The

influence

of

thermo-chemotherapy

on

bladder

tumours

an

immunohistochemical

analysis

To

study

the

influence

of

microwave

induced

thermo-chemotherapy

on

high-grade

urothelial

cell

carcinomas

Five

groups

of

each

three

patients

were

formed

of

whom

initial

biopsies

and

cystectomy

samples

were

collected

Patients

were

treated

days

prior

to

cystectomy

with

mitomycin-C

-LRB-

group

-RRB-

hyperthermia

-LRB-

group

-RRB-

or

thermo-chemotherapy

-LRB-

group

-RRB-

Group

patients

had

been

treated

with

a

cycle

of

six

thermo-chemotherapy

treatments

prior

to

cystectomy

and

group

patients

served

as

control

-LRB-

no

treatment

-RRB-

Tumour

samples

were

stained

with

Haematoxylin

and

Eosin

monoclonal

antibody

and

the

monoclonal

antibody

In

six

out

of

the

nine

patients

treated

with

hyperthermia

a

decrease

in

proliferation

activity

in

the

tumour

was

found

Seven

out

of

nine

patients

treated

with

hyperthermia

showed

a

decrease

in

activity

A

decrease

in

proliferation

activity

and

activity

illustrate

the

potential

role

of

thermo-chemotherapy

as

a

promising

intravesical

treatment

Introduction

Bladder

cancer

is

the

seventh

most

common

cancer

worldwide

accounting

for

of

all

cancers

In

an

estimated

new

cases

in

men

and

in

women

were

found

worldwide

-LSB-

-RSB-

The

highest

incidence

rates

of

bladder

cancer

in

both

sexes

are

observed

in

Europe

North

America

and

Australia

-LSB-

-RSB-

Bladder

cancer

incidence

is

still

rising

moderately

in

most

developed

countries

Of

all

these

malignant

bladder

tumours

more

than

are

transitional

cell

carcinomas

of

which

two

third

is

superficial

and

one

third

is

muscle

invasive

The

management

of

these

two

types

of

transitional

cell

carcinoma

differs

enormously

The

management

of

superficial

bladder

cancer

consists

of

transurethral

resection

in

the

first

place

whereas

the

primary

treatment

for

muscle

invasive

bladder

cancer

consists

of

cystectomy

a

complete

different

approach

After

transurethral

resection

of

a

superficial

bladder

tumour

of

patients

develop

recurrences

despite

the

most

accurate

resection

technique

This

high

risk

of

recurrences

makes

bladder

cancer

one

of

the

most

prevalent

human

tumours

To

decrease

the

number

of

recurrences

after

transurethral

resection

patients

are

treated

subsequently

with

chemotherapeutic

or

immunotherapeutic

agents

Immunotherapy

usually

BCG

treatment

is

more

effective

than

any

intravesical

chemotherapeutic

agent

but

has

more

serious

and

more

frequent

side

effects

So

there

is

a

need

for

more

effective

treatment

options

or

treatment

options

with

less

frequent

and

less

severe

side

effects

A

new

treatment

option

in

patients

with

intermediate

to

high

risk

tumours

is

the

combination

of

intravesical

hyperthermia

and

intravesical

chemotherapy

-LSB-

-RSB-

The

endocavitary

location

and

ease

of

accessibility

by

the

urethra

makes

thermo-chemotherapy

a

good

therapeutic

option

for

superficial

bladder

cancer

Local

hyperthermia

at

temperatures

of

°C

in

combination

with

selected

cytostatic

agents

in

several

tumours

including

transitional

cell

carcinoma

results

in

a

synergistic

anti-tumour

effect

-LSB-

-RSB-

In

this

descriptive

study

the

influence

of

different

treatment

modalities

on

bladder

tumours

-LRB-

thermo-chemotherapy

chemotherapy

and

thermotherapy

-RRB-

was

investigated

by

several

immunohistochemical

stainings

Methods

Subjects

The

study

included

patients

with

high-grade

transitional

cell

carcinoma

of

the

bladder

All

patients

signed

a

patient

informed

consent

and

all

these

patients

were

facing

cystectomy

The

patients

were

divided

in

five

groups

with

each

three

patients

Group

patients

were

treated

days

before

cystectomy

with

an

intravesical

mitomycin-C

-LRB-

MMC

-RRB-

instillation

After

the

bladder

was

emptied

mg

MMC

-LRB-

Kyowa

Hakko

Kogyo

Co.

Tokyo

Japan

-RRB-

in

ml

saline

was

instilled

In

order

to

stabilize

the

MMC

concentration

in

the

bladder

throughout

the

entire

session

the

bladder

was

emptied

after

min

and

with

urine

diluted

solution

was

replaced

by

a

new

solution

containing

mg

MMC

Group

patients

were

treated

days

before

cystectomy

with

sterile

water

and

local

hyperthermia

To

standardize

treatments

the

instillation

was

replaced

after

min

The

local

microwave

induced

hyperthermia

was

delivered

by

the

SB-TS

system

as

described

by

Colombo

et

al.

