f th e v a s c u l a t u r e h a s a n im p o r ta n t r o l e
o r e ffe c tiv e n e s s
o f c e r t a i n a g e n ts o r m o d a l i t i e s on tum or
i n t h e outcom e
resp o n se .
C h e m o th e ra p e u tic a g e n ts depend on th e v a s c u l a t u r e t o p r e s e n t th e d ru g to
t h e tum or c e l l s .
I t haB b een known f o r many y e a r s t h a t t h e o x y g e n a tio n
s t a t u s o f tum ors
i s I m p o r ta n t a t th e tim e o f i r r a d i a t i o n .
oxygen i n th e tum or
The am ount o f
i s a l s o d e p e n d e n t on th e v a s c u l a t u r e ,
s in c e th e
h em o g lo b in c a r r i e d by th e r e d b lo o d c e l l s i s c i r c u l a t e d th ro u g h th e
v a s c u la tu re .
Many f a c t o r s a f f e c t t h e p a t t e r n s and n a t u r e o f th e v a s c u l a r n e tw o rk s
o f tu m o rs .
Some o f t h e s e a r e tum or h i s t o l o g y , l o c a t i o n , a n d t h e a g e o f
th e tum or ( 6 2 ) .
The v a s c u l a t u r e o f tu m o rs h a s b e e n c l a s s i f i e d by R ubin
a n d C a s a r e t t (6 7 ) i n t o p e r i p h e r a l v a s c u l a r i z a t i o n , p e r i p h e r a l v a s c u l a r i ­
z a t i o n w ith p e n e t r a t i n g v e s s e l s , an d c e n t r a l v a s c u l a r i z a t i o n *
At o n s e t
o f tum or g ro w th , t h e tum or c e l l s p ro b a b ly u s e t h e n o rm al t i s s u e ' s v a s c u ­
l a r s u p p ly . .T he demand f o r n u t r i e n t s i n c r e a s e s a s th e tum or grow s i n
m ass.
E v e n t u a l ly , th e s u p p ly o f n u t r i e n t s i s e x h a u s te d by th e i n ­
c r e a s e d demand an d n e o v a s c u l a r i z a t i o n s t a r t s *
S o lu b le f a c t o r s w hich
s t i m u l a t e e n d o t h e l i a l c e l l p r o l i f e r a t i o n h a v e b e e n fo u n d .
Folkm an
( 6 8 ,6 9 ) h a s exam ined one o f t h e s e i n g r e a t d e t a i l , tum or a n g lo g e n e s is
f a c t o r (TA F), b u t t h i s f a c t o r may n o t be s p e c i f i c f o r e n d o t h e l i a l c e l l s .
1*
TAF a s w e l l a s o t h e r f a c t o r s p ro d u c e a n l n f l a m a to r y r e a c t i o n i n s u rro u n d ­
i n g n o rm al t i s s u e s w hich s t a r t s t h e n e o v a s c u l a r i z a t i o n .
T h is p h a se h a s
b e e n term ed th e v a s c u l a r p h a s e an d th e p r e v io u s p h a se was term ed th e
a v a s c u la r phase ( 7 0 ).
The v a s c u l a r p a t t e r n o f a s p o n ta n e o u s ly a r i s i n g C3 H mammary c a r ­
cinom a was exam ined by F a lk ( 7 1 ) .
The s p o n ta n e o u s tu m o r p a t t e r n
d e v e lo p s fro m a c a p i l l a r y n e tw o rk i n t o a n a f f e r e n t s y s te m ( c a p i l l a r y ­
l i k e ) a n d a n e f f e r e n t s y s te m c h a r a c t e r i z e d by l a r g e s in u s e s *
S a e k l e t a l . ( 7 2 ) d e s c r i b e d "n o rm a l" C3 H mouse mammary carcin o m a
v a s c u l a t u r e a s p e r i p h e r a l v a s c u l a r i z a t i o n w ith p e n e t r a t i n g v e s s e l s .
T h ese v e s s e l s c o rk s c re w e d o r s t r e t c h e d from th e p e r i p h e r y i n t o th e
c e n te r.
T h e i r d e s c r i p t i o n was b a se d upon th e c l a s s i f i c a t i o n o f Rubin
and C a s a r e tt.
The v a s c u l a r p a t t e r n o f t h r e e d i f f e r e n t tu m o rs o f m ice
a n d r a t s w ere exam ined by Egawa e t a l . ( 7 3 ) , u s in g a s c a n n in g e l e c t r o n
m ic ro sc o p e a n d t h e f i n e d e t a i l s o f tum or c a p i l l a r i e s w ere ex am in ed .
The m ain f e a t u r e s r e p o r t e d w ere v a s c u l a r i r r e g u l a r i t y , t o r t u o u s l t y ,
s i n u s o i d a l - l i k e s t r u c t u r e s , d i s o r d e r l y ru n n in g c a p i l l a r i e s a n d t a p e r i n g .
S in c e s k in c o v e rs th e e n t i r e body a n d i s u s a l l y i n d i r e c t c o n ta c t
w ith t h e s o u r c e o f h e a t , i t i s l o g i c a l t o exam ine th e e f f e c t s o f h e a t
on s k i n .
T e m p e ra tu re s s l i g h t l y ab o v e n o rm al c a u se I n c r e a s e d b lo o d flo w ,
v a s o d i l a t i o n and i n c r e a s e d v a s c u l a t u r e p e r m e a b i l it y i n s k i n .
Song e t
a l . ( 6 2 ,7 4 ,7 5 ) h a v e r e p o r t e d t h a t h e a t i n g (4 3 °-A 6 s C) th e l e g o f r a t s
c a u s e d a n i n c r e a s e i n t h e v a s c u l a r volum e, v a s c u l a r p e r m e a b i l it y and
b lo o d flo w i n s k i n and m u sc le .
Eddy ( 7 6 ,7 7 ) h a s exam ined th e e f f e c t s o f r a d i a t i o n a n d t h e e f f e c t s o f
h y p e rth e rm ia on t h e v a s c u l a t u r e u s in g th e t r a n s p a r e n t ch eek p o u ch cham ber
i n h a m s te r s .
U sin g 3000 r a d s and m a lig n a n t n e u rlle m m o n a , Eddy found a
15
r e d u c t io n I n b lo o d flo w (2 4 -3 0 h r s . ) and I n h i b i t i o n o f tum or g ro w th an d
n e o v a s c u la rz a tlo n .
Eddy a l s o found t h a t h y p e rth e rm ia c a u se d a d e c r e a s e
I n th e d ia m e te r o f b lo o d v e s s e l s d u r in g h e a t i n g and a somewhat l a t e r
I n c r e a s e I n d i a m e te r .
Eddy a l s o o b s e rv e d t h a t a t te m p e r a tu r e s o f 43°C
p e t e c h l a e , s t a s i s a n d e n d o t h e l i a l d e g e n e r a tio n w ere c h a r a c t e r i s t i c *
Emami e t a l . ( 7 8 ) u s in g rhabdom ysarcom a BA-1112 a n d a n o n - ln v a s iv e
oxygen a c t i v a t i o n te c h n iq u e found h e a t i n g t o 40°C -41°C re d u c e d b lo o d
flo w i n i t i a l l y w h ile l a t e r (7 2 h o u r s ) i t r e t u r n e d to n e a r p r e h e a t v a l u e s .
They a l s o found 43° f o r 40 m in u te s re d u c e d o r e l i m i n a te d c a p i l l a r y
b lo o d f lo w .
Song e t a l . ( 7 5 ,7 9 ,8 0 ,6 2 ) exam ined h y p e rth e rm ic b lo o d flo w I n W alker
c a rc in o m a 256 o f SD r a t s a n d fo u n d no c h a n g e s i n b lo o d f lo w , v a s c u l a r
vo lu m e, a n d v a s c u l a r p e r m e a b i l it y when r a d i o a c t i v e m ic r o s p h e r e s w ere
em p lo y ed .
V aupel e t a l . ( 8 1 ) u s in g th e D S -C arclnosarcom a i n th e k id n e y found
l o c a l i z e d h y p e rth e rm ia c a u se d a s i g n i f i c a n t i n c r e a s e i n tum or b lo o d flo w
fro m 37°C t o 3 9 .5 ° C .
They a l s o r e p o r t e d t h a t a t h i g h e r te m p e ra tu re s
(42 "C ) d e c r e a s e d tum or b lo o d flo w was o b s e rv e d ,
B lc h e r e t a l . (8 2 )
ha v e a l s o r e p o r t e d a n i n c r e a s e d tum or b lo o d flo w a t te m p e r a tu r e s below
41°C .
Some o f th e s e a p p a r e n t c o n f l i c t s may be due t o th e ty p e o f p ro ­
c e d u re s u se d by t h e s e a u t h o r s .
However, one can a r r i v e a t th e g e n e r a l
c o n c lu s i o n , tum or b lo o d flo w I s more s e n s i t i v e t o h e a t th a n norm al
tis s u e .
E f f e c t s o f H y p e rth e rm ia on pH
W arburg, ( 8 3 ,8 4 ) i n 1926 d i s c u s s e d a m e ta b o lic im b a la n c e b etw een
r e s p i r a t i o n a n d g l y c o l y s i s i n m a lig n a n t t i s s u e s *
h a v e a n o b v io u s e f f e c t on t h e l o c a l pH*
T h is im b a la n c e can
S e v e r a l i n v e s t i g a t o r s s tu d y in g
r o d e n t an d human tum or e x p la n t s fo u n d tu m o rs t o h a v e a lo w e r pH th a n
n o rm al t i s s u e s ( 8 5 ,8 6 ,8 7 ,8 8 ) .
G u llin o e t a l* ( 1 8 6 ) fo u n d t h a t th e pH o f
t h e l n t e r s t l t a l f l u i d o f 5 d i f f e r e n t r a t tu m o rs ra n g e d from 6 .9 4 8 to
7 .1 9 3 *
Song e t a l*
(8 9 ) fo u n d t h a t t h e i n t e r t u m o r a l pH was a b o u t 7 .0
a n d th e i n te r m u s c u la r pH was a b o u t 7 .2 i n some r o d e n t s .
B ic h e r e t
a l . ( 8 2 ) h a v e a l s o shown t h a t mean tum or pH was 6 .7 5 i n C3 H mammary c a r ­
cinom a •
The k i l l i n g o f c e l l s w ith h y p e rth e rm ia i n s i n g l e d o s e s h a s been
shown t o be s i g n i f i c a n t l y e n h a n ce d when th e pH f a l l s below a p p ro x im a te ly
7 .0 ( 5 7 ,9 0 ,9 1 ,9 2 .9 3 ) .
Gerweck (9 0 ) exam ined t h e e f f e c t s o f re d u c in g pH
from 7 .6 t o 6 .7 o v e r a ra n g e o f t e m p e r a t u r e s .
He p o i n t s o u t t h a t th e
s e n s i t i z i n g e f f e c t was m ost p ro m in e n t a t te m p e r a tu r e s w hich
g i n a l l y l e t h a l a t n orm al pH ( 7 . 4 ) .
w ere m ar­
O v e rg a ard showed th e i n f l u e n c e o f
h e a t (4 2 .5 " C ) an d pH ( 7 . 2 - 6 . 4 c h a n g e ) , on t h e f re q u e n c y o f tum or p ro ­
d u c ti o n i n v iv o .
He shows a d e c r e a s e o f 67Z (fro m 100Z) a t a pH o f 7 .2
t o 33Z a t a pH o f 7 . 0 .
O v e rg a a rd a n d B ic h e l (9 4 ) u s in g J B - l- E tum or c e l l s and h y p e r t h e r ­
m ia ( 4 2 .5 ° C ) , exam ined w h e th e r t h e r m o - s e n s i t i v i t y i s a s s o c i a t e d more
w i t h th e oxygen s t a t u s o r th e pH.
They c l e a r l y i n d i c a t e t h a t h e a te d
c e l l s (4 2 .5 ° C ) a r e r e s p o n s iv e t o pH a n d n o t d e p e n d e n t on oxygen s t a t u s .
Gerweck an d c o -w o rk e rs (9 5 ) uB lng CH0 c e l l s , d e m o n s tra te d t h a t c e l l
l e t h a l i t y was n o t due t o t h e d e g re e o f o x y g e n a tio n , u n l e s s th e c e l l s
17
w ere h y p o x ic f o r s e v e r a l h o u r s , b u t l e t h a l i t y I n c r e a s e d when th e c e l l s
w ere h e a te d I n a d d e n v iro n m e n t.
Song e t a l * ( 8 9 ) , B lc h e r e t a l » ( 8 2 ) , and V aupel e t a l . (9 6 ) have a l l
shown a d e c re a s e I n th e pH o f h e a te d tu m o rs .
B lc h e r e t a l . (8 2 ) have
shown t h a t th e ln te r tu m o r pH d ro p s from a mean o f
a t te m p e ra tu re s o f 43°C f o r one h o u r.
6 . 8
t o a mean o f 6 .4
Song e t a l . ( 8 9 ) r e p o r t e d t h a t th e
pH dropped from 7 .0 5 t o 6 .6 7 when mouse tum ors w ere h e a te d a t 43.5°C
f o r 30 m in u te s .
D ickson an d Calderw ood (9 7 ) how ever, have found no
d e c r e a s e I n t h e pH o f .r a t tum ors h e a te d a t 42°C f o r one h o u r.
I t i s q u i t e c l e a r t h a t h y p e rth e rm ia a t te m p e ra tu re s from 43°C and
a b o v e a f f e c t s th e pH o f tum ors I n v iv o . At th e s e te m p e r a tu r e s , pH I s p ro ­
b a b ly th e m ost im p o r ta n t p a ra m e te r a f f e c t e d by h y p e rth e rm ia o t h e r th a n
b lo o d flo w .
As
I have a lr e a d y m en tio n e d , s e v e r a l a u th o r s have shown an
i n c r e a s e i n b lo o d flo w a t h y p e rth e rm ic te m p e ra tu re s up t o 40°C w h ile
a lm o s t u n a n im o u sly , m ost I n v e s t i g a t o r s f e e l t h a t a t te m p e ra tu re s above
40°C b lo o d flo w d e c r e a s e s .
I s p ro b a b ly one
I t i s a t th e s e h ig h e r te m p e ra tu re s
t h a t pH
o f th e m ost im p o rta n t f a c t o r i n c e l l d e a th .
Oxygen and H y p erth erm ia
The E f f e c t o f Oxygen on I o n iz in g R a d ia tio n
The most p o w e rfu l r a d i a t i o n s e n s i t i z e r found so f a r i s m o le c u la r
oxygen.
T here a r e c e l l s i n s o l i d tum ors t h a t a r e l e s s s u s c e p t i b l e to
I o n iz i n g r a d i a t i o n b e c a u se o f red u ced e n v iro n m e n ta l oxygen. I f two
g ro u p s o f c e l l s w ere i r r a d i a t e d I n v i t r o , one i n th e p r e s e n c e o f oxygen
a t th e tim e o f i r r a d i a t i o n an d th e o t h e r i n n i t r o g e n , a d i f f e r e n c e i n
th e s lo p e s o f th e two s u r v i v a l c u rv e s w ould be s e e n .
The c e l l s u r v i v a l
18
c u rv e f o r Che c e l l s I r r a d i a t e d I n t h e p r e s e n c e o f n i t r o g e n w ould show a
s l o p e ro u g h ly t h r e e tim e s l e s s (D o ,3 tim e s l a r g e r ) th a n t h o s e c e l l s
I r r a d i a t e d i n th e p r e s e n c e o f o x y g en .
The r a t i o o f th e s lo p e s f o r
o x y g e n a te d c e l l s u r v i v a l c u r v e s , to t h e i r a n o x ic c o u n t e r p a r t s i s term ed
t h e oxygen enhancem ent r a t i o o r O .E .R . ( 9 8 ) .
The O .E .R . h a s b een
e x p e r i m e n t a l l y d e te rm in e d f o r a l a r g e num ber o f c e l l t y p e s , I n v i t r o and
I n v iv o , an d g e n e r a l l y i s
i n t h e o r d e r o f 2 .5 t o 3 . 0 .
I n o r d e r f o r oxygen t o a f f e c t v i a b i l i t y o f c e l l s , i t m ust be p r e s e n t
a t th e tim e o f i r r a d i a t i o n ( 9 9 ,1 0 0 ) .
The c o n c e n t r a t i o n o f oxygen n e c ­
e s s a r y t o h a v e a n e f f e c t a t th e tim e o f I r r a d i a t i o n i s r e l a t i v e l y low*
B ik in d e t a l .
(1 0 0 ) h a s shown t h a t a n oxygen p r e s s u r e o f s e v e r a l mm Hg
I s a l l t h a t i s n e c e s s a r y an d C hat t h e r e i s a n i n s i g n i f i c a n t change i n
t h e r a d i a t i o n s e n s i t i v i t y when t h e oxygen c o n c e n t r a t i o n i s changed from
3% t o 100Z.
F u rth e rm o re , th e oxygen s e n s i t i v i t y a p p e a r s t o b e , I n g e n ­
e r a l , c o r r e l a t e d w ith th e a v a i l a b i l i t y o f oxygen an d n o t w ith I t s u t i l i ­
z a tio n (1 0 1 ).
C r a b tr e e an d C ram er (1 0 2 ) u s e d s e v e r a l p h y s i c a l f a c t o r s
t o s tu d y t h e e f f e c t s o f oxygen c o n su m p tio n on r a d i a t i o n s e n s i t i v i t y .
T he oxygen a l t e r i n g f a c t o r s u se d w ere c o ld te m p e r a tu r e s a n d enzyme
p o i s o n s , b o th o f w hich re d u c e d oxygen c o n s u m p tio n .
They found t h a t
w i t h re d u c e d oxygen co n su m p tio n t h e r e was a n I n c r e a s e i n r a d i a t i o n
s e n s itiv ity .
Most n o rm al c e l l s a r e l e s s th a n 100 m ic ro n s fro m a b lo o d v e s s e l .
I t h a s b een shown t h a t oxygen c a n d i f f u s e o n ly t o a d e p th o f a b o u t 150
m ic ro n s i n m e ta b o liz in g t i s s u e , ( 1 0 3 ) .
S in c e m o st n e o p l a s t i c t i s s u e s
a r e r a p i d l y d i v i d i n g , many c e l l s a r e l o c a t e d a t o r beyond t h e o i^ g e n
d iffu s io n l im it .
T h ese c e l l s a r e th o u g h t t o be h y p o x ic ( 1 0 4 ) .
T hese
c e l l s a r e n o t a c t i v e l y d i v i d i n g and a p p e a r t o be I n a s t a t e o f d o r ­
m ancy.
T h t c e l l s t h a t a r e n e a r a b lo o d v e s s e l a r e w e l l o x y g e n a te d . The
a r e a s w h ich a r e p a s t
g en a n d l i v i n g c e l l s .
tio n s (1 0 5 ).
m ic ro n s fro m a b lo o d v e s s e l a r e d e v o id o f oxy­
2 0 0
B oth l a r g e and s m a ll tu m o rs h a v e h y p o x ic f r a c ­
H ow ever, th e f r a c t i o n o f h y p o x ic c e l l s g e n e r a l l y i n ­
c r e a s e s w i t h th e s i z e o f t h e tum or ( 1 0 6 ) .
Oxygen an d H y p e rth e rm ia
O r i g i n a l l y , th e o x y g e n a tio n s t a t u s m s th o u g h t t o make h y p o x ic c e l l s
more s e n s i t i v e t o h y p e rth e rm ia ( 1 0 7 ,1 0 8 ,1 0 9 ) .
Schulm an an d H a ll ( 1 0 8 ) ,
fo u n d t h a t 43°C was n e c e s s a r y t o s u b s t a n t i a l l y I n c r e a s e th e am ount o f
c e l l k i l l i n g o f a e r a t e d c e l l s w h ile o n ly 41°C was n e c e s s a r y t o s e n s i t i z e
h y p o x ic c e l l s .
On t h e o t h e r h a n d , Hahn (5 9 ) fo u n d t h a t th e s e n s i t i v i t y
o f c e l l s was due t o t h e i r n u t r i t i o n a l h i s t o r y and n o t o x y g e n a tio n s t a t u s
o r g lu co B e c o n c e n t r a t i o n .
Power an d H a r r i s (1 1 0 ) h a v e found t h a t e u o x lc
a n d e x tr e m e ly h y p o x ic c e l l s a r e k i l l e d e q u a l l y a n d f u r t h e r m o r e , t h e
oxy g en enhancem ent r a t i o was u n c h a n g ed .
D urand ( 1 1 1 ) , u s in g m u l t i c e l l u l a r s p h e r lo d s fo u n d t h a t i n c r e a s e d
t h e r m o s e n s i t i v i t y o f h y p o x ic c e l l s may be d u e t o s e c o n d a ry c h a n g es accoroa c co m p an y ln g oxygen d e p l e t i o n .
B ass e t a l . (1 1 2 ) a l s o found no i n c r e a s e
I n th e rm a l s e n s i t i v i t y when th e e f f e c t s o f pH, t r y p s l n l z a t i o n and c e l l
a tta c h m e n t w ere e lim in a te d *
F u rth e rm o re , th e s e a u t h o r s fo u n d t h a t H ela
S3 c e l l s w e re p r o t e c t e d a g a i n s t h e a t by hyp o x ia*
Gerweck e t a l * (9 5 ,1 1 3 ) exam ined th e r e s p o n s e o f c h r o n i c a l l y h y p o x ic
c e l l s t o h y p e r th e r m ia .
They fo u n d t h a t c h r o n ic oxygen d e p r i v a t i o n I n ­
c r e a s e s th e r m a l s e n s i t i v i t y an d t h a t t h i s e f f e c t c o u ld p a r t i a l l y be r e -
v e r s e d by r e a d j u s t i n g th e pH t o p h y s i o l o g i c a l v a lu e s p r i o r t o h y p e r­
t h e r m ia .
T h e se l a s t d a t a i n d i c a t e t h a t o t h e r f a c t o r s p l a y a s i g n i f i c a n t r o l e
i n h y p e rth e rm ic s e n s i t i v i t y .
The l a c k o f oxygen p ro b a b ly s t a r t s m etabo­
l i c c h a n g e s t h a t c a u se d su ch p ro b le m s a s re d u c e d pH.
T hese d a t a p o i n t
o u t t h a t pH i s a t l e a s t a s im p o r ta n t a s oxygen c o n c e n t r a t io n f o r h y p e r­
th e r m ic s e n s i t i v i t y and p ro b a b ly m ore im p o r ta n t .
H y p e rth e rm ic R e o x y g e n a tio n
H ypoxic c e l l s h av e b e e n th o u g h t t o c a u s e th e r e p o p u l a ti o n a tum or
a f t e r a d o se o f r a d i a t i o n , p r i m a r i l y , b e c a u s e th e y w ere shown t o be
r e s i s t a n t to r a d ia tio n .
T h e re a r e i n d i c a t i o n s t h a t h y p e rth e rm ia
a f f e c t s th e s e c e l l s s i g n i f i c a n t l y .
Such f a c t o r s a s th e a c i d i c e n v ir o n ­
m ent a n d th e d e p r i v a t i o n o f n u t r i e n t s w ere shown t o h av e a n im p o r ta n t
e f f e c t on h e a te d c e l l s ( 9 0 ,5 9 ,6 1 ) .
T h e re i s l i t t l e
d o u b t t h a t a t h y p e rth e rm ic t e m p e r a t u r e s , b lo o d flo w
o c c lu s i o n o r r e d u c t i o n , a n d d e c r e a s e d pH a r e m ajo r c o n t r i b u t o r s t o th e
d e s t r u c t i o n o f a h e a te d tu m o r.
On th e o t h e r h a n d , t h e r e i s e v id e n c e
t h a t lo w e r l e v e l h y p e rth e rm ia (4 0 ° C ), may i n f l u e n c e th e o x y g e n a tio n
s t a t u s o f a s o l i d tu m o r.
O tte e t a l . ( 1 1 4 ) an d V au p el e t a l . ( 1 1 5 ) h a v e exam ined th e e f f e c t s
o f 40°C h e a t f o r 30 m in u te s on th e oxygen t e n s i o n o f D S -C arcinosarcom a
o f th e f o o t .
They fo u n d t h a t h e a t i n g t h e tu m o r t o 40°C Im proved th e
tu m o r t i s s u e o x y g e n a tio n and f u r t h e r m o r e , te m p e r a tu r e s o f 43°C o r 45°C
c a u s e d o x y g e n a tio n t o d r a s t i c a l l y d r o p .
B lc h e r e t a l . ( 8 2 ) h a v e a l s o
shown a n i n c r e a s e i n t h e p a r t i a l p r e s s u r e o f oxygen i n r e s p o n s e to
h y p e r th e r m ia .
21
An I n c r e a s e i n Che c o n c e n t r a t i o n o f oxygen p r e s e n t i n tu m o rs , e s p e ­
c i a l l y a t th e tim e o f i r r a d i a t i o n c o u ld i n c r e a s e th e e f f i c i e n c y o f
io n iz in g r a d ia tio n c e l l k i l l i n g .
T herm al D i s t r i b u t i o n
The e f f e c t s o f h e a t on n orm al a n d m a lig n a n t t i s s u e s have been in v e s ­
t i g a t e d f o r many y e a r s and many m ethods o f h e a t i n g h a v e b e e n em ployed.
M icrow ave an d w a te r b a th h e a ti n g seem t o be t h e m ost p r e v a l e n t m ethods .
An e v e n d i s t r i b u t i o n i n te m p e r a tu r e d u r in g h y p e rth e rm ia w ould o b v io u s ly
be n e c e s s a r y f o r good th e r m a l r e s p o n s e , o r a t l e a s t f o r a p r o p e r i n t e r ­
p r e t a t i o n o f th e r e s p o n s e .
M ost a u t h o r s m easu re te m p e ra tu re a t one p o i n t i n t h e tum or ( r o u g h ly
t h e c e n t e r ) , a n d com pare t h i s t o th e te m p e r a tu r e o f t h e w a te r b a th th e
tum or i s im m ersed i n .
T h is c o m p a riso n u s u a l l y y i e l d s d i f f e r e n c e s i n
te m p e r a tu r e o f betw een 0 . 1 aC t o 0 .4 °C ( 5 3 ,4 2 ,5 6 ,4 3 ,1 1 6 ,1 1 7 ) .
W hile
t h i s i s c o n v e n ie n t f o r l a r g e e x p e r im e n ts , i t i s p r o b a b ly n o t s u f f i c i e n t .
T h e re a r e r e p o r t s i n t h e l i t e r a t u r e o f l a r g e g r a d i e n t s i n te m p e ra tu re o f
h e a te d tum or t i s s u e .
1 .3 ° C .
R obinson e t a l . (1 1 8 ) found g r a d i e n t s a s l a r g e a s
Denekamp e t a l .
(1 1 9 ) h av e fo u n d up t o a
i n te m p e ra tu re i n h e a te d tu m o rs .
Hume,
2 .0 °C d i s t r i b u t i o n
R o b in so n and Hand (1 2 0 ) e x ­
am in ed th e e f f e c t s o f m e s e n te r ic b lo o d flo w on te m p e ra tu re d i s t r i b u t i o n .
They fo u n d t h a t th e e q u il ib r i u m te m p e r a tu r e s c l o s e t o t h e v e s s e l s w ere
up t o 2*0°C below l i q u i d b a th t e m p e r a tu r e s .
On t h e o t h e r hand H e tz e l
e t a l . ( 1 2 1 ) u s in g m u l t i p l e p ro b e s m e a s u rin g n in e p o s i t i o n s h av e found
no s i g n i f i c a n t th e r m a l g r a d i e n t .
The p ro b lem o f th e rm a l d i s t r i b u t i o n s i n t i s s u e s h e a te d w ith m ic ro ­
wave te c h n iq u e s i s no l e s s f o rm id a b le th a n w a te r b a th h e a t i n g .
A ll o f
22
Che m a jo r h e a t i n g m ethods p ro b a b ly h a v e t h e i r own te m p e r a tu r e d i s t r i ­
b u t io n p ro b le m s b e c a u s e o f e n e rg y d e p o s i t i o n d i f f e r e n c e s o r d i f f e r e n ­
t i a l e f f e c t s on d i f f e r e n t t i s s u e s *
One m a jo r p ro b le m t h a t w a te r b a th h e a t i n g d o e s n o t h a v e t o overcom e
t h a t m icrow ave te c h n iq u e s m ust overcom e I s t h a t m e ta l I s h e a te d I n a
m icrow ave f i e l d *
n o t a v a ila b le .
Up u n t i l r e c e n tl y * n o n p e rtu r b e d te m p e r a tu r e p ro b e s w ere
M ost a u th o r s u s e d t h e r m l s t e r s o r th e rm o c o u p le s .
S in c e
t h e s e p ro b e s a r e made o f m etal* a t l e a s t I n p a r t , th e y a r e a f f e c t e d when
th e y a r e p la c e d I n a m icrow ave f i e l d .
Such t e c h n iq u e s a s s e q u e n c in g o f
t h e m icrow ave g e n e r a t o r on a n d o f f have b e e n em ployed t o overcom e t h i s
e f f e c t on m e ta l p r o b e s .
T e m p e ra tu re s a r e o n ly ta k e n when th e g e n e r a to r
I s In th e o f f bequence.
W a llen e t a l . (1 2 2 ) u se d m icrow ave h y p e rth e rm ia te c h n iq u e s t o e x a ­
m ine th e r m a l d i s t r i b u t i o n s i n r a t tum ors*
d u r in g h y p e rth e rm ic t r e a t m e n t .
They m easured f i v e l o c a t i o n s
T e m p e ra tu re p r o f i l e s w ere found t o be
r e l a t i v e l y hom ogeneous ( v a r y in g ± 0 .4 ° C ) f o r l a r g e tu m o rs , and w ere
somewhat l e s s hom ogeneous due to h o t t e r c e n t r a l tum or r e g io n f o r s m a l le r
tu m o rs .
New th erm o m e try s y ste m s t h a t a r e n o t a f f e c t e d by m icrow ave h y p e r­
th e r m ia h a v e f i l l e d a g r e a t gap i n o u r know ledge I n th e c a u s e s and
e f f e c t s o f th e rm a l v a r i a t i o n s .
B ut f o r th e m ost p a r t th e s e sy ste m s a r e
to o cumbersome f o r l a r g e s c a l e e x p e rim e n ts u s in g l a b o r a t o r y r o d e n t s .
S ta te m e n t o f th e P roblem
I n g e n e r a l , t h e s e e x p e rim e n ts h av e a tte m p te d t o exam ine I f a m ic ro ­
wave h y p e rth e rm ia s y s te m can b e u s e d t o h e a t a maximum o f two mouse
tu m o rs c o n c o m ita n tly w ith I o n i s i n g r a d i a t i o n and t o u s e t h i s s y s te m to
23
T h e re I s some d o u b t, a c c o r d in g t o c u r r e n t h y p e rth e rm ia l i t e r a t u r e ,
w h e th e r h e a t i n g t o t r a d i t i o n a l h y p e rth e rm ic te m p e r a tu r e s In d u c e s g r a d l e n t s w i t h i n t h e h e a te d volum es ( 1 1 8 ,1 1 9 ,1 2 1 ) . At h i g h e r h y p e rth e rm ic
te m p e r a tu r e s ( 4 2 .5 °C ) "good th e rm a l d o s im e tr y ” may be m ore im p o r ta n t
b e c a u s e t h e te m p e r a tu r e m ust be h ig h enough th ro u g h th e e n t i r e tum or ( o r
h e a te d volum e) t o c a u s e th e r m a l d e s t r u c t i o n , w h ile a t th e lo w e r end o f
th e h y p e r th e r m ic te m p e r a tu r e ra n g e (AO°C) g r a d i e n t s i n te m p e r a tu r e may
be more a c c e p t a b l e e s p e c i a l l y when com bined w ith i o n i z i n g r a d i a t i o n .
A lth o u g h "goad th e r m a l d o s im e tr y ” may n o t b e I m p o r ta n t f o r m ild (40°C )
h y p e rth e rm ia a l o n e , when m ild h y p e rth e rm ia i s com bined w ith I o n i z i n g
r a d i a t i o n t o e n h a n c e th e oxygen e f f e c t i t becom es v e ry im p o r ta n t .
T h is
ste m s from th e f a c t t h a t te m p e r a tu r e s t h a t e x c e e d t h e m ild ra n g e (AO°C)
w i l l re d u c e b lo o d flo w and d im in is h t h e oxygen c o n c e n t r a t i o n a s w e ll a s
i n tr o d u c e th e r m a l d e s t r u c t i o n o f tum or t i s s u e .
I f th e re a re a re a s o f
v e ry low t e m p e r a tu r e , oxygen c o n c e n t r a t io n may n o t be I n c r e a s e d a t a l l ,
th u s n o t a d d in g an y a s s i s t a n c e t o t h e oxygen e f f e c t .
T h e r e f o r e , th e s e
e x p e rim e n ts w i l l exam ine th e r m a l d i s t r i b u t i o n s i n th e h e a te d volum es
( e i t h e r n o rm al t i s s u e o r m a lig n a n t t i s s u e ) an d w hat e f f e c t a i r c o o lin g
( a t a low a i r flo w r a t e ) may h a v e on th e d i s t r i b u t i o n o f te m p e r a tu r e i n
t h e h e a te d volum e o r on th e c o r e te m p e r a tu r e .
The p r e v io u s p a ra g r a p h s h a v e shown t h a t t h e r e i s c o n s id e r a b l e
i n t e r e s t i n t h e u s e o f h y p e rth e rm ia ( p r i m a r i l y a t te m p e r a tu r e s ab o v e
43°C ) a s a n a d ju v a n t t o c o n v e n tio n a l r a d i a t i o n t h e r a p y .
