Value

of

tissue

harmonic

imaging

-LRB-

THI

-RRB-

and

contrast

harmonic

imaging

-LRB-

CHI

-RRB-

in

detection

and

characterisation

of

breast

tumours

The

purpose

of

this

study

was

to

investigate

the

extent

to

which

tissue

harmonic

imaging

-LRB-

THI

-RRB-

speckle

reduction

imaging

-LRB-

SRI

-RRB-

spatial

compounding

-LRB-

SC

-RRB-

and

contrast

can

improve

detection

and

differentiation

of

breast

tumours

We

examined

patients

-LRB-

benign

malignant

tumours

-RRB-

with

different

combinations

of

THI

SRI

and

SC

The

effect

on

delineation

margin

tissue

differentiation

and

posttumoral

phenomena

was

evaluated

with

a

three-point

score

Additionally

not

palpable

tumours

-LRB-

diameters

mm

-RRB-

were

examined

by

contrast

harmonic

imaging

-LRB-

CHI

-RRB-

with

power

Doppler

After

bolus

injection

-LRB-

ml

Optison

-RRB-

vascularisation

and

enhancement

were

observed

for

min

The

best

combination

for

detection

of

margin

infiltration

echo

pattern

and

posterior

lesion

boundary

was

the

combination

of

SRI

level

with

SC

low

THI

was

helpful

for

lesions

OF

more

than

cm

depth

In

native

Power

Doppler

vessels

were

found

in

of

lesions

Within

min

after

contrast

medium

-LRB-

CM

-RRB-

injection

marginal

and

penetrating

vessels

increased

in

benign

and

malignant

tumours

and

central

vessels

mostly

in

carcinomas

-LRB-

p

-RRB-

A

diffuse

CM

accumulation

was

observed

up

to

min

after

injection

in

malignant

tumours

only

-LRB-

p

-RRB-

THI

SRI

and

SC

improved

delineation

and

tissue

differentiation

Second-generation

contrast

agent

allowed

detection

of

tumour

vascularisation

with

prolonged

enhancement

Introduction

As

a

technique

complementary

to

mammography

high-resolution

ultrasound

-LRB-

US

-RRB-

is

well

accepted

for

differentiating

between

cystic

and

noncystic

putative

tumour

lesions

-LSB-

-RSB-

New

developments

such

as

tissue

harmonic

imaging

-LRB-

THI

-RRB-

and

contrast

harmonic

imaging

-LRB-

CHI

-RRB-

have

enhanced

its

value

particularly

for

primary

detecting

tumours

in

dense

inhomogeneous

mammary

gland

tissue

identifying

mammographically

occult

tumours

and

appraising

abnormalities

in

tissue

architecture

-LSB-

-RSB-

Lesions

that

are

only

a

few

millimetres

in

size

become

detectable

and

tumours

can

be

characterised

more

precisely

Ultimately

the

exact

localisation

of

small

tumours

is

a

prerequisite

for

ultrasound-guided

needle

biopsy

vacuum

biopsy

or

preoperative

wire

placement

-LSB-

-RSB-

Harmonic

imaging

allows

better

visualisation

of

tissue

architecture

and

facilitates

recognition

of

parenchymal

changes

with

tumour

infiltration

making

it

easier

to

wire

mark

small

lesions

with

THI

-LSB-

-RSB-

For

tumour

characterisation

it

is

also

essential

to

appraise

vascularisation

in

a

manner

comparable

to

that

achieved

by

dynamic

contrast-medium-enhanced

magnetic

resonance

imaging

-LRB-

MRI

-RRB-

-LSB-

-RSB-

Even

if

computed

evaluation

programmes

with

pixel

analysis

facilitate

appraisal

of

tumour

blood

flow

native

vascular

US

with

power

Doppler

-LRB-

PD

-RRB-

has

proved

to

be

relatively

unreliable

-LSB-

-RSB-

Contrast

medium

enhancement

already

enables

more

distinct

visualisation

of

intratumoral

and

peritumoral

vessels

However

the

brief

diagnostic

time

window

after

bolus

injection

of

US

contrast

medium

-LRB-

CM

-RRB-

is

often

a

limiting

factor

The

combination

of

CHI

with

PD

opens

up

promising

vistas

for

appraisal

of

vascularisation

Preliminary

investigations

indicate

that

tumour

detection

characterisation

and

US-guided

intervention

can

be

improved

by

using

a

CM

of

the

second

generation

with

modified

CHI

technique

-LSB-

-RSB-

The

aim

of

our

study

was

to

evaluate

their

potential

benefits

and

limitations

for

detecting

and

differentiating

breast

tumours

Materials

and

methods

Patients

and

US

A

total

of

patients

-LRB-

age

years

median

years

-RRB-

were

investigated

in

a

multicentre

trial

with

complementary

mammary

diagnostic

procedures

over

a

period

-LRB-

November

to

November

-RRB-

All

women

gave

informed

written

consent

for

their

results

to

be

used

for

programme

research

and

evaluation

On

the

basis

of

US

findings

each

lesion

was

evaluated

based

on

size

shape

-LRB-

ellipsoid

round

irregular

-RRB-

margins

-LRB-

smooth

macrolobulated

microlobulated

speculated

angulated

ill-defined

-RRB-

posterior

sonographic

artefacts

-LRB-

shadowing

through

transmission

no

posterior

artefacts

-RRB-

echogenicity

-LRB-

hyperechogenic

isoechoic

hypoechoic

-RRB-

presence

of

calcifications

and

ductal

extension

Investigations

were

supplemented

by

clinical

examination

and

mammography

in

two

planes

Ultrasound

lesions

were

examined

in

three

planes

using

PD

and

digital

imaging

with

the

GE

Logiq

-LRB-

GE

Medical

Systems

Milwaukee

WI

USA

-RRB-

US

units

All

investigations

were

carried

out

with

a

high-resolution

multifrequency

linear

matrix

array

transducer

-LRB-

Linear

Array

MHz

-RRB-

with

the

modalities

of

THI

spatial

compounding

-LRB-

crossbeam

-RRB-

speckle

reduction

imaging

-LRB-

SRI

-RRB-

and

contrast-medium-enhanced

PD

with

CHI

and

additional

three-dimensional

-LRB-

-RRB-

imaging

Imaging

documentation

of

digital

raw

data

in

single-image

and

short

sequences

was

effected

using

a

Picture

and

Communication

System

-LRB-

PACS

-RRB-

Study

population

The

patient

population

was

divided

into

two

groups

In

group

we

focused

on

the

advantage

of

THI

SC

and

an

adaptive

algorithm

for

SRI

In

group

we

focused

on

CHI

with

PD

Group

Thirty-eight

patients

-LRB-

years

-RRB-

with

benign

and

malignant

tumours

were

examined

in

fundamental

mode

and

with

harmonic

imaging

with

a

high-frequency

matrix-array

transducer

with

the

modalities

of

THI

SC

and

an

adaptive

algorithm

for

SRI

Prospectively

fundamental

and

tissue

harmonic

mode

were

used

alone

and

in

combination

with

all

available

levels

of

SC

-LRB-

cross

beam

low

medium

high

maximum

-RRB-

and

five

levels

of

SRI

In

patients

without

tumour

lesions

criteria

were

differentiation

of

normal

fibroglandular

tissue

from

premammary

and

retromammary

fat

including

the

Cooper

's

ligaments

and

ducts

Criteria

that

were

evaluated

for

differential

diagnosis

in

patients

with

lesions

were

margin

infiltration

of

malignant

tumours

echo

pattern

with

tissue

components

calcifications