-LSB-

-RSB-

This

system

consists

of

a

MHz

intravesical

microwave

applicator

that

delivers

hyperthermia

of

the

bladder

walls

via

direct

irradiation

The

applicator

is

part

of

the

specially

designed

transurethral

catheter

The

catheter

also

contains

five

thermocouples

Two

thermocouples

measure

the

temperature

in

the

prostatic

urethral

tract

the

other

three

are

spread

out

and

pushed

tangentially

against

the

posterior

and

lateral

walls

of

the

bladder

To

avoid

urethral

overheating

the

solution

is

continuously

pumped

out

of

the

bladder

and

re-instilled

after

being

cooled

Hyperthermia

was

delivered

within

a

temperature

range

of

°C

Group

patients

were

treated

days

before

cystectomy

with

two

times

min

intravesical

MMC

-LRB-

mg

in

ml

sterile

water

-RRB-

combined

with

local

microwave

induced

hyperthermia

delivered

by

the

SB-TS

system

Group

patients

were

treated

with

a

cycle

of

six

thermo-chemotherapy

treatments

during

the

last

months

Finally

group

patients

served

as

control

group

These

patients

did

not

receive

any

intravesical

instillations

within

months

prior

to

cystectomy

Immunohistochemistry

All

tumour

tissue

samples

were

fixed

in

a

buffered

formaldehyde

solution

The

specimens

were

embedded

in

paraffin

blocks

and

sections

of

μm

were

cut

All

specimens

were

deparaffinized

and

stained

with

Haematoxylin

and

Eosin

A

microscopic

examination

of

the

samples

was

performed

and

the

extend

of

inflammation

-LRB-

to

-RRB-

haemorrhage

-LRB-

to

-RRB-

were

semi

quantitatively

scored

a

nuclear

protein

present

during

phases

S

and

M

of

cycling

cells

is

accepted

as

a

good

indicator

of

cell

proliferation

-LSB-

-RSB-

Sections

were

deparaffinized

and

immersed

in

a

mM

sodium

citrate

buffer

-LRB-

pH

-RRB-

in

a

microwave

oven

for

two

times

min

to

enhance

antigen

retrieval

After

washing

the

slides

were

incubated

with

in

methanol

to

quench

endogenous

peroxidase

activity

After

incubation

at

room

temperature

for

h

with

the

monoclonal

antibody

clone

-LRB-

BioGenex

-RRB-

diluted

a

biotinylated

antibody

that

recognises

murine

IgG

-LRB-

BioGenex

-RRB-

was

applied

for

min

followed

by

incubation

in

streptavidin-peroxidase

complex

-LRB-

BioGenex

-RRB-

for

min

The

peroxidase

reaction

was

developed

using

mg/ml

diaminobenzidine

tetrahydrochloride

-LRB-

Sigma

-RRB-

in

Haematoxylin

was

used

as

a

light

counter

stain

The

slides

were

dehydrated

and

mounted

with

a

xylene-soluble

mounting

medium

The

mutated

tumour

suppressor

gene

product

can

be

detected

immunohistochemically

and

is

associated

with

a

lower

survival

in

patients

with

bladder

cancer

-LSB-

-RSB-

Sections

were

deparaffinized

and

immersed

in

a

mM

sodium

citrate

buffer

-LRB-

pH

-RRB-

in

a

microwave

oven

for

two

times

min

to

enhance

antigen

retrieval

After

cooling

down

in

a

methanol

solution

was

used

for

min

to

block

endogenous

peroxidase

activity

Slides

were

pre-treated

with

normal

swine

serum

for

min

to

block

non-specific

staining

followed

by

adding

primary

antibody

for

h

at

°C

After

extensive

rinsing

sections

were

incubated

for

min

with

biotinylated

swine

anti

mouse

antibody

-LRB-

dilution

-RRB-

and

then

for

min

with

avidin-biotin

complexes

-LRB-

dilution

-RRB-

at

°C

Diaminobenzidine

-LRB-

DAB

-RRB-

staining

were

finally

followed

by

haematoxylin

nuclear

counter

staining

The

slides

were

dehydrated

and

mounted

with

a

xylene-soluble

mounting

medium

Immunoreactivity

scoring

The

screening

of

tumour

tissue

samples

was

performed

by

two

independent

investigators

-LRB-

CH

and

AH

-RRB-

The

sections

were

screened

for

positive

cells

defined

as

cells

with

nuclear

staining

The

amount

of

or

staining

is

scored

in

percentages

The

threshold

for

positivity

is

positive

staining

The

areas

with

maximal

immunohistochemical

staining

were

used

for

scoring

In

total

tumour

cells

were

scored

In

the

visual

estimation

only

definitely

brown

nuclei

were

recorded

as

positive

The

results

were

expressed

as

percentage

of

immunoreactive

tumour

cell

nuclei

Results

Fifteen

patients

-LRB-

males

females

-RRB-

signed

a

patient

informed

consent

and

participated

in

this

study

Ages

ranged

from

to

years

-LRB-

mean

years

-RRB-

All

patients

underwent

cystectomy

for

transitional

cell

carcinoma

of

the

bladder

Eight

patients

had

a

de

novo

invasive

bladder

tumour

whereas

seven

patients

had

a

history

of

high-risk

superficial

disease

Patient

details

are

summarized

in

Table

Table

details

containing

number

of

previous

occurrences

interval

period

between

initial

diagnosis

and

cystectomy

in

months

pathology

data

of

biopsy

and

cystectomy

-LRB-

grading

according

to

WHO

-RRB-

GroupsPatient

no/age/sexN

previous

occurrencesInterval

biopsy

cystectomy

-LRB-

in

months

-RRB-

Histopathology

initial

biopsyHistopathology

-LRB-

MMC

-RRB-

-LRB-

HT

-RRB-

-LRB-

MMC

HT

-RRB-

-LRB-

History

of

MMC

HT

-RRB-

-LRB-

Control

-RRB-

microwave

induced

hyperthermia

The

initial

biopsies

and

tumour

tissues

obtained

with

cystectomy

were

used

for

histopathological

diagnosis

and

immunohistochemical

analysis

of

and

The

results

from

the

different

treatment

groups

are

summarized

in

Table

In

one

patient

of

the

MMC

group

no

residual

tumour

could

be

retrieved

in

the

cystectomy

specimen

The

proliferation

activity

and

activity

could

not

be

scored

in

that

patient

Table

and

immunoreactivity

scorings

in

percentages

of

all

patients

divided

in

five

different

treatment

groupsGroupsMaterialInflammationProliferation

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

MMC

-RRB-

aBiopsy

Cystectomy

bBiopsy

Cystectomy

cBiopsy

-LRB-

HT

-RRB-

aBiopsy

Cystectomy

bBiopsy

Cystectomy

cBiopsy

Cystectomy

-LRB-

MMC

HT

-RRB-

aBiopsy

Cystectomy

bBiopsy

Cystectomy

cBiopsy

Cystectomy

-LRB-

History

of

MMC

HT

-RRB-

aBiopsy

Cystectomy

bBiopsy

Cystectomy

cBiopsy

Cystectomy

-LRB-

Control

-RRB-

aBiopsy

Cystectomy

bBiopsy

Cystectomy

cBiopsy

Cystectomy

The

extend

of

inflammation

and

haemorrhage

is

semi

quantitatively

scored

-LRB-

to

-RRB-

not

applicable

due

to

absence

of

residual

tumour

The

intensity

of

inflammation

increased

in

three

out

of

nine

patients

treated

with

hyperthermia

In

three

out

of

five

patients

from

the

MMC

group

and

control

group

an

increase

was

seen

The

intensity

of

haemorrhage

increased

in

four

out

of

nine

patients

treated

with

hyperthermia

one

patient

showed

a

decrease

and

four

patients

did

not

show

any

difference

In

the

MMC

group

and

in

the

control

group

two

patients

showed

an

increase

one

patient

a

decrease

and

two

patients

did

not

show

any

difference

In

six

out

of

the

nine

patients

treated

with

hyperthermia

a

decrease

in

proliferation

activity

in

the

tumour

tissue

sample

was

found

-LRB-

Fig.

-RRB-

In

the

MMC

group

one

patient

showed

a

decrease

and

one

showed

an

increase

in

proliferation

activity

In

the

control

group

two

out

of

three

patients

showed

no

changes

whereas

in

one

patient

an

increase

in

proliferation

activity

was

seen

Fig.

and

positive

staining

in

patient

no.

-LRB-

hyperthermia

group

-RRB-

shows

positivity

before

treatment

shows

positivity

after

treatment

shows

positivity

before

treatment

and

shows

positivity

after

treatment

As

regards

seven

out

of

nine

patients

treated

with

hyperthermia

showed

a

decrease

in

activity

-LRB-

Fig.

-RRB-

In

one

patient

no

change

was

found

The

control

group

and

the

group

treated

with

MMC

did

not

show

any

differences

concerning

Discussion

Thermo-chemotherapy

has

shown

to

be

a

promising

method

for

treating

several

kinds

of

malignant

tumours

including

superficial

bladder

cancer

-LSB-

-RSB-

While

hyperthermia

is

important

in

cancer

therapy

it

can

also

damage

normal

tissues

adjacent

to

the

tumour

Fajardo

-LSB-

-RSB-

reviewed

the

effects

of

hyperthermia

from

several

studies

on

various

tissues

of

mammals

and

humans

Hyperthermia

with

a

maximum

applied

temperature

of

°C

showed

no

gross

or

microscopic

alterations

of

the

bladder

of

dogs

and

rabbits

Subsequently

Rath-Wolfson

et

al.

