________________________________________ Pre-Medical Honors Program 2018

Wednesday, November 14, 2018 - Session # 7

Agenda:

4:00 PM – 5:15 PM

Pathology 101 Presentation: Jacob Jay Lindenthal, Ph.D., Dr.PH.

Bleeding Control Workshop

5:30 PM – 6:45 PM

Medical Student Seminar Discussion Groups: Careers in Medicine

Formal Lectures

7:00 PM – 8:00 PM

Medical Imaging Screening for Breast Cancer In The Average Risk and High

Risk Patient

by

Basil Hubbi, M.D.

Assistant Professor

Department of Radiology

8:00 PM – 9:00 PM

Sunlight, Vitamin D, and Cancer

by

George Studzinski, M.D., Ph.D.

Professor Emeritus

Department of Pathology and Laboratory Medicine

Rutgers-New Jersey Medical School

ANNOUNCEMENTS

1. There will be a Cardio-Pulmonary Pathophysiology class scheduled for

Sunday, November 18th from 8:30 am til 12 Noon in room B 552. This

class is free of charge. Sign-up sheets will be posted on google docs. Class

attendance fulfills the weekend requirement for obtaining HONORS at

graduation.

2. The next Basic Life Support Session is scheduled for Sunday, November

18th from 1 pm til 5 pm. Those who register online for this class and

successfully complete it will receive a certification card through the

American Heart Association. Certification will last for two years. In

order to participate in this class, students must matriculate through prior

online registration. The cost of the Basic Life Support course remains at

$ 50.00 by typing in the Promo code: “Minimed”. Students may register

for either class, using the individual link specific for the BLS session:

November 18, 2018: https://uhnj.enrollware.com/enroll?id=2494637

Students must pay ONLY through either credit or debit card online. NO

CASH PAYMENT IS ALLOWED. No walk-in students will be accepted

without prior registration and confirmation. Students who registered

online, should follow the directions sent by the Community Training

Center to attend this class. For further information or for on-line

registration difficulties, call Mr. Dennis Boos or Mr. John Cruz at the

Community Training Center: 973.972.4373; 8 am til 4 pm.

3. Any student who still owes tuition money for our program must submit

payment by check or money order as soon as possible. Failure to do so

may result in not receiving a graduation certificate at the end of the

program. If you have any questions regarding this matter or any other

matter, please direct questions or concerns to Mr. Michael Grabow,

Program Administrator at grabowmi@njms.rutgers.edu or by phone:

973.972.1269.

4. Instructions for taking the Pre-Medical Honors Program Honors Exam:

The Honors Exam consists of 25 questions that test your knowledge of

content covered in the preceptor-led homeroom sessions. It does not

include content from lectures administered by NJMS faculty. You will

have 50 minutes to complete the exam. Please only take the exam once; if

you take the exam multiple times, only your first attempt will be counted.

In addition, there is no cutoff grade for HONORS at this time. After all

students have completed the exam, the top 33rd percentile of students will

receive HONORS.

The exam will be due on Wednesday, November 21st at 11:59pm. No

exceptions to this deadline will be made. We encourage you to complete

this exam as soon as possible as technical difficulties will not be accepted

as an excuse to extend the deadline for the quiz. In an event that you do

experience any kind of technical difficulties or any other kind of problems,

please email us at minimedschool@gmail.com so that we may address

your concerns immediately.

The link to access the exam will be emailed out on Wednesday, November

14th at 9:00 pm. If you do not receive an email by Thursday, feel free to

email us minimedschool@gmail.com so that we can send you the link.

Good Luck on the exam !

5. Please note that there will be NO PROGRAM SESSION on Wednesday,

November 21st, Thanksgiving Eve.

6. Please note that on the last session, Wednesday, November 28th, the

program involves a full evening session starting at 5:30 PM followed by a

graduation ceremony at 8:00 PM. The graduation ceremony should

conclude at approximately 9:00 PM. Although attire for the evening is

totally discretionary, we would suggest that consideration be made for

more formal casual wear given that graduation night has always been

considered a special event. Please invite your family and friends to attend

our graduation ceremony.

We wish Everyone a Happy, Healthful, And Safe

Thanksgiving Holiday Weekend !

CAREERS IN MEDICINEMoving forward as you graduate from Mini-Med!

Mini-Med Fall 2018

DISCLAIMER

●It’s absolutely okay if you don’t know what you want to do right now.

