RHODE ISLAND MEDICAl J ournAl · 2017. 6. 1. · MEDICAl J ournAl RHODE ISLAND JunE 2017 VOLUME 100 • NUMBER 6 ISSn 2327-2228 Recent AdvAnces in neuRosuRgeRy sPecIAL sectIon guest

M E D I C A l J o u r n A lR H O D E I S LA N D

V O L U M E 1 0 0 • N U M B E R 6J u n E 2 0 1 7 I S S n 2 3 2 7 - 2 2 2 8

Recent AdvAnces in neuRosuRgeRysPecIAL sectIon

guest edItoR: ZIyA L. gokAsLAn, Md, FAAns, FAcs

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16 Introduction to Recent Advances in NeurosurgeryZiya L. GokasLan, MD, Faans, FaCs

18 Current Treatment of Metastatic spine Tumors – surgery and stereotactic RadiosurgeryJaReD s. FRiDLey, MD; JaRosLaw T. HepeL, MD;

aDeTokunbo a. oyeLese, MD, phD

21 The Role of Radiation Therapy in the Treatment of Metastatic brain DiseasekunaL sinDHu, bs; soHaiL syeD, MD; Deus CieLo, MD

25 Current strategies in the surgical Management of ischemic strokeCoDy a. DobeRsTein, bs; RaDMeHR ToRabi, MD;

sanDRa C. yan, bs, ba; Ryan MCTaGGaRT, MD;

CuRTis DobeRsTein, MD; MaHesH JayaRaMan, MD

30 a Comprehensive approach to Deep brain stimulation for Movement DisordersuMeR akbaR, MD; waeL F. asaaD, MD, pHD, Faans

34 Rhode island Hospital’s Contribution to the Field of endoscopic spine surgery aLbeRT e. TeLFeian, MD, phD; aDeTokunbo a. oyeLese, MD, phD;

Ziya L. GokasLan, MD, Faans, FaCs

39 updates on Chimeric antigen Receptor-Mediated Glioblastoma immunotherapyGeoRGe Mao, MD; pRakasH saMpaTH, MD;

saDHak senGupTa, phD

43 Recent advances in the Treatment of Gliomas – Comprehensive brain Tumor CentersTeven a. ToMs, MD, MpH; nikoLaos Tapinos, MD, phD

47 Current Concepts in the pathogenesis, Diagnosis, and Management of Type i Chiari Malformations CoDy a. DobeRsTein, bs; RaDMeHR ToRabi, MD;

peTRa M. kLinGe, MD

J. Hepel, MD a. oyelese MD D. Cielo, MD

u. akbar, MD w. asaad, MD

C. Doberstein, MD M. Jayaraman, MDR. McTaggart, MD

a. Telfeian, MD

Z. Gokaslan, MD

s. Toms, MD

p. sampath, MD

n. Tapinos, MD p. klinge, MD


On the cover:

Deep brain simulation

procedure with bilateral

simultaneous micro-

electrode recordings,

performed with an

intraoperative CT scan-

ner at Rhode island

Hospital. photo by

Julie Guerin, brown

university neuroscience

graduate student.

8 COMMENTARY Crimes against humanity

JosepH H. FRieDMan, MD

workplace violence in hospitals and measures to address itHeRbeRT RakaTansky, MD

14 RIMJ AROuNd ThE WORld newport, Rhode island

54 RIMS NEWS

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81 hERITAgE Hopeworth sanitarium

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Founder grew up in Civil War field hospitals, orphan asylumMaRy koRR

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VA SecRetARY 64Dr. David J. shulkin

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75 St. JOSeph SchOOl OF NURSING

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75 OBItUARIeS

Robert emmett Curran, Jr., MD

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dANA leVY GUYeR, Md 73named medical director, Hope

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JAcK A. elIAS, Md 73appointed inaugural senior vice

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elAINe c. JONeS, Md 73honored by american

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urgent Care services to seekonk

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effectiveness of yoga in treating major depression


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PEOPlE/PlACES


76 EdITORIAl

scientific feeding of the people in wartime

78 MISCEllANEOuS

Doctors sought for us military hospital units for mental and nervous disorders

newport Medical society hears talk on drug-store prescribing

off to war: Dr. Murray s. Danforth

Returned from war: Dr. Herman C. pitts

st. Joseph’s Hospital graduates nurses

providence City Hospital: To accept navy patients

78 NECROlOgY Dr. Henry w. burnett

(1873–1917), specialist in children’s diseases

PuBlIC hEAlTh 50 HeaLTH by nuMbeRs

effects of smoking and smoking Cessation during pregnancy on adverse birth outcomes in Rhode island, 2012–2014Hyun (Hanna) kiM, phD

kaRine MonTeiRo, MpH

eLsa LaRson, phD, Ms

Dana MCCanTs DeRisieR, Ms

53 vital statisticsRoseann GioRGianni DepuTy sTaTe ReGisTRaR


P u B l I S h E R

RHoDe isLanD MeDiCaL soCieTy

P R E S I d E N T

saRaH J. FessLeR, MD

P R E S I d E N T- E l E C T

bRaDLey J . CoLLins, MD

V I C E P R E S I d E N T

peTeR a. HoLLMann, MD

S E C R E TA R Y

CHRisTine bRousseau, MD

T R E A S u R E R

Jose R. poLanCo, MD

I M M E d I AT E PA S T P R E S I d E N T

RusseLL a. seTTipane, MD

E x E C u T I V E d I R E C T O R

neweLL e. waRDe, phD

E d I T O R - I N - C h I E f

JosepH H. FRieDMan, MD

A S S O C I AT E E d I T O R

kenneTH s. koRR, MD

PuBlICATION STAff

M A N A g I N g E d I T O R

MaRy koRR

[email protected]

g R A P h I C d E S I g N E R

MaRianne MiGLioRi

A d V E R T I S I N g A d M I N I S T R AT O R

saRaH bRooke sTevens

[email protected]

A d V E R T I S I N g S A l E S

kaRen wooDbine

karenwoodbine.r imj@gmai l .com

E d I T O R I A l B O A R d

JoHn J. CRonan, MD

JaMes p. CRowLey, MD

eDwaRD R. FeLLeR, MD

JoHn p. FuLTon, phD

peTeR a. HoLLMann, MD

MaRGueRiTe a. neiLL, MD

FRank J. sCHabeRG, JR. , MD

LawRenCe w. veRnaGLia, JD, MpH

neweLL e. waRDe, phD

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COMMENTARY

8

9

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crimes against humanity JosepH H. FRieDMan, MD

[email protected]

logist. I’m not a health

care economist or insur-

ance policy expert. But,

like most people, I have

some moral code, and

have read, with great

anger, the various news

reports of a handful of

pharmaceutical compa-

nies destroying lives with

price gouging.

I found the u.s. senate’s special

committee on Aging’s report on price

gouging in the pharmaceutical industry

(https://www.aging.senate.gov/imo/

media/doc/drug%20Pricing%20Report.

pdf), summarizing some of the more

outrageous behaviors I’ve read about

before. this isn’t the routine sort of

price gouging that has been the norm,

where Americans are charged double

or more than canadians or europeans,

or the collusion that characterizes the

otherwise peculiar paradox where the

development of more drugs to treat

multiple sclerosis increases rather than

decreases their price, despite the devel-

opment of generics, and the increased

competition.

the Report focuses on only four com-

panies, noting that three of them had

been newly taken over by hedge funds,

which had no experience with pharma-

ceutical companies or, apparently, with

normal human values. the report opines

that the funds were responding to their

investors, although one assumes that

I am a clinical neuro- the hedge fund managers,

who take a percentage

of the cut, are the major

“deciders” of what hap-

pens and the investors

close their eyes to the car-

nage in order to not sully

the enjoyment of their

increasing bank accounts.

the following charac-

teristics are shared by the

economic model: each

drug was the “gold standard” treatment

for a particular disorder, reducing the

competition; the market was small,

making it unlikely that a competing

company would emerge or that the

affected population would be able to

mount a significant opposition; dis-

tribution of the drug was closed, that

is, a designated distribution company

was used, rather than general pharma-

cies, again, reducing competition; and,

finally, price gouging.

the price gouging is impressive. dara-

prim’s price increased from $13.50 to

$750 per tablet; thiola went from $1.50

to $ 30.00 per tablet; seromycin, a drug

for multiple drug-resistant tuberculo-

sis, an increasingly worrisome scourge

for the whole world, particularly the

poorer parts, went from $500/30 days

to $10,800; valeant, the only actual

drug company among the four targeted

by this report, increased the price of

two drugs for Wilson’s disease, one of

the rare, treatable neurodegenerative

disorders, from $500/30 days to $24,000.

And, in case you think there have been

typos with the number of zeros, you

are mistaken. to top it off, all the drugs

were available before 1990, some in the

1950s and ‘60s.

the senate report indicates that the

investors were fully aware of the busi-

ness model and approved it. I am unsure

if they would endorse the famous line

of gordon gecko, in the movie, Wall

street, “greed is good.” My guess is

that they would not have used the word

“greed,” and they would simply have

said they were doing their job for their

family, making them financially more

secure. I doubt they actually took plea-

sure in thinking about the patients who

would no longer be able to treat their

disorders, about a 20-year-old girl whose

liver and brain are failing, making her

unable to care for herself, and, perhaps,

ultimately, a ward of the state. I doubt

they think about the implications of

not treating multidrug-resistant tB for

the whole world, including, perhaps

their children.

the question is not why they do it.

Bad, immoral people are part of human-

ity. the question is what can we do

about it? It would be nice to post some

photos in the post office, or in the local

newspaper. one of the principal actors

for two of the companies, Martin skrelli,

actually appears to enjoy the attention,

apparently feeling, like book publish-

ers, that a bad review is better than no

review. the senate committee’s report

was a great first step. It recommended

w w w . R i M e D . o R G | a R C H i v e s | J u n e w e b p a G e 8J U N E 2 0 1 7 R h o d e i s l a n d m e d i c a l j o u R n a l

https://www.aging.senate.gov/imo/media/doc/Drug%2520Pricing%2520Report.pdf



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http://www.rimed.org/rimedicaljournal-2017-06.asp

COMMENTARY

Author

Joseph H. Friedman, Md, is editor-in-chief

of the Rhode Island Medical Journal,

Professor and the chief of the division

of Movement disorders, department of

neurology at the Alpert Medical school of

Brown university, chief of Butler Hospital’s

Movement disorders Program and first

recipient of the stanley Aronson chair

in neurodegenerative disorders.

disclosures on website

further steps, of course. It felt that anti-

trust laws were unlikely to be help-

ful, that price transparency would be

extremely helpful, but unlikely without

legislation and that coupons and cost

sharing with the company would be

counterproductive, increasing costs for

insurers and increasing the amount of

drug prescribed. Most helpful, I think,

would be their recommendation to

allow temporary imports of the drug

from other countries. I am pleased to

note that since I wrote the first draft of

this that valeant has been devastated

by a number of revelations, causing a

dramatic drop in its value. I am unsure

of the fate of the other companies, but

recent newspaper reports indicate that

other investment groups have found this

business model appealing and hope to

cash in on our patients’ misery.

We must keep in mind that what

these four companies are doing is

not much different than what we’ve

recently seen with epiPens, narcan

injections and newer forms of insulin.

drug companies are supposed to make

money; however, they also have some

responsibility to their clients, perhaps

not a lot, but some. they are bullies

without a moral conscience. I am not a

believer in violence and abhor the death

penalty, but crimes like these make me

doubt my resolve. v





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COMMENTARY

11

12

en

Workplace violence in hospitals and measures to address itHeRbeRT RakaTansky, MD

gerous places and not

only for patients.

the yearly incidence of

physical abuse of nurses

by patients is reported

to be 30%. When asked

about violence during

their career, 61% of

nurses who reported vio-

lent incidents indicated

patients as the aggressors

(families and others also were perpetra-

tors). drugs and alcohol were involved

in 58% of the incidents. emergency

room nurses were most at risk.

can we predict which patients are

potentially violent?

that is not easy. Persons in police

custody are prime candidates. In the

11 years ending 2011, there were 154

“shootings with injury” on us hospi-

tal grounds. twenty-nine percent of

shootings in the eR were by patients in

police custody, a number of whom were

violent while trying to escape. Patients

with delirium, alcohol or drug intoxica-

tion and psychotic behavior are prone

to violent behavior. Patients, friends

and families stressed by bad news, long

waits and other frustrations may act out

their anger.

the occupational safety and Health

Administration (osHA) reports that

in 2014 there were 8 cases per 10,000

health care employees with violent

injuries (80% inflicted by patients) seri-

ous enough to require time away from

work. the rate in private

industry was less than 2

cases per 10,000.

In addition to being

dangerous, workplace

violence is expensive. In

one hospital system 30

injured nurses (in one

year) incurred expenses of

$94,156 ($78,924 for treat-

ment and $15,232 for lost

wages). the cost of replac-

ing a nurse can range up to $100,000.

the number of violent acts against

health care workers (HcW) is elusive.

First, there is a lack of a standard defi-

nition of violence. nurses and doctors

report less than 30% of the violent

incidents suffered and many health care

workers assume that these incidents are

“part of the job.” Interestingly, urban and

suburban hospitals did not vary in the

rate of violent incidents, though “high

volume eRs and residential and day

social services present the highest risk.”

there is a reluctance to report due to

the feeling that the hospital administra-

tion disapproves of such reports and may

look adversely at HcWs who make such

reports. the new emphasis on “cus-

tomer satisfaction” is also a deterrent to

reporting. the business maxim that the

“customer is always right” has become

prevalent in the medical enterprise, but

is harmful in these cases.

A rapid response by security officers

when a violent act seems imminent or

has happened is standard practice. But

this deprives other areas of the hospital

of security protection. security officers

called to cope with an urgent situation

will not be able to protect the parking

lot, for example. the most frequent site

of shootings (41%) in hospitals is on the

grounds outside the building.

violence impinges on patient care

in number of ways. Medical personnel

may be reluctant to care for potentially

violent patients, thus decreasing the

care available to these patients. And

post-violence psychological trauma may

impair the ability of HcWs to care for

all patients.

so what can be done?

First, heath care facilities should pro-

hibit all firearms from their premises,

except those carried by law enforce-

ment. Metal detectors, however, are not

in general use due to the many entrances

to hospitals, high volume of persons and

the cost of staffing.

osHA has detailed guidelines about

violence in the healthcare setting. they

emphasize three steps: 1. Prevention

(transfer patient to a safe environment,

verbal de-escalation, etc.); 2. Work place

adaptations (panic buttons, site specific

issues such as accessible exit routes, etc.)

and 3. Root cause analyses of all incidents.

education of all HcWs in techniques

of de-escalation should be universal.

verbal techniques to lessen the poten-

tial for violence may be effective. But

training in self-defense may also be rea-

sonable. the American Association for

emergency Psychiatry has a protocol for

Hospitals can be dan-





such interventions. one RI health care

system has initial mandatory training

for nurses, PAs, etc. but not for doctors.

Annual refresher training (best practice

standard) is not offered due to lack

of resources.

simple approaches such as having

security personnel wear clothing that is

not the typical police uniform can avoid

triggering violence in some persons

(such as gang members, patients with

criminal background, etc.) who react

negatively to police. uniformed security

officers, however, are more effective

in other situations, so this approach is

possible only in units with dedicated

security personnel.

Most states, including RI, classify

assaults on HcWs as felonies. Assault

means an action intended to cause

bodily harm (even if no harm results).

In RI “any person” who “knowingly

and willfully” assaults a “health care

provider” during treatment may be

”imprisoned for up to 3 years and fined

not more than $1500.” While this law

is not likely to deter a patient in the

throes of delirium, it may be a deterrent

to others.

verbal and low level physical abuses

are precursors to physical violence. A

“zero tolerance” for all abusive behav-

ior, no matter how minor, with appropri-

ate interventions designed to de-escalate

the situation may prevent major epi-

sodes of violence. this approach means

reporting of all such behavior to the

institution. Most importantly, the staff

must have confidence that the institu-

tion truly believes in this approach and

is fully committed to react promptly.

After a violent incident occurs it is crit-

ical that the staff have prompt therapeu-

tic interventions to assist in coping with

the stress. trained “trauma-informed”

teams with special expertise offering

personalized treatment are already

in place in many RI hospitals and are

important to the health of the victims.

In situations where violent patients

require prolonged care, transfer to a

specialized unit may be the best option.

Just as cases with massive injury are

best treated in a level 1 trauma center,

violent behavior, not responsive to ini-

tial intervention, may be best treated

in a unit with expertise and resources

in the many facets of this behavior.

unfortunately, such units may not be

readily available.

one hospital system (822 beds)

reported 42 workplace violent incidents

in 2012. After adopting a comprehen-

sive approach to workplace violence

there were 19 incidents yearly in 2015

and 2016.

these approaches work. our patients

and staff deserve no less. v

Author

Herbert Rakatansky, Md, FAcP, FAcg,

is clinical Professor of Medicine emeri-

tus,the Warren Alpert Medical school

of Brown university.


COMMENTARY




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RECENT AdVANCES IN NEuROSuRgERY

16

17

en

Introduction to Recent Advances in NeurosurgeryZiya L. GokasLan, MD

GuesT eDiToR

It is absolutely my pleasure to share with you in this issue some of the recent advances in treating a variety of neuro-surgical conditions at the department of neurosurgery of Rhode Island Hospital and Brown university.

the following contributions are included in this special focus section of the Rhode Island Medical Journal:

current treatment of Metastatic Spine tumors – Surgery and Stereotactic Radiosurgery by Jared s. Fridley, Md; Jaroslaw t. Hepel, Md, and Adetokunbo A. oyelese, Md, Phd, describes our multidisciplinary approach to patient care and the incorporation of stereotactic radiosurgery as well as other minimally invasive procedures into our surgical treatment paradigm in caring for patients with metastatic spinal tumors.

the Role of Radiation therapy in the treatment of Metastatic Brain disease by sohail syed, Md, and deus cielo, Md, is a comprehensive review which describes the use of a variety of radiation treatment modalities in managing patients with single and multiple brain metastases.

current Strategies in the Surgical Management of Ischemic Stroke by cody A. doberstein, Bs; Radmehr torabi, Md; sandra c. yan, Bs, BA; Ryan Mctaggart, Md; curtis dober-stein, Md, and Mahesh Jayaraman, Md, summarizes the transformation we have witnessed over the last several years in treating patients with major cerebral vessel occlusion via emergency endovascular thrombectomy, resulting in truly amazing restoration of neurological function for patients who would have otherwise been left with devastating per-manent neurological deficits. our multidisciplinary team of physicians is leading the field in this very exciting area with some of the best outcomes in the world.

Rhode Island hospital’s contribution to the Field of endo-scopic Spine Surgery by Albert e. telfeian, Md, Phd; Ade-tokunbo A. oyelese, Md, Phd, and Ziya L. gokaslan, Md, is a description of the groundbreaking work by dr. Albert telfeian, the director of the center for Minimally Invasive endoscopic spinal surgery at Rhode Island Hospital and Brown university, which allows outpatient endoscopic sur-gical treatment of spinal cord and painful nerve root com-pression, using pencil-tip size incisions. We are truly among the world leaders in this very exciting field, which has dra-matically shortened the recovery time from surgery while drastically improving patient outcomes.

Updates On chimeric Antigen Receptor-Mediated Glioblas- toma Immunotherapy by george Mao, Md; Prakash sam-path, Md, and sadhak sengupta, Phd, is again amazing work, outlining how the patient’s own immune system, specifically his/her own killer t-cells can be conditioned to recognize tumor- specific chimeric antigens in patients with glioblastoma. We are about to start clinical trials to translate this groundbreaking discovery to the care of our patients.

A comprehensive Approach to deep Brain Stimulation for Movement disorders by umer Akbar, Md, and Wael F. Asaad, Md, Phd, is a description of the multidisciplinary approach that our physicians employ in evaluating patients with movement disorders such as Parkinson’s disease and the state-of-the art surgical methods and technology they use in the operating room, with intraoperative, image-guided navigation, and electrophysiological recordings for precise placement of the deep brain electrodes used for stimulation.

Recent Advances in the treatment of Gliomas – comprehensive Brain tumor center by steven A. toms, Md, MPH, and nikolaos tapinos, Md, Phd, is a comprehensive review of the whole spectrum of treatment options including radia-tion, chemotherapy and immunotherapy in patients with gliomas. the article also describes the multidisciplinary approach employed by the comprehensive Brain tumor center at the Lifespan cancer Institute of Rhode Island Hos-pital and exciting ongoing translational research projects in our Brain tumor Research Laboratories.

current concepts in the pathogenesis, diagnosis, and Manage- ment of type I chiari Malformations by cody A. doberstein, Bs; Radmehr torabi, Md, and Petra M. klinge, Md, is an excellent review of the topic on this rare and often poorly understood condition and its neurosurgical treatment. dr. klinge is a worldwide expert and leads the center for csF disorders of the Brain and spine, where we at Rhode Island Hospital and Brown university offer state of-the-art care to our patients.

this is just a brief summary of some of the very exciting work we are doing here at the department of neurosurgery of Rhode Island Hospital, the norman Prince neurosciences Institute and Brown university, on a daily basis.






We are also pleased to share with you that we have just moved into a dedicated neuroscience floor at Rhode Island Hospital, which also houses an 18-bed neuro Intensive care unit and highly specialized physician and nursing teams. similarly, we have a dedicated spine floor with specialized nursing staff where we care for our patients with the whole spectrum of spinal disorders.

Author

Ziya L. gokaslan, Md, FAAns, FAcs

gus stoll, Md, Professor and chair, department of neurosurgery,

the Warren Alpert Medical school of Brown university;

neurosurgeon-in-chief, Rhode Island Hospital and the Miriam

Hospital; clinical director, norman Prince neurosciences

Institute; President, Brown neurosurgery Foundation

correspondenceZiya L. gokaslan, MdRhode Island Hospitaldepartment of neurosurgerynorman Prince neurosciences Institute593 eddy street - APc 6 Providence, RI [email protected]

[email protected]


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current treatment of Metastatic Spine tumors – Surgery and Stereotactic RadiosurgeryJaReD s. FRiDLey, MD; JaRosLaw T. HepeL, MD; aDeTokunbo a. oyeLese, MD, phD

ABSTRACT there has been significant progress and innovation in the treatment of patients with metastatic spinal tumors over the last two to three decades that has impacted our ability to provide individualized care that improves a patient’s quality of life and degree of neurologic impair-ment. Advances in surgical techniques and radiation de-livery modalities have dramatically improved our abil-ity to decrease local tumor recurrence rates, improve pain control, and provide more durable spinal stability. Modern day spine tumor resection and reconstruction techniques have been shown to improve and prolong pa-tients’ ability to ambulate, maintain continence, and re-duce the need for pain medications. spinal radiosurgery, the focused delivery of radiation to a target in the spine, has significantly enhanced the ability to provide a high degree of local tumor control in a non-invasive manner, even for tumors that are deemed radioresistant by con-ventional radiation therapy standards. In most patients, a combination of treatment modalities, including both sur-gery and radiation, is the mainstay of any comprehensive treatment plan for metastatic spinal tumors.

KEYWORdS: spine metastases, separation surgery, spinal radiosurgery, spine tumor, spine decompression

INTROduCTION

Metastases are the most common spine tumor, with up to 40% of cancer patients developing spinal metastases, and 5-10% developing symptomatic epidural spinal cord compression.1 the spine is the most common site of skel-etal metastases, with the thoracic spine being the most frequently involved spinal segment, followed by the lum-bar and cervical spine. Advances in the treatment of can-cer has led to improved patient survival, but also a higher incidence of patients with spinal metastases. the treatment of these patients has evolved substantially over the past sev-eral decades, with dramatic advances in both surgical and radiation therapies. In this paper, we summarize some of the more important advances in these respective fields.

SuRgICAl AdVANCEMENTS

For many years, patients with metastatic spine tumors caus-ing epidural spinal cord or nerve root compression were treated with simple posterior spinal decompression fol-lowed by fractionated external beam radiotherapy. While some patients did improve in terms of ability to ambulate and bowel/bladder function,2 the results weren’t encour-aging. When compared to radiation alone the addition of a simple posterior decompression was not found to add any significant benefit in terms of pain, sphincter function, or improved ambulation.2 the disheartening results of such studies led to a decline in surgical intervention.

the primary problem with a simple posterior decompres-sion of the spinal cord, which is typically done via lami-nectomy, is that in many patients, epidural compression is ventral to the spinal cord, not dorsal. this means that many patients continue to have ventral spinal cord com-pression despite a posterior decompression. Following the disappointing outcomes of earlier studies examining lami-nectomy and radiation for tumor treatment,2 surgeons began developing techniques to directly decompress the spinal cord with ventral tumor resection. the hope was that cir-cumferential decompression of the spinal cord with instru-mented stabilization of the spine might lead to improved outcomes. this was confirmed in a landmark randomized, prospective trial published in 2009 by Patchell et al. compar-ing radiation alone to radiation plus circumferential surgical decompression in patients with a single spinal metastasis compressing the spinal cord.3 the authors found that 84% of patients treated with both circumferential decompression and radiation were able to ambulate after treatment versus 57% patients who underwent radiation alone. In the group of patients unable to walk before treatment, 62% in the sur-gery group regained the ability to ambulate versus 19% in the radiation only group. this contrasts with the results of performing a laminectomy alone with radiation in the study by young et al. in which 45% of patients were able to ambu-late after treatment.2 the surgery plus radiation group was also able to walk for a longer period of time after treatment versus the radiation only group (122 days vs. 13 days). this study provides the best evidence to date that circumferential spinal cord decompression can significantly improve patient quality of life.

Pathologic fractures in patients with metastatic spine

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tumors without epidural compression often present with significant back pain. When unstable these fractures tend to be managed via surgical instrumentation. However, when neither gross instability nor significant epidural spinal cord compression exist, percutaneous vertebral body cement aug-mentation is a non-invasive method that can provide back pain relief. there are two primary methods of cement aug-mentation: balloon kyphoplasty and vertebroplasty, both of which have been shown to be effective for treating pain from pathologic fractures.4 these procedures involve injection of polymethylmethacrylate (PMMA) through the percutaneous insertion of a small metal trocar into the vertebral pedicle, followed by injection of cement under fluoroscopic guid-ance. With balloon kyphoplasty, a small inflatable balloon is inserted into the vertebral body and inflated to augment vertebral body height prior to injection of cement. even in patients with significant vertebral body collapse, cement augmentation can be an effect option for pain relief, with a low overall complication rate.5

AdVANCES IN RAdIATION TREATMENT

Radiation delivery for spinal metastases has evolved sub-stantially since the end of the 20th century. traditional external beam radiation therapy (eBRt) consists of radia-tion delivered in a fractionated dose, typically 30 gy over 10 fractions, and using simple one to two portal configurations that encompasses the area of disease with a wide margin of 1 vertebral level above and below. eBRt has been shown to be effective in treating very radiosensitive tumors such as multiple myeloma and lymphoma as well as moderately radiosensitive tumors such as breast and prostate cancer.6,7 However, eBRt has been shown to not be as effective in the treatment of more radioresistant tumors, such as sarcoma, melanoma and renal cell carcinoma.6,7 to maximize the dose of radiation delivered to a tumor target and minimize radi-ation toxicity to surrounding healthy tissues, advances in both computing hardware and radiation planning software were incorporated into treatment planning. this led to the development of conformal radiotherapy such as intensity modulated radiation therapy (IMRt), which utilizes sophis-ticated 3d planning and multi-leaf collimators that focus radiation to the intended tumor target and minimize dose to adjacent normal tissues. However, the radiation sensitiv-ity of the spinal cord and its intimate location to metastatic disease in the vertebra, limits the safe delivery of only mod-erate doses of radiation (45-50gy in standard fractionation) with this technique.8

the next significant advance in radiation therapy was the development of stereotactic radiosurgery to be delivered to spine lesions akin to stereotactic radiosurgery for brain metastases in the late 20th century. Radiosurgery consists of a single or hypo-fractionated dose of radiation delivered with extreme precision to the tumor target. unlike cranial

stereotactic radiosurgery, spinal radiosurgery has unique technical obstacles. this includes dose limitations due to proximity of the spinal cord and spinal motion during radia-tion delivery. unlike the head, which can be fixated in place using a stereotactic frame, the spine is more difficult to constrain. to overcome the problem of motion, immobiliza-tion devices coupled with real-time image guidance during treatment have been developed which allow for targeting accuracy to 1mm or less. the extreme precision combined with sophisticated dose modulation allows for the delivery of high doses of radiation while still relatively sparing the spinal cord. this results in safe delivery treatment that is effective even for radiation-resistant histologies. using single fraction dose equivalents of 18-24 gy, studies have demonstrated a local tumor control rate of 80-96%,9-11 and a 86% chance of long-term pain relief.12

A NEW PARAdIgM

the success of spinal radiosurgery in terms of local control and pain relief of spinal tumors has dramatically altered treatment paradigms. It has supplanted both eBRt and surgery in the primary treatment of solitary spine tumors without significant epidural compression. In those patients with significant neural element compression, or in those patients with spinal instability due to an unstable patho-logic fracture, surgery remains the gold standard. similarly, eBRt continues to be used for the treatment of radiosen-sitive spinal metastases. to minimize surgical morbidity from an extensive circumferential decompression including vertebral body resection, Laufer et al have advocated ‘sep-aration surgery’ which entails circumferential resection of epidural tumor, a limited resection of vertebral body tumor, followed by adjuvant radiosurgery to the remaining tumor and resection cavity.13 In their series of patients, Laufer et al reported a 4.1 – 22.6% local recurrence rate at 1 year depend-ing on the radiation dose/fraction regimen utilized post-op-eratively. despite these impressive results, further study is needed to determine whether this is a more efficacious strat-egy versus a more aggressive surgical resection and spinal reconstruction.