posterior

lesion

boundary

and

posterior

acoustic

features

After

optimising

system

settings

a

three-level

score

was

applied

to

enable

comparison

of

the

quality

of

scans

with

fundamental

imaging

-LRB-

equal

inferior

superior

-RRB-

Group

One

hundred

patients

-LRB-

years

median

years

-RRB-

comprised

probably

benign

-LSB-

Breast

Imaging

Reporting

and

Data

System

-LRB-

BI-RADS

III

-RRB-

-RSB-

and

malignant

-LRB-

BI-RADS

IV

V

-RRB-

tumours

confirmed

by

vacuum-assisted

biopsy

in

lesions

and

cases

additionally

in

the

course

of

surgery

Tumour

diameters

varied

between

and

mm

-LRB-

mean

mm

-RRB-

Histological

confirmation

was

obtained

in

all

cases

All

patients

were

comparatively

investigated

with

fundamental

B

scan

THI

and

CHI

with

PD

After

the

B

scan

and

evaluation

of

vascularisation

in

native

PD

we

used

an

echo

signal

amplifier

of

the

second

generation

with

low

mechanical

index

-LRB-

MI

-RRB-

technology

A

bolus

injection

of

Optison

was

administered

-LRB-

ml

Optison

diluted

with

ml

with

NaCl

solution

and

subsequent

injection

of

another

ml

NaCl

-RRB-

The

bolus

of

CM

was

injected

intravenously

and

spreading

of

the

contrast

enhancement

and

washout

in

the

tumours

were

followed

for

at

least

min

A

low

MI

-LRB-

-RRB-

was

chosen

to

avoid

early

destruction

of

the

microbubbles

CM

enhancement

was

appraised

for

up

to

min

Moreover

additional

evaluations

of

the

cine

sequences

were

also

possible

retrospectively

in

consequence

of

the

archiving

of

dynamic

digital

images

of

up

to

single

images

and

loop

The

images

archived

in

B

scan

and

THI

could

also

be

processed

retrospectively

with

various

phases

of

SRI

which

enabled

marginal

contours

of

the

tumours

to

be

highlighted

by

homogenising

tissue

structures

The

patients

were

given

detailed

information

before

each

injection

of

CM

particularly

with

respect

to

a

possible

predisposition

to

allergic

reactions

Written

consent

was

obtained

Studies

were

performed

only

in

patients

with

normal

renal

function

Approval

had

been

obtained

from

the

hospital

's

ethics

committee

Histopathological

correlation

Histopathological

correlation

was

determined

based

on

surgical

and

biopsy

findings

Tumour

size

grade

histological

subtype

and

presence

of

invasion

were

documented

Pathological

imaging

correlation

was

performed

in

conjunction

with

both

pathologist

and

breast

imagers

with

regard

to

lesion

location

and

size

to

ensure

that

the

imaged

lesions

were

evaluated

histologically

Breast

biopsy

US-guided

biopsies

were

performed

as

vacuum-assisted

biopsies

mostly

with

an

needle

Up

to

representative

tissue

samples

were

taken

When

there

were

malignant

findings

US-guided

wire

marking

was

mostly

undertaken

before

surgical

excision

Afterwards

follow-up

examinations

were

carried

out

at

intervals

Statistical

analysis

We

carried

out

statistical

analyses

Elementary

statistics

were

computed.Fisher

's

two-tailed

exact

test

was

applied

for

statistical

assessment

of

powers

for

discriminating

different

vascularisation

and

comparison

of

benign

tumours

versus

carcinomas

after

the

use

of

Optison

Results

THI

has

no

effect

on

image

quality

in

the

near

field

THI

needs

at

least

cm

of

tissue

penetration

The

effect

is

best

seen

in

the

middle

and

far

field

especially

around

the

focus

zone

Cutis

and

the

first

mm

of

fat

and

Cooper

's

ligaments

are

already

seen

in

fundamental

mode

with

better

visibility

and

delineation

with

SC

-LRB-

cross

beam

level

medium

-RRB-

and

SRI

The

reflex

of

the

anterior

mammary

fascia

appears

thinner

and

brighter

with

SC

-LRB-

cross

beam

level

medium

to

high

-RRB-

than

in

fundamental

imaging

Ducts

in

deeper

areas

are

best

visualised

with

a

combination

of

SC

and

THI

The

main

disadvantage

is

a

significant

reduction

of

the

frame

rate

caused

by

SC

especially

when

THI

is

possible

in

addition

The

first

impression

from

image

analysis

of

all

combinations

of

SC

and

SRI

was

that

higher

levels

of

SC

could

be

avoided

by

using

in

addition

an

SRI

level

of

or

giving

the

same

advantage

over

the

fundamental

image

with

less

reduction

of

frame

rate

The

best

compromise

for

screening

examinations

of

breast

tissue

is

the

combination

of

SC

-LRB-

level

low

-RRB-

and

SRI

-LRB-

level

or

-RRB-

with

THI

in

small

breasts

Fat

appears

slightly

more

echogenic

which

potentially

helps

to

define

small

tumours

The

main

limitation

of

THI

was

the

reduced

penetration

-LRB-

of

our

patients

-RRB-

In

patients

with

large

breasts

and

abundant

fibrous

tissue

fundamental

imaging

should

be

preferred

Lesion

detection

and

differentiation

In

four

out

of

five

cysts

THI

clears

artifactual

echoes

caused

by

reverberations

noise

and

speckle

so

that

even

small

intracystic

lesions

could

be

depicted

Best

visibility

was

achieved

with

a

combination

of

THI

SC

-LRB-

level

low

-RRB-

and

SRI

giving

clear

cyst

borders

and

the

intracystic

lesion

Using

SC

in

two

out

of

five

cysts

the

typical

dorsal

enhancement

caused

by

sound

transmission

is

less

intense

as

expected

from

the

fundamental

mode

Fibroadenomas

were

best

detected

with

a

combination

of

THI

with

SC

-LRB-

level

medium

-RRB-

and

SRI

-LRB-

-RRB-

showing

better

margin

delineation

even

in

the

edges

Better

differentiation

of

tissue

components

and

tumour

infiltration

could

be

achieved

by

the

same

combination

-LRB-

Fig.

-RRB-

Solid

nodules

generally

appear

more

hypoechoic

compared

with

surrounding

breast

tissue

which

affords

a

better

chance

of

detection

-LSB-

-RSB-

Fig.

on

delineation

of

tumour

margin

and

tissue

differentiation

On

the

left

side

is

fundamental

mode

without

spatial

averaging

and

tissue

harmonic

imaging

-LRB-

THI

-RRB-

On

the

right

side

THI

cross

beam

level

low

speckle

reduction

imaging

-LRB-

SRI

-RRB-

a

Improvement

of

delineation

of

tumour

margin

especially

if

the

tumour

border

is

perpendicular

to

the

ultrasound

beam

-LRB-

fibroadenoma

-RRB-

b

Improvement

of

tissue

differentiation

-LRB-

haematoma

-RRB-

Calcifications

detected

in

mammography

were

seen

in

US

in

six

out

of

ten

patients

Visibility

was

increased

especially

after

using

the

combination

of

THI

and

SRI

or

SC

and

SRI

-LRB-

Fig.

b

-RRB-

Results

for

malignant

tumours

are

summarised

in

Table

Fig.

