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The Future of Glioma Therapy






 

SNI: Neuro-Oncology

The Future of Glioma Therapy

Everyone who is involved in the treatment of gliomas has grown tired of reading journal articles that begin with “the prognosis for gliomas remains dismal.” It is this feeling that led to the inception of this Surgical Neurology International supplement on The Future of Glioma Therapy. Each of the contributors was asked to discuss future possibilities and areas of potential investigation within their field of expertise. This supplement benefits from a breadth of knowledge and experience in disparate areas of glioma therapeutics, from immunotherapy to nanotechnology; from robotic surgery to convection enhanced delivery; from implantable therapeutics to personalized therapy based on molecular subtyping. Hopefully, this supplement will stimulate readers’ imaginations and lead to new avenues of investigation. Someday in the future, reports will begin with “progress in our understanding of glioma biology has translated into significant improvements in our ability to treat this once deadly disease.”

Surgical Neurology International is grateful to Arbor Pharmaceuticals for a generous educational grant, which supported the publication of this supplement.

Daniel L. Silbergeld, MD
Editor, SNI: Neuro-Oncology
University of Washington
Department of Neurological Surgery
Seattle, Washington
E-mail: dls@u.washington.edu


Articles

Personalized Medicine for Gliomas, by Chibawanye I Ene, Eric C Holland

Treatment of Gliomas: How did we get here? by Michelle M Chowdhary, Chibawanye I Ene, Daniel L Silbergeld

Interstitial chemotherapy for malignant glioma: Future prospects in the era of multimodal therapy, by Antonella Mangraviti, Betty Tyler, Henry Brem

Immunotherapy for malignant glioma, by Carter M Suryadevara, Terence Verla, Luis Sanchez-Perez, Elizabeth A Reap, Bryan D Choi, Peter E Fecci, John H Sampson

Convection-enhanced drug delivery for gliomas, by Andrew T Healy, Michael A Vogelbaum

Bionanotechnology and the Future of Glioma, by Peter A Chiarelli, Forrest M Kievit, Miqin Zhang, Richard G Ellenbogen

The future of high-grade glioma: Where we are and where are we going, by Emilie Le Rhun, Sophie Taillibert, Marc C Chamberlain

Robotics in the neurosurgical treatment of glioma, by Garnette R Sutherland, Yaser Maddahi, Liu Shi Gan, Sanju Lama, Kourosh Zareinia

 

 


January Newsletter

 


Features of the Month
Regenerative Medicine in Stroke: Neurosurgical Interventions

by Thomas Carmichael

The Lost Art of Inter-Provider Communication

by Mona Stecker

 

Dear Colleagues,

All of us at SNI wish you a happy and successful 2015.

In December, SNI published 31 papers covering a range of subjects; this newsletter will cover the highlights. More discussion will be given on a few of the papers because they are very significant contributions, and will impact the future of neurosurgery. These papers will help you make informed decisions.

SNI: Spine

Nancy Epstein, editor of SNI: Spine, will update you as usual in her own newsletter, but this is an outstanding paper from her spine supplement:

Church et al reported on their 10-year follow-up of patients with cervical laminoforaminotomy (FOR) for cervical radiculopathy due to soft or hard disc.

“A total of 338 interviews (out of 1085 patients with FOR) were completed with a mean follow-up of 10 years. Approximately 90% of interviewees reported improved pain, weakness, or function following FOR. Ninety-three percent of patients were able to return to work after FOR. The overall complication rate was 3.3%, and the rate of recurrent radiculopathy requiring surgery was 6.2%. Soft disc subtypes compared to osteophyte disease by operative report were associated with improved symptoms (P < 0.05) … radiculopathy due to osteophyte disease is still an excellent indication for FOR, and the results are similar to other forms of radiculopathy surgery.”

The changing practice of spine surgery: In the discussion, the authors state the numbers of spine surgeries that have changed from 1990-2000:

“Patil et al reviewed data from the National Inpatient Sample Database utilizing ICD-9 codes, comparing the years 1990 and 2000. The total number of cervical spine operations nearly doubled from 53,810 in 1990 to 112,400 in 2000. Anterior fusion procedures rose from 17.8 to 69.5% of cervical spine operations, while non-fusion decompressions declined from 70.5 to 24.6%. The inflation-adjusted hospital charges for these procedures rose by 48% to a total exceeding $2 billion in 2000.”