CONCluSION

Recent advances in the surgical and radiation management of patients with spinal metastases has led to significant improvement in patient outcome. despite these advances, treatment remains palliative. the goals of care should be to minimize patient morbidity, and maximize patient quality of life in terms of pain, mobility, and neurologic function. A multi-disciplinary approach to management of these patients that incorporates medical oncology, radiation oncology, and neurosurgery is necessary for optimal treatment planning in this complicated group of patients.






References1. Byrne tn. spinal cord compression from epidural metastases. N

Engl J Med. 1992;327(9):614-619.2. young RF, Post eM, king gA. treatment of spinal epidural me-

tastases. Randomized prospective comparison of laminectomy and radiotherapy. J Neurosurg. 1980;53(6):741-748.

3. Patchell RA, tibbs PA, Regine WF, et al. direct decompressive surgical resection in the treatment of spinal cord compres-sion caused by metastatic cancer: a randomised trial. Lancet. 2005;366(9486):643-648.

4. Fourney dR, schomer dF, nader R, et al. Percutaneous verte-broplasty and kyphoplasty for painful vertebral body fractures in cancer patients. J Neurosurg. 2003;98(1 suppl):21-30.

5. Hentschel sJ, Burton AW, Fourney dR, Rhines Ld, Mendel e. Percutaneous vertebroplasty and kyphoplasty performed at a cancer center: refuting proposed contraindications. J Neurosurg Spine. 2005;2(4):436-440.

6. katagiri H, takahashi M, Inagaki J, et al. clinical results of non-surgical treatment for spinal metastases. Int J Radiat Oncol Biol Phys. 1998;42(5):1127-1132.

7. Maranzano e, trippa F, chirico L, Basagni ML, Rossi R. Man-agement of metastatic spinal cord compression. Tumori. 2003;89(5):469-475.

8. kirkpatrick JP, van der kogel AJ, schultheiss te. Radiation dose-volume effects in the spinal cord. Int J Radiat Oncol Biol Phys. 2010;76(3 suppl):s42-49.

9. sahgal A, Bilsky M, chang eL, et al. stereotactic body radio-therapy for spinal metastases: current status, with a focus on its application in the postoperative patient. J Neurosurg Spine. 2011;14(2):151-166.

10. chang eL, shiu As, Mendel e, et al. Phase I/II study of stereo-tactic body radiotherapy for spinal metastasis and its pattern of failure. J Neurosurg Spine. 2007;7(2):151-160.

11. gerszten Pc, Mendel e, yamada y. Radiotherapy and radiosur-gery for metastatic spine disease: what are the options, indica-tions, and outcomes? Spine (Phila Pa 1976). 2009;34(22 sup-pl):s78-92.

12. gerszten Pc, Burton sA, ozhasoglu c, Welch Wc. Radiosur-gery for spinal metastases: clinical experience in 500 cases from a single institution. Spine (Phila Pa 1976). 2007;32(2):193-199.

13. Laufer I, Iorgulescu JB, chapman t, et al. Local disease control for spinal metastases following “separation surgery” and adju-vant hypofractionated or high-dose single-fraction stereotactic radiosurgery: outcome analysis in 186 patients. J Neurosurg Spine. 2013;18(3):207-214.

AuthorsJared s. Fridley, Md, comprehensive spine center, Rhode Island

Hospital, dept. of neurosurgery, Warren Alpert Medical school of Brown university.

Jaroslaw t. Hepel, Md, director of the Rhode Island Hospital stereotactic Radiotherapy and Radiosurgery Program, Assistant Professor in the department of Radiation oncology, Warren Alpert Medical school of Brown university.

Adetokunbo A. oyelese, Md, Phd, surgical director, comprehensive spine center, and director, neurosurgical trauma and spinal disorders, Rhode Island Hospital; Associate Professor of neurosurgery (clinical), Warren Alpert Medical school of Brown university.

correspondenceJared s. Fridley, Mdcomprehensive spine centerdept. of neurosurgeryRhode Island Hospital593 eddy st.Providence, RI [email protected]


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the Role of Radiation therapy in the treatment of Metastatic Brain diseasekunaL sinDHu, bs; soHaiL syeD, MD; Deus CieLo, MD

ABSTRACT Brain metastasis is the most frequent central nervous system malignancy. Although surgery and chemotherapy have roles to play in the treatment of brain metastasis, radiation therapy remains a mainstay of therapy. We will review the role of fractionated radiotherapy and stereo-tactic radiosurgery in the treatment of newly diagnosed and recurrent brain metastasis.

KEYWORdS: brain metastasis, radiotherapy, stereotactic radiosurgery

INTROduCTION

In adult patients with cancer, 20-40% of ultimately develop brain metastases.1patterns of intracranial disease and fac-tors influencing survival become important considerations when examining potential treatment options. MetH-ods: the records of 729 patients with metastases to the brain treated during the period between 1973 to 1993 were reviewed. ResuLts: Primary tumor histologic type in order of descending frequency included nonsmall cell lung carci-noma (nscLc Historically, the prognosis for these patients was poor, ranging from one month for untreated patients to four-to-six months in patients who received corticoste-roids and whole brain radiation therapy (WBRt).2,3 Recently, changes in management have significantly improved the prognosis of patients, especially those with high functional status at time of diagnosis.4 While surgical resection has been increasingly employed for patients with limited dis-ease, radiation therapy remains the mainstay of treatment for patients, either as a primary or adjuvant therapy. While the precise role of stereotactic radiosurgery (sRs) is still evolving, a considerable body of evidence has confirmed the efficacy of both sRs and WBRt. In fact, the persistence of radiation therapy over time despite the emergence of alter-ative therapeutic modalities suggests that sRs and WBRt are likely to continue to play critical roles in the treatment of this patient population well into the future.

Brain metastases are the most common form of intracra-nial tumors. With an annual incidence of at least 200,000 cases in the united states, they are nearly ten times more common than primary malignant brain tumors.5,6 In 85% of

cases, they are found in the cerebral hemispheres, but they can also involve the cerebellum and, very rarely, the brain-stem.7 While brain metastases most commonly originate from primary tumors in the lungs, breast, or skin (mela-noma), they can ultimately originate from any type of can-cer.1,8patterns of intracranial disease and factors influencing survival become important considerations when examining potential treatment options. MetHods: the records of 729 patients with metastases to the brain treated during the period between 1973 to 1993 were reviewed. ResuLts: Pri-mary tumor histologic type in order of descending frequency included nonsmall cell lung carcinoma (nscLc

With improved management, a significant number of patients with brain metastases are living considerably longer compared to historic figures. In 2008, sperduto et al. pub-lished a new prognostic assessment tool for patients with brain metastases called the graded Prognostic Assessment (gPA). the gPA takes four aspects of a patient’s clinical sta-tus into account: age, karnofsky Performance status (kPs), the number of intracranial metastases, and the presence of extracranial metastases11 and found that a substantial num-ber of patients with brain metastases, especially those with the highest gPA scores, were living longer than one year.4

ThE TREATMENT Of BRAIN METASTASES

treatment regimens for brain metastases are frequently complex and multimodal. For symptomatic relief from brain edema, corticosteroids are used. Antiepileptics are often useful in controlling seizures in symptomatic patients. For definitive treatment, chemotherapy, radiation therapy, and surgery may be used.5

Historically, radiation has played a dominant role in the treatment and palliation of brain metastases and was first described as a treatment for brain metastases in 1954 by chao et al.12 In the 1980s, sRs was widely adopted to treat patients with a limited number of brain metastases.5 In 1990, the role of surgery was first established by Patchell et al., who demonstrated that patients with a solitary brain metastasis who underwent surgical resection and WBRt had lower rates of local recurrence, longer periods of functional independence, and improved overall survival as compared to patients who received WBRt alone.13we randomly assigned patients with a single brain metastasis to either surgical

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removal of the brain tumor followed by radiotherapy (surgi-cal group numerous clinical trials have reinforced the roles of surgery and radiation in the management of these patients.

WBRttumor metastases to the brain disseminate hematogenously and may thus seed broadly within it. the role of WBRt in the treatment of patients with brain metastases is thus two-fold: to target both the macrometastases seen on imaging, as well as any micrometastases undetected by current diag-nostic testing.14 By treating both visible and occult lesions, WBRt can improve neurologic symptoms in 63% of the patients treated.12 Further studies have found that WBRt decreases local recurrence rates, improves neurologic func-tion, and improves overall survival in patients with brain metastases.2,3,15–17 Multiple clinical trials have established the efficacy of WBRt. nonetheless, there is no class I evi-dence that suggests that there is an advantage of a specific dose regimen with respect to overall survival, local control, or neurocognitive function.18 In common practice, though, the two most common schedules remain 30 gray delivered in 10 fractions or 37.5 gray delivered in 15 fractions.

unfortunately, WBRt can cause side effects by causing tissue damage in its intended target or the surrounding tis-sues. In the acute period after receiving WBRt, days to weeks after treatment, patients most commonly may experience fatigue, nausea and vomiting, radiation dermatitis, and alo-pecia. Within one to six months of treatment, patients may experience a transient worsening of symptoms and, rarely, somnolence syndrome. In the delayed period, six months or more after treatment, patients can develop more per-manent side effects, including radiation necrosis, vascular abnormalities, and cognitive deficits.19 Just six months after receiving WBRt, in fact, 50–90% of patients show evidence of radiation-induced cognitive impairment, including effects upon verbal and spatial memory, attention, and novel prob-lem-solving ability.19 As patients with brain metastases live longer, increasing attention is being paid to the neurocog-nitive sequelae associated with WBRt.20 not surprisingly, two controlled trials found worse neurocognitive outcomes in patients treated with WBRt and sRs compared to those treated with sRs alone.21,22 2001, to september 14, 2007. Patients were stratified by recursive partitioning analysis class, number of brain metastases, and radioresistant histol-ogy. the randomisation sequence was masked until assig-nation, at which point both clinicians and patients were made aware of the treatment allocation. the primary end-point was neurocognitive function: objectively measured as a significant deterioration (5-point drop compared with baseline In response to these neurocognitive outcomes, hip-pocampal-sparing WBRt has been advocated and seems to have improved neurocognitive outcomes compared to tra-ditional WBRt.23 nonetheless, it is the total burden of brain metastases that is the most important factor in predicting

the cognitive outcome in patients with brain metastases.23

despite its adverse effects, WBRt remains a cornerstone of management of patients with brain metastases. WBRt is especially useful in treating patients who are not candi-dates for sRs or surgery due to a large number of intracra-nial metastases, poor performance status, tumor location, or leptomeningeal spread.24 unfortunately, WBRt suffers from high rates of recurrence which are highly tumor histology dependent.25,26,27especially of tumor volume, on remission and to evaluate whether particular subgroups of metastases are controlled by low-dose radiotherapy. MetHods And MAteRIALs: contrast-enhanced ct scans before and after radiotherapy were analyzed. IncLusIon cRIteRIA: brain metastases treated with whole-brain radiotherapy (10 frac-tions of 3 gy over 2 weeks thus, providers must exercise clinical judgment in carefully selecting the candidates who are most likely to derive benefit from undergoing WBRt.

the use of WBRt has also been explored as an adjuvant to surgery or sRs. In patients with 1–3 brain metastases, the addition of adjuvant WBRt to sRs or surgery has been shown to improve local control and decrease the risk of neu-rologic death, but it does not appear to extend the length of functional independence or improve overall survival.28, 29 199 underwent radiosurgery, and 160 underwent surgery. In the radiosurgery group, 100 patients were allocated to oBs, and 99 were allocated to WBRt. After surgery, 79 patients were allocated to oBs, and 81 were allocated to adjuvant WBRt. the median time to WHo Ps more than 2 was 10.0 months (95% cI, 8.1 to 11.7 months

Stereotactic Radiation Surgerygamma knife, first developed by the swedish neurosurgeon Lars Leksell in 1951, is the most widely used sRs device.30 192 sources of cobalt-60 are organized around a circular frame that is secured to the patient’s head by four screws to ensure immobilization. during treatment, the sources of cobalt-60 produce gamma ray beams with an average energy of 1.25 Mev. the intersection of the beams, known as the isocenter, can be manipulated to ensure adequate coverage of the targeted lesion. While treatment time is variable, and depends on factors such as the number and morphology of the lesions to be treated, therapeutic radiation is delivered in a high-dose, single fraction. As a result, patients generally may return home on the same day of treatment.

Linear accelerator-based radiosurgery may be deliv-ered in many different forms utilizing rigid, frame-based patient immobilization or mask-based frameless immobili-zation systems. cyberknife, first developed by John Adler at stanford university, utilizes image-guidance technology and a 6-Mv linear accelerator with 12 circular collimators mounted upon a robotic arm to compensate for target move-ment when delivering treatment.31,32emerging technology that is a significant departure from current stereotactic radiosurgery and external beam radiotherapy technologies.






In its clinical application and quality assurance (QA X-ray images taken by mounted cameras during treatment adjust beam trajectory to ensure accuracy.31 Frameless sRs may enhance patient comfort and allows radiation treatment to be delivered in multiple fractions with impacting out-comes.32–3proximity to critical structures and variable tumor volumes. In this study, we investigate whether acceptable treatment plans with excellent conformity and homogene-ity can be generated for complex skull base tumors using the cyberknife(\u00ae 4 In light of the complexity of treating patients with brain metastases, the input and cooperation of neurosurgeons, radiation oncologists, and medical physicists is required to assess the feasibility of sRs treatment plans.

sRs is increasingly being utilized and is capable of deliv-ering high, focal doses of radiation that rapidly drop off out-side of the targeted treatment volume. Patient survival with sRs treatment of brain metastases appears to be less influ-enced by tumor histology than WBRt and offers high rates of local control.35–37the primary therapeutic aim is symptom palliation and maintenance of neurologic function, but in a subgroup, long-term survival is possible. Local control in the brain, and absent or controlled extracranial sites of disease are prerequisites for favorable survival. stereotactic radiosurgery (sRs Patients who receive sRs in the absence of adjuvant WBRt have an increased risk of recurrence in untreated areas of the brain.35,3the primary therapeutic aim is symptom palliation and maintenance of neurologic func-tion, but in a subgroup, long-term survival is possible. Local control in the brain, and absent or controlled extracranial sites of disease are prerequisites for favorable survival. ste-reotactic radiosurgery (sRs6 despite this finding, there is no difference in overall survival between patients who received sRs alone and those who received sRs and WBRt.21,28,38 2001, to september 14, 2007. Patients were stratified by recursive partitioning analysis class, number of brain metastases, and radioresistant histology. the randomisation sequence was masked until assignation, at which point both clinicians and patients were made aware of the treatment allocation. the primary endpoint was neurocognitive function: objec-tively measured as a significant deterioration (5-point drop compared with baseline

Although sRs may be used as monotherapy, avoiding the negative neurocognitive effects associated with WBRt, it should be noted that sRs monotherapy increased over-all survival in patients under 50, but decreased survival in patients over the age of 50 in one study.39 Additionally, sRs is not recommended for tumors greater than 40 millimeters in diameter because of the risk of radionecrosis in neigh-boring tissue. Rtog 90-05 found that the risk of neurotox-icity in patients treated with sRs was related to the size of metastases and established appropriate dose limits for sRs: 24 gray for tumors less than 20 millimeters in diameter, 18 gray for those 21–30 millimeters in diameter, and 12 gray in those 31–40 millimeters in diameter.40

the efficacy of sRs monotherapy in patients with mul-tiple brain metastases is the subject of ongoing research. A recent multi-institutional, prospective observational study in Japan found that the use of sRs alone was non-inferior in patients with 5–10 brain metastases as compared to its use in patients with 2–4 brain metastases. While more data is required to establish the superiority of sRs monotherapy over sRs and WBRt combination therapy in patients with 5–10 brain metastases, this study suggested that sRs alone may be a feasible treatment strategy in patients with up to 10 brain metastases.41

since WBRt often fails to control local disease, the use of sRs as an adjuvant to WBRt alone was explored in Rtog 9508 in patients with 1–3 brain metastases. Both local con-trol and kPs were improved in patients receiving sRs and WBRt versus those who received WBRt alone and patients with solitary metastasis, favorable tumor histology, or Recursive Partitioning Analysis group 1 who received adju-vant sRs had a survival benefit.42 similarly, a trial that ana-lyzed patients with 2–4 brain metastases found that those who received WBRt and adjuvant sRs had lower rates of local recurrence and longer progression-free survival as compared to those who received WBRt alone; however, no statistically significant differences in overall survival were found.43frequently diagnosed in patients with cancer. the prognosis, even after treatment with whole brain radiation therapy (WBRt Likewise, after surgical resection, sRs has been found to increase rates of local control.44

sRs may also be used in the salvage setting. untreated, recurrent brain metastases are typically fatal within 2–4 months. A retrospective review by caballero et al. that ana-lyzed 310 patients who received sRs for brain metastases after prior WBRt found that overall median survival was 8.4 months after receiving sRs. Patients with a solitary brain metastasis had a higher median survival at 12.0 months, while those with multiple brain metastases had a median survival of 7.9 months. In this study, every patient, regard-less of the total number of brain metastases, benefited from receiving salvage sRs.45

CONCluSION

While the treatment of patients with brain metastases remains challenging, the prognosis for these patients has improved significantly over the past two decades. despite the many improvements in management that have been made, radiation therapy remains a cornerstone of treatment. For a significant number of these patients, including those with a large number of brain metastases, poor performance status, and leptomeningeal spread, WBRt remains a clear-ly-defined, first-line treatment option. the role of sRs, in contrast, is rapidly evolving. While sRs monotherapy is appropriate for properly selected patients with 1–4 brain metastases, its sole use in the treatment of patients with






5-10 brain metastases is the subject of ongoing investigation. Additionally, sRs has been shown to increase rates of local control as an adjuvant and salvage treatment in patients receiving WBRt or surgery. As further advances are made in the medical management of patients with brain metastases, including in the emerging field of immunotherapy, radia-tion therapy is likely to remain a useful tool in treating this population of patients.

References1. nussbaum es, djalilian HR, cho kH, Hall WA. Brain metas-

tases. Histology, multiplicity, surgery, and survival. Cancer. 1996;78(8):1781-1788.

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3. sundstrom Jt, Minn H, Lertola kk, nordman e. Prognosis of patients treated for intracranial metastases with whole-brain ir-radiation. Ann Med. 1998;30(3):296-299.

4. sperduto PW, kased n, Roberge d, et al. summary report on the graded prognostic assessment: an accurate and facile diag-nosis-specific tool to estimate survival for patients with brain metastases. J Clin Oncol. 2012;30(4):419-425. doi:10.1200/Jco.2011.38.0527.

5. Lin X, deAngelis LM. treatment of Brain Metastases. J Clin On-col. 2015;33(30):3475-3484. doi:10.1200/Jco.2015.60.9503.

6. gavrilovic It, Posner JB. Brain metastases: epidemiology and pathophysiology. J Neurooncol. 2005;75(1):5-14. doi:10.1007/s11060-004-8093-6.

7. tsao Mn, Lloyd n, Wong Rk, et al. Whole brain radiotherapy for the treatment of newly diagnosed multiple brain metastases. Cochrane Database Syst Rev. 2012.

8. Platta cs, khuntia d, Mehta MP, suh JH. current treatment strategies for brain metastasis and complications from therapeu-tic techniques: a review of current literature. Am J Clin Oncol. 2010;33(4):398-407. doi:10.1097/coc.0b013e318194f744.

9. Lim Lc, Rosenthal MA, Maartens n, Ryan g. Management of brain metastases. Intern Med J. 2004;34(5):270-278. doi:10.1111/j.1444-0903.2004.00579.x.

10. Lohr F, Pirzkall A, Hof H, Fleckenstein k, debus J. Adjuvant treatment of brain metastases. Semin Surg Oncol. 2001;20(1): 50-56.

11. sperduto PW, Berkey B, gaspar Le, Mehta M, curran W. A new prognostic index and comparison to three other indices for pa-tients with brain metastases: an analysis of 1,960 patients in the Rtog database. Int J Radiat Oncol Biol Phys. 2008;70(2):510-514. doi:10.1016/j.ijrobp.2007.06.074.

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13. Patchell RA, tibbs PA, Walsh JW, et al. A randomized trial of sur-gery in the treatment of single metastases to the brain. N Engl J Med. 1990;322(8):494-500. doi:10.1056/neJM199002223220802.

14. Abe e, Aoyama H. the Role of Whole Brain Radiation thera-py for the Management of Brain Metastases in the era of ste-reotactic Radiosurgery. Curr Oncol Rep. 2012;14(1):79-84. doi:10.1007/s11912-011-0201-0.

15. Borgelt B, gelber R, kramer s, et al. the palliation of brain metastases: final results of the first two studies by the Radia-tion therapy oncology group. Int J Radiat Oncol Biol Phys. 1980;6(1):1-9.

16. gaspar L, scott c, Rotman M, et al. Recursive partitioning analysis (RPA) of prognostic factors in three Radiation therapy oncology group (Rtog) brain metastases trials. Int J Radiat Oncol Biol Phys. 1997;37(4):745-751.

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18. gaspar Le, Mehta MP, Patchell RA, et al. the role of whole brain radiation therapy in the management of newly diagnosed brain metastases: a systematic review and evidence-based clinical practice guideline. J Neurooncol. 2010;96(1):17-32. doi:10.1007/s11060-009-0060-9.

19. greene-schloesser d, Robbins Me, Peiffer AM, shaw eg, Wheeler kt, chan Md. Radiation-induced brain injury: A re-view. Front Oncol. 2012;2. doi:10.3389/fonc.2012.00073.

20. sindhu kk, kinsella tJ. the sun Has not yet set on WBRt. J Cancer Res Curr Prev. 2016;5(3):00161.

21. chang eL, Wefel Js, Hess kR, et al. neurocognition in patients with brain metastases treated with radiosurgery or radiosur-gery plus whole-brain irradiation: a randomised controlled tri-al. Lancet Oncol. 2009;10(11):1037-1044. doi:10.1016/s1470-2045(09)70263-3.

22. Brown Pd, Jaeckle k, Ballman k v, et al. effect of Radiosurgery Alone vs Radiosurgery With Whole Brain Radiation therapy on cognitive Function in Patients With 1 to 3 Brain Metasta-ses: A Randomized clinical trial. JAMA. 2016;316(4):401-409. doi:10.1001/jama.2016.9839.

23. oehlke o, Wucherpfennig d, Fels F et. al. Whole brain irradia-tion with hippocampal sparing and dose escalation on multiple brain metastases: Local tumour control and survival. Strhlenher Onkol. 2015; 191(6): 461-9.

24. Regine WF, scott c, Murray k, curran W. neurocognitive out-come in brain metastases patients treated with accelerated-frac-tionation vs. accelerated-hyperfractionated radiotherapy: an analysis from Radiation therapy oncology group study 91-04. Int J Radiat Oncol Biol Phys. 2001;51(3):711-717.

25. scoccianti s, Ricardi u. treatment of brain metastases: review of phase III randomized controlled trials. Radiother Oncol. 2012;102(2):168-179. doi:10.1016/j.radonc.2011.08.041.

References 26–45

Authorskunal sindhu, Bs, is a student at the Alpert Medical school of

Brown university.

sohail syed, Md, Resident, department of neurosurgery, Alpert Medical school of Brown university.

deus cielo, Md, Assistant Professor, department of neurosurgery, Warren Alpert Medical school of Brown university.

correspondencedeus cielo, Mdneurosurgery Foundation593 eddy streetAPc 6Providence, RI 02903401-793-9158Fax 401-444-2775


http://www.rimed.org/rimedicaljournal/2017/06/2017-06-21-neuro-sindhu-referneces.pdf





current Strategies in the Surgical Management of Ischemic StrokeCoDy a. DobeRsTein, bs; RaDMeHR ToRabi, MD; sanDRa C. yan, bs, ba; Ryan MCTaGGaRT, MD;

CuRTis DobeRsTein, MD; MaHesH JayaRaMan, MD

ABSTRACT stroke is a major cause of death and disability in the unit-ed states and rapid evaluation and treatment of stroke patients are critical to good outcomes. effective surgical treatments aim to restore adequate cerebral blood flow, prevent secondary brain injury, or reduce the likelihood of recurrent stroke. Patient evaluation in centers with a comprehensive stroke program and a dedicated neurovascular team is recommended.

KEYWORdS: stroke, embolectomy, cerebrovascular occlusion

INTROduCTION

stroke is the leading cause of long-term adult disability in north America and the fifth leading cause of death.1,2 Although some strokes are hemorrhagic, the majority (87%) are ischemic due to insufficient cerebral blood flow sec-ondary to occlusion or flow limiting stenosis. Brain tissue is exquisitely sensitive to ischemia, and an estimated 1.9 million neurons die every minute that blood flow is not restored. time is brain.3

surgical treatment for stroke can be classified into acute (emergent) or non-acute. Acute interventions, initiated within hours of stroke onset, are aimed at reestablishing cerebral blood flow, restoring lost neurologic function, and preventing permanent tissue damage. non-acute surgical therapies focus on reducing secondary injuries resulting from brain swelling or preventing recurrent stroke.

the effective surgical management of stroke requires con-tinuous and immediately available treatment by dedicated personnel specializing in complex cerebrovascular inter-ventions. these requirements may be best accomplished in facilities with a dedicated neurovascular center and stroke program.

EMERgENT EMBOlECTOMY fOR STROKE

Intravenous tissue plasminogen activator (Iv-tPA) remains an effective medical treatment in stroke patients if adminis-tered within 4.5 hours of symptom onset. However, 20–30% of acute ischemic stroke patients have evidence of large

vessel occlusion (Lvo) involving a major proximal intracra-nial artery and the efficacy of Iv-tPA is significantly reduced in these cases.4 Furthermore, many patients do not fit the strict time window and inclusion criteria for the admin-istration of Iv-tPA and therefore are ineligible to receive treatment.

the recent refinement of endovascular catheter-based surgical techniques, which use a stent-retriever device to directly remove clots from occluded vessels and restore blood flow, have proven effective in reducing morbidity and mortality in stroke patients with Lvo. several recent randomized studies have demonstrated a significant benefit of embolectomy compared to standard medical treatment alone.5,6 due to improved outcomes, embolectomy in com-bination with Iv-tPA has now become the standard of care for patients with Lvo stroke. Figure 1 demonstrates pre- and post-angiographic images in a patient who underwent emer-gent embolectomy and shows the dramatic improvement of cerebral perfusion following recanalization.

