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R. C. Sibley and S. G. Rockson
treated with hyaluronidase demonstrated decreased swelling
and improved histologic features. Additionally, the treated
group demonstrated increased lymphatic vessel density and
increased VEGFR3 expression. Lymphoscintigraphy demonstrated enhanced lymphatic drainage [25]. Pro-brotic
cytokines, TGF-β and IL-4, are signicantly downregulated,
whereas anti-brotic cytokines, IL-12 and IFN-γ, are upregulated, resulting in suppressed brogenesis in mice treated
with hyaluronidase [26]. Hyaluronidase has also been demonstrated to decrease lymphedema volume and reduce neutrophils in the mouse tail model [27].
Benzopyrones
The therapeutic mechanism of benzopyrones is poorly
understood. However, it has been proposed that
α-benzopyrones (e.g., coumarin) activate proteolytic activity of macrophages, and γ-benzopyrones (e.g., diosmin)
increase oncotic pressure and the frequency and intensity of
lymphatic vessel contraction. Benzopyrones are a group of
drugs that have been reported to successfully treat lymphedema, especially when combined with complete decongestive therapy (CDT). However, a Cochrane review found
insufcient evidence to support treatment of patients with
lymphedema with benzopyrones [28]. A recent prospective
randomized controlled trial in BCRL demonstrated that a
product containing coumarin, diosmin, and arbutin (a
diuretic) combined with CDT was more effective than CDT
alone in producing limb volume reduction. While hepatoxicity has been reported with coumarins in the past, this complication is likely dose dependent; no hepatotoxicity was
identied in this study [29].
A Few Notes onNon-pharmacologic
Therapies
The risk factors for lymphedema, including surgery, radiation, infection, and obesity, are all associated with inammation and should be minimized whenever possible.
Lymphedema therapists should be encouraged to use exercise and other physical techniques to reduce brosis. Lowlevel laser therapy (LLLT) demonstrates anti-inammatory
and anti-brotic effects in the mouse model, and a systemic
review and meta-analysis of patient with breast cancerrelated lymphedema found that patients treated with LLLT,
alone or in combination with other treatments, had signicantly decreased pain and swelling [30]. Finally, the inammation associated with lymphedema is decreased by CDT,
and this standard of care should be optimized for all patients
with lymphedema.
References
1. Avraham T, Daluvoy S, Zampell J, Yan A, Haviv YS, Rockson SG,
Mehrara BJ.Blockade of transforming growth factor-beta1 accelerates lymphatic regeneration during wound repair. Am J Pathol.
2010;177:3202–14.
2. Tabibiazar R, Cheung L, Han J, Swanson J, Beilhack A, An A, Dadras
SS, Rockson N, Joshi S, Wagner R, Rockson SG. Inammatory
manifestations of experimental lymphatic insufciency. PLoS Med.
2006;3:e254.
3. Lin S, Kim J, Lee MJ, Roche L, Yang NL, Tsao PS, Rockson
SG. Prospective transcriptomic pathway analysis of human lymphatic vascular insufciency: identication and validation of a circulating biomarker panel. PLoS One. 2012;7:e52021.
4. Schneider M, Ny A, Ruiz de Almodovar C, Carmeliet P. A
new mouse model to study acquired lymphedema. PLoS Med.
2006;3:e264.
5. Hartiala P, Saarikko AM. Lymphangiogenesis and lymphangio-
genic growth factors. J Reconstr Microsurg. 2016;32:10–5.
6. Savetsky IL, Ghanta S, Gardenier JC, Torrisi JS, García Nores GD,
Hespe GE, Nitti MD, Kataru RP, Mehrara BJ.Th2 cytokines inhibit
lymphangiogenesis. PLoS One. 2015;10:e0126908.
7. Shin K, Kataru RP, Park HJ, Kwon BI, Kim TW, Hong YK, Lee
SH.TH2 cells and their cytokines regulate formation and function
of lymphatic vessels. Nat Commun. 2015;6:6196.
8. Nakamura K, Radhakrishnan K, Wong YM, Rockson SG. Anti-
inammatory pharmacotherapy with ketoprofen ameliorates
experimental lymphatic vascular insufciency in mice. PLoS One.
2009;4:e8380.
9. Zampell JC, Yan A, Elhadad S, Avraham T, Weitman E, Mehrara
BJ. CD4(+) cells regulate brosis and lymphangiogenesis in
response to lymphatic uid stasis. PLoS One. 2012;7:e49940.
10. Avraham T, Zampell JC, Yan A, Elhadad S, Weitman ES, Rockson
SG, Bromberg J, Mehrara BJ. Th2 differentiation is necessary
for soft tissue brosis and lymphatic dysfunction resulting from
lymphedema. FASEB J. 2013;27:1114–26.