-LSB-

-RSB-

studied

the

effect

of

hyperthermia

with

a

maximum

applied

temperature

of

°C

and

simultaneous

MMC

treatment

in

sheep

In

this

study

thermo-chemotherapy

showed

no

significant

macroscopic

or

microscopic

differences

in

the

bladder

wall

as

compared

to

a

control

group

with

untreated

sheep

In

the

current

study

the

effect

of

the

combination

thermo-chemotherapy

is

compared

with

solely

hyperthermia

solely

chemotherapy

and

no

treatment

-LRB-

control

group

-RRB-

in

human

patients

with

high-grade

urothelial

cell

carcinoma

of

the

bladder

The

system

SB-TS

used

to

deliver

local

microwave

induced

hyperthermia

makes

it

possible

to

dose

the

hyperthermia

very

precisely

-LSB-

-RSB-

In

this

study

hyperthermia

was

delivered

within

a

temperature

range

of

°C

the

clinical

situation

This

makes

comparison

between

the

different

groups

more

accurate

The

sample

size

of

the

group

studied

is

small

due

to

the

fact

that

recruitment

of

patients

was

difficult

Patients

had

to

agree

on

an

extra

treatment

session

only

two

days

before

cystectomy

which

did

not

give

them

any

benefit

at

all

The

degree

of

inflammation

increased

in

the

group

treated

with

solely

hyperthermia

-LRB-

N

-RRB-

solely

MMC

-LRB-

N

-RRB-

and

the

control

group

-LRB-

N

-RRB-

In

the

group

treated

with

thermo-chemotherapy

days

before

surgery

the

degree

of

inflammation

was

initially

already

maximal

In

the

group

treated

with

a

cycle

of

six

thermo-chemotherapy

treatments

during

the

last

months

the

degree

of

inflammation

apparently

had

returned

to

baseline

again

At

least

one

patient

per

group

-LRB-

except

the

control

group

-RRB-

showed

an

increase

in

the

degree

of

haemorrhage

Patients

from

group

-LRB-

solely

MMC

-RRB-

showed

the

highest

degree

of

haemorrhage

Group

patients

-LRB-

treated

with

thermo-chemotherapy

prior

to

cystectomy

-RRB-

show

in

one

patient

an

increase

in

one

patient

a

decrease

and

in

one

patient

a

stable

extend

of

haemorrhage

This

is

in

line

with

the

results

from

Rath-Wolfson

et

al.

-LSB-

-RSB-

Nevertheless

since

solely

MMC

and

solely

hyperthermia

gives

an

increase

in

haemorrhage

it

would

have

been

logical

to

find

a

higher

extend

of

haemorrhage

after

the

combination

of

both

treatments

Possibly

this

is

not

found

due

to

the

small

sample

size

The

inhibition

of

proliferation

activity

is

one

of

the

most

important

goals

in

cancer

treatment

All

groups

treated

with

hyperthermia

showed

to

a

different

extend

a

decrease

in

proliferation

activity

Most

interesting

are

the

three

patients

treated

with

thermo-chemotherapy

preceding

transurethral

resection

All

three

patients

showed

a

decrease

in

proliferation

activity

The

control

group

on

the

other

hand

shows

in

two

patients

no

difference

and

in

one

patient

an

increase

in

proliferation

activity

In

earlier

in

vitro

studies

using

hyperthermia

and

bladder

cancer

cell

lines

this

decrease

in

cell

proliferation

due

to

hyperthermia

combined

with

chemotherapeutic

agents

was

already

shown

-LSB-

-RSB-

However

in

these

in

vitro

studies

solely

hyperthermia

did

not

cause

a

significant

decrease

in

cell

proliferation

Nevertheless

there

is

a

difference

between

in

vitro

and

in

vivo

studies

This

in

vivo

study

is

the

first

one

showing

a

decreased

proliferation

activity

in

humans

treated

with

microwave-induced

hyperthermia

with

or

without

MMC

The

effect

of

hyperthermia

was

seen

in

six

out

of

nine

patients

treated

with

hyperthermia

preceding

cystectomy

Furthermore

the

group

treated

with

solely

MMC

did

not

show

a

significant

decrease

in

proliferation

activity

This

is

probably

due

to

the

limited

penetration

properties

of

this

intravesical

used

drug

especially

after

one

single

treatment

is

known

to

be

responsible

for

repair

or

apoptosis

in

response

to

DNA

damage

The

activity

in

other

words

the

expression

of

mutant

decreased

exclusively

in

patients

treated

with

hyperthermia

with

or

without

MMC

Previous

experiments

showed

that

the

pathway

is

heat

sensitive

and

that

the

protein

is

inactivated

at

temperatures

above

°C

-LSB-

-RSB-

When

cells

were

heated

to

°C

and

returned

to

normal

temperatures

a

strong

response

with

an

increase

in

protein

levels

was

observed

In

our

study

we

found

the

opposite

but

the

time

interval

between

treatment

and

cystectomy

was

with

days

-LRB-

group

-RRB-

and

several

months

-LRB-

group

-RRB-

significantly

longer

than

the

time

interval

used

by

Guan

et

al.

-LSB-

-RSB-

Furthermore

the

results

of

this

study

are

based

on

a

small

number

of

patients

which

makes

statistic

analysis

unreliable

On

the

other

hand

the

current

results

suggest

that

thermo-chemotherapy

could

be

an

effective

treatment

in

patients

with

a

tumour

suppressor

gene

mutated

tumour

In

all

the

results

show

several

trends

and

encourage

carrying

out

larger

experimental

studies

Conclusion

The

degree

of

inflammation

and

haemorrhage

in

bladder

tumours

did

not

increase

in

patients

treated

with

hyperthermia

This

in

combination

with

a

decrease

in

proliferation

activity

and

a

decrease

in

activity

implies

that

thermo-chemotherapy

is

a

safe

and

promising

treatment

O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O B O O O O O O O O O O O O O O O O O O B O O O O B O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O B O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O B O O O O O B O O O O O O O O B O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O B I I O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O B O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O B O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O B O O O O O O O O O B O O O O O O O B O O O O O O O O O O B O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O B O O O O O O O O O O O O

