1. No category

IMSMAGAZINE
THINK, LEARN, DISCOVER.
CANCER DONATIONS
Find out where your money goes
BIAS IN RANDOMIZED
CLINICAL TRIALS
Learn about evaluating bias in
RCTs from this year’s SURP
Writing Competition winner
PROSTATE
CANCER
IN A NUTSHELL
Screening protocols, preventative
measures, and therapies related to
the most common cancer in men
FALL
2011
TABLE OF CONTENTS
IN THIS
ISSUE...
Commentary ...................................03
Letter from the Editor .....................04
News at a Glance ...........................05
Director’s Message ........................08
IMS SURP Highlight ........................09
Feature ...........................................13
Spotlight .........................................25
Close Up .........................................27
SURP Research Focus ....................29
Philosophy of Science ....................31
Behind the Scenes .........................35
Future Directions .............................37
Funding ...........................................39
Ask the Experts ..............................40
Past Events .....................................41
Diversions .......................................42
13
FEATURE
Prostate Cancer
Learn the ins and outs of prostate cancer from our
very own experts in the field.
Philosophy of Science painting: The School of Athens (1510-1511) by Raphael, IMS SURP Highlight photo courtesy of the IMS Office
MAGAZINE STAFF
Editor-­in-­Chief Natalie Venier
Managing Editor Nina Bahl
Assistant Managing Editors Allison Rosen
Meghna Rajaprakash
Adam Santoro
Departmental Advisor Kamila Lear
Content Committee S. Amanda Ali
Tetyana Pekar
Aaron Kucyi
Rickvinder Besla
Wenjun Xu
Zeynep Yilmaz
Design Editors Tobi Lam
Andreea Margineanu
Merry Wang
Minyan Wang
Photography Paulina Rzeczkowska
Connie Sun
Mohammed Sabri
Yekta Dowlati
Acknowledgements Diego Accorsi, Joyce Hui,
Beatrice Lau, Julie Man,
Avi Vandersluis, Atiqa Malik
Copyright © 2011 by Institute of Medical Science, University of Toronto. All
rights reserved. Reproduction without permission is prohibited.
09
IMS SURP Highlight
Check out the highlights from this year’s Summer Undergraduate Research Program (SURP)
and Summer Student Research Day.
31
Philosophy of Science
Read about how a lack of philosophical
knowledge of the scientific method may affect our research.
Cover Art
By Minyan Wang
The cover features two of prostate cancer’s
most recognizable symbols: the walnut
and blue ribbon. The prostate is classically
described as a walnut-shaped organ, while
the blue ribbon stands as a symbol of prostate
cancer support. We include both to encourage
awareness of the most common cancer in men.
IMS MAGAZINE FALL 2011 PROSTATE CANCER | 02
COMMENTARY
“Just a quick email to congratulate [your
team] on the IMS Magazine. Very interesting content and nice to get a flavour of
what else is happening at IMS.”
– Colin McCartney, Associate IMS Member
“Congratulations! The magazine looks brilliant.”
– Santhosh, IMS student
“[The magazine] looks great and the content is interesting and well put together…
Looking forward to future issues.”
– Wilfred Ip, IMS student
“The magazine looks fantastic and reads
extremely well with an excellent balance of
interesting articles about students, faculty,
staff and the life as an IMS student. ”
– Dr. Karen Davis, IMS Associate Director
What to look for next issue:
The Surgical Management of Obesity by
Dr. Teodor Grantcharov
Commentary
Dear Editor:
I read the most recent (Summer 2011) edition of the IMS Magazine with great interest
and enjoyed its focus on obesity/BMI. The
magazine only briefly mentioned that BMI
varies across ethnic groups. I would like to
elaborate more on these ethnic variations using empirical evidence from my IMS PhD
thesis findings.
Many agree that the definition of obesity
(BMI≥30) is inappropriate in non-white
populations and that lower cutoff values are
required for Asian populations, however no
previous study has been able to pinpoint exactly what the BMI cutoff values should be
for specific Asian ethnic groups. I therefore
conducted a multiethnic cohort study of approximately 60,000 non-diabetic adults aged
30 years or over living in Ontario. Subjects
were identified from Statistics Canada’s population health surveys and were followed for
up to 12.8 years for diabetes incidence using
record linkages to multiple health administrative databases.
The study found that for the equivalent incidence rate of diabetes at BMI 30 in the
White group, the BMI cutoff value was 24
in the South Asian group, 25 in the Chinese
group, and 26 in the Black group. Moreover,
the risk of diabetes was significantly higher
among the South Asian (hazard ratio (HR):
3.40, p<0.001), Black (HR: 1.99, p<0.001),
and Chinese (HR: 1.87, p=0.002) populations than among the White population. The
We really appreciate all of the encouraging
comments and messages we have received
since the release of the IMS Magazine’s inaugural issue. We encourage our readers
to send their feedback -- comments, questions, corrections, or letters to the editor -- to
[email protected]
median age at diagnosis was lowest among
people of South Asian descent (49 years), followed by the Chinese (55 years), Black (57
years), and White (58 years) groups. Please
refer to Chiu M et al. Diabetes Care (2011)
34:1741–1748 for more details.
The evidence of ethnic variations in the relationship between BMI and risk of diabetes
is striking. The visible minority population
is growing in Canada and these results suggest that there is an urgent need for designing
ethnically appropriate diabetes prevention
and screening strategies and for lowering
current targets for ideal body weight for nonwhite populations.
Sincerely,
Maria Chiu
PhD Candidate, IMS, University of Toronto
Doctoral Fellow, Institute for Clinical Evaluative Sciences (ICES)
CIHR Canada Graduate Scholar
Corrections: IMS Magazine Summer 2011
On Saturday, July 30, the IMS will be moving to its new location: Room 2374 in the Medical
Sciences Building, 1 King’s College Circle. Thesis defenses scheduled shortly before or after July
23 will proceed as usual. There may be some room changes. In which case, the IMS office will
advise. On Monday, July 25, it will be business as usual in our new premises. We look forward to
seeing you at our new location!
www.facebook.com/groups/imsmagazine/
Please note the room location.
@IMSMagazine
The IMS Magazine apologizes for any confusion this may have caused.
03 | IMS MAGAZINE FALL 2011 PROSTATE CANCER
Photo courtesy of Spekta, http://en.wikipedia.org/wiki/File/Various_scalpels.png
Tell us what you think
LETTER FROM THE EDITOR
I
Letter from
the Editor
am always fascinated to learn about new scientific research. Having the privilege to study at
the IMS has undoubtedly shown me the many ways in which science can be used to improve
patient care - one of my own inspirations for starting the IMS Magazine. In the past three
issues, we have explored a variety of research areas, from the genetics of childhood aggression,
to multiple sclerosis and binge eating disorders. I have found them all very intriguing topics and
rewarding to learn about.
In this issue of the IMS Magazine, I would like to turn your attention to the topic of my area
of research, prostate cancer. With the help of our very own world-class experts, Dr. Laurence
Klotz, Dr. Neil Fleshner, Dr. Masoom Haider, and Dr. Vasundara Venkateswaran, we hope to
provide you with a better understanding of prostate cancer prevention measures, management
options, and future research strategies. Further, we give you a look into the Active Surveillance
program, a management strategy initiated at Sunnybrook Hospital by Dr. Laurence Klotz, which
is increasingly used worldwide for low-risk prostate cancer patients.
In light of November, prostate cancer awareness month, I hope that this issue of the IMS Magazine
will not only enhance your understanding of the disease, but also emphasize the importance of
early detection. I encourage all those participating in the moustache-growing Movember charity
event to submit your photos to the IMS Magazine Movember Contest (see page 43 for more
information).
Natalie Venier
Editor-In-Chief
Natalie Venier is a third year PhD Candidate at the Institute of Medical Science.
She is currently studying prostate cancer
chemoprevention at Sunnybrook Health
Sciences Centre.
I am also proud to announce the success of the Summer Student Writing Competition, which
was met with great enthusiasm by this year’s SURP students. We received a number of excellent
submissions, including one by Roman Shapiro, the winner of the competition. I encourage you
to read through his interesting article on biases in Randomized Controlled Trials. We hope to
continue to publish some of the other excellent submissions in future issues of the IMS Magazine.
I would also like to take this opportunity to thank the IMS Community for their insightful
feedback in response to the last issue, which I encourage you to read about in our new
Commentary section.
In closing, I would like to thank Dr. Allan Kaplan and the IMS department for their on-going
support with the IMS Magazine. Additionally, I must acknowledge the phenomenal IMS
Magazine Team, whose contributions are invaluable to its production. I’m looking forward to
your feedback.
Photo by Paulina Rzeczkowska
Enjoy!
Natalie Venier
Editor-In-Chief, IMS Magazine
IMS MAGAZINE FALL 2011 PROSTATE CANCER | 04
NEWS AT A GLANCE
NEWS&VIEWS
OCTOBER
19
OGS scholarship
applications due to IMS
office; OGS application
goes offline
28
Banting PDF University
Support Letter ready for
applicants
TBA
Interdepartmental
Halloween party
at a glance...
NOVEMBER
7
7
CIHR CGSM, SSHRC CGSM
& SSHRC Doctoral/CGSD
scholarship applications due
to IMS Office
Frederick Banting and Charles
Best Canada Graduate
Scholarships (Masters Award)
due at IMS Office.
DECEMBER
1
5
TBA
Deadline for John C.
Polanyi Prize nominations
to IMS Office
Delta Kappa Gamma
World Fellowship Award
applications due at SGS
IMSSA Holiday party
IMS STAFF ANNOUNCEMENTS
We are delighted to announce that Professor Brenda Toner has been was appointed as the new Graduate Coordinator at the Institute of Medical Science. Dr. Brenda Toner is the Co-­Head for the Social Equity & Health Research unit in the Social, Prevention and Health Policy Research department. Dr. Toner is also a Professor and Head of the Women’s Mental Health Program, and Director of Fellowship Program in the Department of Psychiatry at the University of Toronto. Congratulations to Professor Toner on her new appointment! We regret to inform you that Dianne Fukunaga is leaving the Institute of Medical Science DQGWKH8QLYHUVLW\RI7RURQWR6KHLVPRYLQJWR$OEHUWDZLWKKHUêDQF©$QWKRQ\'LDQQHÍV
last day with the IMS was on Friday, September 30th.
'LDQQHêUVWMRLQHGWKH,06LQ-XQHDVRXU'HSDUWPHQWDO$VVLVWDQW6KHTXLFNO\PRYHG
up the ranks to assume the role of Student and Faculty Affairs Coordinator, where she provided exemplary service and demonstrated excellence and commitment to her work. Dianne has become an indispensable colleague and she will be greatly missed by everyone in the Department. We extend our best wishes to Dianne in her future endeavors. We will be posting a recruitment notice to hire a replacement. In the interim, Kaki Narh Blackwood has kindly offered to step into the position to cover some of the responsibilities. Please contact [email protected] or call 416-­946-­7143 for student and faculty related inquiries. We will be monitoring both email and voice mail message systems.
05 | IMS MAGAZINE FALL 2011 PROSTATE CANCER
Dr. Brenda Toner
IMS Graduate Coordinator
For more information on
IMSSA/IMSSA-related events, please visit:
http://imssa.sa.utoronto.ca
For information on IMS news and events, please see:
http://www.ims.utoronto.ca
Please send your comments and suggestions to:
[email protected]
Photo courtesy of IMS Office
We extend our sincere thanks and gratitude to Dr. Mary Seeman for all her guidance and contributions as Graduate Coordinator of the IMS.
NEWS AT A GLANCE
IMSSA ANNOUNCEMENTS
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students who submitted nominations and participated so eagerly in this year’s election. :HORRNIRUZDUGWRDQHQMR\DEOHDQGSURGXFWLYH\HDUDKHDG
AWARDS & SCHOLARSHIPS
CIHR Research Awards
Master’s Award: Frederick Banting and Charles Best Canada Graduate Scholarships The Canada Graduate Scholarships Master’s Awards administered by CIHR are intended to provide special recognition and support to students who are pursuing a Master’s GHJUHH LQ D KHDOWK UHODWHG êHOG LQ &DQDGD 7KHVH FDQGLGDWHV DUH H[SHFWHG WR KDYH DQ
exceptionally high potential for future research achievement and productivity.
$SSOLFDWLRQVDUHFRPSOHWHGWKURXJKWKH&,+5ZHEVLWHDQGVXEPLWWHGWRWKH,06RIêFH
Students may only apply to one council (CIHR, NSERC or SSHRC) in a given year. CIHR Doctoral Research Award
Doctoral Research Awards are intended to provide special recognition and support to VWXGHQWVZKRDUHSXUVXLQJD3K'GHJUHHLQDKHDOWKUHODWHGêHOGLQ&DQDGDRUDEURDG
These candidates are expected to have an exceptionally high potential for future research achievement and productivity.
Applications for the CIHR Doctoral Research Award are submitted directly to CIHR. The full program description, application form and instructions are now available on the CIHR website.
Ontario Graduate Scholarships (OGS)
The Ontario Graduate Scholarship program is designed to encourage excellence in graduate studies at the master and doctoral levels. An OGS is awarded for one academic year, which may consist of two or three consecutive terms. The current value of OGS is $5,000 per term. Students may receive a total of $10,000 for two consecutive terms or a total of $15,000, for three consecutive terms.
7KHDSSOLFDWLRQIRUPDQGSURJUDPGHWDLOVFDQEHIRXQGRQWKH2*6ZHEVLWH
SSHRC Doctoral Fellowships
Through its Doctoral Awards funding opportunity, SSHRC offers two types of funding for doctoral students, which applicants apply for by completing one application form:
1. SSHRC Doctoral Fellowships;; and
-RVHSK$UPDQG%RPEDUGLHU&DQDGD*UDGXDWH6FKRODUVKLSV&*6'RFWRUDO6FKRODU-­
ships.
The SSHRC Doctoral Fellowships and Joseph-­Armand Bombardier CGS Doc-­
toral Scholarships aim to develop research skills and assist in the training of highly TXDOLêHGSHUVRQQHOE\VXSSRUWLQJVWXGHQWVZKRGHPRQVWUDWHDKLJKVWDQGDUGRIVFKRO-­
arly achievement in undergraduate and graduate studies in the social sciences and hu-­
manities.
-RVHSK$UPDQG %RPEDUGLHU &*6 'RFWRUDO 6FKRODUVKLSV DUH YDOXHG DW SHU DQ-­
QXPIRUPRQWKV66+5&'RFWRUDO)HOORZVKLSVDUHYDOXHGDWSHUDQQXPIRU
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the number of months of full-­time study (or equivalent) the applicant will have com-­
pleted at the proposed start date of the award.