11. Gousopoulos E, Proulx ST, Bachmann SB, Scholl J, Dionyssiou
D, Demiri E, Halin C, Dieterich LC, Detmar M.Regulatory T cell
transfer ameliorates lymphedema and promotes lymphatic vessel
function. JCI Insight. 2016;1:e89081.
12. Ogata F, Fujiu K, Matsumoto S, Nakayama Y, Shibata M, Oike
Y, Koshima I, Watabe T, Nagai R, Manabe I. Excess lymphangiogenesis cooperatively induced by macrophages and CD4(+) T
cells drives the pathogenesis of lymphedema. J Invest Dermatol.
2016;136:706–14.
13. Ghanta S, Cuzzone DA, Torrisi JS, Albano NJ, Joseph WJ, Savetsky
IL, Gardenier JC, Chang D, Zampell JC, Mehrara BJ.Regulation of
inammation and brosis by macrophages in lymphedema. Am J
Physiol Heart Circ Physiol. 2015;308:H1065–77.
14. Zampell JC, Yan A, Avraham T, Daluvoy S, Weitman ES, Mehrara
BJ.HIF-1α coordinates lymphangiogenesis during wound healing
and in response to inammation. FASEB J. 2012;26:1027–39.
15. Casley-Smith JR, Morgan RG, Piller NB. Treatment of lymph-
edema of the arms and legs with 5,6-benzo-[alpha]-pyrone. N Engl
J Med. 1993;329:1158–63.
16. Zampell JC, Elhadad S, Avraham T, Weitman E, Aschen S, Yan A,
Mehrara BJ. Toll-like receptor deciency worsens inammation
and lymphedema after lymphatic injury. Am J Physiol Cell Physiol.
2012;302:C709–19.
17. Avraham T, Yan A, Zampell JC, Daluvoy SV, Haimovitz-Friedman
A, Cordeiro AP, Mehrara BJ.Radiation therapy causes loss of dermal lymphatic vessels and interferes with lymphatic function by
TGF-beta1-mediated tissue brosis. Am J Physiol Cell Physiol.
2010;299:C589–605.

27 New andEmerging Therapies forLymphedema: Part II
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213
18. Wu M, Du Y, Liu Y, He Y, Yang C, Wang W, Gao F.Low molecular
weight hyaluronan induces lymphangiogenesis through LYVE-1mediated signaling pathways. PLoS One. 2014;9:e92857.
19. Cuzzone DA, Weitman ES, Albano NJ, Ghanta S, Savetsky IL,
Gardenier JC, Joseph WJ, Torrisi JS, Bromberg JF, Olszewski WL,
Rockson SG, Mehrara BJ. IL-6 regulates adipose deposition and
homeostasis in lymphedema. Am J Physiol Heart Circ Physiol.
2014;306:H1426–34.
20. Jiang X, Nicolls MR, Tian W, Rockson SG.Lymphatic dysfunction,
leukotrienes, and lymphedema. Annu Rev Physiol. 2018;80:49–70.
21. Rockson SG, Tian W, Jiang X, Kuznetsova T, Haddad F, Zampell J,
Mehrara B, Sampson JP, Roche L, Kim J, Nicolls MR.Pilot studies
demonstrate the potential benets of antiinammatory therapy in
human lymphedema. JCI Insight. 2018;3:e123775.
22. Tian W, Rockson SG, Jiang X, Kim J, Begaye A, Shufe EM, Tu
AB, Cribb M, Nepiyushchikh Z, Feroze AH, Zamanian RT, Dhillon
GS, Voelkel NF, Peters-Golden M, Kitajewski J, Dixon JB, Nicolls
MR.Leukotriene B4 antagonism ameliorates experimental lymphedema. Sci Transl Med. 2017;9:eaal3920.
23. Gardenier JC, Kataru RP, Hespe GE, Savetsky IL, Torrisi JS, Nores
GD, Jowhar DK, Nitti MD, Schoeld RC, Carlow DC, Mehrara
BJ.Topical tacrolimus for the treatment of secondary lymphedema.
Nat Commun. 2017;8:14345.
24. Ulivieri C, Baldari CT.Statins: from cholesterol-lowering drugs to
novel immunomodulators for the treatment of Th17-mediated autoimmune diseases. Pharmacol Res. 2014;88:41–52.
25. Roh K, Cho S, Park JH, Yoo BC, Kim WK, Kim SK, Park K,
Kang H, Ku JM, Yeom CH, Lee K, Lee S.Therapeutic effects of
hyaluronidase on acquired lymphedema using a newly developed
mouse limb model. Exp Biol Med (Maywood). 2017;242:584–92.
