From: "Steve Harris" <sbharris123@ix.netcom.com>
Newsgroups: sci.med,sci.med.diseases.cancer
Subject: Low Cholesterol-- Honest to God Colon CA Risk?
Date: Wed, 8 Aug 2001 21:28:35 -0600

The majority of studies have found that almost all of the effect of low
cholesterol on cancer mortality shows up in the first few years, while
the effect of high cholesterol on heart disease is persistent. This
suggests that causation is cancer-->low cholesterol, rather than the
reverse. Only two studies have found a major persistent association of
cancer and low cholesterol at durations of 10 years, suggesting that the
causal nature runs the other way, or is due to an undiscovered confounder
(a third factor which causes both low cholesterol and cancer):

Am J Epidemiol 2000 Apr 15;151(8):739-47
Comment in:
 Am J Epidemiol. 2000 Apr 15;151(8):748-51

Which cholesterol level is related to the lowest mortality in a
population with low mean cholesterol level: a 6.4-year follow-up study of
482,472 Korean men.

Song YM, Sung J, Kim JS.

Department of Family Medicine, SungKyunKwan University School of Medicine,
Suwon, Korea. ymsong@smc.samsung.co.kr

To evaluate the relation between low cholesterol level and mortality, the
authors followed 482,472 Korean men aged 30-65 years from 1990 to 1996
after a baseline health examination. The mean cholesterol level of the
men was 189.1 mg/100 ml at the baseline measurement. There were 7,894
deaths during the follow-up period. A low cholesterol level (<165 mg/100
ml) was associated with increased risk of total mortality, even after
eliminating deaths that occurred in the first 5 years of follow-up. The
risk of death from coronary heart disease increased significantly in men
with the highest cholesterol level (> or =252 mg/100 ml). There were
various relations between cholesterol level and cancer mortality by site.
Mortality from liver and colon cancer was significantly associated with a
very low cholesterol level (<135 mg/100 ml) without any evidence of a
preclinical cholesterol-lowering effect. With lengthening follow-up, the
significant relation between a very low cholesterol level (<135 mg/100
ml) and mortality from stomach and esophageal cancer disappeared. The
cholesterol level related with the lowest mortality ranged from 211 to
251 mg/100 ml, which was higher than the mean cholesterol level of study
subjects.

PMID: 10965970 [PubMed - indexed for MEDLINE]


Cancer 1992 Sep 1;70(5):1038-43
Serum cholesterol level, body mass index, and the risk of colon cancer. The
Framingham Study.
Kreger BE, Anderson KM, Schatzkin A, Splansky GL.

Section of General Internal Medicine, Boston University Medical Center,
Massachusetts.

BACKGROUND. Some studies have linked low serum cholesterol levels to
increased risk of colon cancer, particularly in men. Results have been
inconsistent, with preclinical disease frequently offered to explain any
apparent association.  METHODS. The Framingham Study cohort of 5209
persons, initially 30-62 years of age and observed more than 30 years,
was evaluated. Baseline data included lipoprotein fractions, total
cholesterol levels, body mass index, alcohol intake, and cardiovascular
risk variables such as cigarette smoking, hypertension, and glucose
intolerance. RESULTS. In this population, colon cancer in men is related
inversely to serum cholesterol levels, even when the first 10 years of
follow-up are eliminated to reduce the effect of preclinical disease.
This effect is concentrated in the Svedberg 0-20 fraction, corresponding
to low-density lipoprotein levels. Another finding only in men is the
direct relation of body mass index to colon cancer incidence.
CONCLUSIONS. Combined initial low serum cholesterol levels and obesity
appear to indicate a four times greater risk for colon cancer in men as
compared with people with average values of both variables. The reasons
for these observations are unknown.

PMID: 1515981 [PubMed - indexed for MEDLINE]



COMMENT:
That's it. The Korean study is weird because it's, well, Korean. Nobody
else sees anything quite like it. They didn't control for smoking, and
this may explain the large number of cancers they see associated with low
cholesterol. Their only persistent one that is not seen in other studies
is liver cancer. Which makes one wish to know if chronic hepatitis B is
the confounder.

