The
n e w e ng l a n d j o u r na l
The authors reply: We welcome Firth’s support for our contention that South Africa’s problems reflect forces that are causally implicated in creating worldwide disparities in wealth and health.1 Acknowledgment that these deeper causal forces lie behind such seemingly disparate challenges as climate change, HIV–AIDS, and the Ebola epidemic and their global implications could encourage realization of the extent of north–south interdependence in the 21st century.2 The complex notion of an ecologic and systems conception 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. Understanding global health in this way, and the interconnectedness of all life and human well-being on a planet that is ecologically threatened by human
of
m e dic i n e
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. Rockström 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. DOI: 10.1056/NEJMc1413160
Airway Fistula Closure after Stem-Cell Infusion
A
C
96
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 emB 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 marrow–derived mesenchymal stem-cell transplantation for the treatment of patency in the central part of the right bronchial stump (arrow), with a 3-mm orifice. Panel B shows a subtle bronchopleural fistula (circle) at the end of the right main bronchus, communicating with a distal small cavity. Panel C shows the flexible bronchoscopy view 60 days after the infusion 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 rendering of the airway, with interruption of the fistula at its orifice from the right bronchus (circle) where the cells were injected.
D
n engl j med 372;1
nejm.org
january 1, 2015
The New England Journal of Medicine Downloaded from nejm.org at NORTH WEST UNIVERSITY on January 21, 2015. For personal use only. No other uses without permission. Copyright © 2015 Massachusetts Medical Society. All rights reserved.
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 A complete list of authors is provided with the full text of this development of collagenous matrix.4 Encouraged at NEJM.org. by this result and by functional human organ letter 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 marrow–derived mesenchymal stem (FUV). In addition, this study was partially supported by grants the Italian Ministry of Health (R.F.G.R. 2010-2318448 and cells bronchoscopically to treat a 42-year-old male from R.F.G.R. 2010-2312573) and the Seventh Framework Program of firefighter in whom bronchopleural fistula had the European Commission–REBORNE (241879). Disclosure forms provided by the authors are available with developed after right extrapleural pneumonectomy 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 transplanof a tissue-engineered airway. Lancet 2008;372:2023-30. firmed on flexible bronchoscopy (Fig. 1A) and tation [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. Pearsons’s thoracic and esophaand expansion; bronchoscopy was performed, and geal surgery. 3rd ed. London: Churchill Livingstone, 2008:166-86. 10 million autologous bone marrow–derived 4. Petrella F, Toffalorio F, Brizzola S, et al. Stem cell transplanmesenchymal stem cells were injected into the tation effectively occludes bronchopleural fistula in an animal Ann Thorac Surg 2014;97:480-3. pars membranacea of the right main bronchial model. 5. Alvarez PD, García-Arranz M, Georgiev-Hristov T, Garcíastump as close as possible to the orifice of the Olmo D. A new bronchoscopic treatment of tracheomediastinal fistula using autologous adipose-derived stem cells. Thorax fistula. 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 epiLetters to the Editor are considered for publication, subject thelium lying on a fibrotic lamina propria, and 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 marrow–derived mesenchymal stem cells in our letters. (For authors of Journal articles who are responding to letters, we will only publish new relevant relationships patient appeared to help close this small-caliber 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. European Institute of Oncology Milan, Italy [email protected]
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
n engl j med 372;1 nejm.org january 1, 2015
The New England Journal of Medicine Downloaded from nejm.org at NORTH WEST UNIVERSITY on January 21, 2015. For personal use only. No other uses without permission. Copyright © 2015 Massachusetts Medical Society. All rights reserved.
97
n e w e ng l a n d j o u r na l
The authors reply: We welcome Firth’s support for our contention that South Africa’s problems reflect forces that are causally implicated in creating worldwide disparities in wealth and health.1 Acknowledgment that these deeper causal forces lie behind such seemingly disparate challenges as climate change, HIV–AIDS, and the Ebola epidemic and their global implications could encourage realization of the extent of north–south interdependence in the 21st century.2 The complex notion of an ecologic and systems conception 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. Understanding global health in this way, and the interconnectedness of all life and human well-being on a planet that is ecologically threatened by human
of
m e dic i n e
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. Rockström 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. DOI: 10.1056/NEJMc1413160
Airway Fistula Closure after Stem-Cell Infusion
A
C
96
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 emB 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 marrow–derived mesenchymal stem-cell transplantation for the treatment of patency in the central part of the right bronchial stump (arrow), with a 3-mm orifice. Panel B shows a subtle bronchopleural fistula (circle) at the end of the right main bronchus, communicating with a distal small cavity. Panel C shows the flexible bronchoscopy view 60 days after the infusion 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 rendering of the airway, with interruption of the fistula at its orifice from the right bronchus (circle) where the cells were injected.
D
n engl j med 372;1
nejm.org
january 1, 2015
The New England Journal of Medicine Downloaded from nejm.org at NORTH WEST UNIVERSITY on January 21, 2015. For personal use only. No other uses without permission. Copyright © 2015 Massachusetts Medical Society. All rights reserved.
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 A complete list of authors is provided with the full text of this development of collagenous matrix.4 Encouraged at NEJM.org. by this result and by functional human organ letter 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 marrow–derived mesenchymal stem (FUV). In addition, this study was partially supported by grants the Italian Ministry of Health (R.F.G.R. 2010-2318448 and cells bronchoscopically to treat a 42-year-old male from R.F.G.R. 2010-2312573) and the Seventh Framework Program of firefighter in whom bronchopleural fistula had the European Commission–REBORNE (241879). Disclosure forms provided by the authors are available with developed after right extrapleural pneumonectomy 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 transplanof a tissue-engineered airway. Lancet 2008;372:2023-30. firmed on flexible bronchoscopy (Fig. 1A) and tation [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. Pearsons’s thoracic and esophaand expansion; bronchoscopy was performed, and geal surgery. 3rd ed. London: Churchill Livingstone, 2008:166-86. 10 million autologous bone marrow–derived 4. Petrella F, Toffalorio F, Brizzola S, et al. Stem cell transplanmesenchymal stem cells were injected into the tation effectively occludes bronchopleural fistula in an animal Ann Thorac Surg 2014;97:480-3. pars membranacea of the right main bronchial model. 5. Alvarez PD, García-Arranz M, Georgiev-Hristov T, Garcíastump as close as possible to the orifice of the Olmo D. A new bronchoscopic treatment of tracheomediastinal fistula using autologous adipose-derived stem cells. Thorax fistula. 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 epiLetters to the Editor are considered for publication, subject thelium lying on a fibrotic lamina propria, and 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 marrow–derived mesenchymal stem cells in our letters. (For authors of Journal articles who are responding to letters, we will only publish new relevant relationships patient appeared to help close this small-caliber 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. European Institute of Oncology Milan, Italy [email protected]
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
n engl j med 372;1 nejm.org january 1, 2015
The New England Journal of Medicine Downloaded from nejm.org at NORTH WEST UNIVERSITY on January 21, 2015. For personal use only. No other uses without permission. Copyright © 2015 Massachusetts Medical Society. All rights reserved.
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