superficial bladder cancer
hyperthermia
chemotherapy
p53


The use of mechanical bowel preparation in elective colorectal surgery Background Mechanical bowel preparation -LRB- MBP -RRB- prior to elective colorectal surgery has been in use for many years . It is considered important in preventing post-operative infectious complications after colorectal surgery . The evidence to support these claims is lacking within the medical literature and yet this still remains standard practice in many hospitals . A literature search was undertaken to ascertain the evidence available regarding the use of MBP in elective colorectal surgery . BACKGROUND Mechanical bowel preparation -LRB- MBP -RRB- prior to elective colorectal surgery has been in use for many years . Early observational studies and long-standing clinical experience have shown that removal of faecal matter from the bowel lumen prior to surgery has been associated with decreased patient morbidity and mortality1 . It is still commonly used in routine practice today2 . In fact , in a recent survey of members of the American Society of Colon & Rectum Surgeons , 99 % of respondents routinely use MBP although 10 % question its use3 . This is in keeping with common belief that clinical practice often is not evidence based but is based on tradition , previous teaching and anecdote . MBP is considered important in preventing post-operative infectious complications after colorectal surgery2 ,4 -- 10 . Important infectious complications include wound infection , intra-abdominal abscess formation and anastomotic leakage . There are a number of ways in which MBP is thought to act . It may decrease intraoperative contamination with faecal material thereby reducing the incidence of post-operative wound infection and residual intra-abdominal infection6 ,7,9,10 . It may prevent mechanical disruption of the anastomosis by the passage of hard faeces9 and improves the handling of the bowel intra-operatively2 ,7 . It may reduce the bacterial count within the colon7 ,10 . Conversely , it may also be associated with bacterial translocation through the bowel wall hence possibly contributing to post-operative infectious complications5 ,11 . The evidence to support these claims is lacking within the medical literature and yet this still remains standard practice in many hospitals4 ,12 . Primary colonic anastomosis is considered unsafe in unprepared bowel but there is little data to suggest that infectious complications are decreased by MBP10 . Bowel preparation is unpleasant for patients and can be associated with complications such as dehydration , nausea , vomiting , mucosal lesions , hypokalaemia and other electrolyte disturbances1 ,9,11 . The omission of this practice from pre-operative preparation would be welcomed by nursing staff and patients alike . ? METHODS A literature search was undertaken to ascertain the evidence available regarding the use of MBP in elective colorectal surgery . This included a search of PubMed , Medline and Embase using the keywords `` mechanical bowel preparation '' , `` bowel cleansing '' and `` elective colorectal surgery '' , a search of recent relevant journals including Diseases of the Colon and Rectum and British Journal of Surgery and backward chaining from articles obtained . The search was restricted to English language articles and a timescale of 10 years was chosen to give a balanced view of this topic . In this review , mechanical bowel preparation will be defined as an oral preparation given prior to surgery to clear faecal material from the bowel lumen . There are a number of different preparations available including polyethylene glycol , mannitol and sodium picosulphate . Rectal enemas may also be administered before low anterior resections to ensure that the rectum is empty . Elective colorectal surgery is defined as any surgery undertaken on a planned basis for any condition of the colon or rectum requiring bowel resection and primary anastomosis . This will include colorectal carcinoma and inflammatory bowel disease . There are a number of recent randomised controlled trials -LRB- RCTs -RRB- to evaluate the use of MBP prior to elective colorectal surgery ,10,11,13,14 and specifically for left-sided resections5 . Many of these studies are underpowered therefore introducing the possibility of a Type II error and limiting the use of these results in clinical decision-making -LRB- Table I -RRB- . Table I RCTs examining MBP Zmora 2003 Fa-Si-Oen 2005 Ram 2005 Bucher 2005 Miettinen 2000 No . of patients included 415 250 329 153 267 No . of patients excluded 35 0 Not given 0 12 No . of pt -LRB- MBP/no MBP -RRB- 187/193 125/125 164/165 78/75 138/129 Mean age -LRB- MBP/no MBP -RRB- 68/68 68/70 -LRB- median -RRB- 68/68 63/63 61/64 Cancer % -LRB- MBP/no MBP -RRB- 78/78 90/92 75/88 32/28 46/55 L colon surgery % -LRB- MBP/no MBP -RRB- 68/72 48/58 89/85 100/100 45/47 Type of prep Polyethylene glycol Polyethylene glycol Sodium phosphate Polyethylene glycol Polyethylene glycol Antibiotic Yes Yes Yes Yes Yes Same length of prophylaxis No Yes Yes No Yes Rectal enema Yes No No Yes No Anastomosis % -LRB- stapled / handsewn -RRB- Not given 7/93 -LRB- MBP -RRB- 8/92 -LRB- no MBP -RRB- 94/6 -LRB- MBP -RRB- 98/2 -LRB- no MBP -RRB- Not given 60/30 -LRB- MBP -RRB- 62/28 -LRB- no MBP -RRB- Surgeon/trainee % Not given 42/59 -LRB- MBP -RRB- 50/50 -LRB- no MBP -RRB- 37/63 -LRB- MBP -RRB- 32/68 -LRB- no MBP -RRB- Not given Not given Anastomotic leak % -LRB- MBP / no MBP -RRB- 3.7 / 2.1 -LRB- NS -RRB- 5.6 / 4.8 -LRB- NS -RRB- 0.6 / 1.2 -LRB- NS -RRB- 6/1 -LRB- NS -RRB- 4/2 -LRB- NS -RRB- Wound infection % -LRB- MBP / no MBP -RRB- 6.4 / 5.7 -LRB- NS -RRB- 7.2 / 5.6 -LRB- NS -RRB- 9.8 / 6.1 -LRB- NS -RRB- 13/4 -LRB- NS -RRB- 4/2 -LRB- NS -RRB- Intra-abdominal abscess % -LRB- MBP / no MBP -RRB- 1.1 / 1 -LRB- NS -RRB- Not given 0.6 / 0.6 -LRB- NS -RRB- 1/3 -LRB- NS -RRB- 2/3 -LRB- NS -RRB- NS = not significant This lack of power in studies is somewhat overcome by the use of meta-analyses and systematic reviews of the literature but the reader must be aware that these methods also have their limitations . A number of meta-analyses and systematic reviews were used in this review1 ,2,7 -- 9,15 . DISCUSSION Six systematic reviews were identified in the literature assessing the role of MBP in preventing infectious complications following colorectal surgery1 ,2,7 -- 9,15 . The meta-analysis carried out by Platell & Hall7 found a statistically significant increase in the incidence of wound infection in those patients receiving MBP when considering the three included RCTs . This may have been influenced by the rate of wound infection seen in one trial that used a five day regime of MBP . The anastomotic leakage rate was also higher in the MBP group but not significantly so . Each RCT used a different type of MBP and this lack of standardisation affects the validity of the results . The included studies were also underpowered thereby introducing a high possibility that they failed to detect a significant difference in the results -LRB- type II error -RRB- . Evidence from the prospective and retrospective studies was in favour of no MBP in pre-operative period . A subsequent review of the literature by Zmora et al9 appraised four RCTs . One of the studies found an increased risk of anastomotic leakage and intra-abdominal infection but no increased risk of wound infection in the group of patients receiving MBP . The remaining RCTs found no significant difference in intra-abdominal infection rate but a slight increase in wound infection rate in the MBP group . There were conflicting results in the non-randomised studies with some showing an increased rate of infection and others reporting no difference in infection rates between the groups . The remaining four meta-analyses only included RCTs1 ,2,8,15 . All authors agreed that MBP was of no benefit in preparation for colorectal surgery and it may be detrimental to the patients ' outcome1 ,2,8 . Wille -- Jorgensen et al15found that although initial analysis showed a significantly higher rate of anastomotic leakage in the MBP group , this significance disappears when sensitivity analyses are applied thereby weakening the conclusion that MBP leads to an increased rate of anastomotic leakage . Slim et al8 found there was significantly more anastomotic leakage in the group of patients receiving MBP and a tendency to a higher rate of wound infection but this was not statistically significant . This group repeated the analysis excluding the poor quality trials and the results still favoured a no MBP regime although this was not statistically significant . Only two meta-analyses looked at MBP in rectal surgery specifically1 ,15 . Willie-Jorgensen et al15 found that when results were stratified for colonic and rectal surgery there was no trend in either direction . Guenaga et al1 found that the results of stratification favoured no MBP but this was not statistically significant . This is of more clinical importance as it may be difficult to perform a low anterior resection and anastomosis with a loaded rectum15 . Both authors suggest that further trials evaluating the use of rectal preparation with enemas may be useful . Guenaga et al1also mention that the use of pre-operative radiotherapy would be an important consideration in assessment of bowel preparation for rectal surgery as many patients with rectal cancer undergo pre-operative radiotherapy . All but one of the five RCTs examining MBP5 ,10,11,13,14 found no significant difference in the rate of anastomotic leakage and wound infection between patients receiving MBP or not10 ,11,13,14 . The largest trial was undertaken by Zmora et al10 with 415 patients recruited . There are several flaws in the methodology of this trial introducing bias and compromising the validity of the results . There was no difference found in the rate of post-operative infectious complications between the two groups . The rate of diarrhoea post-operatively was significantly more common in the group receiving MBP but this is of little clinical significance , as many patients will experience an increased stool frequency once the bowels become active . The authors acknowledge that separating the role of MBP in post-operative infection rate is difficult and ideally all other measures should be constant . They also note that the study is underpowered to detect a 5 % difference in infection rate . The RCT conducted by Bucher et al5 comparing MBP with no MBP in patients undergoing elective left-sided colorectal surgery found an increase in the total incidence of infectious abdominal complications in the group receiving MBP -LRB- 22 % v 8 % ; p = 0.028 -RRB- . This led the authors to conclude that there was good evidence to suggest that the practice of MBP should be re-evaluated . They gave an enema pre-operatively to all patients undergoing an anterior resection regardless of whether they had been randomised to MBP or not , decreasing the internal validity of the results . If anastomotic leak rate -LRB- a more clinically important outcome than wound infection -RRB- were to be used as the primary end-point then the study would need 514 patients in each group . The trial conducted by Ram et al14 was not properly randomised , introducing methodological bias and limiting the value of the results of this study . There was no definition of sample size and patients with low rectal anastomosis were excluded . Again , the assessor of outcome was not blinded to the intervention , introducing another source of bias . No statistically significant difference in the frequency of infectious complications was observed between the groups yet the authors concluded that `` mechanical bowel preparation is unnecessary for safe elective colonic and colorectal surgery '' . But they recommend MBP in selected cases including the resection of small tumours when palpation of the colon may be necessary or when intra-operative colonoscopy may be performed . Fa-Si-Oen et al13 conducted a well-designed multi-centre RCT , reported in 2005 . Approximately half the resections carried out in this study were left-sided . This is important as it is now generally accepted that right-sided anastomosis is safe without MBP . This study excluded patients undergoing rectal surgery . There was no significant difference in wound infection or anastomotic leak rate but the bacterial swab results used to define wound infection in this study were only correctly obtained in 185 out of 250 patients therefore this may not be an accurate reflection of the true rate of wound infections . This study could not demonstrate an additional protective effect for MBP but it was an interim analysis and was underpowered . As a result , conclusions for clinical practice can not be drawn from these results . Miettinen et al11 reported the results of a prospective , randomised study including patients undergoing rectal surgery . There was no significant difference in infectious complications found between the two groups but it is difficult to conclude on the influence on anastomotic leakage from these results as the study included patients who did not undergo an anastomosis . A number of these reported trials are underpowered thereby limiting their ability to detect a clinically significant difference in outcome between the two study groups10 ,11,13 . One way of overcoming the problem of small sample sizes is to carry out a multi-centre trial where a larger number of patients are easier to recruit . A limitation is that they introduce heterogeneity in operative and peri-operative techniques . This is important , as surgical technique may be the single most important factor in influencing the surgical outcome9 . All these studies agree that elective colorectal surgery may be safely performed without MBP and that there is no evidence to continue this invasive practice with potentially negative side effects . Memon et al16 carried out a retrospective non-randomised trial based on operating surgeon preferences using a questionnaire . The validity of this questionnaire is unclear as no pilot study was carried out prior to the collection of definitive data . Follow-up of the patients was obtained using the hospital records therefore relying on accurate clinical notes , which are not always available . One hundred and thirty six patients who underwent elective left-sided colorectal procedures for non-obstructive large bowel pathologies were identified using the hospital computer system . Coding errors may mean that some eligible patients were excluded from the analysis . This , along with the lack of randomisation , would introduce significant bias . No statistical difference was found between the two groups for all infectious complications and mortality . The authors recognise the limitations of their results and do not recommend any changes in practice but do suggest that a prospective randomised trial should be performed to demonstrate the impact of MBP on morbidity and mortality in patients undergoing elective colorectal surgery . A prospective , observational trial performed by van Geldere et al17 assessed the outcome of 250 consecutive patients who underwent resection and primary anastomosis of the colon and upper rectum under the care of a single surgeon . None of these patients received MBP pre-operatively . Both emergency and elective procedures were included in analysis . Results were favourable with an overall wound infection rate of 3.3 % and an anastomotic failure rate for left-sided resections of 1.2 % . The authors recommend that more powerful randomised trials are needed but in the hands of a single surgeon , primary anastomosis of unprepared bowel is safe with relatively few complications . A small observational study conducted by Ahmad et al4 found an anastomotic leak rate of 4.2 % and a wound infection rate of 8.5 % . The average age of the sample was lower than that of the typical population undergoing colorectal surgery . This fact , plus the small sample size , compromises the external validity or the extent to which the results can be generalised to other samples or situations . CONCLUSION There are a number of meta-analyses , systematic reviews and RCTs looking at the efficacy of MBP in preventing post-operative infectious complications following elective colorectal surgery . Unfortunately many of these trials are underpowered and have a high chance of a type II error10 ,11,13 . Most authors recommend that colorectal surgery is safe without pre-operative MBP but that there may some situations in which it may be beneficial -LRB- e.g. if there is a small tumour or the possible need for intra-operative colonoscopy -RRB- 14 . The implication for clinical practice in this situation is that there is not enough strength of evidence at present to recommend a change in practice . There is a need for further higher powered trials to try to answer this question definitively . The only way that this may be achieved is by multi-centre trials where it is easier to recruit a large number of patients but it must be taken into consideration that this will introduce heterogeneity in the operative and peri-operative techniques which may have an influence on overall outcome9 . There is a need for larger clinical trials in this area to address whether MBP , with its potential side effects , is truly necessary prior to elective colorectal surgery . Further studies are required to assess the use of rectal preparation alone prior to rectal surgery1 ,15 and also to include patients who have undergone pre-operative radiotherapy1 as this is a common occurrence in patients who have rectal carcinoma and these patients may subsequently undergo resection with primary anastomosis . It is clear that further research is needed to clarify the role of MBP in elective colorectal surgery to ensure that the patients are receiving the most appropriate treatment with the least adverse effects .