In addition to improving outcomes, embolectomy has less restrictive enrollment criteria and a longer time treat-ment window (usually 6 hours from stroke onset, though 12 or more hours in suspected basilar artery occlusion). It is estimated that the likelihood of a good outcome decreases by 10% for every 30-minute delay in recanalization from embolectomy, making efficient diagnosis and management critical. computed tomographic angiography (ctA) can rap-idly and accurately demonstrate the presence of an occlu-sion, and should be part of the minimum imaging workup for suspected stroke patients. A national study in 2015, led by members of our neurovascular team, identified several elements that are required to achieve timely revasculariza-tion in Lvo patients.7 expanding upon these findings, our comprehensive stroke center (csc) developed a standard-ized practice to decrease procedure times and initiated a protocol for Lvo patients who first presented to an outside primary stroke center (Psc) to facilitate quick treatment (Figure 2).8 this method was designed to minimize waiting times for suspected Lvo patients, getting them closer to intervention as soon as possible. Initial results demonstrate that when fully executed, median time from Psc arrival to csc intervention was reduced from 151 to 111 min-utes (p<0.0001). this protocol also made patients twice as likely to have a favorable outcome (50% vs. 25%). evidence

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strongly supports that prompt evaluation and treatment of stroke patients with documented Lvo in centers capable of performing embolectomy is crucial to obtaining optimal clinical outcomes.

dECOMPRESSIVE hEMICRANIECTOMY

despite acute interventions such as Iv-tPA and embolec-tomy, up to 10% of ischemic strokes result in large areas of infarction. this can lead to significant brain swelling, raised intracranial pressure (IcP), and in severe cases, life-threaten-ing herniation syndromes. these conditions are associated with worse outcomes, as they promote further reductions

in cerebral blood flow leading to additional ischemic tissue damage (secondary brain injury).

significant edema that occurs in the supratentorial space after a stroke is referred to as malignant infarction of the middle cerebral artery (McA).9 this condition is associated with ct evidence of infarction involving at least 50% of the McA territory or an infarct volume of greater than 145 cm3 on diffusion weighted magnetic resonance imaging (MRI). despite aggressive medical management including hyper-ventilation, barbiturates, hyperosmolar therapy, and corti-costeroids, malignant McA infarctions have been associated with an 80% fatality rate. However, recent multi-center trials and pooled analyses strongly support the role of sur-gical intervention, consisting of a decompressive hemicra-niectomy (dHc), in reducing mortality and disability after malignant McA infarction in select patients.9.10 the surgical procedure involves removal of a large bone flap, followed by insertion of a dural patch. this results in reduced constric-tion of the injured brain and culminates in lower IcP and reduced risk of brain herniation.

three european prospective, multi-center, randomized controlled trials have investigated the benefit of dHc ver-sus medical treatment in patients with space-occupying hemispheric strokes and altered level of consciousness.9,10,11

the destIny trial enrolled patients, between 18 and 60 years of age, within 36 hours of stroke onset. the trial was terminated per the study protocol when statistical signifi-cance was reached for reduction in 30-day mortality in the surgical arm (88% of patients randomized to dHc versus

Figure 1. a) ap view of left iCa angiogram demonstrating MCa occlusion (arrow).

b) ap view of left iCa post-embolectomy angiogram showing recanalization of MCa (arrow)

A B

outside hospitals (psC) notify the CsC immediately upon patient arrival

obtain a CTa in addition to non-contrast CT in all patients with suspected Lvo, although this should not delay iv-tpa administration

share imaging with CsC using a secure cloud-based platform

activation of the neurointerventional surgical team as soon as possible based on Lvo confirmation or clinical stroke severity

additional imaging techniques, particularly those intended to physiologically select patients for embolectomy, may provide additional value but should not delay the procedure

avoidance of routine general anesthesia during intervention

Figure 2. protocol to expedite time to embolectomy






47% receiving conservative therapy survived after 30 days). decIMAL randomized 38 patients, 18–55 years old, within 24 hours of stroke onset. there was a 52.8% absolute reduc-tion in death in the surgical cohort. Lastly, the HAMLet trial included 64 patients between 18 and 60 years of age treated within 96 hours of symptom onset and found that dHc reduced case fatality by 38%. A pooled analysis of 94 patients from all three trials demonstrated a significant increase in favorable outcome in the dHc cohort.11 How-ever, there was no statistically significant evidence in any individual trial regarding improved functional outcomes for patients undergoing dHc.

current evidence suggests a role for dHc in patients younger than 60 with malignant infarction of the McA asso-ciated with altered consciousness who are treated within 48 hours of stroke onset. For patients older than 60, surgical decompression is controversial. there are notable improve-ments in mortality, but many of the surviving patients have severe disability.12

CAROTId ENdARTERECTOMY ANd CAROTId STENTINg

carotid artery stenosis causes up to 10% of all ischemic strokes. the risk of recurrent stroke is significantly higher in patients who have previously suffered an initial stroke or transient ischemic attack (tIA). It is estimated that 25% of patients presenting with a stroke are suffering from a recurrent ischemic episode. the risk of stroke is particularly high in symptomatic patients who have severe narrowing of the extracranial internal carotid artery, and several large randomized studies have demonstrated the effectiveness of carotid endarterectomy (ceA) in reducing future stroke risk in these patients. the north American symptomatic carotid endarterectomy trial (nAscet) reported that in symptomatic patients with greater than 70% carotid ste-nosis who undergo ceA, the absolute risk of future stroke is reduced by 17% compared to medical therapy alone13, which has been confirmed by other large studies.14 Pooled analysis of three large trials of ceA versus medical therapy has shown a 16% absolute risk reduction when ceA was performed in patients with symptomatic stenosis of 70% or more.15 For patients with 50–69% stenosis, there was still a benefit but to a lesser degree. Patients with less than 50% narrowing of the carotid artery do not appear to benefit from surgical intervention.

despite the proven effectiveness of ceA, carotid artery stenting (cAs) has been promoted as an attractive, less invasive option for revascularization. Potential advantages of cAs include decreased patient discomfort and a shorter recuperation period. early studies indicated a higher proce-dural risk during cAs compared to ceA, but these studies have been criticized for inadequate and non-uniform oper-ator experience.16 Furthermore, advances in endovascular

techniques and devices used for cAs have made the proce-dure safer.

the largest trial to date, the carotid Revascularization endarterectomy versus stent trial (cRest) was a prospec-tive, randomized trial of 2,502 patients comparing the effi-cacy of cAs with ceA.17 the primary endpoint was the composite of any stroke, myocardial infarction, or death during the periprocedural period and ipsilateral stroke within 4 years thereafter. the study found that cAs and ceA had similar outcomes, although there were varying complica-tions with each intervention. the rate of any periprocedural stroke or post-procedural ipsilateral stroke within 30 days was significantly higher in the cAs group than in the ceA group (5.5% versus 3.2%). However, the rate of myocardial infarction was higher in the ceA group (2.3% versus 1.0%). overall, the cRest study demonstrated that cAs and ceA had similar short- and long-term outcomes. carotid artery stenting may prove especially useful in cases of surgically inaccessible lesions, radiation-induced stenosis, or and in patients with severe cardiac or pulmonary disease.

to date, studies have shown that surgical interventions aimed at preventing stroke in patients who have already suf-fered a stroke or tIA from extracranial carotid stenosis have proven more effective than medical treatment alone. How-ever, previous studies did not include optimal medical ther-apies such as statins. As advances in the medical treatment of stroke continue, it is imperative to compare these with both ceA and cAs. the cRest 2 trial currently underway attempts to compare current best medical therapy versus ceA and cAs.

ExTRACRANIAl TO INTRACRANIAl ARTERIAl BYPASS

extracranial-intracranial (ecIc) bypass surgery has not been shown to provide any benefit for patients with atheroscle-rotic carotid occlusion or carotid artery narrowing distal to the carotid bifurcation. However, in patients with moyam-oya disease or syndrome, ecIc bypass has been shown to be effective at reducing stroke risk.

Moyamoya can occur in children and adults and is a cere-brovascular condition that predisposes affected patients to stroke due to progressive stenosis of the intracranial internal carotid arteries and their branches (Figure 3a). genetic fac-tors play a role, and moyamoya can be associated with other conditions such as down’s syndrome, sickle cell disease, neurofibromatosis, or previous cranial irradiation. If the dis-ease is unilateral, or is associated with one of these condi-tions, it is called moyamoya syndrome. Moyamoya disease is bilateral and is not associated with other risk factors. Most patients present with stroke or ischemic symptoms with 50–75% of known moyamoya patients experiencing ischemic stroke.18

It has been estimated that up to two-thirds of patients






with moyamoya have symptomatic progression over a 5-year period with poor outcomes without treatment. Medi-cal therapies have not been shown to be beneficial in reduc-ing stroke risk and surgical revascularization (ecIc bypass) is the primary treatment for moyamoya. this procedure utilizes extracranial arterial supply (usually the superficial temporal artery) which is either directly or indirectly anas-tomosed to an intracranial cortical artery (Figure 3b). Fol-lowing ecIc bypass, there is a 96% probability of remaining stroke-free over the subsequent 5 years, and a meta-anal-ysis concluded that 1003 of 1156 patients (87%) derived symptomatic benefit from surgical revascularization.19

fuTuRE dIRECTIONS

time to treatment is a critical factor in improving outcomes in acute stroke, and the development of additional strate-gies to decrease time to intervention are warranted. Field triage based on clinical severity to a comprehensive stroke center can help decrease time to treatment. Perhaps the ultimate solution, Mobile stroke ambulances (composed of trained medical personnel, a ct scanner, and telecommu-nications) can allow ultra-rapid patient assessment, in-field administration of Iv-tPA, and rapid transport to a dedicated neurovascular center. only a few units currently exist, but preliminary reports show improvement in treatment times and clinical outcomes.

the precise time window for acute embolectomy has not been fully evaluated. A select group of patients, with defined

areas of reversible ischemia, may benefit from recanaliza-tion outside of the current time recommendations. Further refinement of patient selection using advanced ct or MR based imaging will likely allow us to offer treatment to a greater group of patients. In addition, as endovascular tech-nologies continue to improve, treatment of non-Lvo stroke patients with occlusion in smaller, more distal vessels may benefit from embolectomy.

despite treatment, many stroke patients have permanent neurologic deficits such as hemiplegia, aphasia, or visual loss. surgical techniques to restore function are needed. stem cell transplantation, neuromodulation and cortical stimulation techniques, and brain-computer interface tech-nologies have potential to improve neurorestoration and warrant future investigation.

References1. Mozaffarian d, Benjamin eJ, go As, et al. executive summary:

heart disease and stroke statistics—2015 update: a report from the American Heart Association. circulation 2015;131:434–41.

2. centers for disease control and Prevention (cdc). Leading causes of death. http:// www.cdc.gov/nchs/fastats/leading-caus-es-of-death.htm (accessed 20 Feb 2015).

3. saver JL. time is brain—quantified. stroke 2006;37:263-266.4. smith Ws, Lev MH, english Jd, et al. significance of large ves-

sel intracranial occlusion causing acute ischemic stroke and tIA. stroke 2009;40:3834-3840.

5. chen cJ, ding d, starke RM, et al. endovascular vs medical management of acute ischemic stroke. neurology 2015;85:1980-1990.

6. Badhiwala JH, nassiri F, Alhazzani W, et al. endovascular thrombectomy for acute ischemic stroke: A meta-analysis. JAMA 2015;314:1832-1843.

Figure 3. a) Lateral left iCa angiogram in a patient with moyamoya disease. The MCa is occluded and there is poor angiographic filling in the MCa

territory. small collateral vessels develop at the iCa terminus (arrow).

b) Lateral left iCa angiogram in a patient who underwent a sTa-MCa bypass for the treatment of moyamoya disease.

A B






7. Mctaggart RA, Ansari sA, goyal M, et al. Initial hospital management of patients with emergent large vessel occlusion (eLvo): report of the standards and guidelines committee of the society of neuroInterventional surgery. J neurointerv surg. 2015; 0:1-9.

8. Mctaggart RA, yaghi s, Baird g,

Haas RA, Jayaraman Mv. de-

creasing procedure times with a standardized approach to eLvo cases. JNIS. 2017;9(1):2-5.

9. vahedi k, vicaut e, Mateo J, kurtz A, orabi M, guichard J, Boutron c, courvreur g, Rouanet F, touze e, guillon B, car-pentier A, yelnik A, george B, Payen d, Bousser M. sequen-tial-design, multicenter, randomized, controlled trial of early decompressive craniectomy in malignant middle cerebral artery infarction (decIMAL trial). Stroke 2007; 38(9): 2506-17.

10. Hofmeijer J, kapelle LJ, Algra A, Amelink gJ, van gijn J, van der Worp HB. surgical decompression for space-occupying ce-rebral infarction (the hemicraniectomy after middle cerebral artery infarction with life-threatening edema trial [HAMLet]): a multicenter, open, randomized trial. Lancet Neurology 2009; 8(4): 326-33.

11. vahedi, katayoun, et al. “early decompressive surgery in malig-nant infarction of the middle cerebral artery: a pooled analysis of three randomized controlled trials.” The Lancet Neurology 6.3 (2007): 215-222.

12. Juttler e, unterberg A, Woitzik J, Bosel J, Amiri H, sakowitz oW, gondan M, schiller P, Limprecht R, Luntz s, schneider J, Pinzer t, Jobohm c, Meixensberger J, Hacke W. Hemicraniec-tomy in older patients with extensive middle cerebral artery stroke. The New England Journal of Medicine 2014; 370(12): 1091-1100.

13. north American symptomatic carotid endarterectomy trial collaborators. Beneficial effect of carotid endarterectomy in symptomatic patients with high-grade carotid stenosis. n engl J Med 1991; 325:445.

14. MRc european carotid surgery trial: interim results for symp-tomatic patients with severe (70-99%) or with mild (0-29%) ca-rotid stenosis. european carotid surgery trialists’ collaborative group. Lancet 1991; 337:1235.

15. Rothwell PM, eliasziw M, gutnikov sA, et al. Analysis of pooled data from the randomised controlled trials of endarter-ectomy for symptomatic carotid stenosis. Lancet 2003; 361:107.

16. Bonati LH, Lyrer P, ederle J, et al. Percutaneous transluminal balloon angioplasty and stenting for carotid artery stenosis. co-chrane database syst Rev 2012; :cd000515.

17. Mantese vA, timaran cH, chiu d, Begg RJ, Brott tg; cRest In-vestigators. the carotid Revascularization endarterectomy ver-sus stenting trial (cRest): stenting versus carotid endarterec-tomy for carotid disease. stroke. 2010 Oct;41(10 Suppl):S31-4.

18. scott RM, smith eR: Moyamoya disease and Moyamoya syn-drome. n engl J Med 2009;360:1226-37.

19. Fung LW, thompson d, ganesan v. Revascularization surgery for paediatric moyamoya: a review of the literature. childs nerv syst 2005;21:358-64.

Authorscody A. doberstein, Bs, department of neurosurgery, Warren

Alpert Medical school of Brown university, Providence, RI.

Radmehr torabi, Md, department of neurosurgery, Warren Alpert Medical school of Brown university, Providence, RI.

sandra c. yan, Bs, BA, Warren Alpert Medical school of Brown university, Providence, RI.

Ryan Mctaggart, Md, Associate Professor, departments of diagnostic Imaging, neurology and neurosurgery, Warren Alpert Medical school of Brown university, Providence, RI.

curtis doberstein, Md, Professor (clinical), department of neurosurgery, Warren Alpert Medical school of Brown university, Providence, RI.

Mahesh Jayaraman, Md, Associate Professor, departments of diagnostic Imaging, neurology and neurosurgery, Warren Alpert Medical school of Brown university, Providence, RI.

correspondence

curtis doberstein, Mddepartment of neurosurgeryRhode Island Hospital593 eddy street, APc 6th FloorProvidence, Rhode Island 02903 401-793-9169Fax: [email protected]


https://www.ncbi.nlm.nih.gov/pubmed/?term=McTaggart%20RA%5BAuthor%5D&cauthor=true&cauthor_uid=26323793

https://www.ncbi.nlm.nih.gov/pubmed/?term=Ansari%20SA%5BAuthor%5D&cauthor=true&cauthor_uid=26323793

https://www.ncbi.nlm.nih.gov/pubmed/?term=Goyal%20M%5BAuthor%5D&cauthor=true&cauthor_uid=26323793

https://www.ncbi.nlm.nih.gov/pubmed/26323793


https://www.ncbi.nlm.nih.gov/pubmed/?term=Mantese%20VA%5BAuthor%5D&cauthor=true&cauthor_uid=20876500

https://www.ncbi.nlm.nih.gov/pubmed/?term=Timaran%20CH%5BAuthor%5D&cauthor=true&cauthor_uid=20876500

https://www.ncbi.nlm.nih.gov/pubmed/?term=Chiu%20D%5BAuthor%5D&cauthor=true&cauthor_uid=20876500

https://www.ncbi.nlm.nih.gov/pubmed/?term=Begg%20RJ%5BAuthor%5D&cauthor=true&cauthor_uid=20876500

https://www.ncbi.nlm.nih.gov/pubmed/?term=Brott%20TG%5BAuthor%5D&cauthor=true&cauthor_uid=20876500

https://www.ncbi.nlm.nih.gov/pubmed/?term=CREST%20Investigators%5BCorporate%20Author%5D

https://www.ncbi.nlm.nih.gov/pubmed/?term=CREST%20Investigators%5BCorporate%20Author%5D


mailto:cdoberstein%40lifespan.org?subject=





A comprehensive Approach to deep Brain Stimulation for Movement disordersuMeR akbaR, MD; waeL F. asaaD, MD, phD, Faans

ABSTRACT deep brain stimulation (dBs) is a well-established form of neuromodulation, used primarily for movement disor-ders such as Parkinson’s disease (Pd) and essential trem-or (et). the selection of patients who will benefit most from dBs depends on a team of clinicians from various disciplines, including neurology, neurosurgery, psychia-try, neuropsychology and rehabilitation specialists. the actual surgical procedure can take many forms. We apply a combination of multidisciplinary, team-based evalua-tions and intra-operative neurophysiology, test stimula-tion and imaging to optimize dBs therapy for individual patients.

KEYWORdS: movement disorders, Parkinson’s disease, essential tremor, deep Brain stimulation, neurosurgery

INTROduCTION

neurosurgery for movement disorders has evolved dramat-ically over the past century culminating in the widespread acceptance and use of deep brain stimulation (dBs). While dBs has been and is being tested for a wide variety of neu-rological and psychiatric conditions (Figure 1), dBs is most widely used to treat the motor symptoms of two common

movement disorders, Parkinson’s disease (Pd) and essential tremor (et). dBs surgery entails the insertion of electrodes (“wires”) into the brain through a small burr-hole and con-nected subcutaneously to a pacemaker-like battery powered device implanted in the chest wall. the implanted pulse generator battery is then programmed to deliver electri-cal stimulation to the brain to regularize, or at least limit, abnormal brain activity.

Pd affects over 1 million people in the united states (us) and the prevalence is expected to double over the next two decades. the cardinal motor symptoms of Pd – bradykine-sia, tremor and rigidity – are often adequately treated with medications early in the course of the disease. As the disease progresses, patients develop medication-refractory tremor, motor fluctuations (early “wearing-off” of medication ben-efit) and dyskinesias, in addition to non-motor symptoms such as mood, cognitive, sleep and autonomic symptoms. the efficacy of dBs for these medication-refractory motor symptoms has been well established through several high-quality, randomized controlled trials.1-3 A meta-analysis of 22 studies demonstrated that subthalamic nucleus (stn) dBs improved motor symptoms (unified Pd rating scale, part 3) by 52%, dyskinesias 69%, off-periods 68%, and activ-ities of daily living by 50%.4 gPi dBs is also effective and is often favored for more severe dyskinesias or dystonias, and

may have a slightly lower risk of cognitive- and mood-related adverse effects.5-7 non-motor symp-toms of Pd do not directly respond to dBs but can improve indirectly. For example, a patient with difficulty sleeping or depressed mood due to exces-sive slowness and stiffness may feel improvement in these symptoms after dBs because of improved overall mobility and physical comfort.

In contrast to the resting tremor of Pd, et tremor is typically postural and worsens with movement. early in the disease, patients with et often manage their symptoms with behavioral modifications, without medications. over time, increasing tremor amplitude may lead to difficulty with fine motor tasks, such as handwriting, eat-ing, drinking and dressing. Medications can reduce tremor by about 50%, but benefit wanes over time as the tremor worsens. In these patients, dBs of the ventral-intermediate nucleus of the thalamus can reduce tremor by ~80% (range ~50–100%).8,9

* approved under FDa Humanitarian Device exemption (HDe) ** approved in europe; usa FDa approval anticipated

Figure 1. approved and experimental applications of Dbs.

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dBs for movement disorders should be considered when the quality of life becomes impaired by motor symptoms that are refractory to medical therapy. Patients should gen-erally have preservation of mood and cognitive functions, and should be medically able to undergo surgery.

ThE COMPREhENSIVE fAST-TRACK PRE-OPERATIVE EVAluATION

even though quality of life in many domains improves with dBs, some areas may worsen. A 4-year follow up study of stn vs. globus pallidus interna (gPi) dBs showed increased risk of speech, gait, cognitive and mood adverse effects, and up to 30% of patients undergoing dBs may have negative outcomes due to inappropriate screening.10 However, com-prehensive and thorough pre-operative screening can detect problems and stratify the risk of post-operative worsening based on baseline functioning. to achieve this, our institu-tion utilizes a unique, multi-disciplinary, pre-operative dBs clinic in which patients are evaluated by neurology, neu-rosurgery, psychiatry, neuropsychology and rehabilitation services (physical therapy, speech therapy and swallowing assessment); these are typically conducted at a single, con-venient location in a one-day visit.

• neurology – confirm diagnosis; ensure medical optimi-zation; assess severity of disease and appropriateness for surgical intervention; identify motor symptom(s) to be treated by surgery; discuss unilateral vs. bilateral; discuss target selection; discuss risks/benefits;

• neurosurgery – discuss surgical options; discuss surgery-re-lated risks; assess overall medical condition to undergo surgery; discuss contraindications for surgery;

• Psychiatry – screen for mood and behavioral problems; ensure chronic, underlying mood issues are adequately treated; discuss risk of mood and behavioral problems with dBs;

• neuropsychology – conduct a thorough assessment of cog-nitive functions; compare baseline performance to peers; discuss risk of cognitive decline after dBs;

• Physical therapy – assess baseline gait and balance; make recommendations to optimize gait before dBs; discuss risk of worsening after dBs;

• speech therapy – assess baseline speech function; make recommendations to optimize speech before dBs; discuss risk of worsening after dBs;

• swallowing assessment – assess baseline swallowing function; make recommendations to optimize swallowing function before dBs; discuss risk of worsening after dBs.

the multidisciplinary team discusses the candidacy of each patient in a meeting at the conclusion of the clinic. the patient is rated on a scale of low, medium or high risk by each specialist based on their evaluations, and the final recommendation is communicated to the patient.

dBS SuRgERY: BENEfITS, RISKS ANd OPTIONS

the primary goals of dBs surgery are safety and accuracy. the risk profile of dBs surgery has been extensively stud-ied.11-13 some risks, such as hemorrhage, are significant and potentially life threatening, but are fortunately rare. other risks include seizure, hardware infection, discomfort, hard-ware failure and suboptimal electrode placement (Figure 2). this last risk is minimized by careful design and meticulous execution of the surgical procedure. there are many differ-ent ways to “do” dBs surgery. Individual surgeons often develop customized, stereotyped workflow preferences to promote reproducibly good results.

dBs is currently approved by the FdA to be implanted while the patient is awake in order to confirm neurologic benefit without intolerable side effects. nonetheless, there is a growing utilization of asleep procedures for the implan-tation of dBs as an off-label approach. But even within these categories of “awake” vs. “asleep” there are many different ways in which surgeons can perform the procedure.

the main technical goal is accurate placement of elec-trodes within a target, typically with about 1mm precision. classically, this is achieved with the use of a stereotac-tic frame affixed to the head while a scan (MRI or ct) is obtained. the target location is then computed with respect to the frame coordinates, and these x, y and z values are manually dialed into an arc attached to the frame. More recently, some centers including ours, have switched to using a different system consisting of a patient-customized 3d-printed stereotactic platform (FHc Inc, Bowdoin, Me). Here, temporary skull screw fiducial markers are implanted a week prior to electrode implantation. these then serve as the reference coordinate system for selecting targets and trajectories by co-registering a ct scan showing these fidu-cials with a “clean” pre-operative MRI. computer assisted design (cAd) software then designs a frame specifically for that patient and the planned trajectories. While adding an extra step, this approach reduces the potential for human or mechanical error (because the targets and trajectories need not be manually transferred to a mechanical frame, which itself would have moving parts and mechanical backlash). It also may increase patient comfort during awake procedures,

Figure 2. Major surgical Complications of Dbs. These data are summarized from Zrinzo et al., and boviatsis et al.12,13






because it does not apply intense pressure to the skull as does a classical stereotactic frame.

In an awake procedure, microelectrode recordings are typ-ically used to map the target region using a combination of neurophysiological patterns and neuronal responses to inter-active patient testing. once the target has been character-ized, the permanent dBs electrode lead is placed according to those findings and test stimulation is delivered. Because the patient is awake, neurologic benefit with no or minimal side effects can be assessed. If these results are satisfactory, the lead is locked in-place. If results are suboptimal, a differ-ent location can be assessed for lead implantation.

Awake procedures are feasible because only the skin per-ceives pain (although some patients will report brief dis-comfort upon passing through the dura); generous infusion of local anesthetic typically eliminates most discomfort. Pd patients, because they are off medications for neurologic assessment during the procedure, typically experience dis-comfort mostly due to the primary disease symptoms, such as rigidity and dystonia.

the need for empirical assessment of lead placement derives from two main factors: first, once the skull is opened for insertion of electrodes, there may be an egress of cere-brospinal fluid (csF) and an ingress of air. good surgical technique aims to minimize these factors but even a slight change in skull contents can cause brain shift of a magni-tude which, although small in absolute terms, may diminish surgical accuracy in a clinically meaningful way.14,15 second, there is debate in the field over the question of whether the visually identified “optimal” target on imaging is truly the best target for that individual patient, both in terms of maximizing benefit and minimizing side effects. therefore, empirical assessment of potential targets adds a level of cer-tainty that is otherwise unavailable.

the first factor, brain shift, can be addressed by the use of intra-operative imaging. Indeed, asleep procedures typically use this as the primary method of achieving accurate elec-trode placement. Many major academic centers now have intra-operative MRI suites which allow visual confirmation of targeting during the electrode implantation procedure. However, many centers use intra-operative ct imaging; the brain tissue resolution of ct, especially intra-operative ct, is less than that of MRI, and so these ct scans are often co-registered with pre-operative MRI. Because most co-reg-istration algorithms are “rigid” (in the sense that they can-not account for brain movement with respect to the skull), brain shift is potentially a limitation with this approach. yet even procedures performed with intra-operative MRI can-not address the second factor, that is, whether the visually identified target truly represents the optimal brain circuit for patient-specific neuromodulation. so far, several studies have compared results of awake vs. asleep dBs and, accord-ing to the fairly course measures used, there do not seem to be major differences.16-18 However, one study has observed

that thresholds to motor side effects may not be predictable based upon the imaging alone,19 and so clinical assessment of these side effects in an awake patient may in some cases yield a larger available dynamic range of stimulation and thus potentially more optimal results.

Most centers implant the battery in a delayed fashion, typically one week later. In the case of awake dBs sur-gery, this allows continuous neurological monitoring of the patient without a period of general anesthesia for battery implantation.

dBS SuRgERY AT RhOdE ISlANd hOSPITAl

our preference is to perform dBs as an awake procedure in order to maximize the possibility of obtaining optimal results for each individual patient. We typically perform microelectrode recordings along three tracks on each side, aligned according to the dimension of highest anatomi-cal-radiographic uncertainty about the target. the best track in terms of neurophysiological patterns and responses is selected first for test stimulation using the permanent dBs electrode. If results are good, the electrode is locked in-place at that location; otherwise additional locations are tested in order of the quality of their neurophysiological signals. In addition, we perform most of our procedures with the aid of an intra-operative ct scanner. this adds an extra level of safety and certainty regarding our targeting, should there be any question about the signals we are observing or about the patient’s condition.