The full program description, application form and instructions are now available on the SSHRC website and in SSHRC’s new Resource Centre.
IMSSA Executive Council 2011-2012
The elections for the 2011-2012 IMSSA Executive
Council took place on October 3, 2011. IMSSA is proud
to announce the names of the newly elected council
members.
President:
Ilyse Darwish
Vice-­Presidents:
Melanie Guenette
Vanessa Zannella
Treasurer:
Nicholas Howell
Secretary:
Laura Park
Director of Academic Affairs:
Leanne De Souza
Director of Social Affairs:
Ilya Mukovozov
Director of Sporting Events:
Yi-­an Chen
Director of Communications:
5LFKLH-HUHPLDQ
GSU Representative:
Laura Finkelberg
Arash Ghashghai
Katarina Lakovic
CIP Representative:
George Ibrahim
IMS Magazine Representative:
Amanda Ali
Toronto General Hospital Site Director: Priyanka Patel
MSB/CCBR/Tanz Site Directors: -RDQD'LGD
Amy Oh
Mount Sinai Hospital Site Director: Tetyana Pekar
MaRS Site Directors: Wilfred Ip
Anna Podnos
Toronto Western Hospital Site Directors: Eric Monsalves
Allison Rosen
Centre for Addiction and Mental Health Site Directors: Yekta Dowlati
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Hospital for Sick Children Site Directors: Anathavalli Kumarappah
Vivian Szeto
Princess Margaret Hospital Site Director: Ryan Rumantir
Sunnybrook Health Sciences Centre Site Directors: Otilia Cristina Nasui
Natalie Venier
St. Michael’s Hospital Site Directors: -RVHSKLQH'Í$EERQGDQ]D
Tony Lin
You can stay up to date on IMSSA events and workshops by checking out the IMSSA
website at http://imssa.sa.utoronto.ca, or \RXFDQMRLQWKHLU)DFHERRN
group at Institute of Medical Science (U of T).
IMS MAGAZINE FALL 2011 PROSTATE CANCER | 06
DIRECTOR’S MESSAGE
Director’s
Message
The IMS Magazine has been a tremendous success and is just one of the many wonderful studentinitiated projects that make the IMS such a very special institute. I fully support the ongoing
publication of the IMS Magazine and look forward to the many opportunities the magazine can
afford us for recruitment and for publicizing the outstanding research that is being conducted by
our faculty and our trainees.
This fourth issue of the magazine focuses on the important area of prostate cancer and highlights
some of the important research that IMS faculty is conducting. Congratulations to Natalie Venier
and her team for their continued hard work and collective creative energies in producing this
wonderful publication. Thanks as well to Kamila Lear for her ongoing assistance in this project.
This summer, the IMS moved into its new space on the main floor of MSB, room 2374. Please
come and visit us as soon you can. We also welcomed two new administrative assistants to our
administrative team: Kaki Narh Blackwood, whose portfolio includes coordinating student defense
examinations and monitoring program progress and completion; and Marika Galadza, whose
portfolio includes general inquiries, room bookings, and the summer undergraduate program. I
look forward to working with Kaki and Marika, as well as with Kamila Lear, our program and
business officer, Hazel Pollard, who is responsible for admissions and enrollment issues, and Dianne
Fukunaga, who deals with awards, faculty appointments, and courses.
I am also pleased to announce the appointment of Professor Brenda Toner as our new Graduate
Coordinator. Professor Toner is currently a Senior Scientist in Social and Epidemiologic Research at
the Center for Addiction and Mental Health, Director of the Fellowship Program and Acting Head
of the Women’s Mental Health Program in the Department of Psychiatry. She brings a wealth of
experience in mentoring students from many disciplines. Dr. Toner will be replacing Professor Mary
Seeman, who will be retiring after almost a decade of involvement as an IMS Graduate Coordinator.
We thank Professor Seeman for her enormous and invaluable contribution to IMS. She has been a
mentor for us all, especially to our students.
Allan S Kaplan, MSc, MD,
FRCP(C)
Director, IMS
Dr. Allan Kaplan became the IMS
Director in July 2011. He is the
Chief of Clinical Research and
Director of Research Training at the
Centre for Addiction and Mental
Health (CAMH), and a Senior
Clinician-Scientist in CAMH’s Mood
and Anxiety Program. He is also
the Vice Chair of Research, Director
of the Clinician Scientist Program
and Professor of Psychiatry at the
University of Toronto.
As I mentioned in my previous Director’s Message, for the first time, the IMS is about to embark
on an extensive strategic planning initiative. Towards that end, we have engaged the assistance of
the Potential Group to help lead us through this process. Over the next six months, the Strategic
Planning Committee will be seeking your input in helping to create a vision for the IMS for the next
5 years. Please participate in this important process; it is a unique opportunity for you to help shape
an inspirational future for the IMS. I look forward to working with all of you as we embark on this
journey together.
Photo by Mohammed Sabri
Sincerely,
Allan S Kaplan MD FRCP(C)
Director, Institute of Medical Science
IMS MAGAZINE FALL 2011 PROSTATE CANCER | 08
IMS SURP HIGHLIGHT
SUMMER UNDERGRADUATE
RESEARCH PROGRAM
Special thanks to all who participated in this year’s lecture series:
Dr. Moloo Badru
Director, Animal Resources Centre, University Health Network
Dr. Jay Keystone
Professor of Medicine, Tropical Disease
Unit, Toronto General Hospital
Prof. Nick Woolridge
Professor and Director, Biomedical Communications, University of Toronto
Dr. Bharati Bapat
Staff Scientist, Mount Sinai Hospital
Mr. Neil Winegarden
Head of Operations, Microarray Centre,
University Health Network
Dr. Lucy Osborne
Affiliate Scientist, Division of Genomic
Medicine, Toronto General Research Institute, University Health Network
Dr. Karen Davis
Professor of Surgery, Associate Director,
Institute of Medical Science, Canada
Research Chair in Brain and Behaviour,
University of Toronto
Participants spend the summer in a laboratory, working on a research project in biomedi09 | IMS MAGAZINE FALL 2011 PROSTATE CANCER
cal research. These students are encouraged
to participate in individual laboratory meetings, data analysis sessions, journal clubs,
and appropriate clinical research rounds
at the affiliated teaching hospitals. In addition, the IMS offers a weekly lecture series
to complement the students’ research. The
lecture series includes research presentations
by IMS faculty, graduate studies information
sessions, and practical skills workshops.
Dr. Ori Rotstein
Surgeon-in-Chief, St. Michael’s Hospital
IMSSA: Student Presentations
Dr. Michael Szego
Fellow of the Joint Centre for Bioethics
Dr. Vasundara Venkateswaran
SURP Director
Photos courtesy of the IMS Office
T
he Institute of Medical Science Summer Student Program provides an
opportunity for undergraduate BSc.
and medical students to become involved
in projects in biomedical research ranging across a broad spectrum of areas, from
molecular biology and cognitive science to
clinical investigation and bioethics.
Dr. Linda Sugar
Professor, Laboratory Medicine and Pathology, University of Toronto and Staff
Pathologist, Sunnybrook Health Sciences Centre
IMS SURP HIGHLIGHT
IMS SUMMER INTERNATIONAL PROGRAM
Canadian Students
York University (2)
University of Ottawa (2)
Guelph University (2)
University of Western Ontario (17)
University of Toronto (47)
Queen’s University (10)
McMaster University (11)
Concordia University (1)
McGill University (3)
University of Manitoba (1)
St. Francis Xavier University (2)
Dalhousie University (1)
University of Oshawa Institute of Technology (1)
International Students
The National University of Ireland, Ireland (1)
University of Edinburgh, UK (1)
City University, UK (1)
Shandong University, China (7)
Shantou University, China (4)
King Saud, Saudi Arabia (8)
Hacettepe University, Turkey (2)
George Washington University, USA (1)
Wayne State University, USA (1)
Yeshiva University, USA (1)
Hillsdale College, USA (1)
National Chiao Tung University, Japan (6)
Photos courtesy of the IMS Office; SURP photo courtesy of Mohammed Sabri
The IMS SURP program offers a special opportunity to host international undergraduate students. Students work on one regular
research project in a laboratory, and participate with domestic students in their weekly
seminars, and IMS Summer Research Day
presentations. This year a large number of
students participated in the SURP program
from various international universities.
IMS MAGAZINE FALL 2011 PROSTATE CANCER | 10
IMS SURP HIGHLIGH T
IMS SUMMER STUDENT RESEARCH DAY
In early August, summer students participate
in the annual IMS Summer Student Research
Day, which includes a keynote speaker, oral
and poster presentations of their research.
Supervisors, along with other IMS faculty,
serve as judges for the summer student presentations.
Dr. Lyle Palmer, Executive Scientific Director, Ontario Health Study gave the inaugural
Ori Rotstein Lecture in Translational Research at the annual SURP Research Day. Dr.
Palmer’s presentation was titled, “The Ontario Health Study: Creating Platforms for
revolutionary science and transformational
biology.”
11 | IMS MAGAZINE FALL 2011 PROSTATE CANCER
Photos courtesy of the IMS Office
As Professor Ori Rotstein’s term as IMS Director ended this past July, IMS faculty, staff
and alumni established an annual lectureship series in his honour. The Ori Rotstein
Lecture in Translational Research provides a
wonderful opportunity to recognize Professor Rotstein’s commitment to the ongoing
development of the Institute, by bringing
together faculty and students for annual scientific exchanges.
IMS SURP HIGHLIGHT
SURP Day Winners
Justin Wang (Oral Presentation)
Laureen Hachem (Poster Presentation)
Olesya Solomonova (Poster Presentation)
Judy Qjang (Poster Presentation)
Joshua Rosenblat (Poster Presentation)
Alannah Smrke (Poster Presentation)
Anna Artymowicz (Poster Presentation)
Vanja Cabric (Poster Presentation)
Melanie Kalbfleisch (Poster Presentation)
Paymon Azizi (Poster Presentation)
Cynthia Chan (Poster Presentation)
Julie Anh Dung Van (Poster Presentation)
Zhe Liang (Poster Presentation)
Michael Catapano (Poster Presentation)
Dylan Kain (Poster Presentation)
Runner Up Winners
Photos courtesy of the IMS Office
Bradley Kaplansky (Oral Presentation)
Katrine De Asis (Poster Presentation)
Amy Lu (Poster Presentation)
Grace Phillips (Poster Presentation)
Brian Vadasz (Poster Presentation)
Annabelle Ong (Poster Presentation)
Adrian Budhram (Poster Presentation)
Jean Michelle Legasto (Poster Presentation)
Miyuki Kumagai (Poster Presentation)
Jai Prashanth Jayakar (Poster Presentation)
Santina Lee (Poster Presentation)
Sonam Maghera (Poster Presentation)
Taylor Kain (Poster Presentation)
Vivian Szeto (Poster Presentation)
IMS MAGAZINE FALL 2011 PROSTATE CANCER | 12
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The prostate is a walnut-shaped exocrine
gland located between the bladder and the
rectum. It has three main functions: production of fluid for semen, production of
prostate specific antigen (PSA), and control
of urine flow.
Like most malignancies, prostate cancer
develops when cells within the prostate grow
uncontrollably. This irrepressible growth
causes the development of small tumours. In
most cases, these prostate tumours grow
relatively slowly. It usually takes years for
tumours to become large enough to be
detectable and it takes even longer for them
to spread out of the prostate. Unfortunately, a
small number of men have aggressive
prostate cancers that grow and spread
quickly.
7YVZ[H[L*HUJLY*HUHKH
:;(.05.
Prostate cancer is typically classified into different stages based on whether it is confined to the prostate or has spread to other parts
of the body. The staging of prostate cancer is important for selecting various management and treatment strategies.
:[HNL0
Illustrations by Oilvia Shim and Andreea Margineanu
In stage I disease, the cancer is confined to the
prostate only. It usually is very minimal, and
requires multiple types of testing modalities to be
detected (i.e. PSA testing and biopsy).
:[HNL00(
:[HNL00)
In stage II disease, the cancer is a more advanced than stage I, although it has not spread beyond
the prostate. It can be classified as stage IIA or stage IIB. In Stage IIA, the cancer is localized to
one lobe of the prostate. In Stage IIB, the cancer is present in both lobes of the prostate.
For more detailed information
on prostate cancer and the
specific staging classifications,
visit:
www.cancer.gov
or
www.prostatecancer.ca
:[HNL000
In stage III disease, the cancer has spread beyond
the outer layer of the prostate on one or both sides
and may have spread to the seminal vesicles.
:[HNL0=
In stage IV disease, the cancer has spread beyond
the seminal vesicles to nearby tissue or organs, such
as the rectum, bladder, or pelvic wall; may include
lymph nodes or bones.
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IMS MAGAZINE FALL 2011 PROSTATE CANCER | 14
FEATURE
Prostate Cancer Prevention
An Overview
Prostate cancer is the commonest non-cutaneous human malignancy and second most
frequent cause of cancer death in males. Recent published data has established that
prostate cancer is preventable. Substantial pre-clinical and epidemiologic studies
have identified antioxidants and other micronutrients as promising agents for prostate
cancer prevention. Key agents currently include vitamin D, lycopene, capsaicin, soy
products, 5ARIs (alpha reductase inhibitors), and dietary and weight modification.
Dr. Laurence Klotz
MD, FACS, FRCSC
Professor of Surgery,
University of Toronto
Despite the evidence that substances can help
prevent or slow prostate cancer progression,
not all results have been positive. Vitamin E
and selenium, both of which appeared very
promising in epidemiologic, pre-clinical,
and clinical studies, were evaluated in a huge
15 | IMS MAGAZINE FALL 2011 PROSTATE CANCER
prospective randomized trial with prostate
cancer incidence as the primary endpoint.
The SELECT trial randomized 31,000 men
between groups given placebo, vitamin E,
selenomethionine, and the combination.
The study was stopped early after a futility
analysis showed absolutely no difference in
prostate cancer incidence (or, indeed, in any
other cancer rate). Further, there was a modest but statistically significant increase in diabetes in the selenium arm. Thus, the current
recommendation is that patients not take
these 2 agents for prostate cancer prevention.