●This conversation is about looking forward and helping you think about what may be interesting to you!

What career are you currently considering?

Go around the room and give an example of what you imagine you want your career to be.

CAREERS IN MEDICINE

● Healthcare is among the fastest growing fields.

● Of the 20 fastest growing jobs, 10 are in the field of medicine.

● There are so many reasons why medicine is growing so fast. Some are

below:

○ Aging Population

○ Advances in Medical Technology

○ Shift from in-patient to out-patient care

● What are some other reasons medicine is growing so fast?

Jobs Growth %

Veterinary

Technician/Technologist

41%

Physician Assistant 39%

Athletic Trainer 37%

Medical Assistant 34%

Veterinarian 33%

Pharmacy Technician 32%

Dental Hygienist 30%

Physical Therapist 27%

Radiation Therapist 25%

Surgical Technician 24%

Registered Nurse 22.2%

Pharmacist 22%

Physicians 14%

FASTEST GROWING MEDICAL CAREERS

Common Misconceptions

#1: Only science majors get into medical school.

● As long as you take the required science sequence, you can major in any subject you

want.

○ A non-traditional major could help you stand out while applying to medical school.

○ Studying the humanities or social sciences can really improve your writing and

communication skills, and it might even improve your MCAT score!

● YOU CAN BE ANY MAJOR AS LONG AS YOU INCLUDE:

○ 1 year of biology with laboratory, 1 year of general chemistry with laboratory, 1

year of organic chemistry with laboratory, 1 year of physics with laboratory, 1

semester of biochemistry, 1 semester of upper division biology (required by some

med schools), 1 year of college-level math (usually a calculus and statistics course)

○ *If you AP out, most schools still like you do a similar course or a higher level

course in that subject in college.

#2: I’m not smart enough for medical school.

● Grades are important but they are not the only thing a school is looking for!

● Make sure you are a well-rounded student: ○ Pursue your interests through hobbies and extracurricular activities. ○ Find volunteer work that is meaningful to you. ○ If research is something you are interested in, look into different

research opportunities.● Don't hesitate to take a gap year to do something that is important to you

and grow as a person.● If you want to give your academics a boost before coming to medical

school, look into a science intensive post-bac or masters program.

#3: There’s only one way to medical school.

●Everyone has their own path to medical school, whether it take 4 years or 15 years!

●The average age of an incoming medical student is 25, which means most will end up taking time between college and medical school.

●Students end up working in other careers, taking research years, or getting additional masters degree before medical school.

○ Some reasons for this include: making money to go to medical school (☹), finding passion later in life, or making their application more competitive!

Suggestions Moving Forward

Think & Be Independently

●Medicine is a very long career, filled with twists and turns. May times the only thing keeping us above water is the fact that we all selected this career for ourselves and there’s no where else we’d rather be!

●Being independent is often really hard, not just for you but also for the people who love you!

●Start small: get your own email address, start calling for yourself, work on learning how to cook/do your own laundry, read the news, begin crafting your own opinions!

You can’t do this by yourself! Seek guidance.●Looking for mentors and guidance is a major key to success!

●You should focus on two different types of guidance

○ PERSONAL MENTORS

■ These are people you admire - use their experiences to shape your own!

■ Examples include: your preceptors, a favorite teacher, a doctors/healthcare

professional you admire, fellow students

○ CAREER DEVELOPMENT GUIDES

■ These are people who will help you navigate your way to your ideal career.

■ Examples include: your guidance counselor, your pre-health advisor in college,

Deans, teaching faculty

● Mentorship is not just handed to you! You often need to seek them out whether it’s

in person, via email, or online!

Keep your eyes and hearts open.

●EYES OPEN:○ Keep your eyes open, and seek experiences which will help you examine and

understand the field of medicine. ○ Opportunities like shadowing will let you see if you’re interested in the day to day

of medicine. ○ Reach will allow you to explore what is yet unknown!○ Seek experiences which challenge you and allow you to discover what you love.

●HEART OPEN:○ You’ll know when you feel like you’re not going down the right path.○ If you realize you don’t really don’t love something, then you probably

shouldn’t be doing it.

Learn how to market yourself!●Starting with applying to college, people are going to ask you about yourself!

○ Spend some time thinking about you!

○ What experiences made you who you are?

○ Write these things down! (trust me when it comes time to writing those essays…they always escape me)

●Document what you’ve done!○ Whether it’s a list on your computer, a resume, or a CV, document what you’ve done

and for how long.