b

Effect

on

visibility

of

calcifications

and

delineation

of

tumour

margin

a

Fundamental

B

mode

b

Tissue

harmonic

imaging

-LRB-

THI

-RRB-

cross

beam

low

speckle

reduction

imaging

-LRB-

SRI

-RRB-

level

Well-differentiated

invasive

ductal

carcinoma

with

microcalcification

and

infiltration

better

seen

in

cross

beam

SRI

There

is

less

attenuation

retrotumoral

due

to

spatial

compounding

-LRB-

SC

-RRB-

Table

of

comparison

of

fundamental

versus

combination

of

tissue

harmonic

imaging

-LRB-

THI

-RRB-

spatial

compounding

-LRB-

SC

-RRB-

-LRB-

cross

beam

level

low

-RRB-

and

speckle

reduction

imaging

-LRB-

SRI

-RRB-

level

-LRB-

existent

in

malignant

cases

-RRB-

pattern/tissue

lesion

acoustic

fundamental

superior

no

difference

combination

superior

Group

Seventy-one

cases

confirmed

by

biopsy

were

classified

as

malignant

-LRB-

BI-RADS

IV

V

-RRB-

and

cases

were

categorised

as

most

likely

benign

-LRB-

BI-RADS

III

-RRB-

Histological

confirmation

by

vacuum

biopsy

was

also

performed

at

patients

expressed

request

and

in

cases

of

malignancy

or

borderline

lesions

also

by

surgery

-LRB-

-RRB-

Histological

appraisal

Benign

lesions

Histological

finding

detected

four

cases

with

a

scar

or

intraductal

inflammatory

origin

or

ductal

lesions

two

cases

of

papillomas

five

cases

of

fibrocystic

mastopathy

and

cases

of

fibroadenomas

Malignant

lesions

Histological

findings

revealed

ductal

carcinomas

in

situ

-LRB-

DCIS

-RRB-

two

lobular

carcinomas

in

situ

-LRB-

LCIS

-RRB-

and

cases

of

ductal

invasive

carcinomas

Sonomorphology

defined

in

particular

the

extent

of

the

tumour

marginal

contours

change

in

tissue

architecture

possible

infiltration

of

surrounding

tissue

intraductal

spreading

altered

echogenicity

of

lesions

with

possible

dorsal

sound

enhancement

or

attenuation

and

unchanged

compressibility

In

PD

CM

enhancement

with

harmonic

imaging

additionally

enabled

detection

of

peritumoral

or

intratumoral

and

irregular

vessels

penetrating

the

tumour

as

well

as

increased

tumour

vascularisation

in

intermittent

dynamic

appraisal

In

particular

irregular

penetrating

vessels

and

prolonged

enhancement

for

more

than

min

were

found

in

only

malignancies

-LRB-

cases

Fig.

d

Fig.

d

and

Fig.

f

-RRB-

In

six

cases

of

DCIS

with

a

maximum

diameter

of

mm

and

low

grading

-LRB-

G

I

-RRB-

increased

vascularisation

could

not

be

demonstrated

even

after

CM

enhancement

All

were

detected

as

small

lesions

using

a

combination

of

THI

with

SC

Five

out

of

six

showed

tiny

peritumoral

vessels

after

contrast

administration

Proliferating

fibroadenomas

and

scars

may

show

an

increased

peritumoral

vascularisation

but

did

not

show

prolonged

enhancement

in

harmonic

imaging

with

PD

-LRB-

Table

-RRB-

Fig.

d

Well-differentiated

invasive

ductal

carcinoma

-LRB-

woman

non-palpable

mass

-RRB-

a

Irregular

tumour

of

mm

with

hidden

distal

border

in

fundamental

B

scan

and

tissue

harmonic

imaging

-LRB-

THI

-RRB-

b

c

In

combination

with

cross

beam

and

speckle

reduction

imaging

-LRB-

SRI

-RRB-

better

delineation

of

the

pectoral

-LRB-

distal

-RRB-

aspect

in

particular

showing

infiltration

of

the

pectoral

fascia

d

Good

visibility

of

the

biopsy

needle

in

THI

and

THI

with

crossbeam

in

three-dimensional

-LRB-

-RRB-

techniqueFig

d

Same

patient

as

Fig.

with

invasive

ductal

carcinoma

a

Unenhanced

power

Doppler

-LRB-

PD

-RRB-

shows

few

peripheral

vessels

b

c

After

administration

of

ml

Option

increasing

enhancement

within

the

lesion

with

prolonged

persistence

of

enhancement

up

to

min

is

seen

d

Beginning

washout

after

minFig

b

Ductal

carcinoma

in

situ

-LRB-

DCIS

-RRB-

-LRB-

woman

no

palpable

mass

-RRB-

Cervical

carcinoma

breast

cancer

in

mother

and

sister

No

clinical

signs

Tumour

proven

by

vacuum-assisted

biopsy

-LRB-

DCIS

-RRB-

a

Fundamental

-LRB-

B

scan

-RRB-

b

Tissue

harmonic

imaging

-LRB-

THI

-RRB-

showing

a

small

distinct

irregular

mass

of

mm

c

f

Same

patient

as

a

b.

c

Power

Doppler

-LRB-

PD

-RRB-

before

administration

of

contrast

d

Pronounced

visibility

of

the

feeding

vessel

in

the

early

phase

e

Late

and

persistent

enhancement

of

the

tumour

typical

for

malignant

breast

tumours

f

Better

delineation

of

the

tumour

even

after

min

in

contrast

harmonic

imaging

-LRB-

CHI

-RRB-

modeTable

of

benign

tumours

versus

carcinomas

Vascularisation

after

administration

of

CM

-LSB-

ml

Optison

-RSB-

Benign

tumours

-LRB-

n

-RRB-

Carcinomas

-LRB-

n

-RRB-

Power

DopplerPower

Doppler

CMPower

DopplerPower

Doppler

CMEarly

phase

-LRB-

min

-RRB-

Marginal

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Penetrating

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

p

-RRB-

Central

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

p

-RRB-

Late

phase

-LRB-

min

-RRB-

Diffuse

-LRB-

-RRB-

-LRB-

p

-RRB-

Marginal

vessels

are

seen

in

both

groups

in

a

high

percentage

Most

carcinomas

show

diffuse

enhancement

through

the

late

phase

-LRB-

statistical

evaluation

with

the

Fisher

's

exact

test

significant

differences

p

-RRB-

The

results

of

our

own

investigations

indicate

that

the

tumours

can

be

identified

better

during

biopsy

in

echo-inhomogeneous

tissue

using

CHI

in

biopsies

of

smaller

tumours

under

mm

in

size

This

enables

false

negative

findings

to

be

avoided

in

the

histopathological

investigations

After

injection

of

CM

satellite

foci

and

lymph

nodes

may

also

show

increased

vascularisation

which

is

manifested

especially

in

harmonic

imaging

with

PD

Discussion

After

clinical

examination

breast

US

is

the

preferred

method

in

symptomatic

patients

In

cases

without

symptoms

breast

US

is

ascribed

a

higher

sensitivity

for

detecting

breast

cancer

in

women

with

dense

breast

tissue

women

under

the

age

of

and

high-risk

women

Mammographically

occult

cancers

can

be

detected

by

US

in

of

cases

depending

on

patients

breast

density

and

age

For

women

without

symptoms

breast

US

should

be

mandatory

and

complementary

to

mammography

in

the

case

of

breast

density

grade

II

-LSB-

American

College

of

Radiology

-LRB-

ACR

-RRB-

-RSB-

or

more

-LSB-

-RSB-

US

is

now

the

more

accurate

imaging

test

in

women

years

or

younger

who

present

with

breast

symptoms

and

should

be

the

initial

imaging

investigation

-LSB-

-RSB-

In

preoperative

assessment

of

the

local

extent

of

breast

cancer

US

showed

higher

sensitivity

for

invasive

cancer

than

for

DCIS

-LSB-

-RSB-

In

nonfatty

breasts

US

and

MRI

were

more

sensitive

than

mammography

for

detecting

invasive

cancer

but

both

MRI

and

US

involved

the

risk

of

overestimating

tumour

extent

-LSB-

-RSB-

Mammographic

sensitivity

decreased

from

in

fatty

breasts

to

in

extremely

dense

breasts

The

respective

diagnostic

accuracy

of

the

different

breast

imaging

modalities

i.e.

mammography

-LRB-

Mx

-RRB-

high-resolution

breast

US

and

dynamic

contrast-enhanced

breast

scanning

-LRB-

MRI

-RRB-

regarding

early

diagnosis

of

familial

-LRB-

hereditary

-RRB-

breast

cancer

were

investigated

Breast

cancer

detection

rates

were

Mx

US

and

MRI

and

positive

predictive

values

were

Mx

US

and

MRI

-LSB-

-RSB-

THI

in

combination

with

digital

encoding

of

the

US

beam

is

an

increasingly

common

option

for

B-mode

imaging

It

reduces

reverberations

sidelobe

effects

and

speckle

Both

image

contrast

and

lateral

resolution

are

improved

in

harmonic

mode

compared

with

conventional

fundamental

US

-LSB-

-RSB-

First

applications

are

reported

for

liver

disease

-LSB-

-RSB-

lymph

node

enlargement

in

children

-LSB-

-RSB-

and

patients

with

pancreatitis

Benefits

of

harmonic

imaging

are

more

apparent

in

obese

patients

improving

accuracy

of

diagnosis

from

to

-LSB-

-RSB-

To

determine

the

impact

of

THI

on

visualisation

of

focal

breast

lesions

Szopinski

et

al.

