The genetic basis of oxygen-deprived tumours

PhD candidate Vinayak Bhandari studies genetic drivers of cancer

The genetic basis of oxygen-deprived tumours

A recent study published in Nature Genetics sought to determine the effects of hypoxia — low levels of molecular oxygen — on the development of cancer, including how it may speed up cancer growth. Lead author Vinayak Bhandari, a PhD candidate in U of T’s Faculty of Medicine and the Ontario Institute for Cancer Research, examined hypoxia in over 8,000 tumors across 19 tumour types.

Hypoxia can have detrimental health effects, one of which is that it can cause cancer cells to proliferate. 

According to Bhandari, normally, blood vessels in our bodies are well-organized and able to transport nutrients, including oxygen, to all cells. This changes in tumours.

“In tumours, the blood vessels are often very disorganized and have sluggish blood flow,” wrote Bhandari in an email to The Varsity. This leads to low-oxygen tumours. “Around half of all solid tumours end up with low levels of oxygen.”

Hypoxic conditions can accelerate the spread of aggressive cancer cells. In tumours, cancer cells exist with different sets of mutations. Some cancer cells will be susceptible to hypoxic environments due to their specific mutation, and these cells often do not survive. 

“But other cells that have a specific mutation may not be affected by low oxygen,” wrote Bhandari. “So you end up enriching the tumour for cells with that aggressive mutation that can survive an extreme environment and you get a more aggressive cancer.”

Despite the threat that hypoxia poses, it has previously been a challenge to study its effects due to the invasive and difficult process of measuring oxygen levels in tumours. 

To remedy this, Bhandari and his team created an innovative method for examining tumour hypoxia in more detail. 

“We used several mRNA signatures to computationally quantify tumour oxygen levels with existing patient data. We then used this hypoxia information and looked broadly at lots of different genomic features of tumours and found some really interesting links in several cancers,” wrote Bhandari. “We then dug deeper into prostate cancer where we have really good long term data for how patients respond to treatments and we looked further into interactions between hypoxia, changes in the DNA and also how tumours change over time.”

Dr. Paul Boutros — former Associate Professor at U of T’s Department of Medical Biophysics, now at the University of California, Los Angeles, and the supervisor for this study — added that hypoxia and its relevance to cancer growth is still not well understood, but that this research is a significant step. 

“I think other researchers are going to be able to take advantage of these data to explore a lot of new angles,” wrote Boutros. 

Boutros believes that other researchers will begin to look at genomics associated with hypoxic cancer cells, and begin to look more into genomic data in a new light. Boutros also adds that this research highlights how hypoxic environments arise due to different factors aside from genetic mutations, including cell morphology and evolutionary properties. 

Bhandari emphasized the multidisciplinary nature of the team involved in the research, and how it was an asset. 

“We were only able to do this because we had biologists, chemists, data scientists, statisticians, engineers, pathologists and radiation oncologists come together to work on this problem in asymmetric fashion. Everyone contributed in important ways over many years and I think this is the best way forward for answering difficult questions.”

Bridging the technological divide in Canadian health care

Electronic Medical Records and patient care

Bridging the technological divide in Canadian health care

In Canada, a battle rages in health care. On one side stands a relatively stagnant health care system, already expensive but comparatively effective, with a legacy of poor technology integration. On the other side, investment in technology has the potential to not only reduce costs but also produce better patient care.  

Initially, further tech-focused investment would make health care even more expensive for the government. In Ontario alone, health care spending equates to 43.2 per cent of all provincial expenditures. Across Canada, health care amounts to about 11 per cent of gross domestic product (GDP), or $4,919 per year per person, as of this year. As a percentage of our GDP, we have the fourth most expensive social health care system of 28 comparatively wealthy countries, falling short of only Switzerland, France, and Norway. However, our above-average spending nets above-average results.

Compared to other wealthy nations, Canadians experience an above-average quality and quantity of health care. Canada consistently ranks highly on the majority indices that measure efficacy, despite having fewer physicians, long wait-times, and less equipment. Canada is ranked first at preventing and reversing debilitating illness, and also boasts above average cancer survivorship rates, above average healthy-age expectancies at 73.2 years, and above-average life expectancies at 81.9 years. These accomplishments have been achieved with our existing low-tech system. For example, we are without a consistent system and centralized database for recording personal medical information or automatically communicating medical files, at times even at the same hospital.

