The n e w e ng l a n d j o u r na l of m e dic i n e

The authors reply: We welcome Firths support
for our contention that South Africas problems
reflect forces that are causally implicated in cre-
ating worldwide disparities in wealth and health.1
Acknowledgment that these deeper causal forces
lie behind such seemingly disparate challenges
as climate change, HIVAIDS, and the Ebola epi-
demic and their global implications could en-
courage realization of the extent of northsouth
interdependence in the 21st century.2 The com-
plex notion of an ecologic and systems concep-
tion of global health3 requires insight into the
power of global political economic structures
either to continue to perpetuate disparities and
the extreme poverty conducive to the emergence,
rapid spread, and intractable establishment of
new infectious diseases and multidrug-resistant
organisms or to reverse such trends. Understand-
ing global health in this way, and the intercon-
nectedness of all life and human well-being on a
activities,4 could allow us to begin to ameliorate
disparities and reduce threats to the state of
health of individuals and whole populations
globally.5 To paraphrase John Donne: No nation
is an island.
Solomon R. Benatar, M.B., Ch.B., D.Sc. (Med.)
Bongani M. Mayosi, M.B., Ch.B., D.Phil.
University of Cape Town
Cape Town, South Africa
Since publication of their article, the authors report no further
potential conflict of interest.
1. Alexander T. Unravelling global apartheid: an overview of
world politics. Oxford, England: Polity Press, 1996.
2. Garrett L. The coming plague: newly emerging diseases in a
world out of balance. New York: Farrar, Straus and Giroux, 1994.
3. Benatar S, Upshur R. What is global health? In: Benatar S,
Brock G, eds. Global health and global health ethics. Cambridge,
England: Cambridge University Press, 2011:13-23.
4. Rockstrm J, Steffen W, Noone K, et al. A safe operating
space for humanity. Nature 2009;461:472-5.
5. Gill S, ed. Global crises and the crisis of global leadership.
Cambridge, England: Cambridge University Press, 2011.

planet that is ecologically threatened by human DOI: 10.1056/NEJMc1413160

Airway Fistula Closure after Stem-Cell Infusion

To the Editor: Large-airway defects and tracheo- effective methods of treatment.1 Bronchopleural
bronchial dehiscence after lung resection present fistula is a pathologic connection between the
a problem for clinicians because there are few airway and the pleural space that may develop
after lung resection. For many patients with em-
A B pyema, the presence or absence of a fistula
makes the difference between recovery, chronic
illness, and death.2,3
In our previous preclinical experiments, we

Figure 1. Repair of an Airway Fistula after Stem-Cell

Infusion.
Panel A shows a flexible bronchoscopic view before
bone marrowderived mesenchymal stem-cell trans-
plantation for the treatment of patency in the central
part of the right bronchial stump (arrow), with a 3-mm
C D
orifice. Panel B shows a subtle bronchopleural fistula
(circle) at the end of the right main bronchus, com-
municating with a distal small cavity. Panel C shows
the flexible bronchoscopy view 60 days after the infu-
sion of mesenchymal stem cells, with visible healing
of the central bronchial dehiscence and no evidence of
the titanium staple on the external aspect of the suture
(arrow). Panel D shows post-treatment volume render-
ing of the airway, with interruption of the fistula at its
orifice from the right bronchus (circle) where the cells
were injected.

96 n engl j med 372;1 nejm.org january 1, 2015

The New England Journal of Medicine

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 correspondence

found that bronchoscopic transplantation of mes- Lorenzo Spaggiari, M.D., Ph.D.