Such a persistent long duration association between low cholesterol and
colon cancer only, is seen in other two other studies: The Framingham
results are shown above.  They must be pulled out of rather special group
of obese men with unexpectedly low cholesterol who will get colon cancer.
The other is the Japanese-American Hawaii study below, in which the long
duration association held only for bowel cancer, and indeed only for men
with cecal bowel cancer (the very people who need colonosopy the worst!)
In this group alone there may be something causal going on (it might be a
good idea for overweight men with really great cholesterols to have
colonoscopy once a year for life). In the rest of the 7 studies below,
most direct causality in the direction cholesterol--> cancer appears to
be ruled out by the fact that the effect fades rapidly over time (unlike
the heart disease connection!). That means there is evidence from them
against the notion that lowering your cholesterol will increase your
cancer risk.

If you are an obese male, it's possible that lowering your cholesterol
will increase your cecal cancer risk, though none of the statin trials
(which have looked at cancer risk) have found such an effect. However, it
is worth noting that there are a number of other cholesterol lowering
studies by many other mechanisms than statins, which have found modest
evidence of an increased bowel cancer risk. This was even true for the
Wadsworth VA study, in which men lowered heart disease risk by drinking
corn oil, but increased their bowel cancer risk to the point that
mortality was a wash (total mortality in the statin trials was helped by
the drug, so we know that answer).

Bottom line: yes, LDL is a causal agent for heart disease. The only
cancer for which there is very good evidence that low LDL might be
causal, is proximal colon cancer (in men). Men:  take your statins and
get that colonoscopy. Especially get it if your cholesterol is down for
any OTHER reason (including diet and your "good genes") than statin use.

Finally, to be fair, it appears that from the literature that an
intervention trial to RAISE LDLs in low cholesterol men who are at
special risk for colon cancer, and have been carefully screened for heart
disease, may be is warrented. Nobody's had the guts to suggest this. Yet.

BMJ 1995 Aug 12;311(7002):409-13

Comment in:
 BMJ. 1995 Nov 25;311(7017):1438

Low serum total cholesterol concentrations and mortality in middle aged
British men.

Wannamethee G, Shaper AG, Whincup PH, Walker M.

Department of Public Health, Royal Free Hospital School of Medicine, London.

OBJECTIVE--To examine the relation between low serum total cholesterol
concentrations and causes of mortality. DESIGN--Cohort study of men
followed up for an average of 14.8 years (range 13.5-16.0 years).
SETTING--One general practice in each of 24 British towns. SUBJECTS--7735
men aged 40-59 at screening selected at random from the 24 general
practices. MAIN OUTCOME MEASURES--Deaths from all causes, cardiovascular
causes, cancer, and non-cardiovascular, non-cancer causes.
RESULTS--During the mean follow up period of 14.8 years there were 1257
deaths from all causes, 640 cardiovascular deaths, 433 cancer deaths, and
184 deaths from other causes. Low serum cholesterol concentrations (< 4.8
mmol/l), present in 5% (n = 410) of the men, were associated with the
highest mortality from all causes, largely due to a significant increase
in cancer deaths (age adjusted relative risk 1.6 (95% confidence interval
1.1 to 2.3); < 4.8 v 4.8-5.9 mmol/l) and in other non-cardiovascular
deaths (age adjusted relative risk 1.9 (1.1 to 3.1)). Low serum
cholesterol concentration was associated with an increased prevalence of
several diseases and indicators of ill health and with lifestyle
characteristics such as smoking and heavy drinking. After adjustment for
these factors in the multivariate analysis the increased risk for cancer
was attenuated (relative risk 1.4 (0.9 to 2.0) and the inverse
association with other non-cardiovascular, non-cancer causes was no
longer significant (relative risk 1.5 (0.9 to 2.6); < 4.8 v 4.8-5.9
mmol/l).  The excess risks of cancer and of other non-cardiovascular
deaths were most pronounced in the first five years and became attenuated
and non-significant with longer follow up. By contrast, the positive
association between serum total cholesterol concentration and
cardiovascular mortality was seen even after more than 10 years of follow
up. CONCLUSION--The association between comparatively low serum total
cholesterol concentrations and excess mortality seemed to be due to
preclinical cancer and other non-cardiovascular diseases. This suggests
that public health programmes encouraging lower average concentrations of
serum total cholesterol are unlikely to be associated with increased
cancer or other non-cardiovascular mortality.