The adoption of Electronic Medical Records

To learn more about Canada’s relationship to health care technology, I investigated Canada’s partial adoption of Electronic Medical Records (EMRs). I spoke with Dr. Muhammad Mamdani, Director of the Li Ka Shing Centre for Healthcare Analytics Research and Training at St. Michael’s Hospital in Toronto; corresponded with Christina Christodoulakis, a PhD candidate in computer science at the University of Toronto; and interviewed Davey Hamada, a registered nurse in British Columbia.

According to Mamdani, “there seems to be a general consensus that the adoption of tech [into health care] is a good thing.” Christodoulakis’ U of T-based research reflects this: she found that in Canada, about seven per cent of tests are ordered because practitioners are unaware of already relevant results. A central database of EMRs that is used and updated consistently would solve this problem. The benefits of EMRs include improved speed of finding records, prevention of handwriting illegibility, aid in the early identification of diseases, assistance in targeting services based on risk, help with long-term monitoring of patients, and improved immunization consistency.

Hospitals and smaller family practices have been slowly and irregularly integrating EMRs for the past 30 years. Most of these earlier databases were designed by software engineers with little input from medical professionals. This meant that their software was not functional for practitioners — sometimes queries were too rigid or irrelevant information was readily displayed while critical information was hard to find. According to Christodoulakis, “some physicians reported that they sometimes stop using EMRs because hunting for menus and buttons disrupts the clinical encounter and hinders doctor-patient interaction.”

At present, software packages from different manufacturers seldom work together. Mamdani explained that “often patient records have to be printed out and delivered by mail.” This slows down the treatment process and further clogs the system. This lack of electronic communication also exists within institutions, where medical professionals print records for hand delivery. The poor integration of software and communication often opens the door for third-party organizations to perform patchwork to mend discontinuous records together, as is the case with Alberta Netcare and ConnectingOntario. But it is important to note that privatizing health care record management can carry serious consequences for patients and the health care system as a whole.

Though records are currently scattered among hard copies and various software, it is possible to unite the system. As Christodoulakis’ research notes, adopting or changing EMR systems requires “training, maintenance, IT support, system upgrade and data storage, governance and migration costs,” often too expensive a barrier for small and medium-sized institutions. Based on an estimate from 2010, the financial cost equates to $10 billion. But integration of an efficient database of medical records is just the tip of the iceberg.

Addressing the divide

According to Hamada, “health care providers have been in many ways slow to adapt to the technological boom.” He explained, “This is in part due to our education, which is lacking in any content regarding technological innovation and also the lack of foresight in the institutions that we work for.” Hamada’s workplace has not adopted EMRs, seldom uses software beyond email, and the state-of-the-art equipment he uses runs on an operating system that has not been supported since 2014.

For Hamada, adapting to changing tech is easy. But at his workplace, a recent change in the process of ordering porter services, or facility managers, continues to confuse many despite having support hotlines available throughout their upgrade. Mamdani and Christodoulakis both confirmed that some health care professionals are resistant to the technology making its debut in the health care system.

This is in part because people dislike change and re-learning concepts, but also due to a lack of transparency in data use. Hamada reports that at his workplace, data is collected but its use is a mystery. “In order for nurses to see data as a positive thing, there needs to be greater transparency and involvement around changes made based on evidence,” he said.

Mamdani, a renowned leader in health care, has emphasized facilitating communication between disciplines throughout his career. He integrates tech, economics, and data science into his team, and advocates for strong leaders to continue to bridge the technological gap. He believes that this systemic divide will continue to exist until teams learn to find a common language and talk to each other.

Mamdani’s team includes a few data scientists who work closely with health care professionals to build a data-friendly culture. Their research has been able to predict, with 80 per cent accuracy, the length of patient stays. Data science facilitates communication with the whole team and allows a more unified progression for the patient’s care. His team has also been able to predict trends in staffing, which saves approximately $200 million for St. Michael’s Hospital and could save up to $800 million for others.