enchymal stem cells derived from bone marrow University of Milan School of Medicine
could close a bronchopleural fistula with the Milan, Italy
extraluminal proliferation of fibroblasts and the and Others
development of collagenous matrix.4 Encouraged A complete list of authors is provided with the full text of this
by this result and by functional human organ letter at NEJM.org.
The preclinical work was supported by a competitive grant
5
replacement elsewhere, we transplanted autol- from Fondazione Umberto Veronesi per il Progresso delle Scienze
ogous bone marrowderived mesenchymal stem (FUV). In addition, this study was partially supported by grants
cells bronchoscopically to treat a 42-year-old male from the Italian Ministry of Health (R.F.G.R. 2010-2318448 and
R.F.G.R. 2010-2312573) and the Seventh Framework Program of
firefighter in whom bronchopleural fistula had the European CommissionREBORNE (241879).
developed after right extrapleural pneumonectomy Disclosure forms provided by the authors are available with
for early-stage malignant mesothelioma. The pres the full text of this letter at NEJM.org.
ence of the bronchopleural fistula was con- 1. Macchiarini P, Jungebluth P, Go T, et al. Clinical transplan-
firmed on flexible bronchoscopy (Fig. 1A) and tation of a tissue-engineered airway. Lancet 2008;372:2023-30.
[Erratum, Lancet 2009;373:462.]
chest computed tomography (Fig. 1B, and Fig. S2 2. Ponn RB. Complications of pulmonary resection. In: Shields
in the Supplementary Appendix, available with TW, Locicero J III, Ponn RB, et al., eds. General thoracic surgery.
6th ed. Vol. 1. Philadelphia: Lippincott Williams & Wilkins,
the full text of this letter at NEJM.org). 2000:554-86.
The patient underwent bone marrow aspira- 3. Temes RT, Griffin N, Konstantakos A. Late postoperative
tion followed by mesenchymal stem-cell isolation complications. In: Patterson GA, Cooper JD, Deslauires J, Lerut
AEM, Luketich JD, Rice TW, eds. Pearsonss thoracic and esopha-
and expansion; bronchoscopy was performed, and geal surgery. 3rd ed. London: Churchill Livingstone, 2008:166-86.
10 million autologous bone marrowderived 4. Petrella F, Toffalorio F, Brizzola S, et al. Stem cell transplan-
mesenchymal stem cells were injected into the tation effectively occludes bronchopleural fistula in an animal
pars membranacea of the right main bronchial model. Ann Thorac Surg 2014;97:480-3.
5. Alvarez PD, Garca-Arranz M, Georgiev-Hristov T, Garca-
stump as close as possible to the orifice of the Olmo D. A new bronchoscopic treatment of tracheomediastinal
fistula. fistula using autologous adipose-derived stem cells. Thorax
At 60 days, bronchoscopy showed a complete 2008;63:374-6.
healing of the resection line, and the orifice that DOI: 10.1056/NEJMc1411374
Correspondence Copyright 2015 Massachusetts Medical Society.
was observed before stem-cell implantation was
no longer visible (Fig. 1C). An analysis of biopsy instructions for letters to the editor
samples showed a hyperplastic respiratory epi-
thelium lying on a fibrotic lamina propria, and Letters to the Editor are considered for publication, subject
to editing and abridgment, provided they do not contain
bands of smooth-muscle fibers were reduced and material that has been submitted or published elsewhere.
replaced by fibroblasts. Immunocytochemical Please note the following:
staining for p40, the DNp63 isoform that is con- Letters in reference to a Journal article must not exceed 175
sidered to be highly specific for differentiation words (excluding references) and must be received within
of squamous and basal cells, showed a well- 3 weeks after publication of the article.
defined layer of basal cells and basal-cell hyper- Letters not related to a Journal article must not exceed 400
plasia consistent with repair. Computed tomog- words.
raphy showed interruption of the fistula at its A letter can have no more than five references and one figure
or table.
orifice from the right bronchus where the cells
A letter can be signed by no more than three authors.
were injected (Fig. 1D).
Financial associations or other possible conflicts of interest
The bronchoscopic transplantation of bone must be disclosed. Disclosures will be published with the
marrowderived mesenchymal stem cells in our letters. (For authors of Journal articles who are responding
patient appeared to help close this small-caliber to letters, we will only publish new relevant relationships
post-resectional bronchopleural fistula. Further that have developed since publication of the article.)
work is required to determine whether this ap- Include your full mailing address, telephone number, fax
number, and e-mail address with your letter.
proach can be replicated.
All letters must be submitted at authors.NEJM.org.
Francesco Petrella, M.D. Letters that do not adhere to these instructions will not be
European Institute of Oncology considered. We will notify you when we have made a decision
Milan, Italy about possible publication. Letters regarding a recent Journal
francesco.petrella@ieo.it article may be shared with the authors of that article. We are

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