Welcome to the latest issue of The Krembil.
The Krembil is the official newsletter of the Krembil Research Institute (formerly the Toronto Western Research Institute). Research at Krembil is focused on finding innovative treatments and cures for chronic debilitating disorders, including arthritis and diseases of the brain and eyes.
Stories in this month’s issue include:
● Krembil Research Day 2021: Trainees share their discoveries in neuroscience, vision and arthritis research.
● Vision Researcher Joins Krembil: Dr. Brian Ballios studies stem cell therapies for inherited and acquired eye diseases.
● Sleep Disorder a Key Factor: Those at risk for obstructive sleep apnea are more likely to get COVID-19 and be hospitalized.
● Signalling Inflammation: Study identifies two proteins linked to joint inflammation and treatment outcomes in arthritis.
● A Question of Quality: Study highlights the need for standardized methodology in survey-based surgery research.
● Stimulating the Brain: Researchers map and model the effects of deep brain stimulation on different brain regions.
Cancer can start from a single defective cell, growing and spreading until it is eventually found through routine screening or once it begins to cause symptoms.
Medical imaging technologies can then be used to find the tumour, and help create a treatment plan.
But the cancer does not stop growing just because a doctor found it and scanned it—the cancerous cells will continue to grow and spread between the time it was imaged and when treatment begins.
Techna Affiliated Scientist Dr. Jean-Pierre Bissonnette led a team to evaluate the spread of non-small-cell lung cancer in 181 patients in a multi-centre international study. All patients had a positron emission tomography/computed tomography (PET/CT) scan at the time of their diagnosis. PET/CT is a very sensitive imaging method that is able to find and localize even small clusters of cancerous cells. However, due to its cost, patients are rarely scanned again before their treatment begins despite the fact that several weeks can pass between diagnosis and treatment.
For all participants in the study, the research team repeated the PET/CT scans immediately prior to therapy. They then calculated the odds that a patient’s cancer had grown enough to move up to the next “stage”—a four-point scale to that reflects how aggressive and widespread a patient’s cancer is—in the time between diagnosis and treatment. After 22 days, there was a greater than 5% chance that the cancer had moved to a more severe stage; after 42 days there was a 15% chance.
These results raise serious concerns for those on the waiting list for cancer treatment. For 10% of all patients participating in the study, their cancer had spread so much in the time between diagnosis and treatment that they required changes to their treatment plan. That suggests that many patients who do not receive a second PET/CT scan may be receiving suboptimal treatment for their lung cancer.
“Our data suggests that treatment should commence within three weeks of diagnostic imaging. Patients with adenocarcinoma or who started at stage IIIB/IIIC are particularly at risk of progressing as they wait for treatment, and it may make sense to prioritize those patients,” Dr. Bissonnette concludes. “This information is particularly relevant now, as the COVID-19 pandemic has resulted in significant delays in access to diagnosis and therapy for cancer patients.”
This work was supported, in part, by The Princess Margaret Cancer Foundation.
Bissonnette J-P, Sun A, Grills IS, Almahariq MF, Geiger G, Vogel W, Sonke JJ, Everitt S, Mac Manus M. Non-small cell lung cancer stage migration as a function of wait times from diagnostic imaging: A pooled analysis from five international centres. Lung Cancer. 2021 Mar 30. doi: 10.1016/j.lungcan.2021.03.017.
A recent study led by Dr. Meiqi Guo, Clinician Investigator at KITE Research Institute, provided the first detailed description of the adverse events experienced by patients admitted to a rehabilitation hospital with a brain injury.
Adverse events during a hospital stay can include issues with admission or transfer of care, delays or errors in treatment, infections acquired in the hospital, falls, patient behaviours such as assault, and issues with medical equipment or building fixtures.
To better understand the safety risks experienced by patients with a brain injury, Drs. Rouaa Mandurah, Alice Kam and Meiqi Guo from the research team reviewed the hospital records of 108 patients admitted to a rehabilitation hospital with a brain injury over a period of five months in 2017. The team also reviewed the incident reports that were filed with the hospital’s voluntary incident reporting system during this period.
The team found that about half of the patients had one or more adverse events during their hospital stay. The majority of these events were considered minor and there were no severe adverse events. About half of the events were incidents such as falls and skin injuries; the rest were associated with patient behaviour such as assault and being missing, or medication-related issues. The team identified 45% of these events as preventable.
