Preventive Oncology & Vaping

Goals:

1. Update methods to implement prevention of

cancer.
2. Discuss ENDS [Electronic Nicotine Delivery Device]
Impact
3. Discuss how FDA/CDC Analyze “EVALI” [E-Cigarette
or Vaping Associated Lung Injury]
 Recap
“Out-takes” Derivative of Prior Presentation
Handout: https://www.scribd.com/doc/252857183/Preventive-Oncology
Power-Point: https://www.scribd.com/doc/252857273/Preventive-Oncology

Topics Covered with Specificity:

• Screening [CME]
• Tobacco [E-Cigs]

Topics Covered Generically:

• Oncogenic Viruses
• Chemical Carcinogens
• Diet

Plan:
• Flip Focus [Tobacco ←→ Cancer Control]
• Original Research re: Anti-Tobacco World
 Section 1: Etiology of Cancer

Chapter 4: Tobacco
Chapter 5: Oncogenic Viruses
Chapter 6: Inflammation
Chapter 7: Chemical Factors
Chapter 8: Physical Factors
Chapter 9: Dietary Factors
Chapter 10: Obesity and Physical Activity
 Giovanni Battista Morgagni
De Sedibus et Causis Morborum per Anatomen
ndagatis (The Seats and Causes of Diseases
nvestigated by Anatomy) demonstrated, in 1682,
the necessity to base diagnosis, prognosis, and
treatment on an exact and comprehensive
knowledge of anatomical conditions.
 Peter Greenwald, MD, DrPH
• NCI’s Associate Director for Cancer Prevention
Division of Cancer Prevention and Control.

• Started the American Stop Smoking Intervention Study

(ASSIST) and the “5 A Day” nutritional program in
partnership with industry and the private sector.

• Started a community clinical oncology network that

spawned the Breast Cancer Prevention Trial (Tamoxifen
halved breast cancer incidence in high-risk women) and the
Prostate Cancer Prevention Trial (Finasteride quartered
prostate cancer incidence).
•
Greenwald’s (1983) “Cancer Control Research Directions and
Opportunities” noted: [1]—the scientific method applied to
cancer control; [2]—the pursuit of excellence in science has
primacy over other considerations; [3]—the need for
translational research builds on strengths across the spectrum
from etiology/discovery to treatment/benefit (both for
individual patients and for public health); and [4]—the NCI
budget ($30 million, at first) segregated money that couldn’t
be used for research, instead of recognizing cancer control
constitutes applied research requiring the same criteria of
evidence and rigorous thinking and careful interpretation and
scientific debate that you need in every other area of science.
 Greenwald [1984]
The scientific approach to cancer control

Five-phase decision-making model:

(1) hypothesis development,
(2) method development,
(3) controlled intervention trials,
(4) defined population studies, and
(5) demonstration and implementation
studies
 Levels of Evidence
• Cancer Screening, Prevention and Treatment
studies can be ranked by noting the strength of
the study-design and endpoint-data.

• Five requirements should be met before

Screening for a particular medical condition as
part of routine medical practice; comparable
scales apply to Prevention and Treatment.

• Endpoints may relate to Incidence, Mortality, or

an Intermediate-Point.
 Carcinogenesis
• Carcinogenesis can be divided conceptually into four steps: tumor initiation, tumor
promotion, malignant conversion, and tumor progression.

• DNA-adduct formation that causes either the activation of a proto-oncogene or the

inactivation of a tumor-suppressor gene can be categorized as a tumor-initiating
event .

• Tumor promotion comprises the selective clonal expansion of initiated cells.

• Malignant conversion is the transformation of a preneoplastic cell into one that

expresses the malignant phenotype.

• Tumor progression comprises the expression of the malignant phenotype and the
tendency of malignant cells to acquire more aggressive characteristics over time.

--Holland-Frei, Cancer Medicine. 6th edition.

 Section 1: Etiology of Cancer

Chapter 4: Tobacco
Chapter 5: Oncogenic Viruses
Chapter 6: Inflammation
Chapter 7: Chemical Factors
Chapter 8: Physical Factors
Chapter 9: Dietary Factors
Chapter 10: Obesity and Physical Activity
 Chapter 5: Oncogenic Viruses
Oncogenic viruses cause cancer, especially in less
industrialized countries and in immunosuppressed
individuals.
They are common causes of lymphomas, and anogenital,
oral, and hepatocellular carcinomas and are associated
with a variety of other malignancies.
Vaccines and antiviral agents may prevent virus-induced
cancers.
Studies of virus pathogenesis will continue to establish
paradigms critical to understanding cancer etiology in
general.
 Oncogenic Viruses
Lymphomas
Epstein-Barr virus
Kaposi’s sarcoma herpesvirus
Merkel cell polyomavirus
Human T-cell leukemia virus
Anogenital & Oral carcinomas
Papillomavirus **
hepatocellular carcinoma
Hepatitis B virus *
Hepatitis C virus *
 Treatment *
• Hepatitis B virus
alpha interferon or nucleos(t)ide analogs that
inhibit the viral polymerase, such as lamivudine,
telbivudine, entecavir, adefovir, and tenofovir.
• Hepatitis C virus
24-48 weeks of pegylated IFN-α and ribavirin
 Agent Orange → Dioxin → Immunosuppression → HPV
You were a 69-year-old man when you noticed development of a solitary left-
neck mass on 4/7/2016….You stopped smoking cigarettes (after unknown pack-
years) in 2003. Examination was normal, except for both matted left anterior
inferior neck nodes and a 2 cm.2 area of palpable induration on the left side of
the posterior tongue. Initially/subsequently, you have had no major problem
eating/drinking.

On 6/6/2016, the biopsy showed epidermoid/squamous-cell carcinoma; it was

well-differentiated, was dysplastic with in-situ carcinoma (KI-67) features, and
was positive for P-16 (HPV-16).