The Prostate Cancer Prevention Trial (PCPT)
and REDUCE trial addressed the role of 5
alpha reductase inhibitors in prostate cancer prevention. The PCPT trial randomized
18,000 healthy men between finasteride
(5ARI) and placebo. Following 7 years of
treatment, the incidence of prostate cancer
on biopsy was decreased by 24.8% in the
finasteride arm. Importantly, the incidence
of high-grade prostate cancers in the finasteride-treated patients was increased. The
REDUCE trial tested the preventive value
of dutasteride in 8231 men with an elevated
PSA (an indicator of possible prostate cancer)
and a negative prior biopsy. The results were
similar; a 23% reduction in the risk of prostate cancer being diagnosed on biopsy after 4
years on the drug compared to placebo. The
initial analysis did not show a significant difference in high-grade cancer; a subsequent
Photo by Connie Sun
T
here is increasing evidence
that the evironment plays an important role in the progression of
prostate cancer. There is a one hundred fold
variation in age-adjusted mortality rates
from prostate cancer between high and low
risk geographic and racial groups. In marked
contrast to this large global variation, autopsy studies confirm that micro foci of prostate
cancer exist ubiquitously in 42-80% of males
over 50 years. In nations with a high incidence of prostate cancer deaths, these foci
appear to be characterized by higher volume,
grade and multifocality compared to patients
from nations with low rates of the disease.
Studies of migrating populations reveal that
men from countries with a low incidence
of prostate cancer (i.e. Japan) acquire an increased incidence rate within 20 years upon
emigration to the West, approaching that of
the host country. A detailed autopsy study in
American trauma victims found that 30% of
men between 30 and 39 had microfocal prostate cancer1 leading to the hypothesis that
environmental influences stimulate latent
prostate cancer to progress to biologically
significant disease.
FEATURE
analysis suggested a small increase in highgrade cancer in the dutasteride arm. One patient (0.04%) was found to have Gleason 8-10
cancer in the placebo arm compared to 12
patients (0.5%) in the dutasteride arm. While
there is evidence that this increase in grade
was an artifact, it has led to concern about
the widespread implementation of 5ARIs for
prevention in healthy men. These patients
also more commonly experienced sexual side
effects. These studies provide further impetus for developing safe preventive agents that
have more acceptable side-effect profiles and
avoid the increased grade phenomenon.
The mechanism by which high-fat diets contribute to cancer progression is thought likely
to be related to increased insulin and/or related growth factor levels. Low-carbohydrate
diets are based on maintaining low insulin
levels. Our hypothesis is that a low-insulinemic diet, by virtue of reducing circulating
insulin and IGF levels, may protect against
the carcinogenic effect associated with highfat intake.
In our laboratory, we have studied the influence of vitamin E, selenium, lycopene, flavonoids, and dietary intervention with a low
carbohydrate diet on the growth, progression,
and gene expression of a transgenic prostate
cancer model (Lady TRAMP). This work was
carried out by Dr. Vasu Venkateswaran and
a number of fellows and graduate students.
Our results are summarized as follows5-11:
day, maintained on either a standard, or high
fat-high carbohydrate diet. This study found,
perhaps not surprisingly, that regular exercise in conjunction with a normal diet inhibited cancer growth. However, the group with
the most rapid cancer progression was the
exercising mice on a high fat-high carbohydrate diet. These animals had a higher energy
intake than the non-exercising animals. Our
hypothesis is that the exercise stimulated an
increase in dietary intake of a ‘bad’ diet, resulting in increased cancer cell proliferation.
We believe this process is mediated through
the insulin-IGF1 axis as well as other pathways. This is something to consider the next
time you eat a Big Mac after a workout!
The relationship between dietary intake
and prostate cancer incidence and mortality is complex. Extensive epidemiologic data
points to a strong positive relationship between fat intake and prostate cancer progression; while a diet rich in fruits and vegetables
(particularly lycopene containing plants like
tomatoes) as well as soy products are suggested to have protective effects. The Japanese
have shifted to a more Western diet over the
last 20 years, and this has been accompanied
by a rapid increase in prostate cancer incidence and mortality, which is now approaching North American rates. Specifically, with
approximately one half the population of the
US, the number of cases has increased over
the last 20 years from 10% to 65% of the US
incidence. Of course, separating the impact
Experimental Results
Vitamin E, selenium, and lycopene dramatically inhibit the development of prostate cancer in this model.
Lycopene is a necessary component of this effect.
Several flavonoids dramatically inhibit the growth of prostate cancer in a xenograft model. This is mediated
through a number of cell cycle specific genes and pathways.
A low carbohydrate diet reduces the growth rate of prostate cancer xenografts in mice on a high-fat diet
compared to an isocaloric high-carbohydrate diet. This is mediated through the IGF family of mitogens.
We have also evaluated the relationship between diet, exercise, and prostate cancer
progression in a xenograft model. This study,
carried out by our IMS graduate students,
compared cancer progression in mice exercised on a treadmill for several hours per
of increased case detection by PSA screening
on these figures is challenging. Nonetheless,
the overwhelming weight of evidence suggests that a diet more oriented towards plants
and away from animal fat is prostate healthy.
This dietary shift also results in lower choles-
terol and triglycerides, leading to improved
cardiovascular health, which shows that a
prostate-healthy diet is really a diet healthy
for the whole body.
References
1. Sakr WA, Grignon DJ, Crissman JD, Heilbrun LK,
Cassin BJ, Pontes JJ, Haas GP. High grade prostatic intraepithelial neoplasia (HGPIN) and prostatic adenocarcinoma between the ages of 20-69: an autopsy study of
249 cases. In Vivo. 1994 May-Jun;8(3):439-43.
2. Lippman SM, Klein EA, Goodman PJ, Lucia MS,
Thompson IM, Ford LG, Parnes HL, Minasian LM, et
al. Effect of selenium and vitamin E on risk of prostate
cancer and other cancers: the Selenium and Vitamin E
Cancer Prevention Trial (SELECT). JAMA. 2009 Jan
7;301(1):39-51.
3. Thompson IM, Goodman PJ, Tangen CM, Lucia MS,
Miller GJ, Ford LG, Lieber MM, Cespedes RD, Atkins
JN, Lippman SM, Carlin SM, Ryan A, Szczepanek CM,
Crowley JJ, Coltman CA Jr. The influence of finasteride
on the development of prostate cancer. N Engl J Med.
2003 Jul 17;349(3):215-24.
4. Andriole GL, Bostwick DG, Brawley OW, Gomella
LG, Marberger M, Montorsi F, Pettaway CA, Tammela
TL, Teloken C, Tindall DJ, Somerville MC, Wilson TH,
Fowler IL, Rittmaster RS; REDUCE Study Group. Effect
of dutasteride on the risk of prostate cancer. Engl J Med.
2010 Apr 1;362(13):1192-202.
5. Haddad AQ, Venkateswaran V, Viswanathan L, Teahan SJ, Fleshner NE, Klotz LH. Novel antiproliferative flavonoids induce cell cycle arrest in human prostate cancer
cell lines. Prostate Cancer Prostatic Dis. 2006;9(1):68-76.
6. Venkateswaran V, Fleshner NE, Sugar LM, Klotz LH.
Antioxidants block prostate cancer in lady transgenic
mice. Cancer Res. 2004 Aug 15;64(16):5891-6.
7. Venkateswaran V, Klotz LH. Diet and prostate cancer:
mechanisms of action and implications for chemoprevention. Nat Rev Urol. 2010 Aug;7(8):442-53. Epub 2010
Jul 20. Review.
8. Haddad AQ, Fleshner N, Nelson C, Saour B, Musquera M, Venkateswaran V, Klotz L. Antiproliferative
mechanisms of the flavonoids 2,2’-dihydroxychalcone
and fisetin in human prostate cancer cells. Nutr Cancer.
2010;62(5):668-81.
9. Hou M, Venier N, Sugar L, Musquera M, Pollak M,
Kiss A, Fleshner N, Klotz L, Venkateswaran V. Protective effect of metformin in CD1 mice placed on a high
carbohydrate-high fat diet. Biochem Biophys Res Commun. 2010 Jul 2;397(3):537-42. Epub 2010 Jun 2.
10. Cervi D, Pak B, Venier NA, Sugar LM, Nam RK,
Fleshner NE, Klotz LH, Venkateswaran V. Micronutrients attenuate progression of prostate cancer by elevating the endogenous inhibitor of angiogenesis, platelet
factor-4..BMC Cancer. 2010 Jun 4;10:258.
11. Venkateswaran V, Klotz LH, Ramani M, Sugar
LM, Jacob LE, Nam RK, Fleshner NE. A combination
of micronutrients is beneficial in reducing the incidence of prostate cancer and increasing survival in the
Lady transgenic model. Cancer Prev Res (Phila). 2009
May;2(5):473-83.
IMS MAGAZINE FALL 2011 PROSTATE CANCER | 16
FEATURE
The Role of Diet and Exercise
in Prostate Cancer
Dr. Vasundara Venkateswaran
PhD
Associate Professor of Surgery,
University of Toronto
17 | IMS MAGAZINE FALL 2011 PROSTATE CANCER
It is essential to appreciate that diet provides
multiple micronutrients and macronutrients
packaged in their most effective form, since
diet is an important aspect of health that an
individual can control. Currently, the strongest association between diet and prostate
cancer appears to be obesity. Prior research
conducted in our laboratory has suggested
that energy balance and fat intake influence
prostate cancer progression. However, the influence of dietary carbohydrates on prostate
cancer progression has not been well characterized. Hence, we tested if hyperinsulinemia
resulting from high intake of refined carbohydrates would lead to more rapid growth
of tumors in the xenograft mouse model of
prostate cancer. Interestingly, this diet was
associated with increased tumor growth,
with activation of signaling pathways distal
to the insulin receptor10. Our research lends
support to the concept that diets associated
with a reduction in insulin levels may have
benefits for prostate cancer patients, particularly for a hyperinsulinemic subset of the
population. Furthermore, it also provides the
rationale for clinical research attempting to
determine if lower prostate cancer risk and/
or improved prostate cancer prognosis can
be obtained through minimization of insulin levels and optimization of macronutrient
intake to meet, but not exceed, nutritional
requirements. Ongoing investigations of
pharmacologic agents such as metformin (a
compound that reduces hyperinsulinemia
and associated metabolic abnormalities) examine if such compounds may also have a
role to play in the treatment of metabolicallydefined subsets of prostate cancer patients.
Besides identification of molecular targets,
other methods of prevention would have to
be incorporated into a prostate cancer prevention strategy. These include personalized
risk assessment and discovery of biomarkers,
Photo by Connie Sun
T
he fact that prostate cancer
is one of the most prevalent cancers
has enormous public health significance. With nearly 25,000 new cases each
year, prostate cancer is a growing problem.
Hence, strategies for prevention of this disease would attenuate its economic, emotional, physical and social impact. Both the substantial variation in the incidence of prostate
cancer worldwide and the increased risk in
the migrant population (moving from lowrisk to high-risk countries) provide strong
support for modifiable environmental factors – particularly diet – in prostate cancer
etiology. Over the years, dietary agents have
gained considerable attention as chemopreventive agents against prostate cancer. Studies suggest that men can reduce their risk of
prostate cancer by making sure they maintain a healthy diet. Dietary factors are one of
the major elements accounting for the international and inter-ethnic differences in the
rate of prostate cancer1. Many agents have
been evaluated for their primary and secondary chemopreventive capacities, including
soy proteins, tomatoes and lycopene, vitamin
E, selenium, fish and marine fats, ω-3 fatty
acids, cholesterol, polyphenols, isoflavones,
red meat, pomegranate, cruciforms and
green tea2-7. There are numerous review articles that discuss mechanisms of action and
implications of dietary agents for chemoprevention of prostate cancer8. These compounds potentially interact with a range of
carcinogenic pathways, including androgen
metabolism, cell cycle processes and apoptosis, maintenance of mitochondrial membrane potentials, insulin-like growth factor
(IGF)-Akt signaling and response to oxidative stress. It is interesting to note that nutrient intake can modify genetic susceptibility
to diseases such as cancer9. This information
is helpful in providing a scientific basis for
cancer prevention via dietary modification.
FEATURE
sensitivity to preventive agents, and surrogate molecular markers serving as intermediate end points. Despite all this, one has to
recognize that the intrinsic heterogeneity of
any given study population makes nutritional studies difficult to perform. This is due to
several factors including variations in individual lifestyles, complexity in food and food
products, as well as the levels of consumption of such foods. Laboratory studies in
preclinical animal models provide important
guidelines in designing, conducting, and interpreting large studies in humans; however,
complications and errors arise while translating data from animal studies to the clinical
setting. This demonstrates the complexity
in interpreting many of the contradictory
reports that can confuse researchers, physicians and the public alike.
Photo courtesy of http://www.sxc.hu/photo/816375
Recent evidence highlights not only the role
of dietary factors but also the inclusion of
physical activity as a key component in the
development and progression of prostate
cancer. Epidemiological and laboratory investigations indicate a negative relationship
between regular exercise and the risk of certain malignancies, including prostate cancer.
A recent review11 has discussed the influence of physical activity on the carcinogenic
process, where physical activity is dependent
on energy contribution and the duration of
exercise. There are several probable biological mechanisms projected to explain the cancer-preventive effects of exercise, including
changes in endogenous metabolic or sex hormone levels and growth factors, decreased
obesity and central adiposity, alterations in
immune functions, and alternations in reactive oxygen species (ROS). Interestingly,
different levels of exercise may influence the
ROS generation in different ways. In fact, it
has been suggested that moderate levels of
exercise may have protective effects while too
much exercise can be harmful. Thus, the determination of the optimal load of physical
activity that can elicit cancer-preventive effects warrants further investigation.
It is imperative to determine the best approach to keep prostate cancer at bay. Although much research still needs to be
accomplished regarding the effect of micronutrients and macronutrients in prostate
cancer progression, it is suggested that one
can maintain overall good health by eating a
well-balanced diet that is low in fat and carbohydrates, but rich in fruits and vegetables,
and accompanied by moderate exercise.
References
1. Chan, J. M., et.al. Role of diet in prostate cancer development and progression. J. Clin. Oncol. 23: pp 8152–
8160, 2005.
2. Fleshner, NE., et al. Dietary Fat and Prostate Cancer.
The Journal of Urology.171 (2): pp S19-S24, 2004.
3. Venkateswaran, V., et al. Antioxidants block prostate
cancer in Lady transgenic mice. Cancer Research. 64: pp
5891-5896, 2004.
4. Haddad, A., et al. Novel antiproliferative flavonoids
induce cell cycle arrest in prostate cancer cell lines. Prostate Cancer Prostatic Diseases. 9 (1): pp 68-76, 2005.
5. Venkateswaran, V. Selenium and Prostate Cancer:
Biological Pathways and Biochemical Nuances. Cancer
Therapy. 4: pp 73-80, 2006.
