SCIENCE TIMES
affecting tumor cell viability but reduced
survival in mice undergoing radiotherapy com-
pared with mice undergoing radiotherapy with-
out steroids. In these tumors, dexamethasone
decreased the proliferation and expression of
many cell cycle–related genes responsible for
cell mitotic assembly, cycle checkpoints, and
DNA damage response. Given that high cell
turnover rates have been shown to correlate
with radiosensitivity,6 the authors speculate that
the decreased proliferation rates and the altered
cell cycle–related expression profile associated
with steroids may be responsible for the shorter
survival linked to their use during radiation. In
addition, the dexamethasone-associated gene
expression signature they found in their mouse
model correlated with shorter survival in The
Cancer Genome Atlas patient data set. In
pursuit of alternatives to dexamethasone for
edema control, Pitter et al went further to test
a murine anti–vascular endothelial growth
factor-A antibody. The anti–vascular endothe-
lial growth factor-A used concomitantly with
radiation provided excellent control of brain
edema without compromising survival.
Collectively, the study from Pitter et al
suggests that the antiproliferative effects of
steroids may confer protection from radiother-
apy- and chemotherapy-induced genotoxic
stress and thus possibly compromise survival in
patients with GBM. The study also suggests that
vascular endothelial growth factor antagonists
could be viable alternatives for reducing brain
edema without such detrimental effects on
survival. Of course, given the retrospective
nature of the aforementioned clinical data and
the preclinical nature of the basic science data,
these conclusions should be interpreted with
caution. Regardless, the results of the current
study raise awareness about the potential benefits
of prudent and restricted use of corticosteroids in
GBM and substantiate the need for a randomized
trial comparing steroids with vascular endothe-
lial growth factor antagonists concomitant with
radiation and chemotherapy in patients with
GBM.
Kenan Alkhalili, MD
Georgios Zenonos, MD
Juan C. Fernandez-Miranda, MD
University of Pittsburgh
Pittsburgh, Pennsylvania
REFERENCES
1. Piette C, Munaut C, Foidart JM, Deprez M. Treating
gliomas with glucocorticoids: from bedside to bench.
Acta Neuropathol. 2006;112(6):651-664.
2. Wang H, Li M, Rinehart JJ, Zhang R. Pretreatment
with dexamethasone increases antitumor activity of
carboplatin and gemcitabine in mice bearing human
N16 | VOLUME 79 | NUMBER 4 | OCTOBER 2016
Copyright © Congress of Neurological Surgeons. Unauthorized reproduction of this article is prohibited.
cancer xenografts: in vivo activity, pharmacokinetics,
and clinical implications for cancer chemotherapy.
Clin Cancer Res. 2004;10(5):1633-1644.
3. Weller M, Schmidt C, Roth W, Dichgans J. Che-
motherapy of human malignant glioma: prevention of
efficacy by dexamethasone? Neurology. 1997;48(6):
1704-1709.
4. Shields LB, Shelton BJ, Shearer AJ, et al. Dexameth-
asone administration during definitive radiation and
temozolomide renders a poor prognosis in a retrospective
analysis of newly diagnosed glioblastoma patients. Radiat
Oncol. 2015;10:222.
5. Pitter KL, Tamagno I, Alikhanyan K, et al. Cortico-
steroids compromise survival in glioblastoma. Brain.
2016;139(pt 5):1458-1471.
6. Kempf H, Hatzikirou H, Bleicher M, Meyer-Hermann M.
In silico analysis of cell cycle synchronisation effects in
radiotherapy of tumour spheroids. PLoS Comput Biol.
2013;9(11):e1003295.
Conduits Between Cancer
Cells and Astrocytes
G
ap junctions are essential communica-
tion conduits of astrocytes. Breaches of
these ubiquitous networking channels
are conceived to be a sinister method of meta-
static proliferation in the central nervous system
(CNS) by breast and lung carcinomas. In
a recent study by Chen et al,1 the relationships
and mechanisms between these gap junction–
forming carcinomas and CNS metastasis were
explored. In addition, Chen et al report inter-
esting findings on what is delivered through
these gap junctions that allows these carcinomas
to proliferate and survive chemotherapeutic
effects.
Astrocyte gap junctions, specifically named
Cx43, allow astrocytes to communicate with
each other. Perversely, it is also apparent that
carcinomas can form these same gap junctions.
This permits the potential for carcinomas to
communicate with astrocytes through these
channels. Chen et al1 report a proliferative
presence of Cx43 at the interface between
CNS-metastatic breast and lung carcinomas
to normal astrocytes (Figure). Further analysis
of the Cx43 gap junctions led the study
investigators to believe that there exists an
additional component that works in synergy
with Cx43 to develop a carcinoma-astrocyte gap
junction enfranchisement.
