IMS Magazine Fall 2011 by IMS Magazine

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 yearâ&#x20AC;&#x2122;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

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.

IMS SURP Highlight

Check out the highlights from this year’s Summer Undergraduate Research Program (SURP) and Summer Student Research Day.

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 theimsmagazine@gmail.com

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.

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Photo courtesy of Spekta, http://en.wikipedia.org/wiki/File/Various_scalpels.png

Tell us what you think

LETTER FROM THE EDITOR

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 yearâ&#x20AC;&#x2122;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. Iâ&#x20AC;&#x2122;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

OGS scholarship applications due to IMS office; OGS application goes offline

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 and the University of Toronto. She is moving to Alberta with her fiancé, Anthony. Dianne’s last day with the IMS was on Friday, September 30th. Dianne first joined the IMS in June 2008 as our Departmental Assistant. She quickly moved 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 sf.medscience@utoronto.ca or call 416-946-7143 for student and faculty related inquiries. We will be monitoring both email and voice mail message systems.

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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: theimsmagazine@gmail.com

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 Congratulations to the newly elected 2011-2012 IMSSA council! Thank you to all students who submitted nominations and participated so eagerly in this year’s election. We look forward to an enjoyable and productive year ahead.

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 degree in a health related field in Canada. These candidates are expected to have an exceptionally high potential for future research achievement and productivity. Applications are completed through the  CIHR website and submitted to the IMS office. 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 students who are pursuing a PhD degree in a health-related field in Canada or abroad. 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. The 2012-2013 application form and program details can be found on the OGS website.

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 2. Joseph-Armand Bombardier Canada Graduate Scholarships (CGS): Doctoral Scholarships. The SSHRC Doctoral Fellowships and Joseph-Armand Bombardier CGS Doctoral Scholarships aim to develop research skills and assist in the training of highly qualified personnel by supporting students who demonstrate a high standard of scholarly achievement in undergraduate and graduate studies in the social sciences and humanities. Joseph-Armand Bombardier CGS Doctoral Scholarships are valued at $35,000 per annum for 36 months. SSHRC Doctoral Fellowships are valued at $20,000 per annum for 12, 24, 36 or 48 months. SSHRC determines the value and duration of an award based on the number of months of full-time study (or equivalent) the applicant will have completed 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: Richie Jeremian 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: Joana Dida 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 Brett Jones 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: Josephine D’Abbondanza 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 you can join their Facebook 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

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) Queenâ&#x20AC;&#x2122;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

PROSTATE CANCER OVERVIEW 10.2 27.5

40.1

34.7

% MORTALITY OF CANCERS IN MEN

Prostate

% INCIDENCE OF CANCERS IN MEN

Lung Colorectal

28.3

Bladder Non-Hodgkin Lymphoma Pancreatic

4.5 5.8

Other

4.2

14.1

12.5

4.7

Canadian Cancer Statistics, 2011

13.4

PREVALENCE IN CANADA

In 2011 there will be 25,500 new cases and 4,100 prostate cancer-related deaths. 70 Canadian men will be diagnosed with prostate cancer every day. 11 Canadian men will die of prostate cancer every day.

122 per 100,000

Most common cancer type in Canadian men.

4 in 28 men will develop prostate cancer. 1 in 28 men will die from prostate cancer.

Canadian Cancer Society, 2011

OTHER RISK FACTORS

<50 50-59 60-69 70-75 >75

A dramatic increase in prostate cancer risk is seen in men over 50 years of age.

0.22% 2.13% 6.71% 5.25% 11.6% Prostate Cancer Canada, 2011

13 | IMS MAGAZINE FALL 2011 PROSTATE CANCER

RACE The risk of prostate cancer is highest among blacks, intermediate among whites, and lowest among native Japanese. There may be a link between levels of testosterone and risk, with black men having the highest levels.

DIET

Studies suggest that a diet high in saturated fat may contribute to prostate cancer.

HEREDITY

Genetics can play a role in whether a man develops prostate cancer. It is estimated that up to 10% of cases diagnosed are due to a genetic mutation that has been passed down.

National Cancer Institute, 2011

Illustrations by Andreea Margineanu

AGE-ASSOCIATED RISK

FEATURE

sacrum

urinary bladder rectum seminal vesicle

prostate urethra penis scrotum

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.

Prostate Cancer Canada, 2011

STAGING

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.

Stage I

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).

Stage IIA

Stage IIB

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

Stage III

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.

Stage IV

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. Prostate Cancer Canada, 2011

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

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.

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FEATURE

The Role of Diet and Exercise in Prostate Cancer

Dr. Vasundara Venkateswaran PhD Associate Professor of Surgery, University of Toronto

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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

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 â&#x20AC;&#x201C; particularly diet â&#x20AC;&#x201C; 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, Ď&#x2030;-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 8152â&#x20AC;&#x201C; 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: 176â&#x20AC;&#x201C;183, 2011.

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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

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

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.

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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

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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

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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).

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FEATURE

Dr. Neil Fleshner MD, FRCSC, MPH Head of Urology, University Health Network Professor of Surgery, University of Toronto

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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.

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The Future of Prostate Cancer Research

FEATURE

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 oneâ&#x20AC;&#x2122;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.

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SPOTLIGHT

Transcranial magnetic stimulation

An investigational tool and potential therapeutic option in movement disorders

By Nina Bahl

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.

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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. Michaelâ&#x20AC;&#x2122;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, â&#x20AC;&#x153;It now seems

Dr. Claudia dos Santos

27 | IMS MAGAZINE FALL 2011 PROSTATE CANCER

Photos by Yekta Dowlati

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

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 â&#x20AC;&#x201C; 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.

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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.

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?

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 â&#x20AC;&#x201C; 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 â&#x20AC;&#x201C; for example, funding issues, equipment problems, and pressures â&#x20AC;&#x201C; 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

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BEHIND THE SCENES

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,

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FUTURE DIRECTIONS

Dr. Aristotle Voineskos

By Zeynep Yilmaz

Combining Genetics and Neuroimaging to Understand the Etiology of Psychiatric Disorders

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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

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.

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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

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)

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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)

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DIVERSIONS

WHAT’S UP, TORONTO?

SUDOKU 2 1 5 8 6 3 6 4

7 4 9

2 6

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

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 theimsmagazine@gmail.com (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

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