-LSB-

-RSB-

performed

a

prospective

study

on

female

patients

THI

improved

the

grey

scale

contrast

between

fatty

tissue

and

breast

lesions

in

lesions

-LRB-

p

-RRB-

compared

with

fundamental

frequency

images

Contrast

improvement

was

greater

in

breasts

with

predominantly

fatty

or

mixed

-LRB-

fatty/glandular

-RRB-

composition

than

in

predominantly

glandular

breasts

Overall

conspicuousness

lesion

border

definition

lesion

content

definition

and

acoustic

shadow

conspicuousness

were

improved

or

equal

in

the

harmonic

mode

for

all

lesions

After

optimising

the

system

settings

our

results

showed

better

delineation

of

tumour

borders

and

infiltration

with

the

combination

of

SC

and

SRI

Better

differentiation

of

tissue

structure

was

seen

in

the

combination

of

THI

and

SRI

microcalcifications

could

be

depicted

best

with

a

combination

of

harmonic

mode

SRI

and

SC

-LSB-

-RSB-

Retrotumoral

tissue

and

the

posterior

lesion

boundary

of

tumours

are

significantly

better

identified

with

high

values

of

SC

One

must

be

aware

of

the

potential

problem

that

the

typical

posterior

acoustic

enhancement

is

significantly

reduced

with

the

result

that

a

cyst

can

be

misinterpreted

as

a

solid

tumour

THI

and

CHI

can

be

helpful

for

detecting

tumours

less

than

mm

in

size

in

echo-inhomogeneous

dense

tissue

for

characterising

tumour

morphology

with

dynamic

enhancement

studies

and

for

performing

a

definitive

core

needle

biopsy

or

vacuum-assisted

biopsy

in

cases

of

tumour

lesions

less

detectable

in

fundamental

B

scan

or

tumours

located

in

the

deep

tissue

near

the

intercostal

muscles

Harmonic

imaging

in

combination

with

SRI

and

cross

beam

can

facilitate

detection

of

intraductal

tumours

such

as

papillomas

With

imaging

the

needle

could

be

more

easily

placed

in

the

middle

of

these

small

intraductal

tumours

during

biopsies

-LSB-

-RSB-

Various

criteria

of

image

morphology

have

proved

useful

in

appraising

whether

a

breast

tumour

is

benign

or

malignant

on

the

basis

of

US

Smooth

marginal

contour

dorsal

US

amplification

displacement

margin

bilateral

US

extinction

and

absence

of

structural

discontinuity

in

that

order

rather

indicate

a

benign

lesion

An

echodense

border

tumour

outliers

jagged

marginal

contour

dorsal

extinction

and

structural

discontinuity

point

to

malignant

lesions

In

consequence

of

the

increasing

improvements

in

tumour

detection

and

morphological

imaging

sensitivity

and

specificities

can

be

achieved

with

US

in

tumour

diagnostics

-LSB-

-RSB-

An

even

higher

diagnostic

certainty

is

aspired

to

This

can

already

be

attained

with

the

combination

of

mammography

and

breast

US

especially

in

dense

and

inhomogeneous

glandular

tissue

-LSB-

-RSB-

Tumour

lesions

of

BI-RADS

IV

and

V

have

to

be

clarified

by

biopsy

in

particular

punch

biopsy

or

vacuum

biopsy

Consequently

US-guided

biopsy

is

appropriate

when

it

allows

unequivocal

lesion

identification

US-guided

interventions

are

required

for

further

clarification

in

mammography

occult

findings

and

preoperative

wire

marking

In

our

own

investigations

harmonic

imaging

was

employed

for

definitive

preoperative

wire

marking

to

carry

out

a

US-guided

vacuum

biopsy

and

also

with

CM

enhancement

for

improved

tumour

detection

Additional

Doppler

methods

have

been

used

to

analyse

breast

tumour

vascularity

-LSB-

-RSB-

Detection

of

penetrating

or

central

vessels

proved

to

be

an

accurate

sign

of

malignancy

-LSB-

-RSB-

With

the

application

of

CM

-LRB-

Levovist

-RRB-

additional

vessels

were

detected

within

the

lesions

increasing

diagnostic

accuracy

Sensitivity

of

colour-coded

US

was

improved

from

up

to

using

the

echo

signal

amplifier

Specificity

was

without

and

with

echo

signal

amplifier

MRI

was

found

to

have

a

sensitivity

of

and

a

specificity

of

up

to

-LSB-

-RSB-

Our

study

with

a

modified

technique

of

CM-enhanced

PD

and

THI

showed

better

visualisation

of

tumour

vascularisation

after

bolus

application

of

Optison

Persistent

enhancement

after

min

was

characteristic

for

malignant

tumours

enabling

tumour

characterisation

as

has

hitherto

only

been

known

from

CM-enhanced

MRI

-LSB-

-RSB-

When

using

CM

containing

protein

special

attention

must

be

paid

to

an

allergic

predisposition

and

kidney

function

disorder

The

use

of

second-generation

CM

necessitates

a

change

in

MI

and

imaging

with

harmonic

imaging

However

the

modified

technique

allows

a

differentiated

diagnosis

of

tumour

morphology

and

vascularisation

-LSB-

-RSB-

To

improve

the

detection

and

assessment

of

intratumoral

vessels

in

malignant

breast

tumours

techniques

to

enhance

visualisation

of

vessels

within

focal

lesions

have

been

developed

and

automated

These

techniques

focus

on

the

early

perfusion

phase

following

CM

administration

Contrast-enhanced

MRI

allowed

semiquantitative

assessment

of

the

kinetics

of

contrast

media

-LSB-

-RSB-

Artefacts

caused

by

pulsation

and

patient

movement

should

be

avoided

More

frequently

postprocessing

has

become

important

in

assessment

of

vasculature

CHI

US

is

already

used

to

distinguish

scars

from

recurrent

tumours

as

well

as

in

the

optimisation

of

US-guided

biopsies

-LSB-

-RSB-

Conclusion

In

conclusion

we

feel

confident

that

US

using

THI

and

CHI

technologies

is

a

valuable

tool

for

evaluating

focal

breast

lesions

in

particular

in

mammography-dense

breasts

If

utilised

extensively

it

will

be

a

cost-effective

tool

to

facilitate

detection

and

differentiation

of

malignant

breast

lesions

in

early

well-treatable

stages

and

will

thus

help

in

reducing

breast

cancer

mortality

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

tissue harmonic imaging
spatial compounding
contrast harmonic imaging


Pneumomediastinum : a rare complication of anorexia nervosa in children and adolescents . A case study and review of the literature Spontaneous pneumomediastinum is uncommon in paediatric practice . We describe two cases of spontaneous pneumomediastinum in a child and an adolescent with anorexia nervosa . Thorough investigation failed to reveal any underlying cause for secondary pneumomediastinum . Pneumomediastinum in anorexia nervosa can be caused by not only elevated intrathoracic pressures , but also by the poor quality of the alveolar walls due to malnutrition . The incidence of spontaneous pneumomediastinum in anorexia nervosa is probably higher than that recorded , since it resolves spontaneously and , therefore , it can remain undetected . We conclude that it is our considered opinion that malnutrition associated with anorexia nervosa predisposes for spontaneous pneumomediastinum due to weakness of the alveolar wall and the loss of connective tissue . Introduction Pneumomediastinum is rarely associated with anorexia nervosa -LRB- AN -RRB- . Approximately 20 cases of pneumomediastinum in anorexia patients are described in the literature . Vomiting , a common symptom in AN , is a known cause of pneumomediastinum -LSB- 13 -RSB- . But of the cases reported in the literature , only a few -LRB- three -RRB- were preceded by vomiting -LSB- 3 , 4 , 12 -RSB- . So , there has to be another cause placing patients with AN at risk for spontaneous pneumomediastinum . We report one case with spontaneous pneumomediastinum as the presenting symptom of AN . In the other case , spontaneous pneumomediastinum is a complication of AN . A review of the literature is given and we discuss the possible pathophysiology of spontaneous pneumomediastinum in patients with AN . Case report Case 1 A 13-year-old girl presented with increasing complaints of an unusual crackling sensation and sound in her neck during three days . At that time , she complained of neck pain and headache . When these complaints started , she had a sore throat with painful swallowing . Further medical history mentioned a Cooper test , a test of physical fitness , at school two weeks earlier . There had been no trauma or injury and no coughing or vomiting . Physical examination showed a respiratory rate of 16 per minute , cardiac rate of 51 per minute , blood pressure of 87/55 mmHg and temperature of 36.5 °C . Her height was 150 cm -LRB- SD − 2 -RRB- , weight 34 kg -LRB- SD − 1.5 -RRB- and body mass index -LRB- BMI -RRB- 15 kg/m2 -LRB- SD − 2.5 -RRB- . There was a slight