26. Cho S, Roh K, Park J, Park YS, Lee M, Cho S, Kil EJ, Cho MJ,
Oh JS, Byun HS, Cho SH, Park K, Kang H, Koo J, Yeom CH, Lee
S.Hydrolysis of hyaluronic acid in lymphedematous tissue alleviates brogenesis via TH1 cell-mediated cytokine expression. Sci
Rep. 2017;7:35.
27. Jeong HJ, Roh KH, Kim GC, Kim YO, Lee JH, Lee MJ, Sim
YJ.Hyaluronidase treatment of acute lymphedema in a mouse tail
model. Lymphology. 2013;46:160–72.
28. Badger C, Preston N, Seers K, Mortimer P. Benzo-pyrones for
reducing and controlling lymphoedema of the limbs. Cochrane
Database Syst Rev. 2004:CD003140.
29. Cacchio A, Prencipe R, Bertone M, De Benedictis L, Taglieri L,
D'Elia E, Centoletti C, Di Carlo G.Effectiveness and safety of a
product containing diosmin, coumarin, and arbutin (Linfadren®)
in addition to complex decongestive therapy on management
of breast cancer-related lymphedema. Support Care Cancer.
2019;27:1471–80.
30. Smoot B, Chiavola-Larson L, Lee J, Manibusan H, Allen DD.Effect
of low-level laser therapy on pain and swelling in women with
breast cancer-related lymphedema: a systematic review and metaanalysis. J Cancer Surviv. 2015;9:287–304.

Lymphatic Education andResearch
https://t.me/medicina_free
Network Centers ofExcellence:
AMultidisciplinary Approach
toLymphatic Care
MelisaD.Grano, RosieFriedman, ArinK.Greene,
andDhruvSinghal
28
The Lymphatic Education & Research Network (LE&RN) is
an international nonprot organization with a mission to
“ght lymphatic diseases and lymphedema through education, research and advocacy” [1]. The number of lymphatic
patients is rising as the amount of cancer survivors grows,
with some estimates projecting a disease burden of 7% or
more of the entire US population [2]. This increase in prevalence brings with it a surge in unmet needs of patients and
increasingly overwhelmed lymphatic caretakers, as general
healthcare professionals are often unfamiliar with the diagnosis and treatment of lymphatic diseases (LD) [3]. To keep
up with this demand, LE&RN established the Centers of
Excellence (COE) in the Diagnosis and Treatment of
Lymphatic Disease [4]. Previously, individual chapters of
LE&RN were meeting patient demand by curating individual ad hoc lists of lymphatic providers, collected by word of
mouth [2]. However, patients struggled to determine which
LD specialists could best meet their specic needs. The COE
designation helps patients navigate healthcare systems by
identifying pre-vetted institutions with qualied providers
that are not only prepared to treat LD but also are able to connect patients with resources for addressing various comorbidities. By establishing COE criteria, LE&RN crafted the
blueprints for standards that institutions must meet. By making these criteria transparent, the COE designation encourages prospective institutions to evolve and strive for
M. D. Granoff · R. Friedman · D. Singhal (*)
Boston Lymphatic Center, Division of Plastic and Reconstructive
Surgery, Beth Israel Deaconess Medical Center, Harvard Medical
School, Boston, MA, USA
e-mail: dsinghal@bidmc.harvard.edu
A. K. Greene
Boston Lymphatic Center, Department of Plastic and Oral Surgery,
Boston Children’s Hospital, Harvard Medical School,
Boston, MA, USA
excellence in lymphatic treatment, leading to optimization in
care of patients [2].
A COE is a designation awarded by LE&RN to institutions that offer comprehensive care for lymphedema [5]. For
centers that do not offer comprehensive care but do have services for patients with lymphedema, other designations can
be given, including Networks of Excellence, Referral
Networks of Excellence, LD Surgery COE, and LD
Conservative Care COE (Fig. 28.1) [4]. These address the
overall shortfall of qualied institutions for lymphedema
care because some institutions offer high-quality services for
the care of patients with LD, but not comprehensive care.
There are 13 major categories by which LE&RN uses to
evaluate applicants, each with multiple criteria, most of
which must be met to achieve the COE designation. The categories used to evaluate potential centers include diagnosis,
imaging, nonoperative management, assessment tools, interventional therapies, surgical treatments, genetics evaluation,
interdisciplinary consulting ability, research, accountability,
collegiality, administration, and community [4]. Once a center has applied for and been awarded a designation, their
information appears on the LE&RN website, which acts as a
centralized, pre-vetted, and reputable source for patients.
