Glioblastoma is a brain tumor condition marked by rapid neurological and clinical demise, resulting in disproportionate disability for those affected. Caring for this group of patients is complex, intense, multidisciplinary in nature, and fraught with the need for expensive treatments, surveillance imaging, physician follow-up, and rehabilitative, psychological, and social support interventions. Few of these patients return to the workforce for any meaningful time frame, and because of the enormity of the financial burden that patients, their caregivers, and society face, (...) utilization reviews become the focus of ethical scrutiny. (shrink)

Segmentation of post-operative glioblastoma multiforme (GBM) is essential for the planning of Tumor Treating Fields (TTFields) treatment and other clinical applications. Recent methods developed for pre-operative GBM segmentation perform poorly on post-operative GBM MRI scans. In this paper we present a method for the segmentation of GBM in post-operative patients. Our method incorporates an ensemble of segmentation networks and the Kullback–Leibler divergence agreement score in the objective function to estimate the prediction label uncertainty and cope with noisy labels and (...) inter-observer variability. Moreover, our method integrates the surgery type and computes non-tumorous tissue delineation to automatically segment the tumor. We trained and validated our method on a dataset of 340 enhanced T1 MRI scans of patients that were treated with TTFields (270 scans for train and 70 scans for test). For validation, we developed a tool that uses the uncertainty map along with the segmentation result. Our tool allows visualization and fast editing of the tissues to improve the results dependent on user preference. Three physicians reviewed and graded our segmentation and editing tool on 12 different MRI scans. The validation set average (SD) Dice scores were 0.81 (0.11), 0.71 (0.24), 0.64 (0.25), and 0.68 (0.19) for whole-tumor, resection, necrotic-core, and enhancing-tissue, respectively. The physicians rated 72% of the segmented GBMs acceptable for treatment planning or better. Another 22% can be edited manually in a reasonable time to achieve a clinically acceptable result. According to these results, the proposed method for GBM segmentation can be integrated into TTFields treatment planning software in order to shorten the planning process. To conclude, we have extended a state-of-the-art pre-operative GBM segmentation method with surgery-type, anatomical information, and uncertainty visualization to facilitate a clinically viable segmentation of post-operative GBM for TTFields treatment planning. (shrink)

While primary malignant brain tumors account for only two percent of all adult cancers, these neoplasms cause a disproportionate amount of cancer-related disabilities and death. The five-year survival rates for brain tumors are the third lowest among all types of cancer. Malignant gliomas comprise the most common types of primary central nervous system tumors and have a combined incidence of five to eight cases per 100,000 people. The median survival rate of conservatively treated patients with malignant gliomas is 14 weeks; (...) with surgical resection alone, 20 weeks; with surgery and radiation, 36 weeks; and with the addition of newer biochemotherapies such as temozolomide and bevacizumab, upward of 14-18 months.The profound cost of caring for terminally ill patients with primary malignant brain tumors raises ethical considerations for the American public; the stewardship of health care dollars for the population at large maintains a juxtaposed tension against a dynamic, necessary balance of hope, care, rehabilitation and research efforts for affected patients and their advocates. (shrink)

Is it ever fair to limit treatment for diseases like glioblastoma for which prognosis is poor? Because resources are finite and health care spending limits the other possible uses for those resources, limiting access to an intervention that does not generate benefits is ethically sound. Ignoring the balance of benefits and burdens associated with treatment ignores opportunity costs and leads us to treat some lives as more valuable than others. Although it is ethically sound to set limits on medical (...) care, I argue that biological age is a poor criterion for allocating resources. (shrink)

Is it ever fair to limit treatment for diseases like glioblastoma for which prognosis is poor? Because resources are finite and health care spending limits the other possible uses for those resources, limiting access to an intervention that does not generate benefits is ethically sound. Ignoring the balance of benefits and burdens associated with treatment ignores opportunity costs and leads us to treat some lives as more valuable than others. It also ignores evidence that patients and families, when presented (...) with adequate information about the benefits and burdens of aggressive treatment compared with palliative care, often prefer the palliative care option.Should the limitations we set on the availability of care be greater for older people than younger people? Since the 1980s, scholars have called for strong age rationing of medical care in which Medicare would not pay for anything other than palliative care after they have achieved average life expectancy. (shrink)

Increasing evidence indicates that extracellular vesicles (EVs) secreted from tumor cells play a key role in the overall progression of the disease state. EVs such as exosomes are secreted by a wide variety of cells and transport a varied population of proteins, lipids, DNA, and RNA species within the body. Gliomas constitute a significant proportion of all primary brain tumors and majority of brain malignancies. Glioblastoma multiforme (GBM) represents grade IV glioma and is associated with very poor prognosis despite (...) the cumulative advances in diagnostic procedures and treatment strategies. Here, the authors describe the progress in understanding the role of EVs, especially exosomes, in overall glioma progression, and how new research is unraveling the utilities of exosomes in glioma diagnostics and development of next‐generation therapeutic systems. Finally, based on an understanding of the latest scientific literature, a model for the possible working of therapeutic exosomes in glioma treatment is proposed. (shrink)