bilateral bulging of the skin of her neck from the mandible to both clavicles , with , on palpation , a crackling sensation as a diagnostic sign of subcutaneous emphysema . Apart from being extremely slim , the skin was normal , with no signs of injury . Cardiac evaluation showed normal heart sounds without cardiac murmur . There was no dyspnoea . On auscultation , there was normal bilateral vesicular breathing . Blood tests revealed no abnormalities . Chest X-ray and computed tomography -LRB- CT -RRB- scan revealed mediastinal emphysema with extension to the neck region -LRB- Fig. 1 -RRB- . There was no pneumothorax and no extension to the retroperitoneum . An oesophageal gastric passage X-ray was normal , without signs of perforation . Laryngopharyngoscopy did not reveal mucosal lesions or signs of submucosal swelling . Electrocardiography was normal , except bradycardia . After admission to the hospital , she showed loss of appetite and further history revealed an anorectic episode , for which , she had been referred by her general practitioner to a psychologist . At the age of 13 years , she weighed 46 kg , diminishing to 37 kg 4 months later . At the time of admission to the hospital , her weight was 34 kg at the age of 13 years and 6 months . There was absolutely no history of vomiting . Fig. 1Coronal computed tomography -LRB- CT -RRB- reconstruction with mediastinal emphysema and subcutaneous emphysema in both axillas and lower neck regions in patient 1 with anorexia nervosa -LRB- AN -RRB- Within a week , the subcutaneous emphysema disappeared . She was referred to an eating disorders clinic to manage her eating disorder . She never showed any signs of purging during treatment and recovered from her AN . Case 2 A 17-year-old girl with known AN and vomiting presented with extreme malnutrition requiring refeeding . She complained of unusual crackling sensation in her neck during eight days , starting after a choking incident while drinking , followed by coughing . The same day , she felt pressure on her chest . During the following days , her neck became swollen and her voice became hoarse . The swelling had already subsided considerably at the time of presentation . Physical examination showed an extreme cachectic girl of 17 years with a respiratory rate of 16 per minute , cardiac rate of 64 per minute , blood pressure of 85/55 mmHg and temperature of 36.0 °C . Her height was 170 cm -LRB- SD = 0 -RRB- , weight 34.4 kg -LRB- SD << − 2 -RRB- and BMI 12 kg/m2 -LRB- SD << − 2.5 -RRB- . There were signs of subcutaneous emphysema in the neck and in both arms . She had dry skin without signs of injury . Cardiac auscultation was normal without cardiac murmur . There was no dyspnoea . Pulmonary auscultation was also normal . Blood tests revealed no abnormalities . Chest X-ray and CT scan revealed subcutaneous emphysema in the neck and mediastinal emphysema with extension to the intra-abdominal , retroperitoneal and epidural regions -LRB- Fig. 2 -RRB- . There was no pneumothorax . Fig. 2Chest CT showing epidural pneumatosis -LRB- arrow -RRB- in patient 2 with pneumomediastinum and AN Laryngopharyngoscopy did not reveal mucosal lesions . The laryngeal mucosa was slightly swollen . After refeeding , she was referred to an eating disorders clinic to manage her eating disorder . Within two weeks , the subcutaneous emphysema further resolved spontaneously . Discussion Pneumomediastinum , the presence of free air contained within the mediastinum , usually results from spontaneous alveolar wall rupture and , far less commonly , from disruption of the upper airways or gastrointestinal tract -LSB- 8 -RSB- . Spontaneous pneumomediastinum can be distinguished from pneumomediastinum secondary to traumatic events , such as chest trauma or thoracic surgery , endobronchial or oesophageal procedures , mechanical ventilation or other invasive procedures -LSB- 13 -RSB- . A large and diverse group of factors has been implicated in the development of spontaneous pneumomediastinum . Various respiratory manoeuvres that have in common the development of high intrathoracic pressures may lead to pneumomediastinum . These include Valsalva manoeuvres , coughing , vigorous crying and vomiting . The mechanism of development of spontaneous pneumomediastinum was originally described by Macklin and Macklin as increased intra-alveolar pressure causing the rupture of alveoli with the escape of air into the mediastinum . The mediastinum is subsequently decompressed by further passage of the air into the retroperitoneal and subcutaneous spaces -LRB- the Macklin effect -RRB- -LSB- 1 , 9 -RSB- . Whereas primary pneumomediastinum is a relatively benign and self-limited disorder , secondary pneumomediastinum due to oesophageal perforation or Boerhaave 's syndrome is a potentially life-threatening disorder because of the inevitable development of mediastinitis . Primary pneumomediastinum rarely requires treatment as the alveolair rupture heals and the leaked air resolves spontaneously . By contrast , secondary pneumomediastinum due to oesophageal perforation often requires surgical intervention -LSB- 8 -RSB- . Pneumomediastinum typically manifests as sudden chest pain or dyspnoea and , less commonly , with dysphagia and hoarseness -LSB- 8 -RSB- . Our first patient , however , presented with a sore throat , painful swallowing , complaints of pain in the neck and headache . The second patient presented with initial chest pain and hoarseness . The detection of subcutaneous air in the neck and anterior chest wall and Hamman 's sign , a crunching sound synchronous with the heartbeat , are important physical findings . Radiographically , pneumomediastinum manifests on the posteroanterior projection as a thin radiolucent line parallel to the outline of the heart , as the mediastinal pleura is displaced laterally , and on the lateral projection as the accumulation of air retrosternally -LSB- 8 -RSB- . When chest pain and dyspnoea occur , panic attacks must be differentiated from pneumomediastinum . Panic disorders are often seen in patients with AN -LSB- 6 -RSB- . As a consequence , we believe that pneumomediastinum should be ruled out in anorexia patients presenting with signs of a first panic attack . Spontaneous pneumomediastinum is rarely associated with AN . Only 21 publications related to this association are reported by Pubmed . Purging behaviour , such as self-induced vomiting , is common among AN patients . Vomiting is a known cause of pneumomediastinum , placing anorexia patients , who frequently vomit , at risk for pneumomediastinum . However , in only a few of the cases described in the literature was vomiting was the preceding event of the pneumomediastinum . In most reports , like in our patients , pneumomediastinum in anorectic patients is not preceded by vomiting -LSB- 1 , 2 , 4 , 5 , 7 , 8 -RSB- . In our patients , the diagnostic procedure did not reveal an oesophageal or upper airway perforation . The pathophysiologic mechanism of air entrance into the mediastinum can be explained by the rupture of an alveolar wall , which is mostly the cause of an air leak into the mediastinum -LSB- 8 -RSB- . Based on the literature and our observations , patients with AN are at risk for spontaneous pneumomediastinum , even if they are not vomiting . We speculate that the state of malnutrition contributes to the risk of spontaneous pneumomediastinum . Animal studies reveal that calorie restriction causes a loss of alveoli and a fall in gas-exchange tissue -LSB- 10 , 11 -RSB- and thinner alveolar walls -LSB- 10 -RSB- . To survive periods of not eating , organisms sacrifice comparatively non-essential structures for gluconeogenesis to provide glucose for the brain and amino acids to maintain muscle . Because the total organismal and lung oxygen consumption fall during calorie restriction , some lung tissue is expendable -LSB- 10 -RSB- . Also in human studies , atrophic changes , such as large alveoli and thin alveolar walls , due to starvation were found in Jewish people in the Warsaw Ghetto -LSB- 14 -RSB- . With thinner alveolar walls and the loss of alveoli , malnourished individuals are at risk of alveolar wall rupture . Since known factors of increased intra-alveolar pressure were absent in our first case and since clinical examination and radiographic study did not reveal an esophageal or upper airway perforation , we must assume that subclinical alveolar leaks with subsequent air dissection , pneumomediastinum and diffuse soft tissue emphysema occurred because of weakness of the alveolar wall and thinning of the connective tissue caused by severe malnutrition . Therefore , even with a minimal increase of intra-alveolar pressure , such as that which may occur during usual daily activities , such as a choking incident , can become the cause of air leaks , as in our second case .