Oxygen c o n -
c e n t r a t l o n h a s b een shown t o be a n I m p o r ta n t a s p e c t i n t h e s u c c e s s f u l
t r e a tm e n t o f m a lig n a n t t i s s u e s i n r a d i a t i o n th e r a p y ( 9 8 ,9 9 ) .
S in c e oxy­
g en h a s p la y e d a n I m p o r ta n t r o l e i n t i s s u e r e s p o n s e t o r a d i a t i o n th e r a p y
24
I t i s l o g i c a l t o exam ine i f c h a n g e s i n t i s s u e oxygen h a v e a n y s i g n i f i ­
c a n t b i o l o g i c a l e f f e c t when m ild (40°C ) h y p e rth e rm ia i s s im u lta n e o u s ly
g iv e n w ith i o n i z i n g r a d i a t i o n .
T h e re i s g ro w in g e v id e n c e ( b o th I n v iv o
a n d i n v i t r o ) t h a t show t h a t lo w e r h y p e r th e r m ic te m p e r a tu r e s c a u s e a
s h i f t i n tum or o x y g e n a tio n t o h i g h e r l e v e l s .
T h is work exam ined a n y
p o t e n t i a l oxygen t e n s i o n i n c r e a s e i n tu m o r t i s s u e In d u c e d by m ild (40°C )
h y p e rth e rm ia w ith o r w ith o u t c o n c o m ita n t oxygen b r e a t h i n g .
I f oxygen t e n s i o n i s i n c r e a s e d i n tum or t i s s u e i n r e s p o n s e t o m ild
h y p e rth e rm ia th e n w hat w ould be t h e outcom e o f s im u lta n e o u s ly com bining
m ild h y p e rth e rm ia a n d i r r a d i a t i o n on r a d i o b i o l o g i c a l h y p o x ia a n d tum or
re s p o n s e ?
G e n e r a l ly , t h e a v a i l a b l e l i t e r a t u r e h a s shown t h a t a t
th e r m o th e r a p e u t ic te m p e r a tu r e s ( 4 2 . 5°C) b lo o d flo w i s ev en more d im i­
n is h e d th a n " n o rm a l” .
T h is f a c t a s w e ll a s d i r e c t oxygen m easurem ents
d u r in g h y p e rth e rm ia ( a t te m p e r a tu r e s g r e a t e r th a n 4 2 .5 “C) d e m o n s tra te s
t h a t h i g h e r te m p e r a tu r e s do n o t i n c r e a s e tum or o x y g e n a tio n d u r in g a con­
c o m ita n t h e a t an d r a d i a t i o n p r o to c o l*
T h e r e f o r e , lo w e r h y p e rth e rm ic
te m p e r a tu r e s m ust be u s e d t o In d u c e I n c r e a s e d tum or o x y g e n a tio n .
T h is w ork w i l l exam ine i f m ild (40°C ) h y p e r th e r m ia , in d u c e d w ith
m icrow ave h e a t i n g te c h n i q u e s , com bined w ith v a r i o u s d o s e s o f s i n g l e
f r a c t i o n r a d i a t i o n a f f e c t s tum or g ro w th o r n o rm al t i s s u e r e s p o n s e .
F o u r s e p a r a t e tum or t h e r a p i e s w ere exam ined f o r b o th n o rm a l t i s s u e
re s p o n s e a n d tum or r e s p o n s e .
The f i r s t th e r a p y in v o lv e d c o n c o m ita n t
m ild (40°C ) h y p e rth e rm ia an d a d o s e o f i o n i z i n g r a d i a t i o n w h ile
b r e a t h i n g oxygen ( a t a flo w r a t e o f 5 l i t e r s / r a i n , ) .
The se c o n d th e r a p y
i s t h e n o n - h y p e r th e r m lc c o n t r o l f o r th e f i r s t t h e r a p y .
u s e s i o n i z i n g r a d i a t i o n w h ile b r e a t h i n g o x y g en .
T h is th e r a p y
The t h i r d th e r a p y u se d
m ild h y p e rth e rm ia a n d c o n c o m ita n t a i r b r e a t h i n g d u r in g i o n i z i n g
25
r a d i a t i o n a n d t h e l a s t th e r a p y was a n a i r - b r e a t h i n g , r a d i a t i o n c o n t r o l .
The r a d i a t i o n d o s e s s u rv e y e d w ere from 3000 t o 6000 r a d s .
The e f f e c tB
o f m ild h y p e rth e rm ia an d o x y g e n a tio n on r e s u l t a n t tum or r e s p o n s e was
shown th ro u g h c o m p arin g tum or volum e c h a n g e s on th e d o s e - r e s p o n s e c u r ­
ves.
T h ese f i g u r e s a r e p l o t s o f th e tim e i t t a k e s t o g e t t o a s p e c i f i e d
volum e (1 4 mm i n t h r e e o r th a g o n a l d im e n s io n s TT / 6 ) v e r s u s d o se o f
io n iz in g r a d ia tio n .
An e n h a n ce d g ro w th d e la y m a n i f e s t s I t s e l f i n lo n g e r
tim e s t o g e t t o th e s p e c i f i e d volum e.
The o v e r l y i n g n o rm al t i s s u e r e s p o n s e t o th e ab o v e m en tio n e d t h e r a ­
p i e s was exam ined by com paring th e tim e i t ta k e s t o g e t to th e maximum
s k i n r e s p o n s e a n d t h e maximum s k i n r e s p o n s e w i t h i n e a c h d o s e i n t e r v a l ,
among th e f o u r s e p a r a t e t h e r a p i e s .
The maximum s k in r e s p o n s e w i t h in
e a c h d o se i n t e r v a l among t h e f o u r t h e r a p i e s , a s w e ll a s th e tim e i t
ta k e s to g e t t o th e maximum s k in re s p o n s e f o r h i g h e r h y p e rth e rm ic tem ­
p e r a t u r e s , w ould show t h a t th e c o n c o m ita n t h e a t a n d r a d i a t i o n t h e r a p i e s
w ould g iv e enh an ced n o rm al t i s s u e r e a c t i o n w ith e a c h d o se i n t e r v a l among
th e f o u r t h e r a p i e s , w h ile th e m ild h y p e rth e rm ic an d c o n c o m ita n t
r a d i a t i o n s h o u ld n o t s i g n i f i c a n t l y a l t e r t h e s k i n r e a c t i o n .
t
M a te r ia ls a n d M ethods
A nim als
A l l o f th e a n im a ls u se d i n t h e s e e x p e rim e n ts w ere C3 H/HENA3 d BR,
i s o g e n i c m ic e . ( H a r la n S p rag u e D aw ley, I n c . ) They w e re h o u se d i n o u r
ALAC a p p ro v e d a n im a l f a c i l i t y .
cage.
S ix 1 8 -2 0 gram m ice w ere h o u sed i n e a c h
The c a g e s w ere s h e lv e d i n a n a u to m a tic w a te r in g r a c k (Lab
P r o d u c ts , I n c . ) .
The
b e d d in g u se d i n th e c a g e s was h e a t t r e a t e d "B e ta
C h ip ” ( N o r th e a s te r n P r o d u c ts C o r p .) .
lib itu m *
Food a n d w a te r w ere p ro v id e d ad
The fo o d p e l l e t s p ro v id e d w ere Mouse Chow 05015 ( R a ls to n
P u r in a C o .) . The a n im a l h o u s in g room te m p e r a tu r e was m a in ta in e d a t
6 8
°
t o 75°F a n d t h e h u m id ity was k e p t w i t h i n 45Z -55Z .
B oth m ale a n d fe m a le m ice w ere u s e d I n a p p r o x im a te ly e q u a l num bers
f o r a l l e x p e r im e n ts .
I n th o s e e x p e rim e n ts w h ere no a n im a l movement was
n e c e s s a r y , a n e s t h e t i c s w ere em ployed.
The a n e s t h e t i c s u se d w ere
t h o r a z l n e , ( c h lo rp ro m a z in e ,)5 0 m g /k g 1m, and k e ta m ln e (4 0m g/kg)lm .
Tumor S ystem
The tum or u se d I n a l l o f t h e s e s t u d i e s was a s p o n ta n e o u s mouse mam­
m ary c a rc in o m a o r i g i n a l l y o b ta in e d from Mr. R o b e rt S e d le c e k a t
M a s s a c h u s e tts G e n e ra l H o s p i ta l ( 1 2 4 ) .
w ere u s e d .
F o u rth and f i f t h p a s s a g e tum ors
T h is tum or o r i g i n a l l y a r o s e s p o n ta n e o u s ly i n a fe m a le m ouse.
T h is w eak ly Im n u n o g en lc tum or was found t o h a v e a volum e d o u b lin g tim e
o f t h r e e d a y s , w h ich c o rr e s p o n d s w e ll w ith t h e p u b lis h e d v a lu e ( 1 2 4 ) .
The f i r s t a p p e a r a n c e o f t h i s tum or was fo u n d t o be te n t o fo u rte e n ^ d ays
a f t e r im p la n ta tio n .
A t y p i c a l g ro w th c u rv e i s shown I n F ig u re 1.
The
s o l i d l i n e p l o t t e d on F ig u re 1 was f i t by co m p u te r u s in g q u a d r a t i c
re g re s s io n a n a ly s is .
Tumor S to ra g e
The o r i g i n a l se c o n d p a s s a g e tum or was s u r g i c a l l y removed from th e
d o n o r , an d grow n i n l a r g e r q u a n t i t i e s .
These tu m o rs w ere removed from
t h e d o n o r s , a n d p la c e d i n s t e r i l e s a l i n e o r i n H a n k 's b a la n c e d s a l t s o l u ­
t i o n a t room te m p e ra tu re *
p o o le d .
F in e m inces o f a few tum ors w ere o b ta in e d and
T h ese p o o le d m in ces w ere c e n t r i f u g e d i n f r e s h H ank’s s o l u t i o n
Tumor Growth, Mouse Mammary Carcinoma
1400-
1200-
n
|
1000-
o
800-
>
600-
400-
200-
o-l
TIME ( t n d a y s )
F ig u r e 1 U n tr e a te d tu m o r g ro w th . The l i n e was f i t th ro u g h t h e p o i n t s
by co m p u ter u s i n g q u a d r a t i c r e g r e s s i o n . Tumor volum e w as c a l c u l a t e d
w ith t h e fo rm u la LxWxHx'fr / 6 .
t w ic e .
The tum or m in ces w ere th e n su sp e n d e d I n g ro w th m edia
(B M E,102F.C .S. 2 92mg/L g lu ta m in e , p e n i c i l l i n , s tre p o m y c in ) s u p p le m e n te d
w ith 7 ,5 3 DHSO.
A lle q u o ts o f t h e c e l l m edia m ix tu re w ere p la c e d I n to
f r e e z e r v i a l s , a n d a llo w e d t o s t a n d a t room te m p e r a tu r e f o r p e r i o d s up
t o 0 . 5 h o u r s b e f o r e f r e e z i n g t o l i q u i d n i t r o g e n te m p e r a t u r e s .
The
m in c e s w ere s t o r e d i n a l i q u i d n i t r o g e n f r e e z e r (MVE C r y o g e n ic s , Model
A p o llo SX-34) u n t i l n e e d e d .
Tumor T r a n s p l a n t a t i o n
The s t o r e d tu m o r m inces w ere rem oved fro m l i q u i d n i t r o g e n , thaw ed
q u ic k ly a 37°C w a te r b a th a n d d i l u t e d t o I n j e c t a b l e c o n c e n t r a t i o n s
w ith s t e r i l e s a l i n e o r H a n k 's s o l u t i o n a s a n a l t e r n a t i v e p r o c e d u r e .
S u b s e q u e n tly t h e tum or was i n j e c t e d by t r o c a r I n t o t h e r i g h t h in d le g
in tra m u s c u la rly .
S i m i l a r l y f o u r t h g e n e r a t i o n tu m o r, n o t s t o r e d i n th e
f r e e z e r was t r a n s p l a n t e d I n t o th e r i g h t h in d lim b o f r e c i p i e n t m ic e .
The d o n o r m ice w ere a n e s t h e s i z e d w ith e t h e r i n a d e s i c c a t o r ,
(then th e
mouse was s e v e r e l y d e p r e s s e d , e u th a n s l a was a c c o m p lis h e d th ro u g h c e r ­
v ic a l d is lo c a tio n .
The tum or b e a r i n g a r e a was s h a v e n a n d c le a n s e d w ith
s e v e n ty p e r c e n t e t h a n o l .
The tum or was th e n s u r g i c a l l y removed and a
p o r t i o n was p la c e d I n t o a 9mm p e t r i d i s h c o n t a i n in g s t e r i l e s a l i n e o r
H a n k 's s o l u t i o n .
Tumor fra g m e n ts (lmm^) w ere t r a n s p l a n t e d by t r o c a r t o
t h e lim b .
R a d ia tio n S o u rce
T he s o u r c e o f I o n iz i n g r a d i a t i o n u s e d I n t h e s e e x p e rim e n ts was a 250
kVp c o n s ta n t p o t e n t i a l x - r a y th e r a p y a p p a r a t u s , m odel 250 CP-1 ( K e li k e t
X -ra y
C o r p .) .
The beam was c o l l im a te d a n d f i l t e r e d w ith 0.44mm Sra,
29
0.25mm Cu and 1.00mm A l.
In th e f i e l d f l a t n e s s .
T here was l e s s chan a f i v e p e r c e n t v a r i a t i o n
The d o s e r a t e was m o n ito re d p e r i o d i c a l l y w ith a
V lc to r e e n c o n d e n se r R -m e te r, (m odel 5 7 0 , V ic to r e e n I n s tru m e n t C o .) .
The
d o se r a t e was 277 r a d s /m in u te s w ith a maximum tim e o f e x p o s u re o f 2 1 .6 6
mln f o r 6000 r a d s .
H y p erth erm ia Equipm ent
A 2450 MHz m icrow ave g e n e r a to r was em ployed f o r a l l h y p e rth e rm ic
tr e a tm e n ts b e c a u se o f I t s
2
cm p e n e t r a t i n g a b i l i t y and th e e a s e a t w hich
i t c o u ld be com bined s im u lta n e o u s ly w ith I o n iz in g r a d i a t i o n .
A m o d ifi­
c a t i o n o f t h i s m icrowave g e n e r a to r was a beam o f f s w itc h w hich tu rn e d
th e beam o f f w ith o u t t u r n in g o f f Che power t o th e e n t i r e g e n e r a to r .
T h is m inor m o d if ic a tio n a llo w e d te m p e ra tu re m easurem ents t o be ta k e n
d u r in g th e h y p e rth e rm ic tr e a tm e n ts w ith o u t h a v in g t o tu r n th e e n t i r e
g e n e r a to r o f f and h a v in g Co w a it f o r th e warm-up tim e o f th e g e n e ra to r*
T h is m inor m o d if ic a tio n a llo w e d te m p e ra tu re m easurem ents to be ta k e n
d u r in g th e h y p e rth e rm ic t r e a tm e n ts w ith o u t h a v in g t o tu r n th e e n t i r e
g e n e r a to r o f f and h a v in g t o w a it f o r th e warm-up tim e o f th e g e n e r a to r .
I n p r e lim in a r y e x p e rim e n ts (u n p u b lis h e d r e s u l t s ) i t was d e te rm in e d
t h a t th e m icrow ave power n e c e s s a ry Co h e a t th e ro d e n t tum ors was
a p p ro x im a te ly 5 w a t t s .
The m icrow ave g e n e r a to r was n o t found t o work
v e ry e f f i c i e n t l y a t t h i s low power o u tp u t.
T h is i n e f f i c i e n c y m a n ife s te d
i t s e l f a s o s c i l l a t i o n s i n th e t o t a l power o u tp u t w hich c a u se d p e r i o d i c
e x c e s s iv e h e a tin g i n th e ro d e n t lim b .
T hese p e r io d s o f e x c e s s iv e
h e a ti n g c a u se d u n a c c e p ta b le norm al t i s s u e damage ( e . g . , l o s s o f th e
e n t i r e tum or b e a r in g lim b ) .
30
To a l l e v i a t e th e ab o v e m en tio n e d p ro b le m a 2450 MHz c o a x i a l d i r e c ­
t i o n a l c o u p le r (M odel 3 0 0 3 -1 0 , N arda M icrow ave C o r p .) waa em p lo y ed * to
sa m p le a f r a c t i o n o f t h e t o t a l o u tp u t o f t h e g e n e r a t o r .
The m a j o r it y o f
t h e t o t a l o u tp u t i s a llo w e d t o p a s s th ro u g h th e c o u p le r u n p e r tu r b e d .
In
t h i s c a s e t h e u n p e r tu r b e d s e c t i o n was d e p o s it e d i n t o a c o a x i a l r e s i s t o r
(M odel 8 4 0 1 , 6000 w a t t a , 50 Ohms, B ir d E l e c t r o n i c C o r p .) .
beam waa u s e d to h e a t th e mouse t i s s u e s .
The sam pled
By u s in g a c o a x i a l d i r e c t i o n a l
c o u p le r a h i g h e r v o l ta g e c o u ld b e a p p li e d t o th e m ag n a tro n o f th e
m icrow ave g e n e r a t o r a llo w in g th e g e n e r a t o r t o o p e r a t e a t a more s t a b l e
power o u t p u t .
A beam s p l i t t e r ( M ic ro la b , D2-1TN) was c o n n e c te d t o th e s a m p le r con­
n e c t i o n o f th e d i r e c t i o n a l c o u p l e r .
T h is a llo w e d th e fo rw a rd m icrow ave
pow er from th e d i r e c t i o n a l c o u p le r t o s p l i t i n t o two e q u a l h a l v e s .
In
th o s e e x p e rim e n ts w here o n ly one mouse was h e a te d a t a tim e , th e beam
s p l i t t e r was n o t em ployed.
A tta c h e d to th e beam s p l i t t e r s w ere two T h r u lln e w a tt m e te rs (Model
4 3 , 50 Ohm Im p ed an ce, B ird E l e c t r o n i c C o r p .) and s t u b t u n e r s (M odel FXR
52-05N M ic r o la b ) .
The w a tt m e te rs w ere f i t t e d w ith 2450 MHz e le m e n ts
(25 w a t t Model 4 3 3 -2 0 B ird E l e c t r o n i c C o r p .)
The w a tt m e te rs w ere used
t o d e te r m in e th e fo rw a rd a n d r e f l e c t e d pow er ( s t a n d i n g w a v e ).
The s tu b
t u n e r s w ere u se d t o e i t h e r i n c r e a s e o r d e c r e a s e th e r e f l e c t e d pow er.
In
th o s e I n s t a n c e s w here one o f th e h e a te d m ice was h o t t e r th a n th e o t h e r
th e r e f l e c t e d pow er o f th e h o t t e r a n im a l was I n c r e a s e d t o a llo w t h e
o t h e r a n i m a l 's tum or t i s s u e t o I n c r e a s e i n te m p e r a tu r e .
T h is m ethod,
a lo n g w ith t u r n i n g o f f th e m icrow ave beam , a llo w e d f o r a r e l a t i v e l y
s t a b l e t i s s u e te m p e r a tu r e t o be m a in ta in e d ( a s d e te rm in e d w ith a s i n g l e
p o i n t te m p e r a tu r e m easurem ent i n th e h e a te d t i s s u e ) .
31
The m icrow ave g u id e s u se d w ere d e s c r i b e d by Sandhu e t a l . ( 1 2 6 ) .
They w ere c o n s t r u c t e d i n o u r l a b o r a t o r y .
B a s ic a lly , th e s e a p p lic a to r s
w ere c o n s t r u c t e d o f b r a s s , f i l l e d w ith a pow dered d i e l e c t r i c m a t e r i a l ,
( p l a s t i c / c e r a m i c s B c c o flo H ik Power k " 6 Em erson a n d C um lnglne) and
to p p e d w ith s o l i d d i e l e c t r i c m a t e r i a l .
The a n te n n a t h a t f i t s i n t o th e
w a v e -g u ld e was i n d i v i d u a l l y m atched t o th e g e n e r a t o r by s n ip p in g o f f
s m a ll p o r t i o n s o f th e w ir e i n a s e p a r a t e s e r i e s o f e x p e r im e n ts .
Therm om etry
A l l o f th e th erm o m etry eq uipm ent u sed i n th e s e e x p e rim e n ts was
c a l i b r a t e d a g a i n s t a N a tio n a l B ureau o f S ta n d a r d s C e r t i f i e d th erm o m eter
(N o. 8 8 0 2 4 , E r t c o ) .
R e c t a l te m p e r a tu r e s w ere ta k e n w ith e i t h e r a B a ile y ty p e K T-29/3
h y p e rd e rm ic n e e d le n i c r o p r o b e , ( B a il e y I n s t r u m e n t s , I n c . ) c o v e re d w ith
h e a t s h r i n k t u b in g a t t a c h e d t o a d i g i t a l te m p e r a tu r e r e a d o u t (B a t
8
B a ile y I n s t r u m e n t s , I n c . ) o r a YSI r o d e n t r e c t a l p ro b e ( S e r i e s 400)
a t t a c h e d t o Y SI, Model 73 ATD, i n d i c a t i n g C o n t r o l l e r (Y e llo w S p rin g s
I n s tr u m e n t C o .) .
The s i n g l e p o i n t te m p e ra tu re m easurem ents w ere ta k e n w ith a ty p e
M T -29-3, h y p o d e rm ic n e e d le m ic ro p ro b e ( B a ile y I n s t r u m e n t s , I n c . ) o r by a
m ic ro th e rm o c o u p le , i n a g l a s s m i c r o p ip e tt e (made i n o u r l a b ) .
The
l a t t e r th e rm o c o u p le h a s th e s e n s in g J u n c t i o n a t th e v e ry t i p o f th e
g l a s s m ic r o p i p e t t e w h ile t h e fo rm e r may n o t be a t th e t i p o f th e
s t a i n l e s s s t e e l h y p o d e rm ic n e e d le .
To rem edy t h i s s i t u a t i o n e v e ry
n e e d le m ic ro p ro b e u s e d was ch eck ed t o d e te rm in e w here th e te m p e ra tu re
s e n s i n g j u n c t i o n was l o c a t e d i n th e n e e d le .
I f th e j u n c t i o n was found
n o t t o be a t th e t i p o f th e n e e d le , t h e n e e d le was c a r e f u l l y c lip p e d
32
u n t i l th e j u n c t i o n was c l o s e r t o th e t i p .
P r o d u c tio n o f T r i p l e M ic ro th e rm o c o u p le s
A l l o f th e t r i p l e m ic ro th e n n o c o u p le s u s e d w ere m a n u fa c tu re d i n o u r
la b o ra to ry .
T h ese t r i p l e m ic ro th e rm o c o u p le s a r e b a s i c a l l y t h r e e s i n g l e
I n d e p e n d e n t th e rm o c o u p le s t w i s t e d t o g e t h e r .
The te m p e r a tu r e s e n s i t i v e
j u n t l o n s o f t h e s e t h r e e th e rm o c o u p le s w ere s p a c e d a p p ro x im a te ly
2
mm
a p a rt.
The w ir e u se d i n th e c o n s t r u c t i o n o f th e s e th e rm o c o u p le s was 0.002mm
t e f l o n c o a te d c o p p e r a n d 0.0035mm t e f l o n c o a te d c o n s t a n t l n ( C a l i f o r n i a
F in e H ire C o .) .
c le a n s c a lp e l.
w ire*
E q u a l l e n g t h s o f b o th ty p e s o f w ir e w ere c u t w ith a new
A s m a ll w e ig h t (a n u t) was a t t a c h e d t o one end o f e a c h
The o t h e r e n d s o f th e s e w ir e s w ere a t t a c h e d t o a c e n t e r p o s t o f a
m odel e n g in e i n s e r i e s w ith a s w itc h and a
6
v o l t H e rc u le s B a t te r y
(U nion C a r b id e ) .
The b a t t e r y w i l l t u r n t h e m o to r a n d th e w ir e s w ere
tw is te d to g e th e r.
One end o f b o th o f th e w ir e s w ere s t r i p p e d o f th e
t e f l o n c o a ti n g an d w elded t o g e t h e r w ith a m ic ro w e ld in g d e v ic e .
The
w e ld in g e q u ip m e n t was p ro d u ce d i n o u r l a b o r a t o r y (b y Mr. C a r r o l l R a n g e ).
The w e ld in g o f th e s e w ir e s was a c c o m p lis h e d u n d e r a d i s s e c t i n g m ic ro ­
s c o p e (B auch an d Lomb S te rio z o o m 7 ) .
C o n t i n u it y o f e a c h c o m p le te d
m ic ro th e rm o c o u p le was t e s t e d w ith a d i g i t a l m u ltim e te r (S im pson, M odel
4 6 1 ) . T h re e o f th e s e c o m p le te d th e rm o c o u p le s w ere p la c e d a p p ro x im a te ly
2
mm a p a r t a n d a s m a ll w e ig h t (a n u t ) was a t t a c h e d to e a c h i n d i v i d u a l
th e rm o c o u p le an d su sp en d e d from a hand s p in n i n g d e v ic e .
The c o m p le te d
t r i p l e m ic ro th e rm o c o u p le s h a v e t h r e e te m p e ra tu re s e n s i n g j u n c t i o n s ,
a p p r o x im a te ly 2 mm a p a r t .
The d ia m e te r o f e a c h t r i p l e m ic ro th e rm o c o u p le
s e n s o r was a p p ro x im a te ly 150 m ic r o n s .
A 27 g au g e n e e d le was g lu e d t o
33
one end ( n o t Che end o f th e th e rm a l j u n c t i o n s ) t o f a c i l i t a t e i n s e r t i o n
i n t o t h e mouse t i s s u e s *
E x a m in a tio n o f th e p o s s i b i l i t y o f "C ro ss T a lk " betw een t h e T herm ocouple
J u n c ti o n s i n a S in g le T r i p l e M ic ro th e rm o c o u p le
The p o s s i b i l i t y o f “ c r o s s t a l k " e x i s t i n g b e tw e ee n t h e t h r e e c l o s e l y
r e l a t e d m ic ro th e rm o c o u p le j u n c t i o n s le d t o two b a s i c e x p e rim e n ts to
i n v e s t i g a t e t h i s phenom enon.
I f "c ro ss ta lk " e x i s t s , a s e rio u s doubt
c o u ld b e p la c e d on th e s e e x p e rim e n ts a s w e ll a s o t h e r e x p e rim e n ts o f
t h i s n a tu r e e m p lo y in g s i m i l a r t r i p l e th e rm o c o u p le s t h a t a r e comm e ric a lly a v a ila b le *
I n t h e f i r s t s e r i e s o f e x p e r im e n ts , a m e ta l b lo c k was a t t a c h e d t o
t h e m ost d i s t a l o f th e t h r e e m ic ro th e rm o c o u p le s , im m e d ia te ly a d j a c e n t
t o a se c o n d in d e p e n d e n t th e rm o c o u p le .
w ere a t t a c h e d t o a se co n d m e ta l p l a t e (
p la te ).
The o t h e r two m ic ro th e rm o c o u p le s
1
mm fro m th e f i r s t m e ta l
A d ja c e n t t o e a c h o f th e se co n d an d t h i r d p r o b e s , w ere in d e p e n ­
d e n t s i n g l e th e rm o c o u p le s , a l s o a t t a c h e d to th e se co n d p l a t e .
Each p a i r
o f th e rm o c o u p le s was c a l i b r a t e d t o c o n firm th e i d e n t i c a l te m p e ra tu re
re a d in g s o b ta in e d .
The f i r s t m e ta l b lo c k ( t h e s m a l le r o n e ) was h e a te d
w ith a r e s i s t a n c e c o l l .
The r i s e i n te m p e r a tu r e o f th e f i r s t p a i r o f
th e rm o c o u p le s was com pared t o th e r e a d in g s o f th e o t h e r two p a i r s .
A
maximum d is c r e p a n c y b etw een e a c h p a i r o f 0 . 1 ’ C was fo u n d .
The s e c o n d e x p e rim e n t t o exam ine t h e p o s s i b l e e x i s t e n c e o f " c r o s s
t a l k " em ployed a s t a t i c m u scle phantom m a t e r i a l (Guy G e l ) .
A g a in , a
t r i p l e m ic ro th e rm o c o u p le was p la c e d Im m e d ia te ly n e x t t o in d e p e n d e n t t h e r ­
m o c o u p le s.
A s m a ll r e s i s t a n c e h e a t e r was p la c e d i n th e phantom
m a t e r i a l 4 mm beyond t h e end i n th e same p la n e a s t h e d i s t a l J u n c ti o n o f
34
Che t r i p l e probe*
A 2°C g r a d i e n t was p ro d u ce d b e tw e en t h e f i r s t and s e ­
cond p ro b e s by a p p ly in g power t o th e r e s i s t a n c e h e a t e r .
The m easured
g r a d i e n t b e tw e en t h e f i r s t an d se co n d j u n c t i o n s on t h e t r i p l e m lc r o th e r m ocouple was I d e n t i c a l t o t h a t o f th e I n d e p e n d e n t th e rm o c o u p le s*
Sim­
i l a r r e s u l t s w ere o b ta in e d when p ro b e s 1 a n d 3 an d p ro b e s 2 a n d 3 w ere
o b se rv e d *
T h ese r e s u l t s a s w e ll a s th e ab o v e m en tio n e d r e s u l t s I n d i c a t e
t h a t e a c h m ic ro p ro b e on t h e t r i p l e m ic ro th e rm o c o u p le f u n c t i o n s In d e p e n ­
d e n tly .
E quipm ent u s e d f o r T e m p e ra tu re D i s t r i b u t i o n
The e q u ip m e n t u s e d f o r t h i s s e r i e s o f e x p e rim e n ts can be d iv id e d
I n to th re e c a te g o r ie s :
a ) r e s t r a i n i n g e q u ip m e n t, b) th erm o m etry e q u ip ­
m ent a n d ; c ) h e a t i n g e q u ip m e n t.
The d e v ic e c o n s tr u c te d to r e s t r a i n th e e x p e r im e n ta l a n im a ls con­
s i s t e d o f two p a r t s , th e b a s e , and th e t r i a n g u l a r a n im a l c o v e r .
The
b a s e o f t h i s h o ld e r was c o n s tr u c te d o f p l e x i g l a s s w ith U sh a p ed p ie c e
o f p l e x i g l a s s a t t a c h e d t o th e b a s e a t a n a n g le o f a p p ro x im a te ly 2 5 0 °.
T h is U sh a p ed p ie c e a llo w s th e e x p o sed lim b t o be im m o b iliz e d .
The
t r i a n g u l a r a n im a l c o v e r i s open a t e i t h e r end a n d h a s a s m a ll n o tc h c u t
o u t o f one s i d e .
The o p e n in g o f th e n o tc h c o rr e s p o n d s to th e U sh ap ed
p ie c e o f p l e x i g l a s s on th e b a s e .
The n o tc h a llo w s o n ly th e r i g h t
h in d lim b t o be e x p o sed from th e t r i a n g u l a r c o v e r .
Therm om etry waB a c c o m p lis h e d th ro u g h th e u s e o f t h r e e t r i p l e r a lc ro th e rm o c o u p le s a t t a c h e d t o a r r a y o f c o n n e c to r c l i p s .
T h ese c o n n e c to r
c l i p s w ere c o n n e c te d t o two th e rm o c o u p le s w itc h boxes i n s e r i e s ( B a ile y
In stru m e n ts, I n c . ) .
C ore te m p e r a tu r e was m easu red th ro u g h th e u s e o f
r e c t a l p ro b e s a s m en tio n e d p r e v i o u s l y .
35 .
The m ethod em ployed to h e a t th e t i s s u e was m icrow ave h e a ti n g .
The
equ ip m en t u se d was d e s c r ib e d i n a p re v io u s s e c t i o n .
P ro c e d u re f o r M easurem ents o f T e m p era tu re D i s t r i b u t i o n
An a n e s t h e t i z e d (c h o lo rp ro m a z in e , k e ta m in e ) C3 H mouse was p la c e d
i n t o th e r e s t r a i n i n g d e v ic e and th e exposed lim b Im m o b ilized by ta p in g
i t t o th e p l e x i g l a s s b o th norm al t i s s u e ( l e g m u sc le ) an d m a lig n a n t
t i s s u e (MCa) w ere exam ined f o r d i s t r i b u t i o n s i n te m p e r tu r e .
T hree
t r i p l e m ic ro th e rm o c o u p le s w ere i n s e r t e d i n t o th e tum or t i s s u e o r norm al
t i s s u e i n one o f two a ra n g e m e n ts .
The two a rra n g e m e n ts a r e s c h e m a tic a lly d e m o n s tra te d i n F ig u re s 2 an d 3.
F ig u r e 2 shows th e p e r p e n d ic u la r a rra n g e m e n t.
T h is f i g u r e shows t h a t
th e f i r s t t r i p l e m ic ro th e rm o c o u p le (p ro b e s # 1 ,2 ,3 ) i s c l o s e r t o th e bone
th a n e i t h e r th e se co n d (p ro b e s # 4 ,5 ,6 ) o r th e t h i r d (p ro b e s # 7 ,8 ,9 ) .
F ig u re 3 shows th e p a r a l l e l (w ith r e s p e c t t o th e bone) a rra n g m e n t.
T h is
f i g u r e shows t h a t th e f i r s t t r i p l e m ic ro th e rm o c o u p le (p ro b e s # 1 ,2 ,3 ) i s
th e c l o s e s t t o th e h i p , b u t i s s t i l l I n th e same p la n e w ith th e o t h e r
p ro b es.
