Transcript Oncology Update - Welcome to the website of Barbee Bancroft

Oncology Update
In the beginning…sperm meets the
egg…
Sperm + egg = zygote
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1 cell, 2 cells, 4 cells, 8, 16, 32, 64, 128
100 trillion cells
Blastocyst
3 germ layers (first evidence of
differentiation)
Differentiation
• The process of growing up
• Start out as an immature, undifferentiated,
embryonic stem cell and go through various
stages of differentiation to become a mature,
fully differentiated adult cell
Ectoderm (epithelial cells)
• “the outer layer exposed to the environment…”
• Skin cells—keratinocytes, melanocytes,
squamous cells, basal cells
• Epithelial cells lining body cavities (what body
cavities?—think about it!)
• Epithelial cells line the bronchioles of the lung,
the esophagus, the stomach, the GI tract, the
vagina, the prostate gland, the bladder, even the
ductal linings of the breast
• (The nervous system also arises from the
ectoderm—but it’s different—more later)
Endoderm
• “innards”
• Glands (thyroid, anterior pituitary,
pancreas, glands that produce milk in the
breast, glands that produce mucous in the
stomach and colon and lungs)
• The prefix for gland is “adeno”…
Mesoderm
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“filler in the middle”
Bones
Muscle
Lymph tissue
Cartilage
Fat
Bone marrow
Maturation and differentiation—an example
in the bone marrow (2 cell lines)
Example of maturation and
differentiation
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Stem cells
Myeloblast (BM)
Promyeloctye (BM)
Myelocyte (BM)
Metamyelocyte (juvenile) (BM)
Band neutrophil (BM and PB)
Segmented neutrophil (BM and PB)
Loss of control of normal maturation and
differentiation in the bone marrow
• Leukemia (“white blood”)
• Acute (total loss of control of differentiation) vs.
chronic (partial loss of control of differentiation)
• Which cell line is involved?
• Myeloid cell line? AML, CML
• Acute myelocytic (myeloblastic) leukemia (AML),
chronic myelocytic leukemia (CML)
• Lymphoid cell line? ALL, CLL
• Acute lymphocytic (lymphoblastic) leukemia
(ALL), chronic lymphocytic leukemia (CLL)
Back to the basics--Neoplasms
• A neoplasm is a “new growth”
• Once this growth is removed, the
pathologist determines whether it is a
benign new growth or a malignant new
growth
• All tumors have to have a name, so…
Nomenclature--is it a benign tumor?
• Add “oma” to the tissue type
• Gland—adenoma; a glandular tumor of the
thyroid is a thyroid adenoma; pituitary adenoma;
adenoma of the breast
• Bone—osteoma
• Fatty tumor—lipoma
• Cartilage—chondroma
• Smooth muscle—leiomyoma (a smooth muscle
benign tumor of the uterus is called a leiomyoma
or FIBROID)
Besides nomenclature, what makes
a benign tumor “benign”?
• It grows slowly
• Histologically the cells are mature and they “stick”
together
• The rate of division is slow
• The benign tumor cells may function as normal cells and
produce hormones from that tissue, over and above the
usual output
(thyroid adenomas producing excessive thyroid hormone
causing hyperthyroidism; pituitary adenomas producing
excessive prolactin causing loss of libido, lactation, and
amenorrhea; adrenal adenomas producing excess
cortisol and causing Cushing’s syndrome)
Benign tumor of the meninges
covering the brain
• Meningioma
• Even tho’ tumors are histologically benign, they can
behave badly by virtue of their location (brain) causing
increased intracranial pressure or by virtue of their ability
to produce excess hormones
• Insulinoma—benign tumor of the beta cells of the
pancreas wreaking havoc with insulin levels and
hypoglycemia
Other characteristics of benign
tumors
• They can be removed and they don’t come back
(usually)
• They generally don’t progress to a malignancy
• The cells do not “shed” and travel throughout the body to
seed somewhere else (i.e., they don’t metastasize)
• There are exceptions to all rules of course
• Neurofibromatosis (Von Recklinghausen’s disease)—too
many to remove and occasionally they will develop into a
malignant tumor
Naming malignant tumors…
• Is it a carcinoma or a sarcoma?