PMID: 7640584 [PubMed - indexed for MEDLINE]



Int J Epidemiol 1992 Feb;21(1):16-22

Cholesterol and cancer in a population of male civil service workers.

Baptiste MS, Nasca PC, Doyle JT, Rothenberg RR, MacCubbin PA, Mettlin C,
Metzger BB, Carlton KA.

New York State Department of Health, Albany 12237-0683.

Cancer incidence and mortality were ascertained in a cohort of 1910 male
participants of the Albany Cardiovascular Health Center (CVHC). The New
York State Cancer Registry, vital records files, CVHC follow-up records,
New York State Retirement System files, and New York State Department of
Motor Vehicles driver's license files were used. Serum cholesterol
measurements as well as values for other exposure variables were obtained
from records of medical examinations which began in 1953-1954. The study
cohort was divided into two groups, based on initial serum cholesterol
measurement (less than or equal to 190 mg/100 ml and less than or equal
to 190 mg/100 ml). For total cancers, both incidence and mortality were
similar in these groups. For digestive cancer, both incidence and
mortality were slightly lower in the less than or equal to 190 mg/100 ml
group. The deficit was not statistically significant. For respiratory
cancer, relative risk and rate ratio estimates were in the range of
1.4-1.7 for incidence and mortality. The excess risk in the less than or
equal to 190 mg/100 ml group was of borderline statistical significance.
The association was concentrated in the lowest cholesterol quintile
rather than suggesting a strong dose-response relationship. The estimates
were not found to be confounded by cigarette smoking, body mass index,
education or age. A reduction in the crude rate ratio estimate from 1.5
to 1.2 was observed when early cases were excluded, suggesting that part
of the observed excess may be due to preclinical cancer.

PMID: 1544748 [PubMed - indexed for MEDLINE]




J Natl Cancer Inst 1991 Oct 2;83(19):1403-7

Prospective study of serum cholesterol levels and large-bowel cancer.

Nomura AM, Stemmermann GN, Chyou PH.

Japan-Hawaii Cancer Study, Kuakini Medical Center, Honolulu.

Based on previous reports, it is uncertain whether serum cholesterol
levels are inversely related to colon cancer risk. In this study, serum
cholesterol levels were measured in 7926 Japanese-American men who were
followed for over 20 years.  Two hundred thirty-one incident cases of
colon cancer and 97 cases of rectal cancer were identified. An increase
in serum cholesterol levels was associated with a decrease in risk for
colon cancer (P value for trend = .01) but not for rectal cancer. This
association appeared stronger as the site of cancer moved from the
sigmoid colon to the cecum. The data were further analyzed by interval
from examination to diagnosis. The inverse association was present for
colon cancer cases diagnosed within 10 years of examination (P value for
trend less than .01), especially for cecum-ascending colon cancer cases
(P less than ..01).  A similar inverse pattern was found for
cecum-ascending colon cancer cases diagnosed after 10 years, but the
association was not statistically significant.  The results suggest that
the preclinical effects of undiagnosed colon cancer contributed to the
inverse association, but these effects do not entirely explain why the
relationship with hypocholesterolemia was stronger in men who were
subsequently diagnosed with right-sided colon cancer.

PMID: 1920483 [PubMed - indexed for MEDLINE]




Nutr Cancer 1991;15(3-4):205-15

Associations between breast cancer, plasma triglycerides, and cholesterol.

Potischman N, McCulloch CE, Byers T, Houghton L, Nemoto T, Graham S,
Campbell
TC.

Division of Nutritional Sciences, Cornell University, Ithaca, NY 14853.

A case-control study investigating the association between plasma lipids
and breast cancer was conducted among women aged 30-80 in Buffalo, NY.
All eligible women from a large breast clinic and two area physicians'
offices were requested to participate over a one-year period. Subjects
completed a health questionnaire and donated a fasting blood sample prior
to diagnostic breast biopsies. The 83 women found to have breast cancer
(cases) had significantly higher plasma triglyceride values than did the
113 women found not to have breast cancer (controls). Lower plasma
beta-carotene values were associated with breast cancer, but only in
those women with elevated triglyceride or cholesterol.  Plasma
cholesterol values were lower in those breast cancer cases presenting
with more advanced stages of cancer, suggesting that metabolic effects of
clinical and preclinical breast cancer may lower cholesterol levels.
Although the limitations of case-control studies are well-recognized,
these data suggest an etiologic role for plasma triglycerides and
beta-carotene or for related dietary factors.