A l l o f th e p ro b e s i n F ig u re 3 a r e i n a p la n e p a r a l l e l to t h a t
o f th e bone.
A f t e r th e p r o p e r a rra n g e m e n t o f p ro b e s h a s been a c h ie v e d , th e open
e n d s o f th e m ic ro th e rm o c o u p le s a r e s t r i p p e d o f th e t e f l o n c o a tin g and
I n s e r t e d i n t o th e c o n n e c to r c l i p s .
The r e c t a l p ro b e was I n s e r te d i n t o
t h e rectu m and ta p e d t o th e t a i l .
M easurem ents w ere ta k e n e v e ry two m in u te s f o r 10 m in u tes w ith o u t
h e a t i n g to e s t a b l i s h a b a s e l i n e .
A f t e r th e b a s e l i n e r e a d in g s were
t a k e n , th e m icrow ave a p p l i c a t o r was p la c e d n e x t to t i s s u e t o be h e a te d
s u c h t h a t th e t r i p l e m ic ro th e rm o c o u p le s w ere a t a r i g h t a n g le t o th e
e le c tr ic fie ld .
A f t e r th e a p p l i c a t o r was i n p o s i t i o n and tu r n e d o n ,
te m p e r a tu r e m easu rem en ts w ere ta k e n e v e ry two m in u te s f o r 30 m in u te s by
t u r n i n g o f f t h e power ( f o r 30 s e c o n d s ) .
The pow er g o in g t o th e a p p l i c a ­
t o r was a l s o m easured e v e ry 2 m n in u te s .
A f t e r a p p ro x im a te ly 10 m in u te s ,
The h e a te d t i s s u e r e a c h e d a p p r o x im a te ly 40"C .
At t h e c o n c lu s io n o f e v e ry e x p e rim e n t t h e t r i p l e m ic ro th e rm o c o u p le s
w e re com pared t o a c e r t i f i e d th erm o m e te r i n a w a t e r b a th .
To d e te r m in e th e a c t u a l a rra n g e m e n t o f th e i n d i v i d u a l m ic r o th e r ­
m o co u p les i n e a c h t r i p l e m ic ro th e rm o c o u p le an d t o f in d o u t w hich co n n ec­
t o r c l i p e a c h m ic ro th e rm o c o u p le was a t t a c h e d , th e c o n t i n u i t y o f e a c h
i n d i v i d u a l p ro b e was t e s t e d w ith a d i g i t a l M u ltlm e r (S im p so n , Model
4 6 1 ).
The c o n t i n u i t y was ch eck ed by p l a c i n g one m u ltim e te r t e s t le a d
a c r o s s b o th c o n n e c t o r s , (o n e f o r th e c o n s t a n t i n w ir e and th e o t h e r f o r
t h e c o p p e r w i r e ) , an d p l a c i n g t h e o t h e r l e a d a t th e w elded j u n c t i o n o f
e a c h i n d i v i d u a l th e rm o c o u p le i n e a c h t r i p l e m ic ro th e rm o c o u p le .
T h is
p r o c e d u r e was a c c o m p lis h e d u n d e r a d i s e c t l n g m ic ro sc o p e (B auch a n d Lomb
S te rio z o o m 7 ) .
37
BONE
(P R O B E S 1, 2 , 3 )
(P R O B E S 4 , 5 , 6 )
1
(P R O B E S 7 , 8 , 9 )
ARRANGEM ENT O F
THE TRIPLE
M ICROTHERM OCOUPLES
IN THE
PERPENDICULAR
DIRECTION
F ig . 2
A rran g em en t o f t h e T r i p l e M ic ro th e rm o c o u p le s i n t h e P e rp e n ­
d i c u l a r D i r e c t i o n . A rran g em en t o f t h e t h r e e t r i p l e p ro b e s
i n th e r i g h t h in d lim b . The f i r s t t r i p l e p ro b e c o n t a i n s
p ro b e s 1 , 2 , 3 , t h e se c o n d c o n ta i n s p r o b e s 4 , 5 , 6 and t h e t h i r d
c o n ta i n s p r o b e s 7 , 8 , 9 .
38
/
ARRANGEMENT OF
/
THE TRIPLE
' MICROTHERMOCOUPLES
IN THE PARALLEL
DIRECTION
BONE
F ig . 3
Arrangem ent: o f th e T r i p l e M ic ro th e rm o c o u p les i n t h e P a r a l l e l
D i r e c t i o n . A rrangem ent o f t h e t h r e e t r i p l e p ro b e s i n t h e r i g h t
h in d lim b , s i d e v ie w . The f i r s t t r i p l e p ro b e c o n ta i n s p ro b e s
1 , 2 , 3 , th e second c o n ta in s p ro b e s 4 ,5 ,6 and th e t h i r d c o n ta in s
p ro b e s 7 , 8 , 9 .
39
P r o d u c tio n o f Oxygen E l e c t r o d e s
A l l o f t h e e l e c t r o d e s u s e d I n t h i s s e r i e s o f e x p e rim e n ts w ere p r o d u se d i n o u r l a b o r a t o r y .
T h ese e l e c t r o d e s a r e b a s i c a l l y C la rk ty p e
e le c tro d e s (1 2 5 ).
The p r o c e d u re em ployed I n th e p r o d u c tio n o f t h e s e e l e c t r o d e s I s a s
f o ll o w s :
R6 g l a s s (fro m G a rn e t g l a s s ) I s c u t I n t o a p p ro x im a te ly 2 In c h
l
le n g th s .
Then t h e g l a s s i s c le a n e d i n a c e t o n e , w a te r a n d l a s t l y m e th a n o l,
a n d d r i e d by fla m in g a f t e r t h e l a s t r i n s e .
The g l a s s p i p e t I s th e n
p u l l e d I n t o a f i n e p o i n t w ith a v e r t i c a l p i p e t p u l l e r .
I n s t r u m e n t s , Model 700C, T lu ju n a , C a l i f . ) .
(D avid Kopf
A p la tin u m w ire o f 12 .5
m ic ro n d ia m e te r (Sigm und Cohn C o r p ., M t. V ernon, N .Y .) i s th e n i n s e r t e d
i n t o t h e p i p e t w ith f o r c e p s , a llo w in g th e t i p o f t h e w ir e t o e x te n d
i n t o t h e p o in te d s e c t i o n o f th e g l a s s p i p e t .
I n o r d e r to p r e v e n t th e
p la tin u m w ire from s l i p p i n g o u t o f th e p i p e t , a s m a ll d ro p o f c o n ta c t
cem ent i s p la c e d a t th e open end o f th e p i p e t .
The g l a s s p i p e t i s
a t t a c h e d t o a m ic r o m a n lp u la to r ( N a r i s h lg e S c i e n t i f i c I n s tr u m e n t L ab.
Type MM-31), and u s in g a m ic ro sc o p e (N ikon 0 .7 X ) , th e m ic ro m a n lp u la to r
i s a d j u s t e d t o p la c e t h e t i p o f th e w ir e ( i n s i d e t h e t i p o f th e p i p e t )
j u s t below t h e f i e l d o f v i s i o n o f th e m ic ro s c o p e .
The lo o p o f th e
m ic r o f o r g e i s p la c e d i n th e m id d le o f th e m ic r o s c o p ic f i e l d s u rr o u n d in g
th e g l a s s p i p e t a n d th e g l a s s h e a te d a lo n g th e l e n g t h o f th e t i p enough
t o s e a l t h e g l a s s t o th e p la tin u m w i r e .
B e fo re h e a t i n g th e g l a s s , a
s m a ll w e ig h t i s a t t a c h e d t o th e p i p e t w ith g l u e , a ll o w i n g th e l i q u i d
g l a s s t o c o n s t r i c e a ro u n d th e p la tin u m w i r e .
A f t e r a d h e r in g th e g l a s s
t o t h e p la tin u m w i r e , t h e t i p o f t h e p i p e t i s g ro u n d t o a p o in t
( N a r i s h ig e S c i e n t i f i c I n s tr u m e n ts £7611-7 g r i n d e r w ith S /P a b r a s i v e
pheet
0M 7438-3).
Then #32 c o p p e r w ire I s a tt a c h e d ( c le a n e d w ith m etha­
n o l) t o a c o n n e c to r w ith s o l d e r .
The p la tin u m w ire fu se d I n to th e
g l a s s p i p e t a f t e r g r in d i n g I s w ashed w ith a c e to n e and a llo w e d t o d ry .
The f i r s t membrane, fo rm v a r i n e th y le n e d i c h l o r l d e 0 .2 5 2 ( E r n e s t F.
F u lla m , I n c . , S c e n e c ta d y , N .Y .), i s a p p li e d to th e oxygen s e n s in g t i p o f
th e e l e c t r o d e and l e t d r y o v e r n i g h t .
S i l v e r p r i n t i s i n j e c t e d i n t o th e
g l a s s p i p e t by u s in g a t u b e r c u l i n s y r in g e and a c o p p er w ire ( a t t a c h e d to
th e c o n n e c to r) i s i n s e r t e d i n t o th e w et s i l v e r p r i n t and a llo w e d to d ry
c o m p le te ly .
U sing a s m a ll p ie c e o f s h r i n k t u b in g , th e c o n n e c to r I s s e c ­
u re d t o th e g l a s s
e le c tro d e .
A second membrane o f r o p le x (Rhom-Haas,
C o r p .) i s a p p li e d t o th e oxygen s e n s in g p o r ti o n o f th e e l e c t r o d e and
a llo w e d t o d ry c o m p le te ly .
The two membranes a r e m eant to be an oxygen
p e rm e ab le membrane.
Oxygen M easurem ents
The p ro c e d u re em ployed f o r m easurem ent o f oxygen t e n s i o n i n t i s s u e s
was d e s ig n e d t o a tte m p t t o m inim ize th e e f f e c t o f m icrow aves on th e e l e c ­
tr o d e s a n d th e c i r c u i t r y .
The method o f in d u c in g 40°C t i s s u e tem p era­
t u r e s h a s been p r e v io u s ly d e s c r ib e d I n th e s e c t i o n e n t i t l e d H y p erth erm ia
e q u ip m e n t.
Only one mouse was h e a te d a t a tim e .
The m ice em ployed w ere th e same a s p r e v io u s ly d e s c r i b e d .
The mice
w ere p re p a re d f o r th e e x p e rim e n t by a n e s t h e t i z i n g them w ith c h lo rp ro m a z l n e , (50m g/kg) and k e ta m in e , (4 0 m g /k g ).
On some o c c a s io n s a d d i t i o n a l
a n e s t h e t i c was n e c e s s a r y d u rin g th e c o u rs e o f th e e x p e rim e n t.
Upon
s u c c e s s f u l a n e s t h e s i a th e h a i r on th e r i g h t h in d q u a r t e r o f th e mouse
was removed and mouse was p la c e d on a K-pad (H a m ilto n a q u a m a tlc ).
K-pad was c o v e re d w ith a t h i n p ie c e o f p l e x i g l a s s .
The
The p l e x i g l a s s was
u sed to p ro v id e a s o l i d s u r f a c e t o im m o b iliz e th e a n im a l.
The K m odule,
s e t a t a te m p e r a tu r e o f 34°C , p r o v id e s s t a b i l i t y I n mouse c o re
te m p e ra tu re *
The mouse was Im m o b ilis e d w ith t a p e a n d two I n c i s i o n s
w e re made I n t h e s k in *
The f i r s t I n c i s i o n was made I n th e lo w e r b ack
p a r a l l e l t o t h e s p i n a l column*
A p o c k e t was made betw een th e s k i n and
t h e u n d e r ly in g m u sc le an d was m o is te n e d w ith s a l i n e t o p r e v e n t d ry in g *
Then th e s i l v e r c h l o r i d e r e f e r e n c e e l e c t r o d e was I n s e r t e d .
In o rd er
t o o b t a i n a good e l e c t r i c a l c o n n e c tio n , c o p io u s am ounts o f e l e c t r o d e
j e l l y w e re sm eared on th e r e f e r e n c e e l e c t r o d e , p r i o r t o t h e I n s e r t i o n
I n t o th e p o c k e t.
The se co n d I n c i s i o n was th ro u g h th e s k in c o v e rin g
th e t i s s u e t o be exam ined I n th e r i g h t h in d lim b .
T h re e te m p e r a tu r e s w ere m o n ito re d I n t h i s s e r i e s o f e x p e r im e n ts .
The f i r s t was th e r e c t a l te m p e r a tu r e ( c o r e t e m p e r a t u r e ) .
T h is measure**
raent was p e rfo rm e d w ith a n e e d le th e rm o c o u p le , ( B a il e y I n s t r u m e n t s ) ,
c o v e re d w ith a s m a ll p ie c e o f e l e c t r i c a l s h r i n k t u b in g , a t t a c h e d to a
d i g i t a l te m p e r a tu r e r e a d o u t ( B a il e y I n s t r u m e n t s ,
B a t-S ), c a lib r a te d
a g a i n s t a n NBS r e f e r e n c e s t a n d a r d , No. 8 8 024, E r t c o ) .
The se co n d tem­
p e r a t u r e m easurem ent was ta k e n a t d e p th I n t h e h e a te d t i s s u e .
m easurem ent was a g a in p e rfo rm e d w ith a th e rm o c o u p le (Type
T h is
M T-29/3 hypo­
d e rm ic n e e d le m ic ro p ro b e , B a ile y I n s tr u m e n ts ) a t t a c h e d to a d i g i t a l
te m p e r a tu r e r e a d o u t ( B a il e y I n s t r u m e n t s , BAT-8 ) a n d was u sed a s th e
r e f e r e n c e t o c o n t r o l th e t e m p e r a tu r e .
was th e s u r f a c e te m p e r a tu r e .
The l a s t te m p e ra tu re m o n ito re d
T h is was p e rfo rm e d w ith a m ic r o th e r -
m o co u p le, f i x e d I n t o a m i c r o p i p e t t e , ( c o n s t r u c t e d I n o u r l a b o r a t o r y a s
d i s c u s s e d p r e v i o u s l y ) a t t a c h e d t o a d i g i t a l te m p e r a tu r e r e a d o u t ( B a ile y
I n s t r u m e n t s , BAT-B). The c o p p e r - c o n s t a n tl n w eld ed j u n c t i o n was p la c e d
a t th e s u r f a c e o f t h e t i s s u e t o be m ea su red .
The oxygen e l e c t r o d e was a t t a c h e d d i r e c t l y t o a h y d r a u l i c m ic r o d riv e
( N a r i s h ig e I n s tr u m e n ts ) an d th e r e f e r e n c e was a t t a c h e d t o a le a d e m in a t l n g fro m a c a b le a t t a c h e d t o th e m ic ro d riv e *
The c a b le s fro m ’ th e
oxygen e l e c t r o d e a n d r e f e r e n c e e l e c t r o d e w ere c o n n e c te d t o a
p r e a m p l i f i e r ( T ra n s ld y n e C o r p .) an d th e n a r e a t t a c h e d t o a g r a p h ic
r e a d o u t ( G ra s s P o ly g r a p h ) .
The te m p e r a tu r e m easurem ent ta k e n a t d e p th
I n th e tum or ( r e f e r e n c e c o n t r o l ) was c o n s t a n t l y r e c o r d e d o n to th e c h a r t
r e c o r d e r w h ile t h e s u r f a c e te m p e ra tu re a n d th e r e c t a l te m p e r a tu r e s were
r e c o r d e d o n to t h e c h a r t r e c o r d e r a t r e g u l a r I n t e r v a l s .
A l l o f th e g a s e s ( e i t h e r a i r o r O2 ) w e re g iv e n a t 5 l i t e r s p e r
m in u te th ro u g h a s m a ll v i a l w h ich s u rro u n d e d th e h e a d o f th e m ouse.
The a i r o r th e O2 flo w r a t e s was c o n t r o l l e d and m o n ito re d d u r in g th e
e x p e r im e n ts .
The m ouse, h o ld in g d e v ic e , m a n ip u la to r , e l e c t r o d e s , th e rm o c o u p le s ,
a n d m icrow ave a p p l i c a t o r ( p r e v i o u s l y d i s c u s s e d ) w ere a l l w i t h in th e con**
f i n e s o f a n e l e c t r i c a l l y g ro u n d ed F a ra d a y c ag e ( c o n s t r u c t e d i n o u r
in s titu tio n ).
A ll o f th e o t h e r e q u ip m e n t ( p r e a m p l i f i e r , c h a r t r e c o r d e r ,
m icrow ave g e n e r a t o r , e t c . ) w ere o u t s i d e o f th e F a ra d a y c a g e .
The p r o c e d u r e u s e d t o c a l i b r a t e t h e oxygen m e a s u rin g e q u ip m e n t was
em ployed t o a tt e m p t t o i n s u r e a c c u r a c y .
B e fo re a n y e l e c t r o d e was u se d in
a mouse i t was a g e d i n s a l i n e t h a t was p u rg ed w ith 5X O2 f o r 5 m in u te s .
T h is r e d u c e s th e oxygen t e n s i o n i n th e s a l i n e fro m 150mm Hg t o 50mm Hg.
The b a s e l i n e r e a d in g was e s t a b l i s h e d th ro u g h th e u se o f g lu c o s e
o x id a s e i n a s a t u r a t e d g lu c o s e s o l u t i o n .
A f te r o b ta in in g p re lim in a ry
e x tre m e m e a s u re m e n ts , th e e l e c t r o d e was p la c e d i n t o mouse t i s s u e f o r
a p p r o x im a te ly 5 m in u te s .
A f t e r th e oxygen e l e c t r o d e was rem oved from
t h e m ouse, i t was p la c e d i n t o f r e s h l y made 50mm Hg O2 s a l i n e to ch e ck
f o r e le c tr o d e p o ls lo n ln g .
T h is p r o c e d u r e , on th e a v e r a g e , was r e p e a te d
tw ic e b e f o r e e a c h e x p e rim e n t t o e n s u r e t h a t th e p r e a n d p o s t e x p e rim e n t
A3
c a l i b r a t i o n s w ould be Che Barne.
I f th e p o s t e x p e rim e n t c a l i b r a t i o n was
n o t w i t h in 3mm hg o f t h e p r e e x p e rim e n t c a l i b r a t i o n , th e e x p e rim e n t was
r e j e c t e d on th e g ro u n d s t h a t th e e l e c t r o d e m ust n o t have f u n c tio n e d p r o p ro p e r l y d u r in g t h e e x p e rim e n t.
The b a s e l i n e d e te r m i n a ti o n was a l s o
p e rfo rm e d b e f o r e and a f t e r e a c h e x p e rim e n t*
A f t e r t h e a n im a l was b ro u g h t up to 4U°C, th e m icrow ave g e n e r a to r
beam was tu r n e d o f f e v e ry m in u te f o r a p p ro x im a te ly 2 0 se co n d s*
The
m ic r o m a n lp u la to r was moved o n e -h u n d re d m ic ro n s e v e ry 5 m in u te s .
The
t i s s u e te m p e r a tu r e a t d e p th , th e s u r f a c e t e m p e r a tu r e , a n d r e c t a l ten tp e r a t u r e w ere ta k e n i n th e m icrow ave o f f tim e a s w e l l ,
a to ta l of a t
l e a s t t e n p o i n t s w ere ta k e n i n e a c h mouse tu m o r.
C o n c o m ita n t H eat (4U°C) a n d I r r a d i a t i o n bqulp m en t
The a n im a ls em ployed f o r t h i s s e r i e s o f e x p e rim e n ts w ere a d u l t C3u
m ice o f b o th s e x e s c a r r y in g a mammary c a rc in o m a I n th e r i g h t h in d l e g .
A nim als u se d i n t h i s s e r i e s o f e x p e rim e n ts w ere n o t a n e s t h e t i z e d .
t o r e s t r a i n t e a c h a n im a l was g iv e n a num bered e a r t a g
Tag C o ., 11U05, S iz e 1 M o n e l).
(N a tio n a l
P rio r
hand an d
The f i r s t tum or d im e n sio n m easurem ents
w ere ta k e n b e f o r e th e a n im a l was p la c e d i n th e r e s t r a i n e r .
s io n s w ere ta k e n w ith a V e r n ie r C a l i p e r ( M a n o s ta t) .
Tumor dim en­
D im en sio n a l c h an g es
w ere c h a r t e d i n t h r e e d im e n s io n s , l e n g t h , w id th an d h e i g h t .
Tumor volum e d e te r m i n a ti o n was o b ta in e d by u s in g th e f o llo w in g fo rm u la :
UjxU^xD -jXlf/b,
The n orm al t i s s u e r e s p o n s e o f m ice was s c o re d w i t h a s k in s c o re
sy s te m m o d ifie d fro m a s y s te m d e s ig n e d by brown e t a l . ( 1 2 3 ) .
j e c t i v e s y s te m had a minimum r e s p o n s e , n u m e r ic a lly l a b e l e d
r e a c t i o n ) an d a maximum re s p o n s e o f 3 .5 ( l o s s o f l i m b ) .
0
T h is su b ­
(no
The m ice used
44
I n t h i s s e r i e s o£ e x p e rim e n ts r e c e iv e d 1 oil 4 t r e a tm e n ts i d e n t i c a l to
th o s e em ployed f o r t h e tum or s t u d i e s , 1) 4U°U h y p e rth e rm ia w h ile
b r e a t h in g
( a t 51/m inJ an d b e in g i r r a d i a t e d w ith v a r i o u s d o s e s o£
r a d i a t i o n , 2)
b r e a t h in g w h ile b e in g i r r a d i a t e d , 3 ) a i r b r e a t h in g w ith
4U*C h y p e rth e rm ia w h ile b e in g i r r a d i a t e d an d 4 ) a i r b r e a c h in g w h ile
b e in g i r r a d i a t e d .
rad s.
The r a d i a t i o n d o s e s s u rv e y e d w ere from 3UUU t o bUUU
T h ese m ice w ere m o n ito re d a p p ro x im a te ly tw ic e w eekly f o r 41) d a y s
a f t e r tre a tm e n t.
B oth th e i r r a d i a t i o n a n d h e a ti n g m ethods w ere d i s c u s s e d p r e v io u s ly *
B r i e f l y , th e x - r a y s o u rc e was a 25UKV, 15MA th e r a p y u n i t w ith a dose
r a t e o f 277 r a d s / m i n u te .
The d o se s o f r a d i a t i o n g iv e n ra n g e d fro m 3UUU
r a d s t o bUUU r a d s i n 251) o r 5UU r a d s i n c r e m e n ts .
The s o u rc e o f h e a t was
a 245U MHz m icrow ave g e n e r a t o r , f i t t e d w ith s tu b t u n o r s , w a tt m e t e r s , a
c o a x i a l d i r e c t i o n a l c o u p le r a n d a beam s p l i t t e r .
TWo m icrow ave a p p l i c a ­
t o r s w ere s im u lta n e o u s ly em ployed t o d e l i v e r th e h e a t to th e tu m o rs .
B o th th e m icrow ave g e n e r a to r an d th e w a tt m e te rs f i t t e d w ith s tu b
t u n o r s , w ere l o c a t e d o u t s i d e th e x - r a d i a t l o n e x p o s u re a r e a .
T h is
a llo w e d c o n s t a n t m o n ito rin g o f th e pow er o u t p u t t o b o th m ice when th e
r a d i a t i o n d o se was b e in g g iv e n .
M icrowave h e a ti n g was a p p l i e d t o th e
tum or a r e a p r i o r to I r r a d i a t i o n o n ly u n t i l 4U°U was r e a c h e d , a t t h a t
t h a t tim e x - i r r a d i a t i o n commenced.
H e a tin g s to p p e d a s soon a s th e t o t a l
r a d i a t i o n d o se was g iv e n .
The s y s te m , em ployed t o r e s t r a i n th e u n a e s t h e t l z e d a n im a ls , was
d e s ig n e d t o d e l i v e r b o th m icrow ave h e a t a n d x - r a d i a t l o n t o th e tum or
volum e s im u l ta n e o u s l y .
T h is was a c c o m p lis h e d by a p p ly in g th e m icrow ave
h e a t fro m t h e b o tto m an d x - r a d i a t l o n from th e t o p .
T h is r e s t r a i n t
a p p a r a tu s h o ld s f o u r a n im a ls a t a tim e .
I n t h i s s e r i e s o f e x p e rim e n ts
two a n im a ls w ere h e a te d s im u l ta n e o u s l y .
The b a se o f th e h o ld e r i s
0 . 5
45
in c h e s h ig h a n d 10 i n c h e s w id e .
The h e ig h t a llo w s th e m icrow ave a p p l i ­
c a t o r s t o be e a s i l y p o s i t i o n e d u n d e r t h e b a s e .
Each o f t h e f o u r a n im a ls
w e re h o u sed i n a s m a l l, h a l f s e c t i o n o f p l e x i g l a s s t u b in g c o v e re d w ith
le a d .
The p l e x i g l a s s g i v e s t h e l e a d ( x - r a y s c a t t e r p r o t e c t i o n ) s t r u c ­
t u r a l s u p p o rt.
A s m a ll n o tc h was rem oved fro m e a c h tu b e t o a ll o w th e
tum or b e a r i n g lim b t o be e x p o s e d .
F o u r h o le s i n t h e b a s e , a s w e ll a s
th e o v e rh e a d p rim a ry beam s to p p e r c o rre s p o n d t o th e a r e a w here th e tum or
b e a r i n g lim b was r e s t r a i n e d .
The p rim a ry beam s to p p e r c o n s i s t e d o f 4mm
o f l e a d g lu e d t o a p ie c e o f p l e x i g l a s s .
c o v e re d th e e n t i r e h o ld in g a p p a r a t u s .
The p rim a ry beam s to p p e r
The m icrow ave a p p l i c a t o r s w ere
l o c a t e d im m e d ia te ly u n d e rn e a th two o f th e f o u r h o le s i n t h e b a s e by a
p le x ig la s s b u ild -u p .
S i n g le p o i n t tum or te m p e r a tu r e m easu rem en ts w ere ta k e n e v e ry two
m in u te s , w ith th e m icrow ave power o f f *
H ypoderm ic n e e d le m ic ro p ro b e s
( B a il e y I n s t r u m e n t s , I n c . , Type M T-29/3) w ere c o n n e c te d t o a d i g i t a l
te m p e r a tu r e r e a d o u t ( B a il e y I n s t r u m e n t s , I n c . , BAT-8 ) by lo n g
( a p p r o x im a te ly 15 f e e t ) th e rm o c o u p le e x te n s i o n c a b l e s .
The d i g i t a l tera-
p e r a t u r e r e a d o u t was l o c a t e d o u t s i d e th e tr e a tm e n t room.
Procedure
A f t e r th e tum or d im e n s io n s w ere ta k e n and th e mouse e a r ta g g e d , i t
was p la c e d u n d e r th e p l e x i g l a s s t u b e .
The t a i l a n d th e tum or b e a r in g
lim b w ere ta p e d t o t h e p l e x i g l a s s b a s e o f th e h o l d e r .
t h e e x p o se d lim b was t a p e d .
Only th e f o o t o f
T a p in g o f t h e lim b was done v e ry l o o s e l y
t o a llo w th e b lo o d flo w i n d i s t a l p o r t i o n o f th e lim b t o be u n p e r tu r b e d .
S im u lta n e o u s i r r a d i a t i o n a n d 40°C h y p e rth e rm ia w ere a tte m p te d p r e v i o u s ly
by t h i s a u t h o r , e m p lo y in g o t h e r ty p e s o f a n im a l r e s t r a i n t w ith p oor
46
re s u lts •
O th e r m ethods o f s e c u r i n g th e e x p o sed lim b ( r u b b e r b a n d , e x ­
c e s s i v e t a p i n g ) may h av e com prom ised th e b lo o d flo w i n th e d i s t a l p o r ­
t i o n o f t h e r e s t r a i n e d fo o t*
Mice whose tu m o rs w ere h e a te d a n d i r r a ­
d i a t e d s u f f e r e d a m p u ta tio n o f th e l e g below t h e p o i n t w here th e r e ­
s t r a i n t s ta r te d *
I n t h o s e p r e v io u s e x p e r im e n ts , a s h ig h a s a p p ro x im a ­
t e l y 402 o f t h e h e a te d a n im a ls l o s t t h e i r f o o t .
I n th e p r e s e n t s e r i e s
o f e x p e rim e n ts o n ly two a n im a ls l o s t th e d i s t a l p o r t i o n o f t h e i r l e g ,
due to p r o b a b le b lo o d flo w o c c l u s i o n .
The tum or o f e a c h a n im a l was
c e n te r e d i n t h e m id d le o f th e h o l e i n th e b a s e (w h ich c o rre s p o n d s to
t h e a r e a t o be e x p o sed t o r a d i a t i o n o r r a d i a t i o n / h e a t ) a n d c le a n s e d
w ith 702 e t h a n o l .
The two m ice t h a t w ere h e a te d , had a hyp o d erm ic
n e e d le m lc ro p ro b e th e rm o c o u p le im p la n te d i n t o ro u g h ly th e c e n t e r o f
e a c h r e s p e c t i v e tumor*
The th e rm o c o u p le s w ere p la c e d i n t o th e tum or
s u c h t h a t th e y w ere a t a r i g h t a n g le to th e e l e c t r i c f i e l d o f th e
m icrow ave a p p l i c a t o r .
A h o le i n th e p l e x i g l a s s tu b e c o n t a i n in g t h e mouse was u s e d to
d e l i v e r e i t h e r co m p ressed a i r ( a t 5 l i t e r s / m i n u t e ) o r 952 O2 , 52
CO2 ( a t 5 l i t e r s m in u t e ) .
The r e s p e c t i v e g a s e s w ere g iv e n to e a c h mouse
p r i o r t o th e o n s e t o f h e a t i n g a n d r a d i a t i o n o r i r r a d i a t i o n .
The g a n t r y o f t h e x - r a y m achine was b ro u g h t down t o th e p rim a ry beam
s t o p p e r o f th e r e s t r a i n i n g d e v ic e a n d th e m icrow ave h e a t i n g commenced.
I r r a d i a t i o n s t a r t e d a s so o n a s th e i n te r tu m o r te m p e r a tu r e re a c h e d 40°C ,
an d c o n tin u e d u n t i l th e r e q u i r e d x - r a y d o se was g i v e n . T e m p era tu re mea­
s u re m e n ts w ere ta k e n i n th e m icrow ave beam o f f mode e v e ry two m in u te s .
I f t h e te m p e r a tu r e o f t h e tum or e x c e e d e d 41°C th e m icrow ave beam was
tu r n e d o f f u n t i l Che r e q u i r e d te m p e ra tu re was a g a in r e g a i n e d .
In a n o t h e r s e r i e s o f e x p e r im e n ts , th e a f f e c t s o f 40®C h e a t a lo n e
on tumor t i s s u e d eterm in ed u s in g th e above p ro ced u re.
R e s u lts
T e m p e ra tu re D i s t r i b u t i o n
A l l o f t h e te m p e r a tu r e d i s t r i b u t i o n d a ta shown I n t h i s s e c t i o n I s
Che t a b u l a t i o n o f 4 a n im a ls , e a c h w ith 9 p o i n t s m ea su re d , f o r e a c h t i s ­
s u e ty p e an d I n e a c h s p a t i a l a r r a n g e m e n t.
The a v e ra g e te m p e r a tu r e shown
I n a l l o f th e t a b l e s a n d f i g u r e s r e p r e s e n t s th e a v e r a g e te m p e r a tu r e mea­
s u r e d by a l l 9 p o i n t s I n e a c h I n d i v i d u a l a n im a l a t t h e s p e c i f i e d tim e I n ­
te rv a l*
The a v e r a g e d e v i a t i o n i n e a c h c a s e was o b ta in e d by c a l c u l a t i n g
th e d i f f e r e n c e I n e a c h o f th e 9 m easu red p o i n t s from t h e a v e r a g e tem p e ra ­
tu re .
The d a ta waa h an d led in t h i s manner b ecau se o f n a tu r a l d if f e r e n c e s
i n th e a v e r a g e measured tem p era tu res.
A c o m p ila tio n o f a l l o f th e a n i­
m als i n ea ch c a s e w i l l g iv e a somewhat la r g e r v a r ia t io n In th e mean tem­
p e r a tu r e .
T hese la r g e r v a r ia t io n s would not a c c u r a te ly r e f l e c t th e a c t ­
u a l d a t a , but would r e f l e c t th e d if f e r e n c e s In th e a v era g e tem perature
betw een a n im a ls .
U n p e rtu rb e d Normal T is s u e T e m p e ra tu re D i s t r i b u t i o n s
T a b le s 1 th ro u g h 4 show th e a v e r a g e te m p e r a tu r e p l u s o r m inus th e
a v e r a g e d e v i a t i o n f o r u n h e a te d n orm al t i s s u e (m u s c le ) on th e l e f t s i d e
o f th e page.
On t h e r i g h t s i d e o f e a c h page a r e th e h ig h te m p e ra tu re
p o i n t s ( to p o f e a c h box) a n d t h e low te m p e r a tu r e p o i n t s (b o tto m o f e a c h
b o x ) f o r t h e same g ro u p o f a n im a ls .
The c o r r e s p o n d in g m easured tem p e ra ­
t u r e v a lu e s a t e a c h one o f t h e s e p o i n t s ( h ig h a n d low ) a r e shown a d j a ­
c e n t t o t h e num bers r e p r e s e n t i n g th e th e rm o c o u p le p o s i t i o n s ( i n b r a c k e t s ) .