Their investigation led them to examine
PCDH7, a membranous protocadherin protein.
PCDH7 facilitates homophilic cell-cell contact
and is expressed widely in astrocytes. Expression
of PCDH7 in carcinomatous cells enables
conduction of these cells to form Cx43 gap
junctions with astrocytes. Coexpression of
PCDH7 with Cx43 was found to be a require-
Figure. Cx43 staining (arrowhead)
at the interface of green fluorescent
protein (GFP) 1 H2030-BrM3
(green) and glial fibrillary acidic
protein (GFAP) 1 astrocytes (blue).
Adapted with permission from Mac-
millan Publishers Ltd: Nature (Chen
Q, Boire A, Jin X, et al. Carcinoma-
astrocyte gap junctions promote brain
metastasis by cGAMP transfer. Nature.
2016;533(7604):493-498), copyright
2016; permission conveyed through
Copyright Clearance Center, Inc.
ment for gap junction formation, and PCDH7
and Cx43 are unable to proliferate in the CNS
without each other.
With the knowledge of these gap junctions,
the next step in the investigation was to find out
how the cancer cell exploits these newly formed
networks. Gene expression patterns revealed that
there was curious activation of interferon and
nuclear factor-kB pathways after coculture
between coexpressive (Cx43 1 PCDH7) met-
astatic cancer cells and astrocytes. These inflam-
matory pathways have been found to inhibit
chemotherapy-induced cellular apoptosis, a pro-
tective mechanism that appeared to be initiated
by metastatic cancer cells.
The root source of the inflammatory cascade
was narrowed down to the cGAS-STING
pathway (an innate immune response against
viral infection) in astrocytes. The initiation of the
STING pathway was investigated further to
reveal that cGAMP was shunted across Cx43
gap junctions from cancer cells. The source of
the cGAMP was derived from the presence of
cytosolic dsDNA of the cancer cell. Effectively,
the cancer cell parasitizes then exploits the
astrocyte to initiate an inflammatory mechanism
for its own protection and proliferation.
This study demonstrates the metastatic pro-
liferation and the delivery of proinflammatory
mediators from the cancer cell to the astrocyte by
these gap junctions. The induced endogenous
inflammatory response protects the cancer
cell from the stresses of chemotherapeutic mech-
anisms and enables its proliferation. Knowledge of
www.neurosurgery-online.com

this conduit to cancer metastasis gives rise to
a potential therapeutic target. Such drugs such as
meclofenamate and tonabersat inhibit the transfer
of dye from coexpressive (Cx43 1 PCDH7)
cancer cells to astrocytes and serve as potential
adjuncts to traditional chemotherapies against
brain metastases.
Reid Hoshide, MD, MPH*
Rahul Jandial, MD, PhD‡
*University of California–San Diego
San Diego, California
‡City of Hope National Medical Center
Duarte, California
REFERENCE
1. Chen Q, Boire A, Jin X, et al. Carcinoma-astrocyte
gap junctions promote brain metastasis by cGAMP
transfer. Nature. 2016;533(7604):493-498.
A Randomized Clinical
Trial of Radiation With or
Without Chemotherapy
for Low-grade Gliomas
G
rade 2 gliomas eventually result in
progressive neurological symptoms in
almost all patients, causing premature
death. Prior trials have demonstrated tumor
regression in recurrent low-grade gliomas after
the initiation of a number of chemotherapies,
including regimens with procarbazine, lomus-
tine, and vincristine1; carmustine plus inter-
feron2; and mechlorethamine, vincristine, and
procarbazine.3 Similarly, the combination of
procarbazine, CCNU, and vincristine (PCV),
when administered as initial therapy, has been
shown to result in tumor regression.4-6
A preliminary trial demonstrated improved
progression-free survival in patients receiving
chemotherapy and radiation therapy (RT) vs RT
alone.7 Patients with supratentorial World Health
Organization grade 2 low-grade gliomas, age of
18 to 39 years with subtotal resection/biopsy, or
age $40 years with any extent resection were
randomly assigned to RT alone or RT and PCV.
Patients were eligible if they had supratentorial
pathologically confirmed grade 2 astrocytoma,
oligodendroglioma, or oligoastrocytoma. All pa-
tients had to have a Karnofsky Performance
Status score of $60 (on a scale from 0 to 100,
with lower numbers indicating greater disability)
and a neurological function score of #3 (on
a scale from 0 to 5, with lower numbers
indicating better neurological function).
In all, 251 patients were accrued from 1998
to 2002. Five-year overall survival rates for RT vs
NEUROSURGERY
Copyright © Congress of Neurological Surgeons. Unauthorized reproduction of this article is prohibited.