Technological change, along with all of its benefits, comes with a very real cost. In Hamada’s workplace, the technology remains in the shadows because qualified health care professionals excel at what they are best at — taking care of people. The numbers show that Canadian health care is effective, even without consistent EMRs or databases that communicate. The cost of tech disturbs that status quo. But a centralized database would likely reduce redundancies in health care and improve efficiency. Advanced analytics has the strong potential to push our health care system to better look after us, especially as our population ages.

Improving outcomes and better integrating the health care system into the digital world is an important pursuit — but it must be checked with an emphasis on people and care over all else. In an ideal application, technology would and should improve our ability to take care of one another.

The Varsity has reached out to Campus Health Services, which declined the interview request, as well as the Gerstein Crisis Centre.

Canada’s chronic drug shortage

U of T alum addresses long-term problem in desperate need of a solution

Canada’s chronic drug shortage

Need a vaccination for an upcoming trip? Is a refill on your prescription required soon? While these might seem like easy problems to fix, getting that vaccine or refill could be harder than you think.

Though Health Canada created a Multi-Stakeholder Steering Committee on Drug Shortages in 2012 to tackle the drug shortage issue and also implemented mandatory reporting of anticipated and actual drug shortages by drug manufacturers in 2017, the problem continues to persist.

Dr. Jacalyn Duffin, Professor Emerita at Queen’s University and graduate of U of T’s Faculty of Medicine, has been a staunch communicator on the issue.

Duffin founded canadadrugshortage.com, a platform that tracks drug shortage issues in Canada. According to Duffin, individuals who rely on generic products are most likely to be affected by drug shortages.

She also pointed out that “people can be affected by it without knowing,” expressing her concern that media attention on the shortages of bupropion and EpiPens takes away from the fact that “there are literally [hundreds] of other drugs in short supply at any given time.”

Since 2010, physicians and pharmacists in Canada have been struggling to get vaccinations and prescription medications to their patients due to a drug shortage problem. As a result, those who require these medications end up relying on alternatives that could be less safe and less effective.

One of the drugs undergoing a national shortage is the antidepressant bupropion. This shortage is especially problematic since there are no available alternatives to the medication.

Also of concern is the shortage of EpiPens, which are manufactured by only one supplier in Canada. This shortage is so extensive that Health Canada has gone so far as to recommend patients keep and use expired EpiPens in cases of an allergic reaction. Considering that about four per cent of Canadians have food allergies, it’s not farfetched to assume that many U of T students would be affected by this shortage.

It might be confusing that drug companies, whose priorities are to research, develop, and supply drugs to people in need, are failing at one of these vital tasks. However, getting a pill or vaccine to the public is a process that involves much more work than one might think.

A single drug must go through review, authorization, manufacturing, procurement, and distribution before it can be delivered to patients by their primary health care providers. A holdup during any one of these processes can cause a drug shortage.

Among the most prevalent of these setbacks are a lack of raw materials, difficulties in manufacturing, regulatory disturbances, business decisions, and unexpected surges in public demand.

Many of these issues are difficult for both pharmaceutical companies and the Canadian government to combat as they arise. For example, raw materials required for certain drugs often need to be imported from other countries. Issues like contaminated supply from one of these imports can cause an immediate holdup in the drug manufacturing pipeline.

The expiration of medications and vaccines is another way in which the science of drugs and vaccines can also play into shortages. Vaccines especially should not be administered after their expiration date, as they lose their potency and efficacy over time. Companies seek to clear their shelves before vaccines expire, as it can be an expensive ordeal to make them just to throw them away, but this makes maintaining a backup supply difficult if a surge in public demand occurs.

“We can’t talk about solutions [until] we understand the causes,” wrote Duffin.

She also added that we can’t understand these causes until shortages are measured and an essential medicines list is made to better monitor drug supplies and sources.

Such a list would include 200–500 medicines that the government would commit to keeping in stock at all times. In a 2016 report, Duffin laid out the costs and benefits of such a commitment and provided examples of where such a list has improved the quality of care in at least seven other countries.

With shortages averaging 1,000 per year in Canada between 2014–2017 and affecting more than 1,200 products, the drug shortage problem is only on the rise. In a more recent report on the current situation, Duffin and her colleagues urged Health Canada to provide an annual report on the drug shortage problem to “define it, explain it and, above all, solve it.”

Until then, U of T students and other residents of Canada will have to hope that a drug shortage won’t affect them next.