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Stimulation programs for pediatric drug research -- do children really benefit ? Most drugs that are currently prescribed in pediatrics have not been tested in children . Pediatric drug studies are stimulated in the USA by the pediatric exclusivity provision under the Food and Drug Administration Modernization Act -LRB- FDAMA -RRB- that grants patent extensions when pediatric labeling is provided . We investigated the effectiveness of these programs in stimulating drug research in children , thereby increasing the evidence for safe and effective drug use in the pediatric population . All drugs granted pediatric exclusivity under the FDAMA were analyzed by studying the relevant summaries of medical and clinical pharmacology reviews of the pediatric studies or , if these were unavailable , the labeling information as provided by the manufacturer . A systematic search of the literature was performed to identify drug utilization patterns in children . From July 1998 to August 2006 , 135 drug entities were granted pediatric exclusivity . Most frequent drug groups were anti-depressants and mood stabilizers , ACE inhibitors , lipid-lowering preparations , HIV antivirals , and non-steroidal anti-inflammatory and anti-rheumatic drugs . The distribution of the different drugs closely matched the distribution of these drugs over the adult market , and not the drug utilization by children . Introduction Most drugs prescribed in pediatrics have not been tested in children . A recent review demonstrates that up to 80 % of prescriptions for children in hospital and in general practice are either unlicensed -LRB- without a license for children -RRB- or used off-label -LRB- outside the product license -RRB- -LSB- 15 -RSB- . Of commercially available drugs in Europe , only 35 % are authorized for use in children -LSB- 4 -RSB- . Although there are reasons why children do not often participate in clinical trials , including ethical , scientific and commercial considerations -LSB- 2 , 25 -RSB- , it is considered unacceptable to treat children with drugs that have not been studied properly . In 1997 , the Food and Drug Administration -LRB- FDA -RRB- and the Congress introduced the Food and Drug Administration Modernization Act -LRB- FDAMA -RRB- , and this was followed by the Best Pharmaceuticals for Children Act . Closely linked to this legislation is the Pediatric Rule -LRB- 1998 -RRB- , which requires the industry to perform research in the pediatric population . In the European Union -LRB- EU -RRB- , final legislation on this topic has been approved and will come into effect at the beginning of 2007 . In both continents , the measures taken to address the problems broadly follow the same pattern . The first incentive is aimed at new medicines and intended for products covered by a patent or a supplementary protection certificate -LRB- SPC -RRB- . For these drugs , a 6-month extension of market exclusivity is granted if a pediatric study is performed . The second incentive has the objective of increasing the knowledge on drugs that are no longer patent protected . In order to obtain the data necessary to establish safety , quality and efficacy specifically in children , either funding for the studies -LRB- USA -RRB- or market exclusivity -LRB- a so-called Pediatric Use Marketing Authorization -- PUMA -RRB- can be given . Central to the second incentive is that experts are involved in determining for which drugs the greatest medical need exists and in ensuring that these drugs will be given priority . In the USA , the FDA plays this central role , and in the EU , a Pediatric Committee will be established within the European Medicines Agency -LRB- EMEA -RRB- which will be given a similar role . The EU Commission apparently follows the approach in the USA with regard to patent-protected drugs because , according to the EU Commission , `` the pediatric exclusivity provision has been extremely successful in the USA in stimulating the development of medicinal products for pediatric use '' -LSB- 1 -RSB- . At the brink of implementing new programs -LRB- EU -RRB- or decisions on continuation of existing programs -LRB- USA -RRB- , we questioned what the influence of the pediatric exclusivity regulation has been on pediatric drug development . We evaluated the drugs that are granted pediatric exclusivity in the USA by studying research that has been performed as a consequence of the exclusivity provision , and by comparing the drugs granted pediatric exclusivity with medicines actually used by children . Materials and methods The drugs granted pediatric exclusivity since the introduction of the FDAMA in July 1998 until August 2006 were retrieved from the FDA website -LSB- 17 -RSB- . All drugs were classified into subgroups according to the Anatomical Therapeutical Classification -LRB- ATC -RRB- system of the European Pharmaceutical Marketing Research Association . The data submitted to the FDA that resulted in granting the exclusivity were examined . For each drug , the publicly available summaries of medical and clinical pharmacology reviews of the pediatric studies were scrutinized . These summaries contain information on the pediatric research performed to obtain pediatric exclusivity . If these summaries were unavailable , the labeling information of the drug with pediatric exclusivity was studied to retrieve information about the pediatric studies performed . Each drug label contains a pediatrics section stating whether the drug is tested in children and , if so , information on the performed studies is given -LSB- 6 , 17 , 26 -RSB- . Data were extracted about the type of study , number and age of participants , whether long-term follow-up -LRB- defined as > 1 year with specific attention for long term effects on growth and development -RRB- was undertaken and whether the study led to a pediatric indication being included on the label . Participants were divided into pediatric age categories according to the International Conference on Harmonization -LRB- ICH -RRB- guidelines : neonates -LRB- birth -- 27 days -RRB- , infants -LRB- 28 days -- 23 months -RRB- , children -LRB- 2 -- 11 years -RRB- and adolescents -LRB- 12 -- 18 years -RRB- . To obtain data about drug use in children , recently published surveys of drug prescribing in hospitals and general practice were reviewed by a systematic search of the literature on drugs used by children . Details on the literature search and selection criteria are provided in box 1 . Drug use in adults was assessed by using the sales figures from public databases and publications thereof -LSB- 7 , 8 -RSB- . The data were categorized according to the ATC system as mentioned above . Literature search and selection strategy Step 1 : literature searches of the PubMed and Embase bibliographic databases for papers published in English between 1990 and July 2005 combining the following search terms -LRB- keywords and appropriate medical subject headings -RRB- : Child , preschool -LRB- or -RRB- child -LRB- or -RRB- infant -LRB- or -RRB- infant , newborn -LRB- or -RRB- adolescent -LRB- or -RRB- pediatric -LRB- or -RRB- paediatric -LRB- or -RRB- paediatrics.Pharmaceutical preparations -LRB- or -RRB- drugs , non-prescription -LRB- or -RRB- drugs , generic -LRB- or -RRB- drug , therapy -LRB- or -RRB- prescriptions , drug -LRB- or -RRB- medicine -LRB- or -RRB- medication.Drug utilization -LRB- or -RRB- pharmacoepidemiology -LRB- or -RRB- drug utilization review . Step 2 : the references contained in articles identified in step 1 were examined to identify further relevant studies . Step 3 : based on the titles and abstracts of the papers , we next identified and then located full-text copies of 35 potentially relevant studies for closer examination . Step 4 : selection of articles by two independent reviewers -LRB- I.B. , R.S. -RRB- , using the following selection criteria : Study performed in the industrialized world , defined as in Europe , North America , Australia and New Zealand.Study population of children from 0 to at least 14 years , to include all age groups -LRB- neonates , infants , children and adolescents -RRB- . Sufficient information in the paper about drug utilization to classify 90 % of the drugs in an ATC drug groups.Avoidance of selection bias by exclusion of voluntary surveys . Step 5 : inclusion of nine papers meeting all selection criteria . Results Pediatric exclusivity provision According to the FDA , 135 drugs -LRB- 130 active moieties -RRB- were granted pediatric exclusivity from July 1998 to August 2006 . Most frequent drug groups were central nervous system drugs -LRB- 19 % -RRB- , such as anti-depressants