SCIENCE TIMES
RT 1 PCV were 63% vs 72%, respectively (P ¼
.13). Five-year progression-free survival rates were
significantly higher in patients receiving RT and
PCV (63%) vs RT alone (46%). Additionally, for
2-year survivors (2 ¼ 211), the probability of
overall survival for an additional 5 years was
significantly higher in patients receiving RT 1
PCV (74%) vs RT alone (59%). At the time of
this initial report, the median follow-up was 5.9
years, and 38% of the patients had died.
Recently, the results of the phase 3 trial with
long-term follow-up were reported in the New
England Journal of Medicine.8 The median
follow-up was 11.9 years, and 55% of the
patients died. Patients in the 2 groups were
balanced with regard to previously verified
prognostic variables, including age, Karnofsky
Performance Status score, neurological func-
tion, Mini-Mental State Examination score,
extent of surgery, histological findings, and
IDH1 R132H mutation status. The median
progression-free survival was significantly higher
in patients receiving RT and PCV (10.4 years) vs
RT alone (4.0 years). The rate of progression-free
survival at 5 years was 61% among patients who
received RT and PCV vs 44% among those who
received RT alone; the corresponding rates at 10
years were 51% vs 21%.
In contrast to outcomes previously reported,7
in the recent analysis with additional follow-up,
patients who received RT and PCV had longer
overall survival than those who received RT
alone. The median overall survival was 13.3
years with RT and PCV vs 7.8 years with RT
alone (P ¼ .003). The rate of overall survival at
5 years was 72% in the group who received RT
plus chemotherapy vs 63% in the group who
received RT alone. The corresponding rates at
10 years were 60% and 40%.
In an exploratory analysis of overall survival
according to individual histological type, the
superiority of RT plus chemotherapy over RT
alone was seen with all histological diagnoses,
although the difference did not reach significance
among patients with astrocytoma. Multivariable
analyses of overall survival revealed the following
favorable prognostic variables: RT plus chemo-
therapy after 1 year of follow-up, histological
findings of oligodendroglioma, and age ,40
years. Although IDH-positive tumors had better
overall prognosis, this was not an independent
predictor of survival in multivariate analysis.
Treatment after disease progression was also
reported prospectively. More patients who
received RT alone than patients who received
RT and PCV underwent surgery or reirradiation
or received chemotherapy after tumor progres-
sion. The most common symptomatic toxic
effects were fatigue, anorexia, nausea, and vom-
iting, which were primarily of grade 1 or 2. Three
patients required red cell transfusions, and
1 patient required platelet transfusions. There
was 1 case of neutropenic fever. All these events
occurred in patients who were treated with RT
plus chemotherapy. There were no grade 5 toxic
effects or reports of myelodysplasia or leukemia.
Late events that were attributed to RT, as
assessed by the Radiation Therapy Oncology
Group–European Organization for Research and
Treatment of Cancer Late Radiation Morbidity
Scoring Scheme, included toxic effects in the brain
in 54 patients (22%): grade 1 events in 38 patients
(15%), grade 2 events in 14 (6%), and grade 3
events in 1 (, 1%).
Further studies are indicated to determine the
optimal chemotherapeutic regimens for these
patients because a wide variety of other potential
chemotherapeutic agents are available. Although
there appears to be a small cohort of patients with
grade 2 glioma who do not benefit from RT plus
chemotherapy, the identification of those patients
remains elusive. Treatment according to genetic
subtype may provide better delineation of res-
ponders to treatment because overall survival and
transformation can vary significantly even in grade
2 gliomas. Although the goal of developing specific
treatments in response to particular mutation
mosaics within each tumor has yet to be realized,
a number of proposals may help to define
therapeutic regimens in a number of patients.9,10
This is particularly relevant in that the most
recent edition of the World Health Organization
classification has been revised to include molec-
ular designation.11 In the future, further molec-
ular diagnosis will need to be incorporated into
large clinical trials and will likely be used to define
specific individual therapeutic plans.
Robert M. Starke, MD, MSc*
E. Sander Connolly, MD‡
Ricardo J. Komotar, MD*
*Department of Neurosurgery
University of Miami School of Medicine
Miami, Florida
‡Department of Neurological Surgery
Columbia University College of Physicians and
Surgeons
New York, New York
REFERENCES
1. Cairncross G, Macdonald D, Ludwin S, et al.
Chemotherapy for anaplastic oligodendroglioma.
J Clin Oncol. 1994;12(10):2013-2021.
2. Buckner JC, Brown LD, Kugler JW, et al. Phase II
evaluation of recombinant interferon alpha and
BCNU in recurrent glioma. J Neurosurg. 1995;82
(3):430-435.
3. Galanis E, Buckner JC, Burch PA, et al. Phase II trial
of nitrogen mustard, vincristine, and procarbazine in
patients with recurrent glioma: North Central
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