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hundreds of patients with excellent results (see end result example in reference 2, Fig. 1D); good cosmet-ics are achieved with no depression of the donor-site area of the fibula, as is the case with a split-thickness skin graft and no problems of late wound breakdown, as regularly occurs with a split-thickness skin graft (i.e., wound dehiscence). Also, we have never experienced functional problems or problems of the donor-site region of the full-thickness skin graft.
As we all know, there are many ways to Rome, and the authors have presented, based on their huge expe-rience, an excellent review. The use of a full-thickness skin graft from the fibula osteoseptocutaneous donor leg for donor-site closure may just add another small brick to their already perfectly flagged road about deal-ing with the fibula flap.
DOI: 10.1097/PRS.0000000000006250
Martin W. Stenekes, M.D., Ph.D.
Department of Plastic Surgery University Medical Center Groningen University of Groningen Groningen, The Netherlands
Max J. H. Witjes, M.D., D.D.S., Ph.D.
Department of Oral & Maxillofacial Surgery University Medical Center Groningen University of Groningen Groningen, The Netherlands
Berend L. van der Lei, M.D., Ph.D.
Department of Plastic Surgery University Medical Center Groningen University of Groningen Groningen, and Bey Bergman Clinics
The Netherlands Correspondence to Dr. van der Lei Department of Plastic Surgery University Medical Center Groningen University of Groningen Hanzeplein 1 P.O. Box 30.001 9700 RB Groningen, The Netherlands
b.van.der.lei@umcg.nl
Instagram: @Professorvanderlei DISCLOSURE
The authors have no financial interest to declare in rela-tion to the content of this communicarela-tion.
REFERENCES
1. Al Deek NF, Kao HK, Wei FC. The fibula
osteoseptocutane-ous flap: Concise review, goal-oriented surgical technique, and tips and tricks. Plast Reconstr Surg. 2018;142:913e–923e.
2. van der Lei B, van Nieuwenhoven CA, de Visscher JG, Hofer
SO. Closure of osteoseptocutaneous fibula free flap donor sites with local full-thickness skin grafts. J Oral Maxillofac Surg. 2008;66:1294–1298.
3. Kearns M, Ermogenous P, Myers S, Ghanem AM.
Osteocu-taneous flaps for head and neck reconstruction: A focused evaluation of donor site morbidity and patient reported outcome measures in different reconstruction options. Arch
Plast Surg. 2018;45:495–503.
4. van der Lei B, Spronk CA, de Visscher JG. Closure of radial forearm free flap donor site with local full-thickness skin graft. Br J Oral Maxillofac Surg. 1999;37:119–122.
Future Concepts: Lymphangiogenesis in Lymphedema Therapy
Sir:
I
read with great interest the article by Saijo et al. entitled “Paracrine Effects of Adipose-Derived Stem Cells Promote Lymphangiogenesis in Irradiated Lym-phatic Endothelial Cells” published in advance online in Plastic and Reconstructive Surgery.1 I applaud theauthors for this study that points out the necessity of alternative methods to treat patients with secondary lymphedema caused by lymph node dissection and/ or radiotherapy. The issues in this article are worthy of comment.
This study was performed to evaluate the lym-phangiogenic effect of adipose-derived stem cells on irradiated human dermal lymphatic endothelial cells. The authors analyzed the level of lymphangiogenic factors secreted from adipose-derived stem cells and found that adipose-derived stem cells had beneficial effects in proliferation, migration, and tube formation of human dermal lymphatic endothelial cells because of increased secretion of basic fibroblast growth factor (bFGF).
In a murine tail model, Ackermann et al. evaluated the effect of platelet-rich plasma and adipose-derived stem cells on lymphangiogenesis.2 The study results
indicate increased epithelization and faster wound healing with platelet-rich plasma, and the authors offered platelet-rich plasma and adipose-derived stem cells as a promising approach for prevention/treat-ment of lymphedema.2 One of the important points of
the study is that they suggested the use of platelet-rich plasma alone or in combination with other treatment methods.
Although platelet-rich plasma has been safely used in many different fields, there is no clinical study regarding the use of platelet-rich plasma in lymph-edema treatment in humans. We assessed the clinical outcomes of platelet-rich plasma use in 45 patients with lower extremity secondary lymphedema caused by injury/trauma.