The Boston Lymphatic Center is an example of a LE&RN
COE.We were proud to be named a COE in 2020, and we
hope that by sharing our experience, other institutions might
have insight into the process of applying for and attaining
this designation. The foundation of our center’s approach to
lymphedema care is a multidisciplinary effort. This begins
with a shared vision that guides the goals of every department involved, best summarized by our mission statement:
“The Boston Lymphatic Center provides compassionate care
and advocacy for individuals with lymphatic disorders while
uniting health care providers and researchers from all disciplines to advance our knowledge of lymphatic disease and
therapy.” Our weekly multidisciplinary conferences, which
bring together nursing, diagnostic radiology, interventional
radiology, nuclear medicine, vascular medicine, lymphatic
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2022
M. V. Schaverien, J. H. Dayan (eds.), Multimodal Management of Upper and Lower Extremity Lymphedema,
https://doi.org/10.1007/978-3-030-93039-4_28
215

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M. D. Grano et al.
Fig. 28.1 Designations awarded to Lymphatic Education & Research Network (LE&RN) Centers of Excellence corresponding to the level of care
provided
surgery, physical therapy, data analytics, and research, are
central to patient care. Furthermore, our principles as a center are best illustrated by our nonclinical activity. We believe
sharing knowledge is critical to furthering the eld of lymphatics and therefore began hosting the Boston Lymphatic
Symposium in 2017, which runs both a patient and clinical
program simultaneously. In addition, to contribute what we
have learned to the medical literature, the Singhal Laboratory
is a clinical and translational research group focused on elu-
cidating the role that lymphatic anatomy variations play in
the development of secondary lymphedema. The Greene
Laboratory is focused on identifying novel mutations for primary lymphedema as well as understanding the pathophysiology of capillary and arteriovenous malformations that can
be associated with primary lymphedema. We also believe
that engagement with the community is central to furthering
our goal of bringing awareness to lymphatic disease. Through
collaboration with the Massachusetts chapter of LE&RN and

28 Lymphatic Education andResearch Network Centers ofExcellence: AMultidisciplinary Approach toLymphatic Care
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217
their work with Governor Charlie Baker, we ofcially began
celebrating World Lymphedema Day on March 6, 2018, by
annually lighting the Zakim Bridge in Boston teal.
In order to simplify the experience for pediatric and adult
patients, the Boston Lymphatic Center has a single toll-free
call line. However, patients ultimately have slightly different
courses based on whether they are an adult or pediatric patient.
For adult patient care, the Boston Lymphatic Center is composed of a clinical triad that includes lymphatic surgery, lymphatic medicine, and lymphatic treatment clinics (physical
therapy). Upon initial evaluation by these clinics, patients are
pipelined into personalized care plans based on our institutional algorithm, which has been previously described [6].
Patients presenting with chronic lymphedema are evaluated by lymphatic medicine to conrm the diagnosis and
optimize medical management, by lymphatic therapy to optimize conservative therapies, and by imaging specialists
(nuclear medicine, diagnostic radiology, interventional radiology) to further characterize their individual disease. The
patient is then presented at the weekly multidisciplinary
meeting, where the determination of whether or not they are
a good surgical candidate is made. Patients with fat- dominant
lymphedema are offered debulking surgery, and patients
with uid-dominant lymphedema are offered a physiologic
procedure, which includes vascularized lymph node transfer
or lymphovenous bypass [7, 8].
Patients presenting for a risk-reducing procedure are evaluated by the lymphatic surgery and lymphatic treatment clinics prior to nodal dissection to establish a baseline measure
of their at-risk extremities. After undergoing oncologic surgery with immediate lymphatic reconstruction (ILR), they
are surveilled regularly by the lymphatic treatment clinic for
a minimum of 4 years. Any patients who develop lymphedema are transferred into the chronic lymphedema arm of
our center, as previously described.
In the rst year of the adult program at the Boston
Lymphatic Center, nearly half of our patients were referred
from outside institutions within New England, and many had
bypassed other tertiary care centers in closer proximity to
their home residences to seek care through our program [6].
The population consisted primarily of breast cancer patients
who were seeking ILR at the time of axillary lymph node
dissection for the prevention of secondary lymphedema.
Fourteen percent of all patients who were referred to our program for the treatment of chronic lymphedema did not actually have lymphedema and were found to have an alternative
diagnosis by our lymphatic medicine team [6]. Adherence to
follow-up was optimized through targeted patient outreach
and coordination with other oncologic appointments.
However, social determinants, nancial factors, and variable
insurance coverage affected patients’ ability to present for a
return visit.
