Involvement

of

calcitonin

gene-related

peptide

in

migraine

regional

cerebral

blood

flow

and

blood

flow

velocity

in

migraine

patients

Calcitonin

gene-related

peptide

-LRB-

CGRP

-RRB-

containing

nerves

are

closely

associated

with

cranial

blood

vessels

CGRP

is

the

most

potent

vasodilator

known

in

isolated

cerebral

blood

vessels

CGRP

can

induce

migraine

attacks

and

two

selective

CGRP

receptor

antagonists

are

effective

in

the

treatment

of

migraine

attacks

It

is

therefore

important

to

investigate

its

mechanism

of

action

in

patients

with

migraine

We

here

investigate

the

effects

of

intravenous

human

alpha-CGRP

-LRB-

hαCGRP

-RRB-

on

intracranial

hemodynamics

In

a

double-blind

cross-over

study

the

effect

of

intravenous

infusion

of

hαCGRP

-LRB-

μg/min

-RRB-

or

placebo

for

min

was

studied

in

patients

with

migraine

without

aura

outside

attacks

inhalation

SPECT-determined

regional

cerebral

blood

flow

-LRB-

rCBF

-RRB-

and

transcranial

Doppler

-LRB-

TCD

-RRB-

determined

blood

velocity

-LRB-

Vmean

-RRB-

in

the

middle

cerebral

artery

-LRB-

MCA

-RRB-

as

well

as

the

heart

rate

and

blood

pressure

were

the

outcome

parameters

No

change

of

rCBF

was

observed

at

the

end

of

infusion

-LSB-

with

hαCGRP

vs.

with

placebo

-LRB-

mean

SD

-RRB-

-RSB-

-LRB-

P

-RRB-

Vmean

in

MCA

decreased

to

with

hαCGRP

versus

with

placebo

-LRB-

P

-RRB-

Since

rCBF

was

unchanged

this

indicates

a

dilation

of

the

MCA

hαCGRP

induced

a

decrease

in

MAP

-LRB-

-RRB-

-LRB-

P

-RRB-

and

an

increase

in

heart

rate

-LRB-

-RRB-

-LRB-

P

-RRB-

CGRP

dilates

cerebral

arteries

but

the

effect

is

so

small

that

it

is

unlikely

to

be

the

only

mechanism

of

CGRP-induced

migraine

Introduction

Based

on

animal

research

showing

calcitonin

gene-related

peptide

-LRB-

CGRP

-RRB-

in

perivascular

nerves

-LSB-

-RSB-

and

a

strong

vasodilator

effect

of

CGRP

on

cerebral

blood

vessels

-LSB-

-RSB-

a

role

for

CGRP

in

the

pathogenesis

of

migraine

pain

was

first

suggested

by

reports

of

increased

CGRP

in

external

jugular

venous

blood

during

migraine

attacks

-LSB-

-RSB-

In

one

recent

study

there

was

however

no

increase

of

CGRP

-LSB-

-RSB-

More

solid

evidence

was

presented

in

a

study

which

demonstrated

that

CGRP

infused

intravenously

in

patients

with

migraine

was

able

to

induce

a

vascular

type

headache

in

great

majority

of

patients

and

in

some

patients

this

headache

fulfilled

all

diagnostic

criteria

for

migraine

without

aura

-LSB-

-RSB-

The

final

proof

of

the

involvement

of

CGRP

in

migraine

mechanisms

was

provided

by

two

phase

II

clinical

trials

-LSB-

-RSB-

demonstrating

significant

efficacy

of

the

specific

CGRP

antagonists

-LSB-

-RSB-

and

-LSB-

-RSB-

Thus

CGRP

is

not

only

able

to

induce

attacks

but

it

seems

to

be

continuously

important

throughout

the

entire

migraine

attack

CGRP

is

one

of

the

most

potent

dilators

of

isolated

cerebral

arteries

known

today

-LSB-

-RSB-

but

possible

species

differences

make

it

difficult

to

predict

the

effect

of

CGRP

in

the

human

cerebral

circulation

Although

the

effect

of

CGRP

on

the

cerebral

circulation

has

been

studied

in

normal

subjects

-LSB-

-RSB-

it

is

important

to

study

it

also

in

patients

with

migraine

in

whom

migraine-like

headache

and

migraine

attacks

are

induced

by

CGRP

-LSB-

-RSB-

The

aim

of

the

present

study

was

therefore

to

investigate

the

cerebral

hemodynamic

effects

of

CGRP

in

patients

with

migraine

outside

of

attack

Patients

and

methods

Patients

Twelve

patients

with

migraine

-LRB-

females

male

mean

age

years

range

years

mean

weight

kg

range

kg

-RRB-

were

included

All

suffered

from

migraine

without

aura

according

to

criteria

of

the

International

Headache

Society

-LSB-

-RSB-

The

subjects

were

not

allowed

to

take

medication

coffee

tea

alcohol

or

tobacco

for

h

before

the

study

and

they

were

not

allowed

to

take

a

triptan

h

or

ergotamine

h

before

the

study

Exclusion

criteria

were

as

follows

use

of

any

kind

of

daily

medication

including

prophylactic

headache

therapy

but

excluding

oral

contraceptives

pregnancy

or

breastfeeding

excessive

use

of

analgesics

or

alcohol

serious

somatic

or

psychiatric

disorders

ischaemic

heart

disease

a

supine

systemic

blood

pressure

more

than

or

less

than

mmHg

at

entry

of

study

Patients

were

informed

that

they

were

free

to

withdraw

at

any

time

and

all

gave

written

informed

consent

The

study

was

approved

by

the

local

ethics

committees

of

Copenhagen

and

Copenhagen

County

-LRB-

KA

-RRB-

and

complied

with

the

Declaration

of

Helsinki

Design

and

procedure

The

patients

with

migraine

were

studied

outside

of

attacks

The

study

used

a

double-blind

placebo-controlled

crossover

design

Subjects

were

randomized

to

receive

μg/min

human

αCGRP

-LRB-

hαCGRP

Clinalfa

Switzerland

-RRB-

or

placebo

-LRB-

NaCl

-RRB-

infused

intravenously

for

min

on

days

separated

by

at

least

week

The

dose

was

chosen

as

the

highest

tolerated

dose

-LRB-

because

of

blood

pressure

reduction

-RRB-

based

on

reports

in

the

literature

-LSB-

-RSB-

Patients

were

randomly

assigned

by

computer

-LRB-

Med

Stat

version

-RRB-

Randomization

and

preparation

of

study

drugs

was

done

by

medical

staff

who

were

not

involved

in

the

study

Five

patients

started

with

placebo

and

seven

with

hαCGRP

This

quota

was

chosen

by

the

computer

and

not

known

before

the

study

The

effectiveness

of

blinding

was

not

estimated

When

subjects

arrived

at

the

laboratory

a

cannula

-LRB-

Viggo

Venflon

mm

-RRB-

was

placed

in

the

right

cubital

vein

for

hαCGRP/placebo

infusion

Baseline

values

of

mean

maximal

blood

velocity

-LRB-

Vmean

-RRB-

in

the

middle

cerebral

artery

-LRB-

MCA

-RRB-

regional

cerebral

blood

flow

-LRB-

rCBF

-RRB-

blood

pressure

heart

rate

and

were

recorded

after

min

of

rest

in

the

supine

position

in

a

quiet

room

Then

hαCGRP

or

placebo

was

infused

intravenously

for

min

by

a

volumetric

pump

-LRB-

Braun

Perfuser

-RRB-

Vmean

blood

pressure

heart

rate

and

end

tidal

were

recorded

every

min

during

and

after

infusion

until

min

after

start

of

the

hαCGRP

infusion

rCBF

was

measured

again

during

the

last

min

of

infusion

and

at

min

after

start

of

hαCGRP/placebo

infusion

At

every

recording

it

was

noticed

if

volunteers

were

flushing

and

information

about

headache

presence

intensity

-LRB-

measured

on

a

scale

-RRB-

and

characteristics

were

obtained

before

during

and

after

the

infusions

The

results

concerning

headache

response

have

been

published

elsewhere

-LSB-

-RSB-

Methods

rCBF

was

measured

with

a

highly

sensitive

brain-dedicated

fast-rotating

single

photon

emission

computerized

tomograph

-LRB-

Tomomatic

-RRB-

Each

study

lasted

min

A

mixture

of

atmospheric

air

and

was

rebreathed

during

the

first

min

through

a

closed

system

from

a

reservoir

-LRB-

Mbq/L

-RRB-

During

the

last

min

the

mixture

was

expired

against

atmospheric

air

rCBF

was

recorded

simultaneously

in

two

slices

positioned

and

mm

above

and

parallel

to

the

orbito-meatal

plane

-LRB-

OM

-RRB-

Each

slice

was

mm

thick

and

the

distance

between

the

centers

of

slices

was

mm

The

full

width

half

maximum

resolution

of

the

instrument

is

about

mm

in

the

horizontal

plane

rCBF

was

calculated

according

to

Celsis

et

al.