…It was not uncommon to have to ford small rivers and streams that were
covered with what seemed to us to be AV gas or other fuel-smelling
substances. As field Infantry, it was rarely possible to clean either yourself or
your clothes and gear of these smelly fluids. It was standard procedure for us
to patrol in and around these areas 4-5 days a week. This went on for most of
us for a period of 8-9 months without much relief. Even in our rear trains areas,
powerful defoliants (“Agent Orange”) had been employed to clear the areas
around our positions….
Exposure to HPV-16 increased the association with
oropharyngeal cancer regardless of tobacco and alcohol use, but
there was no evidence of synergy between exposure to HPV-16
and tobacco or alcohol use. Thus, there are two distinct
pathways for the development of oropharyngeal cancer: one
driven predominantly by the carcinogenic effects of tobacco or
alcohol (or both) and another by HPV-16-induced genomic
instability….Therefore, tobacco and alcohol were important risk
factors for oropharyngeal cancer, but they may not have acted as
cofactors in HPV-mediated carcinogenesis in the oropharynx.

{D'Souza G, et al. Case-Control Study of Human Papillomavirus

and Oropharyngeal Cancer. N Engl J Med. 2007;356(19):1944-56.
http://www.nejm.org/doi/full/10.1056/
NEJMoa065497#t=article}
 Basic Science and Clinical Literature

linking HPV-16 and OSSC

immunotoxicity of Dioxins
immune defects linked to Dioxin
immune defects linked to AO [and HPV-16]
immunotoxicity linked to AO [and Dioxin]
longevity of the AO-exposure
high prevalence of HPV-16
potential to invoke HPV-16 prognostically
DIOXIN-LIKE CHLORPHENOXY HERBICIDES MIGHT
AUGMENT HUMAN COMMON VIRUSES ASSOCIATED
WITH CELL MALIGNIZATION
Therefore, specifically and generally, AO-exposure was a substantial contributing
factor to development of a respiratory-tract cancer located at the tongue-base,
OSCC, due to its having caused immuno-suppression and subsequent HPV-16
infection (given the presence of HPV-16 on biopsy); thus, because there is no
evidence that tobacco/alcohol played any pathogenic role in the etiology of OSCC,
support for this conclusion is generated both by noting positive features (HPV-16)
and rejecting any potential negative features (behavioral). No article in the medical
literature undermines this viewpoint, and it is not merely “speculative” to have
drawn these definitive, indubitable conclusions. This is not only based upon the
preponderance [indeed, “all”] of the evidence, but it is also not merely
“presumptive.” One more point is in-order: sometimes, an expert will be called-
upon to claim linkage of an environmental concern and the development of a
medical disorder and may be tempted to confirm such an association without
having conveyed a reasonable basis for having done so. This is not the situation in
this case, for all information has been assessed from a “disinterested” perspective,
notwithstanding the fact that this physician has been an anti-tobacco super-activist
since the late 1970’s. If anything is unclear, please so advise.
 REFERENCES:

Schecter A., Poiesz B., Brandt-Rauf P., Rapke O., Ball M. Med Sci Res 19:273 (1991).
Ngaon L., Yoshimura T. Asian Pac J Cancer Prev 2:199 (2001).
Butel J.S. Carcinogenesis 21:405 (2000).
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans 68:69 (1997).
Pokrovsky A., Chernykh A., Yastrebova O, Tsyrlov I.B. Biochem Biophys Res
Commun 79:46 (1991).
Tsyrlov I.B., Pokrovsky A. Xenobiotica 23:457 (1993).
Zacharevsky T.K. In: Toxicology in Silico 1:11 (2002).
Wu J., Shur I.N, Tsyrlov I.B. Organohalogen Compounds 70:1471 (2008).
Murayama T., Inoue M., Mori S., Eizuru Y. Biochem Biophys Res Commun 296:651
(2002).
Cinatl J., Vogel J., Kotchetkov R., Wilhelm A., Doerr H. FEMS Microbiol Rev 28:59
(2004).
Diliberto J., DeVito M., Ross D., Birnbaum L Toxicol Sci 61:241 (2001).
Kasai A., Hiramatsu N., Meng Y., Yao J., Maeda S., Kitamura M. Anal Biochem
337:84 (2005).
 Vaccine – Papillomavirus **
•Two preventive vaccines against cancer-causing HPVs, Gardasil
(Merck) and Cervarix (GSK), may confer lifelong immunity.

•Both vaccines cover HPV16 and HPV18 which, together, cause

about 70% of all cases of cervical cancer worldwide.

•Gardasil also includes VLPs based on HPV types 6 and 11, which
rarely cause cervical cancer but together cause about 90% of all
genital warts.

•Large prevention clinical trials targeting the most prevalent HPV

types in different regions of the world are warranted.
 Vaccine - Papillomavirus
•Questions such as the necessity of repeat vaccinations and the longevity of protection
from an HPV infection remain to be determined. It is estimated that if women were
vaccinated against all high-risk types of HPV before they become sexually active, there
should be a reduction of at least 85% in the risk of cervical cancer and a decline of 44%
to 70% in the frequency of abnormal Papanicolaou (Pap) smears attributable to HPV.

•Unfortunately, even after vaccination is implemented, a reduction in the incidence of

cervical cancer could not be expected to become apparent for at least a decade.
Therefore, therapeutic vaccines are still very much needed to reduce the morbidity
and mortality associated with cervical cancer.

•The therapeutic approach to patients with preinvasive and invasive cervical cancers is
to develop vaccine strategies that induce specific CD8+ cytotoxic T-lymphocyte
responses aimed at eliminating virus-infected or transformed cells. Early-phase human
trials using therapeutic vaccines have shown that they are safe; no serious adverse
effects have been reported.
 Section 1: Etiology of Cancer

Chapter 4: Tobacco
Chapter 5: Oncogenic Viruses
Chapter 6: Inflammation
Chapter 7: Chemical Factors
Chapter 8: Physical Factors
Chapter 9: Dietary Factors
Chapter 10: Obesity and Physical Activity
 Chapter 6: Inflammation
•Almost 50% of all cancers can be prevented based
on what we know today. All the studies summarized
previously suggest that inflammation is closely
linked to cancer, and the incidence of most cancers
can be reduced by controlling inflammation.