Patients referred to the pediatrics arm of the Boston
Lymphatic Center tend to have different presentations and
medical needs than the adult program. Between 2009 and
2019, most patients referred to the center were females with
congenital lymphedema [9]. Under a quarter of referred
patients had secondary lymphedema, and 16% had obesityinduced lymphedema (OIL) [9]. The remainder were found
to have diagnoses other than lymphedema upon evaluation,
underscoring the need for greater understanding of lymphedema by the general medical community. Upon referral,
lymphedema diagnosis is similarly conrmed by lymphatic
medicine as in the adult program, and individuals receive
counseling and education about their condition, including
ways to prevent progression and complications. All patients
are initially managed by the lymphatic treatment clinic with
nonoperative medical therapies such as compression garments, placing focus on volume maintenance and infection
prevention. In contrast to the adult pipeline, only 6% of
patients in the pediatric program were treated with surgical
intervention [9]. Those that were treated surgically underwent debulking surgery with suction-assisted lipectomy.
Patients with OIL were referred to bariatric surgical centers,
as OIL does not respond to typical lymphedema treatments,
and lymphatic function cannot be improved without signicant weight loss. Regardless of lymphedema etiology, every
patient that was referred had a tailored approach to treatment
that was made possible by a collaborative effort of the multidisciplinary team.
Summary
At the Boston Lymphatic Center, we are proud to offer comprehensive care to patients both with and without lymphedema and to have earned the LE&RN COE designation. We
hope by sharing our experience, including the specics of
our multidisciplinary approach for both children and adults,
other centers may have insight into how to offer comprehensive care for patients with lymphatic disorders and how to
secure a COE designation.
References
1. Mission | Lymphatic Education & Research Network. https://lym-
phaticnetwork.org/about/mission. Accessed 20 Feb 2021.
2. Chang D, Dayan J, Fried P, etal. Establishing standards for centers
of excellence for the diagnosis and treatment of lymphatic disease.
Lymphat Res Biol. 2021;19:4–10.
3. Rockson SG, Granger DN, Skeff KM, Chaite W.Lymphatic biology
and disease: is it being taught? Who is listening? Lymphat Res Biol.
2004;2(2):86–95.
4. Lymphatic Education & Research Network. https://lymphaticnet-
work.org/centers- of- excellence- standards. Accessed 20 Feb 2021.

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M. D. Grano et al.
5. Lymphatic Education & Research Network. https://lymphaticnet-
work.org/centers-
6. Johnson A, Fleishman A, Tran BN, et al. Developing a lymphatic surgery program: a rst-year review. Plast Reconstr Surg.
2019;144(6):975e–85e.
7. Granoff M, Johnson A, Shillue K, etal. A single institution multidisciplinary approach to power-assisted liposuction for the management of lymphedema. Ann Surg. 2020.
of- excellence. Accessed 20 Feb 2021.
8. Johnson AR, Bravo MG, Granoff MD, etal. Flow-through omental
ap for vascularized lymph node transfer: a novel surgical approach
for delayed lymphatic reconstruction. Plast Reconstr Surg Glob
Open. 2019;7(9):e2436.
9. Sudduth CL, Maclellan RA, Greene AK.Study of 700 referrals to a
lymphedema program. Lymphat Res Biol. 2020;18(6):534–8.

Index
https://t.me/medicina_free
A
Activin receptor-like kinase 1 (ALK-1), 202–203
Adipose deposition, 19, 210–211
Advanced-stage lymphedema, 50
Anti-inammatory and anti-brotic therapeutic approaches, 204,
Atorvastatin, 211
Axillary lymph node dissection (ALND), 169
B
Benzopyrone immunomodulator, 44
Benzopyrones, 212
BioBridge, 207
Bioimpedance spectroscopy (BIS), 29, 32–34, 195
Bone morphogenetic protein-9 (BMP-9), 202–203
Breast cancer-related lymphedema (BCRL), 12, 30, 169, 182, 209
C
Casley-Smith methods, 41
CD4
Chronic lymphedema, 3, 71
Circaid device, 43
9-cis retinoic acid (9-cis RA), 203
Combining microvascular breast reconstruction
Complete decongestive therapy (CDT), 31, 39–44, 47, 182
Completed lymphedema function therapy (CLyFT) Protocol, 73
Complex decongestive physical therapy (CDT), 39–44
Complex lymphoedema therapy (CLT), 10
Comprehensive decongestive therapy (CDT), 10