-LSB-

-RSB-

A

fixed

matrix

of

regions

of

interest

was

superimposed

on

the

rCBF

picture

The

shape

and

size

were

fitted

to

the

outlines

on

the

brain

excluding

extracranial

flow

Regional

mean

values

were

calculated

within

the

predefined

regions

of

interest

The

matrix

was

divided

into

regions

of

interest

representing

the

hemispheric

rCBF

regions

and

the

vascular

territories

of

supply

by

the

anterior

middle

and

posterior

cerebral

arteries

The

maximum

whole

body

radiation

was

approximately

mSV

per

rCBF

measurement

-LSB-

-RSB-

Time

averaged

mean

of

the

maximal

blood

velocity

-LRB-

Vmean

-RRB-

in

MCA

at

the

usual

headache

side

was

measured

with

transcranial

Doppler

-LRB-

TCD

-RRB-

ultrasonography

-LRB-

MHz

Multidop

X

Doppler

DWL

Sipplingen

Germany

-RRB-

A

mean

of

four

consecutive

values

of

Vmean

was

taken

-LRB-

each

representing

the

mean

value

of

typically

four

to

five

heart

beats

automatically

calculated

by

the

computer

-RRB-

Positions

of

the

measurements

were

reproduced

from

day

to

day

by

recording

the

position

in

relation

to

the

angle

and

distance

relative

to

the

orbito-meatal

line

Blood

pressure

and

heart

rate

were

measured

with

an

automatic

inflatable

arm

cuff

-LRB-

Omega

Invivo

Research

Laboratory

New

York

USA

-RRB-

Simultaneously

with

each

rCBF

and

TCD

measurement

the

end

expiratory

was

recorded

by

means

of

a

capnograph

-LRB-

Datex

OY

CD

-RRB-

Statistics

Hemodynamic

responses

are

given

as

mean

and

standard

deviation

-LRB-

SD

-RRB-

Differences

in

blood

velocity

rCBF

blood

pressure

heart

rate

and

over

time

within

the

group

were

analyzed

with

analysis

of

variance

-LRB-

MANOVA

Statgraphics

-RRB-

and

changes

were

then

located

with

a

multiple

range

test

-LRB-

Confidence

intervals

Statgraphics

-RRB-

Differences

in

the

delta

values

-LRB-

baseline

the

last

measurement

during

infusion

and

baseline

the

last

measurement

during

the

study

-RRB-

in

Vmean

rCBF

blood

pressure

heart

rate

and

between

the

effect

of

hαCGRP

and

the

effect

of

placebo

were

tested

with

a

paired

t

test

-LRB-

Statgraphics

-RRB-

In

all

tests

P

was

considered

statistically

significant

Results

During

CGRP

infusion

two

volunteers

experienced

a

substantial

decrease

in

blood

pressure

-LRB-

and

respectively

-RRB-

causing

the

infusion

to

be

terminated

ahead

of

time

Signs

and

symptoms

were

pallor

cold

sweat

stomach

ache

nausea

and

palpitation

The

situation

was

restored

after

placing

the

volunteers

in

head-down

tilt

for

and

min

respectively

No

rCBF

and

TCD

measurements

were

taken

during

this

time

period

and

therefore

results

from

these

two

volunteers

were

excluded

from

the

calculations

below

Changes

in

end

tidal

End-tidal

decreased

significantly

over

time

when

volunteers

were

treated

with

hαCGRP

-LRB-

P

-RRB-

but

not

when

treated

with

placebo

-LRB-

P

MANOVA

-RRB-

The

decrease

at

the

last

measurement

during

infusion

was

when

treated

with

hαGCRP

versus

when

treated

with

placebo

-LRB-

P

paired

t

test

-RRB-

The

peak

decrease

in

end-tidal

induced

by

hαCGRP

-LRB-

-RRB-

occurred

at

min

min

after

end

of

infusion

Transcranial

Doppler

measurements

The

TCD

examination

was

performed

on

the

side

of

usual

migraine

The

following

data

for

Vmean

in

MCA

are

corrected

for

changes

in

according

to

Markwalder

et

al.

-LSB-

-RSB-

Vmean

changed

significantly

over

time

when

patients

were

treated

with

hαCGRP

-LRB-

P

MANOVA

-RRB-

but

not

when

treated

with

placebo

-LRB-

P

MANOVA

-RRB-

At

the

last

measurement

during

infusion

min

after

its

beginning

Vmean

compared

to

baseline

was

when

treated

with

hCGRP

versus

when

treated

with

placebo

-LRB-

P

paired

t

test

-RRB-

At

the

end

of

the

in-hospital

period

-LRB-

min

after

start

of

the

infusion

-RRB-

there

was

no

difference

between

the

two

groups

-LRB-

P

paired

t

test

-RRB-

-LRB-

Fig.

Table

-RRB-

There

was

a

positive

correlation

between

ΔVmean

and

ΔMABP

-LRB-

r

P

-RRB-

Fig.

effect

of

hCGRP

-LRB-

μg/min

-RRB-

for

min

and

the

effect

of

placebo

on

the

mean

velocity

-LRB-

Vmean

-RRB-

in

middle

cerebral

artery

-LRB-

squares

-RRB-

and

the

regional

cerebral

blood

flow

-LRB-

rCBF

-RRB-

-LRB-

triangles

-RRB-

in

the

territory

of

the

middle

cerebral

artery

-LRB-

MCA

-RRB-

used

for

transcranial

Doppler

examination

X-axis

time

from

start

of

infusion

-LRB-

min

-RRB-

y-axis

changes

in

percent

of

baseline

Vmean

-LRB-

squares

-RRB-

decreased

compared

to

baseline

with

hCGRP

treatment

versus

with

placebo

treatment

-LRB-

P

-RRB-

After

min

there

was

no

difference

between

the

two

groups

-LRB-

P

-RRB-

No

change

of

rCBF

-LRB-

triangles

-RRB-

was

observed

at

the

end

of

infusion

-LRB-

P

-RRB-

or

at

the

end

of

study

period

-LRB-

P

-RRB-

Table

maximum

mean

blood

velocity

-LRB-

Vmean

-RRB-

in

the

middle

cerebral

artery

-LRB-

MCA

-RRB-

Time

-LRB-

min

-RRB-

Vmean

in

MCA

-LRB-

cm/s

-RRB-

No

correctionCorrected

for

changesCGRPPlaceboCGRPPlaceboCGRP

Placebo

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Values

within

parentheses

represent

the

standard

deviation

-LRB-

SD

-RRB-

Data

is

shown

with

and

without

correction

according

to

Markwalder

et

al.

-LSB-

-RSB-

The

data

is

shown

as

absolute

data

and

in

percent

change

from

baseline

-LRB-

P

-RRB-

Significant

changes

compared

with

baseline

Regional

cerebral

blood

flow

All

data

have

been

corrected

for

changes

in

rCBF

-LRB-

korr

-RRB-

rCBF

-LRB-

meas

-RRB-

exp

-LRB-

-LRB-

-LRB-

Basal

-RRB-

-LRB-

n

-RRB-

-RRB-

For

comparison

of

Vmean

and

rCBF

we

calculated

rCBF

in

the

territory

of

MCA

the

artery

used

for

TCD

examination

Area-weighted

data

from

the

OM

mm

and

OM

mm

were

used

for

the

results

given

below

There

was

no

change

over

time

neither

when

patients

were

treated

with

hαCGRP

-LRB-

P

-RRB-

nor

when

they

were

treated

with

placebo

-LRB-

P

MANOVA

-RRB-

During

infusion

rCBF

compared

to

baseline

was

when

treated

with

hαCGRP

versus

when

treated

with

placebo

The

difference

between

CGRP

and

placebo

was

not

significant

-LRB-

P

paired

t

test

-RRB-

Furthermore

no

significant

difference

between

CGRP

and

placebo

was

found

at

the

end

of

the

study

period

-LRB-

P

paired

t

test

-RRB-

-LRB-

Fig.