• Carcinomas arise from ectodermal and endodermal
derivatives
• Skin and epithelial cells—lung linings (bronchogenic
carcinoma), lining of the breast ducts (ductal carcinoma)
• Glands lining of the GI tract (adenocarcinoma of the
colon); glands located in the bronchioles
(adenocarcinoma of the lungs)
More nomenclature
• Bronchogenic carcinoma (lung cancer) is
subdivided into 2 types
• Small cell carcinoma (oat cell)(Kulchitsky
cell)
• Non-small cell carcinoma—includes large
cell carcinoma, squamous cell carcinoma,
and adenocarcinoma
Lung cancer statistics in women
• Bigger threat than breast cancer and all other
gynecological cancers combined
• 87% of lung cancers are due to smoking
• Killed nearly 70,000 women in 2003
• Between 1930 and 1997 the death rate from
lung cancer rose 600 percent for women, while
the rate for men during that period decreased
slightly
• Genetic, metabolic and hormonal factors
explain the wide gap between women and men
Naming tumors…
• Type of cell can be used as a descriptor
• Squamous cell carcinoma of the skin, lung,
rectum
• Basal cell carcinoma of the skin
• Melanocyte of the skin is a melanocarcinoma
OR melanoma (shortened version but a
misnomer)
Quick digression: Characteristics of
a malignant melanoma
• Asymmetrical; appearance of a new mole after
40
• Borderline irregular; bleeding
• Color variation
• Diameter greater than 6 mm
• Elevation, erythema
• Funny feeling, fast growing
• Incidence of squamous cell carcinoma and basal cell
carcinoma has nearly tripled in the last 30 years among
women below the age of 40
• Rate of BCC and SCC rose to 32 per 100,000 women
under 40 in 2003, from 13 per 100,000 in the late 1970s
• Beach and tanning salons are the culprits
• American Academy of Dermatology recently found that
only half of the 18- to 24-year olds protect themselves
from the sun
• 61% of women 18 and older think they look better with a
tan
• (Dr. Leslie Christenson, Mayo Clinic; JAMA September 2005).
Naming malignant tumors…
• Is it a sarcoma?
• Sarcomas arise from mesodermal
derivatives
• Bones, muscle, cartilage, lymph tissue,
bone marrow, fat
Naming tumors
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Sarcomas
Bone? Osteosarcoma
Cartilage? Chondrosarcoma
Fat? Liposarcoma
Lymph? Lymphosarcoma (shortened to
“lymphoma”—another misnomer as you
might think it is a “benign” tumor)
Another digression…
• Lymphomas are also divided into 2 major
types…
• Hodgkin’s lymphoma (HL)
• NON-Hodgkin’s lymphoma (NHL)
• Histologic characteristics distinguish the two;
presentation is more aggressive with the NHL;
age is usually young adults with HL; the very
young or the very old are more likely to have
NHL
Mesoderm--sarcomas
• Chondrosarcoma
• (cartilage)
• Rhabdomyosarcoma
• Rhabdo = skeletal
• Myo = muscle
Nomenclature—is it a malignant
tumor?