And in comparing FOR to ACDF, is the anterior or posterior approach better?

“To assess the relative effectiveness of FOR versus ACDF in a controlled population with similar vocational requirements [few such studies exist, per the authors -Ed], Tumialan et al studied 38 military personnel matched for age, treatment level, and surgeon…. Surgical results were comparable, as were operating room time, blood loss, and postoperative narcotic refills. The only complications were two cases of transient recurrent laryngeal nerve palsy in the ACDF group. Significantly, the average time to return to unrestricted full duty was 4.8 weeks (range 1-8 weeks) in the FOR group and 19.6 weeks (range 12-32 weeks) in the ACDF group, a difference of 14.8 weeks. Direct surgical costs were $3570 in the FOR group and $10,078 in the ACDF group. The difference in indirect costs based on time to return to active duty was greater in the ACDF group by $20,094 – $30,553. Of note, the virtually universal use of instrumentation devices likely increases the direct costs of ACDF.” [In addition, the authors cite the adjacent segment degeneration in ACDF that does not occur with FOR, and the multiple complications with ACDF that do not accompany FOR procedures. The associated costs of these complications are also unknown. -Ed]

The authors noted: “ACDF may be more effective than FOR in certain cases. For example, myelopathy or bilateral decompressions at the same level require the anterior approach. Concerns with FOR include same-level degeneration due to facet joint resection and persistent neck pain due to muscle stripping. However, a recent radiographic follow-up study demonstrated a negligible rate of postoperative instability at an average 77 months follow-up among patients undergoing FOR. Moreover, we did not observe persistent neck pain in our study, and minimally invasive FOR may reduce postoperative muscle pain.”

What it all means:

This is superb paper that emphasizes the advantage of Laminoforamintomy over ACDF for cervical radiulopathy by surgeons with long experience. FOR is not a new procedure and had been used commonly 50 or more years ago by neurosurgeons with the same excellent results, before Cloward introduced ACDF, which began paving the road to spinal instrumentation. Yet, training programs worldwide do not teach FOR in spite of the fact that its costs and complications are far lower than ACDF. Is this a result of the biomedical-industrial complex incentivizing spine surgeons to use more costly procedures that have less value? Which is the better, most cost-effective procedure for the patient? If you never learned to do the procedure posteriorly (which includes most neurosurgeons), you will only think of anterior approaches. Cost concerns may change that thinking.

SNI: Stereotactic

Tony DeSalles will write his newsletter on the contents of the newest SNI: Stereotactic supplement, but this paper is of interest:

In the report on “Gamma knife radio-surgery to the trigeminal ganglion for treatment of trigeminal neuralgia secondary to vertebrobasilar ectasia,” Somaza et al, from Venezuela, reported, “…two isocenters were used, one 8-mm isocenter placed on the Meckel’s Cavum and a 4-mm at the exit zone of the trigeminal nerve from the trigeminal ganglion (TG).” They obtained pain relief within 15 days and the pain eventually disappeared completely.

In their discussion, the authors review the evidence for root entry zone radiation; however, the nerve root could not be seen in a brainstem that was distorted by the VB ectasia. The authors also cite Leksell’s original work in which he radiated the TG with success as a “stereotactic radiogangliotomy.” Eventually, in spite of its success at the TG, the radiation was changed to the root entry zone.

What is the cause of Trigeminal Neuralgia? Do we really understand this disease?

In  my 50  years in neurosurgery, I have evulsed the V2, compressed the TG, seen balloon compression of the TG, thermocoagulation of the TG, performed microvasclar decompression of the 5th nerve root, and read about root entry zone radiosurgery. All have similar results. To me, this series of different treatments for the same disease tells me that we do not understand the cause of trigeminal neuralgia. However, we have developed multiple treatments of varying costs. Explain those results to a government that is paying for what we are doing, in an era of cost constraints. Years ago when I was in Argentina, the government decided that all AVMs should be treated by radiosurgery on a cost-benefit basis, so surgery was no longer done. Is that what is coming to countries everywhere, when the government dictates care? Neurosurgeons need to look at these choices honestly and make recommendations based on facts. The cost effective arguments will win. Why isn’t this process being done?