PMID: 1866314 [PubMed - indexed for MEDLINE]




Int J Epidemiol 1990 Jun;19(2):274-8

Serum lipids and colorectal adenoma among male self-defence officials in
northern Kyushu, Japan.

Kono S, Ikeda N, Yanai F, Yamamoto M, Shigematsu T.

Department of Public Health, Fukuoka University School of Medicine, Japan.

Colorectal adenoma is regarded as a precursor lesion of adenocarcinoma.
In view of the controversy on serum cholesterol and colorectal cancer,
the risk of colorectal adenoma was examined in relation to serum total
cholesterol, triglycerides and HDL-cholesterol. In the comparison of 88
men having adenoma and 1055 men with normal colonoscopy, there was no
association between serum total cholesterol and colorectal adenoma. An
increased risk of adenoma was observed at the highest quartile of
triglycerides and at the lowest of HDL-cholesterol. When the three serum
lipids were simultaneously examined, only the relation with
HDL-cholesterol remained unchanged giving odds ratio of 1.7 at the lowest
quartile compared with the upper three combined (p less than 0.05).  The
present study is consistent with the view that the inverse relation
between serum total cholesterol and colorectal cancer is due to the
effects of preclinical cancer. Further clarification is needed on low
HDL-cholesterol and colorectal adenoma.

PMID: 2376436 [PubMed - indexed for MEDLINE]




J Natl Cancer Inst 1989 Dec 20;81(24):1917-21

Cancer incidence and cancer mortality in relation to serum cholesterol.

Tornberg SA, Holm LE, Carstensen JM, Eklund GA.

Department of General Oncology, Radiumhemmet, Karolinska Hospital,
Stockholm, Sweden.

We studied cancer incidence and mortality from cancer and coronary heart
disease in relation to serum cholesterol levels in 92,710 individuals
followed-up in the nationwide Swedish Cancer Register and the Swedish
Cause of Death Register for 18-20 years. According to Cox's proportional
hazard model, total cancer incidence and total cancer mortality were
negatively correlated to serum cholesterol level (P less than .001). The
negative correlations were most pronounced during the first years of
follow-up. Cancer mortality data showed a stronger negative association
to cholesterol than did incidence data during the first 10 years of
follow-up (P less than .05). Mortality from coronary heart disease was
positively correlated to serum cholesterol (P less than .001) during the
entire follow-up. In contrast to most studies that were based on
mortality data, our results of the comparison of incidence and mortality
data of the same cohort are in agreement with those of a
cholesterol-lowering effect of a preclinical cancer. Efforts by
investigators and clinicians to lower serum cholesterol to prevent
cardiovascular disease are, according to the present findings, not likely
to increase cancer mortality risks but would extend life, irrespective of
cause of death.

PMID: 2593170 [PubMed - indexed for MEDLINE]




J Clin Epidemiol 1988;41(6):519-30

Serum cholesterol and risk of cancer in a cohort of 39,000 men and women.

Knekt P, Reunanen A, Aromaa A, Heliovaara M, Hakulinen T, Hakama M.

Social Insurance Institution, Helsinki, Finland.

Serum cholesterol concentration was studied for its prediction of cancer
in 39,268 men and women aged 15-99 years and initially free from cancer.
During a median follow-up of 10 years 1381 cancer cases were diagnosed.
Serum cholesterol level was inversely associated with cancer incidence
among non-smokers.  Age-adjusted relative risks of cancer in quintiles of
serum cholesterol were in male non-smokers 1.0, 0.81, 0.73, 0.69, and
0.46 and in female non-smokers 1.0, 0.75, 0.84, 0.78, and 0.70. The
associations were not found to be confounded by serum vitamins A or E,
serum selenium or several other factors. The association between serum
cholesterol level and risk of cancer varied from strongly negative to
slightly positive according to subpopulation and site of cancer. The
strongest negative associations were found to appear during the first
years of follow-up, especially for rapidly developing cancers. Thus the
increased occurrence of cancer at low cholesterol levels seems mainly to
be due to preclinical cancer.

Publication Types:
Review
Review, tutorial

PMID: 3290396 [PubMed - indexed for MEDLINE]




JAMA 1987 Feb 20;257(7):943-8

Serum cholesterol levels and cancer mortality in 361,662 men screened for
the Multiple Risk Factor Intervention Trial.