Table

-RRB-

Table

cerebral

blood

flow

rCBF

in

the

MCA

territory

recorded

and

mm

above

the

orbitomeatal

plane

-LRB-

OM

-RRB-

Cerebral

blood

flow

-LRB-

ml

g/min

-RRB-

Time

-LRB-

min

-RRB-

MCA

-LRB-

OM

OM

-RRB-

in

the

territory

used

for

TCD

examinationNo

correctionCorrected

for

changesAbsolute

dataAbsolute

dataData

in

of

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Values

within

parentheses

represent

the

standard

deviation

-LRB-

SD

-RRB-

Data

is

shown

with

and

without

correction

according

to

Markwalder

et

al.

-LSB-

-RSB-

The

data

is

shown

as

absolute

data

and

in

percent

change

from

baseline

-LRB-

P

-RRB-

The

absolute

rCBF

data

and

the

rCBF

data

with

correction

concerning

the

MCA

area

relevant

for

TCD

examination

are

given

in

Table

There

was

also

no

significant

difference

in

rCBF

between

CGRP

and

placebo

during

-LRB-

P

paired

t

test

-RRB-

or

after

the

infusion

-LRB-

P

paired

t

test

-RRB-

There

was

a

negative

correlation

between

ΔrCBF

-LRB-

MCA

-RRB-

and

ΔMABP

-LRB-

r

P

-RRB-

rCBF

during

hαCGRP

infusion

was

not

significantly

different

in

any

territory

or

at

any

time

point

Blood

pressure

The

mean

arterial

blood

pressure

-LRB-

MABP

-RRB-

decreased

significantly

over

time

when

patients

were

treated

with

hαCGRP

-LRB-

P

-RRB-

but

not

when

they

were

treated

with

placebo

-LRB-

P

MANOVA

-RRB-

The

maximal

decrease

occurred

at

the

last

measurement

during

infusion

-LRB-

min

after

start

of

infusion

-RRB-

and

amounted

to

with

hαCGRP

treatment

versus

with

placebo

treatment

-LRB-

P

paired

t

test

-RRB-

MABP

had

normalized

at

the

end

of

the

study

period

-LRB-

min

from

start

of

infusion

-RRB-

-LRB-

P

-RRB-

-LRB-

Table

-RRB-

Both

systolic

and

diastolic

blood

pressures

decreased

during

infusion

of

CGRP

compared

to

that

during

infusion

of

placebo

-LRB-

P

-RRB-

Table

mean

arterial

blood

pressure

-LRB-

MABP

-RRB-

systolic

and

diastolic

blood

pressure

-LRB-

mmHg

-RRB-

and

heart

rate

-LRB-

bpm

-RRB-

after

CGRP

and

placebo

treatmentBlood

pressure

-LRB-

mmHg

-RRB-

Heart

rate

-LRB-

bpm

-RRB-

Time

-LRB-

min

-RRB-

MABPSystolic

BPDiastolic

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Values

within

parentheses

represent

standard

deviation

-LRB-

SD

-RRB-

P

Heart

rate

When

patients

were

treated

with

hαCGRP

heart

rate

increased

significantly

over

time

-LRB-

P

MANOVA

-RRB-

but

not

when

they

were

treated

with

placebo

-LRB-

P

MANOVA

-RRB-

The

peak

increase

in

heart

rate

after

hαCGRP

treatment

occurred

min

after

start

of

infusion

reaching

versus

with

placebo

treatment

-LRB-

P

paired

t

test

-RRB-

Heart

rate

after

hαCGRP

treatment

was

still

different

from

that

after

placebo

treatment

at

the

end

of

the

study

period

-LRB-

P

paired

t

test

-RRB-

-LRB-

Table

-RRB-

Other

signs

Flushing

after

hαCGRP

treatment

was

pronounced

and

appeared

only

in

the

face

neck

and

upper

chest

It

appeared

from

min

-LRB-

time

of

first

observation

-RRB-

after

start

of

the

infusion

of

hαCGRP

in

all

patients

until

median

min

after

start

of

infusion

-LRB-

range

min

-RRB-

There

was

no

flushing

when

the

patients

were

treated

with

placebo

The

median

headache

during

infusion

of

hαCGRP

was

versus

in

the

placebo-treated

group

-LRB-

P

-RRB-

During

the

following

h

all

patients

experienced

headache

after

hαCGRP

treatment

versus

the

one

after

placebo

treatment

-LRB-

P

-RRB-

The

median

headache

score

was

after

hαCGRP

treatment

and

after

placebo

treatment

For

details

see

-LSB-

-RSB-

Discussion

The

main

finding

of

the

present

study

was

that

CGRP-infusion

dilated

the

MCA

in

patients

with

migraine

while

cerebral

blood

flow

remained

unchanged

The

dose

of

μg/min

of

CGRP

was

chosen

from

the

literature

in

which

the

same

dose

of

pmol/min

was

given

in

healthy

volunteers

without

any

reported

adverse

events

-LSB-

-RSB-

In

another

study

up

to

μg

CGRP

was

given

as

an

intravenous

bolus

injection

and

all

subjects

had

facial

flushing

-LSB-

-RSB-

The

dose

of

μg/min

for

min

is

probably

the

maximally

tolerated

dose

of

CGRP

in

patients

with

migraine

since

it

resulted

in

a

substantial

decrease

of

MABP

and

a

marked

increase

in

heart

rate

Two

subjects

were

near

fainting

and

had

to

be

withdrawn

In

healthy

volunteers

a

dose

of

μg/min

was

used

without

adverse

events

apart

from

flushing

and

without

any

effect

on

mean

blood

pressure

-LSB-

-RSB-

It

remains

uncertain

whether

the

stronger

circulatory

response

in

the

present

study

was

exclusively

due

to

the

higher

dose

or

whether

patients

with

migraine

are

more

sensitive

to

CGRP

After

min

infusion

at

μg/min

the

mean

plasma

level

was

pmol/L

in

healthy

volunteers

-LSB-

-RSB-

It

can

be

calculated

from

these

results

that

the

plasma

level

would

be

pmol/L

in

our

patients

with

migraine

The

for

CGRP

for

the

dilatory

effect

on

human

pial

arteries

is

pmol/L

-LSB-

-RSB-

The

dose

of

CGRP

used

in

the

present

study

thus

resulted

in

a

plasma

level

very

near

to

the

for

cerebral

arteries

in

vitro

The

blinding

of

the

present

study

can

be

criticized

Signs

-LRB-

increased

heart

rate

-RRB-

and

symptoms

-LRB-

facial

flushing

and

feeling

of

warmth

-RRB-

during

CGRP

infusion

made

it

difficult

to

keep

the

study

completely

blinded

However

the

present

design

is

the

best

one

available

because

no

technique

is

available

to

disguise

such

symptoms

An

interesting

finding

of

the

present

study

is

the

significant

reduction

of

blood

velocity

-LRB-

decrease

-RRB-

in

the

MCA

but

rCBF

remained

unchanged

during

intravenous

hαCGRP-infusion

A

reduced

velocity

in

an

artery

with

unchanged

regional

blood

flow

in

its

territory

of

supply

reflects

dilation

-LSB-

-RSB-

The

relative

diameter

change

can

be

roughly

estimated

from

the

relation

flow

mean

velocity

multiplied

by

the

cross-sectional

area

of

the

artery

-LRB-

-RRB-

When

the

flow

is

constant

velocity

is

a

function

of

the

reciprocal

value

of

and

Va/Vb

-LSB-

-RSB-

We

can

thus

estimate

from

the

change

in

mean

velocity

that

the

hαCGRP

infusion

caused

a

increase

in

MCA

diameter

corresponding

to

increase

of

its

cross

sectional

area

αCGRP

infused

in

a

considerably

lower

dose

-LRB-

μg/min

-RRB-

did

not

change

MCA

velocity

or

rCBF

in

healthy

volunteers

-LSB-

-RSB-

while

the

dose

of

μg/min

in

volunteers

dilated

the

MCA

-LRB-

increase

in

diameter

-RRB-

to

the

same

extent

as

in

the

present

study

-LSB-

-RSB-

The

dilatation

of

MCA

in

the

present

study

could

theoretically

be

due

to

cerebrovascular

autoregulation

secondary

to

decreased

blood

pressure

However

conduction

arteries

like

MCA

do

normally

only

autoregulate

due

to

blood

pressure

changes

to

a

much

lesser

extent

than

arterioles

-LRB-

for

review

see

-LSB-

-RSB-

-RRB-

A

positive

correlation

-LRB-

r

P

-RRB-

between

changes

in

MCA

and

changes

in

MABP

seems

to

support

this

possibility

However

this

correlation

could

also

reflect

that

MCA

and

systemic

circulation

vary

in

parallel

In

healthy

volunteers

using

a

slightly

lower

CGRP

dose

of

μg/min

blood

pressure

was

unchanged

but

MCA

dilated

to

the

same

extent

as

in

the

present

study

-LSB-

-RSB-

This

strongly

indicates

that

MCA

dilation

is

a

direct

effect

of

CGRP

In

rat

MCA

using

the

in

vitro-pressurized

arteriographic

model

luminal

CGRP

was

without

any

dilating

effect

whereas

abluminal

CGRP

dilated

the

artery

-LSB-

-RSB-

This

indicated

that

CGRP

was

unable

to

cross

the

blood

brain

barrier

in

rat

MCA

In

contrast

both

in

patients

with

migraine

-LRB-

Fig.