Many of our procedures are performed as a collaboration between our lead movement disorders neurologist and func-tional neurosurgeon. Both have extensive experience inter-preting neurophysiological signals and assessing clinical responses. this team-based approach affords an added level of confidence about the quality of these procedures and the ultimate clinical benefit.

CONCluSION

dBs is potentially a valuable therapy for patients whose movement disorders are poorly managed on medications alone. comprehensive, multidisciplinary evaluation of patients pre-operatively maximizes good outcomes by screen-ing out those who are more likely to decline after surgery. the surgery itself can be performed using a variety of approaches, but ultimately, surgical safety and precision are the main goals. throughout this process, a team-based approach works to ensure the best course of treatment for each patient.






References1. deuschl, g. et al. A randomized trial of deep-brain stimulation

for Parkinson’s disease. N. Engl. J. Med. 355, 896–908 (2006).2. Weaver, F. M. et al. Bilateral deep brain stimulation vs best med-

ical therapy for patients with advanced Parkinson disease: a ran-domized controlled trial. JAMA 301, 63–73 (2009).

3. Williams, A. et al. deep brain stimulation plus best medical therapy versus best medical therapy alone for advanced Parkin-son’s disease (Pd suRg trial): a randomised, open-label trial. Lancet Neurol 9, 581–591 (2010).

4. kleiner-Fisman, g. et al. subthalamic nucleus deep brain stim-ulation: summary and meta-analysis of outcomes. Mov Disord. 21 Suppl 14, s290–304 (2006).

5. odekerken, v. J. J. et al. subthalamic nucleus versus globus pal-lidus bilateral deep brain stimulation for advanced Parkinson’s disease (nstAPs study): a randomised controlled trial. Lancet Neurol 12, 37–44 (2013).

6. Moro, e. et al. Long-term results of a multicenter study on sub-thalamic and pallidal stimulation in Parkinson’s disease. Mov Disord. 25, 578–586 (2010).

7. combs, H. L. et al. cognition and depression Following deep Brain stimulation of the subthalamic nucleus and globus Pal-lidus Pars Internus in Parkinson’s disease: A Meta-Analysis. Neuropsychol Rev 25, 439–454 (2015).

8. Zhang, k. et al. Long-term results of thalamic deep brain stim-ulation for essential tremor. Journal of Neurosurgery 112, 1271–1276 (2010).

9. Flora, e. d., Perera, c. L., cameron, A. L. & Maddern, g. J. deep brain stimulation for essential tremor: a systematic review. Mov Disord. 25, 1550–1559 (2010).

10. Hariz, M. I. et al. Multicenter study on deep brain stimulation in Parkinson’s disease: an independent assessment of reported adverse events at 4 years. Mov Disord. 23, 416–421 (2008).

11. Ben-Haim, s., Asaad, W. F., gale, J. t. & eskandar, e. n. Risk factors for hemorrhage during microelectrode-guided deep brain stimulation and the introduction of an improved microelectrode design. Neurosurgery 64, 754–62; discussion 762–3 (2009).

12. Boviatsis, e. J., stavrinou, L. c., themistocleous, M., kouyia-lis, A. t. & sakas, d. e. surgical and hardware complications of deep brain stimulation. A seven-year experience and review of the literature. Acta Neurochir (Wien) 152, 2053–2062 (2010).

13. Zrinzo, L., Foltynie, t., Limousin, P. & Hariz, M. I. Reducing hemorrhagic complications in functional neurosurgery: a large case series and systematic literature review. Journal of Neuro-surgery 116, 84–94 (2012).

14. Halpern, c. H., danish, s. F., Baltuch, g. H. & Jaggi, J. L. Brain shift during deep brain stimulation surgery for Parkinson’s dis-ease. Stereotact Funct Neurosurg 86, 37–43 (2008).

15. Ivan, M. e. et al. Brain shift during bur hole-based procedures using interventional MRI. Journal of Neurosurgery 121, 149–160 (2014).

16. chen, t. et al. ‘Asleep’ deep brain stimulation for essential tremor. Journal of Neurosurgery 124, 1842–1849 (2016).

17. chen, t., Mirzadeh, Z., chapple, k., Lambert, M. & Ponce, F. A. complication rates, lengths of stay, and readmission rates in ‘awake’ and ‘asleep’ deep brain simulation. Journal of Neurosur-gery 1–10 (2016). doi:10.3171/2016.6.Jns152946

18. saleh, s., swanson, k. I., Lake, W. B. & sillay, k. A. Awake neurophysiologically guided versus Asleep MRI-guided stn dBs for Parkinson disease: A comparison of outcomes using Levodopa equivalents. Stereotact Funct Neurosurg 93, 419–426 (2015).

19. Ho, A. L. et al. Awake versus asleep deep brain stimulation for Parkinson’s disease: a critical comparison and meta-analysis. J. Neurol. Neurosurg. Psychiatr. (2017). doi:10.1136/jnnp-2016-314500

Authorsumer Akbar, Md, Assistant Professor of neurology, Brown

university Alpert Medical school and Movement disorders Program, department of neurology, Rhode Island Hospital and Butler Hospital; member of the norman Prince neurosciences Institute of Lifespan.

Wael F. Asaad, Md, Phd, FAAns, Assistant Professor of neurosurgery (& neuroscience), Brown university Alpert Medical school and director of Functional neurosurgery, Rhode Island Hospital; member of the norman Prince neurosciences Institute of Lifespan.

correspondenceWael F. Asaad, Md, Phd110 Lockwood st.Ambulatory Patient center, APc 6Providence RI [email protected]


mailto:wasaad%40lifespan.org?subject=





Rhode Island hospital’s contribution to the Field of endoscopic Spine Surgery aLbeRT e. TeLFeian, MD, phD; aDeTokunbo a. oyeLese, MD, phD; Ziya L. GokasLan, MD

ABSTRACT the first academic program in endoscopic spine surgery in the united states opened its doors at Rhode Island Hospi-tal in 2012. Published advances in the field since its incep-tion have included treatments for a myriad of pathologies including lumbar and thoracic disc herniations, spondylolis-thesis, spine tumors as well as treatments for complications of other spinal procedures including spinal fusion, kyphop-lasty, and total disc replacement. In this issue of the Rhode Island Medical Journal we summarize the history of the pro-cedure as well as some of the interesting progress going on in this field in Rhode Island.

KEYWORdS: endoscopic discectomy, minimally-invasive, transforaminal

INTROduCTION

“necessity is the mother of invention,” is a proverb that dates back to 16th century england and describes well the challenge that faces those practicing medicine today and the generation who follow us. With health care costs rising, how will we face the upcoming challenge of providing care to our patient population?

Patients who would have had open-heart surgery in the past, are now candidates for outpatient interventional cardiology procedures. complex intracranial vascular pathologies and skull base tumors that would have been treated with lengthy intracranial surgeries in the past are now treated with inter-ventional radiology procedures and stereotactic radiosur-gery. But what is being done in the field of spine surgery? For the answer to that question, much of the world looks to the research coming out of the institution that is at the center for publishing the latest advances in endoscopic spine surgery: the department of neurosurgery at Rhode Island Hospital and Warren Alpert Medical school of Brown university.

PERCuTANEOuS luMBAR ENdOSCOPIC dISCECTOMY — ThE hISTORY

the natural history of surgical techniques seem to be an evolution of “big to small.” But the history of endoscopic spine surgery is really an evolution of “small to big.” early practitioners developed needle-based procedures to try to

decompress the disc nuclear material to relieve back and radicular symptoms. needles got bigger and the first endo-scopic views of a herniated disc were published by kambin in 1988,1 and the first reported introduction of a modified arthroscope into the intervertebral disc space was reported by Forst and Hausman in 1983.2

In 1990, Parvis kambin described a triangular safe zone bordered by the exiting root anteriorly, the traversing root medially, and the superior endplate of the lower lumbar vertebra inferiorly.3 the anatomic description of this safe zone allowed the advancement of the field of endoscopic spine surgery to outgrow the technique of percutaneous nucleotomy which was limited by the use small needle-like instruments. kambin’s triangle was a working corridor that allowed the introduction of larger instruments and working channels to be introduced even closer to foraminal pathol-ogy without injuring the exiting nerve.

With the idea of a safe working triangle between the exiting and traversing roots in the foramen, the field of endoscopic spine surgery started to leave the safety of the indigo carmine blue stained nucleus and explore the fora-men. An angled lens scope was used by Mayer and Brock in 1993 that allowed more dorsal visualization of annular pathology.4 Foraminoscopy was described by Mathews in 19965 and ditsworth in 1998.6 kambin and Zhou in 1996 described lumbar nerve root decompression by annulectomy and decompression of lateral recess stenosis with the use of forceps and trephines.7 schubert and Hoogland in 2005 described their technique for transforaminal endoscopic removal of a sequestered disc fragment using reemers to expand the foraminal window by removing the ventral por-tion of the superior articular process.8 Multichannel endo-scopes with larger working channels were introduced by tsou and yeung in 19979 and Reuten et al in 2007.10 What would follow would be multiple reports of the clinical suc-cess of direct endoscopic decompression of foraminal pathol-ogy: yeung and tsou in 2002,11 Reutten el al 2007,10 Reutten et al 2008,12 Jasper et al 2013.13

ThE ClINICAl SuCCESS Of ENdOSCOPIC SuRgERY

seven papers published between 2013 and 2014 on awake endoscopic spine surgery indicated the possible efficacy of this procedure performed through a 5 mm incision for the

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treatment of Lumbar radiculopathy.13-19 For patients with single level disc disease, the success rate reported was an 84% reduction in pain, and for patients with multi-level pathology, the average pain relief was 70%.13 In a series of 50 consecutive patients over the age of 75, over 80% of patients described either a “good” or “excellent” outcome: many of these patients were offered fusion surgeries at other centers before being considered for endoscopic surgery.15 Patients who underwent endoscopic treatment for radicular symp-toms due to spondylolisthesis reported a 72% reduction in pain – up front instrumented fusion is currently a mainstay treatment for this pathology.18 Figure 1 displays in a step-by-step manner how the endoscopic technique is used to treat a patient (former nFL player) with lumbar radiculopathy in the setting of spondylolisthesis.

the mainstay for the treatment of lumbar degenerative pathology is conservative treatment with weight loss uni-formly recommended for lumbar radicular symptomatology

in the setting of morbid obesity. But the success of conserva-tive management in reducing obesity is difficult. 82 patients in one study published showed pain reduction close to 70% for patients with BMIs between 30 and 40 but closer to 45% for patients with BMIs over 40.19

the first paper in the world describing the feasibility and technical steps that enable a surgeon to circumnavigate and reach into the epidural space for intracanal pathology was also published in these period, opening the possibility for treating more than routine herniated lumbar discs.14

fAIlEd BACK SuRgERYthere has been a 15-fold increase in complex spinal fusion procedures in the past decade. But innovative treatment strategies for treating the complications from these proce-dures has lagged. In 2015 a series of 3 papers have described innovative minimally invasive treatments for herniated

A. preoperative sagittal T2 MRi showing pathology of L4-5 spondylolisthesis.

B. spinal needle entry into L4-5 disc on lateral fluoroscopic view.

c. small dilator and large crown reamer in L4-5 foramen during foraminoplasty on ap fluoroscopic view.

d. bevelled working canulla in L4-5 foramen on ap fluoroscopic view.

e. endoscopic view of the residual reamed ventral border of the sap (white arrow) and ligamentum flavum (black arrow).

F. endoscopic view of the ligamentum flavum (black arrow), traversing nerve root (black border arrow), and herniated disc (red arrow).

G. intraoperative photograph of the L4-5 herniated disc fragment removed with an endoscopic forceps during the procedure.

Figure 1.






A. sagittal T1 MRi with gadolinium of the thoracic spine demonstrating recurrence of the ventral extradural tumor.

B. axial T2 MRi with gadolinium showing preoperative planning for spinal needle trajectory for transforaminal approach.

c. intraoperative ap fluoroscopic image demonstrating passage of spinal needle into the left T5-6 neural foramen.

d. intraoperative ap fluoroscopy showing reaming of the superior articular process.

e. intraoperative ap fluoroscopic image showing working channel within the left T5-6 neural foramen,

along with ball probe passed to confirm position of T6 pedicle.

F. intraoperative ap fluoroscopy confirms position of malleable curved grasping forcep.

G. patient positioned prone with working channel 5cm lateral to midline and communicating author

shown manipulating bendable grasper in working channel.

h. intraoperative endoscopic view with ball probe pushing on the dorsal aspect of the tumor capsule.

I. intraoperative endoscopic view demonstrating the bendable grasper reaching inside the tumor capsule.

Figure 2.






discs after fusion,20 lumbar radiculopathy after instru-mented fusion,21 and lumbar radiculopathy after interbody fusion.22 All of these “rescue” or “salvage” procedures were performed without general anesthesia on outpatients.

SPINAl TuMORS

In the international journal clinical neurology and neuro-surgery in July 2015, the first report in the world of perform-ing a resection of a spinal canal tumor endoscopically in an awake patient was reported.23 the case was performed on a 15-year-old patient who underwent the procedure in order to avoid a complex instrumented fusion procedure. Figure 2 shows the patient’s MRI, intraoperative x-rays, a photograph from the operating room, and endoscopic images from the surgery. the nBc news story of this historic surgery was shared around the world.

ThORACIC dISC SuRgERY

surgery for the treatment of thoracic disc herniations has for years meant operating through a thoracotomy to remove disc pathology and fuse the spine. In 2016 the first 2 descrip-tions of technical nuances for performing awake endoscopic surgery for thoracic and thoracolumbar disc herniations were published in the Journal of neurosurgery24 and World neurosurgery.25 the advances in this area were the result of a collaboration between physicians at Rhode Island Hospital and surgeons in germany and the netherlands.

ENdOSCOPIC SuRgERY TO TREAT OThER SPINE SuRgERY COMPlICATIONS

kyphoplasty is a treatment for painful compression fractures of the osteoporotic spine. cement leakage can be a disas-trous complication that results from the procedure because an open laminectomy and instrumented fusion can be nec-essary to remove the extravasated cement. this surgery is made even more complicated by the fact that these osteoporotic patients are not favorable candidates for instru-mented fusion procedures. In 2016 the first paper in the world describing an endoscopic solution for this problem in an awake patient was published.26

Artificial lumbar discs or total disc replacement surgery is performed more popularly in europe than in the united states because of difficulty getting this non-fusion technol-ogy approved by insurance carriers. Patients interested in this surgery in the u.s. will sometimes travel to europe for the procedure. Approximately 10% of these surgeries ulti-mately go on to need instrumented fusion due to complica-tions from the original implant. In 2016 the first endoscopic treatment for a total disc replacement surgery was published in the Journal of neurosurgery.27 the surgery in germany to place the artificial disc dislodged a fragment of bone that caused nerve compression. With the patient awake, an

endoscope was used to drill out the fragment to free it and then remove it. the patient was able to avoid a laminec-tomy and fusion and ultimately benefited from a successful total disc replacement. the future of total disc replacement surgery in the u.s. remains to be seen but certainly endo-scopic surgery may have a role in treating the complications seen in this procedure.

CONCluSION: ThE fuTuRE Of SPINE SuRgERYLaser spine surgery that is advertised ubiquitously is not, in fact, performed with a laser. It is, in fact, an aggressive marketing program for a minimally invasive open surgical procedure that is performed with the patient under general anesthesia. endoscopic spine surgery is performed with a working channel rigid endoscope, high definition camera, drills, trephines, articulated graspers, and sometimes, yes, a laser. But it has at its endpoint, the same surgical goal as many more open surgical spine procedures. the essence of what makes it different and the heart of what may be at the future of spine surgery is moving the point of visualization from the surgeon’s eye to the endoscopic camera, which allow us to move the “eye’s” lens remotely to the site of the surgical pathology. Innovation that brings the surgeon’s “eye” to within millimeters from the patient’s pathology allows complex spine surgery to be performed in awake patients through a tube the size of a pencil.

References1. kambin P, nixon Je, chait A, schaffer JL. Annular protrusion:

pathophysiology and roentgenographic appearance. Spine (Phila Pa 1976) 1988;13:671-675.

2. Forst R, Hausmann B: nucleoscopy—a new examination tech-nique. Arch Orthop Trauma Surg 1983;101:219-221.

3. kambin P, ed. Arthroscopic Microdiscectomy: Minimal Inter-vention spinal surgery. Baltimore, Md: urban & schwarzen-burg; 1990.

4. Mayer HM, Brock M. Percutaneous endscopic lumbar discecto-my (PeLd). Neurosurg Rev 1993;16:115-120.

5. Mathews HH. transforaminal endoscopic microdiscectomy. Neurosurg Clin North Am 1996;7:59-63.

6. ditsworth dA. endoscopic transforaminal lumbar discectomy and reconfiguration: a postero-lateral approach into the spinal canal. Surg Neurol. 1998;49:588-597.

7. kambin P, Zhou L. History and current status of percutaneous arthroscopic disc surgery. Spine (Phila Pa 1976) 1996;21(24, sup-pl):57s-61s.

8. schubert M, Hoogland t: endoscopic transforaminal nucleoto-my with foraminoplasty for lumbar disk herniation. Oper Or-thop traumato.l 2005;17:641-661.

9. tsou PM, Alan yeung c, yeung At. Posterolateral transforam-inal selective endoscopic discectomy and thermal annuloplasty for chronic lumbar discogenic pain: a minimal access visualized intradiscal surgical procedure. Spine J. 2004;4(5):564-73.

10. Ruetten s, komp M, Merk H, godolias g. use of newly devel-oped instruments and endoscopes: full-endoscopic resection of lumbar disc herniations via the interlamina and lateral transfo-raminal approach. J Neurosurg Spine. 2007; 6:521-530.

11. yeung At, tsou PM. Posterolateral endoscopic excision for lumbar disc herniation: surgical technique, outcome, and






complications in 307 consecutive cases. Spine (Phila Pa 1976) 2002;27:722-731.

12. Ruetten s, komp M, Merk H, godolias g. Full-endoscopic in-terlaminar and transforaminal lumbar discectomy versus con-ventional microsurgical technique: a prospective, randomized, controlled study. Spine. 2008;33:931–939.

13. Jasper gP, Francisco gM, telfeian Ae. clinical success of transfo-raminal endoscopic discectomy with foraminotomy: a retrospec-tive evaluation. Clin Neurol Neurosurg. 2013;115(10):1961-5.

14. Jasper gP, Francisco gM, telfeian Ae. endoscopic transforam-inal discectomy for an extruded lumbar disc herniation. Pain Physician. 2013;16(1):e31-5.

15. Jasper gP, Francisco gM, telfeian Ae. A retrospective evalua-tion of the clinical success of transforaminal endoscopic discec-tomy with foraminotomy in geriatric patients. Pain Physician. 2013; 16(3):225-9.

16. Jasper gP, Francisco gM, Aghion d, telfeian Ae. technical considerations in transforaminal endoscopic discectomy with foraminoplasty for the treatment of spondylolisthesis: case re-port. Clin Neurol Neurosurg. 2014;119:84-7.

17. Jasper gP, Francisco gM, telfeian A. outpatient, awake, ul-tra-minimally invasive endoscopic treatment of lumbar disc herniations. R I Med J. 2014;97(6):47-9.

18. Jasper gP, Francisco gM, telfeian Ae. transforaminal endo-scopic discectomy with foraminoplasty for the treatment of spondylolisthesis. Pain Physician. 2014;17(6):e703-8.

19. Jasper gP, Francisco gM, doberstein c, cielo d, telfeian Ae. clinical Benefits of ultra-Minimally Invasive spine surgery in Awake obese Patients in an outpatient setting: A Retrospec-tive evaluation of transforaminal endoscopic discectomy with Foraminotomy, JSM Neurosurg Spine. 2014;1041;2(5):1-5.

20. telfeian Ae: transforaminal endoscopic solution to disk re-herniation post-mini-tLIF: case report. Clin Neurol Neurosurg. 131:69-71, 2015.

21. telfeian Ae, Jasper gP, Francisco gM. transforaminal endo-scopic treatment of lumbar radiculopathy after instrumented lumbar spine fusion. Pain Physician. 2015;18(2):179-84.

22. telfeian Ae. endoscopic foraminotomy for recurrent lumbar ra-diculopathy after tLIF: technical report. Surg Neurol Int. 2015 Apr 16;6:62.

23. telfeian Ae, choi dB, Aghion dM. transforaminal endoscopic surgery under local analgesia for ventral epidural thoracic spinal tumor: case report. Clin Neurol Neurosurg. 2015;134:1-3.

24. telfeian Ae, Jasper gP, oyelese AA, gokaslan ZL..technical considerations in transforaminal endoscopic spine surgery at the thoracolumbar junction: report of 3 cases. Neurosurg Focus. 2016;40(2):e9.

25. Wagner R, telfeian Ae, Iprenburg M, krzok g, gokaslan Z, choi dB, Pucci Fg, oyelese A. transforaminal endoscopic Foraminoplasty and discectomy for the treatment of a thorac-ic disc Herniation. World Neurosurg. 2016;90:194-8.

26. Wagner R, telfeian Ae, Iprenburg M, krzok g, gokaslan Z, choi dB, Pucci Fg, oyelese A. transforaminal endoscopic solution to a kyphoplasty complication: technical note. World Neuro-surg. 2016;91:195-8.

27. Wagner R, Iprenburg M, telfeian Ae. transforaminal endoscop-ic decompression of a postoperative dislocated bone fragment after a 2-level lumbar total disc replacement: case report. neu-rosurg Focus. 2016;40(2):e8.

AuthorsAlbert e. telfeian, Md, Phd, department of neurosurgery, Rhode

Island Hospital, the Warren Alpert Medical school of Brown university, Providence, RI.

Adetokunbo A. oyelese, Md, Phd, department of neurosurgery, Rhode Island Hospital, the Warren Alpert Medical school of Brown university, Providence, RI.

Ziya L. gokaslan, Md, department of neurosurgery, Rhode Island Hospital, the Warren Alpert Medical school of Brown university, Providence, RI.

correspondenceAlbert telfeian, Md, Phddepartment of neurosurgeryRhode Island Hospital593 eddy streetProvidence, RI 02903401-793-9132Fax [email protected]


mailto:[email protected]




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Updates On chimeric Antigen Receptor-Mediated Glioblastoma ImmunotherapyGeoRGe Mao, MD; pRakasH saMpaTH, MD; saDHak senGupTa, phD

ABSTRACT glioblastoma multiforme (gBM) is the most malignant of the primary central nervous system (cns) neoplasms, accounting for nearly 80% of all primary brain tumors and is associated with high morbidity and mortali-ty. Immunotherapy is proving to be a fertile ground for next-generation gBM therapy, with large translational research projects and clinical trials currently underway. one particularly promising area is the chimeric antigen receptors (cARs) in the context of lymphocyte adoptive cell therapy (Act), which has achieved success in the treatment of hematological malignancies. In this review, we will discuss cARs and review current challenges facing their use in gBM therapy.

KEYWORdS: glioblastoma, immunotherapy, cAR

INTROduCTION

glioblastoma (gBM) is the most common and most malig-nant of all the primary cancers of the central nervous system. It is an aggressive and heterogeneous cancer characterized by densely packed pleomorphic cells with high mitotic activ-ity, necrosis, and high degree of vascularization. gBM most commonly strikes older individuals, with a slight predilec-tion for males over females. the current standard of care therapy for gBM, which consists of maximum allowable surgical resection, focal beam radiation, and chemother-apy with temozolomide, is not curative. survival remains abysmal, as fewer than 10% of patients survive after 5 years. the difficulty in treating gBM arises from the cancer’s cel-lular heterogeneity, their diffuse infiltration into the brain, protection provided by the blood brain barrier, the chemo- and radiotherapeutic resistance and regenerative capacity of glioma stem cells [1-3].

With these barriers in mind, immunotherapy may offer an avenue of treatment for gBM that may be both safer and more effective. Immunotherapy offers a targeted approach to treatment, via utilization of unique molecular and genetic signature of tumor cells. It has been noted in several malignancies that cancer patients who had more activated immune systems seem to have better outcomes. thus, tech-niques have been developed to enhance a patient’s immune response against gBM. Immunotherapy encompasses a wide

variety of techniques, which are beyond the scope of this review. the most developed of these immunotherapeutic methods is the use of monoclonal antibodies (mAbs). While mAbs have been developed against multiple gBM-specific antigens, they have not yet enjoyed wide success due to a combination of tumor and host factors. other areas of immunotherapy for gBM under current active investigation include dendritic cell vaccines derived from lysed tumor cells, immunomodulatory checkpoint inhibitors, and engineered t-cell based therapies, which will be the focus of this paper.

CARs

Recently reported success of clinical cAR-t cell therapy of gBM [4] has generated hope in the use of this technol-ogy for gBM immunotherapy. cAR-t cell offers an attrac-tive alternative to a limitation inherent in the other t-cell receptor (tcR) dependent cellular immunotherapeutic approaches, namely, that of MHc independent antigen pre-sentation. Precluding the need for tcRs, cAR-t cell strat-egies greatly improve the diversity of antigen targets, and bypasses a mechanism of gBM immune evasion through MHc down-regulation [5]. engineered cAR-ts have much higher affinity to their targeted antigens than t cells. the antigen binding can be further modulated in subsequent development of the cAR-t cells to prevent overly strong immune responses that can result in the potentially fatal cytokine release. since cAR-ts are artificially constructed from functional polypeptide domains, the receptors can be configured by the addition of new effector domains, adding novel features to the cAR-t cell. thus, cAR-t cells can be precisely tailored to the goals of therapy, and be individual-ized to the particular patient and clinical scenario.

cAR-ts are very similar to tcR in structure and func-tion, as they both combine an antigen-binding domain with downstream signal transduction domains. the antigen-bind-ing domain of cAR can be a heavy chain and the light chain fusion protein (scFv) of a prototypical antibody, and the most common design is an scFv domain joined to a transmem-brane cd3 domain. this section of the protein is physi-cally linked to an intracellular cd3- ζ signaling domain and costimulatory domains that couple extracellular antigen recognition to intracellular signal transduction, which sub-sequently affect t-cell immune response (Figure 1). one can also look beyond the traditional antigen-antibody paradigm






Figure 1. Chimeric antigen Receptors (CaRs): Design of CaRs versus TCRs (a), and evolution of CaRs (b).

clinical trials cAR target(s) current Status Special Notes

nCT01454596 eGFRviiisuspended recruitment

status unclear

nCT02664363 eGFRviiinot yet started

recruitmentneoadjuvant

aCT

nCT02209376 eGFRviii in recruitmentsafety/feasibility

study

nCT02575261 epha2 in recruitmentsafety/feasibility

study

nCT02442297 HeR2not yet started

recruitmentinhibitory CaR

model

nCT01109095 HeR2ongoing, not accepting new

patients

Modification of preselected CMv

specific T cells

nCT01082926 iL-13Rα2 Completed

T cells also engineered with

HyTk suicide switch and

resistance to steroids

nCT02208362 iL-13Rα2 in recruitmentsafety/feasibility

study

table 1. List of CaR-T cells currently undergoing clinical trials.

for ligand-binding motifs. For example, the natural recep-tor of a particular tumor specific antigen may be utilized as the ligand-binding domain, thus permitting cARs to bind to non-immunogenic peptides as well as carbohydrate and even lipid-based antigens.

the MHc independent nature of cAR-mediated antigen presentation and their inherent modular properties engi-neered into these cells make the receptors far more versa-tile than tcRs. After the cAR design is decided upon, the underlying genetic sequence that encodes for the cAR is encoded and transfected into the t-cell usually via a viral vector. the modified t-cells are then expanded in vitro and subsequently re-introduced back to the patient [6, 7].