•Proinflammatory conditions such as colitis,

bronchitis, hepatitis, and gastritis can all eventually
lead to cancer. Thus, one must find ways to treat
these conditions before the appearance of cancer.
All these studies indicate that an anti-inflammatory
lifestyle could play an important role in both the
prevention and treatment of cancer.
 Anti-Inflammatory Agents
• Given the 10-year latency between adenoma formation and a cancer event,
prospective trials sufficiently powered to detect colorectal cancer incidence end points
are unlikely in the future. The U.S. Preventive Services Task Force (USPSTF) does not
recommend the use of aspirin or NSAIDs as cancer risk–reducing agents for normal risk
populations.

• Minimal prospective cancer risk reduction data are available at other epithelial organ
sites. Ketorolac, given as a 1% rinse solution, did not reduce the size or histology of
leukoplakia lesions.

• Celecoxib reduces the Ki67 labeling index and increases the expression of nuclear
survivin without significantly changing the cytoplasmic survivin in bronchial biopsies of
smokers.

• Cancer prevention trials of aspirin as interventions for delaying progression from

intraepithelial neoplasias in other epithelial sites remain ongoing for the lower
esophagus.

• No prospective, randomized trials or data are available for breast, prostate, or

gynecologic cancer prevention.
 Anti-Infectives

•Infectious agents that cause cancer include: Helicobacter pylori for

gastric adenocarcinoma; the human hepatitis viruses, hepatitis B virus
(HBV) and hepatitis C virus (HCV) for hepatocellular carcinoma; human
papilloma viruses (HPV) for cervical, anal, vulva, penis, and oral cavity
and pharynx carcinomas; herpes virus-8 for Kaposi sarcoma; Epstein-
Barr virus for Burkitt and other lymphomas; liver flukes for
cholangiocarcinoma; and schistosomes for bladder carcinoma.

•The success of the HPV vaccine at reducing the incidence of

intraepithelial neoplasia of the cervix examplifies the potential of
immuno-chemoprevention for epithelial targets for which an etiologic
agent can be identified.
 Helicobacter pylori

•Intestinal-type gastric adenocarcinoma arises through a multistep

process: chronic gastritis initiated by H. pylori [which infects 50% of the
world’s population] → gastric mucosal atrophy → intestinal metaplasia
→ dysplasia → adenocarcinoma. Infection with H. pylori is associated
with an OR of 2.7 to 6.0 for gastric cancer; CagA increases this risk by
20- to 40-fold; the risk of developing gastric adenocarcinoma with an H.
pylori infection is estimated to be 1% to 3%.

•Eradication of H. pylori with antibiotics and anti-inflammatory agents—

for example, amoxicillin, metronidazole, and bismuth subsalicylate—
increases the rate of regression of nonmetaplastic gastric atrophy and
intestinal metaplasia in geographically diverse regions.

•Combining a proton pump inhibitor (omeprazole) and an antibiotic

(amoxicillin) reduced the risk of gastric cancer in a high-risk population
in China (OR = 0.61; (95% CI, 0.36 to 0.96) for 14.7 years.
 Section 1: Etiology of Cancer

Chapter 4: Tobacco
Chapter 5: Oncogenic Viruses
Chapter 6: Inflammation
Chapter 7: Chemical Factors
Chapter 8: Physical Factors
Chapter 9: Dietary Factors
Chapter 10: Obesity and Physical Activity
 Chapter 7: Chemical Factors
• For common cancers, nongenetic risk factors are
dominant, and the best associations for genetic
risks of sporadic cancers indicate that the risks for
specific genetic traits are typically less than 1.5-fold.

• The role of the tumor microenvironment, the

cancer stem cells, and feedback signaling to and
from the tumor also have been recently recognized
as important contributors to carcinogenesis,
although how chemicals affect these have yet been
clearly demonstrated.
BN-Brachyury vaccine generates T-cell responses by targeting
brachyury, a transcription factor involved in metastasis and
associated with mCRPC aggressiveness.

PD-L1 blockade by M7824 at the tumor:effector cell synapse

can enhance tumor lysis; TGF-β neutralization by M7824 can
further enable immune effector cell activity within the tumor
micro-environment [TME].

ALT-803 expands and activates NK cells and effector T cells.

[Inhibition of the IDO1 enzyme by Epacadostat can decrease

immunosuppressive currents within the TME generated by
myeloid-derived suppressor cells (MDSCs) and regulatory T
cells toward a more immune-permissive state within the TME
by dampening the inhibitory effects of MDSCs.]
 Section 1: Etiology of Cancer

Chapter 4: Tobacco
Chapter 5: Oncogenic Viruses
Chapter 6: Inflammation
Chapter 7: Chemical Factors
Chapter 8: Physical Factors
Chapter 9: Dietary Factors
Chapter 10: Obesity and Physical Activity
 Chapter 8: Physical Factors
•Loss or defects in the ATM or p53 genes result in abrogation of
radiation-induced cell cycle checkpoints, which manifests itself
as the highly cancer-prone human syndromes ataxia
telangiectasia or Li-Fraumeni, respectively.

•The major sensor of radiation-induced damage in cells is the

ataxia-telangiectasia mutated (ATM) kinase.

•The kinase p53 regulates the gene expression of specific genes

such as p21, which inhibits cyclin-dependent kinase (CDK)2- and
CDK4-mediated phosphorylation of the retinoblastoma protein,
resulting in a block in the progression from the G1phase to the S
phase of the cell cycle.
 Skin Cancer
• The incidence of sun-induced skin cancer, especially
melanoma, is on the increase due to higher rates of
sun exposure in the general population.
• The link between UV light exposure and skin cancer
is very strong, but the role of UV light in the etiology
of nonmelanoma and melanoma skin cancer differs.
• Although the risk of nonmelanoma cancer relates to
the cumulative lifetime exposure to UV light, the risk
of contracting melanoma appears to be linked to
high sunlight exposure during childhood.
 Ionizing Radiation

•Twenty years after Hiroshima/Nagasaki, significant increases in

the incidence of thyroid cancer and leukemia were observed;
however, it took almost 50 years before solid tumors appeared
in the population as a result of radiation exposure from the
atomic bombs.