-RRB-

and

in

healthy

volunteers

-LSB-

-RSB-

a

dilation

of

MCA

was

observed

Theoretically

CGRP

could

act

on

an

endothelial

receptor

but

this

is

unlikely

because

the

CGRP

antagonist

could

not

block

the

effect

on

MCA

in

man

-LSB-

-RSB-

Furthermore

in

man

the

calcitonin

receptor-like

receptor

-LRB-

CLR

-RRB-

and

receptor

activity-modifying

protein

-LRB-

RAMP

-RRB-

are

located

mainly

in

the

muscular

layer

of

the

human

MCA

-LSB-

-RSB-

In

the

endothelium

there

was

only

a

minor

amount

of

CLR

and

largely

absent

-LSB-

-RSB-

There

is

thus

no

CGRP

receptor

-LRB-

CLR

plus

-RRB-

on

the

endothelium

The

present

results

with

a

dilation

of

MCA

could

indicate

that

the

blood

brain

barrier

to

CGRP

in

the

MCA

is

less

tight

in

man

than

in

rats

possibly

related

to

the

large

difference

in

size

In

healthy

volunteers

dilation

of

MCA

was

accompanied

by

a

modest

-LRB-

-RRB-

increase

in

rCBF

-LSB-

-RSB-

whereas

in

the

present

study

in

patients

with

migraine

a

increase

in

rCBF

was

not

statistically

significant

-LRB-

Fig.

