Michelle Kameda-Smith

Introduction to Cancer Stem Cells: Past, Present, and Future

The Cancer Stem Cell (CSC) hypothesis postulates the existence of a small population of cancer cells with intrinsic properties allowing for resistance to conventional radiochemotherapy regiments and increased metastatic potential. Clinically, the aggressive nature of CSCs has been shown to correlate with increased tumor recurrence, metastatic spread, and overall poor patient outcome across multiple cancer subtypes. Traditionally, isolation of CSCs has been achieved through utilization of cell surface markers, while the functional differences between CSCs and remaining tumor cells have been described through proliferation, differentiation, and limiting dilution assays. The generated insights into CSC biology have further highlighted the importance of studying intratumoral heterogeneity through advanced functional assays, including CRISPR-Cas9 screens in the search of novel targeted therapies. In this chapter, we review the discovery and characterization of cancer stem cells populations within several major cancer subtypes, recent developments of novel assays used in studying therapy resistant tumor cells, as well as recent developments in therapies targeted at cancer stem cells.

Demographics, Interests, and Quality of Life of Canadian Neurosurgery Residents

BACKGROUND Neurosurgical residents face a unique combination of challenges, including long duty hours, technically challenging cases, and uncertain employment prospects. We sought to assess the demographics, interests, career goals, self-rated happiness, and overall well-being of Canadian neurosurgery residents. METHODS A cross-sectional survey was developed and sent through the Canadian Neurosurgery Research Collaborative to every resident enrolled in a Canadian neurosurgery program as of April 1, 2016. RESULTS We analyzed 76 completed surveys of 146 eligible residents (52% response rate). The median age was 29 years, with 76% of respondents being males. The most popular subspecialties of interest for fellowship were spine, oncology, and open vascular neurosurgery. The most frequent self-reported number of worked hours per week was the 80- to 89-hour range. The majority of respondents reported a high level of happiness as well as stress. Sense of accomplishment and fatigue were reported as average to high and overall quality of life was low for 19%, average for 49%, and high for 32%. Satisfaction with work-life balance was average for 44% of respondents and was the only tested domain in which significant dissatisfaction was identified (18%). Overall, respondents were highly satisfied with their choice of specialty, choice of program, surgical exposure, and work environment; however, intimidation was reported in 36% of respondents and depression by 17%. CONCLUSIONS Despite a challenging residency and high workload, the majority of Canadian neurosurgery residents are happy and satisfied with their choice of specialty and program. However, work-life balance, employability, resident intimidation, and depression were identified as areas of active concern.

Timing of complications during and after elective endovascular intracranial aneurysm coiling

Objective To determine the time to complications during and after elective endovascular intracranial aneurysm coiling. Methods A retrospective chart review of patients undergoing elective endovascular aneurysm coiling between March 2006 and October 2013 in one large Eastern Canadian Neurointerventional Service was performed. Data regarding the incidence, time and type of complication related to the endovascular coiling procedure and clinical outcome at last follow-up were collected. Patient, aneurysm and operation factors were analyzed to determine any factors associated with complication occurrence. Results Of the 150 patient procedures analyzed, 16% experienced a coiling-related complication, although none resulted in death. 6.7% of patients experienced an intraoperative complication, of which thromboembolism was the most common type. The majority of the complications were detected in the first 6 hours after reversal of anesthesia, and a small proportion the next morning prior to discharge. Only 3.3% of patients had persistent neurological deficit after the procedure on last follow-up. Duration of the operation demonstrated a strong association with the occurrence of procedure-related complications. Conclusion This study demonstrates that coiling-related complications of elective endovascular coiling tend to occur either intraoperatively or are detected shortly after reversal of anesthesia. Further investigation with a larger cohort may help to guide important preoperative communication with patients and identify a select group of patients who may not necessarily require prolonged admission to hospital for observation.

Analysis of surgical and MRI factors associated with cerebellar mutism

The surgical risk factors and neuro-imaging characteristics associated with cerebellar mutism (CM) remain unclear and require further investigation. Therefore, we aimed to examine surgical and MRI findings associated with CM in children following posterior fossa tumor resection. Using our data registry, we retrospectively collected data from pediatric patients who acquired CM and were matched based on age and pathology type with individuals who did not acquire CM after posterior fossa surgery. The strength of association between surgical and MRI variables and CM were examined using odds ratios (ORs) and corresponding 95% confidence intervals (CIs). A total of 22 patients (11 with and 11 without CM) were included. Medulloblastoma was the most common pathology among CM patients (91%); the remaining 9% were diagnosed with a pilocytic astrocytoma. Tumor attachment to the floor of the fourth ventricle (OR 6; 95% CI 0.7–276), calcification/hemosiderin deposition (OR 7; 95% CI 0.9–315.5), and post-operative peri-ventricular ischemia on MRI (OR 5; 95% CI 0.5–236.5) were found to have the highest measures of association with CM. Our results may suggest that tumor attachment to the floor of the fourth ventricle, pathological calcification, and post-operative ischemia have a relatively higher prevalence in patients with CM. Collectively, our work calls for a larger multi-institutional cohort study of CM patients to encourage further investigation of the determinants and management of CM in order to potentially minimize its development and predict onset.