6. Venkateswaran, V., et al. Early commencement of
micronutrients is beneficial in reducing the incidence
of prostate cancer and increasing survival in the Lady
transgenic model. Cancer Prevention Research. 2 (5): pp
473-483, 2009.
7. Venier N., et al. Chemopreventative Strategies in
Prostate Cancer: Role of Dietary Agents. Invited Review.
Current Cancer Therapy Reviews. 6: pp 308-316, 2010.
8. Venkateswaran, V., et al. Diet and prostate cancer:
mechanisms of action and implications for chemoprevention. Nature Reviews Urology. 7: pp 442-453, 2010.
9. Huang, H.Y., et al. Customized diets for cancer prevention according to genetic polymorphisms: are we
ready yet? Journal of the National Cancer Institute.
98(22): 1590-1, 2006.
10. Venkateswaran, V., et al. Association of diet induced
hyperinsulinemia with accelerated growth of prostate
cancer (LNCaP) xenografts. Journal of the National
Cancer Institute. 99: pp 1793-800, 2007.
11. Na, HK., et al. Effects of physical activity on cancer
prevention. Ann. N.Y. Acad. Sci. Issue: Nutrition and
Physical Activity in Aging, Obesity, and Cancer. 1229:
176–183, 2011.
IMS MAGAZINE FALL 2011 PROSTATE CANCER | 18
FEATURE
Imaging and Prostate Cancer
Applications of MRI
Clinician Scientist, Ontario Institute for
Cancer Research
Associate Member, Institute of Medical
Science
Associate Professor of Radiology, University
of Toronto, Faculty of Medicine, Department
of Medical Imaging
O
ne of the primary goals of current cancer research is to develop
patient-specific personalized therapeutic approaches that maximize treatment
efficacy while minimizing morbidity. In the
current era of serum prostate specific antigen
(PSA) screening for prostate cancer, detection is occurring at an earlier stage; however,
prostate cancer has a highly variable natural
history and in many cases the cancer will remain indolent throughout the patient’s lifetime. There is a consensus that in the PSA
screening era prostate cancer is being overtreated1.
There is a wide array of options for therapy
including active surveillance (see page 21),
prostatectomy (laproscopic, robotic, retropubic), hormonal therapy, and radiation
therapy (external beam, intensity modulated
radiation therapy, brachytherapy). Selection
of the appropriate treatment is based on risk
stratification. The primary method for risk
stratification hinges on obtaining tissue using a random prostate biopsy of the gland
guided by transrectal ultrasound (TRUS)
consisting of at least 8 needle cores. Using the
19 | IMS MAGAZINE FALL 2011 PROSTATE CANCER
In recent years, of all imaging methods available for clinical use, MRI has shown the
greatest promise of addressing these issues in
the short term. In particular the use of multiparametric MRI, which combines two or
more MRI acquisitions such as T2 weighted
imaging, diffusion weighted imaging, dynamic contrast enhanced imaging or proton
spectroscopy, has been successful in localizing prostate cancer for directed biopsy5-8 and
shown promise in predicting Gleason grade
without the need for biopsy9, 10. There remain
shortcomings. Much of the data supporting
the MRI approach comes from single center
trials, and there are too few prospective trials
showing improved survival. Training of radiologists is lacking and MRI availability is limited, although this is expected to change as
standards develop and evidence of improvements in patient outcome is published over
the next few years. A prospective multicenter
trial is underway in select centers – including
our group, funded by the Ontario Institute
of Cancer Research – to evaluate MRI use
with specific treatments such as active surveillance to see if patients can be better se-
Photo by Paulina Rzeczkowska
Dr. Masoom Haider
MD, FRCPC
histologic Gleason grade of the tissue sample,
the PSA, and the result of digital rectal exam,
the patient is placed in a risk category and
this helps guide management choices. This
approach suffers from two shortcomings.
The first is the sampling problem. TRUS biopsy even with 10 cores is not representative
of the tumor grade at prostatectomy in about
30% of cases and thus the patient’s risk category can be misclassified2. Secondly, the risk
stratification currently used is predictive but
when applied on a patient-by-patient basis
does not always reliably predict an individual
patient’s long-term outcome. Furthermore,
prostate biopsy is painful and caries a small
but significant risk of urosepsis3, while whole
gland therapies carry the risk of sexual dysfunction and urinary continence problems4.
Thus, finding a non-invasive biomarker of
outcome in prostate cancer is one of the principal aims of current research.
FEATURE
T
ADC
DCE MRI - Kep map
Fig 1 Multi-parametric MRI of Patient on Active Surveillance
The T2 weighted image shows a vague area of lenticular shaped altered texture in the anterior prostate. A corresponding and more obvious region of relative low diffusion is seen
on the apparent diffusion coefficient map generated from a diffusion-weighted image (b-value 600s/mm2). A corresponding area of relatively elevated reflux constant (kep), generated
from a Toft’s model applied to dynamic contrast enhanced MRI [DCE MRI] is also seen. The combination of altered texture on the T2 weighted images, corresponding low ADC and
elevated kep is typical of cancer. Targeted biopsy showed performed 24 days later showed a Gleason 7 (3+4) in both directed cores occupying 40 and 70% of the core length.
Figure reference: Orit Raz, et al. MRI for men undergoing active surveillance or with rising PSA and negative biopsies. Nature Reviews Urology 2010: 7, 543-551
lected for treatment or have their treatment
deferred through better surveillance using
imaging and directed biopsy. Research is also
underway to develop computer-aided diagnostic algorithms to reduce interobserver
variability and improve diagnostic performance of radiologists11, 12.
The ability to localize prostate cancer using
MRI has applications other than improved
sampling and Gleason grade prediction.
Studies are underway to further personalize medicine by applying “dose painting”, a
technique where higher radiation doses are
delivered to prostate regions where highergrade tumors are suspected based on MRI,
thus improving therapeutic ratios. Urologists
are studying approaches such as MRI-guided
laser thermal therapy13 and high intensity focused ultrasound14 to guide delivery of focal
therapy. MRI has the advantage of not only
being able to localize the cancer but also
monitor tissue temperature changes, thus allowing for maximal delivery of thermal doses
while sparing critical structures such as the
rectum and neurovascular bundles, reducing complications related to continence and
sexual potency.
If multiparametric MRI proves successful,
then one can picture a near future where a
patient only undergoes a prostate biopsy
when necessary and then has access to highly
effective low morbidity image guided therapies.
References
1. Schroder FH, Hugosson J, Roobol MJ, et al. Screening and prostate-cancer mortality in a randomized
European study. N Engl J Med. 2009;360(13):1320-8.
2. San Francisco IF, DeWolf WC, Rosen S, Upton M,
Olumi AF. Extended prostate needle biopsy improves
concordance of Gleason grading between prostate
needle biopsy and radical prostatectomy. J Urol.
2003;169(1):136-40.
3. Mosharafa AA, Torky MH, El Said WM, Meshref A.
Rising incidence of acute prostatitis following prostate
biopsy: fluoroquinolone resistance and exposure is a
significant risk factor. Urology. 2011;78(3):511-4.
4. Potosky AL, Legler J, Albertsen PC, et al. Health outcomes after prostatectomy or radiotherapy for prostate
cancer: results from the Prostate Cancer Outcomes
Study. J Natl Cancer Inst. 2000;92(19):1582-92.
5. Haider MA, van der Kwast TH, Tanguay J, et al.
Combined T2-weighted and diffusion-weighted MRI
for localization of prostate cancer. AJR Am J Roentgenol. 2007;189(2):323-8.
6. Futterer JJ, Heijmink SW, Scheenen TW, et al.
Prostate cancer localization with dynamic contrastenhanced MR imaging and proton MR spectroscopic
imaging. Radiology. 2006;241(2):449-58.
7. Mazaheri Y, Shukla-Dave A, Hricak H, et al. Prostate
cancer: identification with combined diffusionweighted MR imaging and 3D 1H MR spectroscopic
imaging--correlation with pathologic findings. Radiology. 2008;246(2):480-8.
8. Hambrock T, Somford DM, Hoeks C, et al. Magnetic
resonance imaging guided prostate biopsy in men with
repeat negative biopsies and increased prostate specific
antigen. J Urol. 2010;183(2):520-7.
9. Zakian KL, Sircar K, Hricak H, et al. Correlation of
proton MR spectroscopic imaging with gleason score
based on step-section pathologic analysis after radical
prostatectomy. Radiology. 2005;234(3):804-14.
10. Hambrock T, Somford DM, Huisman HJ, et al.
Relationship between apparent diffusion coefficients
at 3.0-T MR imaging and Gleason grade in peripheral
zone prostate cancer. Radiology. 2011;259(2):453-61.
11. Artan Y, Haider MA, Langer DL, et al. Prostate cancer localization with multispectral MRI using cost-sensitive support vector machines and conditional random
fields. IEEE Trans Image Process. 2010;19(9):2444-55.
12. Langer DL, van der Kwast TH, Evans AJ, Trachtenberg J, Wilson BC, Haider MA. Prostate cancer detection with multi-parametric MRI: logistic regression
analysis of quantitative T2, diffusion-weighted imaging,
and dynamic contrast-enhanced MRI. J Magn Reson
Imaging. 2009;30(2):327-34.
13. Raz O, Haider MA, Davidson SR, et al. Real-Time
Magnetic Resonance Imaging-Guided Focal Laser
Therapy in Patients with Low-Risk Prostate Cancer. Eur
Urol. 2010.
14. Siddiqui K, Chopra R, Vedula S, et al. MRI-guided
transurethral ultrasound therapy of the prostate gland
using real-time thermal mapping: initial studies. Urology. 2010;76(6):1506-11.
IMS MAGAZINE FALL 2011 PROSTATE CANCER | 20
FEATURE
Active Surveillance
P
Philip A. Alves, HBSc
Summer Student
IMS Summer Research Program
Supervisor: Dr. Laurence Klotz
MD Candidate
Schulich School of Medicine & Dentistry
The University of Western Ontario
21 | IMS MAGAZINE FALL 2011 PROSTATE CANCER
rostate cancer is the most prevalent non-skin cancer diagnosed in
men. It is the second most common
cause of cancer death in men. However, a diagnosis of prostate cancer is not necessarily a
death sentence. Men diagnosed with prostate
cancer currently have a 97% cancer-specific
survival rate after 5 years1. This impressive
survival statistic is due in part to adoption of
the prostate specific antigen (PSA) blood test
in the mid 1990s and its widespread use as a
screening tool2. This results in a significant
lead time in diagnosis. As a large proportion
of prostate cancers are very slow growing and
never metastasize, the ubiquity of PSA testing is also responsible for the current overdiagnosis and over-treatment of prostate
cancer. Radical treatments, such as radiation
therapy and surgery, may result in urinary
incontinence and impotence - considerable
consequences for quality of life.
Active surveillance is a conservative management option that closely follows men with
low-risk prostate cancer with regularity to
ensure that aggressive cancers are detected
and amenable to cure, yet avoids overtreating
men with insignificant disease.
Prostate cancer is classified as low-risk based
on the tumour grade on biopsy, stage of progression, and PSA value. Patients with lowrisk prostate cancer may opt to defer treatment in lieu of active surveillance. This will
Photo by Connie Sun; Ribbon photo courtesy of www.istockphoto.com; ID # 12562292
Why an increasing number of prostate
cancer patients are opting to wait and see
rather than obtain treatment
FEATURE
Pick Your Brain...
A column by Aaron Kucyi
Chronic prostatitis is a disorder that occurs in
5-10% of men and is associated with pain of the
prostate and surrounding areas. Also known as
chronic pelvic pain syndrome (CPPS), the disorder
is unrelated to prostate cancer, and its cause is
uncertain. Most research on CPPS has focused
on factors such as inflammation, endocrine involvement, and pelvic floor muscle abnormalities. However, spontaneous pain perception in
CPPS is ultimately a result of brain activity – an
underexplored phenomenon that was recently
investigated for the first time by researchers at
Northwestern University.
allow them an opportunity to monitor the
disease through regular follow up appointments. Curative therapies are recommended
if the preceding criteria advance to indicate
grade progression or volume progression.
Follow up is important. At enrolment, men
have their PSA measured and undergo a digital rectal exam (DRE). PSA values are drawn
and DREs undertaken every 3 and 6 months,
respectively, for the first two years. A confirmatory biopsy will also be scheduled within
the first year after diagnosis to ensure that a
more high-risk tumour was not missed. After the first two years, individuals undergo
PSA measurements every six months and
DREs annually, as well as re-biopsy every two
to three years. Patients will remain on this
schedule of care indefinitely unless there is
tumour grade progression. At this point, radiation therapy or surgical excision with curative intent will be scheduled, although this
is necessary only for a minority of patients.
A rapid rise in PSA, particularly a PSA doubling time faster than 3 years, should necessitate a repeat biopsy or multiparametric MR
imaging. Importantly, patients that progress
In an MRI study of a group of 19 male CPPS patients, activity in the right anterior insula (a painrelated brain region) was associated with fluctuations in the intensity of spontaneous pain over
time. In terms of brain structure, there were no differences in total volume or volume of pain-related
regions between patients and healthy controls.
However, higher gray matter density in the right
anterior insula was associated with higher overall
pain experienced by a patient. Also, the relationship between brain gray matter (neuronal cell
bodies) and white matter (axonal tracts) was disrupted in patients relative to controls. The neural
to high-risk disease appear no more likely to
die than patients who were treated radically
at the outset of their diagnosis2. Why should
a prostate cancer patient with low-risk disease opt for active surveillance over radical
treatment? Firstly, prostate cancer is very
common: Roughly 1 in 7 men will be diagnosed with prostate cancer during their life1,
although many of these men harbour clinically insignificant disease. Perhaps more surprising is that upwards of 1 in 2 men will have
previously undetected tumours at death3.
Furthermore, prostate cancer is slow growing: Tumours often grow over the course of
several decades – many do not transform
into aggressive cancers, therefore offering
a long timeframe for surveillance4. Finally,
men with localized prostate cancer are more
likely to die of other causes than prostate cancer. Patients diagnosed with microfocal low
grade cancer based on an elevated PSA managed with active surveillance are 19 times
more likely to die of other causes than die of
the disease2. These facts support the notion
that radical treatment is often unnecessary,
and many with the disease are well suited for
close monitoring of disease progress.
changes in CPPS are both similar and unique from
other chronic pain disorders. As CPPS is poorly understood and difficult to treat, this work provides
important insights that can open up new directions
for research on the mechanisms underlying the
disorder, and potentially pain management.