48
M easurements w ere made i n both th e p a r a l l e l and p e r p e n d ic u la r d ir e c t io n s
r e l a t i v e t o th e femur ( s c h e m a tic a lly shown in f ig u r e s 2 and 3 ) .
Both
p la n e s had to be a n a ly z e d t o r u le o u t any l a r g e , n a tu r a l g r a d ie n ts or in
th e c a s e o f th e h e a te d lim b s , an y therm al g r a d ie n ts due t o power a b so rp ­
t io n d i f f e r e n c e s .
T a b le 1 shows t h e r e s u l t s o f n o rm al t i s s u e te m p e r a tu r e d i s t r i b u t i o n
m easu rem en ts i n th e p a r a l l e l d i r e c t i o n w ith o u t h e a t i n g .
I n T a b le 1 th e
l a r g e s t a v e r a g e d e v i a t i o n found was £ 0 .9 ° C , w ith th e m a j o r i t y o f th e
o b s e rv e d a v e r a g e d e v i a t i o n s w i t h in a p p r o x im a te ly + 0 .5 ° C .
t h e a v e r a g e te m p e r a tu r e s w ere from 2 3 .I ° C t o 2 7 .9 ° C .
In a l l cases
T h ese l a r g e norm al
v a r i a t i o n s may, i n p a r t , r e f l e c t th e d i f f e r e n c e s i n a n e s t h e s i a .
In a l l
o f t h e s e e x p e rim e n ts th e a n im a ls w ere a n e s t h e t i z e d b e f o r e th e e x p e rim e n t
a n d n o t g iv e n a b o o s t ( s u b s e q u e n t d o se o f a n e s t h e t i c ) d u r in g th e h e a t i n g
p e rio d .
A n o th e r p o s s i b l e e x p la n a ti o n f o r t h i s v a r i a t i o n may be t h a t th e
tim e b e tw e en t h e a d m i n i s t r a t i o n o f th e a n e s t h e s i a and th e o n s e t o f e a c h
e x p e rim e n t v a r i e d from
1 0
m in u te s t o
2 0
m in u te s .
The r i g h t s i d e o f T a b le 1 show s t h a t i n a l l
8
a n im a ls th e w arm est
m easu red te m p e r a tu r e s ( w ith r e s p e c t t o e a c h a n im a l) w e re l o c a t e d on th e
t r i p l e m ic ro th e rm o c o u p le h i g h e s t on t h e m o u se 's l e g ( t r i p l e p r o b e c l o s e s t
t o th e h i p ) .
The c o o l e s t m easured te m p e r a tu r e s w ere m easured i n th e
t r i p l e p r o b e c l o s e s t t o th e f o o t .
Only i n two c a s e s w ere th e lo w e s t
te m p e r a tu r e s found i n th e m id d le t r i p l e m ic ro th e rm o c o u p le .
The a v e r a g e te m p e r a tu r e s an d a v e r a g e d e v i a t i o n s ( l e f t s i d e ) a n d th e
h ig h a n d low te m p e r a tu r e p o i n t s ( r i g h t s i d e ) , f o r m u sc le t i s s u e m easured
i n t h e p e r p e n d i c u l a r p la n e ( p e r p e n d ic u l a r t o th e fem u r) a r e shown i n
T a b le 2 .
The maximum a v e ra g e d e v i a t i o n fo u n d was + 0 .6 ° C , w ith m ost o f
t h e o b t a i n e d v a lu e s w i t h i n
p e r a t u r e s was som ew hat
0 .5 * C .
The ra n g e i n th e a v e ra g e cenr-
h i g h e r th a n i n I t s c o u n t e r p a r t i n th e p a r a l l e l
Normal Tissue
Par a l l e l D irection
Average Temperature House Time
Ho. (Hin.)
Tissue
1
Rectal
2
Tissue
Rectal
3
Tissue
Rectal
Tissue
4
Rectal
Tissue
5
Rectal
6
Tissue
Rectal
7
8
0
2
4
No Heat
Average D eviation
6
8
High and low. P oints
10
0
2
4
6
27.4±0.9 27.310.9 27.210.9 27.2±0.9 27.2+0.8 27,2+0.8 (2)28.6 (2)28.4 (2)28.3 (2)28.3 (1 28.2
2,3)
31.0
30.8
30.8
30.8
(5)24.2 (5)24.4 (5)24.3 (5)24.2 (5)24.2
30.9
30.9
27.910.4 27.710.4 27.610.4 27.310.4 27.210.4 2 7 .H 0 .3 (3)28.9 (3)28.6 (3)28.4 (3)28.2 (3)28.0
29.8
30.5
30.5
30.0
29.9
29.9
(5 27.1 (5 27.0 (5 26.9 (7)26.5 (7)26.5
7J_
_ 7)
7)
27.210.6 27.210.5 27.010.4 26 .9 i0 .3 26.8+0.4 26.710.4 (3)28.4 (3)28.2 (3)28.0 (3)27.9 (3)27.7
30.5
29.9
30.3
(7)26.1 (7)25.9 (7)25.8 (7)25.8 (7)25.7
30.1
30.0
30.0
(1 28.2 H
2,3)
(5)24.2 L
(3)27.9 H
(7)26.4 L
(3)27.6 H
(7)25.6 L
2 3 .U 0 .8 23.1+0.7 23.310.7 23.310.7 23.410.7 23.6+0.7 (1)24.6 (1 24.4 (1 24.5 (1 24.5 (2)24.6 (1 24.7 H
2)
2)
2)
29.0
2B.9
29.0
28.8
28.0
29.0
(7)21.7 (7)21.6 (7)21.7 ( 7 ) 2 1 . 7 (7)21.8 (7)22.0 L
23.810.4 23.810.5 23.710.4 23.710.4 23.6+0.4 23.610.4 (1)24.5 (1)24.5 (1)24.4 (1)24.3 (1 24.2
2)
26.9
26.9
26.9
26.9
26.9
26.9
(9)22.7 (9)22.7 (9)22.7 (9)22.7 (9)22.6
23.7+0.6 2 3 .8 i0 .6 23.710.6 23.610.6 23.7+0.6 23.710.6 (1)25.1 (1)25.2 (1)25.2 (1)25.1 (1)25.1
28.0
28.5
28.0
28.0
28.0
28.0
(7 23.0 (9)22.9 (9)22.9 (8 22.9 (9)22.9
8)
9)
(2)24.3
H
(9)22.6- L
(1)25.1
(9)22.7
H
L
Tissue
Rectal
25.810.7 25.710.6 25.710.5 25.710.6 25.7+0,6 25.7+0.6 (1)27.0 (1)26.9 (1)26.8 (1)26.8 (1)26.8 (1)26.8
29.5
29.5
29.5
29.5
29.0
(8)24.7 (8)24.7 (8)24.8 (B)24.8 (8)24.8 (8)24.8
29.2
H
L
Tissue
26.0+0.3 25.8+0.3 25.710.3 25.610.3 25.610.2 25.510.2 (3)26.5 (3)26.4 (3)26.3 (3)26.2 (3)26.0 (2 25.9
H
Rectal
29.0
29.0
29.0
29.0
23.8
28.9
(7)25.6 (7)25.4 (7)25.3 (7)25.2 (7)25.1 ( 7 I 2 5 .O L
T a b le 1
The l e E t s i d e o f th e t a b l e shows th e a v e ra g e te m p e ra tu re + th e a v e ra g e d e v ia t io n (to p o f each box)
and th e c o rre s p o n d in g r e c t a l te m p e ra tu re s (bottom o f each b o x ). The r i g h t s id e o f th e t a b l e shows th e l o c a ­
t i o n o f th e h ig h (to p o f each box) and low (bottom o f e a ch box) m easurem ent l o c a t i o n s ( w ith in th e p a r e n t h e s i s )
and th e c o rre s p o n d in g te m p e ra tu re m easurem ent.
Hormal Tissue
Perpendicular D irection
Ho Heat
Average Temperature ± Average D eviation
louse Time
No. (Min.)
T issue
1
Rectal
0
2
4
6
8
High and low Points
10
0
2
4
6
8
10
4
Tissue
Rectal
26.210.1 2 6 .U 0 .1 26.010.1 26.0*0.1 26.0*0.1 26.010.1 (1)26.4 (1)26.3 (1)26.2 (1)26.2 (1)26.2 (1)26.2 H
28.1
28.7
28.6
28.6
28.6
28.6
(5)26.0 (5)25.9 (5 25.9 (5 25.9 (5 25.9 (5 25.9 L
8 .9 )
8 ,9 )
8.9)
8 )
28.0*0.6 28.0*0.6 28.0*0.6 27.9*0.6 27.9*0.6 27.910.4 (2)29.0 (2 26.9 ( 2 28.8 ( 2 28.8 ( 2 28.8 (2 28.7 H
3)
3)
, 3>
, 3) 26.9 3)
30.8
30,8
30.7
30.7
(9)26.9 (9)26.9 (4 27.0 (4 26.9 (4
30.6
30.7
(4 26.9 L
9)
9)
9)
9)
27.2*0.4 2 7 .H O .4 27.110.4 27.010.4 27.0*0.4 27.0*0.4 (2)27.8 (2)27.6 (2)27.5 (2)27.6 (1 27.5 (1 27.4 H
2 )
, 2)
29.1
29.1
29.1
29.1
29.0
29.0
(6)26.1 (6)26.1 (6)26.1 (6)26.1 (6)26.1 (6)26.1 1
27.910.4 27.7*0.3 27.510.3 27.510.2 27.4*0.2 27.2*0.3 (2)28.6 (2)28.2 (2)28.0 (2)27.8 (2)27.8 (2)27.7 H
31.0
31.1
30.9
30.8
30.9
30.8
(7)27.3 (7)27.2 (7)27.1 (7)27.0 (7)27.0 (7)26.9 L
5
Tissue
Rectal
27.4*0.5 2 7 .H 0 .4 26.910.5 26.7*0.4 26.6*0.4 26.5*0.3 (1)28.3 (1)28.0 (5)27.8 (1)27.4 (1)27.3 (1)27.1
31.3
31.3
31.2
31.1
(7)26.4 (7)26.2 (7)26.1 (7)25.9 (7)25.8 (7)26.1
31.1
31.1
H
L
6
Tissue
Rectal
27.4*0.2 27.310.2 2 7 .U 0 .2 27.210.2 27.2*0.2 27.2*0.2 (6)27.8 (6)27.6 (6)27.4 (6)27.5 (6)27.4 (6)27.5
29.9
29.8
29.6
29.5
29.4
29.3
(4)26.8 (4)26.7 (4)26.6 (4)26.7 (4)26.6 (4)26.7
H
L
7
Tissue
Rectal
28.8*0.3 29.0±0.3 28.510.3 2B.31Q.2 28.210.2 28.2±0.2 (2)29.4 (2)29.2 (2)29.0 (2)28.9 (2)28.8 (2)28.8
31.4
31.3
31.1
31.2
(7)28.3 (7)28.2 (7)28.1 (7)28.0 (7)27.9 (7)27.9
31.1
31.1
H
L
Tissue
2
Rectal
Tissue
3
Rectal
29.410.3 29.210.3 29.110,3 2 9 .U 0 .2 29.010.2 2 9 .U 0 .2 (1 29.8 (1)29.7 (1)29.6 (1)29.5 (1)29.4 (1)29.5 H
4)
8
Rectal
32.0
32.0
31.8
31.7
31.9
31.8
(5 29.0 (6)28.8 (6)28.7 (6)28.7 (6)28.7 ( 6 28.8 L
6 )
7)
Table 2
The l e f t s id e o f th e t a b le shows th e average tem perature + th e d e v ia tio n (to p o f each box) and th e
corresponding r e c t a l tem peratures (bottom o f each b o x ). The r ig h t s id e o f th e t a b le shows th e lo c a t io n o f
the h igh (top o f each box w ith in th e p a r e n th e sis ) and the low (bottom o f each box w ith in th e p a r e n th e sis )
measured tem perature lo c a t io n s and t h e ir correspond ing tem perature measurements.
Tissue
d i r e c t i o n , 26.0°C t o
2 9 .4 °C .
T h is d i f f e r e n c e may be a t t r i b u t e d to th e
f a c t t h a t more m easurem ents w ere ta k e n i n d e e p e r t i s s u e w hich h a s more
n a t u r a l i n s u l a t i o n i n th e p e r p e n d ic u la r p la n e r a t h e r th a n th e p a r a l l e l
p la n e .
T hese d e e p e r p o i n ts may more c l o s e l y r e f l e c t th e te m p e ra tu re o f
th e b lo o d com ing from th e abdomen.
The r e c t a l te m p e ra tu re s w ere found
a g a i n , t o d e c r e a s e w ith r e s p e c t to tim e I n a l l b u t one e x p e rim e n t.
In a l l c a s e s b u t tw o, th e h i g h e s t m easured te m p e ra tu re was found i n th e
t r i p l e m le ra th e rm o c o u p le c l o s e s t to th e femur*
T a b le 2 , Mouse 5 had
one p o in t (4 m in u te s ) , w here th e h i g h e s t m easured te m p e ra tu re was found
i n th e seco n d t r i p l e p ro b e (p ro b e in th e m id d le ) .
T a b le 2 , Mouse
6
con­
s i s t e n t l y shows t h a t th e second t r i p l e p ro b e c o n ta in e d th e l o c a t i o n o f
th e h o t t e s t m easured te m p e ra tu re .
d a b le f o r two r e a s o n s .
T hese two e x c e p tio n s a r e u n d e rs ta n ­
The f i r s t i s th e r e l a t i v e l y s m a ll v a r i a t i o n s i n
t i s s u e te m p e r a tu r e s found w ith in th e s e two a n im a ls a n d s e c o n d ly , t r i p l e
p ro b e s
1
and
2
h av e more o v e r ly in g t i s s u e t o i n s u l a t e them from th e
s u r f a c e th a n d o e s th e t h i r d t r i p l e p ro b e .
U n p e rtu rb e d M a lig n a n t T is s u e T em p eratu re D i s t r i b u t i o n
T a b le s 3 and 4 show th e a v e ra g e te m p e ra tu re + th e a v e ra g e
d e v i a t i o n ( a t th e to p o f e ach box) and th e r e c t a l te m p e ra tu re ( a t th e
b o tto m o f e a c h box) on th e l e f t s id e o f th e T a b le 5 f o r e i t h e r th e
p a r a l l e l o r th e p e r p e n d ic u la r th erm o co u p le a rra n g e m e n t i n m a lig n a n t
tis s u e .
On th e r i g h t s i d e o f th e e ach t a b l e a r e th e l o c a t i o n s and th e
c o rr e s p o n d in g te m p e ra tu re s o f th e p ro b e s w ith th e h i g h e s t te m p e ra tu re s
( to p o f e a c h box) and th e p ro b es w ith th e lo w e s t te m p e ra tu re s (b o tto m
o f e a ch box)
on th e r i g h t s id e f o r e i t h e r th e p a r a l l e l o r th e p en p en -
d l c u l a r p la n e s i n m a lig n a n t
tis s u e .
A gain, m easurem ents w ere made i n
52
b o th th e p a r a l l e l a n d p e r p e n d i c u l a r p la n e s r e l a t i v e t o th e fem ur
( s c h e m a t i c a l l y shown I n d ia g ra m s an d 2 an d 3 ) t o r u l e o u t a n y l a r g e
n a t u r a l g r a d i e n t s t h a t may e x i s t I n a m a lig n a n t t i s s u e b e a r in g lim b*
T a b le 3 show s t h a t e x tre m e s o f th e a v e r a g e te m p e r a tu r e s m easured w ere
fro m 2 1 .7 °C t o 27*6°C a n d th e maximum a v e r a g e d e v i a t i o n was jf 0 .5 °C I n
t h e p a r a l l e l p la n e w ith o u t m icrow ave h e a t i n g .
I n a l l c a s e s th e r e c t a l
te m p e r a tu r e s d e c r e a s e d w ith tim e*
In a l l b u t one a n im a l, on T a b le 3 , th e w arm est l o c a t i o n m easured was
fo u n d I n one o f t h e t h r e e l o c a t i o n s m easured by t r i p l e p ro b e Number 1
( t r i p l e p ro b e c l o s e s t t o th e h i p ) f o r u n h e a te d m a lig n a n t t i s s u e i n th e
p a r a l l e l d i r e c t i o n . . The c o o l e s t l o c a t i o n s w ere fo u n d t o be i n one o f
t h e t h r e e l o c a t i o n s m easu red by e i t h e r t r i p l e p ro b e num ber 2 o r 3 (num ber
3 i s th e t r i p l e p ro b e l o c a t e d c l o s e s t t o th e f o o t) *
Mice
6
a n d 7 (T a b le
3 ) b o th showed th e c o o l e s t a r e a s t o be w i t h in one o f th e a r e a s m easured
by t r i p l e p ro b e number 1. T h e re a r e two I m p o r ta n t th in g B to n o te a b o u t
th is *
The f i r s t I s t h a t m ost o f th e c o o l e s t m easurem ents ta k e n I n th e s e
two m ice w ere fro m a r e a s t h a t w ere c l o s e to th e s u r f a c e ( e i t h e r p o s i ­
t i o n 1 o r 3) a n d t h e v e ry low a v e r a g e d e v i a t i o n s o f both*
The f i r s t
im p o r ta n t p o i n t n o te d a b o v e I s o b v io u s b e c a u s e th e s e two m e a s u rin g
a r e a s on th e t r i p l e p ro b e may n o t h av e enough tum or t i s s u e o v e r ly in g
them com pared t o l o c a t i o n 2 I n th e f i r s t t r i p l e p r o b e .
P ro b a b ly more
I m p o r ta n t i s th e f a c t t h a t a l l o f th e m easurem ents i n a l l l o c a t i o n s a r e
r e l a t i v e l y c l o s e t o g e t h e r an d su c h s m a ll d i f f e r e n c e s c o u ld a llo w f o r a
much more random I n t e r p r e t a t i o n o f t h e low te m p e r a tu r e l o c a t i o n s .
T a b le 4 shows t h e r e s u l t s o f u n p e r tu r b e d te m p e r a tu r e d i s t r i b u t i o n I n
m a lig n a n t t i s s u e i n th e p e r p e n d i c u l a r d i r e c t i o n .
The a v e r a g e tem ­
p e r a t u r e s m easured w ere from 2 4 .6 °C t o 29*6°C a n d th e maximum a v e ra g e
d e v i a t i o n fro m th e a v e ra g e te m p e r a tu r e was + 0 .6 °C w ith th e r e s t o f th e
d e v ia t io n s l e s s th a n + 0 .5 ° C .
The b o tto m o f e ach box, on th e l e f t hand
s i d e o f th e T a b le 4 , shows t h a t two a n im a ls had a s l i g h t i n c r e a s e i n th e
r e c t a l te m p e ra tu re w ith r e s p e c t to tim e*
House number 3 's r e c t a l
te m p e ra tu re g o e s from 3 3 .0 °C t o 33*2DC and mouse number 7 's r e c t a l tem ­
p e r a t u r e g o es from 30.4°C t o 30.5®C; b o th o f th e s e i n c r e a s e s a r e
i n s i g n i f i c a n t an d w i t h in o r c lo s e t o th e l i m i t o f th e a c c u r a c y o f th e
therm om etry u se d ( 0 .1 ° C ) .
The o t h e r a n im a ls show a d e c re a s e i n th e r e c ­
t a l te m p e ra tu re from th e i n i t i a l m easurem ent to th e l a s t m easurem ent.
The u p p e r p o r t i o n o f e a c h box on th e r i g h t hand s i d e o f T a b le 4 shows
t h a t th e w arm est l o c a t i o n s w ere found w i t h in th e t h r e e te m p e ra tu re
s e n s in g a r e a s m easured by e i t h e r t r i p l e p ro b e number
1
or
2
*
Most o f th e c o o le s t a r e a s ,found w ere m easured w ith t r i p l e p ro b e 3 (p ro b e
f a r t h e s t from th e fe m u r).
A lth o u g h , i n two I n s t a n c e s , mouse 7 and
8
,
th e c o o l e s t l o c a t i o n s w ere m easured w ith in th e a r e a o f t r i p l e probe
number 2 , and i n two o t h e r i n s t a n c e s , mouse 2 a n d 4 , th e c o o le s t m easure­
m ents w ere lo c a te d i n one o f th e th r e e a r e a s m easured by t r i p l e p ro b e
( c l o s e s t , p ro b e to th e fe m u r).
1
The n o n d l s t i n c t n a tu r e o f th e l o c a t i o n o f
th e h ig h a n d low te m p e ra tu re s i n t h i s d a ta i s p ro b a b ly due to th e s m a ll
d e v i a t i o n from th e a v e ra g e te m p e ra tu re o f a l l o f th e s e d a t a .
I t i s Im p o rta n t t o n o te t h a t i n th e u n p e rtu rb e d s t a t e , f o r b o th n o r­
m al a n d m a lig n a n t t i s s u e s i n b o th p l a n e s , t h e r e i s n o t a l a r g e a v e ra g e .
d e v i a t i o n (+ 1 .0 ° C ) ,a lth o u g h th e r e i s a l a r g e d i f f e r e n c e i n th e a v e ra g e
te m p e ra tu re *
T h is i s p r e c i s e l y th e re a s o n t h a t a l l d a ta were
h a n d le d i n t h i s m anner r a t h e r th a n com puting th e mean and s ta n d a r d
d e v i a t i o n f o r th e combined a n im a ls a t e ach i n s t a n t o f tim e .
By u s in g
th e com bined mean and s ta n d a r d d e v i a t i o n m ethod a n a r t i f a c t would be
in tr o d u c e d i n t o th e d a t a .
T h is a r t i f a c t would h av e been due to th e
l a r g e v a r i a t i o n i n th e b a s e l i n e te m p e ra tu re s o f e a c h mouse.
M alignant Tissue
P a ra lle l Dire c tio n
Ho Heat
Average Temperature ± Average Deviation
House Time
No. (M in .)
0
2
4
6
8
High and low Points
10
0
2
4
10
25.1±0.2 2 5 .U 0 .2 2 5 .U 0 .2 25.1+0.2 25.010.3 24.910.2 (2)25.5 (2)25.5 (2)25.5 (1 25.4 (2)25.4 (2)25.3
2)
27.8
27.6
(4)24.7 (4)24.6 (4)24.7 (4)24.7 (4)24.6 (4 24.6
27.7
27.1
27.4
27.2
9)
25.0±0.3 24.8+0.2 24.7±0.2 24.6+0.2 24.410.2 24.3+0.2 (2)25.8 (2)25.4 (2)25.3 (2)25.1 (2)24.9 (2)24.8
30.0
29.9
29.5
29.0
28.9
28.9
(7)24.5 (7)24.3 (7)24.2 (7)24.1 (7)23.8 (7)23.8
H
Tissue
Rectal
26.510.2 26.5+0.2 26.5+0.2 26.410.2 26.4±0.2 26.4+0.2 (2)27.0 (2)26.9 (2)26.9 (2)26.8 (2)26.8 (2)26.8
30.1
29.8
29.8
29.8
30.0
29.9
(7 26.2 (7 26.2 (7)26.2 (7 26.2 (7 26.2 (7)26.1
8 ,9 )
8 .9 )
8.9)
8.9)
H
I
Tissue
Rectal
24.310.3 2 4 .U 0 .2 24.1±0.2 23.810.2 23.710.3 25.610.2 (2)24.8 (2)24.6 (2)24.6 (2)24.3 (2)24.1 (2)24.1
25.5
25.0
24.9
(4)23.7 (6)23.6 (6)23.5 (6)23.3 (4 23.2 (6)23.1
25.0
24.8
24.7
6)
H
L
Tissue
*
Rectal
2
Tissue
Rectal
24.210.4 23.9+0.4 23.6+0.5 23.510.4 23.410.5 23.310.5 (1)25.0 (1)24.6 (1 24.3
Z)
24.0
R e c ta l■
24.6
23.9
23.4
23.9
23.5
(9)23.6 (9)23.2 (9)22.9
T issue 22.010.1 21.810.1 21.8+0.3 21.7+0.1 21.710.1 21.7+0.1 (3)22.1 (2 22.0 (2 21.9
3)
3)
24.5
24.0
23.5
23.5
23.0
23.0
Rectal
(U_21.7 (1)21.7 (1)21.7
T issue 27.610.1 27.4+0.1 27.210.2 27.210.1 27.110.2 27.010.1 (2)27.8 (1 27.6 (2)26.6
6)
29.0
29.6
29.3
29.1
29.5
29.3
(3)27.4 (2)26.8 (6)27.4
Rectal
Tissue
B
6
Tissue
Rectal
l
H
L
(1)24.2 (5)24.2 (5)24.2
H
(9)22.8 (9)22.6 (9)22.6
L
(2 21.8 (2 21.8 (2 21.8
3)
3)
3)
(1)21.6 (1)21.5 (1)21.5
H
(3 27.1 (1 27.3 (1 27.2
6)
6)
, 5)
(6)27.5 (3 27.0 (2)26.5
5)
H
26.810.4 26.7+0.4 26.610.4 26.510.4 26.5+0.4 26.5+0.3 (1)27.3 (2)27.1 (2)27.1 (2)27.0 (2)26.9 (2)26.9
29.8
29.6
29.5
29.5
29.6
29.6
(7)25.7 (7)25.6 (7)25.5 (7)25.5 (7)25.5 (7)25.5
H
L
T a b le 3 The l e f t s id e o f t h i s t a b l e shows th e a v e ra g e te m p e ra tu re + d e v ia t io n (to p o f each box) and th e
c o rre s p o n d in g r e c t a l te m p e ra tu re (b o tto m o f each box) a t 2 m in u te I n t e r v a l s . The r i g h t s i d e o f th e t a b l e
shows th e l o c a t i o n o f th e h ig h (to p o f e a ch box w ith in th e p a r e n t h e s i s ) and th e low (bottom o f e ach box
w ith in th e p a r e n t h e s i s ) m easured te m p e ra tu re l o c a t i o n s and t h e i r c o rre s p o n d in g te m p e ra tu re m easurem ents.
L
L
M alignant Tissue
Perpendic u la r Dir e c t i on
Average Temperature
•mse
No.
T in e
(Min.)
6
8
10
0
2
4
6
8
10
27.4*0.1 27.310.1 27.210.2 27.110.1 27.110.1 27.0*0.2 (3 27.6 (5)27.5 (5)27.4
5)
29,7
30.2 (9)27.1 (9)27.0 (1 26.9
30.1
29.8
30.0
29.9
9)
29.4*0.6 29.6*0.6 29.6*0.4 29.4*0.4 29.4*0.5
(4)31.0 (4)31.2 (1)30.2
33.0
(7)2B.O (7)28.2 (7)28.3
32.9
32.9
33.1
33.2
(5)27.4 (5)27.3 (5)27.3
H
(9)26.8 (1 26.8 (1 26.7
9)
9)
(1)30.0 (1)30.0
(7)28.2 (7)28.1
L
T issue
Rectal
26.910.2 26.8*0.2 26.810.2 26.8*0.2 26.8*0.2 26.7*0.2 (3)27.3 (3)27.2 (3)27.2 (3)27.1 (3)27.1 (3)27.1
29.7
29.6
29.5
29.6
29.5
(1)26.4 (1)26.4 (1)26.3 (1)26.3 (1)26.3 (1)26.3
29.5
11
L
T issue
(1 25.2 (1)25.3 (1 25.2
2)
2)
(7 2 4 .t (7 24.3 (7 24.2
9)
9)
9) _
(9)25.7
(4)25.7
(4)25.7
(7)24.5 (7)24.5 (7)24.4
H
if
L
Rectal
Rectal
Tissue
3
4
4
High and low P oints
H
Tissue
2
2
i Average D eviation
25.7*0.3 25.8*0.3 25.7*0.2 25.810.1 25.8*0.2 25.8*0,2 (5 26.1 (5)26.2 (5 2 6 .ll (5 26.0 (5 26.1 (6)26.1
G)
6)
6)
6)
29.4
29.3
29.2
28.9
9)25.0 (9)25.2 (9)25.1 (9)25.0 (9)25.2 (9)25.2
29.1
28.9
T issue
1
0
Ho lleat
—
—
—
5
Rectal
6
Tissue
Rectal
25.2*0.5 25.010.5 24.7*0.4 24.6*0.4 24.7*0.3 24.610.4 (1)26.0 (1 25.5 (1 25.3
2)
2)
29.1
28.6
28.5
28.7
28.6
(9)24.6 (7)24.3 (7 24.2
28.9
9L_.
(4)25.7
25.2*0.3
25.410.4 25.3*0.3 25.310.3 25.3*0.3
25.2*0.3 (4)25.9 (9)25.8
28.9
28.8
29.2
29.0
29.1
(7)24.6 (7)24.6 (7)24.5
29.1
I
Tissue
Rectal
28,2*0.2 2 8 .U 0 .3 2 8 .2 i0 .2 28.2*0.2 28.3*0.2 28.2*0.2 (3)28.6 (3)28.6 (3)28.6 (3)28.6 (3)28.7 (3)28.6
30.5
30.4
30.4
30.4
• 30.5
30.4
(5 )2 7 .B (5)27.7 (5)27.8 (5)27.9 (5)27.9 (5)27.9
L
H
L
L
H
L
27.7-'0.4 27.9*0.3 27.910.4 28.0*0.4 28.0*0.3 28.0*0.4 (2)28.3 (2)28.4 (2)28.5 (2)28.6 (2)28.6 (2)28.6 II
30.8
30.8
30.7
30.7
(6 27.7 (9)27.3 (6)27.4 (6 27.6 (6)27.6 (6 27.6 L
30.8
30.7
9)
9)
9)
T a b le 4
The l e f t s i d e oE th e t a b l e shows th e a v e ra g e te m p e ra tu re + d e v i a t i o n ( to p o f e ach box) and th e
u*
c o rre s p o n d in g r e c t a l te m p e ra tu re (bottom o f e a ch box) a t 2 m in u te i n t e r v a l s . The r i g h t s i d e o f t h e t a b l e
shows th e l o c a t i o n o f th e h ig h ( to p o f each box w ith in th e p a r e n t h e s i s ) and th e law (bottom o f e ach box w ith ­
in th e p a r e n t h e s i s ) m easured te m p e ra tu re l o c a t i o n s and t h e i r c o rr e s p o n d in g te m p e ra tu re .
e
Tissue
Rectal
H eated Norm al T is s u e T e m p e ra tu re D i s t r i b u t i o n
^
F i g u r e s 4 th ro u g h 7 b a s i c a l l y show th e a v e r a g e te m p e r a tu r e ( s o l i d
sy m b o ls) a n d th e a v e r a g e d e v i a t i o n ( e r r o r b a r s ) a s w e ll a s th e r e c t a l
te m p e r a tu r e s (o p en sym bols o f e a c h h e a te d a n i m a l ) .
E ach open sym bol
c o r r e s p o n d s t o I t s s o l i d c o u n t e r p a r t f o r e a c h a n im a l.
A l l o f th e
e x p e rim e n ts I n v o lv in g h e a t i n g o f e i t h e r m a lig n a n t o r n o rm a l t i s s u e a r e
s l i g h t l y d i f f e r e n t th a n th e p r e v io u s ( u n p e r tu r b e d ) e x p e rim e n ts a lth o u g h
t h e b a s i c d a ta c o l l e c t e d I s s i m i l a r .
B e s id e s th e f a c t t h a t th e tem ­
p e r a t u r e s a r e e l e v a t e d , th e m ost im p o r ta n t d i f f e r e n c e i s t h a t th e number
o f m easu rem en ts i s l a r g e r .
T h is change was made t o a llo w th e t i s s u e to
s t a b i l i z e a t th e e l e v a t e d te m p e r a tu r e .
A n o th e r I m p o r ta n t n o te i s t h a t
t h e f i r s t p o i n t s shown on e a c h f i g u r e a r e f o r te n m in u te s a f t e r th e
o n s e t o f m icrow ave h e a t i n g a s opposed t o no tim e d e la y I n th e c o n t r o l s .
F ig u r e 4 show s th e r e s u l t s o f a s e r i e s o f e x p e rim e n ts u s in g n orm al
t i s s u e s h e a te d t o te m p e r a tu r e s l e s s th a n 40°C ( a p p r o x im a te ly 3 4 °C ).
The
a r r a y u sed I n t h i s s e r i e s o f e x p e rim e n ts was I n th e p a r a l l e l p la n e ( t h e
t r i p l e p ro b e s w ere a l l p a r a l l e l t o th e fem ur b u t I n a n o th e r p l a n e ) .
The
maximum a v e r a g e d e v i a t i o n from t h e a v e ra g e te m p e ra tu re was found t o be
£ 2 .5 °C and i n a l l o f th e s e e x p e rim e n ts th e r e c t a l te m p e r a tu r e s i n c r e a s e d
w ith tim e .
T a b le 5 shows th e p o s i t i o n s and th e a c t u a l te m p e r a tu r e s f o r
th e h ig h a n d low te m p e r a tu r e a r e a s w hich c o rre s p o n d t o f i g u r e 4 .
The
h ig h p o i n t a n d c o rr e s p o n d in g h ig h te m p e r a tu r e a r e shown i n th e u p p e r p o r­
t i o n o f e a c h box a t e a c h I n t e r v a l o f tim e*
L ik e w is e , t h e low p o i n t s and
te m p e r a tu r e s found I n e a c h a r r a y a r e shown i n th e lo w e r h a l f o f e a c h b o x .
W h ile t h e h o t t e s t p o i n t s a r e , f o r th e m ost p a r t , l o c a t e d on t r i p l e p ro b e
num ber 3 , mouse num ber 4 (T a b le 5 ) shows a " h o t s p o t" a t p o s i t i o n number
5 ( c e n t e r te m p e ra tu re s e n s o r , m id d le t r i p l e p r o b e , p a r a l l e l a r r a n g e m e n t) .