•Radon is the second leading cause of lung cancer in America;

radiofrequency and microwave radiation are not carcinogens.

•There is a growing concern about the dramatically increased

use of whole body CT scans for diagnostic purposes.

•Cancer patients who receive radiation therapy are at risk to

develop secondary tumors.
 Section 1: Etiology of Cancer

Chapter 4: Tobacco
Chapter 5: Oncogenic Viruses
Chapter 6: Inflammation
Chapter 7: Chemical Factors
Chapter 8: Physical Factors
Chapter 9: Dietary Factors
Chapter 10: Obesity and Physical Activity
 Cancer Prevention: The Roles of Diet and Chemoprevention
Peter Greenwald, M.D., Dr.P.H., and Sharon S. McDonald, M.S.

Considerable evidence links dietary factors with cancer risk, but ongoing investigation is
needed.

Background: Reduction of cancer risk by either preventing carcinogenesis or stopping

carcinogenesis in its early stages is a logical approach for reducing the cancer burden, both for
high-risk individuals and for the general population. The areas of dietary modification and
chemoprevention show considerable promise as effective approaches for cancer prevention and
are a focus of research efforts.

Results: Diet and cancer studies show that, generally, vegetables and fruits, dietary fiber, and
certain nutrients seem to be protective against cancer, whereas fat, excessive calories, and
alcohol seem to increase cancer risk. Chemoprevention research is closely linked to diet and
cancer research and represents a logical research progression.

Conclusions: Dietary epidemiologic studies have helped to identify many naturally occurring
chemopreventive agents. Currently, randomized clinical prevention trials sponsored by the NCI
include dietary interventions (e.g., low-fat and/or high-fiber vegetables and fruits) targeting
breast and colorectal cancer, chemoprevention trials using micronutrients (e.g., vitamin E,
calcium, vitamin D) aimed at lung and colorectal cancer, and chemoprevention trials testing the
effectiveness of pharmaceutical agents (e.g., tamoxofen, finasteride, aspirin) for breast,
prostate, and colorectal cancer.
 Micronutrients
•Certain agents, including retinoids, beta-carotene, folic acid, calcium
plus vitamin D, vitamin E, and selenium, have received substantial
attention for a possible role in reducing the risk of cancer in humans.

•Some trials have observed statistically significant reductions in the risk

of the primary end point (e.g., retinoids in skin carcinogenesis models,
calcium in colorectal adenomas, antioxidant nutrients in Linxian, China,
for gastric cancer prevention).

•Other trials have observed statistically significant increases in the risk

of the primary end points (beta-carotene and retinoid lung cancer
prevention trials in smokers, vitamin E and prostate cancer, selenium
and nonmelanoma skin cancer).

•Considering the completed trials, there is clear evidence against the

general use of nutrient supplements for cancer prevention.
 Lifestyle
• Doll and Peto claimed that approximately 30% to 40% of
cancers may be avoidable with changes in nutrition; however,
much of this risk of cancer is related to being overweight and
to inactivity.

• Excessive energy intake and lack of physical activity, marked

by rapid growth in childhood and being overweight, have
become growing threats to population health and are
important contributors to risks of many cancers.

• Nevertheless, the cumulative incidence for many cancers has

decreased over the past decade, in part due to the decreasing
prevalence of smoking and use of hormone therapy.
 Strength of the Observational Epidemiologic Evidence
for Physical Activity as a Protective Factor and Obesity as a Risk Factor
for Cancer, By Type of Cancer

Physical Activity Overweight/Obesity

Breast, postmenopausal +++ +++
Breast, premenopausal ++ ++ (protection)
Colon +++ +++
Endometrium + +++
Esophagus, adenocarcinoma ? +++
Kidney/renal cell ? +++
Gallbladder ? ++
Pancreas ? +++
Non-Hodgkin lymphoma ? +
Prostate, aggressive + +
Lung + ?
Ovary ? ?
 Prevention???

1. To identify the major carcinogens that can

reasonably be undermined.

2. To identify the major “preventive” and

“screening” strategies that can reasonably be
implemented.
 Prophylactic Surgery
•Since the heritable component of some cancer predispositions has been linked to mutations in
specific genes, clinical interventions have been formulated for mutation carriers within affected
families.

•The primary interventions for mutation carriers for highly penetrant syndromes, such as
multiple endocrine neoplasia (MEN), familial adenomatous polyposis (FAP), hereditary
nonpolyposis colorectal cancer (CRC), and hereditary breast and ovarian cancer syndromes, are
primarily surgical.

•This chapter addresses breast, gastric, ovarian and endometrial, and MENs and colorectal. For
each, the clinical and genetic indications and timing of prophylactic surgery and its efficacy,
when known, are provided.

•Prophylactic surgery in hereditary cancer is a complex process, requiring a clear understanding

of the natural history of the disease and variance of penetrance, a realistic appreciation of the
potential benefit and consequence of a risk-reducing procedure in an otherwise potentially
healthy individual, and the long-term sequelae of such surgical intervention, as well as the
individual patient’s and family’s perception of surgical risk and anticipated benefit.
 Selective Estrogen Receptor Modulators - Concepts

•SERMs function as estrogen receptor (ER) agonists and antagonists

depending on the SERM structure and target tissue. Predominant ERα
receptors occur in the human uterus, cortical bone, and the liver;
whereas predominant ERβ receptors occur in blood vessels, cancellous
bone, the whole brain, and immune cells.

•During carcinogenesis, the amount of ERα increases while the amount

of ERβ decreases in breast tissues.

•Ideally, a desirable SERM for cancer prevention will function as an

antiestrogen in the breast and uterus, but a partial estrogen agonist in
skeletal, cardiovascular, central nervous system (CNS), GI tract, and
vaginal tissues.

•In addition, an ideal SERM will not have procoagulant effects and will
not cause perimenopausal symptoms such as hot flashes.
 Selective Estrogen Receptor Modulators - Efficacy

• Despite the widespread evidence of breast cancer preventive efficacy

for tamoxifen and raloxifene, only 3% to 20% of eligible high-risk women
agree to take tamoxifen for primary prevention.