○ For example, Mini-Med should be on that list!

○ How would you write Mini-Med on a resume?

●To succeed you have to be able to market yourself to employers/colleges/medical schools/peers leadership on you as a person. Some of that is through essays, others is in person!

Elevator Pitches

Elevator Pitch

The elevator pitch: the hypothetical situation where you find yourself in an elevator with someone that you want to work with, and you have only the time it takes to travel a few floors to introduce yourself, your value, and a proposition. If ever you have a short amount of time to present yourself to someone, here are some things to keep in mind.

• Make it flexible, but know those key elements listed on the next slide intimately.• Use the pitch as a conversation starter, not a monologue.• Be concise. Less is more!• Parties, concerts, exhibitions, family functions, etc. All are great practice arenas

of the “pitch.”

Let’s practice! With a partner, you have 2 minutes to “pitch” yourself! We will be asking a few volunteers to do it in front of the class.

And close with What do you want from this encounter!

QuestionsPlease use this time to ask your preceptors about their path to medicine!

Some Questions

● What got you interested in medicine?

● What is the biggest misconception people have about

medicine/medical school?

● What is the biggest risks you took? Do you regret any of them?

● What is the best piece of advice your received on your path?

● What activities were you involved with in college/high school?

● If you could do it all over what would you change? Would you go

into medicine again?

THANK YOU!

Basil Hubbi, M.D.

Dr. Basil Hubbi has served as Assistant Professor of Radiology and Director of Breast

Imaging at Rutgers New Jersey Medical School since 2009. He graduated Summa

Cum Laude from Rutgers School of Engineering in 1999 and graduated from Rutgers

New Jersey Medical School in 2003. He went on to complete a one year Internship

in General Surgery at Lenox Hill Hospital in New York, NY and a 4 year residency in

Diagnostic Radiology at Rutgers New Jersey Medical School in Newark, NJ followed

by a one year fellowship in Breast and Body Imaging at Rutgers New Jersey Medical

School. His clinical activities mainly focus on all modalities of breast imaging

including mammography, breast ultrasound, and breast MRI as well as breast

interventional procedures including image guided biopsies and pre-operative

localizations. He is a member of the radiology residency faculty and gives local and

regional lectures regularly. Dr. Hubbi has earned numerous teaching awards

including the New Jersey Medical School Golden Apple for Excellence in Teaching

and the Radiology Residency Program Best Teacher of Residents award. He was

also appointed as the Radiology Residency Program Director. His research interests

include radiologic-pathologic correlation of breast carcinoma, improving public

education of breast cancer, improving patient compliance with breast imaging, and

radiology graduate medical education and policy. E-mail:

hubbiba@njms.rutgers.edu

Medical Imaging Screening for Breast Cancer in the Average Risk and High Risk Patient

B. Hubbi, M.D.Assistant Professor of Radiology

Rutgers UniversityNew Jersey Medical School

Newark, NJ

Background• Breast Cancer is the most common cancer in women

worldwide

• Second leading cause of cancer deaths in women in the US after lung cancer

• An estimated 231 840 women in the US will be diagnosed with breast cancer in 2016

• An estimated 40 290 women in the United States will die of breast cancer in 2016

• Mortality from breast cancer has declined steadily since 1990, largely due to improvements in early detection and treatment

Oeffinger, et al. Breast Cancer Screening for Women at Average Risk 2015 Guideline Update from the American Cancer

Society. Journal of the American Medical Association. 2015;314(15):1599-1614.

Screening• Test used in a population to identify an

unrecognized disease in individuals without signs or symptoms

• Performed on people in apparently good health

• Designed to identify disease in a community early to enable earlier intervention and management in the hope to reduce mortality and suffering from a disease

Traditional Forms of Breast Cancer Screening

• Mammography

– Screening

– Diagnostic

• Clinical Breast Examination

– Physician performed

– Self performed

Mammogram

• X-ray exam of the breast used to detect and evaluate the breast and underlying changes

Screening Mammogram

• X-ray of the breast in a woman who has no symptoms

• Goal: To find cancer when it is too small to be felt by a woman or her doctor

• Two pictures of each breast

Diagnostic Mammogram

• X-ray exam of the breast in women reporting breast lumps or other symptoms. Essentially answering a specific problem

– Different from screening mammography in that additional views of the breast are usually taken

– Diagnostic mammography is usually more time-consuming and costly than screening mammography

– Patient remains in department until work-up completed

– Radiologist generally discusses findings with patient

How is it done?