• Malignancies are also named and defined by
their level of differentiation
• Immature, embryonic=“blast”
• retino “blast” oma, glio “blast” oma, neuro “blast”
oma—rapid growing tumors
• Undifferentiated—looks embryonic and it may be
difficult to determine where the tissue of origin is
• Poorly-differentiated
• Well-differentiated
Characteristics of malignant tumors
• Malignant—invasive, lack of cohesiveness (basis for the
Pap smear), proliferates rapidly
• Malignant tumors have the capacity to metastasize
• 72% of lung cancers (especially small cell carcinomas)
have mets at dx; 57% of colorectal cancers; 34% of
breast cancers
• The more primitive the tumor (undifferentiated, the more
likely it will metastasize)—eg, oat cell, small cell of lung
Brain tumors have their own
special nomenclature
• Not called carcinomas even though the nervous system
is an ectodermal derivative
• Cell type + “oma”
• Astrocyte + oma = astrocytoma
• Glioblastoma multiforme
• Medulloblastoma
• Ependymal cell + oma = ependymoma
• Oligodendrocyte + glioma= oligodengroglioma
• Brain stem glioma
Grading and staging malignant
tumors
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Grade I-IV or V—establishes the
aggressiveness of the tumor
The lower your grade, the better
Example: Brain tumors—Grade I
astrocytoma vs. Grade IV astrocytoma
(glioblastoma multiforme)
Grading and staging
• Staging—Stages I-IV – establishes the amount of tumor in the
body
• The lower your stage, the less tumor in the body
• Example: Hodgkin’s disease—Stage I (one group of lymph
nodes)
• Also give the stage a letter—IA (without symptoms), IB (with
symptoms)
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TNM system—tumor size, node involvement, metastases
Example: Breast cancer T1, N1, M0
Tumor size, one lymph node group, no distant metastases
Staging—T1, N0, M0 is Stage I, Stage IIA is T0, N1, M0, Stage
IIB is T2, N1, M0 for examples
Back to the basics of the biology of
cancer…
• Biologists estimate that more than 100
million billion cells must cooperate to keep
a human being healthy over the course of
an 80-year lifespan
• Who’s responsible for this maturation and
differentiation of cells?
Your genes…
• Highly regulated control systems located in the
genetic code
• All cancer cells have serious problems with their
DNA; alterations to the DNA inside cells results
in cells that have “superpowers”; they can grow
anywhere and can continue to divide indefinitely
• Normal human cells stop dividing after 50-70
generations
Proto-oncogenes
• Genes responsible for manufacturing proteins
for normal cell growth; turned off and on when
needed
• HER-2/neu is a protooncogene involved with cell
growth; when this gene is amplified, cells grow
much faster; present in 20-30% of primary
breast cancers
• Amplification of this gene correlates with a poor
prognosis in patients with breast cancer
Targeted therapies
• Biological response modifiers
• Monoclonal antibody that targets the HER2/neu
proto-oncogene
• Trastuzumab (Herceptin) for breast cancer
patients
Oncogenes
• Oncogenes responsible for uncontrolled
proliferation of cell growth
• Suppressor genes—p53 ( a mutation or
dysfunction of this suppressor gene is found in
the majority of tumors);
• BRCA mutations and breast and ovarian cancers
(ovarian cancer occurs in 2 in 5 women with a
BRCA mutation)
• Normal risk for a lifetime for ovarian cancer
without the BRCA mutation is 1 in 75
• BRCA gene and breast cancer
Apoptosis—preprogrammed cell
suicide
• Programmed cell death observed in healthy cells
• Cancer cells bypass this mechanism altho’ some cells of
the immune system can sometimes successfully
command the cancer cell to self-destruct
• COX-2 inhibitors and apoptosis—breast and colon
cancer
• Vioxx (rofecoxib) was removed from the market for
clotting problems in CV patients (high doses, long-term
use for greater than 18 months)
• Continues to be studied for cancer prevention
• Aspirin and other COX inhibitors are also being studied
• EBV produces substances that resemble Bcl-2 (a protein
that inhibits apoptosis) and subsequently block cell
suicide
Tyrosine kinase
• An enzyme required for the uncontrolled
growth of cancer cells
• Targeted therapies—a new class of drugs
called the signal transduction inhibitors
• Inhibit the tyrosine kinase signal
• Imatinib (Gleevec)--CML
• Gefitinib (Iressa)—lung cancer
(investigational for other cancers)
Epidermal growth factor receptors
(EGFR); angiogenesis
• Epidermal growth factor (EGF) can fuel the fire, so to
speak, as can supplying the tumors with blood vessels
• Drugs that block the receptor (EGFR) can slow down the
growth of tumors
• Tarceva (erlotinib) (Lung cancer)
• Cetuximab (Erbitux)—colon cancer (Martha Stewart and
ImClone)
• Bevacizumab (Avastin)—inhibits angiogenesis