CARS fOR gBM IMMuNOThERAPY

Initially achieving success for the treatment of hematologic malignancies, adoptive cAR-t cell therapy is now under active investigation for a variety of solid tumors, includ-ing gBM. Presently, cARs have been developed against six gBM-associated antigens, with four having passed animal trials and currently in clinical trials. these include: egFRvIII [8-13], IL13Rα2 [4, 14-16], HeR2 [17, 18], and ephA2 [19]. epidermal growth factor receptor, or egFR, is directly impli-cated in gBM through either over-amplification of the gene (HeR2/neu) or through constitutively active mutant vari-ants, both of which result in increased growth and survival of the gBM tumor cell [10]. ephA2 is a cell-surface recep-tor that regulates proliferation, migration and angiogenesis, which ultimately affects the invasive and metastatic poten-tial of gBM [20, 21]. IL13Rα2 is a unique decoy receptor for IL13, and binding of the cytokine to the decoy receptor terminates the chain immuno-stimulatory signals that lead to the generation of an appropriate immune response [22].

currently, there are three major clinical trials involving

cAR-t cells against egFRvIII on gBM. All three are in preliminary stages, only one is currently recruiting partic-ipants, whereas the two others have not yet started or have suspended patient recruitment [23-25]. there have been two cAR-t-cell clinical trials involving the use of IL13Rα2 as the target and two clinical trials involving anti-HeR2 cAR-t cells. Lastly, there is currently one clinical trial with the goal of establishing ephA2 as a safe and feasible cAR- target, which is presently in recruitment [30] (Table 1).






lIMITATIONS Of CARS fOR gBM IMMuNOThERAPY

so far, the use of adoptive cAR-t cell therapy for gBM has not yet enjoyed the level of success seen in the treatment of lymphoproliferative disorders such as in ALL and cLL. this is due to a combination of tumor and host factors, the most relevant of which is gBM’s ability to evade immune surveillance and even achieve active suppression of the local immune response. gBM can actively shield itself from immune assault by concealment of targeted cell-surface anti-gens (including MHc proteins) and active secretion of vari-ous ligands that induce t-cell apoptosis and further inhibit the immune response [31-33]. Furthermore the intrinsic cel-lular heterogeneity of gBM provides further passive immu-noresistance and immune escape mechanisms.

OVERCOMINg ThE lIMITATIONS one of the most obvious ways to counteract the problem of tumor heterogeneity is the use of cAR t cells that rec-ognize multiple tumor antigens. By designing cARs with multiple distinct antigen-binding domains and through the introduction of multiple different cARs onto the surface of a single t cell, there is more opportunity to overcome intratumor antigen heterogeneity [34]. cAR-t cells can be further modified to render them unresponsive to the various immunosuppressive and apoptotic-inducing signals secreted by gBM [35, 36]. In addition, checkpoint inhibitors such as nivolumab, which suppress such interaction between the inhibitory ligand and its associated receptor on the t cell, can be given in conjunction with cAR-t cell administration to impair gBM’s immunosuppressive capabilities [37-39].

Further engineering of the cAR-t cells allows for potential improvement in their immune response. examples include the addition of co-stimulatory domains to the intracellu-lar portion of the cAR construct to amplify the immune response generated by the cAR-t cell (Figure 1B). Further amplification may include designing cARs that can inde-pendently secrete critical pro-inflammatory cytokines [40], priming cAR-t cells with viral particles, and/or the appro-priate pre-selection of t cells for cAR engraftment, such as the use of particular t cell subsets that have greater capac-ity to replicate in vivo after exposure to gBM antigens. In addition, cAR-t cells can also be rendered resistant to vari-ous chemotherapeutic agents, so that chemotherapy may be given in conjunction with adoptive t cell therapy [41-43].

one of the major issues confronting cAR-t cells is stim-ulating the appropriate level of immune response that kills the tumor, while causing minimal damage to normal tis-sues. While in vitro cAR-t cells demonstrate specificity for target antigen, in vivo studies have shown that cAR-t cells have resulted in systemic toxicity. three classes of toxici-ties are seen with cAR-t cell therapy. off-target-off-tumor toxicity is cross-reactive due to qualitative defects in scFv

design and/or production. since these antibody fragments are often derived from murine immune systems, human toxicity resulting from murine derived antigen cross-reac-tivity will likely become less of an issue. A more serious problem is the on-target, but off-tumor toxicity observed with cAR-t cell therapy, as the tumor antigens are some-times expressed in or cross react with non-neoplastic cells [44]. one way to offset this type of toxicity is designing a cAR-t cell that becomes activated only when it interacts with multiple different gBM antigens on the surface of the glioma cell [45, 46]. Because there is a dearth of antigens that are only expressed in gBM and nowhere else, investigators have turned to utilizing antigens that are highly expressed in glioma cells, but are also expressed at lower levels else-where in the body. By modulating the affinity of the cAR so that t cell activation occurs only after a defined threshold of binding is reached between the t-cell and its target, this type of toxicity may be abrogated [47]. the last category of toxic-ity due to a dysregulated immune response can range from a mild systemic flu-like illness to a massive overwhelm-ing cytokine release that can result in multiorgan failure, and ultimately death. this may be addressed through the introduction of safety suicide switches into the adoptive t cell, which, when turned on by an exogenous signal (usually introduced by a clinician), results in the death of the t cell.

CONCluSIONthe unique modular nature of cARs allows them to be tai-lor-made to match the need of any particular clinical sce-nario and nature makes cAR-t cell therapy a good potential complement to existing conventional therapies. Protocols are in place to determine their efficacy when used in con-junction with temozolomide. However, the full potential of cAR-t therapy will not be realized until they are designed for the individual patient. Because technology now exists to allow for rapid genome-wide sequencing of individual cells, cAR-t cell therapy allows for targeting of targets unique to the individual cancer patient. And as the patient’s gBM evolves over time, due to selection pressure during therapy, new cAR-t cells may be prepared and reintroduced to the patient in response to the antigenic shift. of course, to iden-tify these shifts, fresh tumor samples and genetic sequenc-ing will be required to identify antigenic changes over time in the tumor organ.

currently, there are still major challenges facing cARs that prevent their widespread use; however, solutions are in development that address most of these hurdles. With the cost of genomic sequencing rapidly decreasing due to technical innovations and economy of scale, a personalized approach to glioblastoma therapy is nearing. cAR-t cells represent a novel therapeutic option that may soon be ready for widespread use in this and other diseases.






References1. schwartzbaum, J.A., J.L. Fisher, k.d. Aldape, and M. Wrensch,

Epidemiology and molecular pathology of glioma. nat clin Pract neurol, 2006. 2(9): p. 494-503; quiz 1 p following 516.

2. Wen, P.y. and s. kesari, Malignant gliomas in adults. n engl J Med, 2008. 359(5): p. 492-507.

3. Lawson, H.c., P. sampath, e. Bohan, M.c. Park, et al., Intersti-tial chemotherapy for malignant gliomas: the Johns Hopkins experience. J neurooncol, 2007. 83(1): p. 61-70.

4. Brown, c.e., d. Alizadeh, R. starr, L. Weng, et al., Regression of Glioblastoma after Chimeric Antigen Receptor T-Cell Therapy. n engl J Med, 2016. 375(26): p. 2561-9.

5. chmielewski, M., A.A. Hombach, and H. Abken, Antigen-Spe-cific T-Cell Activation Independently of the MHC: Chimeric Antigen Receptor-Redirected T Cells. Front Immunol, 2013. 4: p. 371.

6. sadelain, M., R. Brentjens, and I. Riviere, The basic principles of chimeric antigen receptor design. cancer discov, 2013. 3(4): p. 388-98.

7. dotti, g., s. gottschalk, B. savoldo, and M.k. Brenner, Design and development of therapies using chimeric antigen recep-tor-expressing T cells. Immunol Rev, 2014. 257(1): p. 107-26.

8. Bullain, s.s., A. sahin, o. szentirmai, c. sanchez, et al., Genet-ically engineered T cells to target EGFRvIII expressing glioblas-toma. J neurooncol, 2009. 94(3): p. 373-82.

9. gupta, P., s.y. Han, M. Holgado-Madruga, s.s. Mitra, et al., De-velopment of an EGFRvIII specific recombinant antibody. BMc Biotechnol, 2010. 10: p. 72.

10. Johnson, L.A., J. scholler, t. ohkuri, A. kosaka, et al., Rational development and characterization of humanized anti-EGFR variant III chimeric antigen receptor T cells for glioblastoma. sci transl Med, 2015. 7(275): p. 275ra22.

11. Miao, H., B.d. choi, c.M. suryadevara, L. sanchez-Perez, et al., EGFRvIII-specific chimeric antigen receptor T cells migrate to and kill tumor deposits infiltrating the brain parenchyma in an invasive xenograft model of glioblastoma. PLos one, 2014. 9(4): p. e94281.

12. ohno, M., t. ohkuri, A. kosaka, k. tanahashi, et al., Expression of miR-17-92 enhances anti-tumor activity of T-cells transduc-ed with the anti-EGFRvIII chimeric antigen receptor in mice bearing human GBM xenografts. J Immunother cancer, 2013. 1: p. 21.

13. sampson, J.H., B.d. choi, L. sanchez-Perez, c.M. suryadevara, et al., EGFRvIII mCAR-modified T-cell therapy cures mice with established intracerebral glioma and generates host immunity against tumor-antigen loss. clin cancer Res, 2014. 20(4): p. 972-84.

14. krebs, s., k.k. chow, Z. yi, t. Rodriguez-cruz, et al., T cells redirected to interleukin-13Ralpha2 with interleukin-13 mu-tein--chimeric antigen receptors have anti-glioma activity but also recognize interleukin-13Ralpha1. cytotherapy, 2014. 16(8): p. 1121-31.

15. kong, s., s. sengupta, B. tyler, A.J. Bais, et al., Suppression of human glioma xenografts with second-generation IL13R-specif-ic chimeric antigen receptor-modified T cells. clin cancer Res, 2012. 18(21): p. 5949-60.

16. kahlon, k.s., c. Brown, L.J. cooper, A. Raubitschek, et al., Spe-cific recognition and killing of glioblastoma multiforme by in-terleukin 13-zetakine redirected cytolytic T cells. cancer Res, 2004. 64(24): p. 9160-6.

17. Ahmed, n., v.s. salsman, y. kew, d. shaffer, et al., HER2-spe-cific T cells target primary glioblastoma stem cells and induce regression of autologous experimental tumors. clin cancer Res, 2010. 16(2): p. 474-85.

18. Ahmed, n., v.s. Brawley, M. Hegde, c. Robertson, et al., Human Epidermal Growth Factor Receptor 2 (HER2) -Specific Chimeric Antigen Receptor-Modified T Cells for the Immunotherapy of HER2-Positive Sarcoma. J clin oncol, 2015. 33(15): p. 1688-96.

19. chow, k.k., s. naik, s. kakarla, v.s. Brawley, et al., T cells re-directed to EphA2 for the immunotherapy of glioblastoma. Mol ther, 2013. 21(3): p. 629-37.

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24. Pilot Study of Autologous T Cells Redirected to EGFRVIII-With a Chimeric Antigen Receptor in Patients With EGFRVIII+ Glio-blastoma. [cited 2017 1/29/2017]; Available from: https://clini-caltrials.gov/show/nct02209376.

25. eGFRvIII CAR-T Cells for Newly-Diagnosed GBM. [cited 2017 1/29/2017]; Available from: https://clinicaltrials.gov/show/nct02664363.

References 26–47

Authorsgeorge Mao, Md, Fellow, Alpert Medical school of Brown

university, department of Pathology.

Prakash sampath, Md, Brain tumor Immunotherapy Research Program, department of neurosurgery, Rhode Island Hospital, Providence, RI; Brain tumor Laboratory, Roger Williams Medical center, Providence, RI; department of neurosurgery, Alpert Medical school of Brown university, Providence, RI.

sadhak sengupta, Phd, Brain tumor Immunotherapy Research Program, department of neurosurgery, Rhode Island Hospital, Providence, RI; Brain tumor Laboratory, Roger Williams Medical center, Providence, RI; department of neurosurgery, Alpert Medical school of Brown university, Providence, RI.

correspondencesadhak sengupta, PhdAssistant Professordepartment of neurosurgeryBrown universityRhode Island Hospital593 eddy street. APc 635Providence, RI [email protected]


https://ClinicalTrials.gov/show/NCT01454596






http://www.rimed.org/rimedicaljournal/2017/06/2017-06-39-neuro-mao-referneces.pdf

mailto:sadhak.sengupta%40lifespan.org?subject=





Recent Advances in the treatment of Gliomas – comprehensive Brain tumor centersTeven a. ToMs, MD, MpH; nikoLaos Tapinos, MD, phD

ABSTRACT gliomas are a class of primary brain tumors arising from the supporting structures of the brain, the astrocytes and oligodendrocytes, which range from benign lesions to its most malignant form, the glioblastoma. treatment for these lesions includes maximal surgical resection, radiotherapy, and chemotherapy. Recently, novel thera-pies such as immune modulatory therapies and electrical field treatment of the most malignant form, the glioblas-toma, have shown promise in improving survival. We will review recent advances in clinical trials, explore the role of multimodal care in brain tumor therapy, as well as explore advances in molecular biology and nanotech-nology which offer new hope for treatment of this class of disease.

KEYWORdS: glioblastoma, immunotherapy, tumor treating fields, nanotechnology, drug delivery

INTROduCTION

gliomas are a class of tumors which arise from the support-ing structures of the brain, astrocytes and oligodendrocytes. they range in behavior from benign lesions with distinct borders such as juvenile pilocytic astrocytomas, curable with surgical resection alone, to more diffusely infiltrative cancerous lesions, astrocytomas, oligodendrogliomas, and glioblastoma, all uniformly lethal in a matter of several to many years. In this brief review, we will focus on the most lethal of these, the glioblastoma (gBM).

gBM is the most devastating primary malignancy of the central nervous system in adults. currently, standard treatment consists of maximal safe surgical resection or a diagnostic biopsy, followed by radiotherapy (60 gray) with concomitant daily temozolomide chemotherapy, followed by maintenance treatment with temozolomide for 6- to12 months1. However, most patients will die within 1 to 2 years. Median progression-free survival from diagnosis of 6.2 to 7.5 months and median overall survival from diagnosis of 14.6 to 16.7 months have been reported in clinical trials1-4. the reported 2- and 5-year survival rates are 27% and 10%, respectively. during the last decade, all attempts to improve outcomes for patients with glioblastoma have failed when evaluated in large randomized trials2-6. Most recently, the

development of electric current loco-regional antimitotic therapy (“tumor-treating fields”) led to the first reported survivals exceeding 20 months7.

In the united states alone, 12,000 new cases of gBM are diagnosed each year8. one reason cited for the failure to improve survival has been the presence of a robust blood-brain barrier within the tumor, which impedes delivery of traditional cytotoxic and novel molecular therapies9. Most chemotherapeutic agents are hydrophilic, and do not pene-trate the blood brain barrier well. Attempts to deliver che-motherapeutic molecules into the brain have included both osmotic, chemical, and ultrasound mediated opening of the blood brain barrier to improve drug delivery, but none have improved clinical outcomes10. A novel method to bypass this barrier, (i.e., convection enhanced delivery), met with success in delivering high drug concentrations of hydro-philic drugs to brain tumors and led to several clinical trials. However, convection-enhanced delivery has not yet been associated with improved clinical response. this failure has been ascribed to inhomogeneous delivery of the drug to the entire tumor, as well as difficulty in modeling the bulk flow of infusate :drug to the tumor volume11,12.

CARINg fOR ThE glIOMA PATIENT – ThE ROlE Of ThE MulTIdISCIPlINARY ClINIC (MdC)

the care of the patient with glioma is nuanced and complex. Patients with a new diagnosis of glioma are often confused and required to make complex decisions about their care in a relatively short period. unfortunately, the knowledge required to guide a patient through that decision making process is usually beyond the ability of the primary care pro-vider or even the general medical or radiation oncologist. this is where a modern Mdc staffed with neuro-oncolo-gists, neuro-oncological surgeons, radiation therapists, and their support teams are crucial.

At an initial visit, the patient meets the Mdc staff includ-ing nurses, social workers, and the intake team. All data are reviewed and the Mdc team establishes a coordinated care plan. If necessary, advanced imaging such as functional mag-netic resonance imaging (MRI) or diffusion tensor imaging is performed to aid in preparations for surgery (See Figure 1). Further neuropsychological evaluation may be necessary for some low-grade gliomas or those in or near speech and lan-guage areas. Intraoperatively, neurophysiological monitoring

43

46

en






Figure 1. (a) The red arrow points to a small low-grade glioma in the medulla of the brainstem.

(b) DTi was used to show that the descending fibers do not traverse the lesion, but rather are displaced (yellow arrow) by the lesion.

Figure 2. (a) The yellow arrow illustrates a low-grade glioma in the cingulum underlying the motor cortex.

(b) using neurophysiological techniques including motor evoked potential and subcortical fiber tract stimulation, the lesion was successfully removed.

A B

A B

is undertaken to map out motor and sensory areas (See Fig-ure 2) or nearby cranial nerve nuclei. If the lesion is near language areas, an awake craniotomy with speech mapping may be required to achieve maximal safe resection while minimizing the risk of language deficits.

After biopsy or resection, the tissue is studied by a dedi-cated neuropathologist for both histopathology and molec-ular markers. A detailed description of the molecular pathology of glioma is beyond the scope of this manuscript. Postoperative MRI is reviewed for completeness of resection and a care plan is formulated by the team. this care plan may include radiation therapy, chemotherapy, tumor treat-ing fields, or clinical trials. Further discussion with the fam-ily is begun to deliver the diagnosis and care plan, as well as to engage the patient and family with resources such as local

and virtual brain tumor support groups to aid in the social support network for these patients.

Follow-up routinely is weekly during radiation ther-apy, monthly during active chemotherapy and every three months for high-grade gliomas. Routine surveillance scan-ning is often used to identify progression of the disease and allow for more timely intervention upon therapeutic failure.

lANdMARKS IN ThE CARE Of glIOMA

For both low-grade glioma as well as glioblastoma, survival is dependent upon age, the patient karnofsky Performance score, as well as a host of histopathological and molecu-lar pathological factors. the most important factor in the control of clinicians, is, of course, the percentage of tumor






which can be surgically resected13,14. It has been clearly demonstrated that for all types of glioma, the improvement in patient outcomes achieved by the cytoreduction of tumor cells gained is nonlinear and that maximum benefit to the patient is achieved when all tumor which can be removed up to the point of causing a postoperative neurological defi-cit is beneficial for the patient.

the most important clinical advances in glioma ther-apy have occurred within the past 15 years. the molecular biology of gliomas involves a host of genetic and epigene-tic alterations which are of prognostic importance to tumor classification as well as patient survival. For low-grade gli-omas, the most important of the diagnostic and prognostic markers are those of gene rearrangement studies, which suggest the classical oligodendroglioma phenotype and pre-dict responsiveness to chemotherapy, that of chromosome 1p and 19q allelic loss15. Loss of 1p/19q alleles predict both sensitivity to chemotherapeutic agents as well as a progno-sis which is nearly double that of low-grade gliomas without this genomic loss.

In gBM, attempts have been made to characterize mul-tiple molecular phenotypes, but the single gene with the most prognostic value is IdH116. Mutations in IdH1 are classically identified in gBMs arising from lower-grade gliomas (previously commonly called secondary gBMs to distinguish them from those presenting as de novo gBM and often having mutations in the epidermal growth fac-tor receptor) and are associated with improved prognosis. the other commonly cited prognostic factor in gBM is the epigenetic alteration of methylation of the methyl guanine methyl transferase (MgMt) gene promoter17. the MgMt methylation at the promoter reduces the expression of the MgMt gene, needed to repair the damage caused by the chemotherapy temozolomide. thus, patients with methyl-ated MgMt promoter are more susceptible to the effects of the chemotherapeutic temozolomide and are in a better prognostic category.

Prognosis for gBM patients has been among the worst of all malignancies until recently. survival was less than 12 months as recently as 20 years ago, and progress has been slow. the work of Roger stupp, who showed that concur-rent temozolomide along with radiation therapy improved prognosis over sequential radiotherapy followed by temo-zolomide marked the first major advance in glioblastoma survival (to 14.6 months) since the advent of radiotherapy and the introduction of nitrosoureas in the 1970s and 1980s7. More recently, a series of novel devices, drug therapies and immune strategies have begun to improve survival beyond this mark.

NOVEl ThERAPEuTIC AdVANCES

the most recent therapeutic advance to be approved for clinical use in glioma is that of a novel antimitotic therapy called tumor treating fields (ttFs). ttFs are an antimitotic

therapy consisting of an alternating electrical current of 100 – 300 kHz delivered via transducer arrays placed on the scalp. In both recurrent and newly diagnosed gBM, ttFs delivered for at least 18 hours per day have been shown to improve survival7. In newly diagnosed gBM, the addition of ttFs to radiation and temozolomide improved survival to 24.3 months in treated patients versus 20.4 in the con-trol group. one might note that even the control group with radiation and temozolomide were surviving longer than those from a decade ago.

A host of other small molecule inhibitors and novel drug delivery systems such as convection enhanced delivery have been tried in the past several decades but have failed to show meaningful improvements in survival of gBM. More recently, techniques such as immunomodulatory mol-ecules, such as the Pd-1 and ctLA-4 inhibitors have shown improvements in survival of melanoma, lung and renal cell carcinoma and are in trials for gBMs18.

In addition to immune checkpoint inhibitors, other immune strategies such as peptide vaccines, dendritic cell vaccines19, and chimeric Antigen Receptor t-cell (cAR t-cell) strategies20 have shown early promise in improv-ing survival for patients with glioma. these topics will be reviewed in another manuscript in this issue.

ThE ROlE Of RESEARCh IN glIOMA – INSIghTS fROM OuR lABORATORY

despite many decades of work and recent advances, glioma remains a fatal disease. thus, no development of a compre-hensive brain tumor program would be complete without a research effort. this includes clinical trials with industry and large cooperative groups, but some of the most exciting prospects for improvements in glioma therapy lie within the laboratory. It is the goal of our group to bring several of these to clinical trial within the next several years. With this in mind, we will preview two fields of investigation, glioma migration and micro ribonucleic acid (miRnA) of glioblas-toma stem cells.

one of the most vexing aspects of gliomas is that they migrate away from the solid tumor and diffusely infiltrate well beyond apparent margins on MRI. thus, for anything other than compact, grade I (benign) gliomas, surgery alone will never be curative. therefore, we have studied within our laboratory how glioblastoma cells interact with the brain environment to migrate as well as how we might manipulate these pathways to aid in therapy. We are manipulating these pathways to promote the return of remaining cancer cells to the resection site by placing a pro-migratory protein (Lcn2) in a slow release hydrogel placed within the resection cav-ity to hopefully improve the results of radiation therapy. In addition, we have found a small molecule inhibitor of a tyro-sine kinase (Lck), which enables pseudopodia extension and migration in gBM stem cells. We feel that manipulation of the “on” and “off” pathways for migration can be used to






improve patient outcomes and expect to begin clinical trials after we complete our small animal model data.

In addition, our laboratory is investigating the role of miRnA – the regulators of RnA transcription – to identify how regulation of these small switches controls the ability of cancer cells to self renew and replicate in gBM stem cells. thus far, we have narrowed the control of this crucial fea-ture of cancer – the ability of cells to remain stem-like and resist therapy – to 9 likely miRnA candidates. our prelim-inary work suggests that miRnA-mediated control of RnA methylation may be the molecular switch that changes gBM stem cells to the cancer cells we typically associate with gBM. We hope that this signature may yield prognostic data and reveal pathways for therapeutic intervention.

of course, none of this has much meaning without educat-ing the future generation of oncologists and neurosurgeons to care for patients with glioma. We anticipate beginning advanced training of neurosurgical oncology fellows within the year. once this is complete, the comprehensive brain tumor center will close the circle from the patient, to the student, to the laboratory, and back, to be able to provide the best care for patients afflicted with glioma.

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temozolomide for glioblastoma. N. Engl. J. Med. 352, 987–96 (2005).

2. gilbert, M. R. et al. dose-dense temozolomide for newly diag-nosed glioblastoma: a randomized phase III clinical trial. J. Clin. Oncol. 31, 4085–91 (2013).

3. gilbert, M. R. et al. A randomized trial of bevacizumab for new-ly diagnosed glioblastoma. N. Engl. J. Med. 370, 699–708 (2014).

4. chinot, o. L. et al. Bevacizumab plus radiotherapy-temozolo-mide for newly diagnosed glioblastoma. N. Engl. J. Med. 370, 709–22 (2014).

5. Westphal, M. et al. A randomised, open label phase III trial with nimotuzumab, an anti-epidermal growth factor receptor mono-clonal antibody in the treatment of newly diagnosed adult glio-blastoma. Eur. J. Cancer 51, 522–32 (2015).

6. stupp, R. et al. cilengitide combined with standard treatment for patients with newly diagnosed glioblastoma with methylat-ed MgMt promoter (centRIc eoRtc 26071-22072 study): a multicentre, randomised, open-label, phase 3 trial. Lancet. On-col. 15, 1100–8 (2014).

7. stupp, R. et al. Maintenance therapy With tumor-treating Fields Plus temozolomide vs temozolomide Alone for glio-blastoma. JAMA 314, 2535 (2015).

8. dolecek, t. A., Propp, J. M., stroup, n. e. & kruchko, c. cB-tRus statistical report: primary brain and central nervous sys-tem tumors diagnosed in the united states in 2005-2009. Neuro. Oncol. 14 Suppl 5, v1-49 (2012).

9. van tellingen, o. et al. overcoming the blood-brain tumor bar-rier for effective glioblastoma treatment. Drug Resist. Updat. 19, 1–12 (2015).

10. drapeau, A. & Fortin, d. chemotherapy delivery strategies to the central nervous system: neither optional nor superfluous. Curr. Cancer Drug Targets 15, 752–68 (2015).

11. Barua, n. u. et al. A novel implantable catheter system with transcutaneous port for intermittent convection-enhanced de-livery of carboplatin for recurrent glioblastoma. Drug Deliv. 23, 167–73 (2016).

12. Barua, n. u. et al. Robot-guided convection-enhanced delivery of carboplatin for advanced brainstem glioma. Acta Neurochir. (Wien). 155, 1459–65 (2013).

13. smith Js et. al. Role of extent of resection in the long-term out-come of low-grade hemispheric gliomas. J Clin Oncol. 26, 1338-45 (2008).

14. Marko nF et. al. extent of resection of glioblastoma revisited: personalized survival modeling facilitates more accurate surviv-al prediction and supports a maximum-safe-resection approach to surgery. J Clin Oncol. 32, 774 - 82 (2014).

15. cairncross Jg. et. al. specific genetic predictors of chemother-apeutic response and survival in patients with anaplastic oligo-dendrogliomas. J Natl Cancer Inst. 90, 1473 – 9 (1998).

16. verhaak Rg et. al. Integrated genomic analysis identifies clini-cally relevant subtypes of glioblastoma characterized by abnor-malities in PdgFRA, IdH1, egFR, and nF1. Cancer Cell 17, 98 – 110 (2010).

17. Hegi Me et. al. MgMt gene silencing and benefit from temo-zolomide in glioblastoma. N Engl J Med. 352, 997 – 1003 (2005).

18. dunn-Pirio AM et. al. Immunotherapy approaches in the treatment of malignant brain tumors. Cancer doi: 10.1002/cncr.30371 (epub ahead of print) (2016).

19. Prins RM et. al. comparison of glioma-associated antigen pep-tide-loaded versus autologous tumor lysate-loaded dendritic cell vaccination in malignant glioma patients. J Immunother 36, 152 – 7 (2013).

20. Brown ce et. al. Regression of glioblastoma after chimeric an-tigen receptor t-cell therapy. N Engl J Med 375, 2561 – 9 (2016).

Authorssteven A. toms, Md, MPH, vice chair, department of

neurosurgery, Warren Alpert Medical school of Brown university; director, Brain tumor Program; Lifespan Health system, Providence, RI.

nikolaos tapinos, Md, Phd, director of Molecular neuroscience & neuro-oncology, department of neurosurgery, Warren Alpert Medical school of Brown university; Lifespan Health system, Providence, RI.

correspondencesteven A. toms, [email protected]






current concepts in the pathogenesis, diagnosis, and Management of type I chiari Malformations CoDy a. DobeRsTein, bs; RaDMeHR ToRabi, MD; peTRa M. kLinGe, MD

ABSTRACT type 1 chiari malformations (cMs) are a group of con-genital or acquired disorders which include the abnormal presence of the cerebellar tonsils in the upper spinal ca-nal, rather than the posterior fossa. the resulting ana-tomic abnormality causes crowding of the structures at the craniocervical junction and can impair the normal flow of cerebral spinal fluid (csF) in this region. this impairment in csF flow dynamics can led to the devel-opment of syringomyelia or hydrocephalus. type 1 cMs have been associated with a wide array of symptoms re-sulting from either cerebellar and brainstem compression and distortion or disturbances in csF dynamics, and can affect both children and adults. the clinical diagnosis may be difficult. Age usually matters in the clinical pre-sentation, and in symptomatic patients, surgical inter-vention is usually required.