“During the study period, around half of the patients that were admitted to the rehabilitation hospital with a brain injury experienced an adverse event, with 76 events identified in total,” says Dr. Guo. “By reviewing patient records, we were able to detect 75 adverse events; however, the hospital’s voluntary reporting system only captured 32 adverse events—less than half of the total identified events.”
“Patients with acquired brain injuries have complex behavioural and cognitive deficits. Our study results show that that voluntary incident reporting from care providers is not enough: improved incident monitoring strategies are needed,” says Dr. Guo. “With more accurate data for this group of individuals, we can take steps to better respond to safety risks in rehabilitation hospitals and improve patient safety.”
A review of patients’ complete hospital records is currently the best way to identify safety risks that patients with brain injuries face in rehabilitation. However, such reviews are labour-intensive and expensive to implement. To address this, researchers are now exploring the use of artificial intelligence tools to review hospital records and identify adverse events in the hospital.
This work was supported by the UHN Foundation.
Guo M, Mandurah R, Tam A, Bayley M, Kam A. The incidence and nature of adverse events in rehabilitation inpatients with acquired brain injuries. PM R. 2021 Jun 3. doi: 10.1002/pmrj.12650.
A national research project has just launched to study the effectiveness and safety of COVID-19 vaccines in transplant recipients. The Government of Canada, through its COVID-19 Immunity Task Force (CITF) and Vaccine Surveillance Reference Group (VSRG), is investing over $2.84 million in this research program, based at University Health Network and called PREVenT COVID, short for Prospective Evaluation of COVID-19 Vaccine in Transplant Recipients: A National Strategy.
Key support for this project is also being provided by the Canadian Donation and Transplantation Research Program (CDTRP). The CDTRP is a national research network designed to increase organ and tissue donation in Canada and enhance the survival and quality life of Canadians living with a transplant.
“Because people who have received a solid organ transplant and other immunosuppressed individuals are generally excluded from clinical trials of vaccines, little data exists to guide clinical best practices for these populations,” says Dr. Deepali Kumar, project lead, Clinician Investigator at the Toronto General Hospital Research Institute and Director of Transplant Infectious Diseases at the Ajmera Transplant Centre. “Our research will address this knowledge gap by revealing how transplant recipients—who are on immune-suppressing medications to prevent organ rejection—respond to COVID-19 vaccines. We will compare their immune responses to non-transplanted individuals as well as those who have contracted COVID-19.”
With this funding, Dr. Kumar’s team will launch this study across multiple transplant centres to examine short- and long-term antibody responses in transplant recipients following first and second doses of COVID-19 vaccines. The team will compare these responses to those of healthy individuals who have not undergone transplant and those of transplant recipients who naturally contracted COVID-19.
The team will also assess the short- and long-term safety profile of vaccines in transplant recipients, tracking the rates of local and systemic reactions, organ rejection and other transplant complications.
“People who have received an organ or stem cell transplant may have unique immunization needs. For example, we do not know whether the effectiveness of vaccines differ depending on the timing of immunization relative to transplant,” explains Dr. Kumar.
The researchers will then develop a national COVID-19 vaccination safety surveillance system for transplant recipients. This system will build upon the Canadian National Vaccine Safety Network—an ongoing Canada-wide vaccine safety surveillance initiative.
“Our goal is to help coordinate the efforts of provincial and national organizations that are involved in public health and vaccination research and facilitate information sharing among public health agencies and patient partners,” says Dr. Kumar. “This research will build on Canada’s leadership in transplant medicine and inform health policy to best protect transplant recipients from COVID-19.”
COVID-19 vaccination remains one of the most effective ways to protect ourselves and others from COVID-19. This is why vaccination is important for the general population around immunosuppressed individuals who may have a reduced immune response to any authorized COVID-19 vaccine series.
“It is imperative that we study the immune response and safety of vaccines not only in the general population, but in populations with specific health issues, such as persons having received organ transplants,” says Scott Halperin, Co-Chair of the VSRG. “We need to ensure that vaccines are working in vulnerable Canadians: studies like this will help to inform us whether a booster dose is needed in this specific population.”
The Government of Canada established the COVID-19 Immunity Task Force in April 2020 to lead nation-wide efforts to determine the extent of COVID-19 infection in Canada. The Vaccine Surveillance Reference Group was formed in December 2020 to support the monitoring of vaccine safety and effectiveness.