• Breast is compressed between an X-ray plate and a plastic plate. Compression is needed to spread the tissue apart. This ensures little movement and a sharper image. Entire procedure takes approximately 20 minutes.

Digital Mammography

Displayed and Compared to

Priors

BI-RADS

• Breast Imaging Reporting and Data System

• 7 different categories

– 0- Need additional imaging.

– 1,2- Benign. No evidence of cancer. Return in 1 year

– 3- Probably Benign. 98% or more are NOT CANCER. Return in 6 months.

BI-RADS

• 4- Biopsy required. Low to Moderate suspicion for cancer.

• 5- Biopsy required. High suspicion for cancer. At least 95% chance.

• 6- Biopsy proven cancer.

False Positives vs True Positives

• False positive: A positive test result that does NOT correlate with TRUE disease

• True positive: A positive test result that does correlate with TRUE disease

• False negative: A negative test result when the disease IS present

• True negative: A negative test result when the disease IS NOT present

False Positives vs True Positives

• False positive: A positive test result that does NOT correlate with TRUE disease

• True positive: A positive test result that does correlate with TRUE disease

• False negative: A negative test result when the disease IS present

• True negative: A negative test result when the disease IS NOT present

Sensitivity and Specificity

• Sensitivity of a test is defined as the proportion of people who have the disease who test positive for it

• Specificity of a test is defined as the proportion of patients who do not have the disease who will test negative for it

What is the Sensitivity and Specificity of Mammography in the General Population?

• Data from the Breast Cancer Surveillance Consortium shows the Sensitivity and Specificity to be:

Age Sensitivity Specificity

40-44 73.6% 88.2%

45-49 80.3% 89.2%

50-54 82.4% 90.5%

55-59 84.6% 91.5%

60-64 84.9% 91.9%

65-69 84.6% 92.3%

70-74 84.7% 92.9%

75-89 86.6% 93.4%

TOTAL 83.5% 90.9%

Is Mammography Perfect?

• False negative rate of up to 27% in women in their early 40’s

• False negative rate of 17% when screening women across all age groups

So what is mammography good for?

• Mammography is the only screening examination for breast cancer that has been shown to decrease mortality– Evidence from Randomized Control Trials (RCT’s)

conducted in Europe and North America that involved nearly 500,000 women showed statistically significant decrease in mortality

– Statistical analysis of all the RCT’s demonstrated 26% reduction in mortality*

* Kerlikowske, K., Grady, D., Rubin, S.M. et al. Efficacy of screening mammography (A metaanalysis) . JAMA. 1995;273: 149–154

The problem with breast density

• Described as the ratio of fibroglandular tissue (white stuff) to fat (dark stuff)

• Four categories: – Extremely Dense : More than 75% FGT

– Heterogenously Dense: Between 50%-75% FGT

– Scattered Fibroglandular Tissue: Between 25%-50% FGT

– Predominantly Fatty: Less than 25% FGT

Breast “Density”

• Described as the ratio of fibroglandular tissue (white stuff) to fat (dark stuff)

• Four categories: – Extremely Dense : More than 75% FGT

– Heterogenously Dense: Between 50%-75% FGT

– Scattered Fibroglandular Tissue: Between 25%-50% FGT

– Predominantly Fatty: Less than 25% FGT

Dense

Breasts

Limitations of Mammography

• For women with fatty breasts, the sensitivity of mammography is 87% as compared to 63% for women with extremely dense breasts*

• False negative rate of 37% in women with extremely dense breasts*

*Carney PA, Miglioretti DL, Yankaskas BC, Kerlikowske K, Rosenberg R, Rutter CM, et al. Individual and Combined Effects of Age, Breast Density, and Hormone Replacement Therapy Use on the Accuracy of Screening Mammography. Ann Intern Med. 2003;138:168-175.

So how do we improve on mammography for those women deemed High Risk?

What is a high risk patient?

Patients with increased lifetime risk of the development of breast cancer as compared to the general population

What is a high risk patient?