‘Black box’ collects data from the operating room

U of T professor Teodor Grantcharov’s invention could improve medical outcomes

‘Black box’ collects data from the operating room

Akin to a black box in an aircraft, a black box in the operating room (OR) can provide valuable insights.

The OR black box records information during a surgery that is then analyzed to determine how interactions between the surgical team, the environment, and human components factor into patient outcomes.

Dr. Teodor Grantcharov, staff surgeon at St. Michael’s Hospital and professor in the Faculty of Medicine, developed the OR black box in 2017. One of the driving reasons for creating it is that the operating room can be secretive.

“The reason why we developed it is because we felt that we lack transparency, we lack data about our performance as surgeons, as teams, as organizations. We lack data from the operating room,” said Grantcharov.

“Nobody knows what happens there,” said Grantcharov. “Whatever happens there stays there, and we make mistakes, we have successes and failures, but we have very little opportunity to understand them, to study them, and to improve in the future.”

According to Grantcharov, the black box could change this and allow health care providers to recognize and learn from their mistakes, and improve medical outcomes for patients.

“Without data, we can’t improve, and we felt that the OR black box could provide some more insight and some more data that we could use to critically reflect and see opportunities to get better,” said Grantcharov.

The black boxes document everything that occurs in an operating room, and not just the surgical procedure.

It collects video recordings, audio, environmental factors like fluctuations in noise levels and temperature, and minute details like the opening and closing of doors. Furthermore, it collects information on the performance of the surgical team, patient physiology, and the instruments used.

Grantcharov added that the black box analyzes correlations “between performance and outcomes, between stress and performance, between fatigue and performance, and between communication and performance, in any particular outcome.”

Improvements in health care can be made from analyzing such data.

For example, data from the black box indicated that the more people were in the room, the higher the risk of an error.

“We looked at the policy of our hospital which was ‘keep room traffic to a minimum,’” explained Grantcharov.

“So now, we can say for this type of procedure, there shouldn’t be more than 10 people or eight people, and if there are more they [have to] come another day,” continued Grantcharov. “[We] can create the system where we reduce, we restrict access, we can create a system where we eliminate the external communication, especially in most critical steps of the procedure.”

Currently, OR black boxes are used at St. Michael’s Hospital, Humber River Hospital, and North York General Hospital.

To evaluate the effectiveness of the OR black box, Grantcharov and his team need sufficient data to observe trends and draw conclusions.

In fact, associate professor at the Dalla Lana School of Public Health Patricia Trbovich and her research team are using grants from the Natural Sciences and Engineering Research Council and the Ontario Centres of Excellence to examine the data black boxes collect and their overall effectiveness.

The instrument also allows medical staff from around the world to learn from one another.

“We can see, if we do something here and a team of surgeons does the same thing in Amsterdam… what are the things that we do better than them so that they can learn from us,” said Grantcharov. “And we want to see what are the things they do better than us so we can learn from them. There is always something to learn from others.”

The OR black box has been used for minimally invasive procedures like laparoscopic surgeries, in which operations happen through small incisions with the aid of a camera. But Grantcharov added that the black box can capture data from any procedure, even ones outside of the OR.

For Grantcharov, the optimal achievement of the OR black box lies in culture change.

“[It can] allow us to make surgery more open, more transparent, and less mystical for patients. [It makes] the operating room more collaborative,” said Grantcharov.

The Screen Project slashes wait times for breast cancer screening

Women’s College Hospital initiative tests for BRCA1 and BRCA2 gene mutations

The Screen Project slashes wait times for breast cancer screening

Government-sponsored screening for breast and ovarian cancer in Canada can take up to a year to occur and can be denied based on a patient’s risk profile. To shorten wait times and offer universal testing, the Familial Breast Cancer Research Unit at Women’s College Hospital (WCH) has introduced The Screen Project initiative, which aims to make screening universally accessible to patients over 18 in Canada, and hopefully produce better patient outcomes.

The Screen Project has discounted its regular screening price to $99 USD for October, which is Breast Cancer Awareness Month. Ordinarily, the research unit screens patients for $165 USD. Results are expected within two to four weeks.

Why isn’t government-funded screening universal?