Trauma

An explanation of what is happening in mild head injury:

In another of our best papers of 2014 (and also one that supports Blaylock and Maroon’s paper on immunoexcitotoxicity as a cause of chronic traumatic encephalopathy (CTE) published in SNI in 2011), Petraglia et al from the United States report on the development of a model of CTE in mice that is very predictive of what Blaylock and Maroon wrote. The neuroglia are activated by the injury. An inflammatory response is created, and excess of glutamate released, which leads to cell toxicity. The authors did not measure glutamate levels. What is interesting in this paper is the involvement of the astrocytes in this process, and their contribution to depressive and behavioral changes. This is a landmark paper on the early changes in head injury and CTE. Read Blaylock and Maroon’s paper for other cases of this neuroinflammatory response, such as toxins and infections.

“We describe the pathophysiology underlying single and repetitive mild TBI (mTBI) in a novel mouse model of closed head injury. Single mTBI mice demonstrated an increase in tau phosphorylation acutely that lasted to 1 month; however, it cleared by 6 months post-injury. There was also a limited astroglial response. Repetitive mTBI mice exhibited an acute increase in phosphorylated tau accompanied by an astrocytic and microglial mediated neuroinflammatory response. This neuroinflammatory response progressed and persisted up to 6 months, as did the phosphorylated tau deposition. The interplay of tau pathology and neuroinflammation needs to be further elucidated and future studies investigating the effects of repetitive mTBI are required. As we learn more about the interplay between this dynamic neuroinflammatory response and post-traumatic behavior/neuropathology, new avenues for developing improved diagnostic measures as well as translational treatment approaches could open up…. Our repetitive mTBI mice demonstrated depressed behavior at the 1-month time-point, and it is intriguing to think that similar to these other studies, the diffuse reduced hippocampal GFAP we observed might be implicated in this phenotypic behavior. However, it remains unknown which presumptive glial changes are causal for depression.”

What are the implications long term of this work?

Again, more proof of what is happening to athletes with repeated head injuries. Is it a desire for the money in professional sports that is driving athletes to brain damage and death?

Vascular

Do we really understand Posterior Circulation Disease?

In my recent review of the literature soon to be published, Posterior Circulation Disease represents 25-40% of strokes. Yet, a) its very early symptoms are not well known, b) the MRA and CTA imaging are inadequate to show the anatomical lesions, c) surgical treatments are ignored because of an incorrect extrapolation from the corrupt EC-IC bypass study to criticize surgery for all cerebral ischemia except carotid endarterectomy, d) evidence of direct flow related symptoms by new imaging techniques measuring individual blood vessel flow is yet to be appreciated, e) the potential of 7T MR and its excellent anatomical detail will change our view of these diseases but is not widely known, f) the natural history of PCD that is dependent upon different combinations of PC lesions is not known, and g) the collateral flow to the posterior circulation has been rarely studied. With this background,

Intracranial Vertebral Endarterectomy

Uschold et al, from the United States, report on their experience with “Intradural vertebral endarterectomy with nonautologous patch angioplasty for refractory vertebrobasilar ischemia.”

The authors describe a patient with “progressive vertebrobasilar ischemia due to tandem lesions in the right vertebral artery at the origin and intracranially in the V4 segment. The contralateral vertebral artery was occluded to the level of posterior inferior cerebellar artery (PICA) and posterior communicating arteries were absent.” These patients with progressive medical refractory disease represent a subset of PCD that has a high risk for death without treatment. After treating the stenotic origin of the vertebral artery, the authors performed an intradural vertebral endarterectomy with a path graft successfully to restore blood flow to the circulation.

National Stroke Guidelines for PCD are flawed; there is a place for surgery in PCD

Having worked in this area for many years and tried high extra cranial and intracranial VEA with poor success, I applaud Uschold and his colleagues for this excellent work. Initially, it will be ignored as another surgical treatment for PCD that has no value. I believe they have taken the correct steps in using a patch graft. I found that some of the plaques had eroded into to adventitia and could not be removed. There needs to be a whole new approach to PCD as there is little objective data on how to treat the large number patients with vertebral basilar disease with differing natural histories. The National Stroke Guidelines in PCD are seriously flawed and are promoting an uninformed management of PCD. Why?