KEYWORdS: chiari I Malformation, cerebrospinal fluid, hydrocephalus, syringomyelia

INTROduCTION

chiari malformations are a group of disorders defined by structural defects of the cerebellum, pons, fourth ventricle, and upper spinal cord in relation to the foramen magnum and the skull base. In 1891, chiari was the first to describe and define hindbrain herniation, representing downward displacement of the cerebellum, fourth ventricle, and brain-stem.1 type 1 cMs are characterized by herniation of the cerebellar tonsils through the foramen magnum into the upper spinal canal. the resulting compaction and crowding at the craniocervical junction can disrupt normal cerebro-spinal fluid flow, produce the so-called “valsalva-induced” headaches, and may lead to the formation of a spinal cord syrinx or hydrocephalus.2

chiari malformations are still listed as a rare disease by the office of Rare diseases of the national Institutes of Health. the estimated prevalence in the united states of type 1 cMs is less than one percent with a slight female pre-dominance.2 speer et al. have estimated that 215,000 Amer-icans may harbor a type 1 cM.3 However, the routine use of magnetic resonance imaging (MRI) has led to more frequent identification of this disorder and type 1 cMs can be seen

incidentally in approximately 1% to 4% of patients under-going brain or cervical spine magnetic MRI studies.4

Most cases of type 1 cM are sporadic. type 1 cMs can be found in association with other conditions such as neurofibro-matosis, idiopathic intracranial hypertension (IIH), tethered spinal cord, connective tissue disorders, craniosynostosis and skull base abnormalities, intracranial hypotension and cerebellar hypertrophy in polymicrogyria.5 It is still not fully understood whether these co-existing conditions are mere coincidences or true co-morbidities. the precise natural his-tory of this disorder remains unclear although patients gen-erally have symptomatic progression. there have been a few published reports of spontaneous resolution of type 1 cMs but most symptomatic cases require surgical intervention.5.6

PAThOgENESIS

Most cases of type 1 cM are congenital. skull base abnor-malities are seen in approximately 50% of type 1 cM cases, (i.e., basilar invagination, retroflect odontoid, platybasia etc.).7 Although the exact etiology is unknown, this con-dition is thought to be secondary to insufficiency of the paraxial mesoderm after neural tube closure with underde-velopment of the occipital somites.7,8 Milorat and cowork-ers examined reconstructed ct and MRI images in 388 patients with classic type 1 cMs, and morphometric anal-ysis revealed reductions in the posterior cranial size and volume.9 In severe cases, downward herniation of the brain-stem may occur and is sometimes referred to as a type 1.5 cM.7 despite evidence supporting a genetic contribution to type 1 cMs (i.e., twins, familial clusters, and co-segregation with known genetic syndromes), limited research has been conducted to identify the specific genetic factors involved.8

Acquired type 1 cMs can occur when there is a signifi-cant cerebral spinal fluid (csF) pressure gradient across the craniocervical junction, i.e., csF leakage or lumboperitoneal shunts can produce negative downward pressure gradients leading to the development of a type 1 cM. In addition, con-ditions associated with raised intracranial pressure, such as hydrocephalus and IIH, can promote downward pressure gra-dient. the association of cM1 with tethered cord has led to the “caudal traction theory.” 6

syringomyelia is identified in 30-85% of patients.5,10,11 there are many hydrodynamic theories to explain the for-mation of syringomyelia11. Abnormal and increased pulsatile

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Figure 1. (A) sagittal T2 sTiR magnetic resonance imaging showing Chiari i with significant cer-

vical syringomyelia (black asterisk) and the classical “crowding” of the cerebellum and the brain

stem at the level of the foramen magnum (dashed white line equals the McRae line, which indi-

cates the level of the foramen magnum on a midsagittal section of CT or MRi joining the basion

and opisthion). (B) at 3 months follow-up, there is evidence of restored CsF signal anterior to the

brain stem, decompression of the obex and restoration of the cisterna magna associated with an

almost complete resolution of the syrinx.

BA

motion of the cerebellar tonsils (“tonsillar pistoning”) can produce selective obstruction of csF flow during systole. the increased systolic csF waves are then transmitted to the spinal subarachnoid space and drive the csF into the central canal of the spinal cord through engorged perivascu-lar and interstitial spaces and lead to syrinx formation.12,13

dIAgNOSISthe clinical findings vary dependent on the age at pre-sentation. occipital headache and neck pain are the most common symptoms in adults.10 In infants, oropharyngeal dysfunction or sleep apnea and other cranial nerve findings, i.e., strabismus, are the most common presenting symp-toms, while older children often present with headaches aggravated by “ valsalva maneuvers” during coughing and sneezing or strain, and scoliosis.14,15 symptoms are based on the structural and functional (impaired “csF-dynamics”) pathology associated with cM, which often leads to a wide spectrum of focal and non-focal findings in the clinical and neurological presentation, making it difficult to diagnose. even more challenging is the often reported “brain fog” that has been largely attributed to chronic pain, depression and anxiety associated with the unknowns and physical chal-lenges of this disorder. In traditional thinking, a disorder like chiari affecting the craniocervical junction and the cer-ebellum, has not been thought to affect cognitive function: Altered MRI diffusion tensor imaging (dtI) metrics in the genu of the corpus callosum, splenium, fornix have been cor-related with cognitive neurocognitive function in chiari.16

Magnetic resonance imaging is the widely accepted diag-nostic tool for type 1 cMs. the McRae line is a radiographic line drawn on a lateral midsagittal sec-tion of ct or MRI, joining the basion and opisthion representing the level of the foramen magnum. the traditional definition of type 1 cM as greater than 5 mm displacement of the cerebellar ton-sils below the foramen magnum is chal-lenged.15 even a “mild” displacement of 3-5 mm may be considered significant in the presence of neurological signs or symptoms or in the presence of syringo-myelia. Also, the level of tonsillar ecto-pia evidenced in the sagittal MRI varies based on head position, and whether the measurement of the tonsillar posi-tion is based on a brain or spinal MRI. Recently, upright MRIs have challenged this view also, as gravity might reveal tonsillar displacement that was not seen in the traditional supine MRI versions.

the future lies in computation of the csF space at the craniocervical junction and the resulting altered compliance and

failure to synchronize transmission of systolic csF pres-sures between the cranial and cervical subarachnoid space.12

SuRgICAl MANAgEMENTthe management of acquired forms of type 1 cM is directed at correcting the primary causative condition. For example, ventricular shunting for the treatment of hydrocephalus, repairing spinal csF leakage, or correcting a tethered spinal cord usually results in anatomic and physiologic correc-tion of the acquired cM. Intervention to directly treat the acquired cM is typically not necessary.

Asymptomatic patients who have an incidental finding on imaging are usually observed and monitored with follow-up MRI studies. Most patients with symptoms, or those who harbor a large associated spinal cord syrinx, should be rec-ommended surgical intervention. close follow-up and serial MRI imaging is required in patients who undergo observa-tion alone in the presence of a syrinx. Appropriate man-agement of an asymptomatic patient with a small syrinx is controversial.17,18

Many different surgical techniques are utilized to treat type 1 cMs, and there is no consensus. surgical correction of type 1 cMs may include bony decompression of the pos-terior fossa with or without duraplasty, arachnoid dissec-tion, or shrinking of the cerebellar tonsils. the goal of any of these operations is to restore adequate csF flow at the level of the foramen magnum and establishment, basically an “anatomical reconstruction,” of the cisterna magna (Figure 1A, B). Bony decompression alone has been asso-ciated with a decreased risk of csF related complications such as pseudomeningocele, meningitis, and hydrocephalus.






However, multiple studies have shown that reoperation rates are higher for patients who have undergone bony decompres-sion alone.19,20,21 duraplasty involves the use of autologous pericranium or allografts, none of which have been found superior to the other. More involved arachnoid dissection to ensure flow through native csF channels may be required, particularly if scarring or webbing is restricting csF flow. shrinking of the cerebellar tonsils using meticulous bipolar cautery is also controversial, although we do advocate this approach in select cases. A recent meta-analysis suggested shrinking the cerebellar tonsils during the procedure showed better clinical results in patients with syringomyelia.20 shunting of an associated spinal cord syrinx has been largely abandoned. cM1.5 and associated skull base anomalies may require occipital-cervical fusion and instrumentation due to associated craniocervical instability.

fuTuRE dIRECTIONS

All efforts need to be directed to identify potential subgroups of type 1 cMs. this will result in better diagnostic meth-ods and treatment that will eventually be tailored to the individual anatomic and physiologic characteristics. this includes experimental and molecular studies to further our understanding of the genetics and pathophysiology of type 1 cMs. Also, MRI studies need to advance imaging to allow computation of cerebrospinal fluid space before and after surgery and provide a reliable “disease biomarkers.” A large randomized, prospective study evaluating available surgical techniques is required to definitively determine the most successful and safest treatment options for type 1 cMs.

the center for csF disorders of the Brain and spine at the Warren Alpert Medical school of Brown university supports these endeavors, and has recently started exploring cogni-tive mechanisms in conditions such as hydrocephalus, cM and syringomyelia and optogenetic manipulation of cho-roid plexus cells to gain new insights into csF physiology in collaboration with the Brown Institute for Brain sciences and the neuroscience department. the annual csF disor-der symposium at the Brown medical school supports the interdisciplinary management of chiari and related csF dis-orders in collaboration with the chiari and syringomyelia Foundation (http://csfinfo.org/).

References1. schijman, e. History, anatomic forms, and pathogenesis of

chiari I malformations. childs nerv syst. 2004 20: 323-328.2. speer Mc, enterline ds, Mehltretter L, Hammock P, Joseph J,

dickerson M, et al. chiari type I malformation with or without syringomyelia: prevalence and genetics. J genet couns. 2003. 12:297-311.

3. Meadows J, kraut M, guarnieri M, Haroun RI, carson Bs. As-ymptomatic chiari type I malformations identified on magnet-ic resonance imaging. J neurosurg. 2000;92(6):920–926.

4. Briganti F, Leone g, Briganti g, orefice g, caranci F, Maiuri F. spontaneous Resolution of chiari type 1 Malformation. the neuroradiology Journal (2013) 26(3): 304 – 309.

5. Menezes AH. chiari I malformations and hydromyelia-compli-cations. Pediatr Neurosurg (1991) 17:146–154.

6. Milhorat, t.H., nishikawa, M., kula, R.W. et al. Mechanisms of cerebellar tonsil herniation in patients with chiari malforma-

tions as guide to clinical management. Acta neurochir (2010) 152: 1117.

7. sgouros s, kountouri M, natarajan k (2007) skull base growth in children with chiari malformation type I. J neurosurg 107:188–192.

8. Markunas cA, soldano k, dunlap k, cope H, Asiimwe e, sta-jich J, enterline d, grant g, Fuchs H, gregory sg, Ashley-koch Ae. stratified whole genome linkage analysis of chiari type I malformation implicates known klippel-Feil syndrome genes as putative disease candidates. PLos one. 2013, 8 (4): e61521.

9. Milhorat tH, chou MW, trinidad eM, kula RW, Mandell M, Wolpert c, speer M. chiari I malformation redefined: clinical and radiographic findings for 364 symptomatic patients. neu-rosurgery (1999) 44:1005–1017.

10. Bejjani gk, cockerham kP. (2001) Adult chiari malformation. contemp neurosurg 23:1–7.

11. gardner WJ. (1965) Hydrodynamic mechanism of syringomye-lia. J neurol neurosurg Psychiatry 28:247–259.

12. Rusbridge c1, greitz d, Iskandar BJ.J vet Intern Med. 2006 May-Jun;20(3):469-79. syringomyelia: current concepts in pathogene-sis, diagnosis, and treatment.

13. koyanagi, I; Houkin, k. Pathogenesis of syringomyelia asso-ciated with chiari type 1 malformation: review of evidences and proposal of a new hypothesis. neurosurgical review (2010), 33:271-2851.

14. greenlee J, donovan k, Hsan d, Menezes A. chiari I malfor-mation in the very young child: the spectrum of presentations and experience in 31 children under age 6 years. Pediatrics 2002;110:1212-21.

15. tubbs, R.s., Lyerly, M.J., Loukas, M. et al .the pediatric chiari I malformation: a review: childs nerv syst (2007) 23:1239-1250.

16. kumar M1, Rathore Rk, srivastava A, yadav sk, Behari s, gupta Rk. correlation of diffusion tensor imaging metrics with neuro-cognitive function in chiari I malformation. World neurosurg. 2011 Jul-Aug;76(1-2):189-94.

17. Rocque Bg, george tM, kestle J, Iskandar BJ. treatment Prac-tices for chiari Malformation type I with syringomyelia: results of a survey of the American society of Pediatric neurosurgeons. Journal of neurosurgery Pediatrics 2011; 8 (5) 430-437.

18. Landridge B, Phillips e, choi d. chiari malformation type 1: A systemic review of natural history and conservative manage-ment. World neurosurg (2017) epub ahead of print.

19. durham sR, Fjeld-olenec k. comparison of posterior fossa de-compression with and without duraplasty for the surgical treat-ment of chiari malformation type I in pediatric patients: a me-ta-analysis. J neurosurg Pediatr 2008; 2:42.

20. Forander P, sjavik k, soleheim o, et. al. the case for duraplasty in adults undergoing posterior fossa decompression for chiari I Malformation: A systematic review and meta-analysis of ob-servational studies. clinical neurology and neurosurgery 2014; 125, 58-64.

21. Mutchnick Is, Janjua RM, Moeller k, Moriarty tM. decompres-sion of chiari malformation with and without duraplasty: mor-bidity versus recurrence. J neurosurg Pediatr 2010; 5:474.

Authorscody A. doberstein, Bs, department of neurosurgery, Warren

Alpert Medical school of Brown university, Providence, RI.

Radmehr torabi, Md, department of neurosurgery, Warren Alpert Medical school of Brown university, Providence, RI.

Petra M. klinge, Md, Professor of neurosurgery, director of the center for csF disorders of the Brain and spine, department of neurosurgery, Warren Alpert Medical school of Brown university, Providence, RI.

correspondencePetra M. klinge, Mddepartment of neurosurgery, Rhode Island Hospital593 eddy street, APc 6th Floor, Providence, Rhode Island 02903 401-793- 9123Fax [email protected]


http://csfinfo.org/

mailto:[email protected]




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PuBlIC hEAlThhEAlTh BY NuMBERS niCoLe e. aLexanDeR-sCoTT, MD, MpH DiReCToR, RHoDe isLanD DepaRTMenT oF HeaLTH eDiTeD by saMaRa vineR-bRown, Ms

effects of Smoking and Smoking cessation during pregnancy on Adverse Birth Outcomes in Rhode Island, 2012–2014Hyun (Hanna) kiM, phD; kaRine MonTeiRo, MpH; eLsa LaRson, phD, Ms; Dana MCCanTs DeRisieR, Ms

smoking is one of the most common preventable causes of poor pregnancy outcomes and is associated with maternal, fetal, and infant morbidity and mortality.1-3 smoking before pregnancy can cause reduced fertility, infertility, and ecto-pic pregnancy. smoking during pregnancy increases the risk for pregnancy complications (e.g., placental previa, pla-cental abruption, and premature rupture of the membrane) and poor infant outcomes (e.g., low birth weight, preterm birth, restricted fetal growth, sudden infant death syndrome (sIds), born with a cleft lip or cleft palate, and preterm related death).1-3 Maternal smoking after delivery increases an infant’s risk for respiratory tract infections, ear infections, severe asthma, and death from sIds through exposure to secondhand smoke.1-3 In 2002, it was estimated that 5%–8% of preterm deliveries, 13%–19% of term low birth weight deliveries, 23%–34% of sIds, and 5%–7% of preterm-re-lated deaths were attributable to prenatal smoking in the united states.4 two Healthy People 2020 national health objectives address smoking and smoking cessation during pregnancy; 1) reducing the prevalence of cigarette smoking among pregnant women to 1.4% (MIcH-11.3), and 2) increas-ing smoking cessation during pregnancy to 30.0% (tu-6).5

the purpose of this study was to examine the effects of smoking and smoking cessation during pregnancy on adverse birth outcomes in Rhode Island. In addition, it described the prevalence of and disparities in cigarette smoking during pregnancy.

METhOdS

We analyzed aggregate data from the 2012-2014 Rhode Island Pregnancy Risk Assessment Monitoring system (PRAMs) (n=3,642; average weighted response rate=62.9%). PRAMs is a collaborative surveillance project of the centers for disease control and Prevention (cdc) and state health departments, which collects state-specific, population-based data on maternal behaviors and experiences before, during, and shortly after pregnancy.6 self-reported survey data are linked to selected birth certificate data and are weighted to represent all women delivering live infants in Rhode Island.

to estimate the prevalence of prenatal smoking, and to determine prenatal smoking status, the following survey questions were analyzed: “Have you smoked any cigarettes in the past 2 years?” “In the 3 months before you got preg-nant, how many cigarettes did you smoke on an average day?” “In the last 3 months of your pregnancy, how many cigarettes did you smoke on an average day?” Prenatal

smoking status was classified as “did not smoke during pregnancy,” “smoked before pregnancy but quit smoking by the last 3 months of pregnancy” and “smoked throughout the pregnancy.” three measures of adverse birth outcomes collected from the birth certificate files were used in this study: low birth weight (<2,500 grams), preterm birth (<37 weeks’ gestation), and small-for-gestational-age (<10th per-centile). to identify disparities, the prevalence of prenatal smoking was examined by various socio-demographic char-acteristics (maternal age, race/ethnicity, education, marital status, household income, health insurance type, parity, and assistance from WIc program). these characteristics were also used as covariates in the logistic regression model.

All data analyses were performed using sudAAn release 11.0,7 which accounts for the complex sample design of PRAMs. Logistic regression was performed to assess the effects of smoking and smoking cessation during pregnancy on each measure of adverse birth outcomes, while con-trolling for all covariates. the p-values <.05 are considered statistically significant.

RESulTS

prevalence of Smoking during pregnancy, 2012–2014 overall, 8.5% (95% cI: 7.5%-9.5%) of Rhode Island women who delivered a live infant between 2012 and 2014 smoked during the last 3 months of pregnancy. the prevalence of smoking during pregnancy varied significantly among pop-ulations (Figure 1). Women who were aged 20–29 years (11.1%), were White (10.0%), were non-Hispanic (9.9%), were unmarried (14.2%), were on WIc program (13.5%), were publicly insured (14.1%), were multiparous (10.5%), had < high school education (17.6%), had an annual house-hold incomes < $26,000 (15.4%) were more likely to smoke during pregnancy, compared to their counterparts. none of the groups presented in Figure 1, except one group with an annual household income > $67,000, achieved the Healthy People 2020 goal of reducing the prevalence of cigarette smoking among pregnant women to 1.4%.5

prenatal Smoking and Adverse Birth Outcomes, 2012–2014Among women who delivered a live birth during 2012–2014, 80.5% (95% cI: 79.0%–81.9%) were classified as “did not smoke during pregnancy,” 11.1% (95% cI: 10.0%–12.3%) were classified as “quit smoking during pregnancy,” and 8.5% (95% cI: 7.5%–9.5%) as “smoked throughout the





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Figure 1. prevalence of smoking during the last 3 months of pregnancy by socio-demographic

characteristics, Rhode island women who delivered a live birth, Ri pRaMs, 2012–2014 combined

Figure 2. prevalence of adverse birth outcomes by maternal smoking status during pregnancy,

Rhode island women who delivered a live birth, Ri pRaMs, 2012-2014 combined

low Birth Weight preterm Birth

Small for Gestational Age

AOR 95% cI AOR 95% cI AOR 95% cI

Did not smoke during pregnancy

1 1 1

Quit smoking during pregnancy

1.05 0.84-1.31 0.9 0.62-1.31 1.22 0.81-1.84

smoked throughout pregnancy

2.04* 1.57-2.65 1.30 0.87-1.95 2.55* 1.65-3.94

table 1. adjusted odds Ratio (aoR) and 95% Confidence interval (Ci) for each adverse birth

outcome, Rhode island women who delivered a live birth, Ri pRaMs, 2012–2014 combined

pregnancy.” during 2012-2014, 6.4% (95% cI: 6.3%–6.5%) of Rhode Island mothers had a low birth weight baby, 8.6% (95% cI: 7.9%–9.3%) had a preterm delivery, and 10.1% (95% cI: 9.2%–11.1%) had a small-for-gestational-age baby.

Figure 2 presents the prevalence of each adverse birth outcome in relation to prenatal smoking sta-tus. compared to women who did not smoke during pregnancy, women who smoked throughout the preg-nancy were significantly more likely to have a low birth weight baby (6.0% vs. 10.7%), a preterm baby (8.2% vs. 12.9%), and a small-for-ges-tational-age baby (9.1% vs. 18.5%). However, there were no significant differences between women who did not smoke during pregnancy and women who quit smoking during pregnancy in the prevalence of all three measures of adverse birth outcomes.

Table 1 presents the adjusted odds ratios (AoR) and 95% confi-dence intervals (cI) from the logis-tic regression analyses for each adverse birth outcome measure. After adjusting for all socio-demo-graphic factors shown in Figure 1, women who smoked throughout the pregnancy had twice the odds of having a low birth weight baby (AoR=2.04; 95% cI=1.57-2.65; p<.0001) and 2.6 times the odds of having a small-for-gestational-age baby (AoR=2.55; 95% cI=1.65-3.94; p<.0001), compared with women who did not smoke during preg-nancy. However, preterm birth became not significant when all covariates were controlled for. con-sistent with the results in Figure 2, there were no significant differences between women who did not smoke during pregnancy and women who quit smoking during pregnancy in the odds of adverse birth outcomes for all three measures.

lIMITATIONS

the findings in this article are sub-ject to at least two limitations. First,

* p<.0001aoR: adjusted odds Ratio: adjusted for Maternal age, Race, ethnicity, education, Marital status, Household income, Health insurance, parity, and wiC participation.





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the smoking data in this study relied on self-reporting. Preg-nant women might under-report smoking and over-report quitting smoking during pregnancy. second, the PRAMs sample includes only women who delivered a live infant, and excludes women who experienced a miscarriage or still-birth that is likely related to smoking during pregnancy. therefore, the actual prevalence of smoking among all preg-nancies might be higher than the estimates presented here.

dISCuSSION

the main finding of this study is that although smoking during pregnancy significantly increases the risk for certain adverse birth outcomes, quitting smoking during pregnancy substantially reduces these risks. Women who smoked throughout their pregnancy, compared with women who did not smoke during pregnancy, had significantly higher odds of poor birth outcomes (e.g., low birth weight and small-for-ges-tational-age). However, when comparing women who quit smoking during pregnancy with women who did not smoke, no differences were found in the odds of low birth weight, preterm birth, and small-for-gestational-age. the results of this study provide a compelling message that smoking ces-sation is not only possible, but critical, for pregnant smokers to reduce the risk of adverse birth outcomes. In addition, our data also show that 1 in 12 Rhode Island women who delivered a live infant during 2012-2014 smoked in the last 3 months of pregnancy, and there were significant disparities among populations in prenatal smoking prevalence.

these new data can be strategically used by providers to communicate the benefits of quitting, increase motivation to quit, and engage pregnant smokers in supportive services that help them quit and stay quit. For example, the Rhode Island tobacco control Program coordinates with the WIc program to promote motivating cessation messages that link pregnant smokers to free, evidence-based telephonic coun-seling specifically tailored to the needs of pregnant women. through the Rhode Island Quitline (1-800-Quit-now), women can access extended counseling during pregnancy and receive relapse prevention counseling through post-par-tum. When offering cessation services to patients, providers can refer pregnant smokers to the Quitline by fax referral so they have extra support.

Pregnancy appears to motivate women to quit smoking: 55% of Rhode Island women who smoked before pregnancy stopped smoking by the last 3 months of pregnancy in 2014.8 While effective interventions such as motivational inter-viewing, brief cessation counseling (the 5 A’s) and supple-mentary referral to the Quitline help many women, some pregnant women are highly addicted to nicotine and require consistent intervention at each health care encounter.3

Health care providers can help increase smoking cessation among pregnant women by routinely integrating tobacco use assessment and cessation interventions into each prenatal care visit.3 As most women have more than 10 prenatal care

visits during pregnancy, providers have multiple opportuni-ties (from the first prenatal care visit throughout the course of pregnancy) to motivate smokers to quit and provide effec-tive cessation interventions.3 It is also recommended that since nearly 40% of pregnancies in Rhode Island are unin-tended, public health efforts should target all reproduc-tive-age women, regardless of pregnancy status or pregnancy intention, to refrain from smoking to reduce maternal, fetal, and infant morbidity and mortality.

References 1. cdc. PRAMs and smoking. Available at www.cdc.gov/prams/

tobaccoandprams.htm2. cdc. trends in smoking Before, during, and After Pregnancy –

Pregnancy Risk Assessment Monitoring system, united states, 40 sites, 2000–2010. MMWR. november 8, 2013 / 62(ss06);1-19. Available at www.cdc.gov/mmwr/preview/mmwrhtml/ ss6206a1.htm

3. American college of obstetricians and gynecologists. smok-ing cessation during Pregnancy. committee opinion. number 471, november 2010.

4. dietz PM, england LJ, shapiro-Mendoza ck, tong vt, Farr sL, callaghan WM. Infant morbidity and mortality attribut-able to prenatal smoking in the united states Am J Prev Med. 2010;39(1):45–52.

5. us department of Health and Human services. Healthy Peo-ple 2020. Atlanta, gA: cdc. Available at www.healthypeople.gov/2020/topics-objectives

6. cdc. PRAMs. Available at www.cdc.gov/prams/7. Research triangle Institute. sudAAn Language Manual, Re-

lease 11.0. Research triangle Park, nc.8. Rhode Island department Health, PRAMs Program. unpub-

lished Manuscript. trends in smoking Before, during, and Af-ter Pregnancy in Rhode Island: Progress toward achieving the Healthy People 2020 objectives.

AuthorsHyun (Hanna) kim, Phd, is the senior Public Health

epidemiologist in the center for Health data and Analysis, Rhode Island department of Health, and Assistant Professor of the Practice of epidemiology, school of Public Health, Brown university.

karine Monteiro, MPH, is the coordinator of the PRAMs Program in the center for Health data and Analysis, Rhode Island department of Health.

elsa Larson, Phd, Ms, is the Program evaluator for the tobacco control Program, division of community Health and equity, Rhode Island department of Health.

dana Mccants derisier, Ms, is the cessation coordinator for the tobacco control Program, division of community Health and equity, Rhode Island department of Health.

disclosure of Financial Intereststhe authors have no financial interests to disclose.

correspondenceHyun (Hanna) kim, Phd Rhode Island department of Health 3 capitol Hill Providence, RI 02908-5097 [email protected]


http://www.cdc.gov/prams/tobaccoandprams.htm

http://www.cdc.gov/prams/tobaccoandprams.htm

http://www.cdc.gov/mmwr/preview/mmwrhtml/ss6206a1.htm

http://www.cdc.gov/mmwr/preview/mmwrhtml/ss6206a1.htm

http://www.healthypeople.gov/2020/topics-objectives

http://www.healthypeople.gov/2020/topics-objectives

http://www.cdc.gov/prams/

mailto:hanna.kim%40health.ri.gov?subject=




(a) Cause of death statistics were derived from the underlying cause of death reported by physicians on death certificates.

(b) Rates per 100,000 estimated population of 1,056,298 (www.census.gov)

(c) years of potential Life Lost (ypLL).

noTe: Totals represent vital events, which occurred in Rhode island for the reporting periods listed above.