Computed tomographic angiography (CTA), 97
211–212
ketoprofen, 204, 205
pirfenidone, 206
sodium selenite, 206
tacrolimus, 205
+
cells, 210
anatomy, 103–104
blue patent dye injections, 107
complications, 108–109
composite ap, 107
deep inferior epigastric artery perforator, 107
delayed breast reconstruction, 105
donor site closure, 108
groin vascularized lymph node ap, 107
indications, 103
operative techniques, 105–108
patient selection, 104
postoperative care, 108
preoperative assessment, 104
presurgical markings, 104–106
recipient site preparation, 108
revascularization and ap inset, 108
Controlled compression therapy (CCT), 146–148, 193
Conventional high-frequency ultrasound (CHFUS), 54–55
Coumarin, 44
D
Deep inferior epigastric artery perforator (DIEP) ap, 95, 151
E
Early-stage lymphedema, 49–50
Evidence-based algorithmic approach
advanced-stage lymphedema, 50
diagnosis and staging, 47–48
early-stage lymphedema, 49–50
broadipose soft tissue excess, 50
patient selection, 48
preclinical lymphedema, 48–49
prehabilitation, 49
F
Fibroblast growth factor-2 (FGF-2), 200
Fibro-lipo-lymph-aspiration, 78
Fibrosis and extracellular matrix, 210
Flap harvest technique, 106–108
Freiburg life quality assessment for lymphedema (FLQA-L), 36
G
Gastroepiploic lymph node ap, 159
H
Health-related quality of life (HRQoL), 175
Hepatocyte growth factor (HGF), 200
Human microvascular endothelial cells, 207
Hung-Chi Chen (HCC)-Modied Charles procedure, 160–164
Hung-Chi Chen disease, 158
Hyaluronic acid (HA), 202, 210
Hyaluronidase, 211
I
ICG lymphography, 54
Immediate lymphatic reconstruction (ILR), 1, 169, 186–187
Indocyanine green (ICG)
dye, 83
uorescent lymphography, 9, 35
imaging, 49, 152
Inducible nitric oxide synthase (iNOS), 2
Intercostobrachial cutaneous nerve, 126
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2022
M. V. Schaverien, J. H. Dayan (eds.), Multimodal Management of Upper and Lower Extremity Lymphedema,
https://doi.org/10.1007/978-3-030-93039-4
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Index
Interleukin (IL)-4, 209
Interleukin-8 (IL-8), 203
Interlobular dissection, 66
“Intima-to-intima coaptation” anastomosis, 66
International Society of Lymphology (ISL) staging system, 16
Intra-abdominal VLNT
anatomy, 136
complications, 139–140
ap revascularization and inset, 138–139
operative technique, 136–138
patient selection, 136
postoperative care, 139
recipient site preparation, 138–139
small midline laparotomy incision, 137
typical indications, 135
J
Jejunal mesenteric artery, 139
Jejunal mesenteric lymph node ap, 138
JoVi Pak, 43
K
Ketoprofen, 204, 205
Klippel–Trenaunay syndrome, 31, 157
L
Lateral thoracic vascularized lymph node transfer (VLNT) ap, 154
anatomy, 123–124
complications, 127
exposing clavipectoral fascia, 125
ap inset, 126
ap inset with anastomosis, 125
ap marking, 126
marking for, 125
operative technique, 124–126
patient selection, 124
postoperative care, 126–127
reverse lymphatic mapping, 123
typical indications, 123
LDex score, 31
®
LDex
U400, 32, 195
Lesser saphenous vein (LSV), 10
Limb functional assessment instruments, 36, 196
Limb swelling, 29
Lower extremity lymphedema
anatomical changes in, 12–13
anatomophysiology of lymphatic system, 1–2
classication, 2–3
morbidity of, 3
new and emerging therapeutics, 4
pathophysiology of, 2
treatment of, 3–4
Low-stretch bandage, 41
Lymphangiogenic agents, 207
Lymphangiogenic signaling activity, 200
Lymphangiogenic therapeutic approaches, 201
ALK-1, 203
9-cis RA, 203
EPB2, 202
FGF-2 and HGF, 200
hyaluronic acid, 202
interleukin-8, 203
NRP-2, 202
S1P, 202
stem cells, 203, 204
TGF-β inhibition, 202
VEGF-C, 200
Lymphatic education & research network (LE&RN)
chronic lymphedema, 217
COE, 215
compassionate care and advocacy, 215
different presentations and medical needs, 217
treatment of lymphatic diseases, 215
Lymphatic imaging technology, 9
Lymphatic microsurgery
accessory vein with backwall sutures, 171
anatomy, 169
axillary anatomy, 170
combined procedures, 164
complications, 165, 172
excisional procedures, 160–166
fat graft, 172
front wall stitch, 171
HCC stage IV disease, 163, 164
indications, 166
intra-abdominal lymph node aps, 158–159
management of toes, 164
operative technique, 170–171
outcomes, 172
patient selection, 169–170
peripheral lymph node aps, 159
postoperative care, 171–172