Intracranial stenosis: So far, no answer

Wilson et al reviewed the literature on the use of EC-IC bypass or intracranial stenting for intracranial arterial stenosis. The authors concluded that “the ideal management of patients with ICAD cannot yet be defined.” So far, stenting for IC arterial stenosis has been followed with restenosis and a high complication rate. I have some additional comments at the end of their paper. Nestor Gonzalez, an interventionist and neurosurgeon at UCLA is using the EDAS to treat patients with intracranial stenosis, particularly MCA stenotic disease with good long-term results in some early studies.

Tumors

Herati et al, from Germany, reported on the successful treatment of a series of 14/54 patients with temporal jugular paragangliogliomas with preoperative embolization and interdisciplinary microsurgical resection as the preferred treatment for selected patients, due to high tumor control rates and good long-term results.

Hydrocephalus in Mozambique

You can help in many places around the world, and be challenged

In another excellent study, Salvador and colleagues from Portugal analyzed their involvement in the management of infants less than 1 year of age, with hydrocephalus in Mozambique. They estimated that the disease is far more frequent in the population from the number of patients they observed in the major hospital where they worked in Mozambique. Straight tubes as shunts were initially used to treat hydrocephalus, and then, $100 shunts manufactured in India were found to be as good as those in the developed world. They suggest that ETV (Endoscopic Third Ventriculostomy) may be a cost effective treatment for this disease under these population conditions. This is a very informative paper to read in order to understand the problems in the developing world. This paper is worth reading for all neurosurgeons, particularly those interested in providing help to those in developing areas. You CAN make a difference.

Unique Case Reports

Voronovich et al from the United States report on a unique case of a “top of the basilar syndrome” embolus after cardiac procedure. The embolus passed thru a persistent primitive Hypoglossal artery connection to the basilar artery. Using this hypoglossal route to the basilar artery endovascularly, a successful thrombectomy was done.

Psychiatry, Neurology and Neurosurgery — Working together in the 21st century

Arifin et al from Indonesia report on a patient who presented with HA and personality changes. He was found to have a tumor in the Frontal Parietal area and in the CP Angle. The authors reviewed the different psychological changes that occur with brain tumors, particularly selected regions of the frontal lobe, and also in the cerebellum. For years, I had psychiatrists make rounds with us so that we could learn the relationship of psychiatric changes to brain pathology seen neurosurgically. The addition of functional and fiber tract imaging will improve our understanding of these relationships. What these observations meant to me were that psychiatrists, neurologists, and neurosurgeons are all working on the same brain, and in the future, the specialties will merge in their solution to problems in brain pathology. We see this multidisciplinary approach already occurring in functional neurosurgery in regard to DBS treatment of refractory depression, movement disorders, and obsessive compulsive disorders. We are working with neurologists and other specialists in the management of epilepsy. Previous reports on multidisciplinary cooperation in vascular (Kole et al, SNI 2012) and spine surgery (Epstein, SNI 2014; Ausman, SNI 2014) have also appeared in SNI. This is the future of medicine in general, and neurosurgery in particular.

Education in Neurosurgery: Phantom-based training

How to better train neurosurgeons, in less time

Müns et al, from Germany, reported on their development of a virtual reality-based system for training residents in the removal of brain tumors. “Traditional concepts in neurosurgical training are live surgeries or training on animal cadavers. Teaching during surgery results in longer operating times and may increase the overall risk to the patient. In contrast, surgical simulation and skill training offer an opportunity to teach and practice in a nonrisk environment where surgeons can develop and refine skills through harmless repetition. Surgical organizations are calling for methods to ensure the maintenance of skills, advance surgical training, and credential surgeons as technically competent.” The authors demonstrate how a resident’s proficiency and decreased time to perform certain tasks can be achieved. Jens Hasse, who has been in the forefront of advances in simulation in neurosurgery added his comments at the end of the paper: “it is evident that we cannot teach all trainees using the standard apprenticeship, combined with our reduced working hours in the future…. I, therefore, wholeheartedly agree with the conclusion that VR training, as demonstrated here, will be a tool to develop better neurosurgeons in the future.”

This is another first-rate paper, and points the way to developing more proficient and knowledgeable neurosurgeons, with better patient outcomes. For those interested in this subject, this is an excellent place to start.

To see all 31 papers published last month, click here.

SNI: Neuroscience Nursing

In November, the first issue of SNI: Neuroscience Nursing was published. We would like you to notify your nursing colleagues of this free supplement, and encourage them to participate in its development. Please print or forward a copy of this newsletter to them.

Editorial Comments

What are people thinking about the Future?

