Michael D. Cusimano

Identification of human brain tumour initiating cells

The cancer stem cell (CSC) hypothesis suggests that neoplastic clones are maintained exclusively by a rare fraction of cells with stem cell properties. Although the existence of CSCs in human leukaemia is established, little evidence exists for CSCs in solid tumours, except for breast cancer. Recently, we prospectively isolated a CD133+ cell subpopulation from human brain tumours that exhibited stem cell properties in vitro. However, the true measures of CSCs are their capacity for self renewal and exact recapitulation of the original tumour. Here we report the development of a xenograft assay that identified human brain tumour initiating cells that initiate tumours in vivo. Only the CD133+ brain tumour fraction contains cells that are capable of tumour initiation in NOD-SCID (non-obese diabetic, severe combined immunodeficient) mouse brains. Injection of as few as 100 CD133+ cells produced a tumour that could be serially transplanted and was a phenocopy of the patients original tumour, whereas injection of 105 CD133- cells engrafted but did not cause a tumour. Thus, the identification of brain tumour initiating cells provides insights into human brain tumour pathogenesis, giving strong support for the CSC hypothesis as the basis for many solid tumours, and establishes a previously unidentified cellular target for more effective cancer therapies.

Assessment of technical skills transfer from the bench training model to the human model.

BACKGROUND This study examines whether technical skills learned on a bench model are transferable to the human cadaver model. METHODS Twenty-three first-year residents were randomly assigned to three groups receiving teaching on six procedures. For each procedure, one group received training on a cadaver model, one received training on a bench model, and one learned independently from a prepared text. Following training, all residents were assessed on their ability to perform the six procedures. RESULTS Repeated measures analysis of variance revealed a significant effect of training modality for both checklist scores (F(2,44) = 3.49, P <0.05) and global scores (F(2,44) = 7.48, P <0.01). Post-hoc tests indicated that both bench and cadaver training were superior to text learning and that bench and cadaver training were equivalent. CONCLUSIONS Training on a bench model transfers well to the human model, suggesting strong potential for transfer to the operating room.

Idiopathic Normal Pressure Hydrocephalus: A Systematic Review of Diagnosis and Outcome

OBJECTIVEPatient selection for cerebrospinal fluid diversion is difficult, because idiopathic normal pressure hydrocephalus (INPH) mimics other neurodegenerative disorders and no findings reliably predict outcome. The literature was reviewed to identify diagnostic criteria that predict shunt response and to formulate prognostic expectations. METHODSMEDLINE was searched, and 44 articles meeting predetermined criteria were included. RESULTSClinical series were frequently retrospective with small patient numbers and unstandardized outcome evaluation. Clinical findings suggestive of shunt responsiveness were the complete triad (gait disturbance, urinary incontinence, and dementia) with early gait disturbance. Degree of hydrocephalus was not correlated with clinical improvement. Reduction of the subcortical low-blood flow area was correlated with improvement in three small studies. Clinical response to prolonged cerebrospinal fluid drainage predicted shunt outcome in all cases in two small series. Overall, 59% (range, 24–100%) of patients improved after shunting, and 29% (range, 10–100%) of patients experienced prolonged improvement. Complications occurred in 38% (range, 5–100%) of patients, additional surgery was required in 22% (range, 0–47%) of patients, and there was a 6% (range, 0–35%) combined rate of permanent neurological deficit and death. CONCLUSIONShunting INPH is associated with an approximately 29% rate of significant improvement and a 6% significant complication rate. Enlargement of the subcortical low-flow area and clinical improvement secondary to prolonged lumbar drainage may provide additive predictive value above clinical and computed tomographic criteria. A multicenter clinical trial that focuses on the value of ancillary tests, defines the clinical course of a patient with a ventriculoperitoneal shunt, and evaluates the cost effectiveness of shunting INPH is needed to better describe outcome from shunting in INPH.

Effect of visual-spatial ability on learning of spatially-complex surgical skills.

Visual-spatial ability is thought to be important in competency in specific surgical procedures. To test this hypothesis, 37 surgical residents completed six tests of visual-spatial ability, ranging from low-level to high-level visual processing. Using previously validated and objective instruments, we then assessed their ability to complete and learn a spatially-complex surgical procedure. Residents with higher visual-spatial scores in the form-board test and the mental-rotations test did significantly better in the procedure than did those with lower scores. After practice and feedback, residents with lower scores achieved a comparable level of competency. Our results suggest that visual-spatial ability is related to competency and quality of results in complex surgery, and could potentially be used in resident selection, career counselling, and training.