Sherwin RW, Wentworth DN, Cutler JA, Hulley SB, Kuller LH, Stamler J.

Several prospective studies have demonstrated an association between low
serum cholesterol level and subsequent mortality from cancer. This
finding was explored in the large cohort (361,662) of men aged 35 to 57
years who were screened for possible randomization to the Multiple Risk
Factor Intervention Trial. Mortality follow-up revealed a significant
excess of cancer in the lowest decile of serum cholesterol level during
the early years of follow-up, which attenuated over time. In contrast,
the association between high serum cholesterol and coronary heart disease
did not diminish during the average of seven years of follow-up. These
findings are consistent with the inference that the association between
low serum cholesterol level and cancer is at least in part due to an
effect of preclinical cancer on serum cholesterol level. A subset of the
cohort (12,866 men) participated in the randomized Multiple Risk Factor
Intervention Trial protocol, which called for annual measurements of
serum cholesterol level. Among the 150 of these men who died of cancer
during the trial, cholesterol level fell 22.7 mg/dL (0.59 mmol/L) more
than in the survivors over an equivalent period. These data are
consistent with the foregoing inference.

Publication Types:
Clinical trial
Randomized controlled trial

PMID: 3806876 [PubMed - indexed for MEDLINE]




J Chronic Dis 1986;39(11):861-70

Serum cholesterol and the incidence of cancer in a large cohort.

Hiatt RA, Fireman BH.

The relation of serum cholesterol to the development of cancer remains
unclear.  We have examined the incidence of cancer in 160,135 men and
women who were health plan members of the Northern California Kaiser
Permanente Medical Care Program (KPMCP) and who had a multiphasic health
examination in the period 1964 through 1972. In addition to all cancer,
we examined individually the nine most common cancers in men and the 12
most common in women. Cancer diagnoses (N = 7477) recorded by the State
of California Resource for Cancer Epidemiology Section and the health
plan hospital discharge file were used to calculate incidence by quintile
of serum cholesterol. Multivariate analysis adjusted for race, education,
smoking status, alcohol consumption, body mass index and, in women, for
age at menarche, parity, and menopausal status. No strong or consistent
relation of low cholesterol to cancer incidence was found. Of the 21
cancers examined, only lymphoma in men and cervical cancer had
significantly elevated risks at the lowest quintile of serum cholesterol
compared with risks in the highest quintile. Cancer incidence in the
first 2 years after the cholesterol measurement was consistently higher
among persons whose cholesterol levels were in the lowest quintile. This
prospective study did not find evidence that low cholesterol increased
the risk of cancer but supports the idea that preclinical cancer in some
way lowers serum cholesterol.

PMID: 3793838 [PubMed - indexed for MEDLINE]

From: "Steve Harris" <sbharris123@ix.netcom.com>
Newsgroups: sci.med,sci.med.diseases.cancer
Subject: Re: Low Cholesterol-- Honest to God Colon CA Risk?
Date: Thu, 9 Aug 2001 03:36:45 -0600

"Michael Sierchio" <kudzu@tenebras.com> wrote in message
news:3B721F5B.985C5015@tenebras.com...
>
> Steve -
>
> we had a dialogue on this subject some years ago.  At the time,
> my understanding was that you considered low serum cholesterol
> to be a symptom of a disease process --  non-cancerous disease
> of the lung, cancer, leukemia, etc. -- rather than being a risk
> factor for developing disease.  Am I wrong?

No. I did then, and it usually is. Disease causes chronic inflammation
(TNF!), bad nutrition, and loss of weight-- and low cholesterol in the
process. This includes most cancers. However, it's more complicated, and
there may actually be a few diseases for which cholesterol is a genuine risk
factor. Due to review of the literature I have since changed my mind for one
quite specific cancer of the proximal colon in (usually obese men), and
wanted to share that.  There may be more.

SBH

From: "Steve Harris" <sbharris123@ix.netcom.com>
Newsgroups: sci.med.nutrition,sci.med
Subject: Re: Dangers of low cholesterol
Date: Thu, 9 Aug 2001 23:27:43 -0600

Here's a nice little review to remind us of what we're supposed to keep
sight of.