Targeted therapies
• Thalidomide (Thalomid) inhibits growth factors
(IL-6) and angiogenesis (as exhibited in
appendage growth when given during the first
trimester of pregnancy in the 50’s and 60’s)
• Rituximab (Rituxan)—targets a protein marker
on B lymphocytes—CD 20. Used to treat B-cell
lymphomas
Targeted therapies
• Some malignant tumors, especially those that are “male
only” and “female only” have receptors for their
respective hormones
• Breast cancer and estrogen receptors
• ER+ or ER-; If the tumor is ER+ then changing the
hormonal milieu is often very beneficial
• Drugs include nolvadex (Tamoxifen), raloxifene
(Evista)—both drugs block estrogen receptors
• Is there a problem with that? Tamoxifen
(agonist/antagonist)
• Aromatase inhibitors--letrozole (Femara)—inhibits an
enzyme that converts estrogen to its most potent form;
other aromatase inhibitors
• Changing the hormonal milieu in prostate
cancer patients is common—blocking
testosterone, blocking gonadotropin
releasing factor/hormone (Lupron)
• In the “old days” men with prostate cancer
were given estrogen (DES) to change their
hormonal environment
• Let’s change gears for a moment and talk
about “normal proliferation”…
• Normal growth, maturation and
differentiation of cells
Normal proliferation…most occurs during fetal
life; as adults, cells divide as needed to replace
lost cells—epithelial cells do the most dividing
• Dividing cells are more prone to the loss of the
control of growth and DNA mutations
• The older the cells, the more prone to loss of
control—who gets skin cancer?
• Skin (epithelial) cells—how often?
• Sunlight and turnover
• Sunburns as a kid
• Is sunlight a double-edged sword?
Vitamin D and other epithelial cell
cancers…
• Liquid sunshine…
Normal proliferation--cells lining the
bronchioles
• Respiratory cells—how often?
• Cigars, cigarettes, cigarillos, pipes,
passive smoking
• Asbestos
Normal proliferation—cells lining
the gastrointestinal tract
• How often do you replace cell lining the
gastrointestinal tract
• Sloughing cells and dead bacteria
• Genetics and cellular turnover time
• High fat diet, low fiber diet, high
nitrosamines
Breast ductal linings—prolonged
hormone stimulation?
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Estrogen or progesterone?
New evidence? Maybe progesterone in PMF
LIFETIME exposure to hormones
Long period of periods
When did you start your periods, when did you
stop your periods?
• Did you have a period of not having periods?
• Women’s Health Initiative
• And, now what about hormones?
Like when you were pregnant…
• Number of kids
• Kids before the age of 20
Or breast feeding…
Age and risk for breast cancer
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1/2044 @ 20
1/249 @ 30
1/67 @ 40
1/36@50
1/29 @ 60
1/24 @ 70
1/9 @ 80
1/8 @ 90
Prostate epithelial cells…
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The older you are, the higher the risk
Epithelial cells and turnover
A lifetime of testosterone
The prostate increases in size with aging
So, then…what are the 5 most
common cancers in the U.S.?
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Skin
Lung
GI
Breast
Prostate
• All of which have epithelial cells that continue to
grow throughout life-- “exposed to the
environment, exposed to hormones” and have
the potential for growth disturbances
Other tissues that divide constantly
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Bone marrow
White blood cells
Red blood cells
Platelets
Leukemia is a cancer of the bone marrow
AML (t15:17)
CML (Ph chromosome—t9:20)
In children, the lymphocyte is the most rapidly dividing
cell—hence, ALL is most common in kids
Bone turnover
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Bone growth spurts
During the first year
And at puberty
Older adult also has more bone turnover
Highest risk for bone cancer is as an adolescent
and as an older adult
• Adult with Paget’s disease
• Big dogs vs. small dogs
Tissues that have the capacity to divide but
only do so as necessary…
• Liver undergoing active regeneration due
to ETOH abuse
• Hepatitis B and C—active hepatitis
• Inflammation and cancer
Renal tubular cells
• Acute tubular necrosis (ATN) with acute
renal failure
• Renal tubular cells have the capacity to
regenerate
Tissues that “never” have the capacity
to divide—well, almost never…
• Neurons—brain tumors involving neurons are
RARE
• The majority of brain tumors involve the “glial” or
supporting cells of the central nervous system
• Myocardial cells—cancers of the heart muscle
are extremely rare
• Skeletal muscle cells in teenagers and adults—
tumors are rare
Factors that can cause a change in
the growth of tissues…
• Radiation
• Sunlight
• Chemicals—asbestos, benzene, nitrosamines,
pesticides ?