Route Infrastructure and the Risk of Injuries to Bicyclists: A Case-Crossover Study

OBJECTIVES We compared cycling injury risks of 14 route types and other route infrastructure features. METHODS We recruited 690 city residents injured while cycling in Toronto or Vancouver, Canada. A case-crossover design compared route infrastructure at each injury site to that of a randomly selected control site from the same trip. RESULTS Of 14 route types, cycle tracks had the lowest risk (adjusted odds ratio [OR] = 0.11; 95% confidence interval [CI] = 0.02, 0.54), about one ninth the risk of the reference: major streets with parked cars and no bike infrastructure. Risks on major streets were lower without parked cars (adjusted OR = 0.63; 95% CI = 0.41, 0.96) and with bike lanes (adjusted OR = 0.54; 95% CI = 0.29, 1.01). Local streets also had lower risks (adjusted OR = 0.51; 95% CI = 0.31, 0.84). Other infrastructure characteristics were associated with increased risks: streetcar or train tracks (adjusted OR = 3.0; 95% CI = 1.8, 5.1), downhill grades (adjusted OR = 2.3; 95% CI = 1.7, 3.1), and construction (adjusted OR = 1.9; 95% CI = 1.3, 2.9). CONCLUSIONS The lower risks on quiet streets and with bike-specific infrastructure along busy streets support the route-design approach used in many northern European countries. Transportation infrastructure with lower bicycling injury risks merits public health support to reduce injuries and promote cycling.

The results of surgery for benign tumors of the cavernous sinus.

CAVERNOUS SINUS SURGERY has been performed increasingly in the last 2 decades because of new knowledge and technologies. With increasing international expertise in cavernous sinus surgery, the results must be analyzed critically to search for accurate prognosticators of outcome. We performed a retrospective review of 124 patients (40 male, 84 female; mean age, 45 years) who underwent cavernous sinus surgery for benign tumors from 1983 to 1992. Sixty-five percent had tumors encasing the internal carotid artery. Mean follow-up was 29 months (median, 26 mo). Gross total or near-total resection was possible in 80%. Patients with neurilemomas, angiofibromas, epidermoids, chondroblastomas, and hemangiomas were more likely to have total or near-total resection (100% versus 75%, P < 0.025). Disabling complications (five cerebral infarctions, two meningitis, and one hydrocephalus with chiasmal prolapse) occurred only in patients with meningiomas or pituitary adenomas. On follow-up, excellent/good binocular vision was achieved in 53% of patients entering surgery with excellent/good function versus 25% who entered surgery with fair/poor binocular vision (P < 0.025). Ninety-three percent of patients had a Karnofsky score > or = 70 on follow-up. There were a total of 12 recurrences (10%), 6 in patients with meningiomas, 2 in patients with angiofibromas, 2 in patients with craniopharyngiomas, 1 in a patient with a pituitary adenoma, and 1 in a patient with an osteoblastoma. Patients with tumor growth or neurological symptoms indicative of progressive cavernous sinus involvement should undergo cavernous sinus exploration. This surgery has acceptable morbidity and mortality and, if the tumor can be removed easily, the surgeon should try to perform radical tumor resection. To avoid major complications, the surgeon must exercise utmost care to preserve the neurovascular structures of the cavernous sinus, with special attention to tumors that extend into the petroclival region. Better results from surgery can be expected in those patients with neurilemomas, hemangiomas, or epidermoids than in patients with meningiomas, craniopharyngiomas, or pituitary adenomas. Good functional outcome can be expected, particularly if the patients preoperative clinical status is good. Particular attention must be paid to the reconstruction of anatomic barriers in order to prevent cerebrospinal fluid leakage and subsequent meningitis.

Single cell-derived clonal analysis of human glioblastoma links functional and genomic heterogeneity

Significance Glioblastoma is an incurable brain tumor. It is characterized by intratumoral phenotypic and genetic heterogeneity, but the functional significance of this heterogeneity is unclear. We devised an integrated functional and genomic strategy to obtain single cell-derived tumor clones directly from patient tumors to identify mechanisms of aggressive clone behavior and drug resistance. Genomic analysis of single clones identified genes associated with clonal phenotypes. We predict that integration of functional and genomic analysis at a clonal level will be essential for understanding evolution and therapeutic resistance of human cancer, and will lead to the discovery of novel driver mechanisms and clone-specific cancer treatment. Glioblastoma (GBM) is a cancer comprised of morphologically, genetically, and phenotypically diverse cells. However, an understanding of the functional significance of intratumoral heterogeneity is lacking. We devised a method to isolate and functionally profile tumorigenic clones from patient glioblastoma samples. Individual clones demonstrated unique proliferation and differentiation abilities. Importantly, naïve patient tumors included clones that were temozolomide resistant, indicating that resistance to conventional GBM therapy can preexist in untreated tumors at a clonal level. Further, candidate therapies for resistant clones were detected with clone-specific drug screening. Genomic analyses revealed genes and pathways that associate with specific functional behavior of single clones. Our results suggest that functional clonal profiling used to identify tumorigenic and drug-resistant tumor clones will lead to the discovery of new GBM clone-specific treatment strategies.