41
NORMAL
TISSUE
NO AIR
COOLING
PARALLEL
DIRECTION
40
30
38
1
37
34
I
33
I
32
li
1
li
h
I
i
I
I
1I I
I
1
i
v
I’
A
30
O
o
2 0
28
o
o
a
j
o
O
o
i
V
A
31
I
»-
I
1
35
h*—1
38
&
o
a
o
e
27
26
25
10
12
14
t6
IB
20
*■*» SOLID FIGURES TISSUE TEMPERATURE
ooav OPEN FIGURES RECTAL TEMPERATURE
-I----------i______ I______ I______ i______ t
22
24
28
28
30
32
TIME (IN MINUTES)
4
The average tem perature (+ d e v ia tio n ) a t each tim e I n te r v a l i s shown by th e
fig u r e s f o r h eated (34°C) normal t i s s u e measured w ith th e p a r a l l e l arrangem ent,
nr sym bols r e p r e se n t d i f f e r e n t an im als.
Ui
■•j
P a ra lle l
Hormal T issue
House Tine 10
12
No. (H ln J ____________
14
16
18
D irection
No A ir Cooling
20
H (8)35.8 (8)35,2 (8)36.2 (8)36.6 (8)36.3 (8)36.1
22
(8
High and Low Points
24
26
28
30
32
36.5 (5)37.0 (5)36.9 (5)36.5 (5)36.2 (5)29.9
5)
1
L (9)31.4 (9)29.8 (9)31.1 (9)30.9 (9)31.2 (9)30.8
(9)31.3 (9)31.3 (9)31.4 (9)30.5 (9)30.2 (9)25.9
1
K (3)29.6 (7)30.2 (7)30.5 (7)31.2 (7)31.5 (7)32.3
(7)32.7 (7)33.0 (7)34.1 (7)33.9 (7)34.0 (9)33.9
29-1 (9)29.4 (9)30.1 (2)30.1 (6)30.6 (2)31.1
(2)31.3 (2)31.7 (2)32.3 (2)32.4 (2)32.5 (2)32.4
H (7 35.7 (7 36.7 (7 36.9 (7 38.9 (7)39.0 (7 38.0
9)
9)
9)
9)
9)
(9)39.1 (7 38.7 (7 40.3 (7 39.8 (7)39.1 (7 40.5
9)
9)
9)
9)
l (3)30.4 (3)31.3 (3)31.6 (3)31.6 (3)31.7 (3)31.8
(3)32.0 (3)33.7 (3)33.0 (3)33.1 (3)33.1 (3)34.0
H (5)33.6 (5)34.7 (5)33.8 (5)33.7 (5)34.3 (5)34.9
(5)35.3 (5)35.0 (5)35.6 (5)35.9 (5)36.0
l
2
(2
9)
3
4
L (7)32.0 (7)32.6 (7)32.0 (7)32.0 (7)32.5 (7)32.9 (2)33.2
—
(7)33.2 (7)33,8 (7)34.0 (7)34.0
T a b le 5
The l o c a t i o n o f th e h ig h (to p o f each box) and th e low (bottom o f each box) m easured
te m p e ra tu re s a r e in d ic a te d w ith in t h e p a r e n t h e s i s f o r norm al t i s s u e m easured w ith th e p a r a l l e l
a rra n g e m e n t o f m ic ro th e rm o c o u p le s. The c o rre s p o n d in g m easured te m p e ra tu re s a r e a d a c e n t to
each p o s i t i o n .
59
T h is may be due t o a "hoc spot** i n th e m icrow ave a p p l i c a t o r t h a t would
be a p p r o x im a te ly i n t h e same p o s i t i o n .
T a b le 5 show s t h a t th e a r e a s
w ith t h e c o o l e s t te m p e r a tu r e s w ere l o c a t e d w i t h in th e s e n s in g a r e a s o f
t r i p l e p ro b e s 1 a n d 3 p r i m a r i l y a t t h e s e n s in g a r e a s a t th e e x tre m e s o f
Che f i r s t t r i p l e p ro b e ( c l o s e s t t o th e h i p p o s i t i o n s 1 an d 3 ) and th e
t h i r d t r i p l e p ro b e ( c l o s e s t t o t h e f o o t p o s i t i o n s 7 a n d 9 ) .
F ig u r e 5 shows t h e r e s u l t s o f 4 e x p e rim e n ts e x a m in in g a p a r a l l e l a r r a y
( p a r a l l e l t o th e fem u r) o f th e rm o c o u p le s w h ile t h e t i s s u e was h e a te d to
a p p r o x im a te ly 40°C and th e a n im a l was c o o le d w ith f o r c e d a i r
(5 l i t e r s / m i n u t e s ) . T h is c o o lin g was n o t d i r e c t e d a c r o s s th e h e a te d
t i s s u e b u t was d i r e c t e d o v e r t h e r e s t r a i n e d a n im a ls h e a d , c h e s t an d
abdomen*
C o o lin g was u sed t o d e te r m in e w h e th e r i t had a n e f f e c t on
t h e c o r e te m p e r a tu r e o r a s i g n i f i c a n t e f f e c t on t h e te m p e r a tu r e d e v i a t i o n .
The maximum a v e r a g e d e v i a t i o n shown on F ig u r e 5 , was + 2 .0 ° C , w h ile m ost
o f th e a v e ra g e d e v i a t i o n s w ere g r e a t e r th a n £ 0 ,5 ° C .
T a b le
6
shows t h a t
t h e se c o n d a n d t h e t h i r d t r i p l e p ro b e s c o n ta i n t h e a r e a s w ith th e w ar­
m est m ea su red te m p e r a tu r e s i n e a c h a r r a y .
The c o o l e s t l o c a t i o n s seem
t o be l o c a t e d w i t h in t h e f i r s t a n d t h i r d t r i p l e p r o b e s , w ith a l a r g e
m a j o r i t y o f t h e a r e a s o f m easu red lo w e r te m p e r a tu r e s l o c a t e d i n a r e a s
a t t h e e x tre m e s o f e a c h o f th e f i r s t a n d t h i r d t r i p l e p r o b e s .
T hese
e x tre m e s a r e a t s e n s o r 1 o r 3 on t h e f i r s t t r i p l e p ro b e o r s e n s o r 7 on
th e t h ir d t r i p l e p ro b e.
A gain th e s e p o s i t i o n s a r e th e c l o s e s t to th e
s u r f a c e o f th e m u sc le t i s s u e a n d a s s u c h do n o t h a v e a s much o v e r ly in g
in s u la tin g tis s u e .
F ig u r e
6
a n d T a b le 7 show th e r e s u l t s o f e x p e rim e n ts e x a m in in g n o r­
m al t i s s u e te m p e r a tu r e d i s t r i b u t i o n s ( w ith c o re c o o li n g ) m easured w ith
t h e p e r p e n d i c u l a r m ic ro th e rm o c o u p le a rr a n g e m e n t.
NORMAL
TISSUE
PARALLEL
DIRECTION
AIR
COOLING
40
39
38
O
O)
37
111 38
U1
g 35
g
34
Z
33
IU
32
o:
D 31
H
< 30
DC
£
29
§
28
H
27
26
• ■ A T SOLID FIGURES TISSU E TEMPERATURE
25
ooa V
10
12
14
16
20
2 2
O PEN FIGURES RECTAL TEMPERATURE
24
26
28
30
32
TIME (IN MINUTES)
F ig u re 5
The a v e ra g e te m p e ra tu re (+ d e v ia t io n ) a t each tim e i n t e r v a l i s shown by
th e s o l i d F ig u re s f o r h e a te d norm al t i s s u e w ith c o re c o o lin g , m easured w ith th e
p a r a l l e l a rra n g e m e n t. The f o u r sym bols r e p r e s e n t d i f f e r e n t a n im a ls .
IlomiaI Tissue
*
P a r a lle l D irectio n
House l i n e
1
2
3
4
10
12
14
16
18
A ir Cooling
High and low P oints
20
22
24
26
28
30
H (8)40.9
(8)43.4
(8)40.1
(8)38.4
(8)42.1
(8)42.1
(8)40.8
(8)39.6
(8)40.4
(8)40.2
(8)43.1
(1 34.8
2,3)
I ( t 37.0
2)
(2)39.0
(1)36.7
(1)35.8
(1)37.9
(1 38.5
2)
(1)37.8
(1 36.9
2)
(1)37.5
(1)37.4
(1 39.1
2)
(8)36.1
H (4)42.0
(4)41.4
(4)42.2
(9)41.6
(4 39.5
B,9)
(8)40.0
(8)41.2
(8)40.4
(8)40.5
(9)39.7
(3)33.6
L (3)39.2
(3)39.5
(3)39.6
(8 41.4
9)
(1)38.7
3)
(1 )3 8 .B (3)37.7
(1)37.7
(3)38.6
(3)38.0
(1)37.6
(1)37.8
(5)32.2
H (4 35.7
6 )
(6)36.3
(6)36.6
(6)36.5
(6)36.9
(4 37.1
6)
(6)37.2
(6)37.4
(6)37.5
(6)37.8
(3)31.8
(3)30.3
I (7)31.9
(7)32.2
(7)32.3
(7)32.3
(7)32.6
(7)32.7
(7)32.9
(7)33.0
(9)33.2
(4 32.7
7)
(8)30.1
(7)27.6
H (8)40.1
(8)39.0
(5)41.5
(5)40.7
(5)41.0
(5)41.2
(5)40.7
(5)41.1
(5 41.3
8 )
(5)41.3
(5 40.9
6 ,8 )
(2)33.0
L (7)34.8
(7)34.1
(7)36.0
(7)35.5
(7)35.5
(7)36.0
(7)36.0
(7)36.2
(7)36.7
(7)36.4
(7)36.4
(7)29.9
T a b le 6
H ie l o c a t i o n s o f t h e h ig h (to p o f e a ch box) and t h e low (b o tto m o f each box) m easured tem p era­
t u r e s a r e i n d i c a t e d w i t h in t h e p a r e n t h e s i s f o r norm al t i s s u e w ith c o r e c o o lin g m easured w ith th e p a r a l l e l
m ic ro th e rm o c o u p le a rra n g e m e n t. The c o rre s p o n d in g m easured te m p e ra tu re s a r e a d ja c e n t t o e ach p o s i t i o n .
A g a in , a i r c o o lin g was em ployed.
F ig u re b shows a maximum
62
a v e r a g e d e v i a t i o n o f _+ 1 .4 °C a lth o u g h a l l o f th e v a lu e s a r e much lo w e r.
T a b le 7 shows a somewhat random v a r i a t i o n i n t h e d i s t r i b u t i o n , i n th e
l o c a t i o n o f th e a r e a s o f m easu red h ig h a n d low te m p e r a t u r e s .
To p u t i t
a n o t h e r w ay, no o n e t r i p l e p ro b e was c o n s i s t e n t l y I n e i t h e r th e a r e a o f
th e h i g h e s t te m p e r a tu r e s o r th e a r e a s o f t h e lo w e s t te m p e r a t u r e s ,
ho w ev er, I n g e n e r a l m ost o f th e h i g h e s t te m p e r a tu r e s m easured w ere
w i t h i n th e s e n s i n g p o i n t s o f th e se c o n d an d t h i r d t r i p l e p r o b e s .
F ig u r e 7 a n d T a b le b show th e r e s u l t s o t a s e r i e s o f e x p e rim e n ts
m e a s u rin g th e r m a l d i s t r i b u t i o n s , I n a p la n e p e r p e n d i c u l a r to t h e fem u r,
I n h e a te d n o rm al t i s s u e w ith o u t an y a i r c o o li n g .
The s o l i d sym bols
( F ig u r e 7 ) a r e t h e a v e r a g e te m p e r a tu r e s an d th e e r r o r b a rs a r e t h e
a v e ra g e d e v ia tio n .
o p en s y m b o ls .
The c o r r e s p o n d in g r e c t a l te m p e ra tu re a r e shown by th e
F ig u r e 7 show s a maximum a v e r a g e d e v i a t i o n o f
l .y ° C w ith
m ost o f th e m easured v a lu e s g r e a t e r th a n + l.lT C and a n I n c r e a s e i n t h e
r e c t a l te m p e r a tu r e i n t h r e e o u t o f f o u r a n im a ls .
A lth o u g h one a n im a l
had a low r e c t a l te m p e ra tu re i t s t i l l i n c r e a s e d w ith tim e .
T h is
a p p a r e n t d i f f e r e n c e i n th e r e c t a l te m p e r a tu r e s may have been d u e , i n p a r t
t o t h e l e v e l o f a n e s t h e s i a . .T h e a r e a s w ith th e h i g h e s t m easured tem­
p e r a t u r e s f o r m u scle t i s s u e w ith no a i r c o o lin g a s m easured by a p e rp e n ­
d i c u l a r a r r a y seem t o be found w i t h in th e s e n s in g a r e a s o f t r i p l e p ro b e s 2
an d 3 , T a b le U.
The a r e a s o f th e lo w e s t r e c o r d e d te m p e r a tu r e s a s
m easu red w ith t h i s same p e r p e n d i c u l a r a r r a y seem to be d i s p e r s e d o v e r th e
t h r e e t r i p l e p r o b e s . T a b le ti.
I f one com pares F ig u r e s 4 a n d 5 o r F ig u r e s b a n d 7 i t becomes e v i ­
d e n t c h a t a i r c o o lin g , a t th e r a t e o f 5 l i t e r s / m i n u t e , does n o t s i g n i f i ­
c a n t l y a f f e c t th e c o r e te m p e r a tu r e . A ls o , a c o m p a riso n o f F ig u r e s 5 a n d
b shows t h a t I n e i t h e r p l a n e , p a r a l l e l o r p e r p e n d i c u l a r t o th e fem u r,
NOflMAL
TISSUE
PERPENDICULAR
DIRECTION
AIR
COOLED
41
40
39
f,
\
I1
I
36
I 1
37
°
(0
Ui
36
35
if 1 ^ I 1
\
34
33
2
ui
0 C
Z>
I<
tr
ui
a.
§
32
I
<P
°v
A
A
A
©
«
0
9
OF
0
09
9
9
A
A
9
A
A
31
30
29
28
27
aaa f so l
26
to n c u n E s
u s s u e tem perature
ODA9 O P E N FIG U RES RECTAL TEMPERATURE
25
10
12
14
16
IB
20
2 2
24
26
28
30
32
TIME (IN MINUTES)
F ig u re 6
The a v e ra g e te m p e ra tu re (+ d e v ia t io n ) a t each tim e i n t e r v a l I s shown by
th e s o l i d f i g u r e s f o r h e a te d n orm al t i s s u e w ith c o r e c o o lin g m easured w ith th e p e r ­
p e n d ic u la r a rra n g e m e n t. The f o u r sym bols r e p r e s e n t d i f f e r e n t a n im a ls .
P erpendicular D irectio n
Normal T issue
A ir Cooled
High and Low P oints
House Time
No. (Min.)
1
10
12
14
16
IB
20
22
24
26
28
30
32
34
36
H (4)40.8 (4)41.4 (4)41.1 (4)41.6 (3)40.2 (4)40.8 (4)41.6 (4)40.2 (4)41.1 (4)41.6 (4)41.7 (3)34.9 (1 32.0 (1)30.6
8 )
L (7)38.4 (1)39.6 (7)38.5 (7)39.3 (7)38.3 (7)3B.6 (7)39.4 (8)39.3 (7)38.9 (7)39.3 (7)39.7 (7)32.8 (7)30.3 (7)29.0
H (8)41.7 (8)41.3 (8)40.1 (8)40.5 (8)39.4 (8)39.9 (8)41.7 (8)40.4 (8)40.0 (8)40.4 (8)40.8 (3)34.7 (1)31.4 (3)29.8
2
L (4)38.4 (4)38.1 (5)38.6 (2)39.3 (4)37.0 (4)37.3 (4)38.7 (4)38.0 (4)37.6 (3 39.3 (4)38.2 (4)33.1 (4)30.5 (4)29.1
5)
It (9)38.2 (9)38.3 (9)38.2 (9)39.4 (9)39.2 (9)39.3 (9)40.6 (9)40.9 (9)40.8 (9)39.8 (9)40.9 (1)33.6 (2)31.3 (1)31.2
3
I (3)33.9 (3)34.4 (3)34.4 (3)34.9 (3)35.1 (3)35.3 (3)36.2 (3)36.6 (3)36.8 (3)36.5 (3)37.2 (3)32.8 (7)30.5 (7)29.4
4
H (8)39.4 (9 39.2 (5)39.8 (5 42.0 (2 39.3 (5)40.5 (5 39.3 (6)40.9 (5 40.4 (5)40.3 (5)40.9 (1 3 3 .B (1 32.C (1 31.2
4 ,5 )
8 )
6 )
4)
6 )
5)
4)
6 )
L (2)38.8 (5)37.2 (2 39.8 (1 41.0 (5 40.0 (2)39.6 (2)39.4 (2)39.9 (2)39.1 (2)39.2 (2 )3 9 .E (2)33.2 (2)31.4 (2)30.6
2 .4 )
4)
6 )
*
T a b le 7
The l o c a t i o n s o f th e h ig h ( to p o f e a ch box) and t h e low (bottom o f e a ch box) m easured te m p e ra tu re
a r e I n d ic a te d w ith in th e p a r e n t h e s i s f o r norm al t i s s u e w ith c o r e c o o lin g m easured w i t h in t h e p e r p e n d ic u la r
m ic ro th e rm o c o u p le a rra n g e m e n t. The c o rre s p o n d in g m easured te m p e ra tu re s a r e a d ja c e n t t o each p o s i t i o n .
NO AIR
COOLING
PERPENOICULAR
DIRECTION
NORMAL
TISSUE
41
40
09
i
]
aa
°
37
CO
i
P
I
i
Si 33
g
UJ
Q
35
34
9
33
UJ
O
a
32
I I
H if,
f
av
O
av
9
a
&
a
ft
V
ft
OC
3
31
g
30
S!
29
§
2
a
*“ • 27
26
• ■AT SOLID FIGURES TISSUE TEMPERATURE
aaftV O PEN FIG U RES RECTAL TEMPERATURE
25
10
12
14
16
IB
20
______ 1______ '
22
24
26
i
28
_l_
J
30
32
TIME (IN MINUTES)
F ig u re 7
The a v e ra g e te m p e ra tu re (+ d e v ia t io n ) a t each tim e i n t e r v a l i s shown by
th e s o l i d f i g u r e s f o r h e a te d norm al t i s s u e w ith o u t c o r e c o o lin g m easured w ith th e
p e r p e n d ic u la r a rra n g e m e n t. The f o u r sym bols r e p r e s e n t d i f f e r e n t a n im a ls .
Nonna] T issue
P erpendicular D irection
No A ir Cooling
High and Low Point
Mouse Tine
10
12
14
16
18
20
22
24
26
28
30
32
H (7)39.8 (9)41.8 (7)41.4 (7 38.7 (7)38.8 (9)42.0 (9)41.9 (9)39.8 (9)40.5 (9)40.6 (9)42.7 (7)35.5
9)
L (2)36.3 (2)37.1 (2)38.2 (2)35.4 (2)36.6 (2)36.6 (2)37.1 (2)36.0 (2)36.3 (2)36.4 (2)38.0 (5)34.4
1
H (7)42.4 (7)42.4 (7)43.9 (7)44.0 (7)42.2 (7)42.3 (7)40.5 (7)41.4 (7)40.3 (7)39.5 (7)40.2 (3)33.5
2
3
L (4 36.2 (4 36.6 (4)37.5 (4)36.3 (4)36.6 (4)36.8 (4)35.8 (9)36.8 (4)35.8 (4)35.4 (9)36.0 (4)30.9
9)
9)
H (5)41.3 (5)40.8 (5)40.9 (5 40.6 (5)40.6 (5 41.7 (5)41.2 (5 40.8 (5)40.9 (8)41.7 (8)41.9 (1)35.2
8 )
8 )
8 )
L (6)36.3 (6)35.9 (6)36.2 (6)36.2 (6)35.4 (6)36.5 (6)36.1 (6)36.0 (6)35.9 (6)36.8 (6)36.6 (6)31.5
H (5)39.1 (5)39.3 (5)38.6 (5)41.8 (5)40.9 (5)41.1 (5)38.2 (5)41.7 (5)41.3 (6)41.1 (5 40.2 (6)34.9
6 )
4
L (7)37.3 (7)37.5 (7)37.1 (7)39.5 (7)39.0 (7)39.3 (7)36.9 (7)40.0 (7)39.7 (7)39.6 (7)39.0 (7)33.7
T a b le 8
The l o c a t i o n s o f th e h ig h ( to p o f each box] and th e low (bottom o f e ach box) m easured
te m p e ra tu re a r e I n d ic a te d w ith in th e p a r e n t h e s i s f o r norm al t i s s u e w ith o u t c o r e c o o lin g m easured
w ith th e p e r p e n d ic u la r m ic ro th e rm o c o u p le a rra n g e m e n t. .The c o rre s p o n d in g m easured te m p e ra tu re s
a r e a d ja c e n t t o e ach p o s i t i o n .
67
che a v e r a g e d e v i a t i o n s a r e s i m i l a r . T h ese s i m i l a r i t i e s i n
a v e r a g e d e v i a t i o n {+
+ l . y ° C ) , i n d i c a t e c h a t n orm al t i s s u e can be
h e a te d r e l a t i v e l y w e ll b u t w ith th e draw back o f a n a v e ra g e maximum
d e v i a t i o n i n te m p e r a tu r e o f
2 .5 ° C .
H e a ted M a lig n a n t T is s u e T e m p e ra tu re D i s t r i b u t i o n s
F i g u r e s B th ro u g h 11 a n d T a b le s 9 th ro u g h 12 show th e r e s u l t s o f
e x p e rim e n ts e x a m in in g te m p e r a tu r e d i s t r i b u t i o n s d u r in g 4U°C m icrow ave
h e a t i n g o f m a lig n a n t t i s s u e w ith a n d w ith o u t a i r c o o li n g , i n b o th
t h e p a r a l l e l ( t o th e fem u r) an d Che p e r p e n d i c u l a r p l a n e s .
T hese
e x p e rim e n ts w ere p e rfo rm e d e x a c t l y t h e same a s t h o s e p r e v io u s ly
m e n tio n e d f o r h e a te d
n orm al t i s s u e e x c e p t t h a t m easurem ents
w ere ta k e n i n tum or t i s s u e r a t h e r th a n n orm al t i s s u e .
F ig u r e B shows th e r e a d in g s o b ta in e d i n th e
l o c a l h e a ti n g w ith no a i r c o o li n g .
o b s e rv e d was +
1
p a r a l l e l p la n e d u r in g
The maximum
a v e ra g e d e v ia tio n
. 2 °C a n d th e r e c t a l te m p e r a tu r e , o v e r
h e a t i n g p e r i o d , showed a m arked i n c r e a s e .
th e l e n g t h o f th e
T h is m arked
I n c r e a s e i s p ro ­
b a b ly a n a t t e m p t , by t h e n o rm al p h y s io lo g y o f Che a n im a l,
h e a t fro m t h e h e a te d tum or Co th e abdom en.
A n o th e r r e a s o n
t o s h u n t th e
fo r th is
c o r e te m p e ra tu re r i s e may be some s c a t t e r o f che
im p in g in g m icrow ave
po w er.
(a n d th e c o rre s p o n d in g
The l o c a t i o n s i n th e h e a te d tum or t i s s u e
t e m p e r a tu r e s ) o f che a r e a s o f h i g h e s t te m p e ra tu re and lo w e s t te m p e ra tu re
a r e shown i n T a b le 9 .
The num bers i n p a r e n t h e s i s
a r e th e l o c a t i o n of
t h e a r e a o f h ig h te m p e r a tu r e ( u p p e r p o r t i o n o f e a c h
low t e m p e r a tu r e , ( lo w e r p o r t i o n o f e a c h b o x ).
box) an d a r e a s o f
T a b le 9
a r e a s t h a t r e g i s t e r e d th e h ig h an d low te m p e r a tu r e s
n o t c o n f in e d t o an y s p e c i f i c l o c a t i o n w i t h in th e
shows t h a t th e
d u r in g h e a ti n g w ere
tu m o r.
f i g u r e y shows che r e s u l t s o b ta in e d f o r th e rm a l d i s t r i b u t i o n In th e
p a r a l l e l d i r e c t i o n w ith a i r c o o lin g and i n t h i s I n s ta n c e th e maximum
a v e ra g e d e v ia t io n was Hh 1 . 2 °Cf w ith th e m a jo r ity o f th e a v e ra g e
d e v ia t io n s below _+ l.l) ° C .
The s o l i d sym bols (o n a l l of th e f i g u r e s )
I n d i c a t e th e a v e ra g e te m p e ra tu re w ith r e s p e c t to a l l n in e o f th e a r e a s
m easured and th e e r r o r b a rs a r e th e a v e ra g e d e v i a t i o n w ith r e s p e c t to
a l l n in e o f th e a r e a s m easured.
th ro u g h th e u s e o f open sy m b o ls•
The r e c t a l te m p e ra tu re s a r e d e n o te d
The two s o l i d c i r c l e s a t 28 and 30
m in u te s a t g r e a t l y red u c e d te m p e ra tu re w ere due to th e p re m a tu re c e s s a ­
t i o n o f m icrowave h e a ti n g .
A lthough t h e r e i s a w ide d i f f e r e n c e i n th e
r e c t a l tern p e r a t u r e s , a l l f o u r a n im a ls 1 r e c t a l te m p e ra tu re s d id I n c r e a s e
d u rin g th e i n t e r v a l o f h e a tin g and che s o l i d c i r c l e (F ig u r e y) a t 2d and
30 m in u te s show t h a t a p p a r e n tl y t h e r e i s s h u n tin g
men.
o f h e a t to th e abdo­
T hble 10 shows th e l o c a t i o n s o f th e a r e a s w ith
h i g h e s t tem­
p e r a t u r e and a r e a s o f lo w e s t te m p e ra tu re f o r m easurem ents In
th e
p a r a l l e l d i r e c t i o n d u rin g m icrowave h e a tin g w ith a i r c o o lin g .
T a b le 10
shows t h a t th e seco n d and t h i r d t r i p l e p ro b e s seem to c o n ta i n
che a r e a s
I n che h e a te d tum or w ith th e w arm est te m p e ra tu re s w h ile i n two
e x p e ri­
m ents (num bers 2 a n d 4) che c o o le s t te m p e ra tu re s w ere m easured
w ith
t r i p l e p ro b e number
1
.
Even w ith a l a r g e d i f f e r e n c e i n r e c t a l te m p e ra tu re s found i n F ig u re
V, t h e r e i s no s i g n i f i c a n t d i f f e r e n c e i n th e r e c t a l te m p e ra tu re w ith o r
w ith o u t a i r c o o lin g when one com pares F ig u re s
8
and y.
F ig u re
8
and 9
a l s o show no s i g n i f i c a n t d i f f e r e n c e i n che a v e ra g e d e v ia t io n from che
a v e ra g e te m p e ra tu re .
F ig u re s 1U and 11 a n d T a b le s 11 and 12 sum m arize a s e r i e s o f
e x p e rim e n ts ex am in in g th e rm a l d i s t r i b u t i o n i n th e p e r p e n d ic u la r p la n e
69
w ith an d w ith o u t a i r c o o li n g .
T h ese r e s u l t s a r e t a b u l a t e d I n t h e
same m anner a s a r e te m p e ra tu re d i s t r i b u t i o n e x p e rim e n ts
p r e v i o u s ly shown.
fig u re
1
U shows t h e maximum a v e r a g e d e v i a t i o n t o r h e a te d m a lig n a n t
t i s s u e i n t h e p e r p e n d i c u l a r p la n e ( w ith a i r c o o lin g ) was fo u n d to be
nh 2.U°C w ith t h e m a j o r i t y o f t h e a v e ra g e v a lu e s much l e s s (+^ l.U ° G ).
A g a in , t h e r e c t a l te m p e r a tu r e i n c r e a s e d d u r in g t h e p e r i o d o f m icrow ave
h e a t i n g . T a b le 11 show s t h e h ig h an d low te m p e r a tu r e a r e a s a t e a c h tim e
I n t e r v a l f o r te m p e r a tu r e d i s t r i b u t i o n i n t h e p e r p e n d i c u l a r d i r e c t i o n ,
w ith a i r c o o lin g f o r m a lig n a n t t i s s u e .
The w arm est l o c a t i o n s fo u n d
w ere m easured by th e f i r s t t r i p l e p ro b e ( c l o s e s t to t h e fem u r) a n d th e
c o o l e s t a r e a s w ere m easu red by t h e t h i r d t r i p l e p r o b e .
A lth o u g h t h i s
seem s t o be c o n t r a d i c t o r y , I t c o u ld p o s s ib l y be due t o th e I n a b i l i t y o f
m a lig n a n t t i s s u e t o d i s s i p a t e t h e h e a t p r o p e r l y .
T e m p e ra tu re d i s t r i b u t i o n d a ta I n t h e p e r p e n d i c u l a r d i r e c t i o n w ith o u t
c o o lin g a r e shown by F ig u r e 11 a n d T a b le 1 2 .
The maximum a v e r a g e
d e v i a t i o n found i n F ig u re 11 was + U.b°C a n d o n ce a g a i n th e r e c t a l tem ­
p e r a t u r e i n c r e a s e d th ro u g h o u t t h e h e a ti n g i n t e r v a l .
T a b le 12 shows th e
te m p e r a tu r e e x tre m e s ( h ig h a n d low te m p e r a tu r e s ) f o r m easu rem en ts ta k e n
i n th e p e r p e n d i c u l a r d i r e c t i o n w ith no a i r c o o lin g o f m a lig n a n t t i s s u e .
A g r e a t d e a l o f te m p e ra tu re o v e r la p l a shown I n t h i s t a b l e , p ro b a b ly due
t o th e e x tr e m e ly c l o s e m easurem ents o b t a i n e d .
A lth o u g h th e r e c t a l te m p e r a tu r e s i n F ig u re 11 a r e somewhat h ig h e r
th a n F ig u r e 1 0 , t h e r e i s no s i g n i f i c a n t d i f f e r e n c e i n c o re c o o lin g when
a i r c o o lin g ( a t 5 l i t e r s / m i n u t e ) was com pared t o no a i r c o o li n g .
A l l o f th e p r e v io u s te m p e ra tu re d i s t r i b u t i o n d a ta d e m o n s tra te s a tew
b a s i c p o i n t s t h a t n e e d to be c l a r i f i e d .
The f i r s t i s c h a t a i r c o o lin g
( a t a r a t e o f 5 l i t e r s / m i n u t e ) d o e s n o t s i g n i f i c a n t l y a f f e c t th e c o re
PARALLEL
DIRECTION
MALIGNANT
TISSUE
P
41
40
I
30
36
°
k
NO AIR
COOLING
i
I
37
( 0
IS 36
i
t!
i
I1 6
r
l
II
5 35
to
a 34
Z
i
33
UJ 32
CC
31
A
A
O
A
0
O
O
30
o
OQ
a
0
0
0
2 0
28
27
26
2
S
oda Q
10
12
14
16
16
20
22
SOLID riG U H E S TISSUE TEMPERATURE
O PEN FIG URES RECTAL TEMPERATURE
x
24
-L
26
28
30
32
TIME (IN MINUTES)
F ig u re 6
The a v e ra g e te m p e ra tu re (+ d e v ia t io n a t each tim e i n t e r v a l ) i s shown by
th e s o l i d f i g u r e s f o r h e a te d m a lig n a n t t i s s u e (MCa) w ith o u t c o r e c o o lin g m easured
w ith th e p a r a l l e l a rra n g e m e n t o f m ic ro th e rm o c o u p le s. The f o u r sym bols r e p r e s e n t
d i f f e r e n t a n im a ls .
Malignant Tissue
P a r a lle l D irection
Ho Air Cooling
High and Low Points
Mouse Tine
10
12
14
15
18
20
22
24
Ho. (M in.)____________________________________________________________
(6)35.7 (6)37.7 (6)38.1 (6)41.3
26
28
30
32
42.4 (6)34.7 (6)39.9 ( 6 39.9 (9)41,5 (9)41.9 (9)42.5 (9)41.8
9)
9)
(4)32.3 (3)33.9 (4)34:1 (4)36.2 (4)37.3 (4)35.6 (4)35.7 (4)35.9 (4)37.2 (5)37.6 (5)37.9 (5)37.5
(6
(9)39.3 (8)39.8 (8)40.7 (9)41.8 (8)41.3 (6)40.7 (6)41.3 (5)43.4 (6)40.5 (6)40.8 (4 40.4 (6)40.2
6 )
(1)37.0 (1)37.1 (1)38.0 (1)39.1 (1)39.0 (1)38.3 (1)39.6 (1)39.6 (1)39,0 (1)38.9 (1)39.0 (1)38.5
(2)39.0 (2)40.7 (2)40.6 (2)41-7 (4)41.6 (2)40.8 (2)40.0 (2 39.2 (2)40.1 (2 39.3 (2)39.9
4)
4)
(9)37.5 (9)39.0 (9)39.2 (9)39.9 (9)40.2 (9)39.5 (3)39.2 (9)38.1 (8)38.5 (9)38.3 (9)38.8
—
(1)40.2 (1)41.0 (1)40.9 (1)41.4 (1)43.1 (1)42.0 (1)40.3 (1)39.7 (1)40.1 (1)40.8 (1)40.5 (1)36.4
(7)36.5 (7)37.6 (7)37.6 (4 38.1 (4)39.3 (4)38.8 (4)37.4 (4)36.5 (4)36.7 (4)37.3 (4)37.1 (4)34.7
7)
T a b le 9
The l o c a t i o n s o f
te m p e ra tu re s a r e I n d ic a te d
m easured w ith th e p a r a l l e l
t u r e s a r e a d ja c e n t t o e a ch
th e h ig h ( to p o f each box) and th e low (bottom o f e ach box) m easured
w i t h in th e p a r e n t h e s i s f o r m a lig n a n t t i s s u e w ith o u t c o re c o o lin g
m ic ro th e rm o c o u p le a rra n g e m e n t. The c o rre s p o n d in g m easured tem p era­
p o s itio n .