Monthly provisional totals should be analyzed with caution because the numbers may be small and subject to seasonal variation.

* Rates per 1,000 estimated population

# Rates per 1,000 live births

VITAl STATISTICS niCoLe e. aLexanDeR-sCoTT, MD, MpH DiReCToR, RHoDe isLanD DepaRTMenT oF HeaLTH CoMpiLeD by Roseann GioRGianni, DepuTy sTaTe ReGisTRaR

Rhode Island Monthly Vital Statistics Report provisional Occurrence data from the division of Vital Records

RepORtING peRIOd

VItAl eVeNtSdeceMBeR 2016 12 MONthS eNdING WIth deceMBeR 2016

Number Number Rates

Live births 924 11,655 11.0*

Deaths 928 10,014 9.5*

infant Deaths 11 66 5.7#

neonatal Deaths 7 52 4.5#

Marriages 376 7,085 6.7*

Divorces 261 3,002 2.8*

induced Terminations 237 2,278 195.5#

spontaneous Fetal Deaths 57 522 44.8#

under 20 weeks gestation 52 448 38.4#

20+ weeks gestation 5 74 6.3#

RepORtING peRIOd

Underlying cause of death categoryJUNe 2016 12 MONthS eNdING WIth JUNe 2016

Number (a) Number (a) Rates (b) Ypll (c)

Diseases of the Heart 149 2,363 223.7 3,846.0

Malignant neoplasms 190 2,243 212.3 5,444.5

Cerebrovascular Disease 34 436 41.3 505.0

injuries (accident/suicide/Homicide) 79 866 82.0 12,604.0

CopD 31 452 42.8 387.5.

PuBlIC hEAlTh





RIMS IBC 405 PROMENADE STREET, SUITE B, PROVIDENCE RI 02908-4811

MEDICAL PROFESSIONAL/ CYBER LIABILIT Y PROPERT Y/ CASUALT Y L IFE/HEALTH/ DISABILIT Y

RIMS INSURANCE BROKERAGE CORPORATION

Second, have great insurance. When things go wrong, your coverage

really matters. For more than 25 years we

have specialized in physicians’ insurance.

Working with multiple insurers allows us

to offer you choice, competitive rates, and

the benefit of one-stop shopping. Call us.

401-272-1050

First, do no harm.

RHODE ISLAND MEDICAL SOCIETY

Are you e-reading

RIMS NOTES: news You Can use

RIMS NOTES is published electronically on alternate Fridays.

The new biweekly e-newsletter exclusively for RIMS members.

Clear.

Concise.

Informative.

Respectful of your time.

Contact Sarah if you’ve missed an issue, [email protected].






Working for you: RIMs advocacy activities

SEPTEMBER 15

Convivi um4Th ANNuAl RIMS MEMBERS

Members and guests are invited to schmooze, graze,

and relax with colleagues while enjoying live music

WATCh fOR YOuR INVITATION ThIS SuMMER!

SAVE ThE dATE

May 1, MondayAMA Advocacy Resource center executive committee conference call

RIMs Board of directors meeting: sarah J. Fessler, Md, President

May 2, tuesdayRIMs Physician Health committee: Herbert Rakatansky, Md, chair

Meeting with chairman Miller, senate Health and Human services committee regarding legislation

department of Health Health services council regarding Rhode Island Hospital and Women & Infants obstetrics certificates of need

Anti-conversion therapy press conference at the state House

Legislative hearings

May 3, WednesdayLegislative Hearings

RIMs Patient safety Initiative committee meeting

May 4, thursdayLegislative Hearings

May 5, Fridaynew england delegation to the AMA and council of new england state Medical societies reception

May 6, Saturdaynew england delegation to the AMA and council of new england state Medical societies spring meeting

May 8, Mondaydepartment of Health Board of nursing meeting

Legislative Hearings

May 9, tuesdayAMA Advocacy Resource center conference call


RIMs Foundation strategic Planning meeting

May 10, Wednesday Board of Medical Licensure and discipline task Force

Meeting of the governor’s opioid overdose Prevention task Force: sarah J. Fessler, Md, President; gary Bubly, Md, Past President

AMA conference call regarding federal health care reform


RIMs nominating committee: sarah J. Fessler, Md, President

citizen Physicians at WAMs

May 11, thursday consultation with Anchor Medical Associates regarding diabetes prevention strategies


sIM grant steering committee: Peter A. Hollmann, Md, vice President

senator Archambault fundraiser

May 12, Fridayconference call with RI AceP regarding political fundraising

diabetes Prevention stakeholders’ group

Bryant university PA Program fundraising gala for Heart Association, officers’ club, newport

May 16, tuesdaycMe directors’ meeting, Waltham, MA: Patrick J. sweeney, Md, MPH, RIMs cMe chair; RIMs staff

oHIc Health Insurance Advisory committee

senate Majority Leader Mccaffrey fundraiser

May 17, WednesdayRI department of Health’s Primary care Physician Advisory committee

Meeting with Brown medical students regarding citizen Physician

governor’s Food strategy event, state House

Legislative Hearings

senator goldin fundraiser

May 18, thursdayRIMs Foundation consultant interview


House HeW chair Mcnamara fundraiser

May 19, Friday RI Workers compensation Reform 25th Anniversary celebration

conference call with Blue cross dental coverage

May 23 tuesdayLegislative hearings

May 25, thursdayRIMs Foundation strategic planning

May 26, FridayPresentation of two RIMs awards to graduating medical students: sarah J. Fessler, Md, President

May 30, tuesdayMeeting with WAMs faculty regarding special projects

May 31, Wednesdaysenator Lombardi fundraiser

non-Patient centered Medical Home (PcMH) small Practice engagement meeting






MAcRA symposium planned for June 20

Are you ready for MAcRA? Are you struggling to understand what MAcRA means for your organization? Are you having trouble preparing for this new payment program?

our MAcRA symposium will provide expert guidance to help you to better understand the quality payment program, the impact on healthcare providers, and how you can best prepare. A panel discussion of local healthcare professionals will discuss their concerns and how they’re preparing.

JUNe 20, 7:30AMnew england Institute of technology 1 new england tech Boulevard east greenwich

AGeNdA

7:30–8:00 amRegistration/ Breakfast/networking

8:00–9:00 amthe Mechanisms of MAcRA Reporting:

MIPs and APM tracksLeila Volinsky, MHA, MSN, RN

Program Administrator, Massachusetts, Healthcentric Advisors

9:10–10:10 amdemystifying MAcRATerrence McWilliams, MD, MSJ, FAAFP

Chief Clinical Consultant, HSG

10:20–11:50 amPanel discussion

Rhode Island Responses and Perspectives

Moderator:Peter Hollmann, MD

Chief Medical Officer, University Medicine

Panelists:Alan Kurose, MD, MBA, FACP

President & CEO, Coastal Medical

Ann Kashmanian, CPA, MBA Chief Financial Officer & Compliance Officer University Medicine

Lauren Capizzo, MBA, PCMH CCE Director, Practice Transformation Healthcentric Advisors

Healthcentric Advisors is accredited by the Massachusetts Medical society to provide continuing medical education for physicians.

this program has been developed and is presented locally by AcHe-RI. the American college of Healthcare execu-tives has awarded 1.5 AcHe Face-to-Face education credits to this program.

As an independent chartered chapter of the American college of Healthcare executives, AcHe-RI is also autho-rized to award two hours each of AcHe Qualified education credit toward advancement or recertification in the Amer-ican college of Healthcare executives. Participants in this program who wish to have it considered for AcHe Quali-fied education credit should list their attendance when they apply to the American college of Healthcare executives for advancement or recertification.

the event is co-sponsored by: Rhode Island Medical society Hospital Association of Rhode Island Healthcentric Advisors

click here to register

For further information, contact: Amanda Barney [email protected].


https://events.r20.constantcontact.com/register/eventReg%3Foeidk%3Da07ee61qwmf3871df43%26oseq%3D%26c%3D06fcdd20-f037-11e4-bd1b-d4ae52712b64%26ch%3D07020d40-f037-11e4-bd1b-d4ae52712b64

mailto:amandab%40hari.org?subject=MACRA%20Symposium




The Rhode Island Medical Society now endorses Coverys.

It’s a new day.

Coverys, the leading medical liability insurer

in Rhode Island, has joined forces with RIMS

to target new levels of patient safety and

physician security while maintaining competitive

rates. Call to learn how our alliance means a

bright new day for your practice.

401-331-3207

The Rhode Island Medical Society now endorses Coverys.

r i m s c o r p o r a t e a f f i l i a t e s

[email protected]

The Rhode Island Medical Society continues to drive forward into the future with the implementation of various new programs. As such, RIMS is expanded its Affinity Program to allow for more of our colleagues in healthcare and related

business to work with our membership. RIMS thanks these participants for their support of our membership.

Contact Marc Bialek for more information: 401-331-3207 or [email protected]

Neighborhood Health Plan of Rhode Island is a non-profit HMO founded in

1993 in partnership with Rhode Island’s Community Health Centers. Serving

over 185,000 members, Neighborhood has doubled in membership, revenue

and staff since November 2013. In January 2014, Neighborhood extended its

service, benefits and value through the HealthSource RI health insurance ex-

change, serving 49% the RI exchange market. Neighborhood has been rated by

National Committee for Quality Assurance (NCQA) as one of the Top 10 Med-

icaid health plans in America, every year since ratings began twelve years ago.www.nhpri.org

www.ripcpc.com

Doctor’s Choice provides no cost Medicare consultations.

Doctor’s Choice was founded by Dr. John Luo, a graduate of the

Alpert Medical School at Brown University to provide patient

education and guidance when it comes to choosing a Medicare

Supplemental, Advantage, or Part D prescription plan. Doctor’s

Choice works with individuals in RI, MA, as well as CT and

helps compare across a wide variety of Medicare plans including

Blue Cross, United Health, Humana, and Harvard Pilgrim.

RIPCPC is an independent practice association (IPA) of primary care phy-

sicians located throughout the state of Rhode Island. The IPA, originally

formed in 1994, represent 150 physicians from Family Practice, Internal

Medicine and Pediatrics. RIPCPC also has an affiliation with over 200

specialty-care member physicians. Our PCP’s act as primary care providers

for over 340,000 patients throughout the state of Rhode Island. The IPA was

formed to provide a venue for the smaller independent practices to work

together with the ultimate goal of improving quality of care for our patients.


RIMs: your voice for 200+ yearsJoin your colleagues and add your voice

Membership in The Rhode Island Medical Society (RIMS) makes you a part of a dynamic network of physicians, resi-dents, students, physician assistants, and healthcare profes-sionals who represent, like you, the best of the profession.

The ABCs of membershipAdvocacy: RIMs membership offers a cohesive platform for its members to speak with a unified voice on local, state and national issues through committee participation, policy development, legislative representa-tion, educational conferences, and stakeholder seminars.

Benefits: cMe sessions, physician health services, preferred career, financial and personal services from our sponsors, membership portal.

Collegiality: social events, networking opportunities, professional development.

Strength: In numbers. If you are already a member, thank you for your support. If you’re not, join us today. group, military and new practitioner discounts; medical students join for free.

click here to learn more.

contact Mark Bialek, director of Membership

RiMs Leadership: Treasurer José polanco, MD; secretary Christine brousseau, MD; president-elect bradley J. Collins, MD; president sarah J. Fessler, MD; vice president peter a. Hollman, MD; and (seated) immediate past president Russell a. settipane, MD.

a RiMs Mix and Mingle event was held at the Chapel Grille restaurant

in Cranston on april 11.

a Rhode Island Academy of physician Assistants (Riapa) town hall

meeting was held april 11 at kent Hospital on pa practice in the state.

Representatives from the state and national pa organizations and the

Rhode island Department of Health and the Rhode island Medical society

participated in a series of meetings and updates on recertification and

looking at the future of pa practice in the state.

The Rhode island Medical society’s annual cMe event was held on

april 22 at the warwick Country Club. This year’s focus was on building

practitioner Resilience in Challenging Times.






A. LOUIS MARIORENZI, M.D. ARTHROSCOPIC SURGERY*

LOUIS J. MARIORENZI, M.D. JOINT REPLACEMENT SURGERY

GREGORY J. AUSTIN, M.D. HAND SURGERY

MICHAEL P. MARIORENZI, M.D. SPORTS MEDICINE

CHRISTOPHER N. CHIHLAS, M.D. ORTHOPAEDIC SURGERY

KENNETH R. CATALLOZZI, M.D. GENERAL ORTHOPAEDICS

725 Reservoir Avenue, Suite 101 Cranston, RI 02910 • (401) 944-3800

Orthopaedic Associates, Inc.

Orthopaedic Medicine and Surgery with subspecialty expertise*

IRA J. SINGER, M.D. RECONSTRUCTIVE SURGERY AND SPORTS MEDICINE

SIDNEY P. MIGLIORI, M.D. RECONSTRUCTIVE SURGERY AND SPORTS MEDICINE

JOSEPH T. LIFRAK, M.D. GENERAL ORTHOPAEDICS AND SPORTS MEDICINE

LISA K. HARRINGTON, M.D. ADULT RHEUMATOLOGY

ROBERT J. FORTUNA, M.D. GENERAL ORTHOPAEDICS

NATHALIA C. DOOBAY, D.P.M. MEDICINE AND SURGERY OF THE FOOT AND ANKLE

2138 Mendon Road, Suite 302 Cumberland, RI 02864 • (401) 334-1060

RIMS gratefully acknowledges the practices who participate in our discounted Group Membership Program

For more information about group rates, please contact Marc Bialek, RIMS Director of Member Services

IN ThE NEWS

Alpert Medical School, 6 foundations partner to form Brown physicians, Inc. Physician groups include: The Neurology Foundation, Inc.;

University Emergency Medicine Foundation; University

Medicine Foundation; University Surgical Associates, Inc.;

Brown Urology, Inc.; and Brown Dermatology, Inc.

pRoviDenCe – six physician practice foundations have agreed to form a new physician-led federation, Brown Physicians, Inc., in partnership with the Warren Alpert Medical school of Brown university.

Members of the corporation of Brown university joined the presidents of the six foundations in signing a formal agreement at a ceremony at Brown May 25, to create the non-profit Brown Physicians, Inc. (BPI). the foundations are: the neurology Foundation, Inc.; university emergency Med-icine Foundation; university Medicine Foundation; uni-versity surgical Associates, Inc.; Brown urology, Inc.; and Brown dermatology, Inc.

the agreement will take effect on July 1, 2017. At the outset, the foundations will retain their status as individual corporations within the BPI federation. caliendo said the agreement outlines parameters for further integration in the future to achieve evolving goals for expansion and growth.

In forming the partnership, both the physician practice foundations and Brown’s medical school will invest finan-cially to ensure BPI’s success in both the short and long term. the university will contribute funds toward oper-ations during BPI’s first decade and raise funds to endow professorships and make new hires within the partnership. Meanwhile, the members of the foundations will contribute a modest percentage of revenues toward supporting research and other academic activities.

together, the six foundations employ more than 500 doc-tors, all of whom are also members of the Warren Alpert Medical school faculty, and many of whom work side-by-side in local hospitals with physicians and other health care providers employed by the hospitals.

dR. JACK A. ElIAS, senior vice president for health affairs and dean of medicine and biologic sciences at Brown, will join the presidents of the foundations and a second Brown appointee to form BPI’s board of directors. He said the new organization will enable enhanced partnership between the foundations, Brown and its affiliated hospitals as they seek to develop new therapies in laboratories and deliver the best medical care in clinical settings.

“I look forward to working with my colleagues to identify and implement a strategic approach that will help clinicians across important specialties identify efficient, effective ways to improve care for patients across the region,” elias said. “BPI will yield new opportunities for our Brown medical students, focus resources on urgent areas of inno-vative research and enhance our ability to hire the best physician-scientists.”

discussions on the effort to form BPI began among Brown’s medical school leaders, clinical faculty and affiliated health

care providers approximately five years ago, elias noted, and the partners worked over the last 15 months to outline an agreement.

dR. ANgElA CAlIENdO, vice president of university Medicine and BPI’s interim executive director, said the foundations and their physicians will experience many ben-efits from sharing administrative resources, such as greater operating efficiency.

“Forming BPI is an important step, as it provides the foun-dations with the opportunity to enhance coordination of care, improve the quality of care for patients in RI and the region, better position us for success in the changing healthcare environment, and facilitate partnerships with the hospitals,” said caliendo, who is also a professor of medicine at Brown. “the creation of BPI also underscores our commitment to the research and teaching missions of the medical school.”

elias and caliendo noted that the potential for improved patient care in the region is an important focus of the agree-ment. While patients of the six foundations will face no practical changes to how they receive care, they stand to benefit from enhanced administrative and medical coordina-tion. over the longer term, greater collaboration on research can lead to the development of advanced therapies that will ultimately benefit patients.

“We believe that collaborating with our clinical partners to more tightly integrate patient care, research and education will result in a significant and positive impact on the local community,” said university President christina Paxson.

the creation of BPI will enhance the ability of its mem-bers to serve the community’s health care needs, Paxson explained, to optimally educate the next generation of med-ical professionals, to grow combined research portfolios, and to contribute to the state’s plans to cultivate a thriving bio-medical economy in Providence and the greater region. v

dr. Jack A. elias, senior vice president for health affairs and dean of med-icine and biologic sciences at brown, signs a new agreement creating bpi as dr. Angela caliendo, vice president of university Medicine Foundation and interim executive director of bpi looks on.

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IN ThE NEWS

New Secretary of Veterans Affairs, dr. david J. Shulkin, visits providence VA, Veterans home

pRoviDenCe – the new secretary of veterans Affairs, dR.

dAVId J. ShulKIN, visited Rhode Island May 5 to partic-ipate in a cornerstone ceremony at the Rhode Island state veterans Home and visit the Providence vA Medical center.

After the ceremony, the secretary traveled to the Provi-dence vAMc, and received a tour of the virtual Reality lab. dr. noah Philip, director of the neuromodulation clinic, described non-invasive brain stimulation research that will help veterans suffering from Ptsd.

shulkin was then shown dekA, the first computer- driven prosthetic arm capable of multiple simultaneous movements.

next was a tour of the virtual Reality and Motion Analysis Rehabilitation Lab-oratory. dr. susan d’Andrea, lab director, said the system creates realistic and chal-lenging virtual environments for training and rehabilitation.

the secretary then received briefings on selected research and facility achieve-ments, and discussed his priorities.

shulkin said that vA strategy is focused on transparency, and that new access and quality of care information is now avail-able to veterans on the vA access web-site, www.accesstocare.va.gov.

dR. lEIgh hOChBERg, director of the vA center for neurorestoration and neurotechnology, gave a presentation on Braingate, a neuroscience consortium that includes Brown university and the PvAMc, and research on new technologies for brain-computer interface.

dR. JAMES RudOlPh, director of the center of Innovation in Long-term services and supports for vulnerable veterans, gave

dr. Susan d’Andrea, director of the virtual Reality and

Motion analysis Rehabilitation Laboratory, demonstrates

to veterans affairs secretary dr. david Shulkin and Sen.

Jack Reed a virtual reality system that creates virtual envi-

ronments and uses motion-capture cameras to animate an

avatar in the virtual environment based on the motion of

an individual walking on a treadmill in the real world. she

said the system provides effective training by creating re-

alistic and challenging environments with accurate visual

perception of a motor task being performed by the user.

a briefing on research to improve the access, qual-ity and value of care for veterans in nursing homes.

shulkin concluded his visit by challenging Providence vAMc and Rhode Island officials to effectively end veterans homelessness in the state within the next few years, noting the progress already made and how close they are to the goal.

Prior to the cornerstone ceremony, the sec-retary toured the new 208-bed veterans Home,

located on the site of the current Rhode Island veterans Home in Bristol, with gov. gina Raimondo, sen. Jack Reed, sen. sheldon Whitehouse, Rep. Jim Langevin, Rep. david cicilline, kasim yarn, director of the Rhode Island office of veterans Affairs, dr. susan Mackenzie, director of the Providence vAMc, e.J. McQuade, director of the Providence vBA Regional office, and other state and local officials.

scheduled to open in the fall, the facility is being built using new federal design guidelines that maximize independent living. v

dr. leigh hochberg, director of the va Center for neurorestoration and

neurotechnology, left, shows secretary of veterans affairs dr. david

Shulkin, right, and dr. Satish Sharma, providence vaMC chief of staff,

a device for brain-computer interface during a presentation on brain-

Gate, a neuroscience consortium that includes brown university and the

providence va Medical Center.

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http://www.accesstocare.va.gov/




Quit Smoking Study! Refer Your Female Patients

Enrolling participants until 2018!

• Group program at RI Hospital and nicotine patches at no cost

• Compensation and free parking

WE QUIT is enrolling women who want to quit smoking and are concerned about gaining weight after quitting.

Please contact us to request flyers to display in your waiting rooms or exam rooms or to give directly to patients.

Dr. Bloom can also visit your practice to provide more information about WE QUIT.

Phone: 401-450-2731 Email: [email protected]

www.lifespan.org/studies-for-women/WE-QUIT.html

WE QUIT is funded by the National Institutes of Health

Dr. Bloom is a clinical psychologist at RIH and University Medicine and faculty at the Alpert Medical School of Brown University.

Director: Erika Litvin Bloom, PhD

Southcoast health opens Urgent care center in Seekonk

at the ribbon-cutting ceremony for southcoast Health’s new urgent Care center, were, from left, Chief Michael Healy, seekonk Fire Department; nelia

o’Donnell, urgent Care staff; Lori Minor, urgent Care staff; Captain sandra Lowry, seekonk Fire Department; karen scott, urgent Care Manager; kelly

Houde, urgent Care practice administrator; Dr. pamela spatz, urgent Care Medical Director; Renee Clark, Coo of southcoast Hospitals Group; keith

a. Hovan, president & Ceo of southcoast Health, shawn Cadime, seekonk Town administrator; Representative steven Howitt; brad silverman, urgent

Care executive Director; Jeff Harris, Chairperson of seekonk economic Development Committee, Marigloria Murphy, urgent Care staff; Diane sweet,

urgent Care staff; and Rebecca Finlaw, urgent Care staff.

health insurers to end prior authorization for opioid dependency medications Agreements reached with all of Rhode Island’s major commercial insurers

CRansTon – dR. KAThlEEN hITTNER, Health Insurance commissioner for the state of Rhode Island, has executed agreements with all major commercial health insurers in the state to end the practice of requiring prior authorization for certain prescription drugs used to treat patients with opioid dependence disorders.

“I am very pleased to announce these agreements, which will greatly improve access to necessary medications for patients with opioid dependence dis-orders,” dr. Hittner said. “Working together with Rhode Island’s health insurers, we’ve found a way to streamline processes for coverage of these treatments. I am grateful for the insurers’ collabora-tion and commitment to fighting this public health crisis.”

All four major health insurers – Blue cross & Blue shield of Rhode Island, neighborhood Health Plan of Rhode Island, tufts Health Plan, and united Healthcare – joined in the agreement to eliminate prior authorizations for patients pre-scribed medications such as buprenorphine and suboxone. the agreements will allow opioid dependent patients more timely access to medications.

the office of the Health Insurance commissioner is currently conducting a Market conduct examination for Mental Health and substance Abuse Parity. commissioner Hittner said the ongoing examination “led my staff and me to reach out to the insurance carriers and begin to consider ways to improve access to MAt.” v

seekonk – southcoast Health opened its new urgent care center May 1. the 4,800 square-foot center provides imme-diate, non-emergency care. It is staffed by a specialized team of physicians, mid-level providers and a number of ancillary and support staff, and offers a full array of services including on-site radiology and laboratory services, basic orthopedics, gynecologic and minor surgical treatments, and medications.

open seven days a week, the center treats both adults and children (6 months of age and older). Walk-ins are welcome,

and no appointment is needed. Patients are not required to have a southcoast primary care physician, and the patient’s primary care physician is electronically alerted to the visit.

Patients seeking services can now use a new online check-in system. visitors to www.southcoast.org/urgentcare can find the closest center, its current wait time and click “save My spot” to get in line electronically.

the new facility in seekonk is southcoast Health’s fourth urgent care center.


IN ThE NEWS




Offering daily mass and rosary. A health care ministry of the Roman Catholic Diocese of Providence.

- We serve the physical, social, emotional and spiritual needs of older adults and their families- New Rehab Center “Easy Street”, the road to independence

- Located on a beautiful campus in North Smithfield, RI

the Villa at Saint AntoineThe UlTimaTe in assisTed living

401.767.2574

Saint Antoine Residenceexcellence in nUrsing

and rehabiliTaTive care 401.767.3500

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“Easy Street”The rehab cenTeraT sainT anToine

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Southcoast health partners with Stratus Video to improve care for limited english proficiency and deaf/hard-of-hearing patientsHealth system offers video remote interpretation for patients throughout Southeastern Mass.

new beDFoRD – southcoast Health has partnered with language access and telehealth company, stratus video, to better serve its limited english profi-ciency (LeP) and deaf/Hard-of-Hearing patients. the community-based health system now provides easy access to video remote interpretation (vRI) at all three of its hospitals in southeastern Massachusetts.

ever-expanding language diversity, coupled with evolving federal regula-tions of the Americans with disabili-ties Act (AdA), has brought on-demand interpreting from a “nice-to-have” to “mission-critical” for health systems looking to provide quality care for all patients. For southcoast Health, there

were 42,195 interpretation requests across all of its hospitals in Fy 2015, of which 24,486 were for spanish, alone. the health system realized the need to offer its diverse patient population access to a broader array of simple and effective communication tools.

“We are very focused on leverag-ing innovation to promote health and well-being in the communities and populations we serve, and our LeP population is no exception,” said dR.

ROBERT CAldAS, chief Medical offi-cer and senior vice President of south-coast Health. “We have been so pleased with how stratus video Interpreting has helped enhance communication and care delivery in our hospitals that

we are now beginning to discuss rolling the vRI technology out to our affiliated physician practices.”

stratus video Interpreting combines the benefits of face-to-face interpre-tation with the on-demand nature of over-the-phone interpretation. the mobile app is easy to use and can be loaded onto any tablet, smartphone, desktop or laptop, giving users instant access to medically qualified interpreters at a push of a button. on the back-end, the technology incorporates sophisticated automation and intelligent routing, enabling easy integration into existing processes and workflows. v


IN ThE NEWS




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Let’s fight togetherAetna is proud to support the members of the Rhode Island Medical Society.

Aetna is the brand name used for products and services provided by one or more of the Aetna group of subsidiary companies, including Aetna Life Insurance Company and its affiliates (Aetna).

©2016 Aetna Inc. 2016024

Blackstone Valley Surgicare acquired by chartercARe health partners

ann Dugan, administrator, is pictured discuss-

ing blackstone valley surgicare’s capabilities

with Johnston Mayor Joseph polisena and John

Holiver, CharterCaRe Ceo.

JoHnsTon – Blackstone valley surgicare, an ambulatory surgery center in Johnston, has been acquired from surgi-cal care Affiliates by chartercARe Health Partners. the purchase was approved by the Rhode Island department of Health last month.

“this acquisition will ensure chartercARe patients with direct access to a complete range of outpatient sur-gery procedures and will continue the process of complet-ing our service capabilities,” said chartercARe President and ceo John Holiver.

“We are delighted to become part of the chartercARe network”, said Blackstone Administrator ANN dugAN.

OffICE SPACE AVAIlABlEThe Rhode island Medical society has 442

square feet of newly renovated office space

(3 contiguous offices of 200 sq ft, 121 sq ft

and 121 sq ft), complete with convenient sheltered parking

and the opportunity for tenants to share three well-equipped

meeting spaces, break room, office machinery, etc. on the

western edge of downtown providence. suitable for a small

non-profit organization, boutique law firm, Cpa firm or other

office-based small business.

inquiries to Newell Warde, [email protected]

“chartercARe’s breadth of services, contracting expertise and capital strength will ensure stability and growth for our organization in the years ahead.”

Blackstone valley surgicare is fully licensed by the state of Rhode Island, certified by Medicare and accredited by AAAHc, and accepts all major insurance. v


IN ThE NEWS




One Call Does It All!401-354-7115

Phone: 401-354-7115Email: [email protected]

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Rhode Island’sMedical Staffing Experts!