-RRB-

The

discrepancy

may

be

due

to

random

variation

Altered

cerebrovascular

reactivity

in

patients

with

migraine

compared

to

controls

is

another

possibility

The

decrease

of

mean

MABP

from

to

mmHg

observed

in

the

present

study

could

also

be

a

factor

if

autoregulation

was

disturbed

by

CGRP

In

patients

with

subarachnoid

hemorrhage

a

CGRP-infusion

concomitant

with

intravenous

fluid

to

correct

any

drop

in

blood

pressure

resulted

in

a

dilation

of

the

MCA

on

the

vasospasm

side

-LSB-

-RSB-

Blood

pressure

was

unchanged

while

heart

rate

and

cardiac

output

were

increased

and

total

peripheral

resistance

was

decreased

-LSB-

-RSB-

In

two

studies

in

man

-LSB-

-RSB-

an

increase

in

noradrenaline

in

plasma

was

observed

after

CGRP

We

found

in

the

present

study

a

decrease

in

mean

blood

pressure

and

an

increase

in

heart

rate

as

would

be

expected

after

administration

of

a

potent

vasodilator

such

as

CGRP

In

conclusion

the

potent

endogenous

migraine-inducing

molecule

CGRP

resulted

in

a

dilation

of

MCA

and

unchanged

rCBF

CGRP

can

thus

most

likely

cross

the

blood

brain

barrier

to

some

extent

in

the

large

human

cerebral

arteries

The

vasodilator

effect

on

these

arteries

is

in

our

opinion

however

so

small

that

it

is

unlikely

to

be

the

only

mechanism

of

CGRP-induced

migraine

observed

in

our

patients

with

migraine

-LSB-

-RSB-

O O O O O O B O B I 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 O O O O O O O O O B 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 O O O O O O O O O O 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 I I I 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 B I 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 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 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 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 O O O O O O O O O O O O O O O O O O O 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 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 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 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 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 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 B I 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 O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O 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 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 B I 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 B I I I 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 B I 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 O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O 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 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 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 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 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 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 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 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 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Does Microvascular Invasion Affect Outcomes After Liver Transplantation for HCC ? A Histopathological Analysis of 155 Consecutive Explants Macroscopic vascular invasion -LRB- macroVI -RRB- is associated with poor outcomes after liver transplantation -LRB- LT -RRB- for hepatocellular carcinoma -LRB- HCC -RRB- . Whether microvascular invasion -LRB- microVI -RRB- is associated with the same adverse prognosis is unclear . One hundred and fifty-five consecutive patients with confirmed HCC after LT from March 1991 to 2004 at our institution were reviewed . Patients had to satisfy Milan criteria to be accepted for LT. They were followed with surveillance images every 3 months while on the waiting list . Disease-free survival -LRB- DFS -RRB- and overall survival -LRB- OS -RRB- were evaluated by Kaplan -- Meier analysis . Demographic , tumor , and histopathologic characteristics were tested for their prognostic significance . Median follow-up after LT was 30 months . Overall graft survival rates were 87 , 74 , and 65 % at 1 , 3 , and 5 years , respectively . All recurrences -LRB- 22/155 , 14 % -RRB- developed within 4 years after LT with an overall 5-year DFS of 79 % . Vascular invasion , either microVI or macroVI , was more likely in patients with multicentric HCC -LRB- n ≥ 3 , p < 0.001 -RRB- and larger tumor size > 4 cm -LRB- p = 0.04 -RRB- . Tumor size > 5 cm -LRB- p = 0.04 -RRB- , advanced pathological TMN stage -LRB- p = 0.007 -RRB- , microVI -LRB- p = 0.001 -RRB- , and macroVI -LRB- p < 0.001 -RRB- predicted poor tumor-free survival on univariate analysis , but only macroVI was significant in multivariate analysis -LRB- hazard ratio 54.2 , 95 % confidence interval 11 , 266 -RRB- . Furthermore , only macroVI was a significant predictor of mortality after LT -LRB- p = 0.01 -RRB- . Macrovascular invasion is strongly associated with high rates of recurrence and diminished survival after LT whereas microVI is not an independent risk factor . Introduction In 1996 , Mazzaferro et al. 1 documented excellent survival results after liver transplantation -LRB- LT -RRB- in a highly selected group of patients with hepatocellular carcinoma -LRB- HCC -RRB- with a single tumor < 5 cm or as many as three tumors , each smaller than 3 cm . Recent studies have shown that selected patients who do not meet these criteria can still be cured with a transplant ; the challenge now is to decide which factors , other than size and number , carry a sufficiently poor prognosis to deny transplantation .2 -- 5 Gross vascular invasion or radiological evidence of tumor invasion in major veins is a known determinant of poor outcome after resection or transplantation for HCC and is an absolute contraindication to LT. 4 -- 13 Macrovascular invasion -LRB- macroVI -RRB- or gross vascular invasion of major portal or hepatic veins evident visually at time of transplant or on pathological evaluation may also be a predictor of recurrence after LT. 14 Whether microvascular invasion -LRB- microVI -RRB- , defined as microscopic tumor invasion in smaller intrahepatic vessels identified on pathologic analysis , or macroVI should also be considered a contraindication to LT is controversial . Both types of tumor invasion are difficult to determine pre-LT ; therefore , their significance remains uncertain . Several published studies have found histopathological factors , namely , poorly differentiated grade , microVI , and macroVI , to be independent predictors of poor survival after LT. 4,11,15 -- 17 We have previously shown that microVI is an independent predictor of early recurrence after resection for HCC .5 The purpose of this study was to determine if microVI , macroVI , and other pathological factors are associated with tumor recurrence after LT and examine the outcomes thereafter . If these factors are predictors of poor tumor-free survival , then how can we attempt to identify these variables before transplant ? Patients and Methods One hundred fifty-nine consecutive patients with confirmed HCC on liver explant pathology after LT from October 1991 to October 2004 at our institution were reviewed from a prospective database . The cohort includes 32 patients -LRB- 20 % -RRB- with incidental tumors . Patients had to satisfy Milan criteria and have no radiologic evidence of gross vascular invasion to be accepted for LT. Four patients were omitted from analysis for recurrent hepatitis B virus -LRB- HBV -RRB- before antiviral therapy ; after 1991 , hepatitis B immune globulin , lamivudine , or combination therapy was used . Patients with known HCC were followed every 3 months while on the waiting list with either an ultrasound or triphasic computed tomography -LRB- CT -RRB- . Patients with HCC were eligible for deceased donor whole organs -LRB- n = 149 -RRB- and split -LRB- n = 0 -RRB- or living donor LT -LRB- n = 6 -RRB- . Patient , tumor , operative , and treatment characteristics were evaluated using a prospective clinical database and review of all pathological explants . The stage , size , and histopathology of the tumor were determined by analysis of the liver explant . Patients were staged based on the explanted specimens using the TNM staging classification of the American Liver Tumor Study Group18 . Tumor size was measured as the largest diameter of the major tumor in centimeters . MacroVI was defined as gross vascular invasion into major portal vessels or hepatic veins identified either intraoperatively or on pathologic explant , whereas microVI was determined on pathologic analysis as microscopic vascular invasion of small vessels within the parenchyma of the liver . Pretransplant therapy was used in selective cases ; if waiting time was determined to be longer than 6 months , patients commonly underwent radio frequency ablation as a bridge to LT. This was performed in an attempt to keep patients within Milan criteria while on the LT waiting list . Postoperative immunosuppression was similar in all patients and consisted of cyclosporine or tacrolimus and steroids . After LT , patients were followed with Q3 monthly alpha-fetoprotein -LRB- AFP -RRB- and CT along with standard post-LT evaluation . Recurrences were defined as new nodules diagnosed by CT with confirmed biopsy in most cases . Overall survival -LRB- OS -RRB- was death as a result of any cause after LT. Patients were followed until death or study closure -LRB- arbitrarily denoted as October 1 , 2004 -RRB- . Data was collected until May 1 , 2005 to ensure at least 6 months of follow-up for all patients . Statistical Package for Social Sciences software -LRB- SPSS , Inc. , Chicago , IL -RRB- was used for data analysis . Statistical comparison of categorical and continuous variables was performed using the χ2 test and Mann -- Whitney U test , respectively . All data was reported as median with range , mean ± SD or interquartile range -LRB- IQR -RRB- when appropriate . Analysis of patient OS and disease-free survival -LRB- DFS -RRB- was performed according to the Kaplan -- Meier method . Patient survival in different groups was compared using the log-rank test . All variables with a p value less than 0.1 were then included in a multivariate analysis applying the Cox multiple backward stepwise model . Results Patient Characteristics Of the 1,070 LTs performed during the 13-year period from 1991 to 2004 , 159 patients -LRB- 14 % -RRB- had HCC . After omission of 4 patients because of recurrent HBV before the antiviral therapy era , 155 patients were included in this analysis -LRB- Table 1 -RRB- . The average waiting time for LT was 7 months . There was no perioperative mortality . The median age was 57 years -LRB- range 28 -- 70 -RRB- and the majority of patients were men -LRB- 79 % -RRB- . The median age of all patients who underwent LT for any cause was 51 years -LRB- range 16 -- 71 -RRB- . The most common causes of end-stage liver disease and HCC were hepatitis C virus -LRB- HCV -RRB- -LRB- n = 79 ; 51 % -RRB- , alcoholic liver disease -LRB- n = 34 ; 22 % -RRB- , and HBV -LRB- n = 25 ; 16 % -RRB- . Selected patients underwent pre-LT therapy , most commonly radio frequency or percutaneous ethanol ablation -LRB- ablation , 23 % -RRB- , but the majority of patients received no treatment before LT -LRB- 72 % -RRB- . Use of ablation did not result in any adverse outcomes in this series of patients who underwent eventual LT. Table 1Pretransplant Demographics of 155 Patients with HCC Who Underwent LTPretransplant CriteriaN = 155p ValueMedian age -LRB- range -RRB- 57 -LRB- 28 -- 70 -RRB- 0.48 Sex0 .38 Male123 -LRB- 79 % -RRB- Female32 -LRB- 21 % -RRB- Cause of liver disease0 .10 HCV79 -LRB- 51 % -RRB- HBV25 -LRB- 16 % -RRB- Alcohol34 -LRB- 22 % -RRB- Cryptogenic7 -LRB- 4.5 % -RRB- Alpha-1 antitrypsin6 -LRB- 3.9 % -RRB- NASH2 -LRB- 1.3 % -RRB- PBC2 -LRB- 1.3 % -RRB- Pretransplant therapy0 .67 Ablation36 -LRB- 23 % -RRB- Resection6 -LRB- 3.9 % -RRB- TACE1 -LRB- 0.6 % -RRB- EBRT1 -LRB- 0.6 % -RRB- None111 -LRB- 72 % -RRB- The p values were determined by log-rank test as predictor of DFS after Kaplan -- Meier analysis.NASH = nonalcoholic steatohepatitis , PBC = primary biliary cirrhosis , EBRT = external beam radiation therapy Histopathological Analysis The pathologic features for the 155 explants are shown in Table 2 . The median number of tumors was 2 -LRB- range 1 -- 20 -RRB- and 18 % were bilobar . The median size of the largest tumor was 2.6 cm and most tumors were graded as well or moderately differentiated -LRB- 74 % -RRB- . Gross macroVI was evident in 3.9 % -LRB- 6/155 -RRB- of the explants on