Reference:
Farmer MA, Chanda ML, Parks EL, Baliki MN, Apkarian AV,
Schaeffer AJ (2011) Brain functional and anatomical changes
in chronic prostatitis/chronic pelvic pain syndrome. J Urol
186:117-124.
In summary, active surveillance is a prostate
cancer management strategy that allows for
patients with low-risk disease to avoid the
consequences of overtreatment yet feel confident that they will benefit from curative
treatment if necessary. Active surveillance
serves as a prudent model for individualized,
patient-centred cancer care.
References
1. Klotz L, Zhang L, Lam A, Nam R, Mamedov A,
Loblaw A. Clinical results of long-term follow-up of a
large, active surveillance cohort with localized prostate
cancer. J Clin Oncol 2010;28:126–31
2. Croswell JM, Kramer BS, Crawford ED. Screening
for prostate cancer with PSA testing: current status
and future directions. Oncology (Williston Park). 2011
May;25(6):452-60, 463.
3. Sakr WA, Haas GP, Cassin BF, Pontes JE, Crissman
JD. The frequency of carcinoma and intraepithelial
neoplasia of the prostate in young male patients. J Urol
1993;150:379–85.
4. Soloway, M. S. et al. Careful selection and close
monitoring of low-risk prostate cancer patients on active
surveillance minimizes the need for treatment. Eur.
Urol. 58, 831–835 (2010).
IMS MAGAZINE FALL 2011 PROSTATE CANCER | 22
FEATURE
Dr. Neil Fleshner
MD, FRCSC, MPH
Head of Urology,
University Health Network
Professor of Surgery,
University of Toronto
23 | IMS MAGAZINE FALL 2011 PROSTATE CANCER
Prostate cancer is the most commonly diagnosed cancer
among men and the second most common cause of cancer related deaths. This cancer is generally underfunded
relative to its prevalence and mortality rate when compared to the amount of money that has been devoted towards breast cancer research. It is hoped that this gap
will shrink over the coming years.
Photo courtesy of www.istockphoto.com; ID # 7627557
The Future of
Prostate Cancer Research
FEATURE
I
n line with this hope, it seems that research into prostate cancer will flourish over the coming years. With the advent
of novel genetic and molecular tools, new target discovery for
prostate cancer drugs seems likely, and will only continue to improve
in tandem with technological advances.
In this article, the future of prostate cancer research will be discussed
within the context of three sub-topics.
Prevention
The trend of novel studies hints that prevention research will continue to grow from an epidemiologic point of view. We will continue
to learn more about the causes of prostate cancer, particularly the
impact of the environment on this disease. We will also learn more
about genetic risks of this disease; the development of a prostate risk
chip that will better personalize prostate cancer risk for men is likely
in the coming decades. Some of these risk-assessment techniques are
now on the market, and as additional risk SNPs (single nucleotide
polymorphisms in one’s DNA that indicate a higher risk of developing a certain disease) are found, this progress towards individualized
prevention strategies and treatment planning will continue.
Knowledge of the fundamental biology of advanced prostate cancer
will continue to grow as new discoveries are made. The International
Gene Consortium is planning to sequence a number of prostate tumours, which will improve our understanding of the genetic changes
seen in this disease. Continued exploitation of the androgen receptor, a target for therapy, can therefore become more selective and efficacious. Genetic studies have already resulted in the development of
new compounds such as Abiraterone and MDV3100. Targeting other
novel pathways, such as the phospho-AKT and PTEN pathways, may
give rise to novel agents with the ability to improve overall survival
and quality of life among patients with advanced prostate cancer.
In summary, the future for prostate cancer research looks bright. One
of the main challenges facing us is the translation of fundamental
discoveries into targetable agents. If this can be accomplished, there
is hope that these discoveries can help to improve the quality of life
for patients with prostate cancer.
Early Detection
We will continue to incorporate modern imaging into the early
detection of prostate cancer. At this point, men at risk are simply
offered an ultrasound guided prostate biopsy. There is increased
concern about the safety of these biopsies with the increased rise
of ciprofloxacin-resistant E. Coli infections. As a result of this risk,
clinicians are becoming increasingly pressed to utilize less invasive
magnetic resonance imaging (MRI) techniques in the detection of
prostate cancer. Despite the advantages of an MRI-based diagnostic
technique, research is still needed to better develop the imaging protocols to improve this technology.
Photo by Connie Sun
Treatment
With respect to early stage prostate cancer, there is an increasing realization that our current therapies, while effective, can have
a significant impact on quality of life, particularly for urinary and
sexual functions. Thus there will likely be increased research over
the next decade on the topic of focal therapy. This technique aims
to identify the areas of the prostate where there is disease and to use
energy technologies such as heat or freezing to ablate these areas.
This technique is essentially akin to the lumpectomy technique used
to remove breast cancer tumours. Some trials of focal therapy are
now underway, and even more research will be done as technology
improves.
IMS MAGAZINE FALL 2011 PROSTATE CANCER | 24
SPOTLIGHT
Transcranial magnetic stimulation
An investigational tool and potential therapeutic option in movement disorders
By Nina Bahl
A
rguably the most important
organ in the body, the brain is also
the least understood; comprised of
a staggering one hundred billion neurons,
the complexity of the connectivity between
these cells seems nearly incomprehensible.
Accordingly, our understanding of human
neurophysiology has benefited tremendously
from the advent of sophisticated investigational tools, including transcranial magnetic
stimulation (TMS) – a non-invasive method of stimulating the brain. For Dr. Robert
Chen, a senior scientist and movement disorders specialist at Toronto Western Hospital, the utility of TMS has proven invaluable
to his investigations of motor cortex functionality and of the pathophysiology and associated treatments of movement disorders.
For studies involving the motor cortex, as in
Chen’s lab, TMS pulses are typically administered to the region of the brain that controls
a specific hand muscle. Here, stimulation
produces a focal twitch in the target muscle,
which is measured with surface electrodes
placed on the hand, and visualized on an
electromyogram. This muscle response to
TMS is termed the motor-evoked potential,
the amplitude of which is thought to reflect
motor cortex excitability2,3. Thus, human
cortical excitability can be assessed using a
number of specific TMS measures that are
based on this fundamental principle.
While using TMS techniques during a research fellowship at the National Institutes of
Health, Chen quickly appreciated the versatility and uniqueness of TMS as a neurophysiological probe. “It really is a fascinating way
to study the brain,” he affirms. “By stimulating neural regions without any sort of invasive method, you can measure a subject’s re25 | IMS MAGAZINE FALL 2011 PROSTATE CANCER
sponse in a number of ways and reveal fairly
specific information about their [cortical]
physiology. There aren’t many other methods
that can offer such a direct investigation in
humans, so [TMS] is a very powerful tool.”
Upon establishing his laboratory at the Toronto Western Research Institute in 1998,
Chen predominantly adopted TMS techniques for use in his lab, which currently
focuses its studies on patient populations to
elucidate pathological mechanisms in a number of movement disorders. One of the most
commonly studied pathologies in the lab is
Parkinson’s disease (PD), a neurodegenerative disorder that causes a variety of debilitating motor symptoms, including bradykinesia, rigidity, and tremor. “Our [studies]
have revealed several cortical changes in PD
patients – as one example, we see a reduction
in one form of motor cortical inhibition,” he
notes. By understanding details such as these,
the hope is to be able to piece together how
neuronal degeneration in a disorder like PD
translates into its overt symptoms, which is
currently not well understood.
Chen’s team has also used TMS techniques
to explore deep-brain stimulation (DBS),
which is one of the most remarkable neurosurgical advances for PD and a handful
of other movement disorders. “When DBS
emerged as a new treatment around 2000,
our lab began investigating it soon after. One
of the challenges is that we still don’t know
how it works.” Chen aims to reveal potential
mechanisms of action of DBS, and specifically, explore how deep-brain nuclei (where
DBS implants are located) may be modulating the motor cortex to produce clinical improvements in patients with disordered motor control.
Other major TMS investigations in his lab include studies of normal human motor physiology, including the examination of how
different neuronal circuits interact with one
another in the motor cortex. As well, his lab
uses genetic techniques as an adjunct to examine the effects of selected single nucleotide
polymorphisms on brain functionality and
its ability to undergo plasticity and learning.
Undeniably, for Dr. Chen, TMS has proven
Photo by Paulina Rzeczkowska
Stimulation is produced by generating a
brief, high-current pulse in a magnetic coil
that is placed on the scalp of the subject. This
transient current induces a large and changing magnetic field, which subsequently produces an electric current in the underlying
brain1,2.
SPOTLIGHT
itself as a versatile and invaluable research
tool.
Magnetic Stimulation for the Treatment of Motor and Mood Symptoms
of Parkinson’s disease (MASTER-PD):
A multicentre clinical trial
Beyond its use as a neural probe, TMS has
also been studied for its therapeutic potential. A recent meta-analysis by Chen’s team
involving small pilot trials has revealed a reduction of motor symptoms in Parkinson’s
disease patients following high-frequency
repetitive TMS (rTMS) to the motor cortex. High-frequency rTMS is known to induce long-lasting, enhanced excitation in
the brain. Thus, the clinical benefit seen in
PD supports the hypothesis that rTMS may
modulate underactive brain regions to improve symptoms of the disease4.
Larger clinical trials have shown high-frequency rTMS to also be effective in reducing
symptoms of depression when administered
regularly to the left dorsolateral prefrontal
cortex (DLPFC), a region of hypometabolism
in depressed patients2,3. With depression as
one of the most common and incapacitating
non-motor symptoms in PD, these results are
also critical for the PD patient population.
and the Cleveland Clinic – Chen is leading
the sole Canadian site at the University of
Toronto.
MASTER-PD’s researchers hope to recruit
160 PD patients experiencing depressive
symptoms to participate in a randomized,
double-blinded, placebo-controlled study.
Participants will be randomly assigned to
receive either real or sham (placebo) rTMS
via four possible treatment combinations:
1) rTMS to bilateral motor cortex + sham
rTMS to the left DLPFC, 2) rTMS to left
DLPFC + sham rTMS to bilateral motor cortex, 3) rTMS to both bilateral motor cortex
and left DLPFC, or 4) sham rTMS to both
bilateral motor cortex and left DLPFC. The
rTMS interventions will be administered
over the course of two weeks, and all subjects
will undergo a comprehensive assessment of
motor, mood, cognition and quality of life at
different intervals for up to 6 months posttreatment.
“Certainly, this will be the largest study of
rTMS in PD. Hopefully it will be able to
address whether rTMS can be used for the
treatment of motor and mood symptoms in
this patient population.”
And with that, we are reminded of the ultimate goals of Chen’s TMS investigations: to
disentangle the complexities of the brain, and
more pointedly, to use this knowledge to better serve those who suffer from neurological
disease.
*The MASTER-PD trial is supported by the Michael J Fox Foundation.
References
1. Hallett M. (2000). Transcranial magnetic stimulation and the
human brain. Nature, 406(6792): 147-150.
2. Chen R. (2000). Studies of human motor physiology with
transcranial magnetic stimulation. Muscle& Nerve, S9: S26-S32.
3. Hallett M. (2007). Transcranial magnetic stimulation: a
primer. Neuron, 55(2): 187-189.
4. Elahi B, Elahi B, Chen R. (2009). Effect of transcranial magnetic stimulation on Parkinson motor function – systematic
review of controlled clinical trials. Movement Disorders, 24(3):
357-363.
Photo by Paulina Rzeczkowska
“There have been a number of studies proving rTMS efficacy in treating depression,
including a large randomized controlled
clinical trial,” notes Chen. “It is an approved
treatment for depression in Canada, and
more recently, in the US as well.” Despite
the promising rTMS results in PD, however,
Chen realizes that its effectiveness is not yet
as conclusive and explains its lack of approval
as a treatment option. “The problem [with regards to PD] is that there has not yet been any
large-scale clinical trial. The sample sizes so
far have been small – typically only 10 to 20
patients per study,” he explains. “Our metaanalysis tells us there are encouraging results,
but we need to build on that.”
To that end, Chen is currently involved in a
North American multicentre clinical trial,
termed MASTER-PD, that aims to determine
the efficacy of rTMS in modulating brain activity to treat both motor and mood symptoms in PD. Of the five centres participating
– including Harvard, the University of Florida, the University of California Los Angeles,
The versatility of TMS has allowed Dr. Robert Chen to examine human motor cortex physiology, the pathological
disruptions that can lead to movement disorders, and potential therapeutic options.
IMS MAGAZINE FALL 2011 PROSTATE CANCER | 26
CLOSE UP
Interdisciplinary Collaboration in
Critical Care
The holistic approach is greater than the sum of the scientist and the clinician
The various educational backgrounds of the
collaborators give them each a unique perspective on how to achieve the aims of the
RECOVER Program. Batt and dos Santos
are both Assistant Professors of Medicine
at the University of Toronto, and ClinicianScientists at St. Michael’s Hospital, specializing in internal medicine and respirology, and
critical care medicine, respectively. Cameron
completed her graduate training in the IMS
and is now a tenure stream faculty member
in the Department of Occupational Science
and Occupational Therapy in the Faculty of
Medicine at the University of Toronto. Herridge is an Associate Professor of Medicine
and Clinician-Scientist at University Health
Network, focusing in critical care medicine.
Despite their diverse career paths, their common interest in understanding the molecular
mediation and social implications of skeletal
muscle atrophy has united this group into an
interdisciplinary collaborative team.
Critical illness and prolonged life support is
associated with the development of severe
muscle weakness. This association is known
as intensive care unit (ICU) acquired muscle
dysfunction. Dos Santos works to understand the molecular mechanism behind mechanical ventilation-induced lung injury and
multi-organ failure, including failure of the
musculoskeletalsystem. This is largely attributable to loss of muscle tissue, or polymyopathy, but can also be due to nerve damage, or
polyneuropathy. Batt is interested in the mo-
Dr. Jane Batt
lecular regulation of muscle atrophy in acute
illness and end-stage respiratory diseases.
Among other techniques, microarray analysis is used to identify differentially expressed
genes and signalling networks in healthy versus diseased muscle biopsies from a single
patient. According to Batt, “It now seems
Dr. Claudia dos Santos
27 | IMS MAGAZINE FALL 2011 PROSTATE CANCER
Photos by Yekta Dowlati
I
nterdisciplinary collaborations between science and medicine are growing
in recognition, for justified reasons. The
comprehensive and holistic approach offered
by a team of experts is more successful than
the sum of each individual effort when striving to cure disease, improve patient care, and
reduce health care expenditure. Encouraging
a collaborative atmosphere among professionals discourages the competitive environments that are so frequently encountered in
research and medicine, and augments scientific discovery and quality of patient care. An
exceptional group of women investigating
the long-term sequelae after critical illness
offer an example of interdisciplinary collaboration within the University of Toronto. This
group works on the RECOVER Program of
Research, and is lead by Dr. Jane Batt, Dr.