• Viruses—HBV, HCV, HPV, EBV
• Bacteria (1)—Helicobacter pylori
• Genetics—who’s yo’ daddy (or momma)?
Factors that can cause a change in
the growth of tissues…
• Hormones—growth hormones such as insulin-like
growth factor, growth hormone, estrogen, progesterone,
testosterone
• Obesity—increased hormone production in fat tissue—
especially abdominal fat tissue
• Chronic inflammation—ulcerative colitis, celiac disease,
Crohn’s disease, rheumatoid arthritis, hepatitis
Growth disturbances
• May be precursors to the “loss of control”
and the development of cancer
• Fertile soils, so to speak
• BUT, the growth disturbances are NOT
cancer, and they are reversible once the
inciting stimulus is removed
• What are these growth disturbances?
• Regeneration, hyperplasia, metaplasia,
dysplasia
Growth disturbances
• Regeneration—regrowth of damaged tissues (cuts,
burns, the ovary following ovulation, skin damaged by
sunlight, chronic liver infection with viruses, chronic
alcohol and the liver)
• Chronic hepatitis C + alcohol = high risk (100 x greater)
for the loss of the control of growth resulting in
hepatocellular carcinoma and cirrhosis
HPV and cancer
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Cervical cancer
Cancer of the vulva
Rectal cancer
Penile cancer
Oral cancer
Growth disturbances
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Chronic inflammation and regeneration
Helicobacter pylori
Gastric ulcers
Gastric carcinoma
Growth disturbances
• hyperplasia – too many cells
• Physiologic hyperplasia--breast cells at puberty
• Pathologic hyperplasia--atypical hyperplasia of
the breast
Growth disturbances
• Metaplasia – substitution of one adult cell for another
adult cell
• Normal cells lining the bronchii—ciliated columnar cells;
with constant trauma (smoking, for example)—the cells
will “change” to cells that can take the trauma—
squamous cells; this change is known as squamous
metaplasia
• Barrett’s esophagus—stomach cells lining the
esophagus (columnar epithelial cells)(normal lining of the
esophagus is squamous epithelium)
• Acid reflux and irritation of the lower esophagus might
play a BIG role
• Take those PPIs!!
• Metaplasia (the substitution of one adult cell for
another adult cell usually as an adaptive
substitution)—intestinal metaplasia and Barrett’s
esophagus (intestinal metaplasia vs. the normal
stratified squamous cells of the lower 1/3 of the
esophagus)
Growth disturbances
• dysplasia—abnormal cell size and
architectural arrangement of cells
• cervical dysplasia; dysplastic nevus (mole)
• low-grade vs. high-grade dysplasia in patients
with ulcerative colitis
Growth disturbances
• All of the aforementioned growth disturbances
are considered “reversible”
• If the inciting stimulus is removed
• How long do the changes take?
• An example of cervical cancer
• Changes may take 16-25 years
• Human papilloma virus initiates the changes
• Co-infected with HIV or HSV? – promotes the
changes
CANCER PREVENTION
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Annual check-ups—breast, prostate, skin
Colonoscopies every 10 years
Pap smears
HPV vaccine is now available!! YES! When
should it be given?
Eat right
Exercise
Stop smoking
Lose weight
Mammograms every year starting
at 40**
Everybody over 50--colonoscopies
every 10 years
• Yearly stool samples for occult blood
Guys, get those prostates checked!
(starting at age 40)
• Comments from patients during rectal exams: (Dr.
James Ralph)
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“Find Amelia Earhart yet?”
“Can you hear me NOW?”
“Hey, now I know how a muppet feels…”
“How long have you been in politics?”
“Remind me never to become an altar boy.”
“Could you write me a note for my wife, saying that my
head is not, in fact, up there?”
Young guys, examine those
testicles!!
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Heat and testicular cancer?
Undescended testicles
Plastic diapers?
Laptops?
