Unsupervised machine learning models reveal predictive markers of glioblastoma patient survival using white blood cell counts prior to initiating chemoradiation.

Purpose: Glioblastoma is a malignant brain tumor requiring careful clinical monitoring even after primary management. Personalized medicine has suggested use of various molecular biomarkers as predictors of patient prognosis or factors utilized for clinical decision making. However, the accessibility of such molecular testing poses a constraint for various institutes requiring identification of low-cost predictive biomarkers to ensure equitable care. Methods: We collected retrospective data from patients seen at Ohio State University, University of Mississippi, Barretos Cancer Hospital (Brazil), and FLENI (Argentina) who were managed for glioblastoma-amounting to nearly 600 patient records documented using REDCap. Patients were evaluated using an unsupervised machine learning approach comprised of dimensionality reduction and eigenvector analysis to visualize the inter-relationship of collected clinical features. Results: We discovered that white blood cell count of a patient during baseline planning for treatment was predictive of overall survival with an over 6-month median survival difference between the upper and lower quartiles of white blood cell count. By utilizing an objective PDL-1 immunohistochemistry quantification algorithm, we were further able to identify an increase in PDL-1 expression in glioblastoma patients with high white blood cell counts. Conclusion: These findings suggest that in a subset of glioblastoma patients the incorporation of white blood cell count and PDL-1 expression in the brain tumor biopsy as simple biomarkers predicting glioblastoma patient survival. Moreover, use of machine learning models allows us to visualize complex clinical datasets to uncover novel clinical relationships.

Fluoroscopic Cranial Radiation Exposure in Spine Surgery: A Prospective Single-Center Evaluation in Operating Room Personnel.

BACKGROUND: Cranial radiation exposure during instrumented spine surgery is not well documented. We set out to measure this risk to the patient, surgeon, surgical resident, and scrub technician during these procedures. METHODS: Forty-seven individuals were enrolled during a 1.5-year period between October 2014 and March 2016 at the University of New Mexico Department of Neurosurgery. Radiation doses were obtained through electronic dosimeters placed on the surgical cap over the temporal scalp (bilaterally on surgeon and resident assist, unilaterally on surgical scrub on the side facing radiation source) and on the midline of the patient's exposed cranium. RESULTS: Of the 47 procedures, 39 (83%) were open and 8 (17%) were minimally invasive or percutaneous instrumented procedures. A total of 91 motion segments were treated, with a mean of 1.9 levels per case (57% lumbosacral, 34% cervical, and 2.1% thoracic). Total fluoroscopic time was 12.9 minutes. Mean dose per case (mrem/case) was calculated for the spine surgeon (1.4), resident assist (1.4), surgical scrub (1.2), and the patient (3.6). All doses were within federal safety guidelines. A spine surgeon would need to perform more than 1400 cases per year to reach the current federal maximum permissible dose for head exposure. CONCLUSIONS: There was no difference in cranial radiation exposure between operating room staff during spine surgeries. Moreover, the doses measured at the cranium were within national safety limits. Current protective technologies have significantly reduced the amount of ionizing radiation exposure during routine spine procedures; however, changes in behavior or equipment may further reduce radiation exposure to health care workers. CLINICAL RELEVANCE: Radiation exposure to patients and hospital staff remains a major concern in the practice of modern spine surgery. Cranial exposure remains the only established environmental risk factor for brain tumors, such as gliomas and meningiomas. Our study shows that all those exposed to radiation during spine surgery had cranial doses well within the national safety limits.

Stratification of patients is the way to go to develop neuroprotective/disease-modifying drugs for Alzheimer's disease.

Development of effective neuroprotective drugs for Alzheimer's disease (AD) is a formidable challenge because this disease is multifactorial and heterogeneous. Although AD is characterized histopathologically by the presence of numerous amyloid-beta plaques and neurofibrillary degeneration of abnormally hyperphosphorylated tau in the brain, these two hallmark lesions do not exist in any fixed proportion in this disease. Furthermore, in the brains of some normal aged individuals, there are as many amyloid-beta plaques seen as in typical cases of AD. On the other hand, extensive neurofibrillary degeneration of abnormally hyperphosphorylated tau and dementia but in the absence of amyloid-beta plaques occur in several related neurodegenerative disorders called tauopathies. More than one molecular mechanism has been described for the development of amyloid-beta as well as neurofibrillary degeneration of abnormally hyperphosphorylated tau. Thus, AD apparently results from several different etiopathogenic mechanisms and offers numerous rational therapeutic targets. We have discovered that there are at least five different subgroups of AD, and future studies are likely to identify additional subgroups. The employment of these subgroups of AD in clinical trials can markedly increase the success in developing specific and potent therapeutic drugs.

Tau pathology in Alzheimer disease and other tauopathies.

Just as neuronal activity is essential to normal brain function, microtubule-associated protein tau appears to be critical to normal neuronal activity in the mammalian brain, especially in the evolutionary most advanced species, the homo sapiens. While the loss of functional tau can be compensated by the other two neuronal microtubule-associated proteins, MAP1A/MAP1B and MAP2, it is the dysfunctional, i.e., the toxic tau, which forces an affected neuron in a long and losing battle resulting in a slow but progressive retrograde neurodegeneration. It is this pathology which is characteristic of Alzheimer disease (AD) and other tauopathies. To date, the most established and the most compelling cause of dysfunctional tau in AD and other tauopathies is the abnormal hyperphosphorylation of tau. The abnormal hyperphosphorylation not only results in the loss of tau function of promoting assembly and stabilizing microtubules but also in a gain of a toxic function whereby the pathological tau sequesters normal tau, MAP1A/MAP1B and MAP2, and causes inhibition and disruption of microtubules. This toxic gain of function of the pathological tau appears to be solely due to its abnormal hyperphosphorylation because dephosphorylation converts it functionally into a normal-like state. The affected neurons battle the toxic tau both by continually synthesizing new normal tau and as well as by packaging the abnormally hyperphosphorylated tau into inert polymers, i.e., neurofibrillary tangles of paired helical filaments, twisted ribbons and straight filaments. Slowly but progressively, the affected neurons undergo a retrograde degeneration. The hyperphosphorylation of tau results both from an imbalance between the activities of tau kinases and tau phosphatases and as well as changes in tau's conformation which affect its interaction with these enzymes. A decrease in the activity of protein phosphatase-2A (PP-2A) in AD brain and certain missense mutations seen in frontotemporal dementia promotes the abnormal hyperphosphorylation of tau. Inhibition of this tau abnormality is one of the most promising therapeutic approaches to AD and other tauopathies.