O O O B I I O O B I O B I I O O O O O O B I O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O B I I O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O B I I O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O

mechanical bowel preparation
colorectal surgery


Use of FDG-PET in differentiating benign from malignant compression fractures Objective The objective was to evaluate the use of fluorodeoxyglucose positron emission tomography -LRB- FDG-PET -RRB- in differentiating benign from malignant compression fractures . Introduction Differentiating between malignant and benign vertebral compression fractures can represent a diagnostic challenge and is particularly difficult in elderly patients , who frequently have a history of malignancy and are also predisposed to benign compression fractures from osteoporosis or treatment-related changes -LSB- 1 -- 3 -RSB- . Differentiating between benign and malignant compression fractures has important therapeutic and prognostic implications . Computed tomography -LRB- CT -RRB- and magnetic resonance imaging -LRB- MRI -RRB- are routinely used in the evaluation of compression fractures ; however , these imaging modalities do not always permit definite diagnosis -LSB- 2 -- 5 -RSB- . In contrast to MRI or CT , fluorodeoxyglucose positron emission tomography -LRB- FDG-PET -RRB- can yield metabolic information that is based on increased glucose metabolism of malignant and inflammatory lesions . Tumor cells typically accumulate FDG , while traumatic fractures are not expected to significantly accumulate FDG . Therefore , FDG-PET may allow differentiation between malignant and benign compression fractures -LSB- 6 -- 9 -RSB- . The purpose of our study was to evaluate the use of FDG-PET in differentiating benign from malignant compression fractures . Materials and methods This study was approved by the institutional review board of our institution , which waived the need for informed consent . The study was compliant with the Health Insurance Portability and Accountability Act . A retrospective search was performed using Boolean operators -LRB- Folio ; Open Market , Proto , UT , USA -RRB- to identify all patients who had undergone whole-body FDG-PET at our institution from 2003 to 2006 and had the finding of a compression fracture mentioned in the PET report . Imaging studies and reports , medical records , and pathology reports of selected cases were reviewed . Patients We identified 33 patients with compression fractures who underwent whole-body FDG-PET . There were 23 women and 10 men , aged 48 -- 93 years , with a mean age of 72 years . Twenty-nine patients had a history of malignancy -LRB- 1 had leukemia , 5 lung cancer , 1 ovarian cancer , 2 breast cancer , 5 colon cancer , 9 lymphoma , 1 sarcoma , 1 pancreatic cancer , 1 Klatskin tumor , 1 gastrointestinal stromal tumor , 1 laryngeal cancer , and 1 had esophageal cancer -RRB- . The 4 patients without history of malignancy underwent whole body PET for work-up of indeterminate lung nodules detected on prior CT or radiographs . Sixteen patients underwent FDG-PET and 17 patients underwent FDG-PET/CT at time of evaluation . Nine patients underwent CT and 14 patients underwent MRI of the spine within 4 weeks of FDG-PET . Seventeen patients were followed up with serial FDG-PET studies . Nine patients underwent biopsy and the pathologic results were used as a standard of reference . Twenty-four patients who did not undergo biopsy were followed up clinically and with repeat imaging , with MRI , CT , or FDG-PET for a period of 1 -- 3 years and findings at clinical follow-up and imaging studies were used for lesion verification . In these patients , the development of new lesions and/or progression of existing lesions on imaging were used as criteria for malignant compression fractures . Image acquisition Whole-body PET was performed using an ECAT HR + scanner -LRB- CTI Molecular Imaging , Knoxville , TN , USA -RRB- . All patients fasted for at least 6 h prior to image acquisition , and blood glucose levels were measured prior to the injection of FDG . A dose of 15 -- 20 mCi -LRB- 555 -- 740 MBq -RRB- of FDG was administered intravenously 45 min to 1 h prior to scanning . Patients were positioned supine on the scanner and emission images were acquired in 6 -- 7 bed positions from the mandible to the mid-thigh or to the level of the ankles in the case of lower extremity lesions . Transmission images obtained with a rotating germanium 68-rod source were used for attenuation correction . Images were reconstructed using the ordered-subset expectation maximization -LRB- OSEM -RRB- algorithm . Combined PET/CT studies were performed with a 16-section hybrid PET/CT gantry -LRB- Biograph Sensation 16 ; Siemens , Erlangen , Germany -RRB- , which comprises a 16-section high-performance multi-detector row CT scanner with a lutetium oxyorthosilicate-based PET scanner . The PET image spatial resolution was 5.0 mm full width at half maximum , with a section thickness of 3.5 mm . Patients fasted for at least 6 h prior to image acquisition , and blood glucose levels were measured prior to the injection of FDG . Two 10-oz cups of water were administered as negative contrast material 1 h prior to scanning . A dose of 15 -- 20 mCi -LRB- 555 -- 740 MBq -RRB- of FDG was administered intravenously 45 min to 1 h prior to scanning . Patients were positioned supine on the scanner and emission images were acquired in 6 -- 7 bed positions from the mandible to mid-thigh or to the level of the ankles in the case of lower extremity lesions . Images were reconstructed with Fourier rebinning and attenuation-weighted ordered-subsets expectation maximization . A low-dose CT scan was performed prior to PET imaging primarily for attenuation correction , with patients holding their breath mid-expiration , and included an area from the mandible to the mid-thigh or to the level of the ankles in the case of lower extremity lesions . Slice thickness was 5 mm . A diagnostic contrast-enhanced CT was performed subsequent to the PET/CT following the administration of 100 mL intravenous contrast material -LRB- Isovue 300 ; Bracco Diagnostics , Princeton , NJ , USA -RRB- at an injection rate of 2 mL/s using 2.5-mm sections . Image analysis Semiquantitative and qualitative evaluation of PET images was performed on a high-resolution workstation -LRB- Reveal-MVS ; Mirada Solutions , Oxford , UK -RRB- by one investigator , who was blinded to the clinical and pathological results -LRB- MAB -RRB- . The images were displayed in rotating maximum intensity projections and in axial , coronal , and sagittal planes . Semiquantitative analysis of FDG uptake was performed by creating a region of interest over the area of maximal radiotracer activity . Maximum standardized uptake values -LRB- SUVs -RRB- were automatically generated according to the following equation : SUVmax -LRB- bw -RRB- = Ctis/Dinj/bw , where SUVmax -LRB- bw -RRB- is maximum SUV normalized for body weight ; Ctis , tissue concentration expressed as megabecquerels per milliliter ; Dinj , injected dose expressed as megabecquerels ; and bw , body weight expressed as kilograms . Lesions with SUV greater than 3.0 were considered malignant and less then 3.0 were considered benign . However , lesions with SUV between 2 and 3 are often indeterminate and do not always allow definite diagnosis , and also the pattern of uptake has to be considered . Qualitative assessment was made with the specific aim of establishing whether the lesion was benign or malignant . The radiotracer uptake by the lesion was compared with the liver , and those lesions with uptake greater than the liver were classified as malignant . Statistical analysis The recorded data were