Findings from the Princess Margaret Cancer Centre showcase a new approach for treating acute myeloid leukemia—an aggressive cancer of the blood that is known to return following standard treatments.
Recurrence of this cancer is driven by leukemic stem cells. These cells are often resistant to current therapies and can survive when other cancer cells die—making them important treatment targets.
Led by Princess Margaret Cancer Centre Scientist Dr. Steven Chan, the research team conducted a screen of more than 100 drugs known to affect metabolism to find ones that selectively killed leukemic stem cells. Their findings revealed that drugs known as nicotinamide phosphoribosyltransferase (NAMPT) inhibitors were top candidates.
“Unlike normal blood stem cells, leukemic stem cells appear to rely heavily on the NAMPT enzyme to survive. The NAMPT inhibitors that we identified appear to kill leukemic stem cells by disrupting the pathways required for lipid metabolism,” says Dr. Chan.
When the research team treated two laboratory models of acute myeloid leukemia using cells derived from patients with NAMPT inhibitors, leukemia stem cells were much more susceptible to cell death than normal blood stem cells. “This is exciting because our data suggest that NAMPT inhibitors can be used to kill leukemic stem cells without affecting the normal blood system,” says Dr. Chan.
The team focused their experiments on a specific NAMPT inhibitor, known as KPT-9274, which is currently in clinical trials for other types of cancers. In three experimental models of acute myeloid leukemia, treatment with KPT-9274 was effective at killing leukemic stem cells; however, tumour growth in one model remained, suggesting that leukemic stem cells can become resistant to the treatment.
Dr. Chan and his colleagues analyzed the cells that had developed resistance and found that a protein, known as the sterol regulatory-element binding protein (SREBP) became activated when exposed to KPT-9274. Explains first author Amit Subedi, “When we silenced SREBP genes in these cells and treated them with KPT-927, we were able to overcome resistance.”
The team then searched for approved drugs that inhibit SREBP pathways, which led them to the discovery of dipyridamole, a drug used for preventing secondary stroke. The drug combination, when tested in experimental models, killed higher levels of leukemia stem cell than each drug alone and overcame drug resistance.
Comments Dr. Chan, “These results are promising. Future prospective clinical trials are an important next step to validating these findings and building out a more complete picture of the vulnerabilities of acute myeloid leukemia and ways to stamp it out.”
This work was supported by the Acute Leukemia Translational Research Initiative from the Ontario Institute for Cancer Research, the Leukemia Research Foundation, the Canadian Institutes of Health Research and The Princess Margaret Cancer Foundation. J Dick holds a Tier I Canada Research Chair in Stem Cell Biology.
Subedi A, Liu Q, Ayyathan DM, Sharon D, Cathelin S, Hosseini M, Xu C, Voisin V, Bader GD, D’Alessandro A, Lechman ER, Dick JE, Minden MD, Wang JCY, Chan SM. Nicontinamide phosphoribosyltransferase inhibitors selectively induce apoptosis of AML stem cells by disrupting lipid homeostasis. Cell Stem Cell. Epub Ahead of Print
The Krembil Research Institute is pleased to welcome Dr. Brian Ballios as its newest Scientist at the Donald K. Johnson Eye Institute.
Dr. Ballios’ research is focused on developing stem cell therapies for inherited and acquired retinal diseases, such as age-related macular degeneration and retinitis pigmentosa. These diseases result in progressive vision loss for which existing treatments can only slow progression.
“As a physician, I am struck by the immense personal toll of eye disease,” explains Dr. Ballios. “It is very motivating to conduct research that has the potential to make tremendous improvements in patients’ quality of life. I find inspiration in these patients’ journeys and share their eagerness for cures.”
Leveraging his background in engineering and medicine, Dr. Ballios developed the world’s first injectable biomaterial-based delivery system for transplanting stem cells into the retina. This work launched a new field of study into the use of biomaterials to improve cell transplantation in the retina. He also developed methods to efficiently generate light-sensitive cells from stem cells to replace the cells lost in retinal degeneration.
At Krembil, Dr. Ballios’ research program will bring together diverse fields that include retinal neurobiology, stem cell biology and bioengineering. He will continue to develop methods to generate light sensitive cells from stem cells and promote their survival and integration into the damaged eye. He will also develop accurate models of human inherited retinal disease and investigate the unique features of these conditions to improve the effectiveness of cell therapies.