Am J Cardiol 1998 Nov 26;82(10B):14T-17T

Why cholesterol as a central theme in coronary artery disease?

Sacks FM.

Harvard School of Public Health, Boston, Massachusetts 02115, USA.

Evidence from epidemiologic studies and clinical trials have conclusively
demonstrated a direct association between coronary artery disease and
levels of total and low-density lipoprotein (LDL) cholesterol. Data from
a number of studies suggest that even "average" or "normal" cholesterol
levels are too high with respect to coronary artery disease risk. Low
levels of high-density lipoprotein (HDL) cholesterol have also emerged as
a coronary artery disease risk. A recent meta-analysis has eliminated
much of the controversy surrounding triglyceride's contribution to
coronary artery disease risk, establishing triglyceride levels as an
independent risk factor. Lowering lipid levels by any means-including
pharmacologic, surgical, and dietary/lifestyle changes--decreases
coronary artery disease risk.

Publication Types:
Review
Review, tutorial

PMID: 9860368 [PubMed - indexed for MEDLINE]


Here's a meta analysis of the best dietary intervention studies,
which should not be lumped in with the drug studies .
It should be noted that these are mostly low saturated fat
intervention studies, just like mamma told you. Not only do
they show benefit, but those in which cholesterol decreases
the most show the most benefit. Surprise.

Aust N Z J Med 1994 Feb;24(1):98-106

Review of dietary intervention studies: effect on coronary events and on
total mortality.

Truswell AS.

Department of Human Nutrition, University of Sydney, NSW, Australia.

The perfect randomised controlled dietary prevention trial of coronary
heart disease has never been done. The best we can do is to look at all
the trials together. Dietary trials should be separated from drug trials
because they have different characteristics. Fourteen dietary trials
which had disease or death as the end point are collected in this review
for a meta-analysis. Three of the trials had two parts (male/female or
low fat/increased fish), making a total of 17 trials. All were randomised
trials, except the Finnish mental hospital trial which was a 12-year
crossover in two hospitals. The trials were primary or secondary, diet
only or multifactorial; numbers of subjects range from 52 to 57,460. For
total deaths the ratio of intervention/control in all 17 trials is 0.94
(significantly less than 1.00) and for coronary events the pooled odds
ratio is 0.87. But in the seven trials with most effective cholesterol
lowering the odds ratios are 0.89 for all deaths and 0.70 for coronary
events. There is thus no indication of excess all causes mortality in the
dietary trials.  Four recent secondary prevention trials had angiographic
end points. There were a total of 275 subjects; trials were in Holland,
USA, Germany and UK. In all trials plasma cholesterol was effectively
lowered and coronary narrowing regressed a little, or progressed less in
the diet group but significantly compared with controls. These
angiographic trials strongly support the results of the major prevention
trials. Lastly, a set of ten trials with fish oil after coronary
angioplasty are reviewed. In some there appeared to be lower rates of
restenosis, but not in all. The mechanism here is different from the
major trials with plasma cholesterol-lowering diets for longer periods.

Publication Types:
Meta-analysis

PMID: 8002875 [PubMed - indexed for MEDLINE]

From: "Steve Harris" <sbharris123@ix.netcom.com>
Newsgroups: sci.med.nutrition
Subject: Re: cholesterol and mortality
Date: Sat, 11 Aug 2001 01:43:20 -0600

"Marvin Nelson" <flaxforhealth@yahoo.com> wrote in message
news:3b74d1a1@news.polarcomm.com...
> Steve,
>
> Does that mean that a subgroup of cholesterol patients "finally" get
> their cholesterol low only to find shortly afterwards that they have
> cancer. Do you as a doctor get concerned when a patient has
> unexpectantly good results lowering their cholesterol, or if you see an
> obese patient with low cholesterol?
>
> Just wondering,
> Marv


I do now!  Haven't had anybody I can think of get colon cancer after being
under treatment by me for years, so I don't think I've killed anybody with
statins yet. In future I'm going to watch a little harder for this
association. I do push colonoscopy and lots of my patients have had polyps
removed-- it may be that prevention is fouling up any bad effects.  Dunno.
This is all quite new, and it's not even being formally recommended by the
American Cancer Society yet. Somebody needs to do a reanalysis on a big
group of people (Framingham) and see if they can *prospectively* find some
colon cancers or polyps.