therapeutic liposuction, 164
typical indications, 157–158, 169
U-stitch, 171
VLN ap, 159
LYmphatic Microsurgical Preventive Healing Approach (LYMPHA),
4, 169
Lymphatic system
anatomical changes in, 10
imaging options for the diagnosis, 7–9
lymphatic anatomy, 7
lymphatic anatomy in, 9–10
normal lymphatic anatomy, 11–12
Lymphaticovenular anastomosis (LVA), 154
anastomotic congurations, 63
CHFUS, 54, 55
complications, 67–68
detection and selection of venules, 56–57
incision site design, 60–62
indocyanine green (ICG) classication, 61
indocyanine green (ICG) staging, 61
lymphovenous shunt operations, 59
microsurgical lymphovenous anastomosis, 60
patient selection, 59–60
preoperative evaluation, 59–60
primary lower extremity lymphedema, 53
recipient vein dissection, 65
secondary lower extremity lymphedema, 53–54
severity grading of lymphosclerosis, 60
step-by-step operative techniques
careful skin closure, 66
dissection of collecting lymph vessels, 65
dissection of recipient vein, 64
exposure and incision of supercial fascia, 64–65
follow-up, 66–67
“intima-to-intima coaptation” anastomosis, 66
postoperative management, 66–67
preparation of vessels, 65

Index
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221
protection of vessels and anastomosis site, 66
skin incision and retraction, 64
UEL, 54
UHFUS, 54–56
Lymphatic-venous-lymphatic plasty, 74
Lymphedema, 1, 157
adipose deposition, 19
chronic inammation, 17–19
early diagnosis of, 25
early-stage breast cancer, 23
ethology and staging of, 15–16
brosis, 17–18
implementation into practice, 25–26
inammation and brosis in, 209–211
modiable and non-modiable risk factors for, 24
pathophysiology of, 16
prospective surveillance model, 24, 25
risk factors, 23–24
staging of, 72
surgical interventions for, 187–190
Lymphedema life impact scale (LLIS), 36
Lymphedema microsurgery
combined procedures, 186
excisional procedures, 186
lymphovenous bypass procedure
prospective evaluation of, 177
retrospective cohort or comparative studies, 177–178
systematic review, 176
SAL debulking, 175
prospective/retrospective cohort/comparative studies, 184–185
systematic review of, 184
VLNT procedure
prospective cohort/comparative studies, 179–181
randomized controlled trial, 179
retrospective cohort studies, 181–184
retrospective comparative studies, 181
systematic literature review, 178, 179
Lymphedema quality of life (LYMQoL) questionnaire, 36
Lymphedema staging, 87, 157
Lymphedema surgery
degree of pitting edema, 194
detailed treatment history, 194
episodes of lymphedema, 194
L-Dex score, 195
limb functional assessment instruments, 196
limb volume measurements, 195
lymphedema-specic symptoms, 193–194
minimal clinical postoperative measurements/investigations, 194
multimodal evaluation of, 193
physiological lymphedema staging, 196
PROs, 195
Lymphedematous tissues, 210
Lymphoedema, 12
Lymphoscintigraphy, 34–35
Lymphovenous anastomosis (LVA), 157
Lymphovenous bypass (LVB), 1, 35, 47, 87, 182, 193
M
Magnetic resonance lymphangiography (MRL), 36
Manual lymphatic drainage (MLD), 7, 39, 40, 42, 73
Meige’s disease, 15
Mesenchymal stem cells (MSCs), 203
Mesoappendix, 135
Metacarpophalangeal (MCP) joint replacement surgery, 151
Microsurgical breast reconstruction (MBR), 182
Microvascular breast reconstruction (MBR), 181
Milroy’s disease, 15, 209
Moderated lymphedema, 165
Multimodal structured approach
acute-on-chronic worsening, 29
acute onset lymphedema, 29
bioimpedance spectroscopy, 32–33
clinical history, 30–31
clinical staging scales, 31–32
computed tomography/venography, 34
evidence-based evaluation, 30
extremity lymphedema symptoms, 31
ICG lymphography, 35, 36
limb measurements, 32
lymphedema physical therapy, 36–37
lymphoscintigraphy, 34–35
magnetic resonance imaging/angiography, 33–34
MRL, 36
multidisciplinary lymphedema team, 37
physical examination ndings, 31
PROMs, 36
Multiple lymphatic-venous-lymphatic anastomosis, 74
Myobroblast differentiation, 199
N
Neuropilin-2 (NRP-2), 202
Non-pharmacologic therapies, 212
Non-surgical management
CDT
compression garments, 43, 44
exercises, 42
lymphatic uid accumulation, 40
MLD, 41, 42
PCD, 42
protective clothing, 40
skin care and cellulitis risk reduction, 43
wrapping with low-stretch bandages, 40
prehabilitation, 44
Notch-1 and ephrin B2 (EPB2), 202
O
Ohio scar scale, 138
Omental VLNT