• Although aromatase inhibitors may have a more favorable risk to

benefit profile than SERMs, long-term outcomes and toxicity experience
for aromatase inhibitor risk-reducing agent intervention are not
available to date.

• In the National Surgical Adjuvant Breast and Bowel Project, tamoxifen-

treated women with aBRCA2 mutation but not a BRCA1 mutation had
reduced cancer incidence, but subsequent data from another group
have found reduced cancer risk in women with both BRCA mutations.

• Data remain insufficient to recommend the use of SERMs for risk

reduction in women with BRCA mutations.
 Signal Transduction Modifiers - 1
•Difluoromethylornithine (DFMO) is an enzyme-activated irreversible
inhibitor of ornithine decarboxylase (which is transactivated by the c-
MYC oncogene and cooperates with the RAS oncogene in malignant
transformation).

•Topical-DFMO caused regression of cervical intraepithelial neoplasia.

•DFMO has anticarcinogenic activity for nonmelanoma skin cancers,

primarily basal cell carcinoma.

•In combination with an NSAID (sulindac), DFMO reduced adenoma

recurrences, suggesting a synergistic reduction of colorectal cancer risk.

•Preliminary data suggest some cancer risk–reducing agent activity for

the lower esophagus and the prostate.
 Signal Transduction Modifiers - 2
•Metformin reduced the risk of solid tumors by 25% to 30%; there was a
lower incidence of invasive breast cancer in metformin-treated women
with type 2 diabetes mellitus.

•No natural products have been studied in large prospective, cancer

incidence risk–reduction trials.

•Statins and Bisphosphonates are still being studied.

•Multi-agent approaches are being conceptualized.

 Prostate Cancer

•Finasteride [Proscar], a selective, competitive inhibitor of type 2 5α-

steroid reductase, inhibits proliferation in the transformed prostate cell.

•Finasteride appears to be more effective in the promotion phase of

prostate carcinogenesis; use of finasteride for seven years reduced the
incidence of prostate cancer, but it did not significantly affect mortality .

•Dutasteride [Avodart] inhibits both 5α-steroid reductase inhibitor types

1 and 2 isoforms and has similar anticarcinogenesis activity in preclinical
models to finasteride.

•Finasteride and dutasteride reduce the incidence of prostate cancer by

approximately 22%, yet progression of high-grade lesions is unaffected.
 Screening
Lung, colorectal, breast, and prostate cancer are the leading causes of
cancer-related deaths in the United States. Together, these cancers
accounted for an estimated 46% of all cancer-related deaths, or more
than 273,000 deaths, in 2016. This course provides an overview of the
major issues in cancer screening, appropriate adherence to guidelines
and barriers to adherence, controversies regarding guideline criteria,
and the effect of screening on mortality. Also included are detailed
recommendations for the five major cancer types for which guidelines
on screening and counseling have been developed: breast, cervical,
colorectal, lung, and prostate cancers. Recommendations for other
cancers of concern are included as well. Lastly, strategies to enhance
cancer screening are also discussed.
Colorectal Cancer Screening in the USA
In the United States, colorectal cancer (CRC) incidence and mortality have declined by
roughly 3% per year since 2001 (1). Screening probably explains much of this public
health success; however, the optimal method for it remains unclear. Colonoscopy
accounts for at least 60% of all CRC screening in the United States, despite its greater
expense and risk for complications compared with other options (2). Surprisingly little
published evidence supports the predominance of colonoscopy. Unlike for fecal occult
blood testing or flexible sigmoidoscopy, no controlled studies have shown that
colonoscopy reduces CRC incidence or mortality. Most studies have reported that the
cost-effectiveness of other CRC screening methods equals or exceeds that of
colonoscopy (3). Recently, the clinical effectiveness of screening colonoscopy itself
came under fire, with several studies showing excellent protection against left-sided
CRC but far less against right-sided disease (4). Long-awaited trials comparing
colonoscopy with stool blood–based screening methods are under way, but
informative results will not be available for years.

http://annals.org/aim/article/2593601/scientific-basis-guideline-recommendations-
sugar-intake-systematic-review
 Section 1: Etiology of Cancer

Chapter 4: Tobacco
Chapter 5: Oncogenic Viruses
Chapter 6: Inflammation
Chapter 7: Chemical Factors
Chapter 8: Physical Factors
Chapter 9: Dietary Factors
Chapter 10: Obesity and Physical Activity
 Tobacco as a Carcinogen
• The International Agency for Research on
Cancer (IARC) classified cigarette smoke and
smokeless tobacco as Group 1 carcinogens.

• IARC has also identified 72 measurable

carcinogens in cigarette smoke where
evidence is sufficient to classify them as
Group 1 (carcinogenic to humans), 2A
(probably carcinogenic to humans), or 2B
(possibly carcinogenic to humans).
 The Surgeon General vs. the Marlboro Man:
Who Really Won?
• Alan Blum, M.D., curated an exhibition at the
University of Alabama commemorating the 50th
anniversary of the Surgeon General’s Report on
Smoking and Health [January 11, 1964] by
Luther Terry, M.D.

http://www.cancernetwork.com/articles/surgeon
-general-vs-marlboro-man-who-really-won
 Tobacco and Public Health

• EGFRm NSCLC patients derived significant PFS benefit

from TKI over chemotherapy regardless of smoking
status, but the PFS benefit from EGFR TKIs over
chemotherapy is significantly higher in never-smokers
than ever-smokers by meta-regression analysis.

• The Federal Aviation Administration is warning airlines

about fire risks from electronic cigarettes stored in
checked luggage and is recommending that passengers
bring them into the cabins instead.
 Tobacco and Public Health
• “Uptown. The place. The taste.”
• "Uptown—The Disgrace.“

• Snus
• Naswār
• Chew
• Dip
 Adenocarcinoma Epidemic

• The increase in adenocarcinoma of the lung

observed in the United States over recent
decades may reflect changes made to the
cigarette, such as filters, filter ventilation, and
tobacco-specific nitrosamines (TSNA) in smoke
produced by the relatively high amount of burley
tobacco used in the typical US cigarette blend.