As a Valued Sponsor of the Rhode Island MedicalSociety, Favorite Healthcare Staffing provides acomprehensive range of staffing services atpreferred pricing to RIMS members.

Serving the Rhode Island healthcare communitysince 1981, Favorite continues to set the standardfor quality, service, and integrity in medicalstaffing. Call today and let us show you why weare The Favorite Choice of Physician Practicesand Healthcare Professionals across the US!

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Rhode Island Medical Society

Women & Infants awarded $12.2M NIh grantFirst COBRE of its size, only one in the U.S. to focus on women’s health

Research evaluates effectiveness of yoga in treating major depressionResearch led by Lisa Uebelacker, PhD, published in Psychological Medicine

Women & Infants Hospital has been awarded a $12.2 million national Institutes of Health (nIH) center of Biomedical Research excellence (coBRe) grant to boost interdisciplin-ary research related to women’s reproductive health. this is the first coBRe of its size and the only one to focus on women’s health.

“While there are physiological changes in response to pregnancy, some of these changes persist later in life,” said SuRENdRA ShARMA, Md, Phd, a research scientist and professor in the department of Pediatrics at Women & Infants Hospital and the Warren Alpert Medical school. “the question that remains unanswered is how complica-tions suffered by a woman during pregnancy provide insight into other future adverse health outcomes.”

dr. sharma will serve as the principal investigator for the coBRe for Reproductive Health. MAuREEN g. PhIPPS,

Md, MPh, chief of obstetrics and gynecology at Women & Infants, will serve as deputy director of the program.

Four investigators will be participating at Women & Infants Hospital:

lYNAE BRAYBOY, Md, a reproductive endocrinologist, proposes a study on the prediction of preeclampsia and gestational diabetes in in vitro fertilization (IvF) patients.

ShIBIN ChENg, Md, Phd, a research scientist, will continue his studies into preeclampsia, which also focuses on the concept that preeclampsia may be a prelude to Alzheimer’s disease, a significant disease affecting women later in life.

BEATRICE lEChNER, Md, a neonatologist, will continue her studies into complications causing pre-term birth. Along with a high rate of mortality in newborns, preterm birth has also been associated with a high rate of mortality in moth-ers, suggesting its long-term health effects on women.

JESSICA S. SChuSTER, Phd, instructor of pediatrics and a computational biologist in the department of Pediatrics, will continue her study which focuses on women diagnosed with severe preeclampsia and on using contemporary math-ematical and computer science approaches to find answers to scientific questions related to preeclampsia. v

When treating depression, traditional treatment such as medication or psychotherapy is effective for many patients, some may not fully recover even with these treatments. Research-ers sought to determine if the addition of hatha yoga would improve treat-ment outcomes. they found that the benefits of yoga were less pronounced early in treatment, but may accumu-late over time.

the research, entitled “Adjunctive yoga v. health education for persistent major depression: a randomized con-trolled trial,” has been published in Psy-chological Medicine. the research was led by lISA uEBElACKER, Phd, a research psychologist in the Psycho-social Research department at Butler Hospital.

“the purpose of this study was to examine whether hatha yoga is effec-tive for treating depression when used in addition to antidepressant medi-

cation,” explained dr. uebelacker. “We did not see statistically significant differences between hatha yoga and a control group (health education) at 10 weeks, however, when we examined outcomes over a period of time includ-ing the three and six months after yoga classes ended, we found yoga was supe-rior to health education in alleviating depression symptoms.”

According to dr. uebelacker, this is the largest study of yoga for depression to date. the team enrolled individuals with current or recent major depres-sion who were receiving antidepressant medication and continued to have clin-ically significant depression symptoms. Participants were randomized into two groups – those who participated in a hatha yoga class and a control group who took part in a health education class. the intervention phase lasted 10 weeks and participants were followed for six months afterward.

“We hypothesized that yoga partic-ipants would show lower depression severity over time as assessed by the Quick Inventory of depression symp-tomatology (QIds), as well as better social and role functioning, better general health perceptions and physi-cal functioning, and less physical pain relative to the control group,” said dr. uebelacker. “We found that yoga did indeed have an impact on depression symptoms.

the team also included gary epstein-Lubow, Md; Ana M. Abrantes, Phd; Audrey tyrka, Md, Phd; Brandon A. gaudiano, Phd; and Ivan W. Miller III, Phd, of Butler Hospital and the Warren Alpert Medical school; geof-frey tremont, Phd and tanya tran of Rhode Island Hospital and the Warren Alpert Medical school; tom gillette of eyes of the World yoga; and david strong of the university of california, san diego. v


IN ThE NEWS




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Appointments

Jonathan Kurtis, Md, phd, named inaugural Stanley M. Aronson professor

Jonathan kurtis, Md, Phd, director of the center for International Health Research (cIHR), Rhode Island Hospital, and Pro-fessor of Pathology and Laboratory Med-icine at the Alpert Medical school, has been appointed the inaugural stanley M. Aronson Professor. the professorship was established by Alice Montag tisch P’18, P’20 and thomas tisch ‘76, P’18, P’20 in

honor of the founding dean of Brown’s medical school, the late stanley M. Aronson, Md.

dana levy Guyer, Md, named medical director, hope hospice & palliative care dana Levy guyer, Md, has been named medical director of Hope Hospice & Pal-liative care Rhode Island, where she will serve as the physician member of the Rhode Island Hospital interdisciplinary palliative care team.

Formerly, dr. guyer worked as a primary care physician and palliative care consultant at Martha’s vineyard Hospital. she served as medical director at Hospice of Martha’s vineyard and was the palliative care consultant at Martha’s vineyard Hospital oncology clinic.

Jack A. elias, Md, named inaugural Senior Vice president for health Affairs dean of Medicine and Biological sciences Jack A. elias, Md, has been appointed the inaugural senior vice President for Health Affairs at Brown university. In this posi-tion, dean elias will continue to oversee the Alpert Medical school and the divi-

sion of Biology and Medicine’s components of the Brown In-stitute for Brain science (BIBs). He will also oversee the newly constituted Brown Institute for translational sciences (BIts) and Brown Biomedical Innovations Inc. (BBII).

Recognition

elaine c. Jones, Md, honored by American Academy of Neurologyelaine c. Jones, Md, FAAn, has received the kenneth M. viste, Jr, Md “Patient Ad-vocate of the year Award for 2017” from the American Academy of neurology (AAn). she currently serves on the AAn Board of directors.

dr. Jones has served as president of the Rhode Island Medical society, treasurer of the RI Medical Political Action commit-tee, (RIMPAc), vice-chair of the Public Laws committee and co-chair of the Membership committee. dr. Kenneth chen receives Beckwith Family Award kenneth k. chen, Md, was recently presented with the department of Medicine’s Beckwith Family Award for outstanding teaching at the Warren Alpert Medical school.

dr. chen is director of the division of ob-stetric and consultative Medicine and co- director of the Integrated Program for High-Risk Pregnancy at Women & Infants Hospital.

Recipients of the award are nominated and chosen by students, residents, fellows, physicians, and program/course directors in Brown’s department of Medicine. dr. linda Resnik recognized for work with veterans dr. Linda Resnik, a research scientist with the Providence vA Medical center, has been awarded the Paul B. Magnuson Award for her work with veterans who have experienced upper-limb loss. It is presented annually to a vA investigator who exemplifies entrepreneurship, hu-manitarianism and dedication to veterans.

Resnik directed the department of vet-erans Affairs (vA)-funded optimization study, which led to the approval of the Life under kinetic evolution Arm for veterans with upper-limb amputation.

William h. Sabina, Md, named physician of the Year at South county hospitalWilliam H. sabina, Md, chief of emergen-cy medicine at south county Hospital, was named 2016 Physician of the year. ceo Lou giancola described dr. sabina as “incredibly dedicated,” making a positive

impact on south county Health as chief of the emergency de-partment, past president of the medical staff, chairman of the utilization review committee and as a former member of the board of trustees.

PeoPle/Places


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PHYSICIANS DESERVE

ROBERT EMMETT CuRRAN, JR, Md, 76, of seekonk, MA, passed away peace-fully at his home on May 2, 2017 with his family by his side.

He graduated cum laude from the col-lege of the Holy cross in Worcester, MA in 1962. He graduated from cornell Med-ical college in new york city in 1966 where he was inducted into the Alpha

omega Alpha Academic Honor society in his third year.He completed residencies at cornell/new york Hospital

Medical center in new york city; the national cancer Insti-tute at the national Institutes of Health in Bethesda, Md; and the Wilmer Institute at the Johns Hopkins Hospital and uni-versity in Baltimore, Md; and completed a fellowship at the children’s Hospital Medical center in Boston, MA .

dr. curran had a private ophthalmology practice in Pawtucket, for 42 years. He served as the chief of the division of ophthal-mology at Memorial Hospital in Pawtucket from 1977–2013.

He was also clinical Assistant Professor of surgery in ophthal-mology at Brown Medical school from 1977–2016 where he was awarded multiple distinctions for teaching at the eye clinic at Rhode Island Hospital.

over the course of his career, dr. curran published sixteen scientific papers on topics ranging from internal medicine to pediatric ophthalmology.

He is survived by his wife, Margaretta “Peggy” cox curran; his children Robert emmett curran, III and wife Meredith Wirsching of seattle, WA; trevor McIntosh curran of seekonk; and victoria cox curran and husband trevor eppehimer of salisbury, nc; his grandchildren grace and nicholas; his sis-ter kitty Barrett; his brothers-in-law Robert cox, esq., douglas cox, and Jack gallagher; his sisters-in-law kate cox, dr. kath-ryn cox; and cousin Richard curran. He also leaves numerous nieces and nephews who loved their uncle Bob.

donations in his memory may be made to the comprehensive cancer center at the Miriam Hospital cancer center, 164 summit Avenue, Providence, RI 02906.

obituary

St. Joseph School of Nursing graduates 115th classnoRTH pRoviDenCe – the st. Joseph school of nursing, located on the campus of our Lady of Fatima Hospital in north Providence, held graduation ceremonies for its 115th class on May 15, 2017.

graduates in the 115th class are:Miranda Accaputo, sarah Bolano,

Bryana Borrayo, nicole Brouillard, Michelle downer-Pinero, stephanie drewniak, Alexis durfee, Maeghan goff, sadie Hodges, Ashley Ianni, kayla Joseph, nicole Ladebauche, nicole Lajoie, Heather Lallier, Heather La-Pointe, Julie Lee-Alvarez, keri-Lynn Manfredo, carissa Mckendall, katerina

• the Faculty certificate of Merit for out-standing ability in Psychiatric nursing was awarded to chelsey sarachick.

• the Faculty certificate of Merit for out-standing ability in Parent child Health nursing was awarded to Angel Zuleta.

• the Mother Mary evangelist award given by the Alumni Association of st. Joseph school of nursing in recognition of scholastic achievement, professional leadership and nursing performance was awarded to Jenny santana. v

Michalopoulos, shana Mills, sheri Mo-rales, Bridget Murphy, Lindsay nardella, kerri nicolace, Ashley norberg, Laura Patota, kimberly Provencal, Hannah Rigney, katherine Rodriguez, Jenny santana, chelsey sarachick, Franchesca sevigny, Brenda White, Madeline yorty, and Angel Zuleta.

the following awards were given to members of the 115th graduating class:

• the Faculty certificate of Merit for outstanding ability in Medical/ surgical nursing was awarded to chelsey sarachick.

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100 YEARS AgO – JuNE 1917

Scientific feeding of the people in wartimeMuch has been written in these anxious times concerning the conservation of food, and the necessity for planting a greatly increased acre-age in this country in order to offset the losses occasioned by decreased planting in europe,

by submarine activities and by poor crops. More important than the conservation of food, as necessary as that is known to be, is the proper nutrition of the people. this can be accom-plished by an intelligent super-vision of the dietary, so that the greatest number of caloric units may be obtained from the smallest intake of food, and the elimination of expensive food and those of low caloric value. the greater

necessity of proper nutrition for everyone in these times of unusual stress has been appreciated by local organizations of which the Housewives League is an example. In conjunction with other organizers working along similar lines, a series of demonstrations on the proper selection of a dietary are being

poster from the u.s.

Department of agriculture

encouraging americans

to grow their own food

to combat the shortages.

women of the national Housewives League in a car with a sign “use perishables,” in 1917.

The Rhode island branch of the organization was very active throughout the war.

planned at neighborhood clubs, factories and department stores. this is an endeavor in which physicians can be of especial help. It should be a patriotic duty for us to offer gra-tuitous advice on the proper feeding of the family in every home we visit. We can outline a proper diet producing the greatest caloric value which will at the same time be palatable and help to conserve the food supply of the country. special attention should be paid to the diet of babies and in growing

children in order that the unfortunate experi-ence of some european countries shall not be repeated in this coun-try. It is more important than ever before that the milk supply shall be maintained at the high-est possible standard.

It should be a

patriotic duty

for us to offer

gratuitous advice

on the proper

feeding of the

family in every

home we visit.

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Editorial






MiscellaneousHospital units for mental and nervous disordersThe National Committee for Mental Hygiene has created a subcommit-tee on furnishing hospital units for nervous and mental disorders to the united states government; the project has been approved by surgeon general W.c. gorgas of the us Army.

this subcommittee is authorized to secure the services of alienists and neurologists to be commissioned in the officer Reserve corps, medical section, to serve in the neuropsychi-atric units which are to be attached to the base and other hospitals of the military services of the united states. Further information will be given, and application forms sent to physicians qualified in this branch of medicine, on application by letter or in person to the national committee for Mental Hygiene, 50 union sq., new york city.

newport Medical SocietyA meeting was held May 17, 1917 at 8:30 PM at the Historical society building. dr. H.g. giddings of the Boston city Hospital spoke on drug store prescribing in venereal diseases.

Mary E Baldwin, MD, secretary

off to warDr. Murray S. Danforth has left for Washington to join the orthopedic unit which is to sail to europe for service under the British government.

returned from warDr. Herman C. Pitts has recently returned from service in France, where he was one of the surgical staff of the Harvard unit.

Providence City HospitalArrangements have been made with the naval authorities at newport whereby cases of contagious diseases, including tuberculosis, will be cared for in the city Hospital if the necessity arises.

St. Joseph’s Hospitalthe graduating exercises of the Train-ing School for Nurses were held on the evening of May 22 at the eloise, Franklin street. the class consists of nine nurses. dr. Arthur H. Harrington of the state Hospital for the Insane delivered the graduation address.

necrologyDr. Henry W. Burnett, widely known as a specialist in children’s diseases, died at his home, 167 Lloyd Ave., May 7, 1917. dr. Burnett was born in new york city in 1873. He graduated from Long Island college Hospital and later attended king’s county Hospital and Harvard graduate school of Medicine.

He served as resident physician in Butler Hospital, physician in charge of chil-dren’s diseases in Rhode Island Hospital, the north end dispensary, and the st. vincent dePaul Infant Asylum.

dr. Burnett was a member of the board of managers of the Providence district nursing Association, chairman of Baby Welfare committee, Rhode Island Medical society, Providence Medical Association, American Medical Association, Associ-ation of Military surgeons and the new england Pediatric society.

He was formerly a captain in the Medical corps, Rhode Island national guard, and was recently appointed assistant surgeon general of the state. He leaves a widow, mother, two brothers and two children.

st. Joseph’s Hospital graduated nine nurses on May 22, 1917. Many expressed an interest in

participating in the war effort.

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in 1917, charts that accompanied clinical articles looked like this.

These appeared in the June 1917 issue of the Rhode Island Medi-

cal Journal with “a study of Cardiorenal Types” by H.p. Lovewell,

MD, of providence. The review was based on 250 cases from a

course in medicine and pathology at the Massachusetts Gener-

al Hospital, using a classification of Dr. R. Cabot, from a paper

read before the aMa in 1914. Dr. Cabot found that 93% of the

“failing hearts” fell into four groups: rheumatic, arteriosclerotic,

nephritic and syphilitic. of the 250 cases, Dr. Lovewell would put

70 under these four types.

sTuDy oF CaRDioRenaL Types – GLoMeRuLonepHRiTiC GRoup

sTuDy oF CaRDioRenaL Types – aRTeRiosCLeRoTiC GRoup

w w w . R i M e D . o R G | a R C H i v e s | M a y w e b p a G e M A Y 2 0 1 7 R h o d e i s l a n d m e d i c a l j o u R n a l





hERITAgE

Hopeworth sanitarium in Bristol offered rest and work cures Founder grew up in Civil War field hospitals, orphan asylum

MaRy koRR

RiMJ ManaGinG eDiToR

When Herman canfield, sr., a promi-nent ohio lawyer, mayor, senator and Abolitionist was killed at the Battle of shiloh during the civil War, his wife Martha packed up her two boys and headed south, to use her nursing skills to tend the war wounded in field

hospitals. the boys trailed after their mother, and the generals as well.

After the war, she opened the can-field colored orphan Asylum in

Memphis, tennessee, which became home to her two young sons and an army of ‘siblings,’ many street urchins orphaned during the war.

the canfield boys would eventually wind up in Bristol, RI, as the physician directors of the Hopeworth sanitarium.

dR. hERMAN CANfIEld, JR . , first came to Bristol in 1879, several years after graduating from the university of new york Medical department (1876). He was determined to open a sanitarium. With $12 in his pocket, he settled into the town by the bay with his wife and child, and after two years of practice rented the gen. Burnside estate to open his sanitarium. Within 18 months, he purchased a large parcel of land and buildings along the shores of Mount Hope Bay and established the Hopeworth sanitarium in 1883.

Hopeworth was billed as a respite for the “weary invalid.” Accepted were chronic “nervous cases, other than the insane,” patients who suffered from rheumatism, gout, diabetes, diseases of the kidney, stomach and bladder, heart disease – in short, just about every-one, with the exception of those with tuberculosis, infectious diseases, and epilepsy. the sanitarium was also open to selected recovering alcoholics and those with drug addictions, but only with prior screening.

Hopeworth was sit-

uated on 65 acres of

seashore, woodlands,

fields and gardens.

The main building

consisted of 24 bed-

rooms, sitting rooms,

treatment areas, and

dining, music and

billiard rooms.

electrical Room: a brochure sent to physicians advertised the various treatments offered, which included: massage, medical gymnastics,

mechanical vibration, and electricity in its various forms (galvanic, faradic, static, etc.).

Solarium: [Right] an 80-foot conservatory of flowers was often used as a solarium and area for the “rest cure.’





In 1885, Herman’s brother, dR. WIllIAM

E. CANfIEld, joined him. one of their rules was to offer care for two deserv-ing patients who are unable to meet the regular charges. the costs were:• single room, $15–$30 per week,

only general medical direction• suites: $35–$75 week• Additional medical treatment:

$20 per week and upward• Weekly settlement of bills required.

the consulting physicians included:• george W. Porter, Md,

gynecologist, Providence• george L. shattuck, Md,

neurologist, Providence• george s. Matthews, Md,

general medicine, Providence• John W. keefe, Md,

surgeon, Providence• H.c. Pitts, Md, gynecologist

Farm work: [Left] For those disinclined to take the rest cure, the work cure was available to tire but not fatigue the individual. excursion boats also took

residents to different towns along the bay, clambakes, and nearby resorts.

Bowling Alley: [Right] a bowling alley, exercise room, tennis courts and croquet grounds provided residents with ample recreational opportunities.

a barn was expanded to hold carriages, horses and a large herd of Holstein and Jersey cows.

Outdoor life: [Below] built on the shoreline of

narragansett bay in bristol, the sanitarium of-

fered the use of a sloop for the nautical-minded.

the salty air and temperate sum-mers mitigated by bay breezes was proclaimed in the sanitarium’s adver-tisements, as well as its accessibility. It could be reached by electric trains from Providence, which left every hour to the Bristol station on Franklin street, where a carriage would be awaiting.

For out-of-towners, the Federal express train left Washington d.c at 4:20 p.m. and arrived in Providence (with-out changing trains!) at about 6 a.m. For new yorkers, the Providence steamboat Line and the Fall River steamboat Line left Pier 18 in that city at 5 p.m. daily.

In addition, according to the brochure, residents had the luxury of making local and long-distance telephone calls.

Martha canfield became a permanent resident at Hopeworth, until she died there in 1889, according to one account, “from the effects of exposure in her work for the soldiers during the war.”

the canfields sold the facility in 1909, when Herman opened a smaller facility in newton, Mass. He also opened facilities in the caribbean, and died in Florida at the age of 60 in 1914.

In 1959, the main building of the for-mer sanitarium was destroyed in a fire. eventually the land was divided into home parcels and scattered throughout the area are remnants of the old stone-walls and pillars, crumbling sentinels of a bygone era. v

Bath house: [Above] The bath House was situat-

ed along the shoreline. Hydrotherapy in full tubs,

with or without electricity, douches, sprays, packs

and rubs, vapors, etc. at varying temperatures,

was offered to residents in the warm weather.

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the Role of Radiation therapy in the treatment of Metastatic Brain disease

26. nieder c, Berberich W, schnabel k. tumor-related prognostic factors for remission of brain metastases after radiotherapy. Int J Radiat Oncol Biol Phys. 1997;39(1):25-30.

27. sadikov e, Bezjak A, yi Q-L, et al. value of whole brain re-ir-radiation for brain metastases--single centre experience. Clin Oncol (R Coll Radiol). 2007;19(7):532-538. doi:10.1016/j.clon.2007.06.001.

28. kocher M, soffietti R, Abacioglu u, et al. Adjuvant whole-brain radiotherapy versus observation after radiosurgery or surgical resection of one to three cerebral metastases: results of the eoRtc 22952-26001 study. J Clin Oncol. 2011;29(2):134-141. doi:10.1200/Jco.2010.30.1655.

29. Patchell RA, tibbs PA, Regine WF, et al. Postoperative radio-therapy in the treatment of single metastases to the brain: a ran-domized trial. JAMA. 1998;280(17):1485-1489.

30. LekseLL L. the stereotaxic method and radiosurgery of the brain. Acta Chir Scand. 1951;102(4):316-319.

31. dieterich s, Pawlicki t. cyberknife image-guided delivery and quality assurance. Int J Radiat Oncol Biol Phys. 2008;71(1 sup-pl):s126-s130. doi:10.1016/j.ijrobp.2007.08.081.

32. collins sP, coppa nd, Zhang y, collins Bt, McRae dA, Jean Wc. cyberknife(® )radiosurgery in the treatment of complex skull base tumors: analysis of treatment planning parameters. Radiat Oncol. 2006;1:46. doi:10.1186/1748-717X-1-46.

33. garrett Md, Wu c-c, yanagihara tk, Jani A, Wang tJc. Radiation therapy for the Management of Brain Metas-tases. Am J Clin Oncol. 2016;39(4):416-422. doi:10.1097/coc.0000000000000296.

34. Breneman Jc, steinmetz R, smith A, Lamba M, Warnick Re. Frameless image-guided intracranial stereotactic radiosurgery: clinical outcomes for brain metastases. Int J Radiat Oncol Biol Phys. 2009;74(3):702-706. doi:10.1016/j.ijrobp.2008.11.015.

35. nieder c, grosu AL, gaspar Le. stereotactic radiosurgery (sRs) for brain metastases: a systematic review. Radiat Oncol. 2014;9:155. doi:10.1186/1748-717X-9-155.

36. gorovets d, Rava P, ebner dk, et al. Predictors for Long-term survival Free from Whole Brain Radiation therapy in Patients treated with Radiosurgery for Limited Brain Metastases. Front Oncol. 2015;5. doi:10.3389/fonc.2015.00110.

37. Brown WR, Blair RM, Moody dM, et al. capillary loss precedes the cognitive impairment induced by fractionated whole-brain irradiation: A potential rat model of vascular dementia. J Neurol Sci. 2007;257(1):67-71. doi:10.1016/j.jns.2007.01.014.

38. Aoyama H, shirato H, tago M, et al. stereotactic radiosurgery plus whole-brain radiation therapy vs stereotactic radiosur-gery alone for treatment of brain metastases: a randomized controlled trial. JAMA. 2006;295(21):2483-2491. doi:10.1001/jama.295.21.2483.

39. sahgal A, Aoyama H, kocher M, et al. Phase 3 trials of ste-reotactic radiosurgery with or without whole-brain radiation therapy for 1 to 4 brain metastases: individual patient data me-ta-analysis. Int J Radiat Oncol Biol Phys. 2015;91(4):710-717. doi:10.1016/j.ijrobp.2014.10.024.

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Updates On chimeric Antigen Receptor-Mediated Glioblastoma Immunotherapy

26. Phase I Study of Cellular Immunotherapy for Recurrent/Re-fractory Malignant Glioma Using Intratumoral Infusions of GRm13Z40-2, An Allogeneic CD8+ Cytolitic T-Cell Line Ge-netically Modified to Express the IL 13-Zetakine and HyTK and to be Resistant to Glucocorticoids, in Combination With Interleukin-2. [cited 2017 1/29/2017]; Available from: https://clinicaltrials.gov/show/nct01082926.

27. genetically Modified T-cells in Treating Patients With Recur-rent or Refractory Malignant Glioma. [cited 2017 1/29/2017]; Available from: https://clinicaltrials.gov/show/nct02208362.

28. t Cells Expressing HER2-specific Chimeric Antigen Receptors(-CAR) for Patients With Glioblastoma. . [cited 2017 1/29/2017]; Available from: https://clinicaltrials.gov/show/nct02442297.

29. cMV-specific Cytotoxic T Lymphocytes Expressing CAR-Tar-geting HER2 in Patients With GBM. . [cited 2017 1/29/2017]; Available from: https://clinicaltrials.gov/show/nct01109095.

30. cAR-T Cell Immunotherapy for EphA2 Positive Malignant Gli-oma Patients. [cited 2017 1/29/2017]; Available from: https://clinicaltrials.gov/show/nct02575261.

31. Razavi, s.M., k.e. Lee, B.e. Jin, P.s. Aujla, et al., Immune Eva-sion Strategies of Glioblastoma. Front surg, 2016. 3: p. 11.

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34. grada, Z., M. Hegde, t. Byrd, d.R. shaffer, et al., TanCAR: A Novel Bispecific Chimeric Antigen Receptor for Cancer Immu-notherapy. Mol ther nucleic Acids, 2013. 2: p. e105.

35. Foster, A.e., g. dotti, A. Lu, M. khalil, et al., Antitumor activ-ity of EBV-specific T lymphocytes transduced with a dominant negative TGF-beta receptor. J Immunother, 2008. 31(5): p. 500-5.

36. dotti, g., B. savoldo, M. Pule, k.c. straathof, et al., Human cy-totoxic T lymphocytes with reduced sensitivity to Fas-induced apoptosis. Blood, 2005. 105(12): p. 4677-84.

37. Wainwright, d.A., A.L. chang, M. dey, I.v. Balyasnikova, et al., Durable therapeutic efficacy utilizing combinatorial blockade against IDO, CTLA-4, and PD-L1 in mice with brain tumors. clin cancer Res, 2014. 20(20): p. 5290-301.

38. Zeng, J., A.P. see, J. Phallen, c.M. Jackson, et al., Anti-PD-1 blockade and stereotactic radiation produce long-term survival in mice with intracranial gliomas. Int J Radiat oncol Biol Phys, 2013. 86(2): p. 343-9.

39. desai, R., c.M. suryadevara, k.A. Batich, s.H. Farber, et al., Emerging immunotherapies for glioblastoma. expert opin emerg drugs, 2016. 21(2): p. 133-45.

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41. Lamb, L.s., Jr., J. Bowersock, A. dasgupta, g.y. gillespie, et al., Engineered drug resistant gammadelta T cells kill glioblasto-ma cell lines during a chemotherapy challenge: a strategy for combining chemo- and immunotherapy. PLos one, 2013. 8(1): p. e51805.

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43. sengupta, s., P. sampath, and R.P. Junghans, Methods and com-positons for treating cancer, Wo2016089916 A1, 2016 https://www.google.com/patents/Wo2016089916A1?cl=en

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RHODE ISLAND MEDICAl J ournAl · 2017. 6. 1. · MEDICAl J ournAl RHODE ISLAND JunE 2017 VOLUME 100 • NUMBER 6 ISSn 2327-2228 Recent AdvAnces in neuRosuRgeRy sPecIAL sectIon guest