analyzed using JMP statistical database software -LRB- SAS Institute , Cary , NC , USA -RRB- . The findings on the PET images as well as SUV of benign and malignant compression fractures were correlated with the final diagnosis of the lesion and determined either malignant or benign . Sensitivity , specificity , positive predictive value , negative predictive value , and accuracy were calculated . The Student 's t test was used to determine whether there was a statistically significant difference between the SUV for benign and malignant compression fractures . A difference with p < 0.05 was considered to be statistically significant . Results Forty-three compression fractures were identified in 33 patients . Twenty-two fractures involved the thoracic and 21 fractures the lumbar spine . Nine patients underwent biopsy and 24 patients were followed up clinically and with repeat imaging . In the 9 patients who underwent biopsy , there were 3 benign and 6 malignant compression fractures . Of the 24 patients who were followed clinically and with repeat imaging , 6 patients were thought to have malignant and 18 patients were thought to have benign compression fractures . Overall , there were 21 patients with benign and 12 patients with malignant compression fractures . Out of the 43 compression fractures , there were 29 benign and 14 malignant fractures . Based on clinical history -LRB- acute onset of back pain often after minor trauma -RRB- and imaging characteristics on MRI -LRB- bone marrow edema -RRB- there were 5 acute benign compression fractures . Three patients were on bone marrow-stimulating therapy at the time of FDG-PET . Five patients were unable to undergo MRI because of pacemakers -LRB- 3 -RRB- or severe pain . Qualitative PET analysis Forty-three compression fractures were identified in 33 patients . Visual inspection of suspected lesions on FDG-PET characterized 26 compression fractures as benign and 17 fractures as malignant . The malignant lesions demonstrated intense radiotracer uptake -LRB- Figs. 1 , 2 -RRB- , while benign compression fractures showed only mildly increased or no increased uptake on FDG-PET -LRB- Figs. 3 , 4 -RRB- . Histological and clinical follow-up data were analyzed . By FDG-PET , 12 lesions were correctly classified as malignant -LRB- true-positive -RRB- and 24 lesions were correctly classified as benign -LRB- true-negative -RRB- . Two malignant tumors were incorrectly classified as benign -LRB- false-negative -RRB- and 5 benign tumors were incorrectly classified as malignant -LRB- false-positive -RRB- . In the 2 false-negative cases there was moderately increased uptake of the compression fractures , which was thought to represent acute benign fractures prospectively , but was found to be metastatic disease on subsequent biopsy -LRB- Fig. 5 -RRB- . SUV in these patients were 2.5 to 2.8 respectively , and the primaries in these cases were esophageal and lung cancer . Fig. 1a Malignant compression fracture in a patient with lymphoma . Sagittal FDG-PET image demonstrates intense radiotracer uptake in the L1 vertebral body -LRB- SUV = 7.1 ; arrow -RRB- . b Axial FDG-PET image demonstrates tumor infiltration of the L1 vertebral body with associated extra-osseous component -LRB- arrows -RRB- . c Sagittal T1-weighted MRI demonstrates diffuse low signal intensity of the bone marrow of the lumbar spine with compression fracture of L1 -LRB- arrow -RRB- . d Sagittal fat-suppressed T1-weighted MRI following the administration of gadolinium demonstrates diffuse enhancement of the L1 compression fracture -LRB- arrow -RRB- . e Axial image from a CT-guided biopsy demonstrates large extra-osseous soft tissue component -LRB- white arrow -RRB- and infiltration of the L1 vertebral body -LRB- black arrows -RRB- Fig. 2a Malignant compression fracture from metastatic colon cancer . Sagittal fused FDG-PET/CT image demonstrates intense radiotracer uptake in the T7 compression fracture -LRB- SUV = 6.3 ; arrow -RRB- . b Axial fused FDG-PET/CT image demonstrates focal increased radiotracer uptake in the T7 vertebral body -LRB- arrow -RRB- . c Sagittal T1-weighted MRI demonstrates compression fracture of T7 with low signal marrow infiltration -LRB- arrow -RRB- . d Sagittal STIR image demonstrates mild hyperintensity of the T7 vertebral compression fracture -LRB- arrow -RRB- . e Sagittal fat-suppressed T1-weighted MRI following the administration of gadolinium demonstrates diffuse enhancement of the T7 compression fracture -LRB- arrow -RRB- . Malignancy was indeterminate on MRIFig . 3Benign compression fracture in a patient with lymphoma . Sagittal fused FDG-PET/CT image demonstrates compression fracture of T9 -LRB- arrow -RRB- without significant radiotracer uptake -LRB- SUV = 0.7 -RRB- Fig. 4a Benign subacute compression fractures in a patient without history of malignancy . Sagittal FDG-PET image demonstrates mildly increased radiotracer uptake in the upper thoracic spine -LRB- SUV = 1.8 ; arrow -RRB- . b Axial FDG-PET image at the level of T4 demonstrates mildly increased radiotracer uptake -LRB- arrow -RRB- , consistent with subacute compression fracture . c Sagittal CT image demonstrates compression fracture of T4 -LRB- arrow -RRB- and multiple chronic osteoporotic compression fractures throughout the thoracic spineFig . 5a False-negative compression fracture on FDG-PET in a patient with metastatic esophageal cancer . Sagittal fused FDG-PET/CT image demonstrates mild to moderately increased radiotracer uptake in the L2 compression fracture -LRB- arrow ; SUV = 2.5 -RRB- that was thought to represent a benign compression fracture but was found to be malignant on subsequent biopsy . Note the mildly increased radiotracer uptake in the T11 compression fracture -LRB- arrowhead -RRB- , which was thought to represent a benign fracture . b Axial fused FDG-PET/CT image demonstrates increased radiotracer uptake in the L2 vertebral body -LRB- arrow -RRB- . c Sagittal CT image demonstrates L2 and T11 compression fractures -LRB- arrows -RRB- , for which malignancy was indeterminate Three of the false-positive patients were on bone marrow-stimulating agents -LRB- Fig. 6 -RRB- . One of the false-positive patients had an acute compression fracture -LRB- Fig. 7 -RRB- . Except for that patient , there was no significant difference in uptake pattern of benign acute and benign chronic compression fractures -LRB- Fig. 8 -RRB- . Fig. 6a False-positive compression fracture in a patient on bone marrow-stimulating agents . Sagittal FDG-PET image demonstrates diffuse increased radiotracer activity throughout the spine . Note the compression fractures with focal kyphotic angulation at L1 -- L2 -LRB- arrow -RRB- . The patient was thought to have diffuse metastatic disease with malignant compression fracture . b Sagittal FDG-PET image performed 2 months later demonstrates resolution of diffuse radiotracer uptake . Kyphotic angulation from compression fractures remains -LRB- arrow -RRB- . The patient was off bone marrow-stimulating agents for 6 weeks at the time of the studyFig . 7a False-positive compression fracture in a patient with laryngeal cancer . Sagittal fused FDG-PET/CT image demonstrates increased radiotracer uptake in the T12 compression fracture -LRB- SUV = 4.9 ; arrow -RRB- . b Sagittal T1-weighted MRI demonstrates compression fracture of T12 with linear low signal of the superior endplate and preservation of the normal marrow signal -LRB- arrow -RRB- . Note compression fracture of L1 with relative preservation of normal marrow signal -LRB- arrowhead -RRB- . c Sagittal STIR image demonstrates hyperintensity of the superior endplates of the T12 and L1 compression fractures , suggesting acute fractures -LRB- arrows -RRB- . d Sagittal fat-suppressed T1-weighted MRI following the administration of gadolinium demonstrates enhancement of the T12 compression fracture -LRB- arrow -RRB- . Mild enhancement is noted , involving the L1 compression fracture -LRB- arrowhead -RRB- . Findings were thought to be benign on MRI and on follow-up imaging , there was resolution of bone marrow edema and enhancementFig . 