We used platelet-rich plasma applications in com-bination with complex decongestive physiotherapy and compared the results with the control group (ther-apy with only complex decongestive physiother(ther-apy). Lymphoedema Quality of-Life Questionnaire, lower extremity circumference, Numeric Rating Scale, 6-min-ute walking test, and tissue dielectric constant were eval-uated among groups with assigned interventions for 12 weeks. Significant differences in Lymphoedema Quality of-Life Questionnaire, lower extremity circumference,
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Numeric Rating Scale, and tissue dielectric constantvalues before and after treatment were found in the groups; however, in the platelet-rich plasma plus com-plex decongestive physiotherapy group, Lymphoe-dema Quality of-Life Questionnaire values had a larger effect size than in the other group. To our knowledge, this is the first clinical case series assessing the effective-ness of platelet-rich plasma by comparing it with differ-ent treatmdiffer-ent methods in human patidiffer-ents with lower limb secondary lymphedema.3
We performed platelet-rich plasma administration on legs where fibrotic skin and subcutaneous tissue were found in patients with lower extremity secondary lymphedema. The findings in skin and subcutaneous tissue are caused by the changes in the extracellular matrix, such as fibrosis, fat accumulation, an increased number of mast cells and adipocytes, and interstitial protein-rich fluid accumulation.4 Fibrosis is a clinically
serious pathologic process of secondary lymphedema. One of the main mechanisms of fibrosis is elevated bFGF, chymase, and transforming growth factor-β1 expression by mast cells in the fibrotic tissues of sec-ondary lower extremity lymphedema.4
The current study suggests that adipose-derived stem cells may have beneficial effects on lymphedema treatment by in vivo experiments, but I believe these cells might be useful in human therapies in the near future. The only concern that needs attention is the role of bFGF secretion of the cells, whereby bFGF might play an important role in fibrosis5 development that
worsens lymphedema. How can the authors explain this “reverse relation” in their study?
DOI: 10.1097/PRS.0000000000006354
Ahmet Akgul, M.D.
Department of Gerontology Faculty of Health Sciences Center of Gerontechnology Ist-GETAM Istanbul University–Cerrahpaşa Department of Cardiovascular Surgery Bakırköy Dr. Sadi Konuk Training and Research Hospital Istanbul, Turkey Correspondence to Dr. Akgul Department of Gerontology Istanbul University-Cerrahpaşa Faculty of Health Sciences Tevfik Sağlam Street No. 25 Bakırköy, Istanbul 34147, Turkey ahmet.akgul@istanbul.edu.tr DISCLOSURE
The author has no financial interest to disclose. No fund-ing was received for this communication.
REFERENCES
1. Saijo H, Suzuki K, Yoshimoto H, Imamura Y, Yamashita S,
Tanaka K. Paracrine effects of adipose-derived stem cells pro-mote lymphangiogenesis in irradiated lymphatic endothelial
cells. Plast Reconstr Surg. 2019;143:1189e–1200e. E-published ahead of print March 22, 2019.
2. Ackermann M, Wettstein R, Senaldi C, et al. Impact of
platelet rich plasma and adipose stem cells on lymphangio-genesis in a murine tail lymphedema model. Microvasc Res. 2015;102:78–85.
3. Akgül A, Cirak M, Birinci T. Applications of platelet-rich
plasma in lymphedema. Lymphat Res Biol. 2016;14:206–209.
4. Di S, Ziyou Y, Liu NF. Pathological changes of
lymphedema-tous skin: Increased mast cells, related proteases, and acti-vated transforming growth factor-β1. Lymphat Res Biol. 2016;14:162–171.
5. Akgul A, Skrabal CA, Thompson LO, et al. Role of mast cells
and their mediators in failing myocardium under mechani-cal ventricular support. J Heart Lung Transplant. 2004;23:709– 715.
Reply: Paracrine Effects of Adipose-Derived Stem Cells Promote Lymphangiogenesis in Irradiated Lymphatic Endothelial Cells
Sir:
The authors really appreciate Dr. Akgul’s valuable comments regarding our recent article on the lymphan-giogenic effects of adipose-derived stem cells.1 Dr. Akgul
pointed out that basic fibroblast growth factor (bFGF) might worsen lymphedema by contributing to fibrosis. Although tissue fibrosis can cause lymphedema to worsen by impairing lymphatic drainage, there are many uncer-tainties regarding the extent to which bFGF can exac-erbate tissue fibrosis. The concept that bFGF enhances fibrosis is based on the hypothesis that bFGF stimulates fibroblasts, which promotes collagen synthesis. However, some studies have contradicted this. In recent studies, bFGF promoted myofibroblast apoptosis and inhibited transforming growth factor-β signaling (i.e., it had an antifibrotic effect through antagonistic effects on fibro-blast activation and myofibrofibro-blast differentiation).2,3
Therefore, bFGF expression might be enhanced by fibrosis, rather than being a cause of fibrosis.
Recombinant human bFGF (Trafermin; Kaken Phar-maceutical Co., Ltd., Tokyo, Japan), which is a cytokine formulation that is used to accelerate wound healing and improve scar quality, is currently clinically available in Japan. Basic fibroblast growth factor, which specifically binds to the fibroblast growth factor receptor present on vascular endothelial cells and fibroblasts, promotes vascularization and good granulation tissue formation. Until now, there have been no reports regarding recom-binant human bFGF treatment causing the deterioration of lymphedema, followed by increased fibrosis, as adverse events in Japan. Akita et al. reported that histopatho-logic staining revealed greater numbers of organizing collagen bundles in bFGF-treated buttock wounds than in the control wounds, and the bFGF-treated wounds also exhibited improved scar quality during assessments based on a clinical scar scale and color meter analysis.4
In our clinical experience, no fibrosis has been observed in cases of trauma, burns, or chronic ulcers that were treated using bFGF formulations. Thus, we consider that the bFGF released from adipose-derived stem cells