pathologic examination , whereas 21 % -LRB- 33/155 -RRB- of explants had the presence of microVI . Using the pathological TNM classification , 31 patients -LRB- 20 % -RRB- had stage I tumors , 69 patients -LRB- 44 % -RRB- had stage II tumors , 26 patients had stage III tumors -LRB- 17 % -RRB- , and 29 patients had stage IV tumors -LRB- 19 % -RRB- . Patterns of advanced stage were most often because of multifocal HCC or three or greater in number -LRB- 40 % -RRB- . Table 2Pathologic Characteristics of 155 Liver ExplantsCharacteristicN = 155p ValueHR -LRB- 95 % CI -RRB- No . of tumors Median -LRB- range , cm -RRB- 2 -LRB- 1 -- 20 -RRB- 0.23 < 3126 -LRB- 81 % -RRB- > 329 -LRB- 19 % -RRB- Bilobar32 -LRB- 21 % -RRB- 0.15 Size Median -LRB- range ; cm -RRB- 2.6 -LRB- .1 -- 16 -RRB- 0.040.47 -LRB- 0.14,1.61 -RRB- < 5 cm145 -LRB- 94 % -RRB- > 5 cm15 -LRB- 10 % -RRB- Stage I31 -LRB- 20 % -RRB- 0.0071.17 -LRB- 0.39,3.50 -RRB- II69 -LRB- 44 % -RRB- III26 -LRB- 17 % -RRB- IV29 -LRB- 19 % -RRB- Positive lymph nodes3 -LRB- 2.0 % -RRB- 0.31 Vascular invasiona Microscopic33 -LRB- 21 % -RRB- 0.0013.16 -LRB- 0.92,10.93 -RRB- Macroscopic6 -LRB- 4 % -RRB- < 0.00154.2 -LRB- 11.03,266.4 -RRB- None121 -LRB- 78 % -RRB- b1 .0 cGrade Well/mod115 -LRB- 74 % -RRB- 0.36 Poor13 -LRB- 9 % -RRB- N/Ad27 -LRB- 17 % -RRB- Margins Positive2 -LRB- 1 % -RRB- 0.25 Negative153 -LRB- 99 % -RRB- Incidental tumor34 -LRB- 22 % -RRB- 0.19 The p values were determined by chi-square test or log-rank test of variables after Kaplan -- Meier analysis -LRB- univariate -RRB- . HR -LRB- 95 % CI -RRB- represents multivariate analysis of factors affecting recurrence after resection.aFive of six patients had characteristics of both microvascular and macrovascular tumor invasion.bReference category for comparisoncReference category for each categorical variable is assigned HR = 1.0 . dNot available in the analysis Vascular invasion was associated with both the number and size of tumors . Liver explants , with either microVI or macroVI , had more tumors -LRB- 3.8 vs 2.0 , p < 0.001 -RRB- and were larger in size -LRB- 3.6 cm vs 2.8 cm , p = 0.04 -RRB- compared to those without vascular invasion . Specifically , if microVI or macroVI was present on histopathology , 64 and 100 % of the tumors , respectively , were outside of the Milan criteria or were TNM stage III or IV . Histological grade was not associated with either type of vascular invasion ; 85 % of patients with either type of vascular invasion had favorably differentiated tumors . Ablation did not affect the rate of vascular invasion , either microVI or macroVI , in this series . Eleven of 33 patients -LRB- 33 % -RRB- with vascular invasion on explant analysis had undergone ablation of their tumor . Predictors of Recurrence and Survival The 5-year disease-specific survival was 79 % -LRB- Fig. 1a -RRB- . All recurrences developed within 44 months after LT. The 1 - , 3 - , and 5-year overall graft OS rates were 87 , 74 , and 65 % , respectively -LRB- Fig. 1b -RRB- . Only 22 patients -LRB- 14 % -RRB- developed tumor recurrence after LT with a median follow-up of 30 months -LRB- range 6 -- 144 months -RRB- . Eighty-six percent of patients -LRB- 122/155 -RRB- are currently alive and free of cancer . There was no difference in OS in patients with incidental tumors compared to those with known HCC -LRB- data not shown -RRB- , but a significant difference was observed in DFS -LRB- 5-year OS rate 94 vs 74 % , p = 0.02 -RRB- . Figure 1 -LRB- A -RRB- Disease-free survival after LT for HCC of 155 patients . -LRB- B -RRB- Overall graft survival after LT for HCC of 155 patients . The median time to recurrence for the 22 patients who developed recurrent HCC was 16.3 months -LRB- IQR 8.0 -- 28 -RRB- . Tumor size > 5 cm -LRB- p = 0.04 -RRB- , pathological TMN stage -LRB- p = 0.007 -RRB- , microVI -LRB- p = 0.001 -RRB- , and macroVI -LRB- p < 0.001 -RRB- were found to be independent predictors of tumor-free survival . Patients with tumor size of 5 cm or larger had a 5-year DFS of 48 vs 82 % for those with tumors smaller than 5 cm . Advanced TMN stage was also associated with poor recurrence-free survival after LT -LRB- Fig. 2 -RRB- . Twenty-one of the 22 patients -LRB- 95 % -RRB- who developed HCC recurrence were found to have either microVI -LRB- n = 15 -RRB- or macroVI -LRB- n = 6 -RRB- on pathological analysis . This accounts for 68 % -LRB- 15/22 -RRB- of all patients with microVI and 100 % -LRB- 6/6 -RRB- of patients with macroVI in the entire study . Patients with macroVI had a median DFS of only 7.1 months compared to a more favorable DFS in patients with microVI or no vascular invasion -LRB- median not achieved -RRB- -LRB- Fig. 3 -RRB- . No significant differences in DFS based on age , sex type , hepatitis status , tumor grade , bilobar disease , tumor number , ablative therapy , or type of transplant were found on univariate analysis . Pre-LT therapy did not result in any improvement in DFS or OS after LT -LRB- data not shown -RRB- . Figure 2The effect of TNM stage on DFS after LT for HCC.Figure 3The effect of vascular invasion on recurrence-free survival after LT for HCC . In a multivariate analysis including factors with an influence on DFS , only macroVI -LRB- hazard ratio -LSB- HR -RSB- 54.2 , 95 % CI 11.03 -- 266.4 -RRB- was identified to be predictive -LRB- Table 2 -RRB- . This was confirmed with a Cox backward stepwise model of multivariate analysis -LRB- data not shown -RRB- . Discussion In this study , we report our experience with LT for HCC with a specific focus on pathological factors affecting long-term outcomes . Overall survival rates of LT for HCC were 87 , 74 , and 65 % at 1 , 3 , and 5 years , respectively , with a median follow-up time of 30 months . The overall recurrence rate was 14 % with 79 % 5-year disease-specific survival . Patients with incidental tumors had similar OS rates as those with known tumors consistent with previous reports ,8,9,14,15,19 but in this study , a significant difference was found in DFS . Our studies suggest that large tumor size -LRB- > 4 cm -RRB- and multiple tumors -LRB- ≥ 3 -RRB- correlate with an increased incidence of vascular invasion and may provide a surrogate marker for entities that are often difficult to detect before LT. Recurrence rates after LT may not simply reflect only size and number as suggested in the initial Milan series , but may be a complex interplay of host - and tumor-related factors , which are still largely unknown .20 This report suggests that tumor grade , size , number , and microVI do not influence outcome after LT for HCC ; only the presence of macroVI appears to be associated with poor outcomes on multivariate analysis . MacroVI and microVI were more commonly found in multicentric -LRB- three or more -RRB- and large -LRB- > 4 cm -RRB- HCC . Furthermore , 21 of 22 recurrences had evidence of either microVI or macroVI on pathologic examination . Because we are unable to identify these biologic factors preoperatively , markers of histopathologic or biologic variables that predict poor outcomes are extremely important .14,20 -- 22 MacroVI was shown to be an independent predictor of tumor recurrence after LT in some studies .4,9,10,14 The Pittsburgh group found that microVI and major vascular invasion was associated with increased risk of recurrence by multivariate analysis .4,8 In a report of 344 patients with HCC treated by LT , microVI and macroVI were associated with 4.4 - and 15-fold increased risk of recurrence , respectively .8 Shetty et al. 14 found that macroVI , but not microVI , was a significant predictor of DSF and OS after LT for HCC . In this study , microVI is associated with higher stage and recurrent tumors , but does not appear to be an independent factor for survival . The role of microVI on posttransplant recurrence and survival outcomes for HCC still remains unclear . Several published studies have found poorly differentiated histological grade or microVI to be independent predictors of impaired survival after LT. 11,15 -- 17 Jonas et al. 11 found vascular invasion and histological grade to be the only statistically significant independent predictors of poor survival after LT in 120 patients . In their study , only poorly differentiated tumors larger than 5 cm predicted the presence of microVI . But other studies involving LT and HCC were not able to corroborate poor results regarding microVI .3,14,23,24 The close relationship between histological grade and microVI may explain why microVI is often eliminated in multivariate models for analyzing tumor recurrence prognostic factors that include histological grading and vice versa .4,8,11,15,23,25,26 Multiple tumors , larger tumors , and higher grade of differentiation have all been shown to be associated with microVI after resection for HCC . Esnaola et al. 13 reported that tumor size greater than 4 cm and poorly differentiated/undifferentiated histopathologic grade increased the odds of microVI by 3 and 6.3-fold , respectively , but these tumors were primarily in Child class A cirrhotic . The degree of fibrosis and scarring of the liver may play a significant role in the biological behavior and significance of microVI and macroVI . We have previously shown that microVI was a significant predictor of early recurrence and death after resection for HCC in cirrhotic patients .5 Most recurrences were intrahepatic and away from the staple line , suggesting that liver mobilization and manipulation may cause progression of microVI or a new tumor has developed in the presence of ongoing oncogenic stimulus from cirrhosis . For these reasons , prognostic factors for LT from resection studies should be interpreted with caution and a possible rationale why microVI is so important after resection but not after LT. 12,13 Lack of manipulation of the liver and intrahepatic dissection may be a potential explanation for the lack of importance of microVI with LT. Because of the importance of histological features of HCC , some have advocated pre-LT biopsy to examine grade , vascular invasion , and genetic typing .13,15,20 Complications of needle biopsy such as tumor tract seeding and lack of sensitivity have made routine biopsy unfavorable .27 In our experience , needle biopsy was a poor predictor of microVI or macroVI , and therefore was not considered in our pre-LT work-up for HCC -LRB- data not shown -RRB- . There are several limitations to this study and therefore some of the results should be interpreted with caution . The need to standardize grading systems for HCC has long been recognized and would allow us to determine if tumor grade is indeed an important prognostic marker for recurrence and survival . Few tumors in this study were graded as poorly differentiated ; moreover , in 27 patients , their grade was not determined . Results from histopathological analysis are often met with inherent biases from the pathologist and comprehensive evaluation of the whole liver explant may vary among pathologists and institutions . Finally , with very few tumors containing macroVI , strong conclusions about prognostic characteristics concerning macroVI can not be made in this report . Whether microVI is a harbinger of macroVI or in some way correlated with a more aggressive form of HCC remains unclear . The use of pathological and biological features of the tumor may allow us to identify those patients who are at increased risk of recurrence ; then these patients should be considered for adjuvant therapy before evidence of a recurrence . Because vascular invasion is more common in multicentric -LRB- > 3 -RRB- HCC or large tumors -LRB- > 4 cm -RRB- , we propose shortening the interval of pre-LT imaging in patients with these tumors to identify vascular invasion or rapid growth of the tumor before LT. Genetic testing of tumors before LT may be a novel method to predict other prognostic factors affecting recurrence .20 Several studies have reported improved posttransplant survival in HCC patients with transcatheter arterial chemoembolization -LRB- TACE -RRB- or systemic therapy ,28 -- 31 but overall results for adjuvant chemotherapy post-LT were disappointing .32 Because of small numbers , this would be best done in a multicenter-randomized trial . We are currently evaluating the role of tumor size and number in our allocation system in LT for HCC to determine their respective predictive value for prognosis . In summary , LT for HCC can be performed with acceptable survival outcomes . A single tumor characteristic alone does not appear to determine prognosis or outcome . In the present study , macroVI alone was associated with very poor outcomes after LT. Extending criteria of LT for advanced HCC is possible only with better patient selection using improved pre-LT staging and identification of histopathological biological markers such as macroVI that would preclude LT.

