Download Glioproliferative Lesion of the Spinal Cord as a Complication of

The
n e w e ng l a n d j o u r na l
payment change through initiatives such as
Bridges to Excellence and Catalyst for Payment
Reform.1 The recent commitments made by the
large health insurers to greatly increase the percentage of provider payments that are based on
efficiency and quality will affect employees from
firms of all sizes.2
I am unclear what White means by “benefit
standards.” The Affordable Care Act was passed
to legislate both essential health benefits and
criteria for affordability. Most experts agree that
30% or more of current care is unnecessary, and
it is likely that “rich democracies” that attained
of
m e dic i n e
their success through innovation and accountability might favor exactly the direction that has
been taken.
Robert S. Galvin, M.D.
Yale University School of Medicine
New Haven, CT
Since publication of his article, the author reports no further
potential conflict of interest.
1. Aligning Forces for Quality. Beyond widgets: the pursuit of
payment reform. Princeton, NJ: Robert Wood Johnson Foundation, 2013.
2. Evans M, Herman B. Where healthcare is now on march to
value-based pay. Modern Healthcare. January 28, 2015.
DOI: 10.1056/NEJMc1605534
Glioproliferative Lesion of the Spinal Cord as a Complication
of “Stem-Cell Tourism”
To the Editor: Commercial stem-cell clinics
have been highly publicized in the lay press and
operate worldwide with limited or no regulation.1 We report the case of a 66-year-old man
who underwent intrathecal infusions for the
treatment of residual deficits from an ischemic
stroke at commercial stem-cell clinics in China,
Argentina, and Mexico. He was not taking any
immunosuppressive medications. In reports
provided to him by the clinics, the infusions
were described as consisting of mesenchymal,
embryonic, and fetal neural stem cells. Progressive lower back pain, paraplegia, and urinary
incontinence subsequently developed. Magnetic
resonance imaging (MRI) revealed a lesion of
the thoracic spinal cord and thecal sac; a biopsy specimen was obtained (Fig. 1).
Neuropathological analysis revealed a densely cellular, highly proliferative, primitive neoplasm with glial differentiation. Short tandem
repeat DNA fingerprinting analysis indicated
that the mass was predominantly composed of
nonhost cells (see the Supplementary Appendix,
available with the full text of this letter at NEJM.
org). On the basis of histopathological and
molecular studies, this glioproliferative lesion
appeared to have originated from the intrathecally introduced exogenous stem cells. The lesion had some features that overlapped with
malignant gliomas (nuclear atypia, a high
proliferation index, glial differentiation, and
vascular proliferation) but did not show other
features typical of cancer (no cancer-associated
genetic aberrations were detected on nextgeneration sequencing of 309 cancer-associated
genes [see the Supplementary Appendix]). Thus,
although the lesion may be a considered a neoplasm (i.e., a “new growth”), it could not be assigned to any category of previously described
human neoplasm on the basis of the data we
gathered. Radiation therapy led to decreased back
pain, improved mobility of the right leg, and decreased the bulk of the lesion on MRI.
Embryonic and other stem cells have tumorigenic potential and have been proposed as a
source of common origin for cancer. Embryonic
stem cells form teratomas when injected into
mice, and murine neural stem cells can transform into malignant gliomas with minimal genetic changes.2 Furthermore, rapidly dividing
cells in culture can acquire mutations that may
predispose the cells to malignant transfor­mation.
This case and others in which tumors have
developed in the context of stem-cell tourism3,4
(a trend in which patients travel for the purpose
of obtaining therapy) illustrate an extremely serious complication of introducing proliferating
stem cells into patients. Investigators have attempted to reduce the risk of stem-cell–related
tumors in clinical trials by means of the mea-
n engl j med 375;2 nejm.org July 14, 2016
The New England Journal of Medicine
Downloaded from nejm.org on April 29, 2017. For personal use only. No other uses without permission.
Copyright © 2016 Massachusetts Medical Society. All rights reserved.
Correspondence
A
B
C
D
E
F
G
Figure 1. Findings Obtained on MRI, during Surgery, and after Biopsy.
Panels A and B show sagittal, T1-weighted magnetic resonance imaging (MRI) scans of the spine obtained after the
administration of contrast material. Panel A shows areas of enhancement in an intradural mass that extends throughout the lumbar spine (arrow), and Panel B shows the rostral extent of enhancement in the thoracic spine (arrow).
Panel C shows abnormal arachnoid mater (arrow) and an engorged vein (arrowhead) during surgery after a dural
incision was made. Panels D through G show histopathological specimens of lesional cells. Panel D shows intradural
primitive atypical cells after staining with hematoxylin and eosin. Panels E, F, and G show the results of immunohistochemical testing for MIB-1 (MKI67), a marker of cellular proliferation, for OLIG2, a glial marker, and for SOX2,
a glial stem-cell marker, respectively.
n engl j med 375;2
nejm.org
July 14, 2016
The New England Journal of Medicine
Downloaded from nejm.org on April 29, 2017. For personal use only. No other uses without permission.