Claudia dos Santos, Dr. Jill Cameron, and Dr.
Margaret Herridge. Their overarching aims
are to identify the molecular mechanisms
underlying neuromuscular disability, to determine disruption of quality of life, and to
assess the economic burden placed on families and society at large.
By S. Amanda Ali
CLOSE UP
critical illness. Herridge’s collaborative efforts include other intensivists across the
University of Toronto, province, and country,
as well as other professional team members,
such as physiotherapists and physiatrists at
Toronto Rehabilitation Institute.
Dr. Jill Cameron
Photos by Yekta Dowlati
many of the cellular signalling mechanisms
that induce muscle atrophy across a myriad
of disease processes are the same. Working
to understand this process for the purpose of
introducing interventions to combat muscle
atrophy and loss of independence will be applicable across many disease states. Muscle
weakness and dysfunction in respiratory
disease are key causes of poor quality of life,
which massively increase health resource utilization and rob people of independence.”
Working together on the RECOVER Program of Research, this team studies the neuromuscular disability incurred by long term
ventilation in the ICU and its impact on the
individual and the family. Their achievements
have been recognized by the prestigious Canadian Institutes of Health Research (CIHR).
The current RECOVER Program was initiated in 2008 with funding from CIHR, and
Batt, dos Santos, and Cameron each hold a
CIHR Career Scientist award. Conducted
with the Canadian Critical Care Trials Group,
the RECOVER Program involves 11 centres
across Canada, and exemplifies a successful
model of collaborative, translational, and interdisciplinary research. Inter-professional
leadership of core projects is encouraged, for
example, one sub-study that examines early
mobility and electrical muscle stimulation
is lead by physiotherapists. The objective of
the RECOVER Program is to serve as a national and international model of effectively
integrated professionals working to enhance
rehabilitation for patients and families following critical illness.
When asked about the factors that are necessary to facilitate collaborative projects across
disciplines and medical specialties, dos Santos replied, “Although as critical care intensivists we train as subspecialists – we treat
patients as a whole, we take care of all the
organs. Consequently, we have a tradition of
multidisciplinary medicine that is engrained
in the fabric of our practice. Our daily patient
assessment rounds are multidisciplinary:
doctors, nurses, pharmacists, physiotherapists, social workers, dieticians, respiratory
therapists, chaplains, as well as others. This
strong collaborative and entrepreneurial
spirit, combined with our clear sense of purpose (excellence in patient care) and respect
for the work and contribution of each member of the team provides the foundation for
all the work we do: patient care, research, and
teaching.”
As clinicians and scientists specializing in
biomedical and socioeconomic aspects of
ICU acquired muscle dysfunction, the collaborative effort of this team is stronger than
any one of the individual projects. Because
their multidisciplinary training facilitates
understanding from the bench to bedside
and beyond, they are able to synergistically
focus their efforts on maximizing recovery and rehabilitation for patients and their
families.
Dr. Margaret Herridge
Having a family member in critical care can
be devastating to relatives, as it can trigger
shock, anxiety, depression, and stress - all
of which can have detrimental health effects
over time. Cameron’s primary research interest is to examine the experiences of family
members who assume the role of caregiver
for individuals with disability, with the goal
of improving the health outcomes of the
care-giving population. She aims to understand caregivers’ needs, and develop timely
and relevant programs to assist them as they
provide support to patients undergoing longterm recovery and rehabilitation. Herridge’s
interest stems from earlier work done by her
group on long-term outcomes in survivors
of severe lung injury. Along with Cameron,
the goal is to build a rehabilitation and educational strategy for ICU patients, one which
effectively meets the needs of a family after
IMS MAGAZINE FALL 2011 PROSTATE CANCER | 28
SURP RESEARCH FOCUS
Bias in the
Reporting of
Randomized
Clinical Trials
Roman Shapiro
Summer Student Writing Competition winner
R
andomized
clinical
trials
(RCTs) yield the highest grade of
evidence of the efficacy and safety
of cancer treatment1. Most new therapies,
be they drug, radiation, surgery, or some
combination thereof, are evaluated in RCTs
before being approved for routine use in patients2. What makes RCTs useful is the rigour
of their design - they employ randomization
when assigning treatment3, they rely on a
treatment allocation concealment method
to ensure that the randomization scheme
is properly implemented4, and ideally they
blind patients and researchers to treatment
allocation5. With a representative patient
sample, RCTs are expected to approximate
the benefits and harms of a treatment within
the general population. The amount of literature generated from the results of RCTs is a
testament to their importance in therapeutic
decision-making.
29 | IMS MAGAZINE FALL 2011 PROSTATE CANCER
Flask photo courtesy of http://www.sxc.hu/photo/1266835; Author photo by Paulina Rzeczkowska
SUPERVISOR: Drs. Francisco Vera-Badillo and
Ian F. Tannock
SURP RESEARCH FOCUS
Given the rigour of their design, are the results of RCTs fool-proof? There are several
examples where the results of such trials did
not seem to agree with clinical reality. Rofecoxib is a cyclooxygenase-2 inhibitor whose
use for the treatment of arthritis became
widespread after favourable results from
RCTs, only to be taken off the market a few
years later when it was found to increase the
risk of cardiovascular complications6. Reboxetine was touted as an effective anti-depressant until it was discovered that publication
of data had been highly selective – once the
complete body of data concerning drug efficacy and safety were evaluated, it was found
that the drug was not only ineffective in the
treatment of depression, but harmful7.
In the above examples, the reported results
of RCTs did not correspond with reality because of bias in trial conduct, analysis, or
publication6,8. Unfortunately, the degree to
which this sort of bias affects the published
results of any RCT is unknown.
Methods to evaluate bias in RCTs are important for physicians who use results of RCTs
to guide treatment decisions. There is no
objective gold standard to evaluate bias because it is difficult to measure and can only
be estimated9. An optimal assessment of bias
requires unrestricted access to both the procedures used by the trial researchers and the
complete raw data, but such access is very
difficult to attain10. Nevertheless, there are
Not in results
table (NOT R)
Not in abstract
(NOT A)
Adverse
Event
In results table
(R)
certain criteria that can be used to estimate
the degree of bias in RCTs.
One criterion used to assess bias is the systematic evaluation of the reporting of trial
endpoints. Endpoints are outcomes being
measured by the trial, which may include
overall survival, disease-free survival, quality
of life and response rate, among others. RCTs
are designed to recruit a predefined number
of people, and to determine if a statistically
significant difference in primary endpoints
exists9. This does not mean that significant
differences in other endpoints are not important, but statistical tests applied to them are
subject to misinterpretation8. The evaluation
of secondary endpoints should therefore be
regarded as exploratory. If a publication does
not clearly indicate the results relating to the
primary endpoint of the trial and does not
describe the results of secondary endpoints
in its concluding statements, it is biased8.
Another possible criterion for the systematic
evaluation of bias is the reporting of adverse
events (AEs) associated with the experimental treatment. We developed a method to
evaluate this bias, which employed a hierarchy of AE reporting based on the sections of
a publication where AEs are most likely to be
read (Figure 1).
In each of 168 publications of RCTs evaluating breast cancer treatment, every reported
moderate to severe AE that was statistically
Not in discussion
(NOT D)
In discussion
(D)
Not in concluding
statement
(NOT C)
In Abstract (A)
In concluding
statement (C)
NOT R
R + (NOT A) +
(NOT D)
Inadequate
reporting of
adverse events
R + (NOT A) + D
Not in
discussion
(NOT D)
R + A + (NOT C) +
(NOT D)
In discussion
(D)
R + A + (NOT C) +
D
Not in
discussion
(NOT D)
R+A+C+
(NOT D)
In discussion
(D)
Less adequate
reporting of
adverse events
Adequate
reporting of
adverse events
R+A+C+D
Figure 1. Hierarchy of adverse events (AE) reporting. One possible hierarchy scheme is shown, where
the top represents the least adequate reporting of a moderate to severe AE.
different between the experimental and control arms received a score based on its position in the hierarchy. This score was used to
cluster publications that had a similar reporting of AEs. With a large enough sample of
publications, individual clusters could be defined where each represents a certain degree
of bias. A survey querying oncologists about
where they most commonly see the reporting
of AEs in publications of RCTs has been designed to test the validation of the hierarchy
in Figure 1. The results are pending.
There is substantial evidence that bias exists in the conduct, analysis, and reporting
of RCTs8-10. A measure of the degree of this
bias would be of great help to those who must
decide how much to trust the results of these
RCTs, especially when deciding whether
to apply the results to patients. Although
no gold standard exists that can be used to
evaluate the degree of bias in a publication,
methods are being developed for the purpose
of estimating this bias with the hope of minimizing its effect on clinical decision-making.
References
1. Concato J, Shah N, Horwitz RI. Randomized controlled trials, observational studies, and the hierarchy of
research designs. NEJM 2000; 342(25): 1887-92.
2. FDA approval of new cancer treatment uses for marketed drug and biological products. Food and Drug
Administration; c1998. Available from: http://www.fda.
gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm071657.pdf (accessed
August 2011)
3. Altman DG, Bland JM. How to randomize. BMJ 1999;
319: 703-4.
4. Schulz KF, Grimes DA. Allocation concealment in
randomised trials: defending against deciphering. Lancet 2002; 359: 614-8.
5. Schulz KF, Grimes DA. Blinding in randomised trials:
hiding who got what. Lancet 2002; 359: 696-700.
6. Roth-Cline MD. Clinical trials in the wake of Vioxx.
Circulation 2006; 113: 2253-59.
7. Eyding D, Lelgemann M, Grouven U, Harter M,
Kromp M, Kaiser T, Kerekes MF, Gerken M, Wieseler
B. Reboxetine for acute treatment of major depression: systematic review and meta-analysis of published
and unpublished placebo and selective serotonin reuptake inhibitor controlled trials. BMJ 2010; 341: c4737
doi:10.1136/bmj.c4737
8. Boutron I, Dutton S, Ravaud P, Altman DG. Reporting and interpretation of randomized controlled trials
with statistically nonsignificant results for primary outcomes. JAMA 2010; 303(20): 2058-64.
9. Chan AW, Hrobjartsson A, Haahr MT, Gotzsche PC,
Altman DG. Empirical evidence for selective reporting
of outcomes in randomized trials. JAMA 2004; 291(20):
2457-65.
10. Chan AW. Bias, spin, and misreporting: time for
full access to trial protocols and results. PLoS Medicine
2008; 5(11): 1533-35.
IMS MAGAZINE FALL 2011 PROSTATE CANCER | 30
VIEWPOINT
Darwin. Newton. Einstein. Popper?
By Adam Santoro
Should science students be formally educated in the philosophy of science?
Karl Popper proposed that science should not
be defined by its use of inductive methods to
construct theories, since in his view there is
no such thing as confirmation by evidence1.
To Popper, the solution to the problem of
induction was simple: no justification exists
for the use of inductive logic to formulate
31 | IMS MAGAZINE FALL 2011 PROSTATE CANCER
universal statements. Instead, empirical science is demarcated from pseudo-science by a
principle of ‘falsifiability.’ Theories are never
confirmed or made more probable. Rather,
Popper’s principle proposes that scientists
should try to falsify theories, and those
theories that best withstand falsification are
‘corroborated.’ Popper’s idea is ingenious, as
it shifts the focus away from inductive logic
and onto deductive logic. If a theory does not
withstand such a test, then it is inarguably
deduced that it is false. Nonetheless, Popper’s
philosophy is not without its faults. Hypothetico-deductivists contend that – Wait a
moment. Hypothetico-deductivist? Popper?
Isn’t he the guy on the popcorn box?
Science education at numerous ‘top’ universities does not include requisite training
in the philosophical issues underpinning
scientific practice. When does evidence sufficiently justify a theory? How do we know
when inductive inference provides us with
true knowledge? Students must partake in
self-study to answer these questions – if they
are inquisitive. But are science students failing to benefit from a formal education in the
philosophy of science?
A general understanding of the philosophy
of science is clearly advantageous for science
students. A philosophical foundation can allow students to tackle numerous contentious
issues – such as the interpretation of negative results. Above all, it can teach students to
think; it can teach them to consider science
from a broader perspective, and to eliminate
inherent biases in their thought processes.
Students will no doubt formulate their own
opinions on important philosophical issues;
they may, like Hempel1, argue that diversity,
variety, and precision of evidence are of upmost importance, or they may be predictionists and assert that scientific truth can only be
validated by the confirmation of novel predictions. However, if these opinions do not
arise via consideration from formal education, then they inevitably develop from personal contemplation, subconscious (or even
conscious) bias from the literature, and opinions of their supervisor and colleagues. Thus,
students may not be fully equipped with the
knowledge and perspective necessary for insightful deliberation.
Albert Einstein wrote to a colleague2: “When
Image: The School of Athens, (1510-1511), Raphael.
E
mpirical science is characterized
by its ability to construct universal
statements, or ‘theories,’ from singular
observations1. The formulation of a theory
from singular observations requires inductive logic; for example, with enough observed
instances of objects falling to the ground
when dropped, one inductively infers that all
objects fall to the ground when dropped. Yet
the philosophical justification for the use of
inductive logic in science is not entirely obvious. Consider the following: if an observer
views 10 000 swans and notes that each swan
is white, is he justified in concluding that all
swans are white? Why or why not? The lack
of justification for the use of inductive logic
is aptly named the ‘problem of induction.’
There is no universally-accepted solution to
this problem, despite the efforts of some of
the greatest thinkers to have lived.
VIEWPOINT
I think about the ablest students whom I
have encountered in my teaching, that is,
those who distinguish themselves by their
independence of judgment and not merely
their quick-wittedness, I can affirm that they
had a vigorous interest in epistemology. They
happily began discussions about the goals
and methods of science, and they showed
unequivocally, through their tenacity in defending their views, that the subject seemed
important to them.” If it is a philosophical
drive that distinguishes the ‘ablest students,’
then this drive should be encouraged, lest
the future of science be plagued by a glut of
monotonous, formulaic, non-truth seeking
endeavours.