8a Acute and chronic benign compression fractures in a patient without history of malignancy . Sagittal fused FDG-PET/CT image demonstrates multiple compression fractures throughout the thoracic and lumbar spine with mild increased radiotracer uptake at T11 -LRB- SUV = 2.1 ; arrow -RRB- . b Sagittal T1-weighted MRI demonstrates multiple chronic compression fractures -LRB- arrowheads -RRB- . Mild decreased signal intensity of the T11 compression fracture suggests edema -LRB- arrow -RRB- . c Sagittal STIR image demonstrates mild edema in the T11 compression fracture suggestive of an acute fracture -LRB- arrow -RRB- . There is no evidence of marrow edema in the remaining compression fractures Quantitative PET analysis Standardized uptake values were measured in all 43 compression fractures . SUV for benign compression fractures ranged from 0.7 to 4.9 with a mean of 1.94 ± 0.97 standard deviation -LRB- SD -RRB- on FDG-PET . Malignant compression fractures showed SUV from 2.2 to 7.1 with a mean of 3.99 ± 1.52 SD on FDG-PET . The difference between the SUV values of benign and malignant compression fractures was statistically significant -LRB- p < 0.001 , Student 's t test ; Fig. 9 -RRB- . Fig. 9Mean standardized uptake value -LRB- SUV -RRB- of benign and malignant compression fractures . The top of the boxes represent the mean and error bars represent the range of SUV . There is a statistically significant difference between the SUV values of benign and those of malignant compression fractures -LRB- p < 0.001 , Student 's t test -RRB- Statistical analysis Sensitivity , specificity , positive and negative predictive values , and accuracy of FDG-PET in differentiating benign from malignant compression fractures were 86 % , 83 % , 84 % , 71 % , and 92 % respectively . Discussion The correct diagnosis of benign and malignant compression fractures can be problematic , but has important prognostic and therapeutic implications . MRI , CT , or bone scintigraphy are commonly used in the diagnostic work-up of patients with compression fractures . However , in some cases , these imaging techniques do not permit definite diagnosis of the cause of the compression fracture . Diffusion-weighted MRI has been used successfully to differentiate benign from malignant fractures -LSB- 10 -- 13 -RSB- , but benign and malignant compression fractures can show significant overlap on quantitative assessment with apparent diffusion coefficient maps -LSB- 12 -RSB- . Also , some patients are unable to undergo MRI due to pacemakers , claustrophobia , or severe pain . This is especially true in the elderly population . Five of our 33 patients were unable to undergo MRI . In this context , metabolic imaging modalities such as FDG-PET might be used as a management problem solver . FDG-PET has been successfully used to differentiate benign from malignant neoplasms and in the evaluation of metastatic disease -LSB- 14 -- 16 -RSB- . Preliminary studies and case reports have shown that FDG-PET might be helpful in differentiating benign from malignant compression fractures -LSB- 8 , 9 -RSB- . Since elderly patients often have a history of malignancy and are also predisposed to benign compression fractures due to osteoporosis , we thought that FDG-PET might be used as a diagnostic problem solver in this patient population in cases of equivocal MRI or CT findings or if the patient was unable to undergo MRI . In our study , malignant compression fractures demonstrated significantly increased FDG uptake compared with benign fractures . Mean SUV of malignant and benign fractures were 3.99 ± 1.52 SD for malignant lesions and 1.94 ± 0.97 SD for benign lesions . There were 2 false-negative results . In these cases there was moderately increased uptake of the compression fractures , which were thought to be acute benign fractures prospectively , but were found to represent metastatic disease on subsequent biopsy . SUV in these patients were 2.5 to 2.8 respectively . There were 5 false-positive results ; 3 of those patients were on bone marrow-stimulating agents , which mimicked tumor involvement . This effect on bone marrow FDG uptake has been described in the literature -LSB- 17 -RSB- . One to 2 months after cessation of bone marrow-stimulating therapy , FDG uptake returned to normal in our patients . The false-positive results occurred because the investigator was blinded to the clinical history . This is less likely to occur in a clinical setting where this history should be actively sought when interpreting positive findings , especially in cases of diffuse osseous uptake , mimicking a diffuse marrow infiltrative process as was seen in our cases . In fact , when we reviewed the original reports , these cases were reported to be consistent with the known use of bone marrow-stimulating agents . Only mildly increased or no increased uptake was seen in chronic benign fractures and mild to moderately increased uptake was seen in acute benign fractures , which was less than in malignant fractures . This is in contrast to bone scintigraphy , in which increased uptake persists for many months -LSB- 18 -RSB- . Positron emission tomography and PET/CT were equally sensitive in differentiating benign from malignant compression fractures . However , the CT portion of the PET/CT improved the exact fracture localization and was able to provide additional information on fracture morphology , which can be helpful in diagnosing benign vs. malignant fractures . Our study had several limitations . The first is the retrospective nature of the study . Second is the lack of histologic correlation in all cases . Only 9 patients underwent biopsy of the spine . However , we obtained clinical follow-up and serial imaging studies , including serial FDG-PET for a period of 1 -- 3 years to evaluate for benign or malignant fractures . Also , there were no patients with osteomyelitis/discitis , which can mimic malignancy -LSB- 8 , 19 , 20 -RSB- . Another limitation is the lack of inter-observer variability , since only one observer interpreted the images . However , we compared our results with the reports of the original interpreter , who had access to all data . On the original reports , the 3 cases of patients on bone marrow-stimulating agents were interpreted as being consistent with the known use of bone marrow-stimulating agents . Malignancy was said to be indeterminate in the two false-negative reports . However , in our review , we categorized each fracture as either benign or malignant without the option of an indeterminate lesion . In summary , FDG-PET is a useful method of differentiating between benign and malignant compression fractures and can serve as a problem solver in cases of equivocal MRI or CT findings , and in patients who are unable to undergo MRI . We do not recommend FDG-PET as a screening test , but rather as an additional imaging modality in problem cases , particularly in elderly patients with osteoporosis and a history of malignancy . In these patients , FDG-PET has the additional advantage of being able to evaluate the entire skeletal system and screen for metastatic disease .

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O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O B O O O O O O O O O O O O O O O O O O O B O B B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O

spine
compression fractures
malignant
benign