MALIGNANT
TISSUE
PARALLEL
DIRECTION
AIR
COOLED
41
40
II
39
38
o
w
L1 J
U1
EC
(3
Ul
Q
Z
UJ
DC
Z>
(<
DC
UJ
Q.
2
UJ
h
f
37
1
36
35
it
34
33
32
A
A
9
*
9
4
9
A
a
9
A
9
*
v
A
A
31
30
29
28
27
26
o
o
25
0
a
A
A
O
o
a
0
O
a
12
14
o
#■** SOUU riCUHES tISSUE IfMPEFlAlUHE
on * w o m i r i n n n c s
10
a
16
18
20
*
■
22
24
jie c t a l t c m p c h a iu h e
«________________ I
26
28
I________________ I
2 0
32
TIME (IN MINUTES)
F ig u re 9
Ttie a v e ra g e te m p e ra tu re (+ d e v i a t i o n ) a t each tim e i n t e r v a l I s shown by
th e s o l i d f i g u r e s f o r h e a te d m a lig n a n t t i s s u e (MCa) w i t h c o re c o o lin g m easured w ith
th e p a r a l l e l a rra n g e m e n t o f ro lc ro th c rm o c o u p lc s . The f o u r sym bols r e p r e s e n t d i f f e r e n t
a n im a ls .
Malignant Tissue
P a r a lle l D irection
Air Cooled
High and Low Point
Mouse Tine 10
Ho. (Min.)
12
14
______
16
18
20
22
____
24
26
H (7)39.6 (3 40.5 (7)41.3 (7)41.3 (7)40.3 (7)41.0 (7)41.7 (3)41.9 (7)40.5 (5)33.8 (1 31.0 (1)28.2
3.5 )
7)
L (6)36.5 (9)37.3 (6)38.2 (6)38.4 (6)37.6 (6)38.3 (6)38.9 (6)39.6 (6)38.1 (6)32.9 (9)30.4 (9)27.2
1
H (6)37.5 (6)39.7 (6)41.1 (6)41.9 (6)41.7 (6)41.8 (6)42.2 (6)42.2 (6)42.6 (6)41.7 (6)40.3 (6)40.2
L (1)34.1 (1)35.9 (1)37.3 (1)38.1 (1)38.2 (1)38.2 (1)38.5 (1)38.6 (1)38.9 (1)38.5 (1)37.5 (1)37.3
2
H (6)37.0 (6)37.8 (1 38.2 (6)38.9 (6)40.3 (6)41.0 (6)42.5 (6)43.0 (4 41.9 (4 42.1 (4)42.3 (1 34.5
3)
6 )
6 )
6 )
(8)32.6
(2)39.7
(2)40.2 (2)40.2
L (8)35.1 (8)35.5 (8)36.5 (8)36.9 (8)38.4 (8)38.5 (2 40.2 (2)40.5
8 )
3
43,1 (9)41.3 (9)41.0 (9)39.6 ( 8 41.9 (9)41.0 (9)41.1 (9)41.5 ( 8 41.0 (5)36.1
9)
9)
9)
L (7)37.3 (3)38.4 (3)39.0 (3)38.2 (3)38.1 (3)37.1 (3)38.2 (3)38.7 (3)38.8 (3)38.6 (3)38.6 (7)33.9
H (9)40.0 (9)42.6
4
( 8
T a b le 10
The l o c a t i o n s o f th e h ig h (to p o f each box) and th e low (bottom o f each box)
m easured te m p e ra tu re s a r e I n d ic a te d w ith in th e p a r e n t h e s i s f o r m a lig n a n t t i s s u e w ith c o re
c o o lin g m easured w ith th e p a r a l l e l m ic ro th e rm o c o u p le a rra n g e m e n t. The c o rre s p o n d in g m easured
te m p e ra tu re s a r e a d ja c e n t to e ach p o s i t i o n .
MALIGNANT
TISSUE
41
40
39
36
CO
37
UJ
UJ
36
a:
aUJ
35
o
34
33
PERPENDICULAR
DIRECTION
-
'
j
f
Ir
-
rL II±i
1
J
£T
k
T
AIR
COOLED
iPif Mi M f[
1
1
9
9
-
*
.9
3
9
9
a
O
O
9
A
O
9
a
O
a
V
a
A
a
A
A
O
A
9
O
A
O
iA
32
cc
D
H
a
31
*
<
30
-
UJ
29
*
28
*
ac
CL
5
UJ
0
A
27
26
-
25
.
• a * * SOLID FIGURES TISSUE TEMPERATURE
oa&9 OPEN FIGURES RECTAL TEMPERATURE
10
12
14
16
18
20
L
>
22
24
» —
26
—
«
I
28
30
_
-
■
32
TIME (IN MINUTES)
F ig u re 10
The a v e ra g e te m p e ra tu re (+ d e v ia t io n ) a t each tim e i n t e r v a l i s shown by
th e s o l i d f i g u r e s f o r h e a te d m a lig n a n t t i s s u e (MCa) w ith c o re c o o lin g m easured w ith
t h e p e r p e n d ic u la r a rra n g e m e n t o f m icro th erm o co u p les* The f o u r sym bols r e p r e s e n t
d i f f e r e n t a n im a ls .
I
H a lI g n a n t T is s u e
P e r p e n d ic u la r D ir e c tio n
A ir C ooled
H igh and Low P o in t
House Time
Ho. ( H in .)
H
1
L
H
|2
10
12
M
16
18
2 0
2 2
24
26
2
B
30
32
12)38.1 (2)38.6 (2)39.1 (2)39.6 (2 )4 0 .5 (2)40.1 (2 )4 0 .0 (2)40.7 (2)40.6 (2)40.7 (2)40.7 (1 34.8
2 )
(7)32.9 (7 )3 3 .8 (9 )3 4 .9 (9)35.5 (9 )3 6 .6 (7)37.1 (7 )3 6 .8 (7 )3 7 .9 (7)38.1 (7)37.8 (7)38.1 (7)33.6
(2)40,3 (2)40.4 (2)40.7 (2)41.1 (2 )4 1 .0 (2)41.2 (2)41.4 (2)40.7 (2 )4 1 .0 (2)41.3 (2)40.7 (1 35.1
2 ,6 )
L (4 38.6 (4 38.9 (4 )3 9 .0 (4)39.3 (4)39.1 (4)39.4 (4)39.6 (4)39.1 (4)39.3 (4)39.5 (4)39.1 (3 34.5
7)
8 )
7)
H (7 )3 8 .0 (7)39.2 (7 )4 0 .3 (7)40.4 (7)40.4 (7)40.5 (7)40.2 (7)41.3 (7)39.7 (7)40.7 (7)40.8 (7)41.5
3
4
L (5)36.5 (5)37.5 (5 )3 8 .5 (5)38.7 (5)38.7 [5)38.9 (5)38.8 (5)39.5 (5)38.4 (5)39.3 (5)39.3 (5)39.9
H (1)38.3 (1)3B.4 (1 )3 9 .2 (1)39.1 (1 39.8 (2 )3 9 .8 (2)39.9 (6)40.1 (6 )4 1 .3 (6)41.2 (6)41.7 (2)36.9
2 )
L ( 6 37.4 (9 )3 7 .6 (6)38.4 (9)38.6 (4 39.4 (4 39.5 (4 )3 9 .5 (4)39.5 (4)40.7 (4)40.5 (4)40.9 (4)35.9
9)
6 ,8 ,9 ) 8 )
T a b le 11
The l o c a t i o n s o f t h e h ig h (to p o f each box) and th e low (bottom o f e a ch box) m easured
te m p e ra tu re s a r e I n d ic a te d w ith in th e p a r e n t h e s i s f o r m a lig n a n t t i s s u e w ith c o re c o o lin g m easured
w ith th e p e r p e n d ic u la r m ic ro th e rm o c o u p le a rra n g e m e n t. The c o rre s p o n d in g m easured te m p e ra tu re s a r e
a d ja c e n t t o each p o s i t i o n .
-j
Ut
PERPENDICULAR
DIRECTION
MALIGNANT
TISSUE
I
B
f \
NO AIR
COOLING
I
f
t
'i
V
A
oft
V
&
9
ft
o
a
a
A
o
O
9
O
•
SO HO
FIGUnES T issu e TEMPERATURE
ooav o p e n f i g u r e s r e c t a l t e m p e r a t u r e
to
12
14
16
IQ
20
-L
22
-L-
24
26
_u
28
-L_
30
32
TIME (IN MINUTES)
F ig u re 11
The a v e ra g e te m p e ra tu re (+ d e v ia tio n } a t e ach tim e i n t e r v a l i s shown by th e
s o l i d f i g u r e s f o r h e a te d m a lig n a n t t i s s u e (MCa) w ith no c o r e c o o lin g m easured w ith th e
p e r p e n d ic u la r a rra n g e m e n t o f m ic ro th e rm o c o u p le s . The f o u r sym hols r e p r e s e n t d i f f e r e n t
a n im a ls .
Malignant Tissue
Perpendicular Direction
Ho A ir Cooling
High and Low Point
Mouse Tine 10
No. (H ln.)
12
14
16
IB
20
22
24
26
28
30
32
H (1)41.2 (1)41.2 (1)40.3 (1)41.1 (1)40.4 (1)41.4 (1)41.0 (1)39.5 (1)40.6 (1)41.0 (1)40.8 (1)35.8
1
2
L (9)39.8 (9)40.1 (7 39.1 (7)39.5 (3)39.5 (3)40.5 (3 40.0 (3 38.6 (3)39.5 (3)39.8 (4)39.0 (7)34.8
9)
8)
9)
H (3)39.3 (3)39.6 (5)40.9 (5 40.4 (3)40.5 (3)40.3 (3)41.3 (5)41.1 (3)40.1 (3)40.6 (3)40.8 (4 35.9
8)
8)
L (1)38.1 (1)38.5 (1)39.8 (9)39.5 (1 39.4 (9)39.3 (7 40.2 (7)39.3 (7)39.7 (7)39.3 (7)39.6 (7 35.6
9)
9)
9)
3
H (8)40.0 (2 39.3 (2 39.5 (2 39.7 (2)40.4 (2 40.5 (2)40.6 (2 40.5 (6 40.3 (2)40.8 (2 41.0 (2)36.9
6,8)
6,8)
8)
6)
8)
8)
8)
L (5)38.1 (5)37.9 (5)37.9 (5)38.2 (5)38.7 (5)39.0 (5)39.0 (5)39.1 (5)38.9 (5)39.4 (5)39.6 (7)34.B
4
H (8)40.1 (8)41.1 (5 41.1 (5 41.5 (5)39.6 (5 40.6 (8)40.8 (8)40.8 (8)40.6 (1)39.5 (8)40.7 (3)36.9
8)
8)
8)
L (1)39.1 (1)40.1 (1)40.1 (1)40.7 (1)38.6 (1)39.9 (1)40.0 (1)39.7 (1)39.8 (7)38.6 (1)39.9 (1)35.3
T a b le 12
The l o c a t i o n s o f th e h ig h (to p o f each box) and th e low (b o tto m o f e a ch box) m easured
te m p e ra tu re s a r e I n d ic a te d w ith in th e p a r e n t h e s i s f o r m a lig n a n t t i s s u e w ith o u t c o r e c o o lin g m easured
w ith th e p e r p e n d ic u la r m ic ro th e ra o c o u p le a rra n g e m e n t. The c o rre s p o n d in g m easured te m p e ra tu re s
a r e a d ja c e n t to each p o s i t i o n .
78
( r e c t a l ) t e m p e r a tu r e .
S e c o n d ly , t h e r e a r e no d r a m a tic c h a n g e s I n t h e
a v e r a g e d e v i a t i o n I n e i t h e r no rm al o r m a lig n a n t t i s s u e s when th e
p a r a l l e l p la n e I s com pared t o t h e p e r p e n d i c u l a r p la n e w i t h in
of tis s u e .
L a s t l y , m a lig n a n t t i s s u e g e n e r a l l y shows a
e a c h ty p e
somewhat g r e a t e r
te n d e n c y t o have s m a l le r a v e r a g e d e v i a t i o n s th a n n orm al
tis s u e .
T hese
p o i n t s I n d i c a t e t h a t th e ab o v e m icrow ave h e a ti n g s y s te m
c a n be em ployed
t o h e a t tlB s u e s I n v iv o s u c c e s s f u l l y *
M easurem ents o f uxygen T e n s io n
F ig u r e s 12 th ro u g h 15 show t h e r e s u l t s o f a s e r i e s o f e x p e rim e n ts
d e s ig n e d t o exam ine w h e th e r 4U°U m icrow ave h y p e rth e rm ia a f f e c t s
tum or o x y g e n a tio n s t a t u s .
I n a l l f o u r f i g u r e s , f re q u e n c y p e r c e n t I s
p l o t t e d on th e a b c l s s a a n d th e oxygen t e n s i o n , I n m i l l i m e t e r s o f m erc u r y , i s p l o t t e d on th e o r d i n a t e .
A l l o i^ g e n t e n s i o n e x p e rim e n ts
em ployed tu m o rs w ith a d ia m e te r betw een
8
to
1 0
mm*
F ig u r e 12 shows t h e r e s u l t s o f a s e r i e s o f e x p e rim e n ts e x a m in in g th e
d i s t r i b u t i o n o f oxygen t e n s i o n i n tum or t i s s u e .
The m ice u se d i n t h i s
s e r i e s w ere b r e a t h in g co m p ressed a i r flo w in g a t a r a t e o f 5 l i t e r s /
m in u te s .
T h is f i g u r e g e n e r a l l y shows t h a t th e m a j o r it y o f th e
v a lu e s o b ta in e d w ere a t t h e low end o f th e oxygen s c a l e .
A c tu a lly more
t h a n 1 /3 o f o b s e r v a t io n s a r e fo u n d t o be a t l e s s th a n 4mm Hg a n d t h e r e a r e
l e s s th a n 5% o f th e o b s e r v a t i o n s ab o v e 17mm Hg.
A h is to g r a m show ing t h e r e s u l t s f o r oxygen b r e a t h in g w ith o u t
h y p e rth e rm ia i s shown I n F ig u re 1 3 .
th o s e o f F ig u re 1 4 .
T hese r e s u l t s a r e c o m p a ra b le t o
A g a in , a p p ro x im a te ly 1 /3 o f th e o b s e r v a t io n s
r e c o r d l e s s th a n 4 mm Hg a n d t h e r e a r e l e s s th a n 5X o f v a lu e s a b o v e
17mm Hg.
A lth o u g h oxygen b r e a t h in g d id n o t s i g n i f i c a n t l y change
AIR BREATHING - NO HEAT
N*8
OBSERVATIONS * 546
F
R
E
Q
U
E
N
C
Y
7.
1
1
i
I
I
3 -1 0
3 -4
7 -8
OXYGEN PRESSURE
I
1 3 -1 4
1 1 -1 2
21-22
1 7 -1 8
1 5 -1 6
1 9 -2 0
2 3 -2 4
M ILLIM ETERS OF MERCURY
F ig u re 12 The fre q u e n c y o f o c c u re n c e o f oxygen p a r t i a l p r e s s u r e m easurem ents I n a i r b r e a t h ­
in g CjH mouse m a lig n a n t t i s s u e (MCa) (w ith o u t h y p e rth e rm ia ) . N i s th e t o t a l number o f m ice
u sed t o o b ta in 546 o b s e r v a tio n s .
t h e h is to g r a m t h e r e a r e a few m ore v a lu e s i n Che 5~lUmm Hg
ra n g e .
80
T h is s h i f t may n o t be l a r g e enough to be s i g n i f i c a n t i n
a f f e c t i n g tum or r e s p o n s e b e c a u se o f t h e l a r g e num ber o f m easu red oxygen
r e a d in g s below 4mm Hg.
F ig u r e 14 shows t h e r e s u l t s f o r a s e r i e s o f e x p e rim e n ts em p lo y in g
40*0 h y p e rth e rm ia d u r in g a i r b r e a t h i n g .
T h ese d a ta f o llo w F ig u r e 13
q u i t e w e l l w ith a n o t h e r s m a ll s h i f t f u r t h e r t o t h e ' r i g h t ( h ig h e r oxygen
ra n g e ).
A lth o u g h i t i s s m a l l, th e p r o g r e s s io n t o th e r i g h t i s e v id e n t
when F ig u r e s 1 2 ,1 3 ,1 4 a r e com pared*
F ig u re 14 show s t h a t t h e r e a r e
s l i g h t l y more th a n 5Z o f th e m easured v a lu e s ab o v e 17mm Hg a n d a c t u a l l y
a r e o b s e r v a t io n s fo u n d i n t h e 21-22rara Hg ra n g e .
F ig u r e 15 shows t h e o ^ g e n t e n s i o n i n m a lig n a n t t i s s u e when oxygen
b r e a t h i n g i s com bined w ith (4 0 * 0 ) h e a t i n g .
I t i s o b v io u s when F ig u re 15
is
com pared to F ig u r e s 1 2 ,1 3 , a n d 14 c h a t t h e r e i s a f u r t h e r s h i f t to
che
r i g h t ( h i g h e r oxygen c o n c e n t r a t i o n ) .
b re a th in g
v a lu e s
A c t u a l l y , w ith oxygen
d u r in g 40*0 h y p e r th e r m ia , t h e r e a r e o n ly 2,5% o f che m easured
below 4 mm Hg.
A g a in , t h e r e a r e a l s o v a lu e s fo u n d i n th e
21-22mm Hg r a n g e .
T h ese d a ta i n d i c a t e t h a t 40*0 h y p e rth e rm ia a l o n e c a n have a n e f f e c t
on th e tu m o r o x y g e n a tio n s t a t u s b u t 40*0 h y p e rth e rm ia w h ile b r e a t h in g
oxy g en h a s a n ev e n l a r g e r e f f e c t , (when co m p arin g F ig u r e 15 t o F ig u re
1 4 ).
T hese d a ta may p o i n t t o a p o t e n t i a l Im provem ent f o r r a d i a t i o n
th e ra p y .
O verlyin g jjkin R e a c tio n
I n a n y i n v e s t i g a t i o n i n t o tum or r e s p o n s e t o a new com bined th e r a p y
(co m b in ed w i t h r a d i a t i o n ) , t h e r e a c t i o n o f t h e s u r r o u n d in g n orm al t i s s u e
m u st be o b s e rv e d ,
b a s i c a l l y , t h i s i s due to th e d e s t r u c t i v e e f f e c t s o f
OXYGEN BREATHING 48
NO HEAT
N «4
OBSERVATIONS « 4 3 0
■
32F
R
E
Q
U
E
N
C
Y
24-
16-
*
8
B
-
T
0 -2
jc m .
T
5 -6
1
3 -4
7 -8
OXYGEN PRESSURE
9 -1 0
rm
JQjD.
T
T
' 1 3 -1 4
1 7 -1 8
2 1 -2 2
1 1 -1 2
1 3 -1 6
1 9 -2 0
2 3 -2 4
HILLIM ETER S OF MERCURY
F ig u re 13 The fre q u e n c y o f o c c u re n c e o f oxygen p a r t i a l p r e s s u r e m easurem ents i n oxygen b r e a t h ­
in g C3H mouse m a lig n a n t t i s s u e (MCa) (w ith o u t h y p e rth e rm ia ) . H i s th e t o t a l number o f m ice used
t o o b ta in 430 o b s e r v a tio n s .
AIR BREATHING - 40 C HYPERTHERMIA
N»7
OBSERUATIOHS - 331
F
R
E
0
U
E
H
C
Y
%
cm m 3
im
T
3 -6
3 -4
9 -1 0
7 -8
OXYGEN PRESSURE
1 3 -1 4
1 1 -1 2
1 7 -1 8
1 5 -1 6
2 1 -2 2
1 9 -2 0
2 3 -2 4
H IL L IH E T E R S OF NERCURY
F ig u re 14 The fre q u e n c y o f o c c u re n c e o f oxygen p a r t i a l p r e s s u r e m easurem ent In a i r b r e a t h ­
in g CsK mouse m a lig n a n t t i s s u e (MCa) d u rin g 40°C h y p e rth e rm ia . N i s th e t o t a l number o f m ice
used t o o b ta in 331 o b s e r v a tio n s .
OXYGEN BREATHING -
4 0 C HYPERTHERMIA
N -6
OBSERMATIONS -
317
48
32 F
R
E
Q
U
E
N
C
Y
24-
16-
%
8
0
-
I
m
T
1
0 -2
5 -6
3 -4
7 -8
OXYGEN PRESSURE
. T
9 -1 0
1
1 1 -1 2
rm ITI1 tm
I
1 3 -1 4
I1
T
I
1 7 -1 8
1 5 -1 6
2 1 -2 2
1 9 -2 0
T
2 3 -2 4
M ILLIM ETERS OF MERCURY
F ig u re 15 The fre q u e n c y o f o c c u re n c e o f oxygen p a r t i a l p r e s s u r e m easurem ents i n oxygen b r e a t h ­
in g C3 H m a lig n a n t t i s s u e (MCa) d u rin g 40°C h y p e rth e rm ia . N i s th e t o t a l number o f m ice used
to o b ta in 3 1 7 o b s e r v a tio n s .
84
r a d i a t i o n a lo n e b u t In a combined th e r a p y t h i s norm al t i s s u e r e a c ti o n
may be enhanced*
T a b le s 14 a n d 15 exam ine w h e th e r 40°C h y p e rth e rm ia
d u r in g v a r i o u s d o se s o f r a d i a t i o n s i g n i f i c a n t l y i n c r e a s e s th e norm al
t i s s u e r e a c t i o n compared to r a d i a t i o n alo n e *
The sy ste m employed to exam ine th e o v e r ly in g s k in r e a c t i o n I s shown
I n T a b le 13 a n d d is c u s s e d In th e I n tr o d u c tio n *
T h is sy ste m was employed
t o compare th e norm al t i s s u e r e s p o n s e to Che f o u r e x p e rim e n ta l t h e r a p ie s
1) 40°C h y p e rth e rm ia d u r in g I r r a d i a t i o n w ith oxygen b r e a t h in g , 2) oxygen
b r e a t h in g d u r in g I r r a d i a t i o n , 3) 40°C h y p e rth e rm ia d u r in g I r r a d i a t i o n
w ith a i r b r e a th in g and 4 ) a i r b r e a th in g d u rin g I r r a d i a t i o n *
P r e lim in a r y e x p e rim e n ts (u n p u b lis h e d r e s u l t s ) c o n d u c te d a t R osw ell
P a rk M em orial I n s t i t u t e i n d i c a t e d t h a t th e t o t a l r e a c ti o n o f th e norm al
a n d m a lig n a n t t i s s u e s to h y p e rth e rm ia and r a d i a t i o n was a f f e c t e d by th e
method o f lim b r e s t r a i n t *
Those e x p e rim e n ts s u g g e s te d t h a t m inim al
im m o b iliz a tio n o f th e lim b was th e o n ly method t h a t would n o t cau se
c i r c u l a t o r y o c c u lu s io n i n th e lo w e r lim b .
D u rin g most n o n h y p e rth e rm ic
t r e a t m e n t s , m aximal r e s t r a i n t would n o t a f f e c t th e lo w e r lim b s , b u t
h e a ti n g th e tum or volume (w hich i s o v e rla y e d w ith norm al t i s s u e ) red u ced
t h e a b i l i t y o f th e a n im a l to remove th e h e a t from th e o c c lu d e d a r e a
an d below*
T h is o c c lu s io n le a d to th e e v e n tu a l lo s s o f th e lim b o r
" u n a c c e p ta b le norm al t i s s u e dam age".
T a b le 14 exam ines th e tim e i t ta k e s to re a c h th e maximum s k in s c o re
a t e a ch dose l e v e l .
The dose o f r a d i a t i o n ( i n r a d s ) i s shown i n th e f a r
l e f t hand colum n and e a c h tr e a tm e n t I s shown I n th e colum ns a d ja c e n t to
th e dose colum n.
The ty p e o f tr e a tm e n t I s s c h e m a tic a lly r e p r e s e n te d by
(tb+Oj) f o r 40°C h e a t p lu s oxygen b r e a t h in g , (O 2 ) f o r oxygen b r e a t h in g ,
(fi + a i r ) f o r 40°C h e a t p lu s a i r b r e a th in g and ( a i r ) f o r a i r b r e a th in g .
85
S k in S co re System
0 .5
S l i g h t e p i l a t i o n * s l i g h t edem a, l e g and f o o t o n ly s l i g h t l y
e n la r g e d , n o t s i g n i f i c a n t l y d e v ia n t from n o rm al.
1 .0
M ild e p i l a t i o n , m ild edema l e g and f o o t o n ly , some e n la rg e m e n t
o v e r norm al
1 .5
M oderate e p i l a t i o n , up to a p p ro x im a te ly h a l f o f th e i r r a d i a t e d
a re a .
2 .0
M oist d e sq u a m a tio n , s l i g h t , l e s s th a n 10Z o f che exposed lim b .
2 .5
M oist d e sq u a m a tio n , m o d e ra te , up to one q u a r t e r o f th e exposed
lim b in v o lv e d , s m a ll sc a b p r e s e n t .
3 .0
M oist d e sq u a m a tio n , m a jo r, a m ajor p o r tio n o f th e exposed lim b
in v o lv e d , s m a ll sc a b p r e s e n t .
3 .5
L arge s c a b p r e s e n t , tum or p r o tr u d in g th ro u g h s k in hem m oraglc, f o o t
e x tre m e ly a d e m a to u s.
T a b le 13 N um erical S k in S core System u sed f o r th e d e te r m in a tio n o f n o r­
m al t i s s u e r e a c t i o n f o r th e f o u r t h e r a p i e s , 1) 40°C h e a t (A) + 0?
b r e a t h in g 2) O2 b r e a t h in g 3) 40°C h e a t (A) + a i r b r e a th in g and 4 ) a i r
b r e a t h in g d u rin g v a r io u s d o ses o f r a d i a t i o n .
86
A ls o , i t i s im p o r ta n t t o n o te t h a t th e d o s e s o f r a d i a t i o n a r e g iv e n con­
c o m ita n tly w ith th e ty p e o f t r e a tm e n t.
The num bers shown i n T a b le 14
a r e th e mean tim e s ( i n d a y s ) i t to o k to r e a c h che maximum s k in s c o re +
t h e s ta n d a r d d e v i a t i o n .
T a b le 14 i n d i c a t e s t h a t th e r e i s no s i g n i f i c a n t
d i f f e r e n c e i n th e tim e o f th e o n s e t o f th e maximum s k in s c o re w ith in
e a c h r a d i a t i o n d ose g ro u p .
G e n e r a lly , a s th e d o se o f r a d i a t i o n
i n c r e a s e s , th e tim e to th e maximum s k in s c o r e d e c r e a s e s (fro m approxim a­
t e l y 21 days t o a p p ro x im a te ly 17 d a y s ) .
T a b le 15 shows th e maximum s k in s c o re w ith r e s p e c t t o dose o f
r a d i a t i o n and ty p e o f c o n c o m ita n t tr e a tm e n t.
Both th e d o se s o f
r a d i a t i o n and ty p e s o f c o n c o m ita n t tr e a tm e n t a r e th e some a s i n T a b le
14.
The num bers to th e r i g h t o f th e colum n o f r a d i a t i o n d o se s a r e
t h e mean
maximum s k in s c o r e a n d s ta n d a r d d e v i a t i o n .
A gain, T a b le 15,
l i k e T a b le 1 4 , shows t h a t t h e r e i s no s i g n i f i c a n t d i f f e r e n c e s i n th e
mean maximum
s k in s c o re w ith e a ch r a d i a t i o n d o se g roup but a s th e d o se
o f r a d ia tio n
i n c r e a s e s th e mean maximum s k in r e a c t i o n a l s o I n c r e a s e s .
In g e n e r a l , T a b le s 14 an d 15 d e m o n s tra te two p o i n t s .
The f i r s t ,
a lr e a d y w e ll known, i s t h a t a s Che d o se o f r a d i a t i o n I n c r e a s e s th e
amount o f norm al t i s s u e ( o v e r ly in g s k in ) damage I n c r e a s e s .
S e c o n d ly ,
and more im p o r ta n t f o r t h i s w ork, i s t h a t th e r e i s no s i g n i f i c a n t d i f ­
f e r e n c e i n th e norm al t i s s u e re s p o n s e betw een th e d i f f e r e n t t r e a tm e n ts ,
( i . e . , 4U°C h y p e rth e rm ia d oes
n o t i n c r e a s e th e norm al t i s s u e damage o r
m odify th e tim e c o u rs e o f i t s
re sp o n se ).
Tumor R esponse to Combined H eat (4U"U) a n d I r r a d i a t i o n
T h is s e r i e s o f e x p e rim e n ts a tte m p ts t o exam ine th e combined
e f f e c t s o f 4U°C h y p e rth e rm ia an d c o n c o m ita n t i r r a d i a t i o n on tum or g row th
87
Mean Time to Maximum S kin S core
Dose
T re a tm e n t
A + 02
3500
2 1 . 2
3750
2 1 . 0
4000
2 3 .0
+ 3 .3
02
A + A ir
2 1 . 2
± 3 .3
2 1 . 2
4-
4 .0
2 3 .0
X
3 .4
2 2 .3
X
3 .5
2 1 . 0
X
3 ,5
2 1 . 2
4250
2 1 .7 4- 3 .0
2 0 . 6
4500
1 8 .8 +■
2 . 6
2 0 . 6
4750
1 9 .6
-
2 .9
5000
1 9 .6
X
5250
2 1 .3
4-
5500
17.1
X
5750
18 .4
X
6000
1 6 .8
x
A ir
x
3 .3
2 0 . 8
± 3 .0
x
2 .3
2 0 . 0
r 1 .7
X
3 .2
2 2 .5 ± 5 .7
-
2 . 1
2 0 . 6
X 3 .6
1 9 .0
4*
3 .2
2 1 .7
x
2 .7
1 7 .2 =
1 . 6
1 9 .6
X
2 .9
1 6 .6
4-
3 .4
1 9 .2 =
1 . 6
2 .5
2 0 .5
X
1 .7
1 9 .6
X
2 .5
1 9 .5 = 1 .7
0 .5
I6
4.
3 .6
1 9 .0
4.
2 .4
16.2 ± 4 .4
2 , 0
1 8 .5
4>
2 .4
1 8 .5
X
2 . 2
17.9 i 2 .4
1 . 8
18.6
4.
3 .2
1 7 .7
X
2 .4
1 7 .0 = 2 .4
4 .7
17.2
X
5 ,0
1 6 .8
X
4 .7
1 6 .8 = 4 .7
. 0
± 3 .6
Table 14
This ta b le shows the mean tim e to reach th e maximum sk in s c o r e
( i n d a y s) f o r th e f o u r t h e r a p i e s 1) 40*C h e a t (A) + O2 b r e a t h in g 2) Qj
b r e a th in g 3) 40 ®C h e a t (A) + a i r b r e a th in g and 4) a i r b r e a t h in g d u r in g
v a r io u s d o s e s o f r a d i a t i o n . The d o s e i s i n r a d a .
88
Mean Maximum Skin S core
Dose
T re a tm e n t
. A +
°2
A + A ir
°2
A ir
3500
1 .7 ±
0 .6
1 .7 ±
0 .3
1 .6 +
0 .2
1 .6 ±
0 .2
3750
2 .2 ±
0 .3
1 .7 ±
0 .3
2 .2
0 .6
1 .8 ±
0 .3
4000
2 .2 ±
0 .3
2 .2 ±
0 .5
2 .0
0 .0
1 .9 *
0 .2
4250
2 .2 ±
0 .3
2 .1 ±
0 .4
2 .1
0 .4
2 .0 ±
0 .0
4500
2 .3 ±
0 .3
2 .3 ±
0 .3
2 .4
0 .2
2 .0 ±
0 .0
4750
2 .3 ±
0 .4
2 .1 ±
0 .4
2 .2
0 .4
2 .1 ±
0 .2
5000
2 .4 ±
0 .4
2 .5 ±
0 .4
2 .5
0 .5
2 .2 ±
0 .3
5250
2 .4 ±
0 .5
2 .2 ±
0 .3
2 .5
0 5
2 .0 ±
0 .3
5500
2 .4 ±
0 .3
2 .2 ±
0 .2
2 .2
0 .3
2 .1 ±
0 .2
5750
2 .6 ±
0 .2
2 .3 ±
0 .7
2 .6 +
0 .2
2 .2 ±
0 .3
6000
•2.3 ±
0 .3
2 .3 ±
0 .3
2 .4
0 .2
2 .6 ±
0 .2
J.
T a b le 15
T h is t a b l e shows th e mean maximum s k in s c o r e (T a b le 13) for
che f o u r t h e r a p i e s 1 ) 40 °C h e a t (a ) + 0% b r e a t h in g 2) O2 b r e a t h in g
3) 4 0 °C h e a t (A) + a i r b r e a th in g and 4 ) a i r b r e a t h in g d u r in g v a r io u s
d o s e s o f r a d i a t i o n . The d o se I s I n r a d s .