According to Dr. Steven Narod, Director of the Familial Breast Cancer Research Unit at WCH, screening through Canada’s universal healthcare system costs around $2,000–3,000 and wait times can last up to one year. As a result, as little as three per cent of women are eligible for the test per year.

But in 2017, the Familial Breast Cancer Research Unit found that commercial genetic testing could be completed in a shorter amount of time and for a fraction of the cost by sending samples to Veritas Genetics, an American genetic sequencing laboratory with whom the Unit has partnered for The Screen Project.

Veritas Genetics tests for BRCA1 and BRCA2, which are gene mutations associated with breast cancer. Women with a BRCA mutation have up to an 80 per cent lifetime risk of breast cancer and a 40 per cent lifetime risk of ovarian cancer versus a 12 per cent and a 1.3 per cent lifetime risk for women without the mutation, respectively.

How does the project work?

To provide a genetic sample for testing, patients order a genetic test kit from Veritas Genetics, provide a saliva sample, and then ship the kit and sample back to the Veritas Genetics lab. The lab tests the sample and releases the results to the patient and the Familial Breast Cancer Research Unit.

Patients with a negative test result receive an email or letter of notification. But patients who produce a positive test result receive an email or letter, as well as a personal phone call from a genetic counsellor at the Familial Breast Cancer Research Unit.

According to Narod, The Screen Project’s offer of “genetic testing for breast and genetic testing for ovarian cancer” for $165 USD is “ethical and wise,” since it is affordable for most Canadians.

However, Narod notes that the results of The Screen Project raise an ethical concern of whether it is “proper, right, and ethical to offer healthcare services outside of what’s insured by the public healthcare system.”

As The Screen Project continues, Narod plans to track the interest in genetic testing for breast and ovarian cancer in Canada, patient satisfaction afterward, and the actions that the project and patients choose to take to reduce their risk of breast and ovarian cancer following a positive test result.

The brain on cannabis

Research rushes to catch up with legalization

The brain on cannabis

Marijuana is set to become legal across Canada this week, and Canadians must be well equipped to confront any downstream effects this historic move may have. 

The Canadian Tobacco, Alcohol and Drugs Survey found 3.6 million — 12 per cent of Canadians — used cannabis in 2015. Of that population, 24 per cent said they used cannabis for medical purposes. 

Following legalization, individuals should be more cognizant of the effects of marijuana, and specifically ways in which it can affect the brain. 

What does marijuana do to your brain? 

The endocannabinoid system is a complex signaling system in the brain and surrounding tissues. Though it is not well understood, it has been shown to play a role in immune functions and the development of the nervous system. It is also the system that processes cannabis and plays a role in producing the associated neurological effects. 

The system consists of endocannabinoids, cannabinoid receptors, and enzymes that transform endocannabinoids in the body. 

Broadly, endocannabinoids like anandamide and 2-arachidonoylglycerol are a class of cannabinoids — chemicals present in cannabis — that bind to receptors in cells. Once bound, endocannabinoids act on CB1, a cannabinoid receptor that is found in the brain. 

Cannabidiol (CBD) and tetrahydrocannabinol (THC) are the two most well described cannabinoids in marijuana. 

NADIA BOACHIE AND KEITH CHENG/THE VARSITY

CBD does not produce any of the psychoactive effects, and has been found to block some of the effects of THC by interfering with CB1 receptors. 

Structurally, THC is similar to anandamide — a naturally occurring endocannabinoid — and has been shown to activate the endocannabinoid system. 

“[CB1 receptors] are found in many brain regions that control mood, appetite, memory etc. They inhibit the release of an inhibitor transmitter called GABA and this can lead to increased activity of certain brain excitation pathways,” U of T Professor Ruth Ross explained in an email. 

Ross’ research investigates the molecular pharmacology of cannabinoids. 

“There are many unanswered questions about the safety and efficacy of cannabis as a medicine and about the possible harms of cannabis ­— especially for certain people who may be vulnerable to these effects,” Ross added. “We desperately need more solid clinical data from double blind placebo controlled studies on safety and efficacy.” 

Marijuana in other areas of medicine

There is hope that medical research with cannabis and recreational users will benefit from its legalization. 

For example, Ross and her team are working on developing “medicines that target the endocannabinoid system for the treatment of liver disease, pain and brain disorders.”