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

hepatocellular carcinoma
vascular invasion
liver transplantation
recurrence
microvascular invasion


Where

Are

They

Now

A

Case

Study

of

Health-related

Web

Site

Attrition

Background

When

considering

health-related

Web

sites

issues

of

quality

generally

focus

on

Web

content

Little

concern

has

been

given

to

attrition

of

Web

sites

or

the

fleeting

nature

of

health

information

on

the

World

Wide

Web

Since

Web

sites

may

be

available

for

an

uncertain

period

of

time

a

Web

page

may

not

be

a

sound

reference

Introduction

We

've

all

heard

that

a

million

monkeys

banging

on

a

million

typewriters

will

eventually

reproduce

the

entire

works

of

Shakespeare

Now

thanks

to

the

Internet

we

know

this

is

not

true

-LSB-

-RSB-

Robert

Wilensky

The

results

of

a

recent

major

national

survey

found

that

about

million

people

in

the

U.S.

over

half

of

the

adult

population

may

be

seeking

health

information

online

-LSB-

-RSB-

This

compares

with

million

in

million

in

and

million

in

And

according

to

the

American

Medical

Association

on

any

given

day

more

people

go

online

for

medical

advice

than

actually

visit

health

professionals

-LSB-

-RSB-

When

considering

health-related

Web

sites

issues

of

quality

generally

focus

on

Web

content

how

to

find

relevant

information

and

how

to

assess

the

credibility

of

the

publisher

as

well

as

the

accuracy

and

reliability

of

a

document

retrieved

-LSB-

-RSB-

Little

concern

has

been

given

to

attrition

of

Web

sites

or

the

fleeting

nature

of

health

information

on

the

Web

Scientist

and

scholar

Sir

Isaac

Newton

once

said

If

I

have

seen

farther

than

others

it

is

because

I

was

standing

on

the

shoulders

of

giants

-LSB-

-RSB-

Much

if

not

all

scholarship

is

based

on

relation

to

previous

work

and

when

new

scholarly

work

is

produced

it

is

important

that

detailed

and

accurate

information

on

sources

consulted

are

cited

To

facilitate

referencing

scholarly

works

have

been

routinely

collected

and

preserved

in

print

by

libraries

and

database

producers

-LSB-

-RSB-

But

in

terms

of

cataloging

storage

and

retrieval

as

it

relates

to

the

Web

the

status

quo

does

not

apply

With

the

advent

of

the

Web

libraries

must

now

consider

Web

site

information

that

may

be

created

change

move

expire

and

disappear

with

no

record

of

the

information

being

preserved

Few

libraries

made

the

practice

of

collecting

copies

of

Web

pages

-LSB-

-RSB-

Since

Web

sites

may

be

available

for

an

uncertain

period

of

time

a

Web

page

may

not

be

a

sound

reference

If

a

Web

page

or

link

disappears

chances

are

almost

nonexistent

of

locating

the

reference

at

a

later

time

As

a

safeguard

it

has

been

recommended

that

individuals

keep

a

personal

copy

of

Web

pages

as

evidence

that

the

information

existed

-LSB-

-RSB-

To

address

the

issue

of

attrition

a

defined

set

of

health-related

Web

sites

was

examined

at

two

separate

time

intervals

Methods

In

an

earlier

study

a

systematic

survey

was

conducted

to

determine

the

validity

of

health

claims

on

the

World

Wide

Web

for

the

herbal

remedy

Opuntia

-LSB-

-RSB-

From

December

to

May

Web

sites

were

collected

from

which

health

claims

were

identified

Web

sites

were

retrieved

utilizing

multiple

search

engines

and

the

Uniform

Resource

Locator

-LRB-

URL

-RRB-

for

each

Web

site

was

recorded

In

this

study

to

determine

the

degree

of

attrition

each

of

the

Web

sites

obtained

and

recorded

from

the

previous

study

were

revisited

at

a

later

period

of

time

During

May

the

previously

recorded

URL

for

each

Web

site

was

entered

into

the

address

field

of

the

browser

Netscape

Navigator

-LRB-

version

Netscape

Communication

Corporation

Mountain

View

California

-RRB-

It

was

documented

whether

the

original

Web

site

could

not

be

found

moved

to

a

different

URL

location

or

the

URL

and

site

location

was

found

unchanged

from

the

original

search

For

A

Web

site

whose

URL

remained

unchanged

it

was

also

noted

whether

the

Web

site

had

maintained

currency

-LRB-

i.e.