Aggressive pituitary adenomas—diagnosis and emerging treatments

The WHO categorizes pituitary tumours as typical adenomas, atypical adenomas and pituitary carcinomas, with typical adenomas constituting the major class. However, the WHO classification does not provide an accurate correlation between histopathological findings and clinical behaviour. Tumours lacking typical histological features are classified as atypical, but not all are clinically atypical or exhibit aggressive behaviour. Pituitary carcinomas, by definition, have craniospinal or systemic metastases, although not all display classical cytological features of malignancy. Aggressive pituitary adenomas, defined from a clinical perspective, have earlier and more frequent recurrences and can be resistant to conventional treatments. Specific biomarkers have not yet been identified that can distinguish between clinically aggressive and nonaggressive pituitary adenomas, although the antigen Ki-67 proliferation index might be of value. This Review highlights the need to develop new biomarkers to facilitate the early detection of clinically aggressive pituitary adenomas and discusses emerging markers that hold promise for their identification. Defining aggressiveness is of crucial importance for improving the management of patients by enhancing prognostic predictions and effectiveness of treatment. New drugs, such as temozolomide, have potential use in the management of these patients; anti-VEGF therapy, mTOR and tyrosine kinase inhibitors are also potentially useful in managing selected patients.

Pituitary tumor-transforming gene in endocrine and other neoplasms: a review and update

Pituitary tumor-transforming gene (PTTG) was only recently discovered. Its overexpression occurs in a wide variety of endocrine and non-endocrine tumors, including ones of pituitary, thyroid, ovary, breast, prostate, lung, esophagus, colon, and the central nervous system. It affects tumor invasiveness and recurrence in several systems, functions as a securin during cell cycle progression, and inhibits premature sister chromatid separation. PTTG is involved in multiple cellular pathways, including proliferation, DNA repair, transformation, angiogenesis induction, invasion, and the induction of genetic instability. In thyroid carcinomas, PTTG expression is a marker of invasiveness. PTTG is overexpressed in most pituitary adenomas, where it appears to correlate with recurrence and angiogenesis. Increasing evidence also points to the role of PTTG in endocrine organ development. For example, PTTG knockout mice show defective pancreatic beta-cell proliferation. Herein, we review the current knowledge regarding PTTG-mediated pathways based on evidence from in vivo and in vitro studies as well as knockout mice models. We also summarize the issue of PTTG expression and its correlation with clinicopathologic parameters in patients with neoplasms, particularly of endocrine organs. In addition, we discuss in vitro and in vivo therapeutic models targeting PTTG overexpression.

The natural history of brain contusion: an analysis of radiological and clinical progression.

OBJECT Although brain contusions are a common neurosurgical condition, surprisingly little has been written about their natural history. The purpose of this study was to identify factors that predict radiological and clinically significant progression of this pattern of traumatic brain injury in patients who did not initially require surgery. On the basis of their results and the available literature, the authors suggest a management algorithm. METHODS The authors performed a retrospective review of clinical and radiological records of consecutive patients with brain contusions who initially underwent conservative treatment. Significant radiological progression was defined as a 30% increase in contusion size on CT scans. Statistical analysis was performed to identify clinical and radiological predictors of CT contusion progression, the significance of progression, and predictors of clinical outcome. RESULTS Of 98 patients identified with brain contusions who initially received conservative treatment, 44 (45%) had significant progression on CT, and 19 (19%) required surgical intervention. The initial size of the contusion and the presence of subdural hematoma were the only statistically significant predictors of CT progression in the multivariate analysis (p = 0.0212 and 0.05, respectively). Four patients required delayed contusion evacuation (3 had radiological progression on follow-up scans). Good Glasgow Coma Scale (GCS) scores on presentation and younger age were predictors of eventual discharge from the hospital (OR 1.471, CI 1.233-1.755, p < 0.001 and OR 0.949, CI 0.912-0.988, p = 0.011, respectively). No patients with an initial GCS score of 15 or an initial contusion size < 14 ml required delayed evacuation. CONCLUSIONS Contusion progression is a common phenomenon that is seen more commonly in larger contusions. Patients with large contusions and low initial GCS scores are at risk for delayed deterioration. A proposed management algorithm for patients with contusions initially treated conservatively may help practitioners identify the best course of treatment.