• The increasing incidence of lung cancer may be

due to radioactive polonium in cigarettes.
 Aryl Hydrocarbon Hydroxylase
• The normal white population in the United States can be
divided into three separate groups having low,
intermediate, and high inducible aryl hydrocarbon
hydroxylase activities, with frequencies of 44.7 per cent,
45.9 per cent and 9.4 per cent respectively.

• Fifty patients with bronchogenic carcinoma were studied,

and the frequencies of the three groups were 4.0 per cent,
66.0 per cent and 30.0 per cent respectively.

• Whether the higher AHH levels are the cause or the result
of the primary lung cancer is unclear.
 Smoking Topography
• Scientific study of this “elastic” process is
affected by the number of puffs, puff size,
frequency, duration, and velocity.

• Tobacco may [or may not] be a Precipitating

Factor in Angina Pectoris.
 TABLE 4.1 - Level of Evidence for Smoking-Attributable Cancers
According to the United States Office of the Surgeon General
by Cancer Site and Yearly Smoking-Attributable Mortality - 2004

– Cancer Site Yearly Smoking-Attributable Mortality

• Evidence Sufficient to Infer Causal Relationship
– Bladder 4,983
– Cervix 447
– Colon and rectum N/A
– Esophagus 8,592
– Kidney 3,043
– Larynx 3,009
– Leukemia (AML) 1,192
– Liver N/A
– Lung 125,522
– Oral cavity and pharynx 4,893
– Pancreas 6,683
– Stomach 2,484
• Evidence Suggestive but Not Sufficient to Infer Causal Relationship
– Breast
• Inadequate to Infer Presence or Absence of Causal Relationship
– Ovary
• Evidence Sufficient to Infer No Causal Relationship
– Prostate
 Tobacco Control
• There is a causal relationship between cigarette smoking and
adverse health outcomes; quitting smoking improves the prognosis
of cancer patients.

• There is a causal relationship between cigarette smoking and

increased all-cause mortality and cancer-specific mortality.

• There is a causal relationship between cigarette smoking and

increased risk for second primary cancers known to be caused by
cigarette smoking, such as lung cancer.

• There is suggestive evidence (insufficient to infer causation) that

cigarette smoking increases treatment-related toxicity and mortality
(risk of recurrence and poorer response to treatment).
Smoking-Cessation Decreases Risk
• Some effects of “current” smoking are distinct from an “ever” or
“former” smoking history; many effects of smoking are reversible.

• The adverse effects of smoking and the benefits of cessation may

have been under-reported because 30% of cancer patients who
smoke deny tobacco use; this reflects a potential discrepancy
between the effects of smoking based on subjective versus
biochemically-confirmed assessments.

• Complications may arise post-operatively, may preferentially affect

the lungs, may enhance XRT-toxicity, may worsen mucositis, may
yield more hospitalizations, and may even yield ongoing vasomotor
symptoms.
 Smoking Affects Treatment Response

• Head and neck cancers that are human papilloma virus

(HPV) positive are known to have an improved
prognosis as compared with HPV-negative tumors.

• Light or never smokers have a higher rate of EGFR-

positive lung tumors that may respond to biologic
therapy using EGFR tyrosine–kinase inhibitors. {EGFR =
Epidermal Growth Factor Receptor}

• Smokers may be better served with conventional

cancer treatments rather than these biologic therapies.
 Smoking-Cessation
• Use an ongoing SOAP-model, emphasizing the need to
reformulate data.
• Tools abound [ALA, ACS, NCI, ASCO].
• Most smokers are unsuccessful in their attempts to
quit smoking; the most effective evidence-based
treatments increase the odds of quitting by 3-times,
with 12-month cessation rates of approximately 40%
relative to placebo.
• Low-tar cigarettes (as compared to full-flavor varieties)
afford neither an individual nor a public health benefit,
per both laboratory-based and epidemiologic studies.
 Select Treatment Strategies Used for Tobacco Cessation Treatments

• Provide and monitor the use of nicotine replacement or other

pharmacotherapy.
• Provide education regarding the health effects of tobacco use and its addictive
and relapsing nature.
• Identify and change environmental and psychological cues for tobacco use.
• Generate alternative behaviors for tobacco use.
• Assist in optimization of social support for cessation efforts and address
tobacco use in family members.
• Prevent relapse including the identification of future high-risk situations and
plans for specific behaviors in those situations.
• Provide motivational interventions as needed throughout treatment.
• Identify relaxation techniques such as guided imagery and progressive muscle
relaxation.
• Provide behavioral strategies to address depressed mood (e.g., increasing
pleasurable activities).
• Provide crisis intervention including appropriate referrals and emergency
intervention if indicated.
• Recognize and congratulate patients on success with reducing and/or quitting
smoking.
 First-Line Pharmacotherapy Agents for the Treatment of Nicotine Dependence
Agent Dose Mechanism Use
Nicotine Replacement
Transdermal (patches) • 16 h or 24 h Steady state NRT to reduce craving and • 6–10 CPD: 14 mg daily × 8 wks then 7
• 7, 14, or 21 mg withdrawal mg daily × 2 wks
• 1 patch/d • >10 CPD: 21 mg daily × 6 wks, then 14
mg × 2 wks, then 7 mg × 2 wks

Gum • 2 or 4 mg Short-term NRT to reduce craving and • First cigarette >30 min after waking:
• Max: 24 pieces/d withdrawal 2 mg PO q1–2 hr
• First cigarette <30 min after waking: 4
mg PO q1–2 hr

Lozenge • 2 or 4 mg Short-term NRT to reduce craving and • 1st cigarette >30 min after waking: 2
• Max: 20 lozenges/d withdrawal mg PO q1–2 hr
• 1st cigarette <30 min after waking: 4
mg PO q1–2 hr
Nasal spray • 0.5 mg/spray Short-term NRT to reduce craving and 1 spray/nostril q1–5 hr
• Max:10 sprays/hr or 80 sprays/d withdrawal

Inhaler • 4 mg/cartridge Short-term NRT to reduce craving and 1 cartridge inhaled over 20 min q1.5–6
• Max: 16 cartridges/d withdrawal hr

