Thank you.

Yeah,

thank you.

DR sessions and members of 

the symposium.

When clinicians 

extrapolate from the characteristics 

of a disease presented in patients,

you know,

seen by them to a larger universe.

Their their vision may be clouded by 

ethnocentrism.

The tendency to regard ones 

experience as the standard of reference 

epidemiology may provide a 

corrective for ethnocentrism 

and we will try to sketch some of 

the epidemiological highlights of 

colon cancer in the hope that 

will provide a perspective in which 

the clinicians can place their 

own contributions 

based on patient observation.

For this purpose,

we will draw on information assembled 

from international comparisons,

time trends,

migrant populations and the 

precursor lesions of polyps,

uh which have just been so 

uh ably discussed 

then,

uh the probable reason for failure to make 

greater progress in the ideology of large 

bowel cancer is that virtually all the 

studies have been conducted in the high risk 

populations of north America and western 

europe.

For a firmer grip on the 

epidemiology that might lead to 

ideological hypotheses.

one Ought to begin with 

international comparisons.

The initial evidence for striking inter 

population variations and risk 

came from comparative studies of 

mortality.

These have been uh elaborated more 

recently by incidents data from 

tumor registries made possible by 

extension of the network of tumor 

registries to cover some 

populations and eastern 

europe asia africa 

and south America.

Uh some of the results first 

slide please.

And I guess if you can Yeah,

that's fine.

This is a selected 

uh group of comparisons of 

populations.

The purpose is to show the 

magnitude of range of differences 

between high and low risk populations 

on the order of six or seven fold.

This particular comparison is 

for colon cancer incidents,

that is a sigmoid.

And above.

The next slide 

gives the 

that was for males.

They results for females 

show the same range 

of inter population difference.

The 

results no 

fall into roughly three 

groups that is high risk 

represented by Connecticut,

new Zealand.

Then we have a medium 

intermediate risks in most of western 

europe,

United Kingdom Norway and 

then lower risks 

in eastern europe 

Finland at 

japan and south America.

The comparable data 

on carcinoma direct.

Um The next slide 

for males chose 

the the same type 

of of variation 

although a little narrower range.

And the next slide on females 

rectum females 

substantially the same 

picture the same.

This similar 

ordering for colon and 

rectum can be shown in the next 

slide.

Uhh this slide We have one 

axis incidents rights for rectum.

The other axis giving the incidence 

rates for colon.

Uh 

the 

uh rights 

for 

for males,

we can look up the 

and for females.

No,

the uh the white the yellow dot 

is the uh the females and the red 

triangle as a team.

And you can see that uh fairly 

regular ordering.

Now some of the 

enter registry variation in 

column rectum ratios.

We can bring this point out better in the next slide.

This gives the 

directly ratios of the colon 

cancer incidence to the rectum 

incidents.

Uhh and for 

virtually all of the the 

populations,

this ratio does exceed 

unity.

There are certain differences which 

you can see for females ratio 

generally being higher for 

that sex.

Uh part of this variation that you 

see in this slide might be uh due to 

different practices and assignment of tumors 

close to the sigmoid fletcher.

But classification artifacts seem 

unlikely to be the sole 

explanations.

And this set of results raises the 

possibility of population differences 

in anatomical localization of uh 

bowel tumours.

The localization of tumors within the 

colon has been reported to very in 

the literature,

High risk populations,

high risk.

Most of the tumors appear to be on 

the left side.

A typical result being the 

63% of such 

a colon tumors in England.

While in uh low risk 

uh countries,

the tumors seem to be concentrated on the 

right side.

Uh typical result being uh 

65% right sided uh 

localizations in Cali 

Colombia.

In fact,

when we array the registries in ascending 

order of overall cancer incidence,

there is a concentration of tumors 

in the sigmoid segment 

uh in those registries with the 

highest overall incidents,

uh I don't have a slide to show this,

but the data from Connecticut 

show this concentration.

And if we took really low risk populations such 

as the Bombay and Cali,

we would have very 

little concentration in this 

part of the,

of the colon.

Uh The next 

figure,

uhh describes the sex 

ratios for colon cancer incidents.

The point to be made here is that in high 

risk populations,

the male female ratio tends to 

be close to unity.

There's an obvious exception here.

The Hawaiian japanese,

which we will discuss a little later.

While in the lower risk populations,

there is a tendency for female 

predominance.

The picture for rectum is quite 

different.

Higher rates for males prevail at all levels 

of risk.

Next slide,

you can see the there's only 

one exception 

for rectum.

Uh The sex 

ratios,

however,

based on summary age adjusted rates 

obscure some rather interesting sex 

age interactions.

Uh When we look at the populations at 

two extremes of uh colon 

cancer risk,

we see some different sex 

behavior in the 

age specific rates.

Next slide 

Connecticut and colleague Connecticut being 

a high risk population.

We can see that the 

rates for the two 

sexes are very close 

together and with a slight 

male predominance at the older age is 

in Cali on the other hand,

we can see Quite a definite 

female predominance after age 

65.