Copyright © 2016 Massachusetts Medical Society. All rights reserved.
Correspondence
sured administration of pluripotent stem cells or
by differentiating stem cells in vitro into postmitotic phenotypes before administration.5,6
The unregulated commercial stem-cell industry is not only potentially harmful to individual
patients but also undermines attempts to study
stem-cell therapies in clinical trials. This case
provides further support for the conclusions of
an article advocating increased investigation of
commercial stem-cell clinics and increased patient education regarding the risks of stem-cell
tourism.1 Such experimental treatments must be
studied in a safe, regulated environment.
Aaron L. Berkowitz, M.D., Ph.D.
Michael B. Miller, M.D., Ph.D.
Saad A. Mir, M.D.
Daniel Cagney, M.D.
Vamsidhar Chavakula, M.D.
Indira Guleria, Ph.D.
Ayal Aizer, M.D.
Keith L. Ligon, M.D., Ph.D.
John H. Chi, M.D., M.P.H.
Brigham and Women’s Hospital
Boston, MA
Drs. Berkowitz and Miller contributed equally to this letter.
Disclosure forms provided by the authors are available with
the full text of this letter at NEJM.org.
This letter was published on June 22, 2016, at NEJM.org.
1. Bowman M, Racke M, Kissel J, Imitola J. Responsibilities of
health care professionals in counseling and educating patients
with incurable neurological diseases regarding “stem cell tourism”: caveat emptor. JAMA Neurol 2015;​72:​1342-5.
2. Bachoo RM, Maher EA, Ligon KL, et al. Epidermal growth
factor receptor and Ink4a/Arf: convergent mechanisms governing terminal differentiation and transformation along the neural stem cell to astrocyte axis. Cancer Cell 2002;​1:​269-77.
3. Thirabanjasak D, Tantiwongse K, Thorner PS. Angiomyeloproliferative lesions following autologous stem cell therapy. J Am
Soc Nephrol 2010;​21:​1218-22.
4. Amariglio N, Hirshberg A, Scheithauer BW, et al. Donorderived brain tumor following neural stem cell transplantation in
an ataxia telangiectasia patient. PLoS Med 2009;​6(2):​e1000029.
5. Mazzini L, Gelati M, Profico DC, et al. Human neural stem
cell transplantation in ALS: initial results from a phase I trial.
J Transl Med 2015;​13:​17.
6. Fox IJ, Daley GQ, Goldman SA, et al. Use of differentiated
pluripotent stem cells as replacement therapy for treating disease. Science 2014;​345(6199):​127391.
instructions for letters to the editor
Letters to the Editor are considered for publication, subject
to editing and abridgment, provided they do not contain
material that has been submitted or published elsewhere.
Letters accepted for publication will appear in print, on our
website at NEJM.org, or both.
Please note the following:
• Letters in reference to a Journal article must not exceed 175
words (excluding references) and must be received within
3 weeks after publication of the article.
• Letters not related to a Journal article must not exceed 400
words.
• A letter can have no more than five references and one figure
or table.
• A letter can be signed by no more than three authors.
• Financial associations or other possible conflicts of interest
must be disclosed. Disclosures will be published with the
letters. (For authors of Journal articles who are responding
to letters, we will only publish new relevant relationships
that have developed since publication of the article.)
• Include your full mailing address, telephone number, fax
number, and e-mail address with your letter.
• All letters must be submitted at authors.NEJM.org.
Letters that do not adhere to these instructions will not be
considered. We will notify you when we have made a decision
about possible publication. Letters regarding a recent Journal
article may be shared with the authors of that article. We are
unable to provide prepublication proofs. Submission of a
letter constitutes permission for the Massachusetts Medical
Society, its licensees, and its assignees to use it in the Journal’s
various print and electronic publications and in collections,
revisions, and any other form or medium.
the journal’s web and e-mail addresses
To submit a letter to the Editor: authors.NEJM.org
For information about the status of a submitted manuscript:
authors.NEJM.org
To submit a meeting notice: [email protected]
The Journal’s web pages: NEJM.org
DOI: 10.1056/NEJMc1600188
Correspondence Copyright © 2016 Massachusetts Medical Society.
n engl j med 375;2 nejm.org July 14, 2016
The New England Journal of Medicine
Downloaded from nejm.org on April 29, 2017. For personal use only. No other uses without permission.
Copyright © 2016 Massachusetts Medical Society. All rights reserved.