Bupropion (Zyban) 150 mg Block nicotinic receptors and reduces 1 tablet daily × 3 d, then 1 tablet twice
reward daily for 7–12 wks

Varenicline (Chantix) 0.5 or 1 mg Dopaminergic reward and partial 0.5 mg daily × 3 d, then 0.5 mg twice
nicotinic receptor antagonist daily × 3 d, then 1 mg twice daily
 Adult Smoking Habits in Great Britain, 2013

The proportion of the GB adult population who smoke cigarettes has fallen by more than
a half in the last 40 years, from 46% in 1974 to 19% in 2013. Not only have fewer people
taken up smoking, but more of those who did smoke have quit

Women accounted for the fall on the previous year - the proportion of women who
smoke cigarettes fell from 19% to 17% between 2012 and 2013. There was relatively
little change in this proportion for men

Unmarried people were almost twice as likely to be cigarette smokers as married people
The proportion who smoke cigarettes was higher amongst unemployed people, people
working in routine and manual occupations and those with lower level educational
qualifications. These are all factors associated with poverty

E-cigarettes are almost exclusively used by smokers and ex-smokers. Almost none of
those who had never smoked cigarettes were e-cigarette users
 Use of e-cigarettes, and the relationship to smoking

The debate around use of e-cigarettes:

E-cigarettes have been sold since 2004, and in Europe since 2006. Their popularity
and availability has increased, which has led to debate around their use. Some feel
that e-cigarettes could renormalise smoking, or could be a gateway to smoking by
introducing non-smokers to nicotine. Others feel that they could be a useful tool in
the effort to reduce tobacco consumption. To date, e-cigarettes have mainly
been marketed as a cheaper and healthier alternative to smoking. However, the
long-term health effects of using e-cigarettes have yet to be established. This has led
to a World Health Organisation call for tighter controls on e-cigarettes.

ONS has chosen to publish preliminary findings on e-cigarette use in response to the
emerging need for more information. These data were collected between January
and March 2014. Complete 2014 findings are planned for publication as part of the
next Adult Smoking Habits in GB publication in 2015.

https://www.ons.gov.uk/peoplepopulationandcommunity/healthandsocialcare/healtha
ndlifeexpectancies/compendium/opinionsandlifestylesurvey/2015-03-
19/adultsmokinghabitsingreatbritain2013#tab-Use-of-e-cigarettes--and-the-
relationship-to-smoking
E-cigarettes were almost exclusively used by smokers and ex-smokers,
Fig 11.

More than 1 in 10 (12%) of cigarette smokers also used e-cigarettes,

compared with 1 in 20 (5%) ex-smokers and almost none of those who
had never smoked.

These findings reflect those from a YouGov survey commissioned by

Action on Smoking and Health (ASH). Data on e-cigarette use have also
been collected as part of the Smoking Toolkit Study.

E-cigarettes were found to be used mainly as smoking cessation aids and

for the perceived health benefits (compared with smoking tobacco).
Over half of e-cigarette users said that their main reason for using e-
cigarettes was to stop smoking, and about one in five said the main
reason for their use was because they thought they were less harmful
than cigarettes.
Vaping advocates rightly suspect that
these nonprofits have exhibited “mission
creep” as they abandoned their public
health goals by lobbying to ban vaping and
vapor products, which protects deadly
cigarettes and smoking cessation drugs
(whose manufacturers funded the health
groups) from future market competition.
 EVALI
Investigations thus far have shown that a great majority of
cases had histories of cannabis and particularly THC use,
but in roughly 15%, the patients insisted they had used
nicotine vaping products exclusively. Most, but not all, cases
have been in men and in people younger than 30. But no
single characteristic or activity had been seen in every case,
frustrating efforts to identify causes.

In early September, just 3 weeks after the outbreak was

announced, officials in New York state said they had found
vitamin E acetate "in nearly all cannabis-containing [e-
liquid] samples" they had analyzed. Moreover, "[a]t least
one vitamin E acetate containing vape product has been
linked to each patient who submitted a product for testing,"
according to the state health department's announcement.
E acetate looked like another dead end. Now, the new BAL
study may be the smoking gun investigators have been
searching for.
Led by Benjamin C. Blount, PhD, of the CDC's National Center
for Environmental Health, researchers obtained BAL samples
from EVALI patients in 10 states. Of the 29 patients providing
samples, self-reports of vaping history were available from
23, and of those, all but three admitted to THC use. And for
the three who didn't, their BAL samples tested positive for
THC or its metabolites, Blount and colleagues said.
Of 26 samples tested for nicotine metabolites, 16 came back
positive. Results for other e-liquid components such as
petroleum distillates and plant oils "were all below analyte-
specific levels of detection," the report indicated.
Only vitamin E acetate was found in all the samples. But
Blount and colleagues noted a number of important
 MMWR Update:

Demographic, Product, and Substance-Use

Characteristics of Hospitalized Patients in a
Nationwide Outbreak of E-cigarette, or Vaping,
Product Use–Associated Lung Injuries — United
States, December 2019
What is already known about this topic?
Patients with e-cigarette, or vaping, product use–associated lung
injury (EVALI) in Illinois and Wisconsin reported using a variety of
tetrahydrocannabinol (THC)-containing products in the 3 months
preceding illness; a product labeled “Dank Vapes” was most
commonly reported.
What is added by this report?
Nationally, Dank Vapes were the most commonly reported THC-
containing product by hospitalized EVALI patients, but a wide
variety of products were reported, with regional differences. Data
suggest the outbreak might have peaked in mid-September.
What are the implications for public health practice?
These data further support the association of EVALI with THC-
containing products; it is unlikely that one brand is responsible
for the outbreak. CDC recommends that persons not use e-
cigarette, or vaping, products that contain THC.
members, or in-person or online dealers. In addition, persons
should not add any other substances to products not intended by
the manufacturer, including products purchased through retail
establishments. Vitamin E acetate should not be added to e-
cigarette, or vaping, products. However, although it appears that
vitamin E acetate is associated with EVALI, many substances
and product sources are being investigated, and there might be
more than one cause. Therefore, while the investigation
continues, persons should consider refraining from the use of all
e-cigarette, or vaping, products. Adults using e-cigarette, or
vaping, products to quit smoking should not return to smoking
cigarettes; they should weigh all risks and benefits and consider
using FDA-approved cessation medications.†† Adults who
continue to use e-cigarette, or vaping, products should carefully
monitor themselves for symptoms and see a health care provider
immediately if they develop symptoms similar to those reported
in this outbreak (8). Irrespective of the ongoing investigation, e-
cigarette, or vaping, products should never be used by youths,
young adults, or pregnant women.
 Cigarette Smoking Among U.S. Adults drops to All-Time Low