“Coming to UHN is about joining an ecosystem of discovery. We have the best-of-the-best clinicians and vision science researchers,” says Dr. Ballios. “The Donald K. Johnson Eye Institute and the Krembil Research Institute bring together these leaders with a shared goal: to restore vision and improve the lives of patients.”
In 2017, Dr. Ballios was the inaugural recipient of Fighting Blindness Canada’s Clinician-Scientist Emerging Leader Award. His research has also been funded by the BrightFocus Foundation and the Retina Foundation of Canada. This year, he was awarded a Career Development Award from the Foundation Fighting Blindness U.S. He is currently the J. Ardeth Hill – Fighting Blindness Canada Professor in Ocular Genetics at the University of Toronto.
At the University of Toronto, Dr. Ballios completed his Doctor of Medicine and Doctor of Philosophy degrees through the combined MD/PhD program, a clinical residency in Ophthalmology and postdoctoral training in the Department of Ophthalmology and Vision Sciences. At Massachusetts Eye and Ear and Harvard University, he completed a clinical fellowship in Inherited Retinal Diseases.
Welcome to Krembil, Dr. Ballios!
Female ophthalmologists face a significant pay gap, despite being comparably productive to males, according to new research published in the journal Ophthalmology.
Several studies to date have suggested that female physicians earn less than men; however, most of these studies have been based on self-reported incomes or Medicare/Medicaid payments that capture only a subset of physician payments.
The new study looked at whether male and female ophthalmologists’ overall payments are different within the Ontario fee-for-service billing system. The research team was led by Dr. Tina Felfeli, a resident physician in the Department of Ophthalmology and Vision Sciences at the University of Toronto, and Dr. Yvonne Buys, a Clinician Investigator at the Donald K. Johnson Eye Institute.
“Fee-for-service systems, in which doctors are paid a set amount for each service they provide, are less susceptible to pay disparities,” explains Dr. Buys. “Nonetheless, we know that pay gaps still exist between male and female physicians. We wanted to determine whether male and female ophthalmologists have different incomes despite similar workloads, and how the pay gap in ophthalmology compares to other medical specialties.”
The researchers examined sex differences in yearly income received by 807 ophthalmologists across nearly three decades, controlling for factors such as age and productivity. They then compared the pay differences observed in ophthalmology to those present in other physician specialty groups; surgical, medical non-procedural and medical procedural specialties.
The study revealed that representation of female physicians increased across specialties, from 17% in 1992 to 36% in 2018. Over this period, female representation in ophthalmology increased from 11% to 22%. Despite this 100% increase, ophthalmology continued to have the lowest proportion of female physicians. In the other three specialty groups, women comprised between 25% and 41% of physicians in 2018.
The team also found that females had lower incomes than males across specialties, despite being comparably productive. Amongst the top billers, the pay gap was most pronounced in ophthalmology, where males earned 17% ($161,900) more than females in 2018. By contrast, males earned only 8–12% more than females in other specialities.
The current findings suggest that the pay gap may be related to the proportionate representation of females within a specific medical specialty. Thus, ophthalmology, which has the lowest proportion of females, also has the largest sex difference in annual income.
“Moving forward, we need to determine the root causes of the pay gap in ophthalmology and other medical specialties. Previous studies have pointed to sex differences in practice patterns and opportunities to perform the most lucrative procedures, such as surgeries, but more research is needed,” says Dr. Buys. “Addressing sex-based inequities and systemic barriers to women’s success is essential for safeguarding inclusion in the medical profession.”
This study made use of de-identified data from the ICES Data Repository, which is managed by the ICES with support from its funders and partners: Canada’s Strategy for Patient-Oriented Research (SPOR), the Ontario SPOR Support Unit, CIHR and the Government of Ontario. The opinions, results and conclusions reported are those of the authors. No endorsement by ICES or any of its funders or partners is intended or should be inferred.
This work was supported by the UHN Foundation.
Felfeli T, Canizares M, Jin Y-P, Buys YM. Pay Gap Amongst Female and Male Ophthalmologists Compared to other Specialties. Ophthalmology. 2021 July 13. doi: 10.1016/j.ophtha.2021.06.015
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