Multiple recurrences require long-term follow-up in patients diagnosed with spindle cell oncocytoma of the sella turcica

Spindle cell oncocytoma (SCO) of the sella turcica is characterized as a WHO grade I non-endocrine neoplasm of the sella turcica. Histologically, these tumors contain spindled and variably oncocytic cellular processes. Although SCOs lack immunoreactivity for neuroendocrine markers and pituitary hormones, they are clinically indistinguishable from non-functioning pituitary adenomas. In contrast to the initially described benign clinical course, several reports have subsequently illustrated cases with multiple recurrences with or without histological features of anaplasia in the form of nuclear pleomorphism, frequent mitoses, high Ki-67 index, and/or necrosis. With a follow-up of 14years, we report a case of SCO with multiple recurrences along with an exhaustive clinico-pathological review of all 41 cases of SCO reported in the literature, of which recurrence has been described in 11 cases. Collectively, this report highlights the importance of long-term follow-up and the possible need for adjuvant radiotherapy in patients diagnosed with a sellar SCO and provides a comprehensive review of this rare nonadenomatous sellar tumor.

Development of an Atypical Teratoid Rhabdoid Tumor in a Meningioma

We describe an atypical teratoid rhabdoid tumor (AT/RT) with a component of low-grade and anaplastic rhabdoid meningioma in a 7-year-old child. The AT/RT was uniformly negative for INI1 and displayed immunoreactivity for vimentin, P53, CD99, cytokeratins with AE1/AE3 antibodies, epithelial membrane antigen, β-catenin, smooth muscle actin, E-cadherin, and S-100 protein. AT/RT was continuous, with small foci of recognizable low-grade and anaplastic meningioma. The low-grade meningioma was INI1 positive with scattered INI1-negative nuclei, whereas the remaining tumor components were INI1 negative. A recurrent tumor 6 months after partial resection contained only INI1-negative AT/RT. This case supports the hypothesis that rare examples of AT/RT may emerge from a preexisting “parent” neoplasm as a result of a second hit mutation.

Operative Landscape at Canadian Neurosurgery Residency Programs

Background Currently, the literature lacks reliable data regarding operative case volumes at Canadian neurosurgery residency programs. Our objective was to provide a snapshot of the operative landscape in Canadian neurosurgical training using the trainee-led Canadian Neurosurgery Research Collaborative. METHODS Anonymized administrative operative data were gathered from each neurosurgery residency program from January 1, 2014, to December 31, 2014. Procedures were broadly classified into cranial, spine, peripheral nerve, and miscellaneous procedures. A number of prespecified subspecialty procedures were recorded. We defined the resident case index as the ratio of the total number of operations to the total number of neurosurgery residents in that program. Resident number included both Canadian medical and international medical graduates, and included residents on the neurosurgery service, off-service, or on leave for research or other personal reasons. RESULTS Overall, there was an average of 1845 operative cases per neurosurgery residency program. The mean numbers of cranial, spine, peripheral nerve, and miscellaneous procedures were 725, 466, 48, and 193, respectively. The nationwide mean resident case indices for cranial, spine, peripheral nerve, and total procedures were 90, 58, 5, and 196, respectively. There was some variation in the resident case indices for specific subspecialty procedures, with some training programs not performing carotid endarterectomy or endoscopic transsphenoidal procedures. CONCLUSIONS This study presents the breadth of neurosurgical training within Canadian neurosurgery residency programs. These results may help inform the implementation of neurosurgery training as the Royal College of Physicians and Surgeons residency training transitions to a competence-by-design curriculum.

BMI1 is a therapeutic target in recurrent medulloblastoma

Medulloblastoma (MB) is the most frequent malignant pediatric brain tumor, representing 20% of newly diagnosed childhood central nervous system malignancies. Although advances in multimodal therapy yielded a 5-year survivorship of 80%, MB still accounts for the leading cause of childhood cancer mortality. In this work, we describe the epigenetic regulator BMI1 as a novel therapeutic target for the treatment of recurrent human Group 3 MB, a childhood brain tumor for which there is virtually no treatment option beyond palliation. Current clinical trials for recurrent MB patients based on genomic profiles of primary, treatment-naive tumors will provide limited clinical benefit since recurrent metastatic MBs are highly genetically divergent from their primary tumor. Using a small molecule inhibitor against BMI1, PTC-028, we were able to demonstrate complete ablation of self-renewal of MB stem cells in vitro. When administered to mice xenografted with patient tumors, we observed significant reduction in tumor burden in both local and metastatic compartments and subsequent increased survival, without neurotoxicity. Strikingly, serial in vivo re-transplantation assays demonstrated a marked reduction in tumor initiation ability of recurrent MB cells upon re-transplantation of PTC-028-treated cells into secondary recipient mouse brains. As Group 3 MB is often metastatic and uniformly fatal at recurrence, with no current or planned trials of targeted therapy, an efficacious targeted agent would be rapidly transitioned to clinical trials.