The number of adult cigarette smokers in

the United States has hit an all-time low of
13.7 percent in 2018.
Reconsidering Electronic Nicotine Delivery Systems and Tobacco Control Policy
iewed. Each study’s portrayal was compared/contrasted with
mary data. Studies supporting ENDS were “positive” and those
supportive, “negative.” The capacity for ENDS to achieve
acco harm reduction [THR] from smoking was recognized.

ults. Core citations were based upon flawed/faulty scientific

adigms, and the summary thereof corrupted the rendition of
ny allegedly-negative studies.

nclusion. Given that ENDS constitute a realistic/effective

thod to achieve cigarette-use abatement and consequent THR,
icy statements by health groups and agencies should comport
h evidence to-date. Noting multiple errata in this meta-
alysis, the ACS should immediately reverse policy
ommendations that don’t recognize that ENDS are ~95% less
mful than tobacco cigarettes; don’t deliver carcinogenic (tar)
1. Professor, Department of Health Services Administration, Drexel University, Philadelphia,
Pennsylvania

1. William T. Godshall, M.P.H., Executive Director, Smokefree Pennsylvania, Pittsburgh,

Pennsylvania

Robert B. Sklaroff, M.D.

Smylie Times Building, Suite 500C
8001 Roosevelt Boulevard
Philadelphia, Pennsylvania 19152-3041

Stephen F. Gambescia, Ph.D.

Professor
Drexel University, Department of Health Administration
1601 Cherry Street, Room 774
Philadelphia, Pennsylvania 19102-1320
Sfg23@drexel.edu
484-557-4339

William T. Godshall, M.P.H.

Executive Director
Smokefree Pennsylvania
1926 Monongahela Avenue
We questioned1 why some public health advocates—
prominently, Glantz2—demonize Electronic Nicotine
Delivery Systems [ENDS], despite the fact inter alia
that ENDS are ~95% less harmful than tobacco
cigarettes.3 When used as per proper education,
ENDS constitute an important tool to achieve
smoking cessation4 through tobacco harm reduction
[THR] from smoking,5 prompting Public Health
England6 to launch a Pro-ENDS Campaign to
achieve THR. {ENDS is used throughout to
distinguish vaping e-cigarettes from smoking
combustible-tobacco.}
Overall, the ACS’s questionable proposed interventions
reflect intransigence, lest its prior counter-productive
activism be overtly attenuated. Indeed, the ACS continues
including anti-ENDS and anti-THR policies/laws/regulations
that paradoxically protect cigarettes and discourage smokers
from switching by: [1]—banning all vapor sales, [2]—
banning flavored vapor sales, [3]—banning ENDS in
workplaces, [4]—taxing vapor products, and [5]—increasing
the legal age for ENDS sales to 21. Indeed, the ACS (plus
other health groups) continues litigating for reimposition of
the FDA’s Deeming Rule’s sales ban of all ENDS products in
America retroactive to August 8, 2018.
Such Statements fuel the FDA’s attack on ENDS28—publicized
in the print29 media (notably uncritical) and broadcast30
media (suggesting a political motive for a sudden
crackdown)— prompting one ENDS company, Juul31, to
improved cessation or with reduced consumption, even among
heavier smokers” and the second33 found that “ENDS use was
not associated with successful smoking cessation among Youth
Quitline smokers.” In neither instance, however, did the
methodology include initial education regarding ENDS-use; in
both instances, ENDS didn’t cause harm (as asserted in the
aforementioned ACS text).
Thus, it is necessary to vet the third34 citation (Kalkhoran &
Glantz), which found, “As currently being used, ENDS are
associated with significantly less quitting among smokers.”
It—and its appendix35—must therefore constitute the sole
ACS’s reference requiring thorough scrutiny for, if definitively
refuted, the gravamen upon which the ACS’s posture has
been built must necessarily be reconsidered. {The Lancet
advises use of guidelines36 in meta-analyses; this article,
Portrayal of Fourteen Studies Improperly
Viewed as Unsupportive of ENDS

Adkison et al.63 inter alia surveyed 5939

current and former smokers in four countries
at two different study waves one year apart
(2008-2009 and 2010-2011) who were not
educated regarding ENDS, generating data
that are almost a decade remote; cessation
was verified biochemically. Baseline smokers
o High risk: loss to follow-up >25%, differential loss to follow-up
o Low risk: participants randomized to ENDS-use
o High risk: participants self-selecting to use ENDS

 Performance bias
o Low risk: blinding during phases of study where possible
o High risk: participants and personnel unblinded to intervention

 Detection bias
o Low risk: use of objective measures to assess smoking cessation (e.g., biochemical
verification)
o High risk: use of self-report only to assess smoking cessation

 Attrition bias
o Low risk: low loss to follow-up
o High risk: high loss to follow-up or differential loss to follow-up

 Reporting bias
o Low risk: no evidence of under-reporting of results
o High risk: evidence of selective reporting of results
1.Sklaroff R, Gambescia S. Health groups slay
vaping with faint praise [Internet]. American
Thinker 10 September 2018. [cited 20 September
2018]. Available from:
https://www.americanthinker.com/blog/2018/09/hea
lth_groups_slay_vaping_via_faint_praise.html

1.Glantz S. Two more well-done studies show e-cig

use associated with significantly less quitting
smoking [Internet]. UCSF Center for Tobacco
Control Research and Education 11 March 2015.