The pattern of 

uh of uh just depicted 

for Cali and other low risk 

communities at corresponds 

closely to that observed for the subset 

Of seeking a sending tumors 

in higher risk 

populations uh for both the female 

predominance after age 65 has 

established this next slide,

please.

We had the result for colleagues and 

in Norway,

which is one of the intermediate risk there 

for sake um and ascending.

We do get this 

crossover with higher female 

risks and the older age 

range.

The in 

contrast the 

we get a similarity in contours of the age 

specific rates for colon and 

rectum cancers.

Using the rectal sigmoid lectures the 

dividing line Uh 

in very high risk populations where the 

male rights after 65 are clearly 

higher.

In both.

Next slide 

we have this male 

predominance,

but it's a more marked 

for your rectum.

From these and related observations,

we make injector that the entity colon 

cancer may have at least two separate components seek 

him ascending and as using as a 

label and sigmoid rectum.

It appears to be the latter which accounts for the 

enhanced risks observed in the north 

America and western europe.

If environmental factors are 

responsible,

the intensity of exposures and resultant 

incidents may have been changing over time 

Connecticut is one of the registries in which we 

have information on this point.

Next slide,

please.

Uhh in 

in Connecticut for the sigmoid,

I'm looking at the two 

time period Ends of the 15 Year Time 

Period.

The male predominance appears to 

be a little more firmly established.

Uhh next slide 

These for transfers and 

descending in the later time 

period.

This friend to male dominance 

seems to be going on.

Next slide 

for Sikkim and descending.

Males have not become dominant yet.

But you can see that the gap is 

narrowing.

So uh 

one might speculate if if we can turn 

the incidents in the United 

States as an 

epidemic.

one can speculate if this 

epidemic will reach a climax with 

the presence of a male 

predominance in the 

lesions in the Sikh um and 

a sending no colon.

Uh In addition to these inter population 

comparisons,

it's useful to discuss 

changes which have appeared in 

certain migrant populations 

when the colon cancer 

experience of the Hawaiian japanese is 

contrasted with that for 

japan and US white,

a displacement and risks as can be observed.

Next slide,

it's this is the baseline for 

japan.

The line for US whites,

the host populations.

And you can see the uh 

positioning of the mortality rates 

for the the migrants 

generation themselves,

the esa and their native born descendants among 

males has been pushed up towards the 

U.

S.

Right?

This tendency is 

less marked for the females 

and it is this 

phenomenon I believe,

which produces this unusual 

sex ratio for the Hawaiian japanese,

which occurred in an earlier slide where there 

was a excess of 

risk of colon cancer among 

the male population.

There's uh suggests that there is 

a greater male volatility and 

biological uh response to 

changed conditions 

in the 

a latent period between exposure 

and development of neo plas.

Ums one of course tries to look 

for precursor lesions and to use 

such information and attempt to transform 

the epidemiology of colon cancer 

into the epidemiology of a 

precursor lesion.

The Early landmark in this direction 

was a paper by Helwig in the 1940s,

which looked at adenomas polyps 

as a candidate precursor.

His line of attack was too search for 

congruence is in the anatomical distribution 

of cancers and polyps.

Uh time doesn't allow to 

consider the findings of 

people,

you know,

following Hellwig and the different 

interpretations of these uh findings.

It started,

I'm going to make a general observation 

as I say,

that they were unable to resolve the 

the polyps cancer congruence 

problem and related issues with 

observations solely from 

high risk populations.

Uh This is probably not surprising 

since when you have little background variation in 

the distribution and biologic behaviors of 

lesions,

it becomes very difficult to 

detect patterns and relationships.

A single population might have 

permitted test of a very simple palla 

cancer models such as the 

constant probability of transition 

independent of anatomical 

localization.

But when you have more complicated 

models,

uh,

I think that you need greater 

background variation and experience 

for this reason,

studies of 

precursor lesions needed to 

be carrying out carried out in populations 

with widely different colon cancer 

incidents.

Uh,

since hell Wigs data were on record.

Uh Professor Korea and 

Colombia and I decided that 

uh work of this type should be 

done in a low risk population represented 

in Cali Colombia and Korea has 

published on the study of 

Of 1500 

bottle specimens from 

necropsies there.

The results that I'm going to give 

are are 

still in the infancy 

and they have to be treated as 

exploratory and illustrative and certainly 

not as uh as definitive.

However,

when we compare these results with 

those from Helwig,

from results more recently obtained 

in New Orleans by Professor 

Strong and his group and 

results from 

the japanese migrants in Hawaii 

and from populations in 

japan.

Certain uhh 

patterns emerge next slide.

Uh This compares the 

distribution of aveeno 

metis and hyper plastic polyps in the 

autopsy specimens in 

college Korea when he did the 

work because 

uh concentrated 

on adenomas polyps,

he felt that uh this 

distribution would turn out to be 

quite different than in the United States is 

reported by Helwig and indeed it is uh 

you uhh first one 

explanation these location of 

these lesions are plotted with 

respect to distance from the anus.

And uh but they on this 

particular scale uh they're plotted in 

terms of relative distance.

Uh that is converting the total length 

of the of the ball 

from the illegal cycle valve to the 

To the and this is 100%.