I had the opportunity to take an excellent
graduate class this year. In the class, each student argued in favour of a prominent scientific theory from the literature. Unknowingly
at the time, the class provided me with great
insight into the thought processes students
had about serious philosophical issues. For
example, it was a common theme for a presenter to argue in favour of a theory because
much more evidence was available. However,
it was never stressed as to why an abundance
of evidence should offer indubitable support
for a theory (see: problem of induction). Do
inductive conclusions have more credence if
they are supported by a greater variety of evidence? What about theories that have with-
stood falsification? Do scientists even try to
directly falsify their own theories?
I met with the course coordinator, Dr. Jennifer Ryan, to discuss the course and her
opinions on graduate education. Dr. Ryan
echoed many of my beliefs; she felt that it is
extremely important for students to be formally introduced to reasoning and problem
solving. Her course was initially structured
to have students present various theories
in the literature (rather than have a debate
about them). “When I first taught the course,
I found that students had a very difficult time
writing their own thoughts. [After restructuring the course], the students were forced
to come down on one side of an issue. I think
that when students feel that it is OK to question the status quo, it becomes amazing. They
question the evidence and the methods. They
need to be pushed to think outside the box.”
However, she also stated that the issue is complex; there is also an onus on the supervisor
to encourage outside-the-box thinking. The
effects of education in the classroom would
be limited if there is pressure from above.
Popper’s influence might be relatively unknown among science students, but Albert
Einstein’s is not. In a letter, he states3: “I fully
agree with you about the significance and
educational value of methodology as well as
history and philosophy of science. So many
people today – and even professional scientists – seem to me like somebody who has
seen thousands of trees but has never seen
a forest. A knowledge of the historic and
philosophical background gives that kind of
independence from prejudices of his generation from which most scientists are suffering.
This independence created by philosophical
insight is – in my opinion – the mark of distinction between a mere artisan or specialist
and a real seeker after truth.”
Perhaps it is time for students to be trained
as real seekers of scientific truth rather than
highly advanced ‘doers’ of science. A good
start towards this goal would be to introduce
requisite training in the philosophy of science.
Disclaimer: The opinions expressed by the author
are in no way affiliated with the Institute of Medical Science or the University of Toronto. Comments are welcome at theimsmagazine@gmail.
com.
References
1. Curd, Martin, and J. A. Cover. Philosophy of Science:
The Central Issues. New York: W.W. Norton &, 1998.
Print.
2. Einstein, Albert. “Ernst Mach.” Physikalische
Zeitschrift 17: 101–104.
3. Einstein to Thornton, 7 December 1944, EA 61-574.
IMS MAGAZINE FALL 2011 PROSTATE CANCER | 32
VIEWPOINT
POSITIVE PRESSURE
The research bias towards positive results
Science involves the discovery of new results, both positive and negative. Negative results can be just
as important as positive results, as the dissemination of negative results can prevent other scientists
from needlessly repeating the same experiment, therefore saving time and resources. However, negative results are often taboo in individual labs and in peer-reviewed publications in major journals. Why
does this bias exist, and what can be done about it?
T
he scientific process involves
studying the world through observation and experimentation in order to attain knowledge (the word science
comes from the Latin word scientia, meaning knowledge). Hypotheses are formed and
experiments are conducted to assess the validity of these hypotheses. This is a self-correcting cycle and it is designed to hone in on
increasingly precise and accurate theories.
At the onset of a study, a hypothesis is created, and a corresponding null hypothesis
is also formed. While a hypothesis asserts a
relationship between two variables, the null
33 | IMS MAGAZINE FALL 2011 PROSTATE CANCER
hypothesis is a default position; for example,
the null hypothesis states that there is no relationship between the two variables under
study. A key concept in science is that experimental results are interpreted relative to the
null hypothesis. At their most basic, positive
results reject the null hypothesis, while negative results fail to reject it. It is important to
note that rejecting the null hypothesis means
that there is a high degree of probability it is
incorrect and that the alternative hypothesis
may be true – this is never absolute. Thus,
a hypothesis can never be fully proven; evidence either supports or falsifies it.
Despite the lucid nature of the scientific
method, the idea of science as a pure practice striving towards truth is flawed. There
are a number of scientific biases, despite
many countermeasures put in place to combat them. Scientists at every level encounter
a multitude of problems – for example, funding issues, equipment problems, and pressures – that often occlude their ability to treat
all results as equally important. In particular,
publication bias is the tendency to publish
positive results more than negative results.
Since this leads to an overrepresentation of
positive data, it can also lead to an overall bias
in published literature; therefore, addressing
Photo courtesy of http://www.sxc.hu/photo/1275249
By Allison Rosen
VIEWPOINT
this bias should be of high importance to the
scientific community.
one can hope that more journals will soon
follow suit.
Negative results from lab to
publication
Dr. Karen Davis, Associate Director of the
IMS and also Editor of the journal Pain, believes the publication of negative results to
be important. She discussed the implications
that could arise from the lack of publication
of negative results: “Failure to communicate
potentially important negative findings could
result in the continued acceptance and development of unfounded ideas, unnecessary
replication of experiments that waste time
and money, the clinical application of potentially dangerous therapies, or a delay in the
development of alternate ideas.”
In medical research, discovering that a drug
is efficacious, for example, or that a lifestyle
factor influences health, is clearly important.
But is it any less important to discover that a
drug does not work, or that a lifestyle factor
has no effect on a health outcome? Much of
academia is focused on the ethos of “publish
or perish,” yet the world of publishing is built
around positive, rather than negative, results.
A recent correspondence in Nature further
expounds the issue by illustrating how repressing negative results can skew the literature. National Institutes of Health researcher
Nitin Gupta (2011) writes that it is important
to publish negative results because, when
combined with significant results from other
studies in meta-analyses or reviews, less robust results may be discovered. Inclusion of
negative results in these compilations can aid
in more accurate comparisons and corrections across studies.
Gupta explains his opinions using a hypothetical experiment that failed to reach the
P<0.05 significance level. If the experiment is
repeated 19 more times, resulting in 20 total experiments, then statistically, one of the
results is going to be significant at the predetermined P<0.05 significance level. If the
one experiment eliciting positive results is
the only version of the study published, then
the results presented to the scientific community are not the closest representation of
accuracy possible.
The Journal of Cerebral Blood Flow & Metabolism has recently introduced a section
for articles in their journal “intended to provide a forum for data that did not substantiate the… hypothesis (i.e. a difference between the experimental groups), and/or did
not reproduce published findings.” A study
recently highlighted several other journals
that already make room for negative results:
The Journal of Negative Results in Biomedicine, the Journal of Negative Results – Ecology and Evolutionary Biology, and the Psychology Journal of Articles in Support of the
Null Hypothesis are listed examples (O’Hara,
2011). These wise advances are promising;
Dr. Davis expanded on her role as a journal
editor, clarifying the process by which she
edits academic articles, whether positive or
negative. “The main issue about journal publications of negative findings, in my opinion, should solely be made on the quality of
the study,” she attests. With major journals
restructuring to make room for negative
results, and academics like Dr. Davis commenting on the importance of these sorts of
changes, it is evident that this issue is one of
concern.
While it seems clear that, at least philosophically, negative results are important, most
students and researchers are mainly concerned with daily experimental challenges,
publication of papers and completion of their
degrees, and not with scientific philosophy or
the overall integrity of the scientific community. Thus, research priorities are swayed in
a direction where negative results are not a
focal point.
and networking are for,” Moayedi states. “You
get to chat with people about what you’ve
tried, and what worked and didn’t work.”
Moayedi also suggests that some negative
data may be presented in supplementary data
sections. While it is possible to hear of negative results through personal communication, it is evident that one cannot grasp the
same level of detail that would alternatively
be accessible through a scientific publication
focused on negative findings.
The bottom line
Whether through specialty journals or journal sections, word of mouth or open access
databases, negative results need to be aired
in order to maintain the integrity of our
scientific community. At present, although
some students and researchers speak highly
of the importance of negative data, one is
hard-pressed to find much research on such
results. A change is needed, and many journals seem to be moving in the right direction.
With time, one can hope that the top priorities of scientists will expand to include not
only making positive discoveries, but making
negative ones too.
Disclaimer: The opinions expressed by the author
are in no way affiliated with the Institute of Medical Science or the University of Toronto. Comments are welcome at theimsmagazine@gmail.
com.
References
Gupta, N., Stopfer, M. 2011. Negative results need airing
too. Nature 470:39
O’Hara, B. 2011. Negative results are published. Nature
471:448-449
Massieh Moayedi, a PhD candidate in the
IMS, agrees that negative results are important to disseminate, and suggests that publishing them “within the context of positive
results” might encourage publication. When
asked if the pressure to generate positive results in the lab affects the quality of his research, Moayedi asserts that if anything,
it forces him to be more meticulous. “One
needs to be as rigorous about negative results
as we are about positive results,” he claims.
IMS Magazine also asked Moayedi about his
opinions regarding whether publishing negative data would prevent unnecessary replication of experiments. “That’s what conferences
IMS MAGAZINE FALL 2011 PROSTATE CANCER | 34
BEHIND THE SCENES
Spotlight on
Kamila Lear
An inspiring balancing act
By Meghna Rajaprakash
35 | IMS MAGAZINE FALL 2011 PROSTATE CANCER
BEHIND THE SCENES
M
ost students know Kamila
Lear as the friendly Program and
Business Officer of the Institute
of Medical Science. But little do they realize
that in addition to playing a critical role at the
IMS, Lear is a part-time Sociology student at
U of T, a mother of two, a fitness enthusiast,
and an avid cook. Lear has a remarkable ability to juggle numerous responsibilities and
adapt quickly to dynamic situations, qualities that likely stem from her interesting past.
Lear was born in England, but her parents
immigrated to Canada when she was very
young. She was raised in Pointe-Claire, a municipality located on the West Island of Montreal. Although most of the residents in her
town were English-speaking, Lear’s parents
insisted that she learn French – a skill that
she began to appreciate more as she matured.
“I strongly believe that being raised as a bilingual child provided me with a significant
advantage when it came to education, employment, and social situations,” Lear attests.
Lear nurtured her interest in French language
and culture by enrolling at a French private
school called College Saint-Anne de Lachine.
She continued her education in French as she
pursued post-secondary training in Business
Administration. Alongside her studies, she
also took interest in learning culinary arts,
sign language, life drawing, art history and
needlepoint design. Lear’s early talent for
balancing many interests and activities was
the foundation to her later successful career.
Photos courtesy of Kamila Lear
Despite her love for Montreal, Lear settled
down in Toronto, where she has lived for
the past 25 years with her husband and two
sons. She began working at the University of
Toronto as the Student Liaison Officer and
Graduate Administrator in the Department
of Occupational Science and Occupational
Therapy. During this period, she was granted
an Excellence in Service award for her commitment to student services.
recruitment, student services, and business
administration,” she says.
Currently, Lear is involved in many key aspects of the IMS department, including strategic planning, preparing complex statistical
reports and reviews, advising and implementing departmental policy, assisting in the
development of new courses and programs,
and managing budgets and student issues.
Although she carries a heavy workload, Lear
enjoys her multifaceted job, particularly because she has an opportunity to work with
students.
“There are a number of things I enjoy about
my job. But, first and foremost would be
my interaction with IMS students. The IMS
seems to attract the best and the brightest
students. I believe that building stronger connections with IMS students will help us understand where we need to focus our efforts
to improve their graduate experience.”
Lear envisions a bright future for the IMS as
the department launches new initiatives. She
is especially excited about bringing about
positive change for students through a new
strategic planning process in the upcoming
year.
“There have been a lot of changes at the IMS
recently, which makes for an exciting time.
We moved to our newly renovated location
on the second floor. It is also a pleasure to
have our recently appointed IMS Director,
Dr. Allan Kaplan, join our IMS team. Under
Dr. Kaplan’s directorship, we will be launching a new and important strategic plan that
will give the IMS the integrity to make informed decisions as we move forward.”
Besides her work responsibilities, Lear serves
in many support roles for students. She is the
Departmental Advisor for the IMS Magazine
and played a critical role in the initiation and
development of the magazine. She also prepares content for publication in the “News &
Views at a glance” and “Ask the Experts” sections of the magazine. Lear is very happy to
work with Natalie Venier and the IMS Magazine team towards what she describes as “one
of the best publications around campus.”
Through her dedication to students, her ability to multitask, and her inspiring vision for
the future of the IMS, Lear truly distinguishes herself as a very valuable member of the
IMS team. Her passion for the IMS resonates
in her advice to students:
“Take advantage of this wonderful time in
your student-life by getting involved in extra-curricular activities through the IMS and
IMSSA. These opportunities will allow you
to develop important life skills and network
with students and faculty.”
Insiders Information
Favourite food: Seafood pasta
Favourite sports team: The Habs, naturellement!
Favourite quote: “Education is the most powerful
weapon which you can use to change the world.” Nelson Mandela
Favourite subject in school: Literature
Most interesting life experience: Climbing the Sydney
Harbour Bridge, in Sydney, Australia. At the top of the
bridge is the most breathtaking view of Sydney Harbour
and the Opera House.
Pet Peeve: Pessimism
Who inspires you? My family – they are the reason I
strive to do my best in everything I take on in my life.
Shortly thereafter, Lear took on the role of
IMS Program and Business Officer, a position that enabled her to capitalize on her
skills sets and interests.
“I was attracted to the position because it
gave me the opportunity to draw on my previous experience in admissions and awards,
IMS MAGAZINE FALL 2011 PROSTATE CANCER | 36
FUTURE DIRECTIONS
Dr. Aristotle Voineskos
By Zeynep Yilmaz
Combining Genetics and Neuroimaging to Understand the Etiology of Psychiatric Disorders
37 | IMS MAGAZINE FALL 2011 PROSTATE CANCER
in September 2010, he has become an Assistant Professor in the Department of Psychiatry at the University of Toronto in March
2011 and an Associate Member at the IMS in
July 2011. The fact that he has received funding from some of the most prestigious and
competitive funding agencies such as the Canadian Institutes of Health Research (CIHR)
and National Alliance for Research on
Schizophrenia and Depression (NARSAD)
further shows that Dr. Voineskos has proven
himself to be a role model to which many
young medical and research trainees aspire.
Born and raised in Toronto, Dr. Voineskos attended the University of Western Ontario for
his undergraduate studies and was accepted
to the University of Toronto Medical School
after his third year at UWO. It was during
this time that he started developing an in-
Photo by Paulina Rzeczkowska
H
ow many graduates do you
know who have earned their
academic appointment only six
months after completing their PhD? In a day
and age where academic jobs are sparse and
highly competitive, most of us may think of
such an accomplishment as unlikely and farfetched. But then again, Dr. Aristotle Voineskos is not your average young researcher.