American Cancer Society* Describes High Risk Groups as:

– BRCA Mutation

– First degree relative (mother, sister, daughter) of a BRCA carrier

– Lifetime risk of 20% or greater based on disease models

*Saslow et al. American Cancer Society Guidelines for Breast Screening with MRI as an Adjunct to Mammography. CA Cancer J Clin. 2007;57:75-89

Model Characteristics Races Evaluated Recommended by ACS

GailRace

Age at menarche

Age at first live birth

Number of previous breast

Biopsies

Number of first-degree relatives with

breast cancer

Does not include paternal family

history

White

African American

NO

ClausNumber of relatives with breast cancer

Ages at diagnosis of these relatives

Maternal and paternal family history

White NO

BRCAPROPersonal history of breast cancer

or a history of breast or ovarian

cancer among her first-degree and

second-degree relatives

White with some data for

African American

YES

BODICEAEstimates the likelihood of carrying

BRCA1 or BRCA2 mutation as well as

the risk for developing breast or

ovarian cancer

White YES

Tyrer-Cuzick

Age at first period

Age at first live birth

Family history of breast cancer in first-

degree relative

Number of breast biopsies

showing atypical hyperplasia

Race/ethnicity

White and other races

YES

Breast MRI

• MRI uses a powerful magnetic field, radio frequency pulses and a computer to produce detailed pictures of organs, soft tissues, bone and virtually all other internal body structures

• MRI does not use ionizing radiation

Breast Coil

• Patient placed in prone position, minimizing effect of respiratory motion

• Unilateral or Bilateral breast coil

• Most coils are open at the side to allow lateral access for intervention

Imaging Protocols

• T2W Fast Spin Echo with or without fat suppression

• T1W with fat suppression without and with Gadolinium. Subtraction of noncontrast from contrast images.

• Sagittal or Axial plane

Contrast Material

• Gadolinium injected at usual dose of 0.1 mmol/Kg as a bolus

• Subsequent T1W contrast enhanced images obtained continuously over 5 minutes approximately 6-8 minutes after initial contrast bolus

Increased density of microvessels and increased permeability results

in preferential uptake of Gadolinium by breast cancers relative to

normal breast parenchyma

Breast MRI Performance in the Diagnosis of Breast Cancer Across All Women

Study Sensitivity Specificity

Warner (2004) 77% 95%

Kuhl (2005) 91% 97%

Kriege (2004) 80% 90%

Leach (2005) 77% 81%

Sardanelli (2011) 91% 97%

Weinstein (2009) 71% 79%

Le-Petross et al. Magnetic Resonance Imaging and Breast Ultrasanography as an

adjunct to Mammographic Screening in High Risk Patients. Seminars in Ultrasound

CT and MRI. 2011;32:266-272

Breast MRI Performance in the Diagnosis of Breast Cancer Across All Women

MRI Sensitivity ranges from 77-91% and

Specificity ranges from 79-95%

Mammography Sensitivity Ranges from 73-

84% and Specificity ranges from 88-90%

Breast MRI Performance in the Diagnosis of Breast Cancer Across HIGH RISK Women

Saslow et al. American Cancer Society Guidelines for Breast Screening with MRI as an

Adjunct to Mammography. CA Cancer J Clin. 2007;57:75-89

Study Sensitivity Specificity

The Netherlands 80% (33%) 90% (95%)

Canada 77% (36%) 95% (99%)

UK 77% (40%) 81% (93%)

Germany 97% (33%) 95% (97%)

USA 100% (25%) 95% (98%)

Italy 100% (16%) 99% (0%)

Breast MRI Performance in the Diagnosis of Breast Cancer Across HIGH RISK Women

Saslow et al. American Cancer Society Guidelines for Breast Screening with MRI as an

Adjunct to Mammography. CA Cancer J Clin. 2007;57:75-89

MRI Sensitivity ranges from 71-100% and

Specificity ranges from 81-99%

Mammography Sensitivity Ranges from 16-

40% and Specificity ranges from 93-99%

*Saslow et al. American Cancer Society Guidelines for Breast Screening with

MRI as an Adjunct to Mammography. CA Cancer J Clin. 2007;57:75-89

Insufficient Evidence to Recommend MRI

• Lifetime risk of 15-20%

• Lobular Neoplasia consisting of Lobular Carcinoma in Situ (LCIS) or Atypical Lobular Hyperplasia (ADH)

• Heterogeneously or Extremely dense breast on Mammography

• Women with a personal history of breast cancer

What about Breast Ultrasound?• Ultrasound imaging

• Involves the use of a small transducer (probe) and ultrasound gel placed directly on the skin

• High-frequency sound waves are transmitted from the probe through the gel into the body

• The transducer collects the sounds that bounce back and a computer then uses those sound waves to create an image

Breast Ultrasound

• Indicated for women and girls <30 years old presenting with a breast complaint (lump, nipple discharge, focal noncyclical pain)

• Used to assess findings which persist after additional mammographic imaging or as an adjunct to mammographic evaluation of a breast abnormality in women > 30 years

• Guidance for breast intervention

Breast Ultrasound

What about using Ultrasound for Screening?