So that most of the of 

the tumors up to the sigmoid 

fletcher would be in this the 

1st 10 

From 10 to 90% on this 

note.

For then there is a similar 

distribution for hyper plastic 

polyps.

There is a concentration in 

the in the 

rectum as one would expect.

But there are some surprising features about 

this which I'll return to 

when we compare 

Cali with Hellwig and with new 

Orleans in the 

the high risk colon population than the U.

S.

Have a higher prevalence of 

adenomas polyps at all ages in both 

sexes.

And this difference is 

accentuated particularly for 

females when you limit the contrast 

to multiple at anomalies.

That is multiplicity is is not a 

feature in a uh this low 

risk uh population in new 

Orleans.

The adenomas were also larger and they 

had a much higher 

proportion of adenomas 

with a tapia's 

also a much higher proportion of 

the new Orleans.

Adenomas were concentrated in 

the in the 

sigmoid recto 

sigmoid area.

Uh This uh 

is replicated now in 

the observations on the japanese 

migrants.

That is the Hawaiian japanese.

Haven't adenomas polyp distribution 

closely resembling that.

And all these features exhibited by 

blacks and whites in New Orleans.

The observations from 

Japan taken in Miyagi 

prefecture have a 

polyp distribution for adenomas which 

resembles that of the low risk 

college population.

That is uh we now have uh to 

a high low risk contrast which show 

essentially the same results.

Now when Korea did the work on 

hyper plastic polyps in Colombia,

I think that he was doing it primarily for 

sake of completeness recording the observations and 

uh those plus you know,

juvenile polyps.

He like other pathologists.

I didn't think that 

uh there was going to be any no 

relationship uh demonstrated 

with with the tumors and 

the location of the 

these hyper plastic pileups.

Got uh 

And I think the 

feeling was based on on 

the Marfa logic evidence,

but big,

big surprise.

It turns out that in the 

in the Hawaiian japanese and the 

native japanese,

that uh there is a great 

difference in the distribution 

of hyper plastic polyps,

that that is while hyper plastic polyps 

are certainly concentrated in the 

in the area between the flexion er 

and the anus.

There's just a much 

greater frequency of such polyps 

in the Hawaiian japanese 

popular as opposed to 

japan.

And this same finding is 

emerging from the 

comparisons in new Orleans with 

the colleagues.

So new Orleans with 

the colleagues,

so that while the 

pathologists have been slow 

to,

I have not have thought that there 

was anything in the morphological studies that 

would really uh yield 

suggestive leads these 

epidemiologic comparisons now point to 

great differences in these 

parents of these hyper plastic.

Just how this will 

relate in the long run to the 

distribution of 

of all right 

of of rectal 

cancers remains to be seen.

My feeling is that uh 

that these type of observations are 

likely to uh stimulate uh 

work in the area of,

you know,

cell kinetics which uh your doctor 

lukin will be discussing 

this afternoon and that 

uh this 

will be one 

area in which the say the colon 

cancer task force and the colon cancer,

you know,

segment of the cancer institute will be 

spending much more time on 

so to uhh 

summarized uh 

we have might have proposed 

the following as a working model 

in low risk populations where the disease 

is endemic Colon cancers are 

concentrated in the Sikh,

um and ascending colon female cases 

are preponderant and most of 

the rise to the maximum incidence level 

occurs by age 50 55.

If,

when a new ideological factor 

is introduced,

A transition from an endemic to an 

epidemic phases first expressed as a 

rise in sigmoid cancers among older 

men over 55.

A rise in female sigmoid cancer 

follows later and the time lag is 

reinforced by a tendency for these female 

cases to appear at somewhat older ages.

As exposures to a 

suspect undefined ideological 

factor becomes more intense and prolonged.

A later phase is characteristically 

arise and seek them and ascending colon 

cancers more marked for males and for 

females so that the female excess 

and seek um cancer prevailing under endemic 

conditions is as dis 

minister diminished.

The present 

observations on the prevalence of polyps 

suggests.

Some link with the level of colon cancer 

incidents in the given communities,

not only with respect to magnitude of prevalence,

but also with respect to distribution by 

age,

sex,

anatomical localization and 

multiplicity.

I think these clues lead to 

uh some ideas on 

ideology which I think time 

will prevent uh me from 

discussing this 

morning,

but 

there is the possibility I think 

of of of linking 

up studies of 

ideology and testing them with respect 

to this uh difference in 

anatomical distribution for both.

Um 

polyps and cancers.

one thing which is occurring 

and this japanese 

population which is very suitable for 

epidemiologic studies of 

dietary hypotheses.

And I won't go into it any further than 

to say this,

that the associations with 

uh some of the differences between the case and 

control series appear to be 

much more marked for those cancers 

which are uh 

in the rectal sigmoid,

you know,

fletcher and above that is such associations 

for tumors in the in the lower rectum 

is uh is virtually 

absent so that we may be 

able to uh bring 

about a synthesis of uh 

of studies and the 

traditional epidemiology logic 

type represented by case control 

and prospective cohort 

studies with findings 

uhh made by uh no 

geographical a 

pathologist.

Okay,

okay.