Having graduated from the IMS with a PhD
FUTURE DIRECTIONS
for fruitful collaborations as well as new ways
to think about neuropsychiatry, leading Dr.
Voineskos to go back to Boston later on during his PhD studies to continue learning
about these cutting-edge techniques.
Having started his graduate training in Dr.
Kennedy’s neurogenetics laboratory, Dr.
Voineskos has also done some work in PET
imaging in the earlier days of his training.
Under the mentorship of Dr. Martha Shenton
at the Brigham and Women’s College at the
Harvard Medical School, he gained vast experience working with diffusor tensor imaging (DTI), a more advanced MRI technique.
DTI allows for the measurement of structural
properties in different brain regions, which
fits well with Dr. Voineskos’s passion for understanding how risk genes influence brain
structures in patients with severe psychiatric disorders, particularly schizophrenia. He
also credits the opportunities he had in the
Geriatrics Program at CAMH for shaping
his research scope. Being given a chance to
work as a part of the team and be involved in
data collection and scans led him to a whole
different area of collaboration and research
opportunities: recruitment of a healthy aging
control cohort, as well as studying healthy
aging and Alzheimer’s disease. His current
research combines multi-modal neuroimaging and genetics approaches to map gene effects in the brain with the aim of discovering
vulnerability pathways for severe mental illness. His research findings on the role of the
BDNF gene in Alzheimer’s disease have been
featured widely in the news media earlier this
year.
terest in genetics and the brain. Following
completion of his medical degree, his combined clinical and research interests led to
a residency choice in psychiatry at the University of Toronto. He recalls his rotation at
the First Episode Schizophrenia Program at
the Centre for Addiction and Mental Health
(CAMH) as a third-year resident, and how
this experience shaped his future research
interest in schizophrenia as a brain disorder.
During the fourth year of his residency training, he started his PhD with the IMS under
the primary supervision of Dr. James Kennedy. A year later, he had the serendipitous opportunity to spend six months at the Harvard
Medical School to learn about brain imaging
techniques. This opportunity opened doors
Dr. Voineskos recognizes the influence of
many mentors on this work and credits them
greatly with where he is now as a scientist.
He emphasizes the importance of the mentorship of Dr. Shenton at Harvard and Dr.
Kennedy as his supervisors, and states that
apart from research training, he has learned
so much from them about how to get funding, grant writing, and the importance of networking. He also thanks Dr. Nancy Lobaugh,
his clinical mentors Drs. Gary Remington
and Jeff Daskalakis in the Schizophrenia Program at CAMH, as well as Drs. Bruce Pollock and Benoit Mulsant in the Geriatrics
Program for their mentorship and support.
Last but not least, he acknowledges the role
IMS has played in his training and career.
“I’d like to thank Dr. Mary Seeman for being
flexible and allowing me to be away for my
imaging training,” he says and continues, “the
door was always open at the IMS, and the
staff has been wonderful and very helpful in
answering my questions on procedures and
timeline.” Having delivered the very prestigious Salter-Siminovich lecture in the 2011
IMS Scientific Day this May, Dr. Voineskos
has always seen the Scientific Day as a great
opportunity to exchange ideas and learning
more about the research of his peers. He also
recalls having enjoyed taking IMS courses,
which gave him the chance to meet faculty,
explore areas relevant to his research in an
in-depth fashion, as well as publish highcaliber scientific papers resulting form his
course work. As the Director of the Kimel
Family Translational Imaging-Genetics Research Laboratory at CAMH, Dr. Voineskos
is eager to pass his research experience to
a new generation of research trainees: he is
currently supervising two Master’s level IMS
students and is looking forward to expanding
his laboratory.
One piece of advice Dr. Voineskos has for
IMS students has undoubtedly shaped his
young but stellar career, “having a great set of
mentors is at least as important as your specific research focus; keeping an open mind
may open many doors for you in an unexpected fashion.” He highlights the benefits
of learning as much as possible from each
mentor and taking their best qualities to better yourself and your research skills. He also
reminds the students the importance of hard
work and staying motivated to succeed. Having been an avid participant in sports from
a young age, he also emphasizes the importance of work-life balance.
Indeed, this is not the typical career of a
recent PhD graduate. At the age of 33, Dr.
Voineskos has achieved success that many
senior researchers have not had in their long
careers. His stellar accomplishments surely
are inspirational to graduate students interested in research as well as aspiring medical
trainees and residents. Most importantly, the
achievements of Dr. Voineskos serve as a testament to the importance of a solid research
training, dedication, devotion, flexibility and
eagerness to learn from others as the hallmarks of success and a fruitful research career.
IMS MAGAZINE FALL 2011 PROSTATE CANCER | 38
FUNDING
Cancer Donations
Making Your Dollar Count
By Tetyana Pekar
What should individuals look for in a
charity and where would donations make
the most impact?
Firstly, it is important to examine the charity’s mandate, which should be readily available on its website. The CCS, for example, in
addition to funding cancer research, seeks to
decrease cancer incidence rates and improve
the quality of life for those living with cancer.
It accomplishes this goal through health promotion and public policy changes and by developing and funding programs for patients
and caregivers2. Therefore, it is not surprising
that the CCS has made a decision to spend
less money, proportionally, on research, in
order to focus on these areas of their strategic plan. As such, when the priority is to contribute solely to research, individuals should
donate directly to research institutions.
39 | IMS MAGAZINE FALL 2011 PROSTATE CANCER
It is also advisable to evaluate how the charity allocates their donations and revenue, and
the transparency of this information on the
organization’s website. For the CCS, this information is readily available on their website and a quick look reveals that some of the
information in the CBC report is misleading.
In particular, administration costs amount
to just 4% of the CCS’s total revenue4. Low
overhead costs may not necessarily be a good
thing from a business standpoint, as employees need adequate salaries and equipment to
be proficient at their jobs. The CBC Marketplace analysis also includes the money spent
on marketing and prizes of lotteries under
fundraising costs, artificially manipulating
the relative percent spent on fundraising. In
actuality, while the CCS spent $22,988 million on marketing and prizes, they made only
$23,869 million in revenue, which results in a
net gain of a modest $881 million3, 4.
Finally, it is of benefit to consider the effectiveness of the programs that have been
funded, supported or initiated by the charity.
Without evidence of results, money spent on
cancer education and promotion is not justified. Charities should have a method for evaluating the success of their programs. Monitoring, evaluating and openly disclosing the
effectiveness of the organization’s programs
are critical attributes of outstanding charities.
In addition to the above considerations, it is
important to identify a cause where donations make the most impact. Charity Intelligence Canada (CIC) facilitates this process
by pinpointing the most effective and effi-
cient charities, as well as underfunded causes.
A recent CIC report focusing on cancer suggests donating to some of the least funded
cancers in Canada: pancreatic, stomach,
lung and colorectal. According to CIC, these
cancers together represent 46% of potential
years of life lost (an estimate of the average
years of life an individual would have lived if
they had not died prematurely) and have the
lowest 5-year survival rates; yet, they receive
only 15% of cancer-specific research funding
and only 1.6% from cancer-specific charities5. Unsurprisingly, the CIC report states
that when evaluating the donations based
on potentials years of life lost, Canadians donate 151 times more to breast cancer-specific
charities than to the four most lethal cancers
combined5.
Given these considerations, donors should
be careful when considering potential charities and causes. A more detailed examination
enables donors to make the most impact with
their money by contributing to effective and
underfunded charities.
References
1. http://www.cbc.ca/news/canada/story/2011/07/04/
cancer-society-funding.html
2. http://www.cancer.ca/Canada-wide/About%20us.
aspx?sc_lang=en
3. http://www.globalphilanthropy.ca/index.php/blog/
comments/cbc_report_on_canadian_cancer_society_thoughts_on_transparency_media_cover/
4. http://www.cancer.ca/Canada-wide/About%20us/
CW-Financial%20statements.aspx?sc_lang=en
5. Charity Intelligence Canada - Cancer Report: Framing the Crisis and Previewing the Opportunity for
Donors. Greg Thomson and Karen Greve Young April
2011
Photo courtesy of http://www.sxc.hu/photo/954631
T
he canadian cancer society (ccs)
came under scrutiny in early July
when a CBC News story revealed that
the organization spends proportionally more
money on fundraising and administrative
costs than on research. According to CBC’s
Marketplace analysis, research spending decreased from 40.3% of the total expenditures
in 2000 to 22% in 2011, while fundraising
increased from 26% to 42.7% during that
time1. Researchers quoted in the article and
commentators on the webpage were angry
at the “inefficient” and “wasteful” spending.
Although many believe that the CBC story
is misleading, it highlights the importance
of identifying charities whose mandate and
spending align with donor’s priorities.
Ask
the
Experts
Dear Experts,
Last year I applied for several external Master’s student awards. Unfortunately, I did not
receive any. I am planning to transfer to a
PhD program next year; I haven’t had any
publications since then. Should I apply for
an external award again this year? Are there
specific requirements about the number of
publications a Master’s student or a PhD student must have in order to defend?
- Award Woes
Dear A.W.,
Both publications and awards are great to
have on one’s CV. The more publications, the
greater the likelihood of getting awards, and
the more awards, the greater the likelihood
of obtaining further awards. That being said,
neither publications nor awards are prerequisites to either transfer or defend.
Dear Experts,
I am set to have my PAC meeting in a few
weeks. I tend to get very nervous at my PAC
meetings and often blank out on simple
questions. Do you have any advice?
- Presentation Jitters
Dear P.J.,
It is a good idea to let your committee know
in advance that you tend to become nervous
during exam-like situations. Also let them
know that you have studied hard and that
when you blank out it is not because you
don’t know the answer. It is also a good idea
to consult with student services about programs that will help you with nervousness.
The problem is a common one and lots of
help is available. The graduate coordinators
may be able to suggest specific avenues of
help as well.
Dear Experts,
I’m hoping to start a Master’s program next
year. What are some key qualities I should
look for in a supervisor?
- Searching for Supervisors
Dear S.S.,
You will want a supervisor who is doing the
kind of work you are interested in and who
is doing it well (e.g. publishing, receiving external grants, enjoying the respect of peers).
Visiting the laboratory and talking to present and past students will give you an idea
of the supervisor’s accessibility, mentoring
style, and general “likeability” – all important
qualities.
Dear Experts,
Recently a graduate student, who is registered with the IMS, joined my lab. I have a
cross-appointment with another graduate
department which has very strict criteria for
Program Advisory Committee (PAC) meetings (i.e. progress reports, time restrictions
on presentations, etc.). Can I advise my IMS
student to follow the same criteria for their
PAC meetings?
- PAC Concerns
Dear P.C.,
It is up to the supervisor (in consultation
with the student and the PAC members)
to decide how the PAC meetings should be
structured. The more formal, the better prepared the student will be to face exams. The
students are advised to prepare an outline of
their presentation beforehand and distribute
it to the committee. They are also advised to
take minutes during the meeting, write them
up, and distribute them to the committee afterwards.
Dear Experts,
I recently was invited for an admissions
interview from my graduate program.
What kinds of questions can I expect?
How can I prepare?
- Imminent Interview
Dear I.I.,
The interviewer will want to know what
you are interested in doing during graduate school and why. Interest, understanding, curiosity and enthusiasm are usually
what they look for. There won’t be any
“trick” questions. They will want to know
what motivates you and why you are applying.
EXPERT TIP
Grant writing is a skill that can only
be perfected with practice.
Do you have a question for the experts?
Please send it to theimsmagazine@gmail.
com (ATTN: Experts)
IMS MAGAZINE FALL 2011 PROSTATE CANCER | 40
IMS students reveal their hidden talents at IMSSA’s Annual Talent Show. This event
raised $1100 for the construction of a hospital ward
in Jinja, Uganda. (Sponsors:
Steamwhistle and Pizza
Nova.)
Talent Show photos courtesy of IMSSA
Summer student photo courtesy of Ryosuke Ikeda
PAST EVENTS
Summer Student photo by Mohammed Sabri
Summer Research Day photos courtesy of IMSSA
PAST
EVENTS
Left: Philip Alves, Ryosuke Ikeda and Fatma
Aksoy enjoy their summer student experience
at Sunnybrook Hospital.
Right: Zeynep Yilmaz and
Atiqa Malik volunteer
their time to assist summer students at the IMS’
Summer Research Day.
Left: Dr. Lyle Palmer gives
the inaugural Ori Rotstein
Lecture at this year’s
Summer Research Day.
Right: Later he assists in
judging student presentations. (right)
41 | IMS MAGAZINE FALL 2011 PROSTATE CANCER
DIVERSIONS
WHAT’S UP, TORONTO?
SUDOKU
2
1
5
8
6
3
6
4
9
7
4
9
2
6
6
9
2
5
1
4
5
3
1
1
3
4
For the Halloween buff
6th Annual Toronto After Dark Film Festival – October 20-27, Toronto Underground Cinema
(http://torontoafterdark.com/2011)
Halloween Howl - October 22 & 29, Toronto Zoo
(http://www.torontozoo.com/events/?pg=HalloweenHowl)
For the budding philanthropist
Ontario Lung Association – The Amazing Pace – October 29 – starting location Yonge/Dundas Square (http://www.theamazingpace.ca)
1
7
8
1
3
YOUR EVENTS GUIDE FOR THE SEASON
2
For the arts lover
The Rendezvous with Madness Film Festival – November 4-12, multiple venues
(http://www.rendezvouswithmadness.com)
Maya: Secrets of their Ancient World - Opens November 19, Royal Ontario Museum
(http://www.rom.on.ca/exhibitions)
For the Holiday spirit enthusiast
Cavalcade of Lights – November 26, Nathan Phillips Square (http://www.toronto.ca/special_events/cavalcade_lights)
Skating at the Harbourfront Centre – starting November
(http://www.harbourfr ontcentre.com/skating)
Christmas by Lamplight (“Step into a Dickens Christmas”) - December 10, 17 & 18, Black
Creek Pioneer Village (http://christmasbylamplight.ca)
Movember
competition
Movember (the month formerly known as November) is a moustache-growing charity event held
during November of each year to raise funds and awareness for men’s health. If you plan on growing
a moustache worthy of publication, please send your photo to [email protected] (ATTN:
Movember Competition) by December 1, 2011. If you are voted to have the best ‘stash, we will
publish a photo of you and your moustache in the next issue of the IMS Magazine!
Solution to Sudoku from Summer 2011 issue of
the IMS Magazine
Answer: This is a magnified photo of…
(1) A neural stem cell
“Piled Higher and Deeper” by Jorge Cham http://www.phdcomics.com
IMS MAGAZINE FALL 2011 PROSTATE CANCER | 42
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