Ross said that many medical claims are made about cannabis, but it can actually make some conditions worse. 

“It is almost unknown of any person who has overdosed on cannabis,” Andrea Furlan, Associate Professor in the Faculty of Medicine and Staff Physician and Senior Scientist at the Toronto Rehabilitation Institute, wrote to The Varsity. 

According to Ross, “Cannabis even at high doses does not have the type of physiologically dangerous effect that we might see with opioids, which cause respiratory depression and can cause death.” 

However, because of the psychoactive effects associated with marijuana, it could result in “acute psychosis, paranoia, anxiety, or fear,” and such effects could cause harm to individuals or those around them. 

Despite low chances of overdosing on marijuana, several studies have sought to compare long-term use of cannabis versus alcohol in the developing adolescent brain. One study concluded that “lasting effects of adolescent cannabis use can be observed on important cognitive functions and appear to be more pronounced than those observed for alcohol.”

The Canadian Institutes of Health Research is prioritizing research on neurodevelopment, prevention, harm and treatment of problematic cannabis use, potency and product safety, social determinants of health, relationship of cannabis use and mental health, potential applications of cannabis, and pain management. 

“We hope that with legalization there will be more scientists interested in this area, and that Canada will be a leader in research in the world,” Furlan said. 

The heart-stopping truth about smoking cessation drug

U of T prof finds varenicline to have adverse side effects

The heart-stopping truth about smoking cessation drug

As of 2014, approximately 5.4 million Canadians smoked daily or occasionally. The fight for smoking cessation has largely been made possible by varenicline, a prescription drug used to reduce the effects of nicotine.

A recent study spearheaded by Andrea Gershon, Lung Health Lead at the Institute for Clinical Evaluative Sciences (ICES) and an associate professor in U of T’s Department of Medicine, pointed to some alarming side effects of varenicline.

According to the study, the use of varenicline is associated with an increased number of serious cardiovascular events in the 12 weeks after starting varenicline use. The study reported a 34 per cent increase in risk of cardiovascular events in patients who had previously experienced cardiovascular episodes and a 12 per cent increase in those who had not.

In this study, serious cardiovascular events referred to heart-related conditions such as heart attacks, insufficient blood flow to the heart, heart failure, ischemic heart disease and stroke, abnormal heart beats, and peripheral vascular disease. The researchers also looked for possible neuropsychiatric effects of varenicline, but no serious effects were observed.

Approximately four patients out of 1,000 experience critical varenicline-induced cardiovascular events. Yet the difference between relative increased risk and absolute increased risk should be noted. “If the risk to begin with is pretty low, then [even with a high relative risk,] the absolute risk will also be low,” said Gershon.

The study was observational in nature, and Gershon took advantage of extensive patient data that was at her disposal. “Every time somebody goes to see a doctor or goes to the hospital, someone or some institution gets paid, and all that information is collected in the large health administrative databases.”

This data, run through the ICES, was collected prior to and after patients went on the medication, and then it was analyzed to determine the rate of incidence of cardiovascular events in patients.

This method was relatively beneficial due to the large sample size, which reduced bias. In general, using observational data can save time and money and increase the study’s scope.

There are, however, limitations — observational studies cannot determine causation. Observational data cannot determine whether patients were using other drugs to help quit smoking, or whether the patients quit smoking while taking varenicline.

Gershon stressed that this study addressed limitations commonly associated with an observational study, and she said that the paper underwent “a very strict peer review” process.

Though the study’s authors suggest that more research is required to confirm their findings, until evidence emerges to prove otherwise, it can be assumed that varenicline does increase the risk of cardiovascular events.

In a 2013 review published by the Cochrane Tobacco Addiction Group, varenicline was found to be the most effective drug for smoking cessation. Smokers were more than twice as likely to quit on varenicline than on a placebo, making it a commonly prescribed smoking cessation aid.

“I think quitting smoking is really important… the benefits of quitting smoking outweigh the risks of this medication,” said Gershon. “It’s complicated — just because somebody takes varenicline, that doesn’t mean they’ll be successful in quitting smoking. How motivated are they? How committed are they? What are their risk factors? It’s hardly an easy decision.”

Every patient is different and extraneous factors such as being predisposed to adverse cardiovascular events will influence how they will react to varenicline.