and psycholeptics , cardiovascular drugs -LRB- 16 % -RRB- , mainly ACE inhibitors and lipid-lowering preparations , systemic anti-infectives -LRB- 12 % -RRB- , among which largely HIV antivirals , cytostatics -LRB- 11 % -RRB- , and alimentary tract medication -LRB- 12 % -RRB- , among which proton pump inhibitors and oral antihyperglycemic medication -LRB- Table 1 -RRB- . Table 1Active moieties granted pediatric exclusivity according to ATC groupDrug categoryNumber of drugs -LRB- % of total -RRB- Most frequent drug classesNumber of drugsCentral nervous system24 -LRB- 19 % -RRB- Anti-depressants8Psychostimulants , agents used for ADHD and nootropics4Anti-epileptics3General anaesthetics3Anti-migraine preparations2Cardiovascular system21 -LRB- 16 % -RRB- ACE inhibitors , plain6HMG-CoA reductase inhibitors5Beta-blocking agents4Alimentary tract and metabolism16 -LRB- 12 % -RRB- Drugs for peptic ulcer and gastro-oesophageal reflux disease5Oral blood glucose lowering drugs4Anti-infectives for systemic use15 -LRB- 12 % -RRB- Direct acting antivirals10Antibacterials for systemic use4Antineoplastic and immunomodulating agents14 -LRB- 11 % -RRB- Other antineoplastic agents5Antimetabolites3Alkylating agents2Musculo-skeletal system7 -LRB- 5 % -RRB- Anti-inflammatory and anti-rheumatic products , non-steroids6Drugs affecting bone structure and mineralization1Respiratory system10 -LRB- 8 % -RRB- Antihistamines for systemic use4Drugs for obstructive airway disease3Decongestants and other nasal preparations for topical use2Sensory organs10 -LRB- 8 % -RRB- Antiglaucoma preparations and miotics4Decongestants and anti-allergics3Dermatologicals6 -LRB- 5 % -RRB- Corticosteroids , potent -LRB- group 3 -RRB- 3Genito-urinary system and sex-hormones3 -LRB- 3 % -RRB- Other urologicals , including antispasmodics2Blood and blood forming organs2 -LRB- 2 % -RRB- Anti-thrombotic agents1Systemic hormonal preparations1 -LRB- 1 % -RRB- Hypothalamic hormones1Parasitology1 -LRB- 1 % -RRB- Anti-malarials1Total130 -LRB- 100 % -RRB- From 118 drugs -LRB- 91 % -RRB- , information about studies performed in children to obtain pediatric exclusivity could be retrieved from the FDA summaries of medical and clinical pharmacology reviews -LRB- n = 61 -RRB- of the pediatric studies or the prescribing information as provided by the manufacturer -LRB- n = 57 -RRB- . No information could be found on 12 of the drug entities , mainly including over the counter drugs . The product label of 13 drugs merely stated that safety and/or efficacy in the pediatric population had not been established . For the remaining 105 drugs , in total , 326 studies were performed for the approval of pediatric exclusivity . At least 40,075 pediatric patients participated in these 326 studies -LRB- the number of participants was not noted for 27 of these studies -RRB- . In the majority of the applications , children over a wide age range were included . Information on the age of participants was not provided for 54 of the 326 studies . Children participated in 224 of the remaining 272 studies -LRB- 82 % -RRB- , adolescents in 177 -LRB- 65 % -RRB- , infants were included in 105 -LRB- 39 % -RRB- of the trials , and neonates in 38 trials -LRB- 14 % -RRB- . Only 1 -LRB- 0.4 % -RRB- study included preterm infants . The objective of most -LRB- 62 % -RRB- of the 326 studies was to determine the safety and efficacy of a drug . Pharmacokinetics and/or pharmacodynamics were studied in 147 -LRB- 45 % -RRB- trials , efficacy-only in 13 -LRB- 4 % -RRB- and safety-only in 38 -LRB- 12 % -RRB- . From the 299 studies in which information about the number of participants was given , on average 134 children participated per study . This varied from 8 children in a safety and efficacy study of a HIV antiviral in neonates , to 994 children participating in a safety database of an antibiotic . Long-term -LRB- > 1 year -RRB- follow-up was either done or planned for 25 -LRB- 21 % -RRB- of the 118 drugs . For 42 % of the drugs granted pediatric exclusivity and for which information was available -LRB- 50 out of 118 -RRB- , the information obtained from the pediatric studies led to an approved pediatric indication . The 130 active moieties granted pediatric exclusivity were categorized according to the ATC system . The results are shown in Table 1 . Drug utilization by children and adults The search strategy retrieved nine papers addressing drug utilization in children -LRB- Table 2 -RRB- . The data were summarized by calculating a weighted average for each drug category with weights proportional to the number of prescriptions -LRB- Table 3 -RRB- . Drugs most often used by children are respiratory drugs , anti-infectives for systemic use and dermatologicals . Table 2Characteristics of included studies on pediatric drug utilizationAuthor -LRB- year -RRB- SettingPopulation sizeAge range -LRB- y -RRB- Number of prescriptionsNiclasen -LSB- 14 -RSB- -LRB- 1995 -RRB- Pharmacy dispensing records in-and outpatients1 ,7040 -- 145,876 Rokstad -LSB- 21 -RSB- -LRB- 1997 -RRB- Prescriptions of general practitionersa0 -- 198,215 Thrane -LSB- 28 -RSB- -LRB- 1999 -RRB- Pharmacoepidemiological prescription database outpatients48 ,0910 -- 15154,189 Schirmb -LSB- 24 -RSB- -LRB- 2000 -RRB- Pharmacy dispensing records outpatients15 ,0010 -- 16373,925 Lewis -LSB- 12 -RSB- -LRB- 2001 -RRB- Prescriptions pediatric outpatients12 ,6280 -- 1633,140 Pandolfini -LSB- 16 -RSB- -LRB- 2002 -RRB- Prescriptions general pediatric hospitals1 ,3250 -- 144,265 Schirm -LSB- 23 -RSB- -LRB- 2003 -RRB- Pharmacy dispensing records outpatients18 ,9430 -- 1666,222 Ufer -LSB- 30 -RSB- -LRB- 2003 -RRB- Pharmacy dispensing records outpatients357 ,7840 -- 16644,817 Sanz -LSB- 22 -RSB- -LRB- 2004 -RRB- Prescriptions outpatients by GPs and pediatricians12 ,2640 -- 1427,486 a Not statedb Not included in weighted average due to presentation of data in paper -LRB- percentage of children using a drug category -RRB- . Table 3Drug utilization pattern in childrenDrug category % of prescriptionsFrequent used drug classesRespiratory system30 % Drugs for obstructive airway diseaseNasal preparationsCough and cold preparationsAntihistamines for systemic useGeneral anti-infectives , systemic28 % Antibacterials for systemic useDermatologicals12 % Antifungals for dermatological useEmollients and protectivesCorticosteroids , dermatological preparationsSensory organs7 % OphtalmologicalsOtologicalsCentral nervous system4 % Analgesics / antipyreticsPsychostimulants , agents used for ADHD and nootropicsAnti-epilepticsHormones3 % Corticosteroids , for systemic useBlood and blood forming organs3 % Vitamin KAlimentary tract and metabolism2 % Drugs for peptic ulcer and gastro-oesophageal reflux diseaseInsulins and analoguesMusculo-skeletal system2 % Anti-inflammatory and anti-rheumatic products , non-steroidsGenito-urinary system and sex-hormones2 % Hormonal contraceptives for systemic useCardiovascular system1 % DiureticsOther < 1 % Total105 % -LRB- exceeds 100 % due to rounding -RRB- The pattern of drug use in adults based on sales over the last 12 months to May 2005 -LRB- Table 4 -RRB- shows that drugs used for central nervous system , cardiovascular , alimentary tract and metabolism disorders make up over 50 % of the market . Table 4Drug utilization patterns in adults , according to the drug sales in North America over the period May 2004 -- May 2005Drug categoryAdult prescriptionsCentral nervous system23 % Cardiovascular system19 % Alimentary tract and metabolism14 % Respiratory system9 % General anti-infectives , systemic8 % Musculo-skeletal system6 % Genito-urinary system and sex-hormones6 % Other2 % Antineoplastic and immunomodulating agents4 % Dermatologicals3 % Blood and blood forming organs3 % Sensory organs2 % Total100 % Discussion The introduction of the pediatric exclusivity laws in the USA has led to pediatric drug trials for 135 drugs tested in the past eight years . Over 300 studies were performed with over 40,000 pediatric patients participating . Based on these data , the FDA claims `` the pediatric exclusivity provision has done more to generate clinical studies and useful prescribing information for the pediatric population than any other regulatory or legislative process to date '' -LSB- 20 -RSB- . The EU Commission and other policy makers see a rapid adaptation of similar legislation in Europe essential to boost pediatric drug research in the EU as soon as possible -LSB- 1 , 3 , 19 -RSB- . Although it is true that more pediatric studies have been done , we question the content of the research . A major discrepancy is apparent between the drug prescription pattern in children and the drugs granted pediatric exclusivity . The