•Assessed the effects of adding annual screening breast ultrasound performed by expert trained physicians to annual screening mammography

•High Risk patients

•Adding a single screening US to

Mammography will yield an additional 4.3

cancers per 1000 high-risk women, but

will also substantially increase the number

of false positives (PPV for M= 22.6%;

PPV for M+US = 11.2%). TWICE THE

NUMBER OF BIOPSIES

• Only 7.4 % of lesions recommended

for biopsy based on ultrasound were

found to be cancer

•Compared with 38% of lesions

recommended for biopsy based on

mammography

Ultrasound as Screening Tool

• Advantages:– Can find more cancers in high risk women at a

smaller size than mammography

– No radiation concern

• Disadvantages:– High sensitivity and low specificity substantially

increasing biopsy rate

– Operator dependent with wide variability

– Long exam

Breast Ultrasound

No major professional society in the US or elsewhere recommend the use of screening ultrasound for breast cancer

Summary

• Mammography remains standard of care for screening for breast cancer

• Screening mammography has been shown to decrease mortality from breast cancer

• MRI is superior to both mammography and ultrasound in identifying breast cancers but limited by decreased specificity

• Use of MRI in women with low-to-moderate risk is not recommended

• Ultrasound is limited by time, operator dependency, and high false positive rate

Oeffinger, et al. Breast Cancer Screening for Women at Average Risk

2015 Guideline Update from the American Cancer Society. Journal of the

American Medical Association. 2015;314(15):1599-1614.

Updated ACS Guidelines

• Women with an average risk of breast cancer should undergo regular screening mammography starting at age 45 years – Strong Recommendation

• Women aged 45 to 54 years should be screened annually• Women 55 years and older should transition to biennial

screening or have the opportunity to continue screening annually

• Women should have the opportunity to begin annual screening between the ages of 40 and 44 years

• Women should continue screening mammography as long as their overall health is good and they have a life expectancy of 10 years or longer

Updated ACS Guidelines

Thank You

NOTES 

George Studzinski, M.D., Ph.D.

Dr. George Studzinski is Professor Emeritus in the Department of Pathology and Laboratory Medicine. He completed his undergraduate studies and majored in Biochemistry at the University of Glasgow, Scotland. He subsequently also completed his undergraduate medical education at the same institution as well as earning his doctoral degree in Experimental Pathology and where he also completed his residency in Pathology and Laboratory Medicine. He has authored numerous articles and reviews in the field of cancer and aging especially researching the effects of Vitamin D on cancerous cells. Dr. Studzinski also has extensively taught classes in General Pathology to graduate, medical, and dental students over a few decades and has received many honors; has served on numerous committees at Rutgers-New Jersey Medical School; at the National Institutes of Health (NIH), and at other research societies. E-mail: studzins@njms.rutgers.edu.

George P Studzinski, MD, PhD

Professor Emeritus, Pathology and Laboratory Medicine

Rutgers-New Jersey Medical School,

Newark, NJ , USA

" Sunlight, Vitamin D and Cancer."

OH

OHHO

Vitamin D3 1, 25-dihydroxyvitamin D3

( Active Form )

HO

7-dehydrocholesterol

( Precursor )

HO

In 1822, Sniadecki recognized the importance

of sun exposure for the prevention and cure of

rickets. Like in other European cities, children

in Warsaw, Poland, developed a severe bone-

deforming disease now known as rickets.

[Mozolowski W. Jedrzej Sniadecki (1768–1838)

on the cure of rickets. Nature.1939;143:121–

124.]

In nineteen thirties my father, a graduate of

the Warsaw Medical University, used a UV

lamp to provide me with vitamin D at an early

age.

An estimate of premature cancer mortality in the United

States due to inadequate doses of solar ultraviolet-B

radiation.

Grant WB Cancer 94, 1867-1875, 2002

Mortality rates in white Americans were twice as high in New

England as they were in the southern states for cancers of -

Bladder, breast, colon, corpus uteri, esophagus,

ovary, rectum and stomach.