89
i n v iv o .
The t r e a tm e n ts exam ined a r e i d e n t i c a l t o th o s e
p r e v i o u s ly m en tio n e d i n th e r e s u l t s o f th e s t u d i e s on n orm al t i s s u e
re s p o n s e *
B r i e f l y , t h e f o u r tr e a tm e n ts a r e :
d i a t i o n , w ith oxygen b r e a t h i n g ,
2
1 ) 40°0 h e a t d u r in g i r r a ­
) oxygen b r e a th in g d u r in g i r r a d i a t i o n ,
3) 4U°C h e a t d u r in g i r r a d i a t i o n w ith a i r b r e a t h in g a n d f i n a l l y , 4 ) a i r
b r e a t h in g d u r in g i r r a d i a t i o n .
I n a l l o f th e s e e x p e rim e n ts t h e r e a r e
fro m 3 t o U a n im a ls a t e v e ry p o in t*
The raw d a ta (tu m o r d im e n s io n a l
c h a n g e s ) w ere f e d i n t o th e i n s t i t u t i o n a l co m p u ter (I.B .M .
3611) a n d
p l o t t e d w ith th e u s e o f S A S/graph p ro g ram .
U e n e r a l ly , F ig u re lb i s a p l o t o f tum or r e s p o n s e t o h e a t a lo n e and
F ig u r e s 17-21 a r e p l o t s o f tum or r e s p o n s e t o c o n c o m ita n t h e a t and
v a r i o u s d o s e s .o f i r r a d i a t i o n *
I n a l l o f th e s e f i g u r e s , volum e ( i n mnr^
i s p l o t t e d on t h e a b s c i s s a an d tim e ( i n d a y s ) a f t e r t r e a tm e n t i s p l o t t e d
on th e o r d in a te *
U e n e r a l ly , F ig u r e s 22 a n d 23 a r e d o se re s p o n s e c u rv e s*
T h e se c u rv e s a r e p l o t s o f th e tim e ( i n d a y s ) t h a t i t to o k e a c h a n im a l
t r e a t e d to r e a c h a volum e o f 1437 mar*
t h r e e d im e n s io n s
r a d s ) on a b s c i s s a .
( o r 14 mm d ia m e te r m easu red i n
x f T /b ) on th e o r d i n a t e v e r s u s t h e d o se o f r a d i a t i o n ( i n
In a l l o f th e f i g u r e s m e n tio n e d i n t h i s s e c t i o n o f
t h e " R e s u lts " t h e s o l i d l i n e s p l o t t e d w ere f i t by c o m p u ter u s in g q u a d ra ­
t i c re g re s s io n a n a ly s is .
F ig u r e l b shows th e r e s u l t s o f 4U°C h e a t w ith o u t a n y r a d i a t i o n
th e r a p y on t h e l o c a l c o n t r o l o f th e I m p la n te d mouse tum or i n th e l e g o f
e a c h a n im a l.
F ig u re l b shows t h a t t h e r e i s no s i g n i f i c a n t r e s p o n s e i n
term s o f g ro w th d e la y , when 4U°c m icrow ave h e a ti n g i s u se d w ith o u t any
r a d ia tio n th e ra p y .
F u th e rm o re , when F ig u r e l b i s com pared t o F ig u re 1
(tu m o r g ro w th c u r v e , M a t e r i a l s a n d M ethods) i t i s c l e a r l y e v id e n t t h a t
t h e r e i s a lm o s t no d i f f e r e n c e betw een Che two c u r v e s , i n d i c a t i n g c h a t
h e a t (4U"C) a lo n e does n o t g r e a t l y a f f e c t g row th of th e tum or.
T h is
c o m p ariso n shows t h a t any re s p o n s e (40°C m icrow ave h e a tin g and v a r io u s
d o s e s o f r a d i a t i o n ) I s due t o th e I r r a d i a t i o n p lu s h e a t o r I r r a d i a t i o n
a lo n e b u t n o t t o th e h e a t a lo n e .
F ig u r e s 17—21 show th e r e s u l t s o f a s e r i e s o f e x p e rim e n ts ex am in in g
t h e e f f e c t s o f h e a t and c o n c o m ita n t i r r a d i a t i o n on th e grow th o f
im p la n te d tu m o rs.
th e c u r v e s .
These f i g u r e s a r e r e p r e s e n t a t i v e o f a l l 12 o f
In a l l c a s e s th e open c i r c l e s and d a sh ed l i n e s a r e f o r th e
t r e a tm e n t, 4U°C h e a t w h ile th e mouse was b r e a th in g oxygen, th e s o l i d
c i r c l e s a n d s o l i d l i n e s a r e f o r th e tr e a tm e n t o f oxygen b r e a th in g a lo n e ,
t h e open s q u a re s and " d a sh d o t" l i n e s a r e r e p r e s e n t a t i v e o f 4l)°C h e a t
w h ile th e mouse was b r e a th in g a i r and th e s o l i d s q u a re s a n d d o t te d l i n e s
a r e f o r th e tr e a tm e n t o f a i r b r e a th in g a lo n e .
A ll o f th e above men­
t io n e d t r e a tm e n ts r e c e iv e a ra n g e o f r a d i a t i o n d o se s ( s i n g l e f r a c t i o n )
from 3UUU r a d s to bUUU r a d s .
I n a l l c a s e s th e e x p e rim e n ts w ere t e r ­
m in a te d when th e volume o f th e tum or a p p ro a c h e d 2UUU mnr*.
T h is volume
was ch o sen so aB t o l i m i t th e d is c o m fo r t o f th e tum or b e a rin g a n im a l.
T hese d a ta show a r a t h e r w ide v a r i a t i o n i n th e g row th p a t t e r n s a f t e r
th e s p e c i f i c tr e a tm e n t.
T hese d a ta can be e x p la in e d by c o n s id e r in g th e
i n h e r e n t random re s p o n s e o f tum ors to any form o f th e r a p y .
The f i r s t
h a l f o f th e m easurem ents i n e a c h f i g u r e a r e r e l a t i v e l y c lo s e i n term s o f
i n c r e a s i n g volum e, b u t a s some o f th e tum ors i n c r e a s e i n s i z e a n d a r e
to o ^ g e n b r e a th in g d u r in g i r r a d i a t i o n a lo n e .
a c o n s is te n t In c re a se a c ro s s a l l of
F u rth e rm o re , t h e r e i s
th e d o se p o i n t s .
F ig u re 23 shows t h a t th e tr e a tm e n t of 4U“C h e a t d u rin g i r r a d i a t i o n
w ith a i r b re a c h in g (open s q u a r e s , d ash ed l i n e ) a l s o g iv e s a d e la y i n th e
tim e i t ta k e s to g e t to th e s p e c i f i e d volume (1437 mm^) when compared
TUMOR RESPONSE40*c Heat for 30 min
19001800-
91
170016001500140013001200 11001000900800S 7004 0 c h e a t a lo n e for 30 m ins
§600500400300200-
100-
20
50
Time (in d a y s )
F ig u re 16 Tumor r e s p o n s e to 40°C h e a t a l o n e . The tum or b e a r in g
m ice w ere t r e a t e d when t h e tum or d ia m e te r was a p p ro x im a te ly 7mm.
TUMOR RESPONSE 3000 rads
1300-
1400-
E taoo1100£ 1000_ O 4 0 * C H e a t d u ring Irra d ia tio n w ith o x y g en b re a th in g
_ • O x y g en b re a th in g d u rin g I r r a d ia tio n
. - a 4 0 * C H e a t d u rin g ir r a d ia tio n w ith a ir b r e a t h in g
. . ■ A i r b r e a th in g d u rin g Irra d ia tio n
"si
60
7S"
T
so
T
100
T
110
T
120
TIME flndays)
F ig u r e 17 Tumor re s p o n s e 3000 r a d s . The tum or b e a r in g m ice w ere t r e a t e d when th e tum or
d ia m e te r was a p p ro x im a te ly 7mm. T hese d a ta in c lu d e a n im a ls t h a t d ie d p re m a tu re ly from
m e t a s t a t i c c o m p lic a tio n s .
TUMOR RESPONSE 4000 rads
1500-
uj
1000-
500-
ab
—O 40*C H e a t d u rin g ir r a d ia tio n w ith o x y g en b re a th in g
• O x ygen b re a th in g d u rin g ir r a d ia tio n
— □ 40*C Heat during Irradiation w ith air breathing
..■ A ir breathing during Irradiation
0 - ______
TIME
(in
days)
F ig u re 18 Tumor r e s p o n s e 4000 r a d s . The tum or h e a r in g m ice w e re t r e a t e d when t h e tum or
d ia m e te r was a p p ro x im a te ly 7mm. T hese d a ta in c lu d e a n im a ls t h a t d ie d p re m a tu re ly from
m e t a s t a t i c c o m p lic a tio n s .
TUMOR RESPONSE 4500 rads
2000-1
1500-
.
•*o
o 4 (J* cH eat during irra d ia tio n w ith
oxygen b r e a t h in g
• O x y g e n b re a th in g d irin g I r r a d ia t io n
500-
i - . —0 40*c H e a t d u rin g Irra d ia tio n w ith
a ir b re a th in g
. . . . J A Ir breathing during Irradiation
D »I 0 I 0
0
- •
TIME (in days)
F ig u r e 19 Tumor re s p o n s e 4500 r a d s . The tum or b e a r in g m ice w ere t r e a t e d when t h e tum or
d ia m e te r was a p p ro x im a te ly 7mm. T hese d a ta in c lu d e a n im a ls t h a t d ie d p r e m a tu r e ly from
m e t a s t a t i c c o m p lic a tio n s .
TUMOR RESPONSE 5250 rads
2000-1
O. II
1500-
CJ
6
E
-\
c
ui
S
3
-I
O
1000-
d
**
•
U *
/
•
° 0
/
>
/
■ i
“
%s
/
/
/
o
/
q
o
/
/ ' ■ — - — O40*c H eat d u rin g irra d ia tio n w ith
oxygen b re a th in g
•O xygen b re a th in g d u ring irra d ia tio n
X
y
□
Sa
8 A
• V /
/
o
D
*
H40*c H eat d u rin g Irrad iatio n w ith
a ir breathing
u 0
■A ir b re a th in g d u rin g ir r a d ia tio n
o o
500-
a
.P W r tm y s
Q
. ■
0 B
o
iS
2S
3S
S
si
eS
7S
e5
U
eJ
10S
iiX
i3 T
TIME (in d a y s)
F ig u re 20 Tumor re s p o n s e 5250 r a d s . The tum or b e a r in g m ice v e r e c r e a te d when t h e tum or
d ia m e te r was a p p ro x im a te ly 7mm. T hese d a ta In c lu d e a n im a ls t h a t d ie d p re m a tu re ly from
m e t a s t a t i c c o m p lic a tio n s .
TUMOR RESPONSE 5500 rads
a 4 0 c H e a | during irradiation
with a ir breathing
~ ._ 0 4 0 'c Heat during irradiation
with oxygen breathing
eOxygen breathing during
irradiation
■ Air breath in g during
irradiation
1500-
1000-
500-
a
3 . a
i» «
•
o °
.
D I _Jui - _
“ . ' I 0 %8 g oou ° '
oO
1°“'H
oO
o-
10
TIME (in days}
F ig u re 21 Tumor re s p o n s e 5500 r a d s . The tum or b e a r in g m ice w ere t r e a t e d when t h e tum or
d ia m e te r was a p p ro x im a te ly 7mm. T hese d a ta in c lu d e a n im a ls t h a t d ie d p re m a tu re ly from
m e t a s t a t i c c o m p lic a tio n s .
Co a i r b r e a c h in g d u r in g lr r a d ia C l o n ( s o l i d s q u a r e s , s o l i d l in e ) *
T re a t­
m ent 3 , (40®C) h e a t d u r in g I r r a d i a t i o n w ith a i r b r e a t h in g a t th e h ig h e r
r a d i a t i o n d o se s a p p a r e n tl y has a lo n g e r grow th d e la y tim e th a n t r e a t ­
m ent l t 40°C h e a t d u r in g i r r a d i a t i o n w ith oxygen b r e a t h in g , F ig u re 22.
T h is d i f f e r e n c e i s q u i t e s m a ll ( l e s s th a n 10 d a y s ) and p ro b a b ly n o t
s ig n ific a n t.
The d i f f e r e n c e i n th e i n i t i a l s lo p e betw een tr e a tm e n t 1,
F ig u re 22 and tr e a tm e n t 3 , F ig u re 23 may be d e p e n d en t upon th e tim e o f
e x p o su re to h e a t .
F o r e x am p le, a t th e low dose en d , th e e x p o su re to
h e a t i s l e s s th a n 15 m in u tes and maybe th e mouse b r e a th in g oxygen
tr e a tm e n t can g e t more oxygen i n t o th e h e a te d t i s s u e f a s t e r th a n th e
mouse b r e a t h in g a i r ( tr e a tm e n t 3 ) .
T h is c o u ld p o s s ib ly e x p la in why
tr e a tm e n t 3 seem s t o g e t more e f f e c t i v e a s th e d ose o f r a d i a t i o n
I n c r e a s e s a f t e r a p p ro x im a te ly 4000 r a d s .
I t i s im p o rta n t to n o te a g a in
Chat th e h e a t i s o n ly g iv e n f o r a s h o r t tim e b e fo r e and d u rin g le n g th
o f th e i r r a d i a t i o n , so a s th e d ose I n c r e a s e s th e le n g th o f tim e o f
h e a ti n g a l s o i n c r e a s e s .
G e n e r a lly , F ig u re s 22 and 23 d e m o n s tra te t h a t 4 0 “C h e a tin g d u r in g
i r r a d i a t i o n w ith e i t h e r oxygen b r e a th in g o r a i r . b r e a th in g a r e more
e f f e c t i v e t h e r a p i e s th a n e i t h e r i r r a d i a t i o n w ith a i r b r e a th in g o r oxy­
gen b r e a th in g w ith o u t h e a t .
F u rth e rm o re , oxygen does ( t o a s m a ll
e x t e n t ) a f f e c t th e outcom e o f th e c o n c o m ita n t th e r a p y .
D is c u s s io n
T h is s tu d y has u sed m icrow ave e n e rg y d e p o s it io n a s a method to
p ro d u ce m ild (40°C ) h y p e rth e rm ia i n mouse tum ors and to i n v e s t i g a t e
w h e th e r th e s e h y p e rth e rm ic te m p e ra tu re s a f f e c t tum or o x y g e n a tio n and
r e s u l t a n t re s p o n s e t o c o n c o m ita n t h e a t and i o n iz in g r a d i a t i o n .
Dose Response
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F ig u re 22
Dose re sp o n se to concom itant 40SC h e a t and r a d i a ti o n d u rin g oxygen b r e a th in g .
Dose R esponse
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F ig u re 23
Dose re sp o n se co con co m itan t 40°C h e a t and r a d i a t i o n d u rin g a i r b r e a th in g .
VO
VD
One o f th e m ost im p o r ta n t a s p e c t s o f h y p e rth e rm ia a t an y tem p e r a t u r e i s th e d i s t r i b u t i o n o f te m p e ra tu re w i t h in th e h e a te d volume*
A lth o u g h t h i s i s b a s i c a l l y d e p e n d e n t upon th e n a t u r e o f th e m icrow ave
e q u ip m e n t, i t s t i l l m ust be exam ined i n th e i n v iv o system *
T h is w ork
exam ined two b a s i c a s p e c t s o f te m p e r a tu r e d i s t r i b u t i o n a t 40°C .
The
f i r s t a s p e c t was t h e d i s t r i b u t i o n o f te m p e r a tu r e I n two p la n e s i n n orm al
a n d m a lig n a n t t i s s u e s d u r in g m icrow ave h e a t i n g .
S e c o n d ly i t was d e t e r ­
m ined w h e th e r a i r , a t 5 l i t e r s / m i n u t e , f lo w in g o v e r th e h e a d , c h e s t and
abdomen o f th e h e a te d a n im a l h a s a n e f f e c t on e i t h e r th e te m p e ra tu re
d i s t r i b u t i o n i n t h e h e a te d t i s s u e volum e o r t h e r e c t a l ( c o r e ) te m p e ra ­
tu re .
B a s i c a l l y th e s e d a ta show a maximum a v e r a g e te m p e r a tu r e d e v i a t i o n o f
+ 2 .5 ’ C f o r m u sc le t i s s u e an d a maximum a v e r a g e te m p e r a tu r e d e v i a t i o n
o f _+ 2 .0 °C f o r m a lig n a n t t i s s u e .
I t i s a l s o e v id e n t t h a t a i r c o o li n g ,
a t a flo w r a t e o f 5 l i t e r s / m i n u t e d oes n o t h av e a s i g n i f i c a n t e f f e c t
on r e c t a l ( c o r e ) te m p e r a tu r e .
On f i r s t g l a n c e , th e s e d a ta would su p ­
p o r t R o b in so n e t a l . ( 1 1 8 ) , a n d Denekamp e t a l . ( 1 1 9 ) , f o r w a te rb a th
h e a t i n g a n d c o n t r a d i c t o u r p r e v io u s w ork, ( 1 2 1 ) .
I n r e v ie w , R obinson
e t a l . ( 1 1 8 ) , an d Denekamp e t a l . ( 1 1 9 ) , found te m p e ra tu re g r a d i e n t s
a s l a r g e a s 1.3°C an d 2 . 0 eC r e s p e c t i v e l y w h ile H e tz e l e t a l . ( 1 2 1 ) ,
fo u n d no s i g n i f i c a n t v a r i a t i o n i n te m p e ra tu re f o r w a te r b a th h e a t i n g .
The o n ly d i f f e r e n c e s betw een th e d a ta p r e s e n t e d h e r e ( F ig u r e s 4 th ro u g h
1 1
) a n d o u r p r e v io u s w o rk , ( 1
2 1
) , a r e th e m ethod o f in d u c in g h y p e r t h e r ­
m ia and th e maximum te m p e r a tu r e s a llo w e d .
H e tz e l e t a l* ( 1 2 1 ) u se d a
te m p e r a tu r e maximum o f 43®C a n d w a te r b a th h e a t i n g , w h ile t h e p r e s e n t
w ork u se d a 40°C maximum an d m icrow ave h e a t i n g .
By com paring f i g u r e s
4 a n d 5 , one n o t i c e s t h a t th e random d i s t r i b u t i o n o f te m p e ra tu re i s
c o n s l s t a n t from te m p e r a tu r e maximum t o te m p e r a tu r e maximum*
In o t h e r
w ords t h e r e seem s t o be a s much v a r i a t i o n a t th e lo w e r h y p e rth e rm ic
te m p e r a tu r e s ( 3 4 “C) a s a t 40°C ( £ 2 . 5 QC and + 2 .0 °C r e s p e c t i v e l y ) *
T h e r e f o r e , th e maximum te m p e r a tu r e s c a n n o t e x p l a i n t h i s d i f f e r e n c e I n
t h e te m p e r a tu r e d e v i a t i o n I n t h e s e d a t a com pared t o o u r p r e v io u s d a t a .
H ence th e d i f f e r e n c e m ust be I n th e m ethod o f h e a t i n g .
The random d e­
v i a t i o n d i f f e r e n c e s s e e n i n t h e s e d a ta c a n o n ly be e x p la in e d by con­
s i d e r i n g t h e f a c t t h a t t h e e n e rg y d i s t r i b u t i o n p a t t e r n s o f m icrow ave
a p p l i c a t o r s a r e n o t u n ifo r m , t h e r e f o r e t h e h e a t i n g p a t t e r n s I n th e
h e a te d t i s s u e s w ould n o t be u n ifo rm *
S in c e th e h e a te d volum es (7mm i n
t h r e e o r th a g o n a l d im e n s io n s ) a r e s m a ll an d th e m icrow ave a p p l i c a t o r s
h a v e a som ew hat l a r g e r I r r a d i a t i n g s u r f a c e (3cm x 3cm) t h e r e I s th e
p o s s i b i l i t y o f n o t p l a c i n g th e volum e o f t i s s u e I n e x a c t l y th e same
p o s i t i o n e a c h tim e t h e e x p e rim e n t I s p e rfo rm e d .
T h e re fo re , in e x p e ri­
m en ts i n v o lv i n g s m a ll tu m o rs o f m ic e , w a te r b a th h e a t i n g may be more u s e ­
f u l i n p ro d u c in g h y p e rth e rm ia a lth o u g h f o r c o n c o m ita n t h e a t an d i o n i z i n g
r a d i a t i o n e x p e rim e n ts w a te r b a th h e a ti n g s w i l l n o t a ll o w good d o s im e try
a n d e n e rg y d e p o s i t i o n o f i o n i z i n g r a d i a t i o n .
A n o th e r r e s u l t t h a t s h o u ld be
u n ifo rm h e a t i n g i n b o th p la n e s
a d d r e s s e d i s th e a p p a r e n t l y more
( p a r a l l e l t o th e fem ur o r p e r p e n d ic u la r
t o t h e fem u r) f o r m a lig n a n t t i s s u e ( f i g u r e s
t o n o rm al t i s s u e ( f i g u r e s 4
8
th ro u g h
1 1
) , a s com pared
th ro u g h 7 ) . T hese d i f f e r e n c e s c o u ld
p o s s i b l y be e x p la in e d by th e d i f f e r e n c e s i n b lo o d flo w i n t h e s e two
ty p e s o f t is s u e s .
Song e t a l . h a s r e p o r t e d t h a t h e a t i n g (43°C -46°C )
t h e l e g o f r a t s c a u s e s i n c r e a s e d v a s c u l a r volum e a n d v a s c u l a r p re m e a b lllty
i n s k in a n d m u scle ( 7 4 ,7 5 ,6 2 ) w h ile Eddy a n d Emami e t a l . have
found a d e c re a s e i n tum or b lo o d flo w I n re s p o n s e to h y p e rth e rm ia
( 7 6 ,7 7 ,7 8 ) .
On th e o t h e r hand Song found no change i n h e a te d tumor
b lo o d flo w ( 7 5 ,6 2 ) and V aupel e t a l . a n d B lc h e r e t a l . have found an
i n c r e a s e i n tum or b lo o d flo w a t te m p e ra tu re s below
40°C ( 8 1 ,8 2 ) ,
A ll
o f th e s e r e s u l t s i n d i c a t e t h a t n orm al t i s s u e s seem t o be a b le t o d i f ­
f u s e th e h e a t more e a s i l y th a n m a lig n a n t t i s s u e and t h i s , i n i t s e l f ,
c o u ld p ro b a b ly e x p la in th e l a r g e r g r a d i e n ts i n te m p e ra tu re s e e n in
n orm al t i s s u e a s compared to m a lig n a n t t i s s u e .
A n o th e r a p p a r e n t d i f f e r e n c e betw een t h i s work and o u r p re v io u s work
( 1 2 1 ) , i s t h a t , I n th e s e d a t a , a i r c o o lin g does n o t s i g n i f i c a n t l y a f f e c t
th e c o re ( r e c t a l ) te m p e ra tu re w hereas i n o u r p re v io u s s t u d i e s ( 1 2 1 ) a i r
c o o lin g d id s u p r e s s c o re te m p e ra tu re I n c r e a s e .
The b a s ic d i f f e r e n c e In
th e s e two s e p a r a t e s t u d i e s was th e r a t e o f flo w o f c o o lin g a i r a c r o s s
th e mouse d u r in g h e a ti n g .
I n th e s e s t u d i e s th e r a t e o f flow was v ery
low (5 l i t e r s / m i n u t e ) , w h ile i n o u r p re v io u s work th e r a t e o f flo w was
much g r e a t e r a lth o u g h n o t m easured.
F i v e / l i t e r s m inute was c h o sen f o r
t h i s s e r i e s o f e x p e rim e n ts b e c au se t h a t was th e flow r a t e o f th e
oxygen t o th e mouse d u rin g th e s e r i e s o f e x p e rim e n ts ex am in in g i f AO°C
h y p e rth e rm ia has a n e f f e c t on t i s s u e o x y g e n a tio n s t a t u s .
oxygen
I f th e
flo w d e p re s s e d th e c o re te m p e ra tu re d u r in g th e oxygen con­
c e n t r a t i o n d e te r m in a tio n e x p e rim e n ts o r s i g n i f i c a n t l y a f f e c t e d th e
h e a te d t i s s u e te m p e ra tu re d i s t r i b u t i o n , th e n a l l o f th e h e a te d a i r
b r e a t h in g c o n t r o l s would have t o be c o o le d w ith com pressed a i r a s w e l l .
Our p re v io u s work (1 2 1 ) d e m o n stra te d t h a t th e r e c t a l te m p e ra tu re c o u ld
be c o n t r o l l e d t o some e x te n t th ro u g h th e u se o f a i r c o o lin g a t a v e ry
fast
flo w
ra te .
The d a ta i n t h i s s tu d y d e m o n s tra te s q u i t e c l e a r l y
103
C hat a i r
c o o lin g a t 5 l i t e r s / m i n u t e d o e s n o t a f f e c t th e c o re tem­
p e r a t u r e a n d d o e s n o t s i g n i f i c a n t l y change th e te m p e ra tu re d i s t r i b u t i o n
i n t h e h e a te d t i s s u e s .
A n o th e r f a c t o r t h a t I s im p o r ta n t I s th e m ethodology em ployed to
exam ine te m p e r a tu r e I n a h e a te d volum e.
Some i n v e s t i g a t o r s m easure
i n t r a t u m o r a l te m p e r a tu r e s w ith n e e d le ty p e m ic ro p ro b e s ( 1 2 7 ,1 2 8 ,4 7 ) .
W hile t h i s I s a v e ry u s e f u l and a c c u r a t e method t o m easure te m p e ra tu re
a t one p o i n t , one m ust k e e p i n mind two t h i n g s :
The f i r s t i s t h a t t h e r e
w i l l be a d i s t r i b u t i o n o f te m p e r a tu r e a ro u n d th e s i n g l e m easured v a lu e ,
b e i t a s m a ll v a r i a t i o n o r l a r g e v a r i a t i o n a s shown by t h i s work and by
o t h e r a u th o r s ( 1 2 1 ,1 1 8 ,1 1 9 ) ;
S e c o n d ly , H e tz e l e t a l ,
(1 2 1 )
p o in te d
o u t t h a t th e s e n s in g t i p o f t h e s e n e e d le th e rm o c o u p le s may n o t be e x a c t ­
l y a t th e t i p o f th e s t a i n l e s s s t e e l n e e d l e .
The c o p p e r c o n s t a n t l n
j u n c t i o n may f l o a t w i t h in th e n e e d le a n d may n o t be e x a c t l y a t th e t i p
o f t h e th e rm o c o u p le a n d t h e r e f o r e may n o t be i n c o n t a c t w ith th e t i s s u e
o f m ea su rem e n t.
The m ethodology em ployed i n t h i s work a n d i n th e p r e ­
v io u s w ork ( 1 2 1 ) a tt e m p t s t o c o n t r o l t h i s ty p e o f p ro b le m a n d exam ines
more th a n one p o i n t a t any i n s t a n t o f tim e .
I t i s im p o r ta n t t o n o te
t h a t a l l o f th e s i n g l e p o i n t t i s s u e te m p e r a tu r e m easu rem en ts i n t h i s
w ork w ere ex am ined a n d c o r r e c t e d f o r t h i s p ro b le m .
The c o r r e c t i o n was
c a r r i e d o u t by c l i p p i n g th e t i p o f th e n e e d le ( c a r r y i n g t h e th erm o co u p le
j u n c t i o n ) u n t i l th e j u n c t i o n was c l o s e r t o th e t i p
1
( w ith in a p p ro x im a te ly
mm).
The te m p e r a tu r e d i s t r i b u t i o n d a ta i n d i c a t e s t h a t m icrow ave h e a ti n g
te c h n iq u e s c a n b e em ployed t o e l e v a t e and m a in ta in tum or te m p e r a tu r e t o
i n v e s t i g a t e o t h e r h y p e rth e rm ia r e l a t e d b i o l o g i c a l r e s p o n s e s , su c h a s
t i s s u e o x y g e n a tio n .
As shown i n F ig u r e s 1 2 -1 5 , m icrow ave h y p e rth e rm ia
d o es h av e a n e f f e c t on tum or t i s s u e o x y g en atio n *
h is to g r a m s f o r b o th
0
I t I s c l e a r t h a t th e
)(ygen b r e a t h in g and a i r b r e a th in g a n im a ls d u rin g
4 0 8C h y p e rth e rm ia w ere s h i f t e d s l i g h t l y to th e h i g h e r end o f th e s c a l e
( i . e . , m ore i n t r a l e s l o n a l o x y g e n a tio n ).
T h is i n c r e a s e may be an im por­
t a n t f in d i n g f o r r a d i a t i o n th e r a p y b e c a u se o f th e oxygen e f f e c t .
B rie f­
l y s t a t e d , c e l l s t h a t a r e i r r a d i a t e d i n oxygen a r e more s e n s i t i v e to
r a d i a t i o n th a n h y p o x ic c e l l s .
I t h a s b e e n shown t h a t o n ly $ few mm Hg
i n c r e a s e i n oxygen te n s io n i s a l l t h a t I s n e c e s s a ry to i n c r e a s e r a d i a ­
t i o n s e n s i t i v i t y o f h y p o x ic t i s s u e a r e a s ( 1 0 0 ) .
So one c o u ld co n clu d e
t h a t 40°C h y p e rth e rm ia c o n c o m ita n t w ith r a d i a t i o n would i n c r e a s e th e
r a d i a t i o n s e n s i t i v i t y o f th e h e a te d t i s s u e s , w ith r e s p e c t to r a d i a t i o n
a lo n e .
F ig u re 22 a n d 23 do show a somewhat lo n g e r grow th d e la y f o r th e
two t h e r a p i e s com bining 4 0 aC h e a t w ith c o n c o m ita n t r a d i a t i o n th e r a p y .
The c o n te n tio n t h a t h y p e rth e rm ia ( 40°C) c a u s e s an i n c r e a s e i n tumor
t i s s u e o x y g e n a tio n h a s been s u p p o rte d by o t h e r g ro u p s u s in g o t h e r s y s ­
tem s a s w e ll a s t h i s tum or sy ste m ( 1 1 4 ,1 1 5 ,8 2 ) .
L ubbers e t a l . (12 9 )
h av e s t a t e d t h a t oxygen b r e a th in g a lo n e I s n o t s u f f i c i e n t to I n c r e a s e
l o c a l tum or o x y g e n a tio n and F ig u r e s 12 an d 13 show t h a t t h e r e i s no
s i g n i f i c a n t d i f f e r e n c e betw een th e a i r b r e a t h in g h is to g ra m ( f i g u r e
a n d th e oxygen b r e a t h in g h is to g r a m (F ig u r e 1 3 ) .
h a s had a n e f f e c t on l o c a l t i s s u e o x y g e n a tio n .
1 2
)
T h e r e f o r e , 40°C h e a t
A lth o u g h th e r e I s no
d i f f e r e n c e , betw een th e u n h e a te d c o n t r o l s , th e r e a r e s l i g h t d i f f e r e n c e s
betw een th e a i r b r e a th in g and oxygen b r e a t h in g h e a te d h is to g r a m s .
These
d i f f e r e n c e s c o u ld be e x p la in e d th ro u g h b e t t e r oxyhem oglobin s a t u r a t i o n
(HbOj) o f s i n g l e r e d b lo o d c e l l s w ith in tum or m ic r o v e s s e ls ( 1 1 5 ). These
same a u th o r s a l s o p o in t o u t t h a t h ig h e r h y p e rth e rm ia te m p e ra tu re s (4 3 DC)
105
d e c r e a s e th e oxyhem oglobin s a t u r a t i o n v a lu e and t h e r e f o r e may e lim in a te
t h i s o b se rv e d e f f e c t .
I f th e oxygen s t a t u s o f th e tum or i s im proved a s shown i n f i g u r e s 15
a n d 16, I t i s l o g i c a l t o exam ine an y p o t e n t i a l I n c r e a s e d e f f e c t s o f th e s e
c o n c o m ita n t h e a t a n d i r r a d i a t i o n e x p e rim e n ts on th e o v e r ly in g norm al
tis s u e s .
V h ile o t h e r a u th o r s have exam ined th e e f f e c t s o f h e a t on n o r­
m al t i s s u e s ( 4 6 ,4 7 ,5 5 ,4 3 ,5 4 ,5 6 ,6 5 ) m ost o f th e s e a u th o r s have u se d tem­
p e r a t u r e i n th e h ig h e r h y p e rth e rm ic ra n g e , 4 2 .5 “C and above*
To my
k n o w ledge, th e c l o s e s t work t o t h a t shown h e re i s t h a t o f O vergaard ( 4 7 ) .
O v erg aard ( 4 7 ) , u se d a te m p e ra tu re 41°C and exam ined th e e f f e c t o f
s e q u e n c e on th e TER.
G e n e r a lly , l o c a l h e a t below 42“C f o r one h o u r does n o t produce any
s i g n i f i c a n t a b n o rm al s id e e f f e c t s i n m ost norm al t i s s u e s s t u d i e d .
M eyers e t a l . (5 5 ) h av e u sed up to 43°C f o r one h o u r w ith no s i g n i f i c a n t
re s p o n s e and fu rth e rm o re th e y s t a t e t h e r e i s no q u a l i t a t i v e d i f f e r e n c e
i n dammage betw een h e a t (4 3 aC) and i r r a d i a t i o n , and i r r a d i a t i o n a lo n e *
Ho q u a l i t a t i v e d i f f e r e n c e betw een h e a t p lu s i r r a d i a t i o n and i r r a d i a t i o n
a lo n e was se e n by F i e l d e t a l . (6 5 ) f o r o t h e r ty p e s
o f t i s s u e s s k in ,
i n t e s t i n e , and c a r t i l a g e .