Mutations in growth factor receptor signaling pathways are common in cancer cells, including the highly lethal brain tumor glioblastoma (GBM) where they drive tumor growth through mechanisms including altering the uptake and utilization of nutrients. However, the impact of changes in micro‐environmental nutrient levels on oncogenic signaling, tumor growth, and drug resistance is not well understood. We recently tested the hypothesis that external nutrients promote GBM growth and treatment resistance by maintaining the activity of mechanistic target of rapamycin complex (...) 2 (mTORC2), a critical intermediate of growth factor receptor signaling, suggesting that altered cellular metabolism is not only a consequence of oncogenic signaling, but also potentially an important determinant of its activity. Here, we describe the studies that corroborate the hypothesis and propose others that derive from them. Notably, this line of reasoning raises the possibility that systemic metabolism may contribute to responsiveness to targeted cancer therapies. (shrink)

BackgroundThe Supreme Court of Canada removed the prohibition on physicians assisting in patients dying on 6 February 2015. Bill C-14, legalising medical assistance in dying in Canada, was subsequently passed by the House of Commons and the Senate on 17 June 2016. As this remains a divisive issue for physicians, the Canadian Neurosurgical Society has recently published a position statement on MAID.MethodsWe conducted a cross-sectional survey to understand the views and perceptions among CNSS members regarding MAID to inform its position (...) statement on the issue. Data was collected from May to June 2016.ResultsOf the 300 active membes of the CNSS who recevied the survey, 89 respondents completed the survey, 71% of whom were attending neurosurgeons and 29% were neurosurgery residents. Most respondents,74.2%, supported the right of physicians to participate in MAID with 7.8% opposing. 37% had current patients in their practice fitting the criteria for MAID. 23.6% had been asked by patients to assist with MAID, but only 11% would consider personally providing it. 84% of neurosurgeons surveyed supported the physicians’ right to conscientious objection to MAID while 21% thought attending surgeons should be removed from the inquiry and decision-making process. 43.8% agreed that the requirment to refer a patient to a MAID service should be mandatory. Glioblastoma multiforme, quadriplegia/quadriparesis secondary to spinal tumour/trauma and Parkinson’s disease were the most common suggested potential indications for MAID among the neurosurgical population.ConclusionsOur results demonstrate that most neurosurgeons in Canada are generally supportive of MAID in select patients. However, they also strongly support the physicians’ right to conscientious objection. (shrink)

: This paper examines the nature of the harm-benefit tradeoff in early clinical research for interventions that involve remote possibility of direct benefit and likelihood of direct harms to research participants with fatal prognoses, by drawing on the example of gene transfer trials for glioblastoma multiforme. We argue that the appeal made by the component approach to clinical equipoise fails to account fully for the nature of the harm-benefit tradeoff—individual harm for social benefit—that would be required to justify such (...) research. An analysis of what we label "collateral affective benefits," such as the experience of hope or exercise of altruism, shows that the existence of these motivations reinforces rather than mitigates the necessity of justification by reference to social benefit. Evaluations of social benefit must be taken seriously in the research ethics review process to avoid the exploitation of research participants' motivations of hope or altruism and to avoid the possibility of inadvertent exploitation of high-risk research participants and the harms that would associate with such exploitation. (shrink)

Introduction In 2013, Dr. J. Muizelaar and Dr. R. Schrot, two neurosurgeons at the University of California Davis Medical Center (UCDMC), were found guilty of research misconduct due to failure to comply with institutional policies as well as Food and Drug Administration (FDA) regulations governing human subjects research. At issue here, however, is the difference between research and innovative therapy in the clinical setting of patient care where clinical judgment is reasonably to be privileged. Methods The UCDMC investigative document is (...) reviewed along with standard literature on clinical ethics and clinical data about glioblastoma multiforme (GBM) cancer. Results In this paper I argue that, by tendentiously focusing on policies, regulations, and procedures governing human subjects research, the UCDMC investigation failed to account for the centrality of clinical judgment and clinical ethics pertinent to judicious review of this matter, especially given the unique clinical context of terminally ill patients having exhausted standard care treatment options for glioblastoma multiforme (GBM) cancer. Conclusions The UCDMC investigation raises serious problems for clinicians who are engaged in innovative therapy in the clinical setting, requiring a regulatory framework separate from the normal Institutional Review Board (IRB) process. (shrink)