Grant WB:

Detailed analyses of cancer rates in the various regions of

US showed that these were inversely proportional to the

amount of UV-B to which the population was exposed,

even when corrected for other known factors.

It is estimated that 85,000 fewer cases and 30,000 fewer

deaths (out of projected 1,285,000/555,000) would occur if

the entire U.S. population received UV-B exposure

equivalent to that in the southern part of the country. By

way of comparison, additional deaths from melanoma and

other skin cancer would be 3,000.

The Promise of Vitamin D as a Cancer

Therapeutic:

Sunlight generates vitamin D and seems to lower

cancer incidence.

Human (and mouse) cancer cells can be

“normalized” by active vitamin D (1,25D).

Lots of anecdotes how vitamin D improves health

and longevity.

Main Functions of 1,25 D3

Classical function: elevates serum calcium

level and bone mineralization by increasing

intestinal absorption and renal reabsorption of

calcium and phosphorus

Effect on differentiation and proliferation:

Inhibition of proliferation in many malignant cells, including colon, breast, and prostate cancer cells.

Induction of differentiation in some cancercells, such as leukemia cells.

HL60 (an acute promyeloblastic

leukemia cell line)

Macrophage-like cell

(Adherent)

1,25D3

1,25 D3

Monocytoid cell

(Nonadherent)

CD11b

CD14 CD14

CD11bCD14

CD11b

CD14CD14

CD11b

1,25 D3 Induced Differentiation of HL60 cells

Differentiation markers:

CD14

CD11b

MSE

1,25D

VDR

A. Proliferation

p21, hOP, 24OH,etc

C/EBP

CD14 MSE

?

GF/Cytokines

Raf-1

PP

Grb

MEK1/2

ERK1/2

KSR-1

p90RSK

C/EBP

P

Ras Sos

+

C. Late Differentiation

Raf-1

PP

Grb

MEK1/2

ERK1/2

Ras Sos

p90RSKc-myc,

Ets

GF/Cytokines

Differentiation

Targets

Proliferation

Targets

p90RSK

?

Differentiation

Other

targets

?

B. Early Differentiation

Raf-1

PP

Grb

MEK1/2

ERK1/2

Ras Sos

KSR-1

p90RSK

CD14

GF/Cytokines

Induction of differentiation in some cancercells, such as leukemia cells.

However,

1. The concentrations required to achieve

differentiation and/or cell cycle arrest far exceed the

levels of circulating 1,25D.

2. High concentrations of 1,25D are incompatible with

life, due mainly to arterial and multiple organ

calcifications.

16Calcification in heart

17Calcification in lung

18Adrenal glands showing caseous necrosis and calcification

Clinical trials of Calcitriol (I,25D)

or analogs generally failed to

show anticancer activity.

Table . Selected completed/terminated clinical trials with calcitriol during the years 2009-2015.

STUDY

NUMBER

TYPE OF

CANCER

COMPOUNDS PHASE COMMENTS/

COMPLETION YEAR

NCT00794547Non-small-cell lung

carcinoma Calcitriol, cisplatin, docetaxel I/II

Pharmacokinetics studies; results

published

/ 2013 (Ramnath N at all 2013)

NCT00524589Androgen independent

prostate cancer Calcitriol, dexamethasone II

Interventional studies;

closed due to absence of results / 2014

NCT01093092Inoperable advanced solid

tumors

Calcitriol, cisplatin,

gemcitabine hydrochloride I

Pharmacological studies;

terminated due to absence of results /

2015

NCT01293682 Breast cancer Calcitriol IIEfficacy and feasibility studies;

closed due to absence of results / 2015

But, “Absence of proof is not

proof of absence.”

Vitamin D supplementation

Improved clinical outcomes associated with vitamin D

supplementation during adjuvant chemotherapy in patients with

HER2+ non-metastatic breast cancer. Zeichner SB, Koru-Sengul 2, Shah

N, Liu Q, Markward NJ, Montero AJ, Glück S, Silva O, Ahn ER. Clin Breast

Cancer; 2015;15:e1-11.

A retrospective review of all patients (n = 308) given trastuzumab-based

chemotherapy between 2006 and 2012 at the University of Miami.

CONCLUSION: Vit D supplementation in patients with nonmetastatic

HER2(+) breast cancer is associated with improved DFS.