This month, there is an unusual number of editorials on various subjects:

1) Mary-Kate Hunnicutt, a pre-medical student, writes about her concerns for the future of medicine as a profession. Read her comments to see what young people are thinking as they approach the choice of a profession.

“There is a growing number of injustices forced upon medicine by the government’s increased control and the concomitant gradual loss of physician autonomy. I’m not the only Pre-Med student worried about the future of medicine. Many medical students are already thinking of going into fields such as vein specialty and plastic surgery, where there is less government involvement.”

“Sadly, while technology has tremendously advanced and communication has become more efficient, interaction with patients has paradoxically decreased. Tape recordings, computerized notes, and technological advances have displaced face-to-face communication, and the human touch and bedside manners for which physicians have been known in former times.”

2) Clayton Frederick Miller who is retiring from neurosurgery after 35 years in practice writes “Why I am concerned about the future of Medicine.” He sees “over diagnosis and over treatment.” The full text is worth a read for all neurosurgeons, coupled with Hunnicutt’s paper above. Rick has some powerful examples to support his position: “I find far too much emphasis placed and energy expended on identifying opportunities for intervention, sometimes based on little more than junk science or empty tradition, and only very rarely supported by outcome studies … A flawed, antique, fee-for-service compensation model with misaligned incentives is encouraging excessive intervention, thereby fueling the unsustainable annual increase in the cost of US healthcare, which now stands at 18% of Gross Domestic Product (GDP), representing a very big business.”

3) Clark Watts, an Associate Editor-in-Chief for SNI and former Editor of Neurosurgery, a lawyer who worked with members of Congress in the United States, and a respected member of the neurosurgical community, wrote “Neurosurgery: A profession or a trade association?” He documents how the AANS changed neurosurgery from a professional medical association to a trade association by forming a separate corporation. He predicted the changes in spine surgery from simple to more complex procedures to generate more revenue for neurosurgeons that we are seeing today, and the association of neurosurgeons with the biomedical industrial complex in consulting roles to generate more personal revenue. The comments from Hunnicutt and Miller ring true with Watts’ history of the development of the AANS into a trade association. Is neurosurgery a business or is it a profession with the interests of the patient placed before those of money?

4) To follow Watts’ editorial, I have written a sequel to my 2003 editorial in Surgical Neurology entitled “The Death of Spine Surgery.” What I predicted 11 years ago is now coming true. I make some  recommendations on what spine surgeons should do to provide a 21st century approach to patients with back and neck pain, by forming multi-disciplinary teams to rationally manage these patients who represent 75-100% of what a neurosurgeon does. Ten percent of patients with back and neck pain have a surgical solution. What are neurosurgeons doing with the other 90% of the patients? Sending them to someone else? Does that make sense? Are we physicians or technicians?

5) Edward Gordon, a world-recognized futurist, lecturer, and advisor to corporations and communities on the skills shortage problem, wrote about the lack of skilled workers for today and tomorrow’s world, and what can be done about it.

“The media’s continuing fixation on the Federal Reserve’s monetary medicine for unemployment obscures the growing uncomfortable reality that monetary/fiscal policy alone cannot fix the structural failures of the ossified U.S. education-to-employment system. Washington leaders inside the beltway and people across America are just starting to understand this new reality as the skilled workforce crisis deepens.”

To any observer, it is clear that there is a relationship among many of the subjects about which neurosurgeons are writing and what is happening in society today. What is that message? What are our goals as a society? What are our goals as physicians? Where are those physicians who will stand up against the crowd mentality and speak the truth instead of what is politically correct?

SNI is committed to providing excellent science, and the truth as seen from many points of view, with an opportunity for open discussion. Our major focus — from the founding of Surgical Neurology by Dr Paul Bucy — to SNI now, is what is best for our patients. Physicians are the only people solely dedicated to protect and defend their patients in this era of government, industrial, insurance, biomedical industry, and multiple third parties involvement in health care. It is our goal to see that the needs of our patients are paramount. The patient comes first. That also applies to physicians’ behavior. That is what the editorials and papers above all say. A simple rule in medicine is to “treat your patients like they are your family.” SNI will continue to be an advocate for patients as members of our family. That is all they ask us to do.

SNI would like to thank Elekta for their continued support of SNI as a major supporter.

James I. Ausman, MD, PhD,

Editor in Chief,

Surgical Neurology International