Weight loss…
Abdominal obesity and
cancer…inflammation
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NHL -- +95%
Breast (PMF) – 112%
Pancreatic -- +176%
Kidney -- +375%
Colorectal -- +46%
Ovarian -- +51%
Uterine -- +525%
Breast cancer prevention
• Failure to limit adult weight gain may account for
one-third of all breast cancers (Thompson HJ,
Cancer Prevention Laboratory @ Colorado State
University, Fort Collins, CO)
• Weight gain of more than 11 pounds as an adult,
along with less than 30 minutes of physical
activity daily, is linked to an increased risk of
breast cancer
Cancer prevention
• Does HT increase your risk of breast
cancer?
• HT—yes, slightly
• ET only—no, maybe
• Fat tissue and hormones?
Foods and cancer protection
• Indole-3 carbinols—huh? Brassica veggies
• Broccoli,
• Brussels
sprouts
• Cabbage
• May reverse the changes observed with cervical
dysplasia
And don’t forget your cauliflower…
• “Cauliflower is nothing but a cabbage with
a college education.”
---Mark Twain (1835-1910)
Do forget your french
fries…acrylamides (?)
Is soy protective? Depends on
when you add it to your diet…
• Add 25 gm of soy products per day—soy beans,
soy milk, soy burgers, soy sauce (not!) at
puberty NOT at menopause
Cut back on grilling…if you have to grill, marinate the meat
(in a sweetened oil and vinegar sauce overnight to
reduce HCA formation)
• Most of the HCAs are found in the crisp black
outer crust of the steak or meat that has been
grilled, so the more the meat is well done, the
higher the risk.
• Microwave to precook it before grilling.
Microwaving evaporates much of the water,
zapping the HCAs in the process
• Flip the burgers constantly
• Add fruit to the meat before it is grilled, such as
ground tart cherries, and reduce the HCA
content by up to 90%.
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(Science News 155;264:1999)
Cut back on the booze…
• Folic acid supplements
• Alcohol is on the list of “probable cause” for
cancers of the colon, rectum and breast;
“convincing cause” of cancers of the mouth and
pharynx, larynx, esophagus, liver, and “possible
cause” for lung cancer.
Sip a bit of tea…
• Green or black—but not herbal tea.
• Polyphenols—catechins may have a couple of ways
they protect against cancer
• Decrease the division of cells
• Increase the excretion of carcinogens
• Anti-angiogenesis
• BMJ 318:1086, 1999; Nature 398:381, 1999; Medical
Tribune 39#9:13, 1998 and 40#9:2, 1999.
Coffee enemas
• With the re-emergence of complementary and alternative
therapies, daily coffee enemas have re-emerged as
detoxifying agents in an alternative cancer therapy
program known as the Gonzalez/Kelley treatment
regimen for pancreatic cancer.. The mechanism of action
--smooth muscle relaxation of the hepatic ducts resulting
in increased secretion of toxins from the liver into the GI
tract and out of the body.
• Rectal administration only
Better yet…
• Combine tomatoes with broccoli—
synergistic action
• Eat whole foods, not supplements!
• Cook the tomatoes—increase potency
• Add a bit of olive oil…
Eat grapes…
• Loaded with ellagic acid which blocks the body’s
production of enzymes necessary to stimulate
cancer cell growth
• Packed with phenols and antioxidants as well
• Other foods: apples, strawberries, raspberries
Colon cancer prevention—dietary
changes
• Don’t forget fiber
• Vitamin D detoxifies our digestive juices
• Increased folic acid converts homocysteine to
methionine which protects DNA from damage
• Calcium also plays a role in colon cancer
prevention
Exercise
Stop smoking
• Chemicals and by-products of cigarette
smoke
• Head and neck cancer
• Lung cancer
• Bladder cancer
• Cervical cancer in the presence of HPV
Vitamin D
• Get that prostate out
in the sun
• But don’t do it halfassed…
Get the whole thing out in the sun
where there is plenty of vitamin D!!
• PSA—a protein located
on epithelial cells;
increases with increased
proliferation or increased
size of the prostate gland
• PSA velocity
Thank you.
• Barb Bancroft, RN,
MSN, PNP
• [email protected]
• www.barbbancroft.com