majority of drugs granted pediatric exclusivity are rarely used by children , and drugs that are frequently used by children are underrepresented in the pediatric studies to obtain exclusivity . This difference is not accounted for by the licensing status of the used drugs . For instance , in general practice , 37 % of the prescriptions of respiratory drugs are still used in an unlicensed or off-label manner -LSB- 27 -RSB- . This suggests that the pediatric studies did not address the real needs in pediatric drug development . Whilst the pediatric exclusivity scheme has stimulated pediatric research quantitatively , the nature of the scheme has led to priorities for the type of research that are largely driven by the adult market for medicines rather than by the needs of the pediatric population . An important built-in motive in the stimulation program for performing pediatric studies is the financial benefit gained from the exclusivity provision . The drugs granted pediatric exclusivity include 5 out of the `` Top 10 '' prescription drugs with the highest sales figures in North America in 2005 : atorvastatin -LRB- Lipitor -RRB- , simvastatin -LRB- Zocor -RRB- , omeprazole -LRB- Nexium -RRB- , lansoprazol -LRB- Prevacid -RRB- , and sertraline -LRB- Zoloft -RRB- . Sales of these 5 drugs amounted to $ 24.1 billion US in 2005 -LSB- 9 -RSB- . Extension of the SPC on the basis of pediatric exclusivity has also been granted to other adult best-selling drugs , such as pravastatine , enalapril , metformin , amlodipine , paroxetine , fluoxetine , and rofecoxib -LRB- currently withdrawn -RRB- . It is thus clear that the patent extension has an enormous financial benefit for the pharmaceutical companies , which easily outweighs the cost of the average pediatric trial -LSB- 1 -RSB- . This is not only the case for best-selling drugs but also for drugs with a smaller market share . A Tufts University report indicates that an estimated $ 35 million US in undiscounted profits per drug can be earned by obtaining pediatric exclusivity based on median 2004 sales for all pediatric exclusivity drugs after accounting for costs and market protection extensions -LSB- 29 -RSB- . Although the increased profit was intended by the legislator , we doubt if the other intention , which aimed at providing data to reduce the volume of drugs taken by children that are off-label or unlicensed , has also been met . Our approach to define essential drugs for children by volume and by number of children that need a certain medicine is incomplete , as indications and severity of the conditions for which the drug is prescribed also play an important role -LSB- 10 -RSB- . Secondly , the method employed in our literature search may have introduced some bias toward outpatient drug consumption , thus underestimating the use of , for example , anesthetic or cardiovascular drugs . Clearly , hypertension or lipid disorders occur in children , and knowledge about these drugs in this population is important . However , these conditions are certainly not major causes of morbidity , and subsequent drug use in children and the research priorities lie elsewehere . Furthermore , there are specific issues in pediatric clinical pharmacology that have remained unaddressed by the current product-related approach . First , the age distribution of the children participating in the trials does not reflect the actual medical needs . Drug use in children follows a pattern , with a relatively high percentage of children using a prescription drug in the first year of life -LSB- 24 -RSB- while the proportion of off-label and unlicensed drug use is highest -LRB- ∼ 90 % -RRB- in the vulnerable group of neonatal ICU patients -LSB- 5 -RSB- . These data are not reflected in the participation in the trials to obtain pediatric exclusivity , with neonates and infants being included in , respectively , 14 and 39 % of the study groups . In fact , it is surprising to see that the majority of applications included children of a wide age range , thereby ignoring the delineation of age groups as defined in the ICH guidelines . This is problematic , as in the pediatric population significant age-related differences may exist in the pharmacokinetics and the effects of drugs -LSB- 11 -RSB- . Secondly , the effects of drugs -LRB- that are intended for chronic use -RRB- on development and maturation of children are largely unknown , but this issue has hardly been addressed . Third , off-label drugs are hardly or not studied . Only ten drugs in this category are under consideration for study by pharmaceutical companies -LRB- FDA website -RRB- . From these ten drugs , six already have been refused by industry for studying , and have been referred to the National Institutes of Health to obtain the necessary information for rational use in pediatric populations . These clinical trials are at the moment awaiting funding -LSB- 13 , 18 -RSB- . Surprisingly , in the same Tufts study that reports on a profit of $ 35 million US per drug granted exclusivity , it is also suggested that the current incentives for studying non-patent protected drugs are too low -LSB- 29 -RSB- . Finally , methodological research has remained underfunded by this approach . Any expansion of research will require specialized techniques that allow samples and data to be obtained in children with minimal discomfort and risk . For instance , most pharmacokinetic assays require an amount of blood that is too large for the average neonate , so highly sensitive assays need to be developed . Accurate assessment of drug effects on neuro-development and behavior also require further development , independently of studies with particular compounds . The recently approved EU guidelines contain differences from the USA that may remedy some of the deficiencies indicated . It contains a section for the stimulation of off-patent drugs that can be granted a special label -LRB- PUMA -RRB- , and data protection if data necessary to establish safety , quality and efficacy in children are submitted . The ` Medicines Investigation for the Children of Europe ' program , funded by the EU , will be created to stimulate research of off-patent drugs . The proposed establishment of a Pediatric Committee , operating within the European Medicines Agency , will guard study of significant drugs for children and avoid unnecessary studies , provide free advice to industry , and stimulate long-term pharmacovigilance . It will also play a role in the implementation of the requirement for industry to submit data they already hold on use of their medicines in children . New drugs will not be granted Marketing Authorisation unless the need for pediatric research has been waived by the Pediatric Committee , or deferral of initiation or completion of an already approved Pediatric Investigation Plan has been agreed to by this committee . In addition , an EU network of investigators and trial centers will be formed -LSB- 1 -RSB- . Although elements of this network are now beginning to form , their funding is unclear and certainly not at the level provided to the patent holders by a patent extension . Also , it is not immediately clear why the EU measures will deliver , when this was not achieved with the formation of Pediatric Pharmacology Research Units and the oversight of research priorities by the FDA in the USA . In conclusion , the schemes implemented in the US generated new knowledge and led to the rapid development of an infrastructure to carry out pediatric drug trials . Although these are certainly positive developments , we do believe that the findings of this survey warrant additional efforts to stimulate research on drugs used more frequently by children , and generally applicable methodological research , as at least the short-term effect of these initiatives seems to have drawn the focus of industry-sponsored research to the most profitable part of the market . The funding of the research we propose should not be problematic . The pediatric exclusivity schemes generate a flow of public money to the sponsoring drug companies because generic replacement and price reductions are postponed . There is no particular reason why these public funds could not be at least partly applied in an alternative manner .

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 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 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 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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 O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O 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 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