algorithm for ap harvest technique, 131
anatomy, 129–130
complications, 132
laparoscopic ap harvest technique, 131
laparoscopic visualization, 131
open ap harvest technique, 131–132
open mini-laparotomy or laparoscopic technique, 130
patient selection, 130
policeman of the abdomen, 129
postoperative care, 132
recipient site preparation, 130–131
revascularization and inset, 132
typical indications, 129
vascular anatomy of, 130
Orthotopic VLNT, 88
P
Parkes Weber syndrome, 31
Patient-reported outcome measures (PROMs), 36, 175, 195
PhotoDynamic eye, 35

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Index
Physiological lymphedema staging, 196
Pirfenidone, 206
Pitting edema scale, 31
Pneumatic compression device (PCD), 42
Prehabilitation, 47
Primary lower extremity lymphedema (LEL), 53
Primary lymphedema, 15, 30
Prospective surveillance model (PSM), 24, 25
R
Radionucleotide lymphoscintigraphy, 196
S
Secondary lymphedema, 15, 30, 53
Secondary lymphedema risk-reduction evidence base, 24
Self-lymphatic drainage (SLD), 39
Sentinel lymph node biopsy (SLNB), 3
Single site multiple lymphatic-venous anastomosis technique
(ss-MLVA), 73, 79
anatomy, 72–73
anesthesia, 75
complications, 78
loupes and operating microscope surgical procedure, 76–77
lymph nodal-venous shunts, 71
microsurgical approach, 71
minimally invasive technique, 78
operative techniques, 75
outcomes, 78–82
patient positioning, 76
patient selection, 73–75
postoperative care, 77
preoperative and postoperative, 77–78
preoperative investigations, 73–75
recipient site preparation, 76
typical indications, 71–72
Skin paddle, 98–100
Sodium selenite (Na
SeO3), 206
2
Sphingosine-1-phosphate (S1P), 202
SPY Phi, 35
Stage-guided CLyFT Protocol, 77
Suction-assisted lipectomy (SAL) debulking, 1, 47, 176, 184–186, 193
Suction-assisted protein lipectomy (SAPL), 153
chronic lymphedema, 141–142
complications, 146, 155
controlled compression therapy, 146–148
cosmetic liposuction surgery, 153
efcacy of liposuction, 142
excess subcutaneous adiposity, 141–142
ICG mapping, 153
indications and patient selection, 152–153
ISL grade II edema, 148
liposuction of arm lymphedema, 145
magic bullet, 151
operative technique, 144
postoperative care, 146, 155
preoperative planning, 142–144
two-phase approach, 152
typical indications, 141
Supercial circumex iliac vein (SCIV), 84
Supercial inferior epigastric vein (SIEV), 84
Supermicrosurgical end-to-end (EE) anastomosis, 66
Supraclavicular vascularized lymph node transplant procedure
anatomy, 117, 118
complications, 121
distal transverse cervical vessels, 120
external jugular vein, 118
lymphovenous anastomosis, 121
omohyoid muscle, 119
operative technique, 118–120
patient selection, 117–118
postoperative care, 120–121
preoperative investigations, 117–118
presurgical markings, 118
sternocleidomastoid, 118
typical indications, 117
T
T helper (T
) 2 cytokines, 209
h
Tacrolimus, 205, 211
Tacrolimus (FK506), 206
Taiwan lymphoscintigraphy staging (TLS) system, 32, 111, 196
Total breast anatomy restoration (TBAR), 103
Transforming growth factor-beta (TGF-β), 202
Turner/Noonan syndrome, 31
U
Ubenimex, 211
Ultrahigh-frequency ultrasound (UHFUS), 55–56
Upper extremity breast cancer-related lymphedema (BCRL), 76
Upper extremity lymphedema (UEL), 54, 160
anatomical changes in, 12–13
anatomophysiology of lymphatic system, 1–2
classication, 2–3
morbidity of, 3
new and emerging therapeutics, 4
pathophysiology of, 2
treatment of, 3–4
V
Vasa lymphatica, 7
Vascular endothelial growth factor (VEGF), 199–200, 209
Vascularized lymph node transplantation (VLNT), 1, 47, 60, 117, 157,
169, 183, 193
anatomy, 96–97
anatomy of inguinal region, 96
axillary lymph node ap harvest, 84–85
“bridging” mechanism, 87
complications, 86, 100, 155
forearm of the radial vessels, 90
gravity-dependent position, 88
groin and axillary donor sites, 83
groin lymph node harvest, 85
harvesting lymph nodes, 83
indications, 84
lower leg of posterior tibial vessels, 91
mechanism of action, 95
obstructive lymphedema, 95
omental/jejunal mesenteric aps, 87
omentum and supraclavicular lymph nodes, 83
operative technique, 97–100
patient selection for, 88, 97
postoperative care, 85–86, 100, 155
postoperative management for, 91–92
“pumping” mechanism, 87
recipient site selection selection, 89–91
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