updated

-RRB-

since

the

original

posting

Since

it

is

conceivable

that

inaccessibility

of

Web

sites

may

be

due

to

temporary

server

problems

another

attempt

was

made

to

access

the

sites

at

different

periods

of

time

For

each

HTTP

Error

or

similar

message

obtained

from

the

initial

URL

checks

an

attempt

to

access

these

sites

was

made

during

June

on

various

days

and

times

of

day

in

the

manner

described

above

Results

Results

indicate

that

when

each

URL

address

from

the

original

set

of

Web

sites

was

re-entered

into

the

address

field

of

the

browser

-LRB-

-RRB-

of

the

sites

could

not

be

found

-LRB-

-RRB-

had

moved

to

a

new

URL

address

and

-LRB-

-RRB-

of

the

sites

could

be

found

from

the

original

URLs

obtained

in

the

previous

study

Of

the

Web

sites

that

moved

to

a

new

URL

address

only

sites

provided

a

link

from

the

original

URL

to

redirect

the

viewer

to

the

new

location

Of

the

Web

sites

still

in

existence

-LRB-

-RRB-

provided

update

information

from

the

original

posting

The

information

is

summarized

in

Table

Table

Attrition

of

Health-related

Web

Sites

for

a

Three-year

Period

Web

Site

Sponsor

-LRB-

No

of

Sites

-RRB-

Not

Found

Moved

To

New

URL

URL

Redirected

URL

to

Site

as

Original

Maintenance

Update

Provided

Herbal

Vendor

-LRB-

-RRB-

Food/Recipes

Products

-LRB-

-RRB-

Educational

Institution

-LRB-

-RRB-

Government

Institution

-LRB-

-RRB-

Historical

Essay

-LRB-

-RRB-

Travel

and

Tourism

-LRB-

-RRB-

Message

Board

-LRB-

-RRB-

Reference

Guide

-LRB-

-RRB-

Print

Media

-LRB-

-RRB-

Expert

-LRB-

-RRB-

Doomsday

Group

-LRB-

-RRB-

Totals

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Includes

book

excerpts

newspaper

and

magazine

articles

newsletters

a

calendar

reprint

and

a

radio

broadcast

transcript

Original

Web

site

addresses

and

content

are

available

on

the

World

Wide

Web

at

In

this

study

attrition

is

defined

as

the

unavailability

of

a

Web

site

when

known

to

be

previously

accessible

based

on

a

known

URL

address

This

did

not

include

sites

that

were

redirected

to

a

new

URL

Approximately

three

years

after

initial

posting

over

two-thirds

of

the

health-related

Web

sites

reviewed

could

not

be

found

or

had

moved

with

no

forwarding

URL

and

about

one-third

of

the

remaining

sites

maintained

currency

of

information

It

appears

that

links

are

terminated

as

Web

sites

are

moved

or

removed

or

as

servers

close

down

This

supports

the

notion

that

it

is

difficult

if

not

impossible

to

locate

information

that

was

previously

found

on

the

Web

and

if

a

reference

to

an

item

is

provided

there

is

no

guarantee

that

viewers

will

be

able

to

find

the

site

at

a

later

date

In

this

study

a

comprehensive

data

set

of

Web

sites

on

a

specific

health-related

topic

was

obtained

and

attrition

was

examined

Obviously

an

example

from

a

single

health-related

topic

is

limited

in

what

conclusions

should

be

drawn

These

findings

can

not

be

generalized

to

other

medical

topics

But

this

raises

the

question

that

other

health-related

sites

on

the

World

Wide

Web

may

vary

in

their

degree

of

attrition

and

warrants

further

research

into

methods

of

dealing

with

attrition

with

other

medical

topics

Discussion

The

average

life

of

a

Web

page

is

about

days

-LSB-

-RSB-

The

perceived

value

of

the

Web

lies

in

the

immediate

accessibility

to

a

seemingly

endless

pool

of

information

with

no

central

controlling

authority

This

also

makes

the

Web

difficult

to

maintain

According

to

Chris

Sherman

Associate

Editor

of

SearchEngineWatch.com

-LRB-

-RRB-

as

automatic

maintenance

most

search

engines

remove

missing

URLs

from

their

index

when

they

recrawl

and

find

that

the

pages

are

gone

-LSB-

-RSB-

A

different

problem

arises

though

when

an

organization

has

gone

out

of

business

but

its

site

still

exists

This

is

a

much

more

difficult

problem

to

handle

and

to

date

no

search

engine

exists

to

locate

or

remove

these

sites

Enhancements

in

Web

technologies

hope

to

improve

the

problem

of

attrition

A

prime

example

is

the

Internet

Archive

The

Internet

Archive

The

Internet

Archive

-LRB-

-RRB-

is

a

digitallibrary

of

Web

pages

created

with

the

lofty

goal

of

cataloging

all

of

the

past

and

present

publicly

available

material

on

the

World

Wide

Web

-LSB-

-RSB-

Accessible

to

the

public

for

free

it

contains

more

than

terabytes

of

data

and

is

growing

by

to

terabytes

a

month

Since

the

Internet

Archive

has

been

storing

Web

pages

including

graphics

files

from

publicly

accessible

Web

sites

A

feature

implemented

October

known

as

the

Wayback

Machine

allows

users

to

go

back

and

view

earlier

versions

of

current

Web

sites

or

of

Web

sites

that

no

longer

exist

The

Wayback

Machine

serves

as

a

source

to

find

Web

pages

when

the

page

or

host

can

not

be

located

-LSB-

-RSB-

When

a

user

encounters

a

File

Not

Found

or

similar

message

on

the

Web

the

Wayback

Machine

can

be

accessed

to

find

a

facsimile

of

the

Web

page

Though

a

significant

accomplishment

towards

recovering

lost

Web

pages

the

Wayback

Machine

has

limitations

It

is

not

searchable

by

keywords

or

text

in

the

manner

of

a

general

search

engine

The

user

must

know

the

precise

URL

of

a

particular

Web

page

or

site

to

access

the

Archive

Having

entered

a

URL

address

the

viewer

is

presented

with

a

list

of

dates

that

designates

when

a

particular

page

was

archived

Also

though

the

Internet

Archive

contains

more

than

terabytes

of

data

much

is

still

missing

For

example

it

does

not

contain

the

older

gopher

content

and

other

non-Web

files

prior

to

and

a

relatively

small

number

of

pages

exists

from

with

content

increasing

to

recent

times

Issues

of

Quality

and

Content

The

question

may

arise

as

to

whether

a

relationship

exists

between

Web

site

quality

and

attrition

Are

poor

quality

sites

more

likely

to

disappear

in

time

than

sites

of

higher

quality

A

consensus

has

yet

to

be

reached

as

to

the

properties

a

Web

site

needs

to

have

to

be

considered

high

quality

Wilson

states

that

quality

remains

an

inherently

subjective

assessment

which

depends

on

the

type

of

information

needed

the

type

of

information

searched

for

and

the

particular

qualities

and

prejudices

of

the

consumer

-LSB-

-RSB-

Yet

many

organizations

and

individuals

have

identified

standards

of

quality

that

should

be

applied

to

the

Web

-LSB-

-RSB-

A

practical

approach

for

assessment

has

been

described

by

Risk

that

provides

benchmarks

of

quality

-LSB-

-RSB-

It

includes

assessing

a

site

for

information

that

is

accurate

current

has

a

clear

source

is

referenced

has

disclaimers

and

cautions

if

appropriate

clear

clean

and

pleasing

design

features

and

a

well-defined

purpose

These

criteria

were

applied

to

the

original

sites

in

this

study

by

this

author

to

examine

whether

attrition

may

be

influenced

by

quality

If

a

site

possessed

at

least

of

these

attributes

it

was

considered

high

quality

to

attributes

it

was

considered

moderate

and

or

less

it

was

considered

poor

quality

The

results

are

summarized

in

Table

It

appears

that

although

the

high

quality

sites

make

up

only

a

small

portion

of

the

total

number

of

sites

retrieved

-LRB-

-RRB-

half

of

the

original

high

quality

sites

-LRB-

of

-RRB-

could

be

located

from

the

original

URL

or

were

redirected

to

a

new

URL

Conversely

only

of

the

poor

quality

sites

were

accessible

from

the

original

URL

entry

and

only

one

poor

quality

site

was

redirected

to

another

URL

from

the

original

site

This

suggests

that

Web

sites

of

higher

quality

may

be

less

subject

to

attrition

than

those

of

poorer

quality

and

warrants

further

research

on

the

relationship

between

Web

site

quality

and

attrition

with

other

medical

topics

Considering

subject

matter

and

attrition

it

may

be

that

certain

topics

-LRB-

such

as

herbal

remedies

-RRB-

can

have

periods

of

enthusiasm

by

the

public

then

wane

which

may

be

the

case

with

these

sites

Perhaps

information

on

more

mainstream

topics

-LRB-

such

as

health

risks

and

smoking

-RRB-

is

less

vulnerable

to

attrition

Table

Quality

of

Health-related

Web

Sites

and

Attrition

Web

Site

Quality

-LRB-

No

of

Sites

-RRB-

Not

Found

Moved

To

New

URL

URL

Redirected

URL

to

Site

as

Original

High

-LRB-

-RRB-

Moderate

-LRB-

-RRB-

Poor

-LRB-

-RRB-

Totals

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Quality

assessed

by

author

based

on

attributes

described

by

Risk

-LSB-

-RSB-

High

or

more

Moderate

to

Poor

or

less

Future

Considerations

It

has

yet

to

be

determined

with

certainty

the

forces

that

influence

the

survival

of

Web

sites

With

the

complex

and

dynamic

nature

of

information

flow

on

the

Web

is

there

a

form

of

natural

selection

at

work

in

health

Web

site

survival

If

attrition

is

not

related

to

the

site

's

quality

or

subject

matter

perhaps

those

with

strong

commercial

backing

may

survive

with

greatest

frequency

At

this

point

we

can

only

speculate

what

will

endure

In

some

instances

Web

site

attrition

may

be

desirable

A

common

complaint

against

search

engines

is

that

they

return

too

many

pages

and

that

many

of

the

pages

have

low

relevance

to

the

query

-LSB-

-RSB-

The

most

efficient

search

engines

index

only

a

fraction

of

the

total

number

of

documents

on

the

Web

-LSB-

-RSB-

and

if

sites

of

poorer

quality

go

away

ideally

this

should

help

retrieval

of

documents

of

higher

relevance

to

the

user

Most

quality

issues

with

the

Web

focus

on

consumers

-LSB-

-RSB-

however

a

recent

major

poll

revealed

that

physicians

are

using

the

Internet

to

increase

their

medical

knowledge

and

improve

the

care

they

provide

to

patients

-LSB-

-RSB-

Medical

information

can

change

rapidly

with

continuing

breakthroughs

and

advances

in

medical

knowledge

Availability

of

information

through

the

Web

would

facilitate

access

to

the

most

up-to-date

information

on

current

medical

topics

and

scientific

discoveries

Future

research

that

is

directed

toward

making

sure

Web

site

viewers

always

know

the

site

will

be

accessible

at

a

later

time

will

enhance

the

Web

as

a

valuable

medical

information

resource

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

world wide web
attrition
internet archive
web site quality