Serum vitamin D levels and cancer

Low Serum Vitamin D Levels Are Associated With Inferior Survival in

Follicular Lymphoma: A Prospective Evaluation in SWOG and LYSA Studies.

Kelly JL, et al. J Clin Oncol. 2015; 33:1482-90.

[< 20 ng/mL]

•Serum 25-Hydroxyvitamin D Concentrations ≥40 ng/ml Are Associated with

>65% Lower Cancer Risk: Pooled Analysis of Randomized Trial and

Prospective Cohort Study. Sharon L. McDonnell , et al. Published: April 6 2016

http://dx.doi.org/10.1371/journal.pone.0152441

•Conclusion based on data obtained from studies of multiple invasive cancers in

women aged 55 years and older.

Association of Vitamin D Levels with Outcome in Patients With Melanoma

after Adjustment for C-Reactive Protein. Shenying Fang, et al. J Clin Oncol.

March 21, 2016

Conclusion: Lower vitamin D levels in patients with melanoma were associated with

poorer outcomes. The median vitamin D level was 25.0 ng/mL( measured as 25-D).

So- How can the barriers be overcome?

1. Restoration of adequate funding for vitamin D

and cancer studies.

2. Better understanding of the mechanisms that

underlie anti-cancer effects of 1,25D.

3. Additional evidence from correlations of the

levels of circulating vitamin D ( usually 25-D)

with cancer incidence, progression, and the

response to conventional therapy.

4. Search for factors that confound the above

studies.

5. Standardization of procedures and patient

stratification in Clinical Trials.

6. Importantly, mechanism-based scheduling,

dosage, and combination with non-toxic

agents which enhance the effect of vitamin D

compounds.

So - How can the barriers be overcome?

6. Importantly , mechanism-based scheduling,

dosage, and combination with non -toxic

agents which enhance the effect of vitamin D

compounds.

Carnosic Acid promotes monocytic

differentiation initated by 1,25-dihydroxy

vitamin D3

Danilenko M, Wang X, and Studzinski, G.P.

J. Natl Cancer Institute 93:1224-23, 2001.

• Carnosic acid is an anti-oxidant derived from the plant Rosemary

• Has little pro-differentiation activity, but markedly increases differentiation induced by 1,25D3

• Increases expression of the receptor for 1,25D3

Synergistic antileukemic activity of carnosic acid-rich rosemary extract and the 19-nor Gemini

vitamin D analogue in a mouse model of systemic acute myeloid leukemia. Shabtay A, Sharabani H,

Barvish Z, Kafka M, Amichay D, Levy J, Sharoni Y, Uskokovic MR, Studzinski GP, Danilenko M. Oncology.

2008;75: 203-14.

Doxercalciferol

(1-D2)

• Vitamin D2 derivative hydroxylated in C1 alfa position.

• Since it lacks the hydroxyl group on C25, needs to beactivated in the body- mostly by the liver.

• Approved by FDA for human use- mostly for chronickidney diseases.

• Has been found safe in myelodysplastic syndromes- apreleukemia condition.

31

PJ Cook et al. Nature, 1-6 (2009) doi:10.1038/nature07849

H2AX Y142 phosphorylation discriminates

between apoptotic and repair responses to DNA damage.

Autophagy

Protective Cells downsize

Cytotoxic Results in necrosis-like cell death

Several regulators (eg Beclin, BNIP3, etc)

Multiple markers (eg p62, LC3).

In malignant cells with DNA damage, 1-D2/Carnosic acid

combination induces activation of the caspase cascade and

autophagy by –

1,25D-> VDR-> -> TXNIP-> ASK1-> JNK-> Bim->Caspases-

>Beclin/BNIP3L

Cell Death

Differentiation

agents

1-D2/CAAraC

DNA

Damage

Cell death

Apoptosis

Autophagy

Necrosis

Cell death

VDR

BRAF

TXNIP

ASK1

JNK1

BIM

BNIP3L

Conventional therapy Enhancement of cell death (ECD)

Our studies show that the enhancement of AraC-induced cell

death is associated with increased DNA damage and higher

levels of DNA damage response (DDR) markers. An important

component of the enhanced cytotoxicity is apoptosis that results

from exposure of cells with DNA damaged by AraC to the

differentiation-promoting combination of 1-OH-D2 and CA.

• Thank you

• 谢谢 (Xie Xie)

• Dziekuje

• תודה (todá)

NOTES 

NOTES