T a b le s 14 a n d 15 do n o t show any s i g n i f i c a n t d i f f e r e n c e betw een th e
f o u r tr e a tm e n ts ( h e a t and oxygen d u r in g i r r a d i a t i o n , oxygen b r e a th in g
d u r in g i r r a d i a t i o n , a i r b r e a th in g d u r in g h e a tin g and i r r a d i a t i o n , and a i r
b r e a t h in g d u r in g i r r a d i a t i o n ) a t e a ch r a d i a t i o n dose on th e mean maximum
s k in s c o r e o r th e mean tim e a f t e r tr e a tm e n t to a c h ie v e th e maximum s k in
sc o re .
T hese t a b l e s show t h a t th e s k i n re s p o n s e was p r im a r ily c a u se d by
th e dose o f r a d i a t i o n and n o t th e d o se o f h e a t .
These d a ta a l s o show
t h a t c o n c o m ita n t h e a t and i r r a d i a t i o n can be g iv e n a t 40°C w ith o u t
( s i g n i f i c a n t l y a l t e r i n g th e s k in re s p o n s e (com pared t o i r r a d i a t i o n a lo n e
a t th e same d o se )*
The r e s u l t s o f O vergaard (4 7 ) show a s l i g h t i n ­
c r e a s e i n s k in re s p o n s e when h e a t (41°C f o r 60 m in u te s ) p lu s s im u lta ­
n e o u s i r r a d i a t i o n was com pared t o I r r a d i a t i o n a lo n e , b u t th e te m p e ra tu re s
u se d by O vergaard w ere 1.0**C h i g h e r a n d th e l e n g t h o f e x p o su re to th e
h e a t was lo n g e r (o n e h o u r com pared t o 30 m in u te s ) th a n th e d a ta shown
h e re .
Even w ith te m p e ra tu re a s low aB 41"C t h e r e may be a n e f f e c t o f
h e a t a lo n e (e v e n th o u g h i t i s a s m a ll e f f e c t ) w h ile Che r e s u l t s p r e ­
s e n te d h e re show t h a t a te m p e ra tu re o f 40°C d o es n o t a f f e c t th e s k in
r e a c tio n *
Any r e a c t i o n a t t h i s te m p e ra tu re I s due o n ly t o th e r a d i a ­
t i o n when 40°C h e a t was s im u lta n e o u s ly combined w ith r a d ia tio n *
O th e r a u th o r s have s t a t e d t h a t th e b e s t tim e to a p p ly h e a t i s d u r in g
i r r a d i a t i o n ( 4 1 ,4 6 ,4 7 ) . R obinson e t a l* ( 4 1 ) r e p o r te d a pronounced TER
(T herm al enhancem ent r a t i o ) , when h e a t and i r r a d i a t i o n a r e g iv in g con­
c o m i ta n t ly .
G i l l e t t e and E n sle y (4 6 ) exam ined c o n c o m ita n t h e a t (4 2 .5 °C )
a n d i r r a d i a t i o n and th e y con clu d ed t h a t h e a t m axim ally a f f e c t s b o th th e
s k in and tum or w hich r e s u l t s i n a t h e r a p e u t i c g a in (co m p a riso n o f th e
th e rm a l enhancem ent f o r tum or to th e rm a l enhancem ent f o r s k in ) o f u n i t y .
L a s tly
O vergaard (4 7 ) u s in g th e same mouse a n d tum or sy ste m s we em­
p lo y e d , found t h a t s im u lta n e o u s
h e a t (41°C t o 4 3 .5 °C ) a n d i r r a d i a t i o n
I n c r e a s e d th e tum or re s p o n s e and a l s o th e o v e r ly in g norm al t i s s u e r e s ­
p o n s e , g i v in g no t h e r a p e u t i c a d v a n ta g e .
In o t h e r w o rd s, th e th e rm a l
enhancem ent r a t i o ( t h e r a t i o o f d o se s o f i o n iz in g r a d i a t i o n w ith o u t
h e a t a n d w ith h e a t to g iv e th e same l e v e l o f damage) f o r tum or t i s s u e
a n d th e th e rm a l enhancem ent r a t i o f o r o v e r ly in g s k in in c r e a s e d a s w e l l,
g i v in g no Im provem ent i n o v e r a l l th e r a p y ( w ith
tis s u e ).
r e s p e c t t o norm al
The r e s u l t s f o r th e work p r e s e n te d h e re a r e somewhat d i f f e r e n t th a n
th o s e m en tio n ed I n th e p r e c e e d in g p a r a g r a p h .
The b a s ic d i f f e r e n c e I s
I n Che a llo w a b le te m p e ra tu re u se d by o t h e r I n v e s t i g a t o r s .
The tem­
p e r a t u r e s u sed w ere ab o v e 4 l°C w h ile th e te m p e ra tu re em ployed i n t h i s
w ork was 4 0 aC, w hich I s n o t a t a th e rm a l th e r a p y h e a t l e v e l .
S e c o n d ly ,
t h e work p r e s e n te d h e r e h a s a d i f f e r e n t b a s i s th a n th e a u th o r s who a r e
I n t e r e s t e d In th e rm a l enhancem ent r a t i o .
W hile m ost a u th o r s have ex­
am ined h e a t and I r r a d i a t i o n t o s e e w hich seq u en ce o f tr e a tm e n t i s th e
m ost b e n e f i c i a l (when a t h e r a p e u t i c d o se o f h e a t and a t h e r a p e u t i c dose
o f r a d ia tio n i s g iv e n ),
1
have a tte m p te d t o enhance th e oxygen e f f e c t o f
r a d i a t i o n th ro u g h th e u s e o f a non t h e r a p e u t i c "d o se " o f h e a t combined
w ith v a r io u s t h e r a p e u t i c d o se s o f r a d i a t i o n .
F ig u r e s 22 an d 23 show t h a t by com bining h e a t (4 0 °C ), oxygen and
i r r a d i a t i o n th e tim e i t ta k e s f o r th e tum or t o r e a c h a s p e c i f i e d volume
( i n t h i s c a s e 1437mm^ o r 14mmxl4mmxl4mmx^/6) i s i n c r e a s e d compared to
a l l o t h e r t r e a tm e n ts .
A ll tr e a tm e n ts w ith h e a t c a u se i n c r e a s e i n t h i s
same tim e ( t o r e a c h 1437 mm^) when com pared to I r r a d i a t i o n a lo n e . Even
more s t r i k i n g , F ig u re s 22 a n d 23 show t h a t h e a t and oxygen b r e a th in g
d u r in g I r r a d i a t i o n more c o n s i s t e n t l y in c r e a s e s th e tim e t o th e s p e c i f i e d
volume th a n d oes th e same tr e a tm e n t em ploying a i r I n s te a d o f oxygen.
M o le c u la r oxygen h a s been shown to be th e m ost p o w e rfu l r a d i a t i o n
s e n s i t i z e r found t o d a t e .
C e l ls t h a t a r e i r r a d i a t e d I n th e p re s e n c e o f
oxygen a r e more s e n s i t i v e (by up t o a f a c t o r o f 3 ) th a n c e l l s t h a t a r e
n o t.
R a d ia tio n th e r a p y h a s a tte m p te d t o e x p l o i t oxygen a s a r a d i a t i o n
s e n s i t i z e r i n many w ays, m ost w ith o n ly l im it e d s u c c e s s , b u t a l l h e lp in g
t o make r a d i a t i o n more e f f e c t i v e l y d e s tr o y tum or c e l l s *
Some o f th e s e
m ethods a r e f r a c t i o n a t i o n o f r a d i a t i o n d o se s t o a llo w f o r b e t t e r tumor
o x y g e n a tio n ( 1 3 0 ) , h y p o x ic c e l l s e n s i t i z e r s w hich m im ic oxygen d u r in g
r a d i a t i o n r e s p o n s e (1 3 0 ) " I n d i r e c t " r a d i a t i o n s e n s i t i z e r s w hich a f f e c t
r e s p i r i n g c e l l s a llo w in g oxygen to p e n e t r a t e h y p o x ic a r e a s o f tum ors
( 1 3 1 ) , an d h y p e r b a r ic oxygen d u r in g i r r a d i a t i o n
(1 3 0 ).
H y p erth erm ia
was o r i g i n a l l y th o u g h t to a f f e c t h y p o x ic c e l l s more th a n o x ic c e l l s b u t
Gerweck ( 9 0 ) a n d O v e rg a a rd and B lc h e l (9 4 ) d e m o n s tra te d t h a t PH was th e
im p o r ta n t f a c t o r in v o lv e d i n h y p e rth e rm ic s e n s i t i z a t i o n o f o x ic a s w e ll
a s h y p o x ic c e l l s , a t th e t r a d i t i o n a l h y p e rth e rm ic te m p e ra tu re s ( p r im a r ­
i l y 42.5®C and a b o v e ) .
F ig u re 23 shows t h a t th e m easured oxygen i n ­
c r e a s e fo u n d may be in v o lv e d i n a h y p e rth e rm ic r e s p o n s e , b u t a t n o n t r a d i t l o n a l te m p e r a tu r e s (4 0 °C ) a n d o n ly a t th e tim e o f i r r a d i a t i o n .
S u p p o rt o f th e th o u g h t t h a t oxygen t e n s i o n may be in c r e a s e d i n r e s p o n s e
t o m ild h y p e rth e rm ia and th u s a f f e c t r a d i a t i o n s e n s i t i v i t y d u r in g con­
c o m ita n t th e r a p y can be found i n F ig u r e s 12 th ro u g h IS*
T hese d a ta show
a s h i f t t o th e h i g h e r end o f th e oxygen c o n c e n t r a t io n s c a l e w ith h y p e r­
th e rm ia a t 40*C.
I t i s e n t i r e l y p o s s i b l e t h a t h e a t (40°C ) an d a i r b r e a t h in g d u r in g
i r r a d i a t i o n d oes n o t re o x y g e n a te c e l l s t o th e same e x t e n t t h a t h e a t
(40°C ) an d oxygen b r e a t h in g d u r in g i r r a d i a t i o n d o e s .
The d i f f e r e n c e
shown i n F ig u r e s 17, th ro u g h 2 1 , do show t h a t 4 0 “C h e a t and oxygen
b r e a t h i n g d o e s I n c r e a s e th e oxygen t e n s i o n ( t o h ig h e r oxygen con­
c e n t r a t i o n l e v e l s ) th a n 40°C h e a t d u r in g a i r b r e a t h i n g .
The c o n d itio n
o f 40°C h e a t and a i r b r e a t h in g p ro b a b ly does n o t I n c r e a s e th e oxygena­
t i o n t o a h ig h enough l e v e l t o g r e a t l y a f f e c t r a d i o s e n s i t i v i t y .
I f one
c o n s id e r s th e p l o t o f r e l a t i v e r a d i o s e n s l t l v l t y ( y a x i s ) v e r s u s oxygen
t e n s i o n (x a x i s ) , i t c o u ld be p o s s i b l e t h a t th e t r e a tm e n t o f 40°C h e a t
w ith a i r b r e a t h i n g e l e v a t e s th e r e l a t i v e r a d i o s e n s l t l v l t y to a f a c t o r
of
1
.5
- 2
w h ile oxygen b r e a t h in g d u r in g h e a tin g e l e v a t e s th e r a d io s e n ­
s i t i v i t y t o a h ig h l e v e l , p o s s ib ly
2
. 0 - 2 . 5 , th e r e b y a llo w in g a s l i g h t l y
b e t t e r tum or re sp o n se * (F o r exam ple s e e F ig u re 5 - 3 on r e f e r e n c e 130)
A gain t h i s i s born o u t i n th e r e s u l t s o f F ig u re s 22 and 2 3 .
F u r th e r ­
m ore, t h i s th o u g h t w ould e x p la in why th e tr e a tm e n t o f 40°C h e a t and a i r
b r e a t h in g d u r in g i r r a d i a t i o n 's d o s e -r e s p o n s e c u rv e m a n if e s ts i t s e l f w ith
a d i f f e r e n t s lo p e ( a s compared to 40*C h e a t , oxygen b r e a th in g d u rin g
Irra d ia tio n )*
S in c e F ig u re s 14 and 15 show a s l i g h t s h i f t i n th e
oxygen c o n c e n tr a tio n when oxygen ( a s com pared to a i r ) i s in h a le d d u rin g
m ild h y p e rth e rm ia and a t h i g h e r d o ses o f r a d i a t i o n (shown on F ig u re s 22
and 23 ) th e two t r e a tm e n ts ( + O2 *
+ a i r ) a r e v e ry s i m i l a r and i t may
be p o s s ib l e t h a t w ith th e h e a ti n g d u r in g oxygen b r e a t h in g th e r e I s a
f a s t e r I n f l u x o f a v a i l a b l e oxygen.
G e n e r a lly , th e s e d a ta d e m o n s tra te t h a t t h i s h e a ti n g sy stem can be
u se d to in d u c e h y p e rth e rm ia I n ro d e n t t i s s u e s *
In a l l o f th e e x p e r i ­
m ents in v o lv in g m ild h y p e rth e rm ia and c o n c o m ita n t io n iz in g r a d i a t i o n two
a n im a ls w ere h e a te d s im u lta n e o u s ly w ith no s i g n i f i c a n t d i f f e r e n c e s b e t ­
ween th e two l o c a l l y h e a te d tum or te m p e r a tu r e s .
A lth o u g h th e tem per­
a t u r e d i s t r i b u t i o n d a ta shows a r a t h e r l a r g e d e v ia t io n in te m p e ra tu re in
norm al t i s s u e , t h i s i s e x p la in e d th ro u g h two m eans;
The f i r s t i s t h a t
th e blood flo w th ro u g h norm al t i s s u e can co n d u ct h e a t away more e f f i ­
c i e n t l y a n d , s e c o n d ly th e a p p l i c a t o r s d o , by t h e i r p h y s ic a l c h a r a c t e r i s ­
t i c s , have h o t s p o t s .
K orm ally such h o t s p o ts c o u ld be e x p lo ite d by
a l i g n i n g th e tum or t i s s u e i n th e h o t s p o t.
I n summary, t h i s h e a tin g
sy ste m d oes a llo w f o r th e p ro d u c tio n o f a s t a b l e and r e l a t i v e l y u n ifo rm
te m p e ra tu re d i s t r i b u t i o n I n m a lig n a n t tis s u e *
110
The se co n d c o n d it io n s u p p o rte d by th e d a ta p r e s e n te d i s two f o l d ,
a n d in v o lv e s tum or o x y g e n a tio n and r e s u l t a n t re s p o n s e to r a d i a t i o n
th e r a p y .
F i r s t , tum or oxygen t e n s i o n i s i n c r e a s e d d u r in g m ild (40°C )
h y p e rth e rm ia .
S e c o n d ly , t h i s o x y g e n a tio n s h i f t may p la y a p a r t i n a
somewhat im proved tum or re s p o n s e t o s i n g l e f r a c t i o n r a d i a t i o n th e r a p y .
T h is a u th o r a s w e ll a s R obinson e t a l . (1 1 3 ) a n d Denekamp e t a l .
(1 1 9 ) h a s shown t h a t th e r e a r e th e rm a l g r a d i e n ts i n te m p e ra tu re d u rin g
h y p e rth e rm ic t r e a tm e n ts .
T here c o u ld e x i s t ( a t th e tim e o f h e a tin g ) two
p o p u la tio n s o f c e l l s i n a tu m o r, th e f i r s t b e in g th e c e l l s a t th e p r e ­
s c r i b e d te m p e ra tu re and th e s e c o n d , th o s e c e l l s t h a t d id n o t a c h ie v e th e
t h e r a p e u t i c te m p e r a tu r e .
The c e l l s a t th e p r e s c r ib e d te m p e ra tu re would
d i e due to th e rm a l d e s t r u c t i o n (assu m in g th e te m p e ra tu re was a t o r above
a p p ro x im a te ly 4 2 .5 ° C ) .
However, t h i s c a s e i s n o t th e m ain c o n c ern f o r
th e e n s u in g d i s c u s s i o n , r a t h e r th e c e l l s t h a t a r e a t te m p e ra tu re s a t th e
low end o f th e d i s t r i b u t i o n i n te m p e ra tu re .
T hese tum or c e l l s do n o t
s e e a t h e r a p e u t i c tr e a tm e n t te m p e ra tu re b u t some n o n - th e r a p e u t ic tem p era­
t u r e ( e .g .,4 0 ° C t o 4 l ° C ) .
In a s t r i c t s e n s e th e s e c e l l s have s u rv iv e d
th e th e rm a l th e r a p y and i f a d ose o f r a d i a t i o n fo llo w s th e dose o f h e a t
t h e s e s u r v i v i n g c e l l s may n o t have to f a c e th e f u l l e f f e c t s o f se q u en ­
t i a l h e a t and r a d ia tio n .
I f I r r a d i a t i o n p re c e d e s th e t r i a l tre a tm e n t
a n d some o f th e s e h e a te d c e l l s do n o t s e e th e e le v a te d te m p e r a tu r e s ,
th e y to o may c o n tin u e to s u r v i v e .
Now, i f one c o n s id e r s c o n c o m ita n t
h e a t and i r r a d i a t i o n w ith in th e fram ew ork o f th e above s c e n a r i o , th e
p i c t u r e f o r c e l l s t h a t may h av e e sc a p e d th e rm a l I n ju r y i s much more
b le a k .
Even th e c e l l s a t lo w e r te m p e ra tu re s w ould have a h e a t r e l a t e d
m echanism o f c e l l i n a c t i v a t i o n , nam ely h y p e rth e rm ic in d u c e d o ^ g e n a t l o n
changes.
To r e s t a t e t h i s e n t i r e th o u g h t, g e n e r a ll y one c o u ld s a y t h a t ,
w i t h in th e tum or t i s s u e h e a te d to t h e r a p e u t i c l e v e l s , t h e r e a r e a r e a s o f
t i s s u e t h a t w i l l n o t s e e a t h e r a p e u t i c te m p e ra tu re and a s such th e y w i l l
n o t be d e s tr o y e d by a th e rm a l m echanism .
When combined Cheat and
r a d i a t i o n ) tr e a tm e n t i s em ployed w ith an i n t e r v a l betw een them , th e
c e l l s c o u ld be I n a c t i v a t e d th ro u g h two b a s ic m echanism s:
ra d ia tio n
I n a c t i v a t i o n o f o x ic c e l l s , o r h y p e rth e rm ic i n a c t i v a t i o n o f h y p o x ic
c e lls .
O b v io u sly , a l a r g e g ro u p o f c e l l s may be on th e b o r d e r lin e b e t ­
ween th e h y p o x ic c o n d itio n and th e o x ic c o n d itio n .
I f th e s e c e l l s d id
n o t " s e e " a t h e r a p e u t i c te m p e ra tu re , th e n th e y c o u ld p o t e n t i a l l y r e p r o ­
d u ce th e tum or u n l e s s th e c o n c o m ita n t th e r a p y ( h e a t w ith s im u lta n e o u s
i r r a d i a t i o n ) was em ployed.
I f h e a t and s im u lta n e o u s i r r a d i a t i o n was
em ployed, even i f th e s e "h y p o x ic " c e l l s a v o id e d a t h e r a p e u t i c h e a t d o s e ,
th e y c o u ld s t i l l be i n a c t i v a t e d th ro u g h a t h i r d p o s s i b l e mechanism
( i . e . , h y p e rth e rm ia o x y g e n a tio n ).
In many c a s e s r e s u l t s have shown t h a t c o n c o m ita n t h e a t and i r r a ­
d i a t i o n i s th e b e s t th e r a p y i n term s o f tum or re s p o n s e ( 4 6 ,4 7 ,4 1 ) , b u t
some a u th o r s have found t h a t th e o v e r ly in g s k in a l s o shows an enhanced
r e a c t i o n , th e re b y n u l l i f y i n g th e tum or re s p o n s e enhancem ent ( 4 6 ,4 7 ) .
To be e f f e c t i v e c l i n i c a l l y , any tum or th e r a p y m ust a f f e c t th e tumor
more th a n s u rro u n d in g norm al t i s s u e .
By re d u c in g th e te m p e ra tu re u sed
i n c o n c o m ita n t h e a t and I r r a d i a t i o n t r e a t m e n t s , th e o v e r ly in g norm al
t i s s u e c o u ld be s p a re d s e v e r e h y p e rth e rm ic a f f e c t s , b u t n o t th e
ra d ia tio n e f f e c ts .
The r a d i a t i o n e f f e c t s on norm al t i s s u e s a r e , when
h a n d le d p r o p e r l y , a c c e p t a b l e and t r e a t a b l e .
Such a combined th e r a p y
(c o n c o m ita n t 40°C h e a t and e x t e r n a l beam r a d i a t i o n th e r a p y ) a lth o u g h
p l a u s a b l e , i s h ig h ly u n l ik e ly a t t h i s tim e f o r many r e a s o n s .
The f i r s t
112
r e a s o n I s t h a t more In v iv o d a ta m ust be g e n e ra te d on t h i s ty p e o f
t h e r a p y 's e f f e c t i v e n e s s com pared to c u r r e n t p r o to c o ls w ith o th e r tumor
s y s te m s .
A n o th e r re a s o n I s c h a t h i g h e r te m p e ra tu re s (43°C ) a lo n e a r e
c a p a b le o f d e s tr o y in g tum or c e l l s i n v iv o a n d can be e f f e c t i v e l y and
e f f i c i e n t l y se q u en ced w ith d o se s o f r a d i a t i o n th e r a p y to m axim ally
a f f e c t m a lig n a n t t i s s u e and m in im a lly a f f e c t o v e r ly in g norm al t i s s u e .
L a s t l y , t e c h n i c a l c o n v e n ie n c e and d o s im e try would p ro b a b ly l i m i t a com­
b in e d th e r a p y i n a tr e a tm e n t c l i n i c *
I f m icrow ave h y p e rth e rm ia was to
be g iv e n d u r in g r a d i a t i o n th e r a p y , I n d iv i d u a l r a d i a t i o n tr e a tm e n t tim es
w ould in c r e a s e b e c a u se o f such th in g s a s equipm ent s e t up and b e c a u se o f
t h e l e n g th o f tim e i t ta k e s to b r in g th e tum or up to a s p e c i f i e d tem­
p e ra tu re .
These problem s would c a u se a r a d i a t i o n th e r a p y u n i t to go
u nused f o r lo n g e r p e r io d s o f tim e , th u s n o t e f f i c i e n t l y t r e a t i n g a s many
p a t i e n t s p e r d ay .
T hese d a ta I n a n o th e r s e n s e do have c u r r e n t c l i n i c a l s i g n i f i c a n c e
w ith r e s p e c t to t h e r a p i e s in v o lv in g com bined h y p e rth e rm ia and i n t e r s t i ­
t i a l r a d io th e r a p y ( 1 3 2 ).
many y e a r s .
I n t e r s t i t i a l r a d io th e r a p y h a s been u se d f o r
T h is form o f r a d i a t i o n th e r a p y can be combined w ith
h y p e rth e rm ia by em ploying ra d io f re q u e n c y h e a ti n g te c h n iq u e s .
H igher
te m p e ra tu re s (43°C -44°C ) w ould o b v io u s ly be more a c c e p t a b l e th a n 40°C
b e c a u se o f th e tu m o rc ld a l n a tu r e o f h y p e rth e rm ia ( a t h ig h e r tem p era­
t u r e s ) a lo n e o r I n c o m b in a tio n w ith r a d i a t i o n .
The e f f e c t s o f concom i­
t a n t h e a t (4 0 “C) and r a d i a t i o n would s t i l l be Im p o rta n t a s lo n g a s th e r e
a r e a r e a s w here th e te m p e ra tu re d id n o t r e a c h th e t h e r m o - th e r a p e u tic
le v e l.
I t I s p la u s a b le t h a t h y p e rth e rm ic o x y g e n a tio n c o u ld p la y a r o le
I n com bined h e a t and I n t e r s t i t i a l r a d io th e r a p y t r e a tm e n ts b e c au se o f
113
te m p e ra tu re d i s t r i b u t i o n s .
W ith b o th th e h e a ti n g and th e I o n iz in g
r a d i a t i o n s o u rc e s i n th e tum or p r o p e r , i t becomes p o s s ib l e t h a t some
h y p o x ic tum or c e l l s do n o t " s e e " a th e r m o th e ra p e u tic d ose o f h e a t b u t
a t a s l i g h t l y e le v a te d te m p e ra tu re a r e "pushed" i n t o a h ig h e r oxygena­
t i o n l e v e l th u s e n h a n c in g th e oxygen e f f e c t o f r a d i a t i o n th e r a p y .
Many o t h e r e x p e rim e n ts s h o u ld be d e s ig n e d to exam ine w hat e f f e c t
m ild h y p e rth e rm ia h a s on th e outcom e o f a combined h e a t and i r r a d i a t i o n
th e ra p y .
O th e r p h y s ic a l and p h y s io l o g i c a l p a ra m e te rs m ust be i n v e s t i ­
g a te d w ith r e s p e c t to c o n c o m ita n t h e a t (40°C) and I r r a d i a t i o n p ro c e ­
d u res.
Such p h y s io l o g i c a l p a ra m e te rs a s b lo o d flo w , im m u n o lo g ical s t a ­
t u s and PH m ust be exam ined to s e e i f one o r a l l th e s e p la y s an im por­
t a n t r o l e i n th e re s p o n s e o f tum ors Co t h i s k in d o f c o n c o m ita n t th e r a p y .
On th e p h y s ic a l s id e o f th e s e ty p e s o f e x p e rim e n ts o t h e r te m p e r a tu r e s ,
e . g . 39°C o r 41°C , m ust be combined c o n c o m ita n tly w ith o t h e r ty p e s o f
r a d i a t i o n , e . g . n e u tr o n s , and th e r e s u l t a n t tum or re s p o n s e s com pared to
c u rre n t th e ra p ie s .
W hile th e s e a r e j u s t a few o f th e a r e a s t h a t sh o u ld
be i n v e s t i g a t e d t h e r e a r e many m ore.
C oncom itant 40“C h y p e rth e rm ia and i r r a d i a t i o n d oes have an e f f e c t on
tum or g row th w h ile n o t s i g n i f i c a n t l y a l t e r i n g th e norm al t i s s u e r e a c t i o n
from t h a t o f r a d i a t i o n a lo n e .
W hile t h i s i s o n ly a b e g in n in g , th e r e may
be room a n d a need f o r c o n tin u in g b i o l o g i c a l i n v e s t i g a t i o n s o f con­
c o m ita n t 40°C h y p e rth e rm ia and i r r a d i a t i o n t h e r a p i e s .
J u s t a s 43°C
h y p e rth e rm ia h a s i t s p l a c e , m ild (40°c) h y p e rth e rm ia may f in d i t s own
n i t c h i n c a n c e r th e r a p y .
114'
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THE EFFECTS OF MILD HYPERTHERMIA ON TUMOR OKYGENATION
AND RESULTANT RESPONSE TO RADIATION THERAPY
124
by
M ic h a e l D en n is O 'H ara
December 1984
A d v is o rs :
D r. F re d H e tz e l/D r* H a l t e r C h avln
M a jo r:
B i o l o g ic a l S c ie n c e s
D e g re e:
D o c to r o f P h ilo s o p h y
T h is d i s s e r t a t i o n d e m o n s tra te s two b a s i c c o n c e p ts .
F irs t, a
m icrow ave h y p e rth e rm ia sy ste m p ro d u ce d i n o u r l a b o r a t o r y can be em ployed
to
l o c a l l y h e a t e i t h e r o n e , o r two mouse tu m o rs s im u lta n e o u s ly .
S e c o n d ly ,
t h a t t h i s s y s te m can be u s e d t o I n v e s t i g a t e th e e f f e c t of
40°C m icrow ave
h y p e rth e rm ia on tum or o x y g e n a tio n and tum or re s p o n s e to
c o n c o m ita n t h e a t
( 4 0 DC) a n d i r r a d i a t i o n .
The m icrow ave h y p e rth e rm ia eq u ipm ent u sed o p e r a t e s a t .2450 MHz and
i s c a p a b le o f h e a t i n g two a n im a ls a t th e same tim e d u r in g i r r a d i a t i o n
o r one a n im a l a t a tim e f o r te m p e ra tu re d i s t r i b u t i o n s t u d i e s o r oxygena­
t i o n s tu d i e s *
40®C.
I n a l l c a s e s th e h e a te d t i s s u e te m p e ra tu re was h e ld a t
The d o s e s o f r a d i a t i o n em ployed w ere from 3000 t o 6000 r a d s in
250 o r 500 r a d in c r e m e n ts .
A ll o f th e a n im a ls em ployed In th e s e s t u d i e s
w ere C3 H m ice an d th e tum or u se d in some o f th e s e s t u d i e s was a mouse
mammary ca rc in o m a Im p la n te d in th e l e g .
T herm al d i s t r i b u t i o n e x p e r i ­
m en ts em ployed t h r e e t r i p l e m ic ro th e rm o c o u p le s I n e i t h e r o f two a r r a y s ,
p a r a l l e l o r p e r p e n d i c u l a r t o th e fem u r.
A l l o t h e r e x p e rim e n ts u se d
s i n g l e p o i n t d e te r m in a tio n o f a c h ie v e d te m p e r a tu r e .
The oxygen con­
c e n t r a t i o n d e te r m i n a ti o n was c a r r i e d o u t w ith oxygen e l e c t r o d e s d u r in g
h y p e rth e rm ia .
M easurem ents were ta k e n w ith and w ith o u t 40°C m icrow ave
h y p e rth e rm ia and w ith and w ith o u t oxygen b r e a t h in g .
The e f f e c t o f 40°C
m icrowave h y p e rth e rm ia in d u ce d oxygen in c r e a s e on r e s u l t a n t tum or and
norm al t i s s u e re s p o n s e to h e a t and r a d i a t i o n was exam ined.
The r e s u l t o f th e te m p e ra tu re d i s t r i b u t i o n e x p e rim e n ts
in d ic a te
t h a t h e a te d norm al t i s s u e s can have an a v e ra g e d e v ia t io n from th e
a v e ra g e te m p e ra tu re o f up t o + 2.5°C w h ile m a lig n a n t t i s s u e can have an
a v e ra g e d e v ia t io n a s l a r g e a s
m a lig n a n t
+ 2 .0 °C .
N e ith e r th e norm al o r th e
t i s s u e shows any s i g n i f i c a n t d i f f e r e n c e in th e a v e ra g e
d e v ia t io n betw een th e
p a r a l l e l o r p e r p e n d ic u la r d i r e c t i o n s .
The
r e s u l t s o f th e oxygen e x p e rim e n ts c l e a r l y i n d i c a t e t h a t t h e r e i s a
s l i g h t i n c r e a s e i n o x y g e n a tio n
d u r in g 40°C h y p e rth e rm ia .
The con­
c o m ita n t h e a t and i r r a d i a t i o n e x p e rim e n ts d e m o n s tra te t h a t t h i s
s l i g h t l y in c r e a s e d oxygen te n s io n d u r in g
h e a ti n g may have in c r e a s e d
th e re s p o n s e o f th e tum or w h ile n o t s i g n i f i c a n t l y e f f e c t i n g th e
o v e r ly in g norm al t i s s u e w ith in each r a d i a t i o n d ose g ro u p .
CURRICULUM VITAE
NAME:
MICHAEL DENNIS O'HARA
CURRENT ADDRESS:
25302 L y n c a s tle
F arm ington H i l l s , MI 48018
BUSINESS ADDRESS:
Henry F ord H o s p ita l
D iv is io n o f R a d ia tio n B iology
2799 West Grand B o u lev ard
D e t r o i t , MI 48202
313/876-2227
BIRTHDATE:
May 16, 1954
HOME ADDRESS
30 T o e ls ln Rd.
C heektow aga, N.Y. 14225
EDUCATION:
D 'Y o u v ille C o lle g e , B u f f a lo , New Y ork, B.A. 1977
S.U .N .Y . a t B u f f a lo , B u f f a lo , New Y ork, M .Sc. 1978
Wayne S t a t e U n i v e r s i ty , D e t r o i t , M ichigan, Ph.D .
ACADEMIC HONORS:
D e a n 's L i s t D 'Y o u v ille C o lle g e S p rin g 1976, F a l l
1976 and S p rin g 1977.
U n d e rg ra d u a te R e se a rc h RPMI M ycology, F a l l 1976.
U n d e rg ra d u a te R e se a rc h RPMI R a d ia tio n B io lo g y ,
S p rin g 1977.
R e s e a rc h A s s i s t a n t RPMI 1977-1979.
G ra d u a te T e a ch in g A s s i s t a n t W.S.U. 1980-1981.
WORK EXPERIENCE:
Town & C ountry Anim al C l i n i c , Cheektowaga N.Y.
V e te r in a r y A s s i s t a n t , 1972-1977.
R osw ell P a rk M em orial I n s t i t u t e , H e a lth R e s e a rc h .
R e se a rc h A s s i s t a n t , 1977-1979.
Henry Ford H o s p i ta l , d e p t, o f T h e r a p e u tic R a d io lo g y .
R e s id e n t, R a d ia tio n B io lo g y , 1979 t o p r e s e n t .
SOCIETIES:
R a d ia tio n R e se a rc h S o c ie ty
I .S .O .T .T .
Sigma XI
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